1

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

                      FOOD AND DRUG ADMINISTRATION

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

                   BLOOD PRODUCTS ADVISORY COMMITTEE

                              73RD MEETING

                        Thursday, June 13, 2002

                               8:00 a.m.

                        Holiday Inn Gaithersburg
                     Two Montgomery Village Avenue
                         Gaithersburg, Maryland 

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly the Food and Drug Administration makes no representation as to its accuracy.

                                                                 2
                              PARTICIPANTS

      Kenrad E. Nelson, M.D., Chairman
      Linda A. Smallwood, Ph.D., Executive Secretary

      MEMBERS

                James R. Allen, M.D.
                Mary E. Chamberland, M.D.
                Charlotte Cunningham-Rundles, M.D., Ph.D.
                Donna DiMichele, M.D.
                Michael G. Fitzpatrick, Ph.D.
                Harvey G. Klein, M.D.
                Judy F. Lew, M.D.
                Daniel L. McGee, Ph.D.
                Terry V. Rice
                Paul J. Schmidt, M.D.
                Sherri O. Stuver, Sc.D.

      CONSUMER REPRESENTATIVE

                Robert J. Fallat, M.D.

      NON-VOTING INDUSTRY REPRESENTATIVE

                Toby L. Simon, M.D.

      TEMPORARY VOTING MEMBERS

                Liana Harvath, Ph.D.
                Blaine F. Hollinger, M.D. 

                                                                 3

                            C O N T E N T S

                                                          Page No.

      Welcome, Statement of Conflict of Interest
                Linda F. Smallwood, Ph.D.                        5

      Current IGIV Supply
                Mark Weinstein, Ph.D.                            9
                Richard Barr, M.D.                              18
                Tom Moran, M.D.                                 20

      Recent Western Blot Shortage
                Paul Mied, Ph.D.                                39

           Presentations:
                Wendy Chen, Calypte                             56
                Celso Bianco, M.D., ABC                         58
                Christopher Bentsen, M.D., Bio-Rad              64
                Bruce Phelps, M.D., Chiron                      65

      Electronic Submission of Applications
                Michael Fauntleroy                              78

                   I. STANDARDS FOR RECOVERED PLASMA

      Introduction and Background
                Elizabeth Callaghan                            108

      Presentations
                Sharon O'Callaghan                             115
                Kay Lewis                                      134

      Industry Presentations
                PPTA - Barbee Whitaker, M.D.                   153
                AABB - Kay Gregory                             164
                ABC - Jeanne Dariotis                          186
                ARC - Don Fipps                                200

      Open Public Hearing
                BCA- Laura McDonald                            213
                AdvaMed - Carolyn Jones                        216
                Chiron - Susan Stramer, Ph.D.                  236

      Open Committee Discussion and Questions for
      the Committee                                            249

             II. UNIFORM DONOR HISTORY QUESTIONNAIRE (UDHQ)

      Introduction and Background
                Alan Williams, Ph.D.                           278

      Overview of AABB Task Force UDHQ Project
                Joy Fridey, M.D.                               288 

                                                                 4

                       C O N T E N T S(Continued)

                                                          Page No.
      UDHQ Cognitive Studies
                Paul Beatty, Ph.D.                             327

      FDA Status of Review of AABB Task Force UDHQ
                Judy Ellen Ciaraldi, BS, MT(ASCP) SBB          359

      Open Public Hearing

                AABB - Celso Bianco, M.D.                      374
                ARC - Rita Reik, M.D.                          375
                PPTA Source - Jan Hamilton, M.D.               379
                Talisman, Ltd. - Paul Cumming, Ph.D.           382

      Questions for the Committee/Committee Discussion         385 

                                                                 5

  1                      P R O C E E D I N G S

  2            Welcome, Statement of Conflict of Interest

  3             DR. SMALLWOOD:  Good morning.  Welcome to

  4   the 73rd Meeting of the Blood Products Advisory

  5   Committee.  I am Linda Smallwood, the Executive

  6   Secretary.  At this time, for your hearing, I will

  7   read the Conflict of Interest Statement that

  8   applies to both days' session of this meeting.

  9             The following announcement is made part of

 10   the public record to preclude the appearance of a

 11   conflict of interest at this meeting.  Pursuant to

 12   the authority granted under the Committee Charter,

 13   the Director of FDA's Center for Biologics

 14   Evaluation and Research has appointed Drs. Liana

 15   Harvath and Blaine Hollinger as temporary voting

 16   members.

 17             Based on the agenda, it has been

 18   determined that there are no products being

 19   approved at this meeting.  To determine if any

 20   conflicts of interest existed, the agency reviewed

 21   the agenda and all relevant financial interests

 22   reported by the meeting participants.

 23             In accordance with Title 18, United States

 24   Code 208, Dr. Harvey Klein has been granted a

 25   general matters waiver that permits him to 

                                                                 6

  1   participate fully in the committee discussions.  We

  2   would like to note for the record that Dr. Toby

  3   Simon is participating in this meeting as an

  4   industry representative acting on behalf of

  5   regulated industry.

  6             With regard to FDA's invited guests, the

  7   agency has determined that the services of these

  8   guests are essential.  There are interests which

  9   are being made public to allow meeting participants

 10   to objectively evaluate any presentation and/or

 11   comments made by the participants.

 12             For the discussions on the Uniform Donor

 13   History Questionnaire, Dr. Joy Fridey is employed

 14   by the Blood Bank of San Bernardino and Riverside

 15   County, California as Senior Vice President of

 16   Medical Affairs.  For the discussions of a Warning

 17   Label for Hetastarch, Dr. Gary Haynes has an

 18   unrelated grant supported by the American Red Cross

 19   Plasma Services.

 20             In addition, listed on the agenda are

 21   speakers making industry presentations on the

 22   Standards for Recovered Plasma.  These speakers are

 23   employed by industry and, thus, have interest in

 24   their employer and other regulated firms.

 25             FDA participants are aware of the need to 

                                                                 7

  1   exclude themselves from the discussions involving

  2   specific products or firms for which they have not

  3   been screened for conflict of interest.  The

  4   exclusion will be noted for the public record.

  5   This is in reference to the committee members.

  6             With respect to all other meeting

  7   participants, we ask, in the interest of fairness,

  8   that you state your name, affiliation and address

  9   and any current or previous financial involvement

 10   with any firm whose products you wish to comment

 11   upon.

 12             At this time, are there any declarations

 13   to be made regarding this meeting?  Hearing none, I

 14   would like to, at this time, introduce to you the

 15   members of the Blood Products Advisory Committee.

 16             As I call the names of the members, would

 17   you please raise your hand.

 18              The Chairman, Dr. Kenrad Nelson.  Dr.

 19   James Allen.  Dr. Mary Chamberland.  Dr. Charlotte

 20   Cunningham-Rundles.  Dr. Donna DiMichele.  Dr.

 21   Michael Fitzpatrick.  Dr. Harvey Klein.  Dr.

 22   Raymond Koff.  Dr. Judy Lew.  Dr. Daniel McGee.

 23   Mr. Terry Rice.  Dr. Paul Schmidt.  Dr. Sherri

 24   Stuver.  Dr. Robert Fallat.  Dr. Toby Simon.  Dr.

 25   Liana Harvath.  Dr. Blaine Hollinger. 

                                                                 8

  1             I just have a few announcements to make.

  2   If you will note on your agenda, there have been

  3   some changes made from previous versions of the

  4   agenda and I would just like to inform you of

  5   those, so you will not be confused.

  6             If you had seen a previous version of the

  7   agenda that identified End User Notification, that

  8   has been deleted.  Also, a presentation on Rapid

  9   HIV Tests has been deleted, and we have added to

 10   the agenda a presentation on IGIV Supply.

 11             Also, I would like to announce that there

 12   will be a workshop sponsored by the FDA on August

 13   7th and 8th on Safety and Efficacy of Methods for

 14   Reducing Pathogens in Cellular Blood Products used

 15   in Transfusions.

 16             Also, at this meeting, because of a change

 17   in our charter, our consumer representative, Dr.

 18   Fallat, who was formerly non-voting, will now be

 19   voting with the committee.

 20             As far as audiovisual aids, we have a

 21   remote mouse, so that those that are using the

 22   podium here, that is available for your use, and if

 23   you have any problems, please see the audiovideo

 24   technician over here to my left. Would you raise

 25   your hand, please. 

                                                                 9

  1             At this time, I will turn the proceedings

  2   of the meeting over to the chairman, Dr. Kenrad

  3   Nelson.

  4             DR. NELSON:  Thank you, Dr. Smallwood, and

  5   welcome.

  6             The first topic is a discussion of the

  7   current IGIV Supply.  Dr. Weinstein.

  8                       Current IGIV Supply

  9             DR. WEINSTEIN:  Good morning.  My name is

 10   Mark Weinstein.  I am the Director of the Division

 11   of Hematology in the Office of Blood at CBER.

 12             [Slide.]

 13             Today, I will give you an update on the

 14   status of IGIV distribution in the United States.

 15   I will briefly discuss the reasons for a shortage

 16   of immune globulin products that started in 1997,

 17   the evidence that we had for the shortage at that

 18   time, and the actions that FDA took to alleviate

 19   the shortage.  I will then discuss the current

 20   situation and some future directions.

 21             [Slide.]

 22             In November of 1997, FDA became aware of

 23   an acute shortage of IGIV.  At that time, we did

 24   not monitor the distribution of plasma derivatives

 25   as we do now.  We learned of the shortage through 

                                                                10

  1   numerous persistent reports of shortage nationwide

  2   from many sources including patient groups,

  3   individual patients, hospitals, distributors, and

  4   physicians.

  5             FDA contacted manufacturers and

  6   distributors and further verified these reports.

  7             Another indication of the shortage was

  8   seen by the increase in the cost of products.  The

  9   cost of products rose dramatically over the next

 10   several years.

 11             [Slide.]

 12             This graph shows the shortfall in

 13   production that occurred in 1997.  It is about down

 14   from about 15 percent of what would have been

 15   expected had the rate of increase been the same as

 16   it had been for the previous four years.

 17             [Slide.]

 18             The principal reason for the reduction in

 19   IGIV distribution had to do with compliance issues

 20   and problems with industry meeting good

 21   manufacturing practices.  An additional element was

 22   our CJD policy at the time, which called for

 23   withdrawal of products made from plasma pools that

 24   contained units from individuals recognized post-donation to

 25   have had classic CJD. 

                                                                11

  1             In addition, the use of product for

  2   approved and unapproved uses also increased at a

  3   higher than expected rate.

  4             [Slide.]

  5             FDA took a number of actions to alleviate

  6   the shortage.  These included facilitating

  7   increased production and distribution without

  8   compromising the safety or efficacy of these

  9   products.

 10             These actions included shortening the time

 11   of reviewing lot release protocols, expediting the

 12   review of license supplements related to IGIV, and

 13   streamlining clinical trial design.

 14             Streamlining trial design involved working

 15   together with Immune Deficiency Foundation and

 16   industry to develop protocols that required fewer

 17   patients and shorter time frames while assuring the

 18   safety and efficacy of the licensed products.

 19             A Dear Doctor letter was sent out to

 20   provide guidance for prioritizing the use of IGIV.

 21   The letter indicated what the approved uses of IGIV

 22   were and other uses for which there was some or

 23   little clinical support.

 24             We required manufacturers to report

 25   monthly distribution of plasma derivatives to the 

                                                                12

  1   FDA.  This helps us to monitor the amount of

  2   product on the market and to get a sense of whether

  3   a significant increase or decrease of product

  4   distribution is occurring.

  5             There was also a change in the CJD policy

  6   in 1998, which reduced the number of withdrawals by

  7   no longer requiring that product be withdrawn

  8   because of a concern with classic CJD.  We note,

  9   however, that our current policy calls for

 10   withdrawals if there is concern about the presence

 11   of a variant CJD.

 12             [Slide.]

 13             This graphs shows the yearly increase in

 14   IGIV distribution on a yearly basis.  So, for

 15   example, you have figures here from May of '98 to

 16   April of '99 compared to May of 2001 to April of

 17   2002.  You can see that there is a steady increase.

 18   In fact, there is approximately a 50 percent

 19   increase in level of IGIV distribution compared to

 20   the '98 figures.

 21             [Slide.]

 22             This graphs shows similar distribution

 23   data, but reported on a monthly basis.  You can see

 24   that there is a general trend upward, but there is

 25   considerable monthly heterogeneity variation over 

                                                                13

  1   the past year and a half.

  2             Now, it is important to realize that these

  3   figures represent only part of the total amount of

  4   product that is available for use.  There are other

  5   reservoirs of product that are in the hands of

  6   distributors, in hospital pharmacies, as well as

  7   the inventory of manufacturers.

  8             In fact, at the present time, we know of

  9   at least 1,000 kilograms of IGIV that are in the

 10   hands of distributors, and this additional amount

 11   of material acts as a buffer to the monthly

 12   variations or swings in distribution from

 13   manufacturers.

 14             [Slide.]

 15             An additional indication of the

 16   improvement in the supply of IGIV can be seen in

 17   this graph of the average cost of IGIV.  This

 18   average is made up of summing the cost of seven

 19   brands of IGIV and producing the average cost.

 20             The cost of IGIV rose dramatically from

 21   the level of 1998, which is at $32.73 per gram, to

 22   a high of $48.49 per gram in 2001, but as you can

 23   see, the price is now declining.  The 2003 figure

 24   is a fiscal year projection from FFF, a major

 25   distributor of immune globulin products to 

                                                                14

  1   hospitals.

  2             [Slide.]

  3             To recap, IGIV distribution has increased

  4   by 50 percent since 1998.  The average price of

  5   IGIV has declined from a high of $48.49 in 2001 to

  6   a level of $45.74 per gram projected for 2003.

  7             Although there have been variations in

  8   monthly distribution levels over the past year and

  9   a half, there are significant amounts of IGIV in

 10   the distribution pipeline that act as a buffer to

 11   variations in release from the manufacturers.

 12             [Slide.]

 13             In summary, the supply of IGIV has

 14   improved significantly since 1997.  However,

 15   importantly, more improvements can be made.  We

 16   recognize that there is still a high demand for the

 17   product, that more product would be desirable, and

 18   that competition is good for the industry and for

 19   the public.  FDA encourages manufacturers to submit

 20   applications for new products.

 21             The classification of whether a submission

 22   is to be reviewed as a Fast Track priority review

 23   or a standard review is a function of assessing the

 24   medical need at a particular point in time balanced

 25   against other priorities and the limited resources 

                                                                15

  1   of the FDA.

  2             We encourage manufacturers to come and

  3   talk to us and bring data to help us decide what

  4   designation classification a submission should

  5   receive.

  6             Thank you for your attention.

  7             DR. NELSON:  Thank you, Dr. Weinstein.

  8             Questions?  Yes, Harvey.

  9             DR. KLEIN:  Do we have any idea about why

 10   things are better now, is it that there is more

 11   plasma being collected, more fractionation

 12   capability, or is it that there are fewer recalls?

 13   Do we have any quantitative information, and is

 14   there sufficient fractionation capability, so that

 15   if the curve of distribution continues to rise,

 16   there will still be available fractionation

 17   products?

 18             DR. WEINSTEIN:  I think that the elements

 19   that you mentioned, both further manufacturing

 20   capacity, new products coming on-board, increased

 21   production by certain manufacturers, importation of

 22   materials, these are all reasons why this increase

 23   has occurred.

 24             There is always concern about situations

 25   where a given company may not be able to produce a 

                                                                16

  1   product at a desired rate.  We know that these

  2   situations can occur at any time.  This is still an

  3   industry that has relatively few manufacturers

  4   involved in it, and if one of those manufacturers

  5   does have a problem, there can be a dramatic

  6   significant effect on the total availability of

  7   immune globulin.

  8             So, these elements, the fragility of this

  9   market is something that we are very aware of, but

 10   I am reporting on what the data is at the present

 11   time.  Conditions can change, and our priorities

 12   will change with the conditions.

 13             DR. ALLEN:  How does the supply track

 14   versus the demand or the need, and is there much of

 15   the product that gets outdated, or does the FDA not

 16   receive information on that?

 17             DR. WEINSTEIN:  We don't have direct

 18   information about that part of the equation.  The

 19   hard numbers that we have really are the numbers

 20   that we get from our required data collection from

 21   manufacturers.  We get estimates of availability by

 22   making direct inquiries to distributors, finding

 23   out how much material is in the pipeline.

 24             We also rely on our good communications

 25   with the patient organizations to find out what 

                                                                17

  1   their situation is and whether they are reporting

  2   that there is lack of material available.

  3             But the idea of an acute shortage, how do

  4   we know when an acute shortage occurs here, and

  5   those were the items that I pointed out before,

  6   this idea of a nationwide surge in reports about

  7   product deficiencies, that is what would be called

  8   an acute shortage situation.

  9             DR. NELSON:  Presumably, a fair amount of

 10   the reason for the increase in recent years is off-label

 11   use?

 12             DR. WEINSTEIN:  A lot of demand for the

 13   product is through off-label use.

 14             DR. NELSON:  You can't estimate that?

 15             DR. WEINSTEIN:  Right, that is very

 16   difficult to estimate.

 17             DR. SCHMIDT:  Mark, the expiration date

 18   that is given, is that from lot release or lot

 19   production, and how long is it?  That is the first

 20   question.

 21             The second question is did you see, on

 22   those monthly distribution, did you see any major

 23   changes from that Dear Doctor letter that was sent

 24   out in terms of prioritizing IGIV in terms of

 25   reduction or anything of that nature? 

                                                                18

  1             DR. WEINSTEIN:  I believe that is a two-year time

  2   period for most of the immune globulin

  3   products, lot release from the last sterile

  4   filtration, I believe.  As far as the

  5   prioritization or how the product is used, the

  6   approved uses in the Dear Doctor letter are still

  7   the ones that are currently in effect.

  8             As far as knowing what the off-label uses

  9   are, whether there has been an upsurge in that, we

 10   simply don't have figures on where the principal

 11   uses are now for these other potential uses of

 12   product that are not approved.

 13             DR. SCHMIDT:  Can the outdated material be

 14   reprocessed?

 15             DR. WEINSTEIN:  No, the outdated material

 16   would-- in fact, there is very little outdated

 17   material, that the stuff is gobbled up very

 18   quickly.

 19             DR. NELSON:  There are a couple of people

 20   that wanted to also testify from the Immune

 21   Deficiency Foundation.

 22             DR. BARR:  Good morning.  My name is

 23   Richard Barr and I am the chairman of the Board of

 24   Trustees of the Immune Deficiency Foundation.  I am

 25   also an adult patient diagnosed with common 

                                                                19

  1   variable immune deficiency.

  2             [Slide.]

  3             This morning, I would like to update this

  4   committee on the Foundation's continuing concern

  5   regarding the status of the immune globulin supply.

  6   Tom Moran, the IDF president, will be assisting me

  7   with this task.

  8             Our fundamental perspective is that

  9   despite the increasing IGIV supplies over the past

 10   several years, our community is still in jeopardy

 11   because of the facts we will outline this morning.

 12             IDF, by history, is the national

 13   organization dedicated to improving the lives of

 14   primary immune-deficient patients through research,

 15   education, and advocacy.  Primary immune deficiency

 16   diseases are inherited disorders in which parts of

 17   the body's immune system are missing or do not

 18   function properly.

 19             The World Health Organization has

 20   identified more than 100 different primary immune

 21   deficiency diseases.  Approximately, 50,000

 22   Americans suffer from a clinically significant

 23   primary immune deficiency disease, 70 percent of

 24   these patients use immune globulin intravenous,

 25   IGIV, regularly to maintain their health. 

                                                                20

  1             For our members, IGIV is literally a life-saving

  2   therapy.  In 1997, an acute shortage of IGIV

  3   in the United States began and resulted in product

  4   unavailability and negative health consequences for

  5   many patients who require this therapy to maintain

  6   their health.

  7             As documented in IDF's 1998 surveys of

  8   physicians and patients, which were presented to

  9   this committee and other government bodies, we

 10   determined that 40 percent of primary immune-deficient

 11   patients in the United States got sick,

 12   some seriously, as a result of missing or

 13   postponing their infusions.

 14             Tom Moran is now going to bring this

 15   discussion into the present.

 16             DR. MORAN:  Thank you, Richard, and thank

 17   you, Mr. Chairman, for having us in.  Mark, thank

 18   you for your earlier comments.

 19             I am Tom Moran.  I am president of the

 20   Immune Deficiency Foundation.

 21             In response to the IGIV shortage, as Mark

 22   alluded to in his presentation, individual patients

 23   and physicians, the Immune Deficiency Foundation,

 24   industry, and the FDA all implemented actions to

 25   understand the causes of the shortage, reduce its 

                                                                21

  1   impact, and eventually increase the available

  2   supply of IGIV.

  3             Working with industry, IDF provided

  4   emergency distribution of IGIV to patients and

  5   their health care providers.  Working with the FDA,

  6   we encouraged the priority rationing of IGIV within

  7   health systems, and based on discussions between

  8   FDA scientists and clinical immunologists, the FDA

  9   streamlined clinical trial and licensing protocols

 10   to encourage new manufacturers to enter the U.S.

 11   market and to assist existing manufacturers to

 12   develop and license next generation products.

 13             Dr. Barr alluded to the continuing

 14   vulnerability in our community despite an increase

 15   in IGIV supply over the past several years, which

 16   was demonstrated in Dr. Weinstein's testimony.

 17             Our concern, our vulnerability is based on

 18   the following four observations or facts.

 19             First, although distribution of IGIV has

 20   increased from approximately 15,000 kilos during

 21   1998, to a level approaching 23,000 kilos in 2002,

 22   we cannot measure the adequacy of this level in

 23   either relative terms or in terms of the health

 24   status of our patients.  We have no confidence in

 25   IGIV distribution estimated prior to PPTA providing 

                                                                22

  1   consolidated industry data beginning in 1998, so we

  2   do not know where we stand today in relation to

  3   pre-shortage levels.  Also, the market's appetite

  4   for IGIV seems to be insatiable evidenced by the

  5   fact that current inventory levels of IGIV equal a

  6   three-week supply at the manufacturers' level,

  7   despite this increased release of product.

  8             Secondly, distribution of IGIV does not

  9   track medical necessity, but rather is determine by

 10   distribution channels and market forces, and as Dr.

 11   Barr will discuss in a moment, we have good

 12   evidence that a substantial percentage of our

 13   community is still untreated or undertreated as an

 14   artifact or a hangover of the shortage.

 15             Third, the concentration of manufacturing

 16   capacity within five companies leaves consumers in

 17   a position that manufacturing or compliance issues

 18   at a single company could impact 20 percent of the

 19   market, which the market is not able to absorb.  As

 20   a reminder, two of these five companies remain

 21   under consent decree for good manufacturing

 22   practices, also consolidations among manufacturers,

 23   such as the potential merger announced by two of

 24   the five companies I have just noted continue to

 25   reinforce this trend toward concentration of 

                                                                23

  1   resources.

  2             Fourth and finally, other uses for immune

  3   globulins, including as a response to specific

  4   bioterrorism threats or actions, could have a

  5   significant and immediate effect on IGIV supply.

  6             In an effort to minimize the risks

  7   associated with this set of circumstances, and

  8   based upon our disastrous experience with the IGIV

  9   shortage, IDF took the unusual step of recruiting

 10   two European manufacturers, and through a related

 11   organization, has assisted them in conducting U.S.

 12   clinical trials, so as to help to diversify the

 13   production capacity available to the U.S. market.

 14             These trials are being conducted under the

 15   revised trial guidelines recommended by the FDA in

 16   March 2000, and we trust that their licensing

 17   applications will be handled expeditiously as

 18   promised by the agency in that statement.

 19             We are also consultants to several

 20   currently licensed manufacturers in developing next

 21   generation products or new routes of administration

 22   for immune globulin products.

 23             We recognize that CBER, the Office of

 24   Blood, Research and Review, the Division of

 25   Hematology are currently operating under extreme 

                                                                24

  1   resource constraints, and must balance the

  2   interests of primary immune-deficient patients with

  3   alpha-1 antitrypsin deficiency, hemophilia, and

  4   many other at-risk populations.  We are all

  5   dependent on FDA to wisely allocate its limited

  6   staff resources.

  7             At IDF, we have the responsibility to

  8   inform this committee and the agency about the

  9   circumstances facing our community.

 10             To close this presentation, Dr. Barr will

 11   provide you the results of a survey of IGIV users

 12   in our community completed this past January.

 13             DR. BARR:  Thank you, Tom.

 14             As Tom stated, our community feels

 15   continued jeopardy based on the volatility of the

 16   marketplace, concentration of production capacity

 17   within the plasma derivative industry, and

 18   unplanned contingencies.

 19             Common sense and experience instruct us

 20   that while specific problems in IGIV supply are not

 21   predictable, they are inevitable under the present

 22   circumstances.  The root concern for our community

 23   is not market economics or competitive diversity,

 24   it is a concern for the health and well-being of

 25   our constituents. 

                                                                25

  1             In this context, we have troubling

  2   evidence that suggests significant undertreatment

  3   is occurring in our community as a result of the

  4   shortage, and that current distribution levels have

  5   yet to remedy this problem.

  6             If I could have Slide 1 and 2.

  7             [Slide.]

  8             The IDF recently conducted a follow-up

  9   review of the primary immune-deficient patient

 10   population.  The results of this study point to a

 11   significant amount of undertreatment for primary

 12   immune-deficient patients, especially as it relates

 13   to IGIV supply.

 14             [Slide.]

 15             The most disturbing finding of this study

 16   was that 16 percent of the patients who were on

 17   IGIV therapy in 1996 were no longer using it in

 18   2001, but were still alive and still affected by a

 19   primary immune deficiency disease.

 20             [Slide.]

 21             Another fact leading to a concern for

 22   undertreatment is that 11 percent of the patients

 23   reported that they receive IGIV infusions every

 24   five weeks or less often.  Because the recommended

 25   dosing frequency is every three or four weeks at a 

                                                                26

  1   minimum, in view of the half-life of the product,

  2   the IDF is concerned that a less frequent schedule

  3   may place these patients at increased risk for

  4   infection.

  5             There are many possible explanations for

  6   this finding including that providers stop trying

  7   to find a stable IGIV supply and abandon this

  8   treatment in frustration, or that managed care

  9   settings, such as infusion sites and hospitals,

 10   abandoned or severely restricted access to this

 11   therapy, and have not moved back to appropriate

 12   treatment regimens.

 13             Regardless of the cause, the fact remains

 14   that our patients are still not realizing the

 15   benefits of a sufficient IGIV supply.

 16             In closing, IDF remains concerned with

 17   IGIV availability despite the positive direction

 18   that the distribution data show.

 19             The volatility in the market and the

 20   concentration of manufacturing capacity, combined

 21   with our data that a significant number of primary

 22   immune-deficient patients are undertreated, leaves

 23   our community with a supply that is inadequate to

 24   have filtered down to all primary immune-deficient

 25   patients and a situation that leaves us vulnerable 

                                                                27

  1   to an unpredictable, but inevitable supply

  2   disruption.

  3             Our intention is that by keeping this

  4   issue in the forefront, we can take actions now

  5   that will mitigate consequences of such an event.

  6             We thank the committee for your attention

  7   and we would be happy to answer any questions.

  8             DR. NELSON:  Thank you, Dr. Barr.

  9             DR. SCHMIDT:  Has anybody shown any

 10   interest in studying the 16 percent who

 11   discontinued therapy--that would be about 50

 12   people--to see what difference it made in their

 13   lives if they were no longer getting the material?

 14             DR. MORAN:  Fifty of the sample of 300,

 15   yes.  This survey was conducted in November,

 16   December, and we just interpreted the data in

 17   January.  The next step is to follow up and to get

 18   exactly what you are talking about.

 19             Yes, Mary.

 20             DR. CHAMBERLAND:  Sort of a companion

 21   question.  Do you have plans to try to conduct a

 22   survey of providers to get their perspective?  This

 23   is a survey of patients only as I understood it,

 24   and I think in the past, you have also surveyed

 25   providers. 

                                                                28

  1             DR. MORAN:  Yes.  We are, as an

  2   organization, extremely concerned with what appears

  3   to be patterns in treatment that on the surface

  4   seem to be not at adequate levels, and the answer

  5   to your question is yes, and the same follow-up

  6   effort with respect to going to patients will also

  7   be following up with providers.

  8             I think one of the issues might be there

  9   was, during the shortage, a tendency, particularly

 10   among managed care settings, to move, say,

 11   infusions from three to four weeks or four to six

 12   weeks, and clearly, if there hasn't been a

 13   disastrous health outcome, there may be a tendency

 14   to stay at that level since for the people that are

 15   footing the bill, they are going to be saving money

 16   as a result of that decision.

 17             This is speculation, but the answer to

 18   your question is yes.

 19             DR. FALLAT:  What is the half-life of

 20   IGIV, and by shifting to a longer time period, do

 21   you not actually inefficiently use the supply?

 22             DR. BARR:  Inefficiently use it.

 23             DR. FALLAT:  Yes.

 24             DR. BARR:  The half-life is every three to

 25   four weeks, and you are not efficiently utilizing 

                                                                29

  1   the supply.  The patient are also really

  2   undertreated.  We are allowing essentially what we

  3   would measure the trough level, the level of IgM in

  4   the patient's bloodstream just pre-infusion to get

  5   lower and lower, and essentially subject the

  6   patients to, you know, potentially life-threatening

  7   and serious infections.

  8             Anecdotally, we have seen from a number of

  9   our patients, they were left with a mind-set during

 10   the shortage that,  you know, we had a finite

 11   supply and it was in their best interest to really

 12   preserve that supply, because they needed it as a

 13   life-saving therapy.

 14             So, the tendency, I think, among some

 15   patients was to try to use as little as possible to

 16   sort of stretch it out, and even from the patient's

 17   perspective, perhaps also the provider and the

 18   physician, that we are trying to not exhaust this

 19   finite supply of IGIV was sort of the mentality of

 20   the population, and I think it is still pervasive

 21   to some degree.

 22             DR. CUNNINGHAM-RUNDLES:  This is another

 23   tiny bit of background information about what the

 24   long-term effects might be, I think, of patients

 25   who are not getting enough gamma globulin, and this 

                                                                30

  1   is a current theme in clinical immunology right at

  2   the present time because there have been four

  3   separate articles in peer review journals

  4   discussing the lung function of patients who are

  5   being treated with IVIG.

  6             I think the first, most stunning ones that

  7   said that 80 percent of patients who were getting

  8   the previously accepted dose of IVIG, in fact, had

  9   developed bronchiectasis.  There was another

 10   article in the Annals of Internal Medicine in the

 11   fall in which 40 percent of all the patients in

 12   Holland were surveyed, their pulmonary functions

 13   and such, and coming to the conclusion that these

 14   patients were also being undertreated given again

 15   the standard dose.  Those patients' dose actually

 16   was doubled.

 17             Now, that being in the Annals of Internal

 18   Medicine, coupled with the articles from Finland,

 19   Holland, and also from France, about X-link to

 20   gammaglobulinemia patients having slow onset of

 21   pulmonary dysfunction, I think the current tenor in

 22   the United States of physicians who treat these

 23   patients will be to increase the dose rather than

 24   to decrease it.

 25             From an academic point of view, this is 

                                                                31

  1   bound to trickle down, and I think that adds into

  2   the issue of how good our supply is in this case if

  3   everyone is going to perhaps add 25 percent more

  4   gamma globulin or, the worst case scenario, 50

  5   percent more for every patient, that will have an

  6   impact again on the ultimate availability, I think.

  7             That is certainly a tenor at current

  8   meetings regarding these patients.

  9             DR. NELSON:  Thank you, Charlotte.

 10             DR. DiMICHELE:  I just wanted to ask just

 11   for my own edification, what type of physicians

 12   treat immune deficiencies?  In other words,

 13   certainly immunologists do, but what percent of

 14   immunodeficiency patients are treated by

 15   specialists who are well aware of supply, what they

 16   can and can't do, and how many are actually treated

 17   by maybe primary care physicians for whom

 18   information dissemination might be a problem, and

 19   thus, you know, the treatment inequity resulting

 20   from that?

 21             DR. MORAN:  I don't recall the exact

 22   statistic, I will say that as a caveat.  We did a

 23   survey in 1995-96, and if I recall, it is something

 24   on the order of 50 percent or fewer were treated by

 25   clinical immunologists, and the majority of 

                                                                32

  1   patients were treated in different settings.

  2             We are planning an update to that survey

  3   as part of the other surveys that were mentioned

  4   earlier to begin sometime in the next month of two,

  5   so we will get revised data, but there is a

  6   tendency in medicine in general, I think, for

  7   patients with these types of disorders or chronic

  8   disease to be treated much more in the primary care

  9   arena than specialists.

 10             DR. DiMICHELE:  Which kind of brings up

 11   the issue of access to care versus access to

 12   product.

 13             DR. MORAN:  Exactly right.

 14             DR. DiMICHELE:  And in terms of your

 15   figures being interpreted.

 16             DR. MORAN:  That's correct.

 17             DR. ALLEN:  You made a statement at one

 18   point about patients perhaps undertreating

 19   themselves, which raises in my mind--and I honestly

 20   don't know since I do public health, and not

 21   clinical medicine--is this product used as a home

 22   therapy, in other words, patients keeping a supply

 23   at home and doing their own infusion?

 24             DR. BARR:  Some patient home infuse.  I

 25   home infuse.  But they don't keep a supply at home. 

                                                                33

  1   Typically, the home health care agency would

  2   deliver the product, you know, the day of the

  3   infusion for the patient to self-infuse at home or

  4   to have a nurse infuse at home.  Many patients are

  5   infused in hospital outpatient settings, also in

  6   physicians' offices.

  7             MR. RICE:  Tom, you mentioned the same

  8   thing that Dr. Weinstein had mentioned, that two of

  9   the five companies are planning to merge, and I can

 10   understand perhaps--I don't know you have responded

 11   to that or what kinds of assurances you have been

 12   looking for in light of that--I mean I can

 13   understand that maybe there is an efficiency and

 14   maybe a bolus amount of product that might occur

 15   from a concentration of resources, but as we have

 16   seen in the hemophilia community the catastrophic

 17   shutdown of Cogenate from the Bayer Corporation,

 18   when there is fewer people manufacturing a product

 19   and one goes down, it is even worse  no matter how

 20   good the bolus amount might be for short term, what

 21   about that long-term picture and how that might

 22   affect you?

 23             DR. MORAN:  That is really the basis of my

 24   comment, if you go down from five sources to four,

 25   then, you are increasing your exposure, as you just 

                                                                34

  1   stated, as an arithmetic certainty.

  2             With respect to potential benefits, and so

  3   forth, the companies have come to us and described

  4   what their objectives are, and we are in

  5   discussions with them about that, but I think the

  6   reason for mentioning that, and also referencing

  7   the two companies under consent decree, is again

  8   just a simple sense of vulnerability that fewer

  9   sources of product would entail.

 10             DR. HOLLINGER:  I take it that most of

 11   these are IgG deficiencies, not necessarily IgA or

 12   IgM, and what is considered a critical level of IgG

 13   in individuals?  Like we have critical levels for

 14   so many other things, what is considered a critical

 15   level, understanding that there are variations?

 16             DR. MORAN:  I think we will refer that

 17   question to Dr. Cunningham-Rundles, who is right at

 18   the table.

 19             DR. CUNNINGHAM-RUNDLES:  I think most of

 20   the patients who are infused these days have the

 21   diagnosis common variable immune deficiency or

 22   substantial antibody deficiency with IgG

 23   deficiency.  So, common variable is when two of the

 24   three subclasses, or two of the three isotypes are

 25   down, so IgG, usually A and very often M as well, 

                                                                35

  1   so it can be across the board.

  2             People with just plain IgA deficiency

  3   generally don't get gamma globulin, though.

  4             DR. HOLLINGER:  And a critical level,

  5   what, 500, 300, 200, 100, 20?

  6             DR. CUNNINGHAM-RUNDLES:  That's impossible

  7   to say because you can have a person who has a

  8   level of 300, and have wonderful antibody function,

  9   or a level of 1,000 and terrible antibody function,

 10   so the level of gamma globulin isn't so important

 11   as the real functional component.  So that has to

 12   be measured separately.

 13             If you have to give a textbook answer, you

 14   would say that normal people run, say, 500 to 1500,

 15   that normal is normal.  So under 500 is not normal

 16   exactly, but you might become symptomatic at, say,

 17   400 or 300, certainly much less than that

 18             DR. NELSON:  What proportion of the IVIG

 19   is used for primary immunodeficiency as opposed to

 20   other, like off-label uses?  My impression was that

 21   the latter has grown rather dramatically, but do

 22   you have any data on that?

 23             DR. MORAN:  Well, primary

 24   immunodeficiencies are one of I believe it is six

 25   license indications, and I think estimates vary 

                                                                36

  1   between 20 and 30 percent, probably on the lower

  2   end, 20 to 25 percent would be used by primary

  3   immune-deficient patients.

  4             The other license indications may account

  5   for another 25 percent, and off-label indications

  6   may be 50 percent or higher.  This is speculative.

  7   It is based on some research, but it is a guess up

  8   to a point.

  9             DR. DiMICHELE:  I have another related

 10   question. If I understand correctly, FFF was

 11   involved in creating emergency depot systems for

 12   distribution of product during shortage, and I was

 13   wondering if you could comment on the role of

 14   emergency depots in sort of alleviating the

 15   shortage, getting product to patients, et cetera,

 16   what role did it play in this shortage?

 17             DR. MORAN:  Well, in fact, FFF was the

 18   distributor that the IDF selected to handle what we

 19   call our Safety Net Program, and I think between

 20   the fall of 1998, really through the present time,

 21   there has been a substantial amount of gamma

 22   globulin distributed through the mechanism.

 23             It was literally a lifesaver in our

 24   community, and it was done very efficiently and

 25   very effectively.  The typical kind of call that 

                                                                37

  1   would come in would be from a nurse or a pharmacist

  2   or a physician saying I have got three patients

  3   coming in on Friday--maybe this call came in on a

  4   Wednesday--and we can't get any IGIV, and so it was

  5   really day after day, month after month, and it

  6   became year after year of filling those kind of

  7   just-in-time requests.

  8             We frankly think that that turned the tide

  9   within our community because, as someone pointed

 10   out, if there is 5-or 6 million grams consumed by

 11   primary immuno-deficient patients, even during the

 12   shortage when there were 15 million grams released,

 13   it is a question of trying to allocate that

 14   product, target it at the patients who arguably

 15   will certainly need it with respect to life-sustaining

 16   reasons.

 17             So, as soon as it became known

 18   pharmacists, hospitals, physicians, and patients

 19   that there was this resource available, this just-in-time

 20   resource, as a backup, I think that went a

 21   long way to ameliorating the negative health

 22   effects that Dr. Barr alluded to.  At the IDF, we

 23   are very proud of that, and FFF did an outstanding

 24   job in supporting us in that.

 25             DR. FITZGERALD:  This is maybe more to 

                                                                38

  1   Mary than to you, but the discussions, one of the

  2   things you mentioned in your presentation was

  3   homeland defense.  In discussions of responses to

  4   bioterrorism, some of the protocols that have been

  5   discussed include using IVIG versus IM.

  6             Is there somebody looking at the possible

  7   or potential for how much might be needed and what

  8   protocols would be addressed for that?

  9             DR. CHAMBERLAND:  I, myself, can't speak

 10   directly to that, but I do know that there are

 11   people both at CDC and certainly at the FDA, that

 12   are involved in a lot of the discussions in

 13   consideration.

 14             I don't know if anybody from FDA is

 15   present to supplement.

 16             DR. EPSTEIN:  Part of the issue has to do

 17   with  vaccinia immune globulin, and the question

 18   how much can be generated, how soon, to support any

 19   kind of vaccination program, either of first

 20   responders or in circumstances of an outbreak, and

 21   research mainly by scientists at FDA has shown that

 22   there are IGIV preparations that contain levels of

 23   antibodies to vaccinia due to childhood

 24   immunizations, which stopped in the very early

 25   seventies, and that the titers are lower than in a 

                                                                39

  1   fresh vaccinee, but are potentially useful.

  2             So, there is the question whether one

  3   could utilize any existing stocks of IGIV to deal

  4   with any large number of vaccinee or vaccinations,

  5   smallpox vaccine, so we are aware of that, and we

  6   are looking at it, and we are also aware of the

  7   possibility that one might be able to conserve

  8   product use by IM dosing versus IV dosing.

  9             But I just think that all of those issues

 10   are very much under discussion and that there is

 11   not much that I could say definitively except that

 12   it would potentially become yet another medical

 13   demand for IGIV products.

 14             DR. NELSON:  Thank you.

 15             The next item is a discussion of the

 16   recent HIV Western Blot shortage.

 17             Dr. Mied.

 18                   Recent Western Blot Shortage

 19             DR. MIED:  Thank you, Dr. Nelson.

 20             [Slide.]

 21             On April 17, 2002, Calypte Biomedical

 22   Corporation of Alameda, California, issued a News

 23   Release in which it "announced that it has begun to

 24   wind down its operations." These operations include

 25   the manufacture of the Cambridge Biotech HIV-1 

                                                                40

  1   Western Blot Kit.

  2             The Cambridge kit is one of three

  3   currently available HIV-1 supplemental tests

  4   licensed by FDA for testing of blood and plasma

  5   donor specimens or as an aid in medical diagnosis.

  6             The other two licensed supplemental tests

  7   are the Genetic Systems HIV-1 Western Blot

  8   manufactured by Bio-Rad Laboratories, Inc., of

  9   Hercules, California, and the Fluorognost HIV-1 IFA

 10   kit manufactured by Sanochemia of Vienna, Austria.

 11   Performance of a licensed supplemental test

 12   following a reactive donor screen is required under

 13   current regulations (See 21 CFR 610.40(e)).

 14             On May 13, 2002, Calypte Biomedical

 15   Corporation issued a Press Release announcing the

 16   continuation of ongoing business and that "the

 17   company does not intend to wind down its business

 18   as previously announced."

 19             In the interim, however, pending

 20   replenishment of inventories, shortages of Western

 21   Blot Kits may continue to occur, especially for use

 22   in diagnostic testing, since that constitutes the

 23   market segment with the greatest demand for Western

 24   Blot Kits.

 25             On May 10, 2002, in response to inquiries 

                                                                41

  1   from public health testing sites and clinical

  2   testing laboratories, CDC issued a Morbidity and

  3   Mortality Report, an MMWR, that outlined options

  4   for clinical testing laboratories and public health

  5   laboratories for supplemental testing to detect HIV

  6   antibodies using test kits approved by FDA in the

  7   event that the Cambridge Biotech HIV-1 Western Blot

  8   Kit is unavailable.  Some blood and plasma

  9   establishments have also experienced delays in

 10   obtaining HIV-1 Western blot kits.

 11             [Slide.]

 12             The following current options exist for

 13   blood and plasma establishments for use of licensed

 14   HIV-1 supplemental tests to validate the results of

 15   donor screening for antibodies to HIV:

 16             First, use a licensed Western Blot Kit.

 17   Supplemental testing can be performed on serum and

 18   plasma using the Genetic Systems HIV-1 Western Blot

 19   (Bio-Rad Laboratories, Inc., Hercules, California).

 20   Information about the availability of this test kit

 21   can be obtained on-line at www.biorad.com or by

 22   contacting the company directly at 1-800-2-BIORAD.

 23             The Cambridge Biotech HIV-1 Western Blot

 24   Kit may also be available for use.  Information

 25   about the availability of this test kit can be 

                                                                42

  1   obtained on-line at www.calypte.com or by

  2   contacting the company directly at 1-877-CALYPTE.

  3             The second option is to use the licensed

  4   Sanochemia IFA test.

  5             Supplemental testing can be performed on

  6   serum or plasma using the Fluorognost HIV-1 IFA kit

  7   manufactured by Sanochemia, Vienna, Austria.

  8   Information about the availability of this product

  9   can be obtained by accessing the product web site

 10   at www.fluorognost.com or by calling Fluorognost at

 11   (203)-227-6880.  Sanochemia provides both a self-taught

 12   course on performing the HIV-1 IFA and a

 13   proficiency panel free of charge.

 14             [Slide.]

 15             Future Options for Consideration.  In the

 16   event that approved supplemental tests become

 17   unavailable, FDA would consider whether it is

 18   appropriate for establishments to use under the IND

 19   mechanism foreign supplemental tests that are

 20   brought forward in pursuit of licensure.

 21             FDA is also interested in facilitating the

 22   development and approval of alternative testing

 23   strategies that could provide additional options

 24   for supplemental testing of blood samples from

 25   donors with reactive screening tests for HIV. 

                                                                43

  1             It is our current thinking that additional

  2   options for supplemental testing might be developed

  3   based on suitable scientific data contained in

  4   application submissions, for example, the

  5   validation of nucleic acid testing, or NAT, for use

  6   in supplemental testing algorithms.

  7             Scientific considerations suggest that a

  8   reactive NAT on an individual unit could be taken

  9   to confirm a repeatedly reactive screening test for

 10   antibodies to HIV. Conversely, a negative NAT might

 11   be taken as conclusive in some circumstances.  FDA

 12   would review data from studies performed by

 13   industry should they wish to pursue such options.

 14             Secondly, a role for reference

 15   laboratories.  FDA is interested in hearing

 16   comments on the issues related to the creation of a

 17   role for reference laboratories in providing

 18   supplemental testing for antibodies to HIV.

 19             Thank you.

 20             DR. NELSON:  Thank you, Dr. Mied.

 21             Questions?  Yes, Paul.

 22             DR. SCHMIDT:  Of the, is it 13 million

 23   units of blood collected in the country a year,

 24   what number are going to require this supplemental

 25   testing, and how does that face up to other uses of 

                                                                44

  1   the supplemental test in diagnostic clinics, and

  2   things like that?  How much of the problem is a

  3   blood supply problem?

  4             DR. MIED:  In the donor setting, the

  5   repeatedly reactive rate for HIV antibody is

  6   approximately 0.1 percent or 1 in 1,000.  So, out

  7   of 13 million donations of blood only, we are

  8   talking about 13,000 HIV Western blots would need

  9   to be run.

 10             We have found that the total market for

 11   HIV Western blot testing is approximately 35,000

 12   tests per month, so if you look at it on a

 13   percentage basis, the blood and plasma market plus

 14   military testing, on the whole, totals no more than

 15   10 percent.  From what we can see, the diagnostic

 16   testing market is about 90 percent of total Western

 17   blot demand.

 18             DR. SIMON:  In terms of your possible

 19   future options, I wasn't clear what you meant by a

 20   role for reference laboratories.  How would that

 21   help if there is a shortage of test material?

 22             DR. MIED:  There may be existing

 23   laboratories that could qualify as reference

 24   laboratories for the purpose of providing

 25   supplemental testing, or perhaps a whole new 

                                                                45

  1   laboratory structure could be created.

  2             We would welcome comments on possible

  3   options as to how this could be done, how it could

  4   be provided perhaps as a service.

  5             DR. SIMON:  But wouldn't the reference

  6   laboratories use commercial reagents, or are you

  7   saying that they would use some other source?

  8             DR. MIED:  They would use commercial

  9   reagents, but we are certainly interested in

 10   listening to alternatives, and those alternatives,

 11   as I said, could include new alternative testing

 12   algorithms that could be approved, that could

 13   obviate the need for Western blot.

 14             DR. NELSON:  Actually, since blood donors

 15   are screened with NAT, those that are NAT-positive

 16   wouldn't need a supplemental test.  Would that

 17   solve a lot of the problem as far as the blood

 18   donors are concerned?

 19             DR. MIED:  Dr. Nelson, currently, they are

 20   screened with pooled sample NAT, and you may have a

 21   repeatedly reactive test from an EIA, a sample that

 22   is repeatedly reactive with on EIA, but is negative

 23   on pooled sample NAT, which on subsequent testing

 24   could be reactive on an individual sample NATION.

 25   This is the type of data FDA welcomes, how such an 

                                                                46

  1   algorithm could work.

  2             DR. NELSON:  I guess if the person was on

  3   therapy, that might happen, I agree.

  4             DR. ALLEN:  Are there currently

  5   manufacturers, particularly the NAT testing, who

  6   are considering submitting the data that you are

  7   asking for, or is this really perhaps way down the

  8   line before that might become a possibility?

  9             DR. MIED:  No, we don't think it's way

 10   down the line.  We know there are some studies in

 11   progress right now. We will have to see what the

 12   result in, in terms of product submissions from the

 13   manufacturer.

 14             DR. HOLLINGER:  Paul, at 35,000 tests a

 15   month, that does not seem to be a large number.

 16   Why is it that the manufacturers are not producing

 17   the Western blot kits?  What is the reason that

 18   there is a reduction in these kits?

 19             DR. MIED:  Well, at time we had four

 20   licensed Western blot manufacturers.  One has

 21   ceased producing Western blots, but another one was

 22   the Genetics Systems' Western Blot, which has

 23   continued on the market even though Bio-Rad, which

 24   had another of the licensed Western blots, now

 25   Genetics Systems is part of Bio-Rad, so we have 

                                                                47

  1   lost one Western blot being a manufacturer has

  2   discontinued production of it, and the other one

  3   was a company with essentially two products that

  4   decided to go with one.

  5             So, we current have two licensed Western

  6   blots, and we are interested in doing what we can

  7   to encourage more manufacturers to get into

  8   supplemental test production.

  9             DR. NELSON:  Jay.

 10             DR. EPSTEIN:  Thanks, Kenrad.

 11             I just wanted to follow up because I think

 12   that what you are hearing, similar to the

 13   presentation on IGIV, the FDA does not control the

 14   market forces.  We do what we can to work with

 15   manufacturers either to get them into compliance or

 16   to help them streamline their product submissions,

 17   come to license more quickly, and so forth.

 18             But I think what you are hearing is that

 19   there are these forces that make the market

 20   irrational, but we don't control them, and what we

 21   are looking for are ways to perhaps better engineer

 22   the public health system, so that we are able to

 23   have safeguards, either providing products for

 24   patients with critical need or making critical

 25   diagnostics available, still under the general 

                                                                48

  1   umbrella of licensed mechanisms and quality

  2   oversight, but to do something about the fact that

  3   we have these irrational market forces.

  4             DR. HOLLINGER:  I understood that, Jay,

  5   but I guess my question was a more generic question

  6   of why, I mean if the market is out there, is it

  7   liability, are there other issues that they just

  8   don't have the manufacturing to produce these kits

  9   or something, is it not profitable?  I am just

 10   trying to figure out what is the reason why there

 11   is this issue here.

 12             DR. EPSTEIN:  I don't know that I am in a

 13   better position to answer that question than

 14   anybody else.  I can tell you what we heard.  The

 15   things that we hear are that these are not

 16   profitable products.

 17             We hear that producing them under GMP

 18   creates a barrier.  We also hear that companies

 19   basically want to make home run products, there is

 20   not a lot of incentive for the companies with the

 21   capability to make these products, to make products

 22   that have small volume sales.

 23             These are just the kind of things that we

 24   hear.

 25             You know, every company wants to sell 

                                                                49

  1   millions of screens, and few companies are willing

  2   to make products that are only a few tens of

  3   thousands of supplemental tests.

  4             DR. HOLLINGER:  Does this mean that

  5   perhaps in the future, for products like this, that

  6   are going to be required, and so on, that they are

  7   going to have to be manufactured by the government

  8   then or something else if they are not going to be

  9   picked up by industry?

 10             DR. EPSTEIN:  I think that that would be

 11   one sort of option that could be considered.  This

 12   is why we are saying we need to call for options.

 13   There are other ways one could look at this.

 14             For example, the blood industry itself

 15   could establish a reference laboratory using

 16   licensed reagents.  If they are not available from

 17   other sources, that entity could itself become a

 18   manufacturer, but it could be linked to a stable

 19   revenue, because it is sponsored by the

 20   organizations that need to use the product.  The

 21   blood product testing would be done by laboratories

 22   supported by and then serving the collection

 23   industry.

 24             So, there are ways that the thing could be

 25   stabilized.  The government I think has reasonable 

                                                                50

  1   reluctance to just step in and become a

  2   manufacturer, it doesn't want to do that.

  3             DR. NELSON:  Yes.  The microphone.

  4             MR. STEVENS:  Chip Stevens from Sanochemia

  5   Fluorognost, makers of the Fluorognost HIV-1 IFA.

  6   I am not here to talk about our product, this is

  7   not the place.  It is an FDA-approved product with

  8   very high quality sensitivity and specificity.

  9             On the request of the CDC and certain

 10   members of the FDA, when the Cambridge issue came

 11   up, we increased our production 3-fold to meet the

 12   crisis.  Since the crisis started, half of the

 13   state health departments have been qualified on our

 14   test, and have either established it as their test

 15   or as a Plan B.

 16             In that time, but one blood center has

 17   called us. We, at great financial risk, we are a

 18   company that produces one diagnostic product.  The

 19   HIV-1 Western Blot costs about 13 to $14 to

 20   manufacture and produce, get out on the market.

 21   Most people are willing to pay about 13 or $14 for

 22   that, and that is a reason you have a shortage,

 23   that is why you have companies merging, going out

 24   of business.

 25             We produce an IFA product, a very quality 

                                                                51

  1   at great financial risk, we built our inventories

  2   and have not gotten much of any response from the

  3   blood bank.  I would request before you look at

  4   lowering the standards, holding a safety net for

  5   NAT, using that as your confirmatory, that you look

  6   at the market itself.

  7             We work real hard.  We don't want to be

  8   another manufacturer that goes down trying to help

  9   the market, meet the marketplace.  We have product

 10   available, and we are ready to meet the marketplace

 11   need.

 12             DR. NELSON:  Thank you.  Mike.

 13             DR. BUSCH:  Mike Busch.  I personally

 14   think, well, one, is that we pay about $50 per

 15   strip for Western blots.  That is the discount

 16   rate, large volume purchases, but in a sense, you

 17   know, the problem is the rest of the world is long

 18   past Western blot and IFA's. They are using

 19   recombinant antigen-based supplement assays that

 20   perform very well in a sensitivity/specificity

 21   context.

 22             The problem is the market is so small, and

 23   the barrier, the cost barrier, to produce and

 24   license these products through FDA, has led to the

 25   failure of most of these products to come formally 

                                                                52

  1   to FDA.

  2             The few examples where I have been

  3   involved where recombinant-based assays have come

  4   to FDA, the criticism historically was that, you

  5   know, you look at lots of seroconversion panels and

  6   you will find that they can't always pick up when

  7   the most sensitive EIAs can.  They are better than

  8   blots, but they are not as sensitive as the EIAs in

  9   certain panels.

 10             Now, that is a dead issue since we screen

 11   the blood supply with NAT, so we have RNA to cover

 12   that early window period, but still the fundamental

 13   problem is I just don't think any of these

 14   companies are going to bring state-of-the-art

 15   assays to this country for full FDA licensure, and

 16   I think the option of trying to figure out some way

 17   where large blood center or other reference labs

 18   can gain access to these products and perform them

 19   in a context that FDA accepts is the best solution.

 20             DR. STRAMER:  Susan Stramer, American Red

 21   Cross.

 22             I just want to make the committee aware of

 23   two points.  One, the accumulated NAT data we have,

 24   and NAT has been referenced as one possible

 25   alternative to the Western blot, where that is an 

                                                                53

  1   option for NAT positives whether they are detected

  2   in pools and then resolved to an individual

  3   donation, that is all well and good, but that

  4   represents only 5 to 7 percent of the total usage

  5   of Western blot.  So, that will eliminate only a

  6   small portion of the need.

  7             Then, if you look at the Western blot

  8   positive, the other side of the coin, are the

  9   Western blot positive samples that aren't NAT

 10   negative, as Dr. Nelson mentioned, if an individual

 11   is on treatment long term, non-progressors who may

 12   have very low viral load.

 13             In our screening program at the American

 14   Red Cross, we found 41 such samples that are

 15   Western blot positive and NAT negative, so to look

 16   at options to decrease the burden on the

 17   supplemental tests, which even when they are FDA

 18   licensed lack the same quality as our primary

 19   screening tests, what we are doing, that is, Red

 20   Cross, in collaboration with Blood Systems

 21   Laboratories, is we are validating a dual EIA

 22   strategy, the same as we use for HTLV today because

 23   of the issue of no supplemental test that is

 24   licensed by FDA.

 25             So, what that would entail are the two 

                                                                54

  1   tests that are FDA licensed for screening that have

  2   been through the most robust validation, the

  3   largest amount of data accumulated from users on

  4   the test, and probably the most confidence that we

  5   have on any test kits available.

  6             So, we would do the dual EIA the same way

  7   as we apply the HTLV algorithm, and only concordant

  8   EIA repeat reactives would go on to Western blot

  9   for further resolution, and discordance would not

 10   require any testing.

 11             So, if testing about 500 Western blot

 12   positives that are NAT positive, we found that to

 13   be reactive on both EIAs--this is data to date, we

 14   are not completed with the study yet--and of

 15   Western blot indeterminates and negatives, we are

 16   able to eliminate over 90 percent of repeat

 17   reactive samples on either of the two screening

 18   tests, so this will greatly diminish the burden of

 19   volume that is required for the supplemental tests.

 20             So, we believe that this will be a viable

 21   option. Our plan is to collate the data provided to

 22   FDA for review, and hopefully, have further action

 23   at that time.

 24             Thank you.

 25             DR. NELSON:  Thank you.  There is also a 

                                                                55

  1   lot of data in the international setting using that

  2   algorithm of dual EIA, and the data so far is

  3   pretty good.  Of course, they are often in higher

  4   prevalence populations than the donor population,

  5   so I think it needs to be looked at in the blood

  6   donor population, as well.

  7             Toby.

  8             DR. SIMON:  I think we have had two very

  9   interesting presentations on significant shortage

 10   issues.  I think Dr. Epstein's comments are very

 11   good in terms of focusing us on the fact that the

 12   market forces can be irrational, can cause

 13   problems.

 14             I do think, as this committee discusses

 15   this and other items, one of the things we need to

 16   keep in mind is that the cost of regulation has a

 17   heavy impact on these markets.  We are looking at,

 18   I think, a number of instances in which the cost of

 19   regulation may have impacted supply, and that is

 20   something I think that needs to be considered as we

 21   look at the economics and its impact on patient

 22   care.

 23             DR. NELSON:  Somebody mentioned the--maybe

 24   that was the IVIG--the consent decree, a few

 25   companies, was the consent decree related to this 

                                                                56

  1   product production or something else, do you know?

  2   Were they related to GMP problems with

  3   manufacturing this product or some other product?

  4             DR. MIED:  Not for the Western blots that

  5   I am aware, no.

  6             DR. NELSON:  Wendy Chen from Calypte.

  7             DR. CHEN:  Thank you, Dr. Nelson.  My name

  8   is Wendy Chen.  I am the director of Product

  9   Technology at Calypte Biomedical Corporation.  I

 10   would like to thank the committee for giving this

 11   opportunity to read the following statement.

 12             Calypte Biomedical Corporation,

 13   headquartered in Alameda, California, is a public

 14   healthcare company dedicated to the development and

 15   commercialization of urine-based diagnostic

 16   products and services for HIV-1, sexually

 17   transmitted diseases, and other infectious

 18   diseases.

 19             Calypte's existing products include the

 20   Cambridge Biotech HIV-1 serum Western Blot

 21   supplemental test, as well as the only two FDA-approved HIV-

 22   1 antibody tests that can be used on

 23   urine samples - a screening EIA and a supplemental

 24   Western Blot.

 25             On April 17, 2002, Calypte announced that 

                                                                57

  1   the company had begun to wind down manufacturing

  2   operations and might file for bankruptcy.  Faced

  3   with limited operating cash, Calypte began laying

  4   off its workforce and closing its facilities while

  5   at the same time, continuing to aggressively seek

  6   partnerships and additional funding.

  7             Calypte announced that we would not longer

  8   be able to sustain operations from existing

  9   revenues and current financing lines.

 10             On May 13th, Calypte received a commitment

 11   for investment in new equity from a group of

 12   private investors to be used to fund the Company's

 13   operations and to move forward with the

 14   implementation of its business plan.

 15             In light of this new funding, operations

 16   in our Alameda, California and Rockville, Maryland

 17   production facilities were not completely shut

 18   down, key staff were brought back and production

 19   was resumed.

 20             On May 24th, Calypte announced the

 21   completion of $2.7 million in financing.

 22             To date, Calypte has been able to bring

 23   back 42 key employees and because steps were taken

 24   to allow operations to restart smoothly, we have

 25   been able to resume production of all products with 

                                                                58

  1   minimal interruption.  Additionally, we have

  2   retained an inventory of its HIV-1 Urine EIA

  3   screening test and will be submitting additional

  4   product to the FDA for lot release in early July.

  5             We are now happy to report that we have

  6   received FDA lot releases for new inventory of both

  7   the Cambridge Biotech HIV-1 serum Western Blot

  8   supplemental test, as well as the Cambridge Biotech

  9   HIV-1 Urine Western Blot supplemental test.  All of

 10   our HIV testing products are again available and

 11   are being distributed.

 12             Calypte looks forward to continuing to

 13   work closely with the FDA to continue to supply our

 14   HIV testing products to the market as quickly as

 15   possible.

 16             Thank you.

 17             DR. NELSON:  Thank you.  Questions or

 18   comments?

 19             The next speaker is Chip Stevens from

 20   Fluorognost. You made a comment at the microphone.

 21   I don't know if you want to say anything else.  No?

 22   Okay.

 23             Celso Bianco from America's Blood Centers.

 24             DR. BIANCO:  We had prepared a statement

 25   that is quite long, so I will try to summarize it, 

                                                                59

  1   but I respectfully request that the whole statement

  2   become part of the record.

  3             American's Blood Centers, as you all know,

  4   is a national network of locally-controlled, not-for-profit

  5   community blood centers that collect

  6   about half of the U.S. blood supply.

  7             While we are hopeful that the anticipated

  8   shortage of HIV-1 Western blot kits has been staved

  9   off for now, the incident highlights the need for

 10   multiple suppliers of the tests for which we rely

 11   for donor counseling and donor re-entry.

 12             More importantly, it also suggests the

 13   need for alternative approaches to the use if

 14   supplemental tests and the management of those

 15   tests.

 16             I think this is an opportunity--and I will

 17   try to summarize this--to address the major issues

 18   that we have with supplemental tests.

 19             First of all, the current screening tests,

 20   since they are being applied to an essentially

 21   negative population with very few positives,

 22   produce a lot of false positive test results, and

 23   we know that.

 24             Donors with repeatedly reactive screening

 25   test results, they must undergo confirmation 

                                                                60

  1   according to the current regulatory process.  The

  2   number of HIV tests for confirmation is limited.

  3   There are no confirmatory tests or additional more

  4   specific supplemental tests for the other

  5   retrovirus that we test for, this HTLV I/II.

  6             The current supplemental tests, like HIV

  7   Western blots are less than optimal, and I must

  8   mention that the Cambridge Western Blot has in its

  9   package insert that when it is supplied to a normal

 10   population that is negative on the ELISA screen,

 11   that Western blot will produce 15 percent of the

 12   time indeterminate test results simply because of

 13   the definition of negative as stated in the

 14   approval of the test.

 15             I mentioned the HTLV, and even in the case

 16   of HTLV, there was a question from Dr. Paul Mied

 17   about laboratories.  There are laboratories,

 18   including one laboratory that is the State of

 19   California laboratory, that will provide

 20   confirmation, for instance, for HTLV using home

 21   brew tests that they have developed, but those are

 22   not tests licensed by FDA.

 23             If we look strictly at the Final Rules on

 24   Donor Notification that were issued on June 11th,

 25   it says that we must attempt to obtain results of 

                                                                61

  1   supplemental tests obtained under 610.40, and all

  2   the rules require that we make the confirmatory

  3   tests as part of the donor screening process even

  4   if subsequently we do not re-enter the donor.

  5             We believe that there are potential

  6   solutions.  Dr. Stramer just mentioned one approach

  7   that I think very interesting and useful of the

  8   dual EIA that she is doing in collaboration with

  9   Sally Caglioti from Blood Systems.

 10             There are other potential ways by which we

 11   could approach it.  I am not choosing one, I am

 12   just raising them. I would like to see all of us

 13   think outside the box and get out of this trap of

 14   the screening and the supplemental tests.

 15             One thing that is very important, FDA has

 16   contributed a lot in the presentations before,

 17   about a year ago, to this committee on the approach

 18   to donor management after NAT licensure.  We would

 19   like to see that guidance out.  We like the

 20   schemes, we like the fact that it resolves, for

 21   instance, indeterminate Western blots in a way that

 22   we could not resolve before.

 23             We would like, at the same time, to

 24   revisit the Western blot criteria and get rid of

 25   the issue of non-viral bands as indeterminate, 

                                                                62

  1   because today we have a much better armamentarium,

  2   much better tools to resolve those issues.

  3             We would like, even if it is a small

  4   number, as Dr. Stramer mentioned, not to have to do

  5   a Western blot or a RIBA after we have a screening

  6   test that is positive for HCV and a NAT that is

  7   positive.

  8             This donor is positive.  The performance

  9   of RIBA in this situation just delays the

 10   notification of the donor, delays the initiation of

 11   lookback, delays the implementation of treatment,

 12   let's say, for HIV, even with the risk, and

 13   counseling, even with the risk of secondary

 14   transmissions.

 15             We would like to think maybe that when we

 16   have no chance of resolving the Western blot or the

 17   confirmatory tests or the supplemental tests for

 18   HTLV, and it is unlikely that we are going to see

 19   one, maybe to classify these individuals as

 20   patients, and allow the current medical system that

 21   can use research tests, that can use other

 22   approaches, to attempt to resolve the future of the

 23   those donors.  The only thing that we have to do

 24   for the safety of the blood supply is not to re-enter these donors.

 25             We can consider revising an evolving 

                                                                63

  1   system as new tests, new technologies come up, to

  2   consider changing those confirmatory algorithms

  3   instead of just being part of strict regulatory

  4   mechanisms.

  5             Finally, as a suggestion, another

  6   suggestion, we would like FDA to, as in the case of

  7   what happens now with the licensure of the NAT for

  8   HIV, and allowing the elimination of the HIV p24

  9   antigen screening test, that the donors that have

 10   been in the past deferred because they had

 11   nonspecific test results of p24, to allow

 12   essentially an automatic re-entry of those donors,

 13   because at that time, it was the lack of power of

 14   the resolution systems that did not allow these

 15   individuals to be entered.  Today, with NAT, they

 16   could be eligible to donate.

 17             ABC hopes that FDA will use this

 18   opportunity to revise its regulations, promote new

 19   technologies for blood donor screening and for

 20   supplemental tests, and apply current scientific

 21   information on the epidemiology of transfusion-transmitted

 22   diseases to rationalize donor

 23   deferrals, notification, counseling, and re-entry,

 24   and we are ready to help in any way we can.

 25             We accept the challenge from Dr. Mied that 

                                                                64

  1   we have to produce the data.

  2             Thank you.

  3             DR. NELSON:  Thanks, Celso.

  4             Questions or comments?

  5             Thank you.

  6             The next person that will present is

  7   Christopher Bentsen from Bio-Rad.

  8             DR. BENTSEN:  Good morning.  I would like

  9   to read a brief statement into the record.

 10             Bio-Rad Laboratories, Genetic Systems

 11   Brand, HIV-1 Western Blot was licensed by the FDA

 12   with the use of serum plasma and dried blood spots

 13   on November 13th, 1998.  This was the fourth and

 14   most recent Western blot license by the FDA and

 15   appears to be only one of two remaining Western

 16   blots on the market.

 17             Bio-Rad Laboratories acquired the Genetic

 18   Systems Western Blot when it purchased Genetic

 19   Systems Corporation and Sanofi Diagnostics Pasteur

 20   on October 1st, 1999.  Over the past year, Bio-Rad

 21   Laboratories in Redmond, Washington, has increased

 22   production of the Western Blot Kit in order to meet

 23   the increased market demand, and based on Company

 24   estimates, Bio-Rad believes it can meet current 

                                                                65

  1   customer demands for its Western Blot Kits by the

  2   end of this summer.

  3             Thank you.

  4             DR. NELSON:  Any questions?

  5             All right.  Thank you very much.

  6             Finally, Bruce Phelps from Chiron

  7   Corporation.

  8             DR. PHELPS:  Thank you, Dr. Nelson, for

  9   this opportunity to speak with you this morning.

 10             [Slide.]

 11             I would like to bring to the attention of

 12   the committee an alternative to the Western Blot

 13   which Chiron Corporation has manufactured since

 14   1996, and that is the RIBA HIV-1/HIV-2 strip

 15   immunoassay.  This particular test was submitted to

 16   the FDA for review in 1996.

 17             [Slide.]

 18             There were several concerns raised by the

 19   FDA after this review of the submission in 1997, in

 20   a list of questions that came back to Chiron

 21   Corporation.  Among those concerns listed on this

 22   slide there were some performance issues relative

 23   to equivalence to the Western blot, interpretation

 24   of the plus/minus band densities on the antigen

 25   bands that were developed during the assay, and 

                                                                66

  1   also the lack of HIV Type O specific sequences in

  2   this particular assay formulation.

  3             I would like to provide some information

  4   and data on the performance of the assay relative

  5   to these aspects in later slides.

  6             Similarly, there were a couple of

  7   manufacturing issues that were of a concern, lot-to-lot

  8   reproducibility in particular, variability

  9   of the IgG control band densities, and process and

 10   methods validation issues, and I would like to just

 11   touch base momentarily on those issues also.

 12             [Slide.]

 13             This is a summary of data from a

 14   publication that was published in the Journal of

 15   Clinical Microbiology by Kline, et al., in 1996.

 16   It was a population of HIV-1 and HIV-2 positive

 17   specimens, as well as a fairly significant number

 18   of negative specimens that were tested, and this

 19   shows the performance of the kit relative to the

 20   Western Blot.

 21             As you can see, in terms of sensitivity,

 22   its sensitivity was significantly increased

 23   specifically with respect to HIV-2.  In a

 24   population of 215 specimens, the RIBA test

 25   correctly categorized all 215 as HIV-2 positive, 

                                                                67

  1   whereas, the Western Blot--and this was the

  2   Cambridge Western Blot, by the way, that was tested

  3   in this study-- only 158 of those specimens were

  4   actually correctly called as positive, and 57 fell

  5   into the indeterminate category.  So, there is an

  6   improvement in sensitivity with the RIBA.

  7             In this particular population, we did

  8   miscall one as a confirmed positive on the HIV-1.

  9   It fell into an indeterminate category.  With RIBA,

 10   an indeterminate is any kind of a band pattern that

 11   does not meet the criteria for an HIV-1 or HIV-2

 12   positive.  It's a 1 plus, but there may be other

 13   plus/minus bands that are present, that are just

 14   above the level of detection, but aren't dark

 15   enough to be considered a positive 1-plus band, so

 16   they would fall into the indeterminate category.

 17             With respect to the specificity, as you

 18   can see, there were three that were falsely

 19   positive on the RIBA test, two, HIV-1 and one, HIV-2,

 20   however with the Western Blot, five of these

 21   individuals were designated as falsely positive, so

 22   there is an improvement also in specificity with

 23   respect to false positivity.

 24             There were 22 of these individuals that

 25   fell into the indeterminate category on RIBA, but 

                                                                68

  1   152 in terms of the Western Blot, and only 391 were

  2   actually correctly called negative by the Western

  3   Blot, whereas, 523 were called correctly by the

  4   RIBA.  So, there is a significant improvement in

  5   terms of specificity with the RIBA assay also.

  6             [Slide.]

  7             With respect to the plus/minus band

  8   density, this was a concern of the FDA relative to

  9   the interpretation of the plus/minus bands.

 10   Ordinarily, they are basically interpreted as

 11   negative, which leads to these sensitivity and

 12   specificity data.  This is using the data from the

 13   last slide just as an example.

 14             Under those conditions, you remember there

 15   was one of the HIV-1's that were missed, so that

 16   gives a sensitivity of 99.8 percent on HIV-1, but

 17   100 percent on the dual infectives and on the HIV-2's.  With

 18   the three false positives, that is a

 19   specificity basically of 0.6 percent with RIBA.

 20             If we were to call the plus/minus bands

 21   positive, I think as was suggested by FDA, we would

 22   obviously throw this HIV-1 into a positive

 23   category, giving 100 percent sensitivity across the

 24   entire population, however, this estimates that all

 25   of the indeterminates would probably fall into the 

                                                                69

  1   positive range also, and this is probably a best

  2   case, because there would be some of the negative

  3   populations in this particular instance that would

  4   have had multiple plus/minus bands, and a

  5   plus/minus is considered positive.  Some of those

  6   would be thrown into the positive category also.

  7             So, you can see the specificity of the

  8   test is significantly impacted and becomes much

  9   reduced, and any of the advantages over Western

 10   Blot would be lost.

 11             So, that is an issue that would need to be

 12   resolved with this assay, we understand that.

 13             [Slide.]

 14             On this slide is shown the HIV-1 subtype

 15   sensitivity.  We did look at multiple HIV-1

 16   subtypes all the way A through F, and particular O.

 17   There were 45 specimens, Type O specimens that were

 18   tested, and you will see in this particular

 19   instance, all of these, all subtypes were detected

 20   as 100 percent as HIV-1 positive, so even though

 21   there is no specific antigen sequence for HIV-O, we

 22   do detect it in the RIBA and would correctly

 23   confirm those samples.

 24             [Slide.]

 25             In terms of manufacturability, since 1996, 

                                                                70

  1   when we started manufacturing this material for ex-U.S.

  2   markets, we have produced 15 lots.  That

  3   amounts to over 10,000 kits and over 315,000

  4   strips.

  5             In 2001, last year, we sold 942 of these

  6   test kits in multiple markets around the world.

  7   You can see the 10 countries listed here where we

  8   have entered in the market and are continuing to

  9   supply adequately to support supplemental testing

 10   in these markets.

 11             Also, just this year, we are entering the

 12   market in Brazil and Venezuela and in Mexico.  So,

 13   you can see that in ex-U.S. markets, this is a

 14   viable alternative to Western Blot and has been

 15   accepted by many users as a reasonable means of

 16   confirming HIV positive results.

 17             [Slide.]

 18             Also, in that time period, we have

 19   produced multiple lots of the antigens used on the

 20   strips.  In this instance, you can see five to six

 21   lots since 1996 of each of the antigens that have

 22   been used and that are coded on the strip, which

 23   leads us to some of the validation issues.

 24             [Slide.]

 25             With that number of lots that have been 

                                                                71

  1   produced since 1996, we would anticipate that it

  2   should be acceptable and enough to allow us to

  3   utilize retrospective validations as a means of

  4   confirming the manufacturability of this particular

  5   kit and these reagents.

  6             This is somewhat related to the issue that

  7   was brought up recently about the cost

  8   effectiveness and the profitability of these kinds

  9   of assays.  If we were to do prospective validation

 10   as required by the current regulations, that would

 11   require at least 24 antigen lots at an estimated

 12   cost of almost $5 million for us to produce.

 13             In addition, we would have to produce

 14   three, full-scale RIBA validation lots at almost

 15   another million dollars plus the verification

 16   testing, to a total of about almost $6 million just

 17   to do complete prospective validation under the

 18   current regs.

 19             Our estimate is for the total HIV

 20   supplemental testing market in the U.S., for the

 21   Western Blot, is currently only $0.8 million.  So,

 22   you can see there is really no cost effective way

 23   that we could continue to satisfy the regulatory

 24   requirements and, at the same time, provide what

 25   the market needs for supplemental testing. 

                                                                72

  1             But I did want to bring this to the

  2   attention of the committee.  This is an alternative

  3   that we have produced.  We are producing it for ex-U.S.

  4   markets very effectively, and if the FDA saw

  5   fit to provide some additional focus on this, we

  6   would be willing to consider bringing this forward

  7   as an alternative to Western Blot.

  8             Thank you.

  9             DR. NELSON:  Thank you, Dr. Phelps.

 10             Questions?

 11             When you did the validation testing, you

 12   tested a number of samples that were negative on

 13   the EIA, but that isn't the way the test would be

 14   used, right, it would be a confirmatory test where

 15   only EIA positives would be tested?

 16             DR. PHELPS:  That is correct, yes.

 17             DR. NELSON:  So that the nonspecificity

 18   shown in  your data shouldn't be a problem if the

 19   test is used the way it would be planned to be

 20   used.  The real issue is the sensitivity of the

 21   true positives picked up in this.

 22             DR. PHELPS:  That is correct.  In the

 23   clinical validation, however, it is required to

 24   show specificity with negative populations, and

 25   that is why that data was generated, but you are 

                                                                73

  1   correct, it would only be EIA repeat reactives that

  2   this test ordinarily would be used with.

  3             DR. NELSON:  I am surprised that the

  4   Western Blot didn't have a higher problem with

  5   nonspecificity than shown in your panel, because

  6   when there have been vaccine trials where people

  7   prior to receiving vaccine, HIV vaccine, have been

  8   required to have Western Blot even if the EIA is

  9   negative up to 10 to 15 percent of the population

 10   has been excluded based on bands on the Western

 11   Blot.

 12             DR. PHELPS:  Right.  Again, that

 13   particular study was with confirmed HIV-1, HIV-2

 14   specimens, so it has already gone through a number

 15   of screens prior to that, so that is why the data

 16   looked fairly clean.

 17             DR. NELSON:  Thank you.

 18             DR. BUSCH:  Your comment about vaccine

 19   trials is I think very important because we are

 20   beginning, in blood donor settings, we have picked

 21   up a small number, but a number of donors who are

 22   false positive on the IM Western Blot, but who were

 23   so because of vaccine trial participation.  You

 24   know, these vaccine trials are beginning to expand

 25   here in the U.S. and globally, and there is a clear 

                                                                74

  1   need to develop screening and more important

  2   supplemental assays that can accurately

  3   discriminate vaccine responses for infection on top

  4   of a vaccination.

  5             I think one of the problems that we have

  6   is that the companies that have the capacity to

  7   develop appropriate recombinant antigen-based

  8   supplementals are simply not participating in the

  9   market in bringing these assays forward

 10   particularly in the U.S., so just another issue

 11   that makes us, to me, need to get companies like

 12   Chiron and Intogenetics, et cetera, somehow

 13   bringing assays into the U.S. market.

 14             DR. FITZPATRICK:  Since the blood donor

 15   screening market is only about 10 percent of the

 16   Western blot market, have you looked at what the

 17   clinical market for RIBA is as a diagnostic?

 18             DR. PHELPS:  In terms of the total--again,

 19   I am not trying to make a business case of that

 20   last slide--but in terms of the total Western blot

 21   that we sell through Ortho Clinical Diagnostic, in

 22   our joint business with Ortho, that 8/10ths of a

 23   million dollars represents the entire market for

 24   both diagnostics and blood screening.

 25             So, if you take the total testing that is 

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  1   done, Cambridge and other Western blots, is

  2   probably around 1 or 1.2 million I would expect

  3   maximum in terms of a dollar market.

  4             DR. CHAMBERLAND:  I just want to clarify

  5   also on that slide, you had these various costs

  6   that totaled 5.8 as prospective validation, that is

  7   ongoing validation, not a one-time thing, but

  8   something that would be done on an ongoing basis?

  9   Could you clarify?

 10             DR. PHELPS:  Right.  That would be the

 11   cost whether we decided prior to approval to

 12   provide all 24 lots and 3 lots of RIBA or if we did

 13   it as a concurrent validation.  That would be one

 14   alternative, is to move forward producing the

 15   material, but making these lots concurrently and

 16   then providing the final data package to FDA for

 17   approval, but that would be the total cost of what

 18   we estimate to be required by the current

 19   regulations.

 20             That means 3 lots of each of the antigens

 21   and 3 lots of the final kit at full production

 22   capacity.

 23             DR. LEW:  Since you did bring up the

 24   business aspect, though, just calculating the

 25   numbers from what other people have said, if there 

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  1   is 35--that is what I heard, I think, 35,000 kits,

  2   or how many kits--

  3             DR. PHELPS:  35,000 tests is what I

  4   understand.

  5             DR. LEW:  --tests that are needed per

  6   month, that is, by year, 420,000, I mean to me it

  7   seems like we are guessing that there is only $2

  8   million profit total for all companies?  That

  9   doesn't quite make sense because those kits are

 10   kind of expensive.

 11             DR. PHELPS:  I would have to defer to

 12   others with respect to the total diagnostic market.

 13   I know for blood screening--

 14             DR. LEW:  Blood screening is only 10

 15   percent, I know you mentioned that.

 16             DR. PHELPS:  Correct.

 17             DR. LEW:  But when they were talking about

 18   all clinical diagnostic use, it was 35,000, so that

 19   is almost half a million, I mean close to.  It

 20   seems like there is more profit out there than is

 21   being stated.

 22             DR. PHELPS:  I understand that that number

 23   was raised.  I can't confirm that it is 35,000 a

 24   month.  I only know the blood screening

 25   particularly. 

                                                                77

  1             MR. STEVENS:  Just from our figures,

  2   marketing, and to back up the FDA's figures we were

  3   given, it is approximately 35,000 tests a month.

  4   The IFA and Western blot, average selling is above

  5   $20, which brings you about $8 million a year.

  6             DR. NELSON:  You have also shown that

  7   there is an international market, although probably

  8   less robust, but maybe the European market is

  9   pretty good.  It looks like this is not a huge

 10   profit item, but it still is critically important

 11   to medicine and public health.

 12             DR. PHELPS:  Just one added point, we are

 13   also in the process of producing a RIBA HTLV kit

 14   also, as you are aware of, Dr. Nelson.

 15             DR. FITZGERALD:  If we combined the ABC

 16   statement and looked at two different aspects,

 17   because we are actually looking at two different

 18   things here, one is deferring a donor and releasing

 19   or not releasing a unit, and the other is following

 20   up the donor and determining whether the donor

 21   should be a patient, so if we look at the ABC

 22   statement, which suggested that the supplemental

 23   tests not be donor screening tests and fall under

 24   that validation criteria, but be a diagnostic and

 25   fall under that criteria, do you know or would 

                                                                78

  1   anybody have an estimate of the difference of

  2   bringing a test to market in that respect versus as

  3   a donor screening test?

  4             DR. PHELPS:  My understanding, at least as

  5   a manufacturer, is that even in the context of a

  6   diagnostic test, the validation criteria still

  7   remain the same.  The only difference, at least

  8   with HIV, that I am aware of is that the FDA, I

  9   believe has indicated that for diagnostic tests,

 10   the Type O specific sensitivity is not a

 11   requirement as it is for screening tests.

 12             DR. NELSON:  Any other comments?

 13             Thank you.

 14             DR. PHELPS:  Thank you.

 15             DR. NELSON:  The next item is an

 16   informational item on Electronic Submission of

 17   Applications.  Michael Fauntleroy.

 18              Electronic Submission of Applications

 19             MR. FAUNTLEROY:  How are you?  I am not

 20   the scientist, I am not the IT guy either.  I am

 21   the policy and guidance person within CBER, who is

 22   responsible for bringing us in to the 21st century.

 23             If we could take a moment right now and

 24   just think for a second.  When most of us were in

 25   high school, we didn't have computers, we didn't 

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  1   have condensed mikes in front of us as we do,

  2   everybody on the panel.

  3             Most of us are carrying cell phones,

  4   pages, or PDAs, and so it is logical for us to move

  5   forward as a review, agency review center for this

  6   regulated industry to move into the 21st century,

  7   and my task today is to bring you some information

  8   about how CBER is moving forward into the 21st

  9   century.

 10             But before I move forward, I would just

 11   like to thank you for the opportunity to do this,

 12   because I enjoy this challenge.

 13             Now, if I can remember technology, okay,

 14   here we go.  I am not used to this aspect of the

 15   technology, and generally have the computer right

 16   here or I have a gentleman in the room presently

 17   handle my slides for me.

 18             [Slide.]

 19             What I would like to talk to you about

 20   today, as you see before you, is a series of items.

 21   Don't worry, I am not going to go through all 132

 22   slides, I don't have the time.  I would love to

 23   because it's important good information, but I am

 24   going to talk to you today about our philosophy and

 25   maturation within CBER, our electronic document 

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  1   room, and hopefully, within the 30 minutes I have

  2   been allotted, the electronic IND and secure e-mail.

  3             Secure e-mail is the newest, hottest thing

  4   within the Center, and I am sure that you will be

  5   very interested as we have been hearing all these

  6   business case discussions, well, this was a program

  7   brought forward as a response to business' desire

  8   for more rapid communication with us.

  9             [Slide.]

 10             Our basic philosophy is one of

 11   partnership.  In this world of regulated industry,

 12   we are looking for feedback from you and with you

 13   in the development of the electronic document

 14   paradigm.

 15             Now, we encourage within this

 16   communication.  Why do we encourage communication?

 17   Because it is very hard from a guidance document or

 18   from any other manner of communication except

 19   person to person, to understand individual

 20   thoughts.

 21             Now, if you think about it here for a

 22   second, the majority of the crowd in here has

 23   either been married, is married, or divorced, and

 24   one of the biggest problems in there is always 

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  1   communications.  You can never get it from a piece

  2   of paper, you have to sit down and wrestle with it

  3   person to person.  This is why I have my e-mail

  4   address and my phone number on the covering of

  5   every slide.  We need to talk.

  6             But what do we talk about, because in this

  7   day and age of electronic documents, you could have

  8   a plethora of things going on?  Well, we talk about

  9   standards.  The guidance brings forward manners in

 10   which standards for information dissemination

 11   should be utilized, and at the end of the day, we

 12   hope to be in the same place where the reviewers

 13   who have been trained on utilization of different

 14   documents will be able to use and leverage their

 15   experience from document to document because they

 16   are being brought forward in a consistent manner.

 17             Now, these documents are fully modular.

 18   What is the advantage of fully modular

 19   presentations?  Well, for industry who are putting

 20   together these various submissions, this means that

 21   your regulatory affairs group, your clinical

 22   writers, and various other groups that are involved

 23   in this process don't have to wait until the last

 24   minute to try and get a document put together.

 25             You can start when you finish your 

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  1   development of the product, put your CMC section

  2   together.  You can then, as you have your clinical

  3   reports put together, paginate those individuals in

  4   the electronic submission paradigm, put those

  5   together.  It is a plug and play.  As you finish

  6   information, you can put it into context.  You do

  7   not have to wait for everything to be done to go to

  8   the next step.

  9             Now, how do our reviewers access this?

 10   Well, information access is done through a series

 11   of items, either through the roadmap to get to the

 12   table of contents paradigm that we have, through

 13   submission indexes which allow word searches on

 14   various items that are put into the document, so if

 15   you want to find a Western blot, information on

 16   that within the submission, you would type that

 17   into your Adobe interface and it would give you the

 18   series of hits of the use of Western blot within

 19   the document rendition.

 20             Folder structures.  Well, if you don't

 21   like individual tables of contents, you can go to

 22   the submission within our electronic document room--which I

 23   will be talking to you about--which will

 24   allow a reviewer to go to the item that they are

 25   responsible for, get to that item's table of 

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  1   contents, and move forward.

  2             In essence, we are allowing for faster

  3   information access through the use of the

  4   electronic submissions paradigm, which brings us to

  5   this point, that we are also in guidance

  6   development for PMAs, 510(k)'s, IDE's.  We have

  7   presently already accomplished the paradigm for the

  8   IND and the BLA, and all the multiple iterations of

  9   the BLA, such as the rolling BLA, the ECTD BLA

 10   iteration, because of the advent of the CTD's

 11   adoption, and other items.  Still, the straight BLA

 12   can be submitted.  These are things that are all

 13   being done within CBER.

 14             [Slide.]

 15             Now, the maturation process.  By virtue of

 16   being able to rattle off all the items that I just

 17   have--I missed a slide and since I am not in

 18   control of my computer, I am just going to jump

 19   over it--when in doubt, ask.

 20             That is the take-home message here.  It

 21   may sound like a simple one, but when in doubt,

 22   ask.  Don't wait until the last minute, don't be

 23   afraid to talk to the FDA as a regulated industry,

 24   because this is truly a paradigm that is going to

 25   flourish through information dissemination and 

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  1   communication.  That is what is the bottom line

  2   here.  You must talk with us, there must be an

  3   information exchange either through guidance which

  4   gives you part of the picture, but not all the fine

  5   points because of the nature of the evolutionary

  6   process of electronic documents.

  7             And please don't wait until a month before

  8   the submission to call us.  Talk to us early, talk

  9   to us often. I do return all phone calls and e-mails.

 10             Now, to the present slide, submission

 11   maturation.

 12             [Slide.]

 13             By virtue of me just being able to stand

 14   here and talk to you about these documents, is a

 15   sign of growth.  We are receiving submissions

 16   within CBER, it is commonplace now.  It does not

 17   require a great degree of panic from fear,

 18   uncertainty, and doubt by reviewers because they

 19   have never seen these documents.  An electronic IND

 20   is fairly commonplace, and the submission of a BLA

 21   electronically, totally electronically, no paper

 22   copies, is also commonplace with CBER.

 23             So, these are items and functions that you

 24   can use to expedite the review process because you 

                                                                85

  1   facilitate information exchange and discussions

  2   through the delivery mechanism of an electronic

  3   document.

  4             Now, we are no longer having to discuss

  5   pagination, submission software standards.

  6   Everybody understands we have them and understand

  7   them.  People seem to know what a roadmap file is

  8   and understand why hyperlinks need to be blue.

  9             For those who don't know, we have blue

 10   hypertext links within CBER, so that whenever you

 11   see blue, a reviewer knows that there is an

 12   opportunity to access additional information.  They

 13   have been seeing it this way for the four years

 14   that I have been in this position, so they

 15   understand now like any child you have trained,

 16   like Pavlov's dog, you see blue text, there is a

 17   link there.  There is no ifs, ands, or buts, it's

 18   without question.

 19             [Slide.]

 20             Now, for an especially rewarding and

 21   challenging discussion from a development impact is

 22   the Electronic Document Room.

 23             [Slide.]

 24             At present, the EDR in CBER is the

 25   archival and functional repository for electronic 

                                                                86

  1   submissions and related regulatory communications.

  2   That is for the electronic submissions.

  3             My future vision, and one that we are

  4   moving forward with is that we will be using the

  5   Electronic Document Room for all regulatory

  6   communications generated with CBER and for security

  7   mail repositories for the archiving unit, and

  8   hopefully be able to scan in documents into this

  9   particular venue, so that reviewers will have

 10   access to the information 24/7, as you would say.

 11             This way, there is no down time waiting

 12   for information to come to their office for review

 13   by our Document Control Center.  We are not waiting

 14   a day, two days, in some cases longer, to receive

 15   the information for us to be able to give you a

 16   response in your product development.

 17             Now, this particular effort has been

 18   brought forward in accordance with the

 19   Configuration Maturity Model standard IT software

 20   development model, so that it is repeatable.

 21             Oversight.  This is where things get

 22   interesting. This is not an IT initiative.  This is

 23   a CBER initiative driven by, and in service to, the

 24   reviewers.

 25             Why do I say that?  Because we have a 

                                                                87

  1   Joint Application Design Group.  That group

  2   consists of reviewers, RPM's, and various and

  3   sundry people in different roles from every office

  4   in the Center, who give us feedback on how things

  5   should be moved forward.

  6             From there, it moves to a Project Advisory

  7   Group. This group says yea or nay to moving a

  8   development item forward and what the importance is

  9   of it, and then from there, if there are any

 10   changes because something wasn't looked at in its

 11   fullness initially, we have a Configuration Control

 12   Board, once again managed with, full of people who

 13   are reviewers.

 14             So, the end user, the stakeholder is

 15   responsible for the development effort.  Yes, I get

 16   to bring forward the vision, but we work for this

 17   together in developing the vision.

 18             [Slide.]

 19             Now, what does the vision consist of?

 20   Well, the EDR is an HTML interface.  For those who

 21   are uninitiated, it's a web design.  This is why

 22   you can reach it from high-speed access at home, as

 23   some of our reviewers have been able to do and are

 24   presently doing, so they can review electronically

 25   without moving volumes to their residence, because 

                                                                88

  1   many of us are flexi-place reviewers, and they can

  2   either download the information, which they do have

  3   the option, if they don't have that kind of access,

  4   carry it home and review the information, so it is

  5   now portable.

  6             I challenge you to move a 20-volume

  7   submission with any rapidity in a review effort.

  8   It gets very hard on the back quickly.

  9             Now, in the background of this HTML

 10   interface, we have documentum running.  We also

 11   have our operating system servers, which utilize

 12   Windows NT 4.0.  Also running in the background is

 13   the Internet Information Server and Oracle. This is

 14   what sets up the system that the reviewers have the

 15   ability now to access the documents that you

 16   delivered to us for review.

 17             So, what are the features and functions?

 18   Well, I am glad I asked me that question since you

 19   weren't going to.

 20             [Slide.]

 21             Well, docbases.  What is the one thing

 22   that most people who are at work want to deal with?

 23   Well, they really don't want to deal with work, but

 24   they want to go ahead and do their job quickly and

 25   efficiently without interference. 

                                                                89

  1             To do this, we have upfront set up a quick

  2   queue, where if you know your document number, type

  3   it into the Quick Find option, readily find the

  4   document.  It pulls it up for you, gives you the

  5   interface to the roadmap file or to the file

  6   structure, and you can go into it immediately.

  7             Well, there is also a cabinet structure,

  8   so after you have gone through the secure HTML

  9   interface and logged on with your CBER password,

 10   which is the same as your network logon password.

 11   You can either go to your Reviewer Cabinet, the EDR

 12   user documents, which are SOPs and training manuals

 13   that are listed on-line.

 14             You can go to your IND or BLA cabinet,

 15   which is at present organized by year.  You can

 16   access the submission by picking a cabinet.  The

 17   submissions are delineated by a tracking numbers,

 18   which are your STNs or your IND numbers.

 19             You can then find the actual amendment you

 20   are looking for either by utilization of the

 21   roadmap file or by the CBER receipt date, which is

 22   listed with your file.

 23             Well, we have also enhanced the

 24   functionality of this by including the product

 25   name, sponsor name, and indication with every file 

                                                                90

  1   that is listed by leveraging information in our BIM

  2   system, Biologics Information Management System,

  3   and RMS-BLA.  So, we have a tie-in with our

  4   databases to the document repository, and the

  5   information is the same.  This allows people not to

  6   be confused by disparate information in places, and

  7   from the high level, you can also download the

  8   information as you so desire.

  9             [Slide.]

 10             Within the IND and BLA cabinets by year,

 11   you have your STN and IND listings, you have

 12   various functions.  You have your roadmap file,

 13   which is your correspondence history.  Every

 14   submission that a sponsor brings forward, we

 15   replace the roadmap file, because it has no

 16   regulatory information, and it then builds us a

 17   cumulative history of every submission to the file.

 18             At this point, it is a good time to

 19   mention the sidebar of we strongly discourage mixed

 20   media submissions. The purpose of the EDR and

 21   electronic submissions can only be enhanced further

 22   for the reviewer by once you submit an electronic

 23   document, to continue to submit all amending

 24   information as an electronic submission, so that

 25   the entirety of the submission is located on the 

                                                                91

  1   server through the HTML interface for the reviewer

  2   to access.

  3             This allows us to do the job efficiently

  4   and to have all the information for your file

  5   centrally located.

  6             In addition to that information, we have

  7   CBER Letters Folders, Meeting Summary Folder, a

  8   Review Memo Folder, Secure E-mail, and

  9   Teleconferences.  In other words, we have a folder

 10   for all the major products that are available or

 11   being made by the CBER reviewers in the review

 12   process.

 13             The intent is to put it all on-line, so

 14   that there is ready and available access to

 15   facilitate the review process and discussions with

 16   the regulated industry, because you have an

 17   available document versus, well, excuse me, I don't

 18   have the document in my office, I will have to wait

 19   two days for it, I will call you back, or let me

 20   work from my notes.  This is a little bit more

 21   efficient than that.

 22             [Slide.]

 23             Now, to make this really work, I imagine

 24   that you are probably wondering, well, if you don't

 25   know the STN number or the IND number, how can you 

                                                                92

  1   find your document.

  2             Well, we have High-Level Search categories

  3   within this repository, so you can search for

  4   groups of activities, such as all BLA's, all IND's,

  5   all IND documents as far as generated

  6   correspondence, or all BLA-generated

  7   correspondence.  This will be expanded as we bring

  8   more guidance to the forefront.

  9             So, for example, if you are looking at

 10   your BLA as a reviewer, and you don't quite

 11   reminder the STN number or you haven't made a copy

 12   of the link in My Cabinets, so that you can readily

 13   access that roadmap quickly and easily, you can

 14   search for the document by office, product name,

 15   applicant name, STN, trade name, reviewer name,

 16   submission type, submission status, cabinet year,

 17   submission date, CBER receipt date, and/or

 18   keywords.  In other words, it is a pretty

 19   exhaustive set of possibilities to find the

 20   documentation.

 21             [Slide.]

 22             Now, the EDR Inbox.  We all have a system

 23   within our offices of filing information, locating

 24   information, understanding where information is.

 25   Well, the EDR Inbox, unlike My Cabinets, my 

                                                                93

  1   document cabinet, which will allow the reviewer to

  2   copy a link to the item, the EDR Inbox will allow

  3   us to route electronically review documents to

  4   individual reviewers for them to review.

  5             In other words, that large cabinet-type

  6   feature in every office, which is called a Mailbox,

  7   is emulated by the EDR Inbox, so the reviewers will

  8   know in the future rollout that this information is

  9   located in your Inbox.

 10             If you have received an electronic

 11   document for review, this is where you look for it.

 12   This carries a link to the file or some other bit

 13   of information that tells you where you need to go

 14   to execute your functions, review functions.  Now,

 15   those items were routing correspondence and

 16   notifications now.

 17             Review Notification.  I just had to

 18   digress for a second.  Reviewers presently receive

 19   an e-mail every time an electronic submission is

 20   loaded.  That e-mail includes, if it is not an

 21   original submission, because the BIMS database in

 22   RMS-BLA would not have the original submission

 23   information in it yet, that notification will

 24   include your sponsor name, your STN or IND number,

 25   your proposed use, your product, anything a 

                                                                94

  1   reviewer needs to know basically at a high level as

  2   to what this information pertains to.

  3             In the future, when we work out our

  4   routing system, which we are presently discussing

  5   at a high level and a small group of individuals

  6   working out the paradigm, they will receive their

  7   routing forms, their administrative data entry

  8   forms, everything else they need, so that instead

  9   of filling out paper, they will fill out the

 10   electronic version of the paper form that they have

 11   been using and upon signature, it will dump that

 12   information directly into the databases.  This is

 13   in development as we speak.

 14             [Slide.]

 15             Now, this is a picture that some of you

 16   may find interesting if you know what it is.  This

 17   is or these are actual pictures of our Document

 18   Control Center, in our area that we receive

 19   submissions in on a daily basis.

 20             This is why we are going electronic,

 21   because we have a ton of paper to manage on a daily

 22   basis.  We do not receive a small amount of

 23   submissions a year, we receive well over 9,000 IND

 24   amending submissions a year to manage.  It is not

 25   small amount.  It breaks down to quite a large 

                                                                95

  1   number.

  2             So, as a response to the electronic IND,

  3   when many of the industry sponsors that I was

  4   working with said, okay, well, we can do an

  5   electronic IND, but how do we manage the individual

  6   amending submissions.  Many of them will just be a

  7   page, two pages, very difficult to burn a CD-ROM or

  8   to go through that exercise.

  9             So, we came up with this particular

 10   delivery system.

 11             [Slide.]

 12             First and foremost, for the Phase II Pilot

 13   Program, that accrual is closed.  For the Phase I,

 14   we are still allowing for sponsors to come forward

 15   and to set up their VPN access, so that we can

 16   receive electronic documents directly in exchange

 17   with them, so that they can be reviewed quickly.

 18             Where does this basically pay off?  At the

 19   end of the BLA discussion, for labeling

 20   discussions.

 21             For the Phase II pilot, the scope is the

 22   delivery/receipt and archiving of regulatory

 23   documents and submissions.  What we are building in

 24   an individual mechanism whereby you can e-mail us

 25   through a secure connection featuring an electronic 

                                                                96

  1   signature, your IND or BLA amendment.

  2             We have already completed the alpha

  3   testing with seven industry sponsors, and they have

  4   all come through the alpha testing quite quickly

  5   and easily.  It has been a smashing success.  We

  6   are now pausing before we go to beta where we are

  7   now going to, in the beta test, actually receive

  8   regulatory submissions electronically, and not have

  9   a backup paper copy come forward.

 10             This is where the electronic routing and

 11   review paradigm that we are building will also be

 12   tested.  This is here and now.  This is not 2004,

 13   this is what we are doing now and will be delivered

 14   by October.  That is our timeline for that.  Any

 15   more interest?

 16             [Slide.]

 17             So, how do we plan to do this?  Well, it

 18   will be an e-mail, very much like a cover page, and

 19   I will get into some more of the particulars.  We

 20   are going to utilize standards, the General

 21   Considerations Guidance document for electronic

 22   submissions, we are utilizing those standards.

 23             We have presently enacted a file size

 24   limit of 4 megabytes.  That is not the limit for

 25   the software, but we want to strongly discourage 

                                                                97

  1   anybody from thinking about delivering an

  2   application utilizing secure e-mail.

  3             Now, you may ask why.  Well, the reason

  4   why is we want you to bring forward the CD-ROM

  5   version of this or the DLT tape if it's a BLA, so

  6   that we can set up a target.  So, when you bring

  7   forward the original submission, we set up the file

  8   structure within the Electronic Document Room, give

  9   you an IND or STN number, and you utilize that

 10   number in the secure e-mail delivery system, so

 11   that it is readily identifiable.  You will

 12   understand why in a minute.

 13             [Slide.]

 14             I am going to go past that, because that

 15   is kind of uninteresting at this point.

 16             [Slide.]

 17             Once the message is received by CBER

 18   secure e-mail, it will be decrypted by the

 19   Messaging Management System, MMS, and routed into

 20   an exchange public folder on an exchange server, so

 21   you sent the message.  In three to 10 minutes

 22   typically, that message will hit a public folder.

 23   Once that message hits a public folder, because it

 24   is associated with an IND number or a BLA number,

 25   quote, unquote "STN number," we can pull up through 

                                                                98

  1   RMS, BLA or BIMS, the review team names, and we

  2   will send an e-mail to the team letting them know

  3   that they have the possibility, the potential of

  4   looking at this message before it has gone through

  5   the rest of the process, which should take

  6   milliseconds if there is not a problem.

  7             But any way you look at it, once it has

  8   been decrypted, moved forward, it is now available

  9   for the review team in a public folder.  After it

 10   moves through the rest of the process, it will be

 11   archived and made available in the Electronic

 12   Document Room, in the actual folder utilizing a

 13   distinct CBER tracking number which, through a

 14   return receipt message, we will send back to you,

 15   so that when you want to discuss your submission,

 16   and you want to discuss a particular amendment to

 17   that submission, you have the tracking number that

 18   has been generated through the secure e-mail

 19   paradigm that will allow you to talk to the

 20   reviewer about the specific set of documents or

 21   responses that you have brought forward to the

 22   Center.

 23             There is not a discussion about, well,

 24   which one is it, which amendment is it, our numbers

 25   are different than your numbers.  That is all going 

                                                                99

  1   to be eliminated.

  2             Now, to accomplish this, submission

  3   identifier must be in the cover page header,

  4   submissions identifier, your STN/IND number,

  5   similar to fax cover page, as you see, application

  6   I.D., subject.  Those two lines must be filled out.

  7             [Slide.]

  8             Process.  As you know, we are at the FDA,

  9   it's a regulated industry, a regulating group of

 10   industry, we are going to have a process.  Every

 11   bureaucracy has one.  Now, when the exchange script

 12   runs, notifications will be went to the RPM and the

 13   review team.  The RPM is central to the system.

 14   Why?  Because any messages going out from the

 15   Center will be coordinated through the RPM for the

 16   reviewers.  This way, you only receive official

 17   Center opinion.

 18             [Slide.]

 19             This is a slide that basically talks about

 20   what is going to happen in the background in terms

 21   of validating the electronic signature, moving to

 22   the EDR, et cetera.

 23             [Slide.]

 24             What are the hardware functions for the

 25   Secure E-mail Messaging Pilot, we are utilizing an 

                                                               100

  1   Exchange Server 5.5, Tumbleweed MMS 4.7.  We are

  2   using the MMS for encryption and decryption.  We

  3   can send and receive messages, exchange public

  4   folder architecture, and pilot participants should

  5   be compliant with industry standards, x.509

  6   certificates, SMIME.

  7             We are also going to be using PDF for the

  8   actual signature, and CBER is going to be the

  9   signature authority. Every version of Adobe Acrobat

 10   5 or 4 has an electronic digital signature in it,

 11   has the capability.

 12             I am not going to discuss right now how

 13   that is going to be managed.  If you do have

 14   questions in that area, I do have the lead IT

 15   person here.  His name is Joseph Montgomery.  If

 16   you would stand, Joe?  He is in the back.  Please

 17   feel free to talk to him about it.  We have worked

 18   in partnership for a long time now, a very good

 19   man.

 20             [Slide.]

 21             Recap on the Secure E-mail Pilot Program.

 22   Reviewers will be able to access Secure E-mail

 23   through their public folder structure.  Submissions

 24   will be archived in the Electronic Document Room.

 25   They will be associated with marketing applications 

                                                               101

  1   or investigational new drug applications.

  2             [Slide.]

  3             INDs.

  4             [Slide.]

  5             I am just going to give you a quick recap

  6   here on INDs because of time constraints.  We have

  7   recently promulgated on March 26, 2002, a final

  8   guidance document for the submission of electronic

  9   investigational new drug applications, commonly

 10   called an IND.

 11             This guidance can be found on our web

 12   site.  It features pretty much the BLA thought and

 13   philosophy and functionality, but it has a twist.

 14   The twist is that there are five individual folders

 15   that are of tremendous importance, and they are

 16   analogous to the review disciplines.

 17             Those folders are Administrative, CMC,

 18   Pharm Tox, Clinical, and everybody has to have an

 19   Other because you never know what you may have to

 20   deal with, but those four folders, being analogous

 21   to the review disciplines, individuals will be

 22   challenged to bring forward the information in the

 23   appropriate folder, so you not only have the

 24   roadmap file, which delineates the entire history

 25   of the correspondence, but if a reviewer so 

                                                               102

  1   desires, they can go to their folder, which will

  2   never change or move, which will have all the

  3   amending information tagged by amendment number.

  4             To keep the folder static, we have

  5   implemented a new naming convention, so if you have

  6   files coming in your second amendment, that

  7   amendment will have the prefix 0002, the contents

  8   as far as the file name, .PDF, .XPT for assess

  9   transport file.  They will be able to search these

 10   file folders.

 11             They will be able to use submission

 12   indexes, and for the clinical review area, which

 13   has the majority of the amending submissions, we

 14   have the highlight called a Cumulative Table of

 15   Contents for protocols and for adverse events.

 16             That Cumulative Table of Contents is the

 17   same roadmap file within the clinical folder, but

 18   only delineating protocols and revised protocols

 19   and adverse events.

 20             This way, if a clinician needs to quickly

 21   see the status of a protocol on-line, they can go

 22   through the hierarchy, find this Cumulative Table

 23   of Contents for protocols, and click on that, pull

 24   up the appropriate protocol, the same thing for the

 25   adverse events. 

                                                               103

  1             I thank you for your time and do you have

  2   any questions?

  3             DR. NELSON:  Any questions?

  4             DR. ALLEN:  I have got three or four

  5   questions, which I will just do one and let you

  6   respond to it.

  7             I think this is a tremendous effort and

  8   applaud the effort to move in this direction.  I

  9   hope it goes well. I was talking with one person

 10   who is working on some of the AIDS vaccines, and I

 11   know that that is a separate area, but he was

 12   indicating that their submission is going to be

 13   somewhat higher than the Statue of Liberty.  I

 14   think it was 344 feet of paper.  So, this is the

 15   right way to go.

 16             What type of secure backup arrangements do

 17   you have in case there is a catastrophic occurrence

 18   with the servers or the primary servers where these

 19   are kept?

 20             MR. FAUNTLEROY:  Well, naturally, we had

 21   redundancy as far as when the message comes in, we

 22   are archive the message in a naive state.  Then, we

 23   run it through the process, and we archive it in a

 24   different set of servers.

 25             Joe, if you would care to elaborate on 

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  1   that further, because he is the IT lead.

  2             MR. MONTGOMERY:  Actually, as Michael

  3   said, we are archiving the messages as they come

  4   in.  We are staging those in the area that the

  5   administrators can get to, and we are actually

  6   maintaining multiple copies of the actual

  7   submission itself, archiving the original copy,

  8   which is one of the standards we have to abide by.

  9             We also forward on the message into the

 10   Electronic Document Room as the final repository

 11   for it, and that is where our reviewers can access

 12   it.

 13             DR. ALLEN:  Second, I noticed you

 14   described earlier on that we are using HTML format,

 15   and then I noticed in one of the later slides, you

 16   are talking about PDF.

 17             Are you using both?

 18             MR. FAUNTLEROY:  Yes.  HTML in the web

 19   interface.  PDF is the document standard for text

 20   presentations.  The assess transport is the

 21   standard for the data presentation. We do accept

 22   ASCII files for the pharm tox information in the

 23   BLA because of the software program we utilize for

 24   the analysis of pharmacodynamic and bioequivalence

 25   data, which is WinNonlin. 

                                                               105

  1             DR. ALLEN:  When the reviewers go in, they

  2   can add comments or make notes as they are

  3   reviewing, or what is the process for their

  4   feedback?

  5             MR. FAUNTLEROY:  Two ways of accomplishing

  6   it.  They add their annotations to the file on-line

  7   and then save their annotations if they so desire,

  8   as an PDF file, and bring that to the PDF iteration

  9   that they are reviewing, or most commonly, as we

 10   instruct most reviewers to do, is download the

 11   file, a copy of it, and do their annotations, copy,

 12   paste, whatever they need to from that file.

 13             The reason we suggest this strongly to

 14   reviewers is that the file on the server is read-only, and

 15   so it is an unadulterated copy of the

 16   submission at all times.

 17             DR. ALLEN:  Final question.  Is there a

 18   mechanism for keeping a permanent record of

 19   everyone who accesses the documents and modifies or

 20   adds comments as part of the review process?

 21             MR. FAUNTLEROY:  In our 3.0 release of the

 22   EDR, we will have a fully robust audit trail that

 23   will allow us to know what reviewer touched what

 24   part of the file, how long they were there, and

 25   what they did. 

                                                               106

  1             DR. ALLEN:  Thank you.

  2             DR. HOLLINGER:  Can I just follow up on

  3   one of Jim's questions?  The backup, is the backup

  4   also off-site as well as on-site in several areas,

  5   or just one off-site or what?

  6             MR. MONTGOMERY:  We have an off-site

  7   location where we are sending tapes, as well.  We

  8   are backing them up on archived media, DOT media,

  9   and then we are sending them off-site, so we do

 10   have an off-site location.

 11             DR. HARVATH:  I wanted to ask about the

 12   adverse event reporting because, as you know, that

 13   is a major issue with many investigators,

 14   especially studies involving oncology patients, and

 15   the National Cancer Institute has developed the

 16   ADEERS reporting system, which is already I believe

 17   readily accepted by FDA, at least in the Oncology

 18   Group.

 19             So, will this be fully integrated with

 20   that system, so that one can use the adverse event

 21   reporting systems through ADEERS, and have that

 22   accepted with the format that you are using?

 23             MR. FAUNTLEROY:  We are not integrating it

 24   into the IND submission.  Now, if you want to send

 25   us the electronic file in the appropriate PDF 

                                                               107

  1   version, we will readily accept it as an adverse

  2   event report, but as far as integration where a

  3   reviewer through a link submitted would go out from

  4   our server site and access that database, that will

  5   not happen.  That is a real term security issue for

  6   us.

  7             DR. HARVATH:  Is FDA thinking of having a

  8   more consistent form for reporting adverse events,

  9   is there any movement in that area that you have

 10   heard of?

 11             MR. FAUNTLEROY:  Not to date.  When I do

 12   hear of it, we will move more towards that

 13   standardization in line with the additional policy

 14   decisions.

 15             DR. FITZGERALD:  I realize that this isn't

 16   a medical device, but I just wondered if, since you

 17   are designing this, and FDA, are you planning to

 18   internally comply with your own 510(k)

 19   requirements.

 20             MR. FAUNTLEROY:  Well, at this point in

 21   time, I can't tell you if we plan to comply because

 22   I am not familiar with the 510(k) requirements.  I

 23   have to learn then to write the guidances and to

 24   get the feedback from the reviewers, so we are

 25   complying with our 21 CFR requirements, 21 CFR 11 

                                                               108

  1   requirements, which I would imagine are just as

  2   stringent easily.

  3             DR. NELSON:  Any others?

  4             Thank you, Mr. Fauntleroy.

  5             We are at the coffee break period, and we

  6   will return at 11 o'clock.

  7             [Break.]

  8             DR. NELSON:  We are switching topics now.

  9   For the next bit, we will be discussing Standards

 10   for Recovered Plasma.  As introduction and

 11   background, Elizabeth Callaghan from FDA.

 12                I.  Standards for Recovered Plasma

 13                   Introduction and Background

 14             MS. CALLAGHAN:  Thank you, Dr. Nelson.

 15             My name is Elizabeth Callaghan and I work

 16   in the Division of Blood Applications.

 17             Because of the concerns for the safety,

 18   purity, and potency of products made from recovered

 19   plasma, FDA is asking the committee's advice on

 20   developing standards for the product.  I would like

 21   to give you a brief summary of some of the issues

 22   that FDA has seen regarding recovered plasma.

 23             [Slide.]

 24             Recovered plasma is a by-product derived

 25   from whole blood collection and used for further 

                                                               109

  1   manufacture into injectable and non-injectable

  2   products.

  3             It is distinguished from source plasma by

  4   the mode of collection and by the requirements for

  5   testing, storage, pooling, dating, and labeling.

  6             [Slide.]

  7             Source plasma is collected by

  8   plasmapheresis, either manual or automated, and is

  9   frozen immediately after collection.  Recovered

 10   plasma, on the other hand, may be separated from

 11   individual units of whole blood by aseptic

 12   techniques up to five days after expiration or

 13   obtained from fresh frozen plasma collected by

 14   apheresis that has expired.

 15             [Slide.]

 16             Recovered plasma has no expiration date.

 17   Source plasma, on the other hand, has a 10-year

 18   dating period.

 19             Both recovered plasma and source plasma

 20   are used for further manufacture into the same

 21   final products, IVIG, Factor VIII, Factor IX,

 22   albumin, IVD components.

 23             [Slide.]

 24             There are four cites in the Code of

 25   Federal Regulations which pertain to recovered 

                                                               110

  1   plasma.  The first, 606.100(b)(18) is under the

  2   Standard Operating Procedure section.  It says that

  3   if you manufacture recovered plasma, you must have

  4   procedures in place that detail the separation,

  5   pooling, labeling, storage, and distribution of the

  6   product.

  7             [Slide.]

  8             606.121(e)(5) is under the Labeling

  9   Section for blood and blood components.  It says

 10   that recovered plasma labels shall include:  (i) In

 11   lieu of an expiration date, the date of collection

 12   of the oldest material in the containers.  (ii) The

 13   statement "Caution for Further Manufacturing Use

 14   Only" for recovered plasma being made into

 15   injectable products; or "Caution for Further

 16   Manufacturing into Non-injectable Products Only" is

 17   applicable.

 18             [Slide.]

 19             (iii) continues with the labeling

 20   requirements, and it says, For recovered plasma not

 21   meeting the requirements for manufacture into

 22   licensable products, the statement "Not for Use in

 23   Products Subject to License Under Section 351 of

 24   the Public Health Service Act."

 25             This is usually for products such as 

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  1   chemistry controls for chemistry analyzers.

  2             [Slide.]

  3             606.160(b)(2)(iii) is in the Records

  4   Section, and it says that blood establishments must

  5   have records of separation and pooling of recovered

  6   plasma.

  7             606.106(d) is everybody's personal

  8   favorite, I am sure.  When there is no expiration

  9   date, the records shall be kept indefinitely.

 10             [Slide.]

 11             To allow for recovered plasma to be

 12   shipped in interstate commerce because it is an

 13   unlicensed product, the manufacturer of the

 14   recovered plasma must have a short supply agreement

 15   with the consignee.  These short supply agreements

 16   should stipulate the conditions for production,

 17   storage, and shipping of the product that is agreed

 18   upon between the manufacturer of the recovered

 19   plasma and the consignee who is buying it.

 20             [Slide.]

 21             Some of the compliance issues associated

 22   with recovered plasma include:  misbranding of

 23   plasma units; lack of shipping and disposition

 24   records; inadequate quarantine and destruction of

 25   unsuitable units; shipment of untested, 

                                                               112

  1   therapeutic, or autologous units.

  2             [Slide.]

  3             Lack of short supply agreements; lack of

  4   product quality and consistency due to storage,

  5   temperature, and preparation failures;  non-uniform

  6   labels - registered facilities do not have to send

  7   their labels to CBER for review, so the labels can

  8   be very inconsistent, and not give the information

  9   that we would require if we had reviewed them.

 10   Obviously, that leads to labels that are incomplete

 11   or inaccurate.

 12             Sharon O'Callaghan and Kay Lewis from the

 13   Office of Compliance will give you further

 14   information following my presentation about

 15   compliance issues.

 16             [Slide.]

 17             Some of the manufacturing issues

 18   associated with recovered plasma include:

 19             Lack of consistency in Standard Operating

 20   Procedures.  Registered facilities who make

 21   recovered plasma do not have to even send their

 22   Standard Operating Procedures in to FDA for review,

 23   and being that there are no standards, there is no

 24   consistency in what people are putting into the

 25   SOPs for making the product. 

                                                               113

  1             Complexity of the donor screening

  2   procedures.  Recovered plasma should be collected

  3   from donors who meet all normal donor suitability

  4   requirements.  Unfortunately, autologous donors in

  5   a lot of cases do not meet this criteria.  In

  6   addition, they are frequently screened with

  7   abbreviated questionnaires, and if this happens,

  8   you shouldn't be using this product to make

  9   recovered plasma for further manufacture into

 10   injectable products.  Keeping track of which units

 11   you should or should not use can be a major problem

 12   in logistics.

 13             Infectious disease testing requirements.

 14   Source plasma and recovered plasma have different

 15   disease testing requirements.  By virtue of the

 16   fact that recovered plasma is made from whole blood

 17   units, they are tested for all required infectious

 18   disease markers.  Source plasma is not required to

 19   be tested for hepatitis B core antibody or for

 20   HTLV-I or II.  These differences in testing can

 21   create some questions.

 22             There are minimal labeling requirements,

 23   as you can see from the regs that I presented in

 24   the previous slides.  Storage and shipping

 25   requirements defined under short supply agreements 

                                                               114

  1   are not always consistent with each other, and if a

  2   manufacturer has more than one short supply

  3   agreement with several manufacturers, he might have

  4   a hard time keeping track of who needs what and

  5   their short supply agreement, and giving consignees

  6   inappropriate units.

  7             [Slide.]

  8             To allow for the manufacture of a more

  9   consistent product, FDA is considering developing

 10   standards governing the manufacture and shipping or

 11   recovered plasma.

 12             In addition, voluntary standards or

 13   recovered plasma are under discussion within the

 14   blood industry and FDA will need to decide whether

 15   to adopt industry standards through agency guidance

 16   or rulemaking.

 17             Would you like me to go through the

 18   questions?  Okay.

 19             [Slide.]

 20             The first question we have is:  Should FDA

 21   develop specific product standards for recovered

 22   plasma?

 23             [Slide.]

 24             If yes, should the standards for recovered

 25   plasma include: 

                                                               115

  1             (a)  Negative screening test results for

  2   anti-hepatitis B core and for anti-HTLV I/II?

  3             (b)  Specifications for allowable storage

  4   conditions and dating periods?

  5             (c)  Labeling requirements similar so

  6   source plasma to distinguish appropriate use for

  7   manufacturing tin injectables versus non-injectables based

  8   on the preparation and storage

  9   conditions?

 10             [Slide.]

 11             Do committee members have additional

 12   suggestions regarding product standards for

 13   recovered plasma?

 14             DR. NELSON:  Thank you.  Questions?

 15             The next presentation, also by the FDA, is

 16   Sharon O'Callaghan, and I guess she is not related

 17   to the first speaker, only by name, the same county

 18   in Ireland, I guess.

 19                          Presentations

 20             MS. O'CALLAGHAN:  No, there is a

 21   difference, there is an O in front of my name.

 22             I am in the Office of Compliance and

 23   Biologics Quality in the Division of Inspection and

 24   Surveillance.  I manage the Biological Product

 25   Deviation Reporting System in the Office of 

                                                               116

  1   Compliance.  I wanted to present some information

  2   and data from the reports that we received in FY

  3   2001, that involved recovered plasma.

  4             These are not my slides.  This is another

  5   presentation that I do, that some of you probably

  6   have seen.

  7             Does everybody have the handouts then?

  8   Okay.

  9             DR. NELSON:  Is it feasible to do this?

 10             MS. O'CALLAGHAN:  I can provide you with

 11   the handouts I guess later.  It is going to be a

 12   little more difficult, but we can manage this I

 13   think.

 14             The data that I wanted to show really

 15   depicted the number of reports that we received in

 16   2001, almost 24,000 reports, and of those, about 30

 17   percent of them involved products of recovered

 18   plasma.

 19             The most frequent type of information or

 20   type of BPD report that we received is post-donation

 21   information, and that is really the one

 22   that is representative of the recovered plasma

 23   issues, as well.

 24             The most frequent one involving recovered

 25   plasma is travel to CJD risk areas especially with 

                                                               117

  1   the new implementation of the CJD guidance

  2   recently.

  3             Also, a number of reports are submitted

  4   related to a donor having a history of cancer,

  5   donors receiving tattoos, history of disease in

  6   surgery, IV drug use, and male-to-male sex.

  7             In all of these, not only is recovered

  8   plasma reported, but also the other products, as

  9   well, but one of the things that we have noticed

 10   with the recovered plasma is that there has been a

 11   lot of inconsistencies among the establishments as

 12   far as the action that they are taking on the

 13   product when they get this type of information.

 14             For example, with the history of cancer,

 15   FDA does not have requirements for history of

 16   cancer, but there are some standards with AABB that

 17   identify history of cancer issues, but there are

 18   some firms that are recalling plasma based on the

 19   fact that they recalled the red cells or platelets

 20   or other products, some because it is recovered

 21   plasma, they are not taking any action.

 22             That is true in some of the other areas as

 23   well, like under donor screening is another area

 24   that we received a number of reports involving

 25   recovered plasma where the donor history question 

                                                               118

  1   was incomplete or incorrect.

  2             That could range from any of the high-risk

  3   behaviors such as tattoos, male-to-male sex, that

  4   type of thing, to the history of disease, history

  5   of surgeries, history of cancer.  Also, donor-giving

  6   information which warranted deferral and the

  7   donor wasn't deferred, for example, taking

  8   medication, again history of cancer and history of

  9   disease.

 10             These seem to be the most problematic

 11   areas as far as what the establishments are

 12   supposed to do with the recovered plasma.  Also,

 13   another area that we have seen a number of reports

 14   is under quality control and distribution,

 15   specifically related to unsuitable units being

 16   distributed where the red cell was clotted or

 17   hemolyzed, and there seems to be some confusion or

 18   discrepancies between whether or not the recovered

 19   plasma is really affected by having the clot in the

 20   red cell.

 21             Some places, like I said, will recall

 22   those products and get them back and destroy them.

 23   Some places will say because it's recovered plasma

 24   we will just go ahead and let it go and not notify

 25   anybody. 

                                                               119

  1             In other cases, the notification for

  2   recovered plasma is based on what the customer has

  3   requested.  In some cases, the plasma fractionaters

  4   may say only notify us of these particular

  5   situations, anything else we don't want to know

  6   about, which makes it very problematic for the

  7   blood establishment if they have multiple customers

  8   that they have to try to keep track of, when they

  9   are going to notify, when they are not, and that

 10   type of thing.

 11             So, without having any numbers, that is

 12   really the point that I wanted to make here, was

 13   that there is this inconsistency, and based on the

 14   action that the firm takes is going to depend upon

 15   whether or not we would consider it for recall,

 16   which Kay Lewis is going to talk about, you know,

 17   if the firm doesn't take any action, then, we are

 18   not going to classify that, because there is no

 19   action to classify, as I recall.

 20             I will let Kay do her thing, hopefully,

 21   her slides are here, unless you have questions

 22   right now.  I don't know whether it is better for

 23   Kay to present and then we can handle questions

 24   together.

 25             DR. NELSON:  Questions?  Mary. 

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  1             DR. CHAMBERLAND:  A couple.  I was

  2   wondering, and maybe it was on your handout, are

  3   you able to do a side-by-side comparison between

  4   recovered plasma and source plasma with respect to

  5   postdonation information issues, and are there

  6   clear differences between the two in the kind of

  7   information that comes back.  That was my first

  8   question.

  9             MS. O'CALLAGHAN:  One of the biggest

 10   differences with source plasma and whole blood

 11   collection in general, is that there is a lot more

 12   tattoos and piercings, there is a lot more

 13   incarcerations, where in the whole blood industry,

 14   there is more travel to the CJD risk areas and

 15   travel to malarias, which the malaria travel

 16   doesn't impact on the source plasma.

 17             DR. CHAMBERLAND:  My second question was

 18   you mentioned one of the problems is the

 19   inconsistency from blood collector to collector in

 20   terms of how they deal with postdonation

 21   information like history of cancer or some of these

 22   issues.

 23             In the source plasma industry, is there

 24   more uniformity as to how this postdonation

 25   information is addressed?  What do they use in 

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  1   terms of assist in decisions?

  2             MS. O'CALLAGHAN:  I think, for the most

  3   part, the source plasma industry is pretty

  4   consistent across the board as to when they are

  5   going to notify and retrieve products, where we

  6   really don't see that consistency in the whole

  7   blood industry.

  8             You know, the whole blood industry will be

  9   more consistent with red cells, platelets, even FFP

 10   in most cases, but it is the recovered plasma that

 11   varies.

 12             DR. CHAMBERLAND:  Is that something that

 13   is done out of their professional organization, you

 14   know, do they promulgate some sort of standards or

 15   guidance, whatever you want to call it, but is it

 16   published information about how to deal with

 17   postdonation information?

 18             MS. O'CALLAGHAN:  I don't know if they

 19   have.  I think there is other people that are

 20   probably in a better position to answer that, but

 21   just from the reports that I see, they are pretty

 22   consistent across the board, you know, from even

 23   one firm to another, making sure that they are

 24   notifying when they need to.

 25             DR. NELSON:  Actually, the recovered 

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  1   plasma, really, there are two different categories.

  2   One is the autologous and the other is the

  3   recovered.  You mentioned that there is a

  4   substantial difference in screening, and I

  5   understand that, but would it be an option of the

  6   committee to consider those as two different

  7   categories of recovered plasma, because I think

  8   they are.

  9             MS. O'CALLAGHAN:  A number of years ago,

 10   we did see a fair number of reports where the

 11   recovered plasma from an autologous donor who

 12   didn't meet allogeneic criteria was released.  We

 13   haven't really seen that in the past, I would say

 14   probably the past two or three years we haven't

 15   seen that, so I don't know if other things were put

 16   into place to prevent that from happening or why

 17   they are not reporting those, but, yes, that might

 18   be--because there are some things where it wouldn't

 19   really affect even though the donor wasn't screened

 20   completely because of being a autologous donor,

 21   that may not impact on the recovered plasma.  It

 22   might be possible to separate those.

 23             Anything else?

 24             DR. ALLEN:  Is a question such as a prior

 25   history of cancer, a concern from the perspective 

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  1   of donor safety or of infusion transfusion

  2   recipient safety?

  3             MS. O'CALLAGHAN:  It is probably a little

  4   of both. Like I said, FDA has not required

  5   screening for cancer, but industry has accepted

  6   that as deferral mechanism, because if they accept

  7   a donor who has a history of cancer, it would be

  8   something that would be reportable.  History of

  9   cancer is just another whole ball of wax anyway

 10   because there are so many varied opinions about how

 11   that type of thing impacts on products.

 12             DR. ALLEN:  I realize that there are

 13   demographic differences between source plasma

 14   donors as a group and your blood recovered plasma

 15   donors as a group.

 16             Is there any evidence that a requirement,

 17   such as the periodic physical examination by a

 18   physician, that that increases the safety or would

 19   be something that would be necessary in any way for

 20   blood donors?  I mean it hasn't been, it seems to

 21   have worked well, but what is the FDA's thought on

 22   that based on information that might be available?

 23             MS. O'CALLAGHAN:  Well, based on the

 24   information that I see through the BPD reports, in

 25   the source plasma industry, when the physical is 

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  1   being performed, that is typically where the

  2   postdonation information is obtained, where the

  3   tattoos and piercings are identified, and even

  4   though the donor is being asked the same question

  5   every time, the donor is not providing that, and it

  6   is only until they get to that physical that they

  7   match up the body map and see that there is new

  8   tattoos and new piercings, and then the donor will

  9   say, oh, I guess I did have that, you know, I

 10   forgot to tell you.

 11             In the blood industry, there doesn't seem

 12   to be a point in time in a donor's history where

 13   this information will most likely come out.  So,

 14   that is big difference in the source plasma.

 15             DR. DiMICHELE:  I just wanted to ask a

 16   question of clarification.  You said that certainly

 17   donor deferment issues were different for recovered

 18   plasma and source plasma.  Based on what you said,

 19   though, they seem to be a little bit more stringent

 20   for recovered plasma, which comes from whole blood

 21   components, than they are for source plasma, is

 22   that correct?

 23             MS. O'CALLAGHAN:  More stringent meaning?

 24             DR. DiMICHELE:  In other words, there are

 25   more deferment criteria potentially for recovered 

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  1   plasma than there is for source plasma, is that not

  2   correct?

  3             MS. O'CALLAGHAN:  Well, for example, like

  4   the malaria deferral would apply in whole blood,

  5   but not in source plasma.

  6             DR. DiMICHELE:  Right.  Certainly, some of

  7   the screen tests, like you said, for hep-B core and

  8   HTLV-I/II, et cetera.

  9             MS. O'CALLAGHAN:  And there is HBC and

 10   HTLV-I.

 11             DR. DiMICHELE:  So, the issue in recovered

 12   plasma, then, is not the stringency of criteria for

 13   donor deferment, and even the compliance issues are

 14   really donor deferment compliance issues in

 15   general, correct?

 16             MS. O'CALLAGHAN:  Right.

 17             DR. DiMICHELE:  So, the real issue that we

 18   are discussing here, just so I can put it in some

 19   sort of frame of reference, is that where the lack

 20   of standardization is and where the potential for

 21   error is, is that once that plasma is recovered,

 22   that is where you go into a gray zone in terms of

 23   what goes into what and where it goes from there,

 24   is that correct?

 25             MS. O'CALLAGHAN:  Yes, and I think that is 

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  1   what Elizabeth pointed out, with the labeling

  2   differences and at any point--

  3             DR. DiMICHELE:  Storage differences and

  4   what have you.

  5             MS. O'CALLAGHAN:  Right.  Once it becomes

  6   a recovered plasma unit, then, all bets are off.

  7             DR. DiMICHELE:  So, it is more processing

  8   issues.

  9             MS. O'CALLAGHAN:  Right.

 10             DR. DiMICHELE:  And the potential of

 11   stability of certain components vis-a-vis

 12   processing issues rather than infectious issues.

 13             MS. O'CALLAGHAN:  Yes, I think so.  I

 14   think that is a fair statement.

 15             DR. DiMICHELE:  Thanks for that

 16   clarification.

 17             DR. SIMON:  Since the cancer issue has

 18   been brought up, I just wanted to point out the FDA

 19   did have a conference on this several years ago,

 20   and I think Elizabeth Callaghan organized it, and I

 21   believe there was a pretty strong consensus that it

 22   was not a safety measure of significance either for

 23   the patient or the donor.

 24             So, I don't think that these postdonation

 25   reports need to be of concern other than the issue 

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  1   of inconsistency.

  2             DR. NELSON:  There are very few proven

  3   issues on this, but there are like 12 percent of

  4   cancers are related to infections, many of which

  5   aren't screened.  I would say HHV-VIII is perhaps

  6   one example, and, you know, whether or not cancers

  7   that have not been identified as virally related or

  8   infection related, in fact, are.  I am sure we will

  9   find more examples in the future.

 10             So, there may be some circumstances where

 11   deferral of a patient with cancer might be

 12   appropriate, I don't know.

 13             DR. EPSTEIN:  Toby, I would agree that the

 14   finding of a previous workshop was that there was

 15   little direct evidence for transmission of cancer

 16   by transfusion, however, FDA's point of view has

 17   been that the scientific question is unresolved,

 18   and we have recently developed a funded contract

 19   with the NCI to do a major epidemiologic study to

 20   get the answer.

 21             DR. LEW:  One of the things I was

 22   impressed upon when I went through at least the

 23   literature that was provided on this issue, is that

 24   I am having a hard time trying to figure out

 25   exactly some of the differences that have been 

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  1   brought up through the questions here in terms of

  2   what truly are the infectious disease issues,

  3   because I don't know what the different questions

  4   are exactly for recovered plasma, source plasma,

  5   and the different types of recovered plasma.

  6             There is clearly a lot of different ways

  7   of collection and also some things that could have

  8   to do with manufacturing and processing that are

  9   different, that may have an effect.

 10             A table might be useful just to look at

 11   those differences because when I try to answer the

 12   questions, each question, I have other questions to

 13   ask before I can answer it.

 14             MS. O'CALLAGHAN:  So, what you are looking

 15   for is kind of a comparison between recovered

 16   plasma and source plasma, a listing for each one.

 17             DR. LEW:  Right, all alluded to saying,

 18   well, there is different questions that we ask the

 19   donors before collection, but I don't know exactly

 20   which questions are different, and is alluded to

 21   there is different infectious disease testing, but

 22   it doesn't say exactly which.

 23             Also, you just brought up today in passing

 24   the different populations for these types of

 25   collections.  I think all those things are very 

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  1   important in answering some of these questions.

  2             MS. O'CALLAGHAN:  Okay.

  3             DR. SIMON:  We can give some information.

  4   The suitability criteria set by FDA and the ones

  5   that are different, ones specifically applied to

  6   red cells or platelets, so, for example, plasma

  7   donors wouldn't be asked about aspirin, which is an

  8   issue with platelets, or about malaria because it

  9   is an issue with red cells, and then the other

 10   major differences that the plasma donors can donate

 11   with greater frequency and have these be annual

 12   physical examination and are checked by serum

 13   protein electrophoresis every four months.

 14             Then, the testing differences, the tests

 15   that aren't required for plasma safety,

 16   particularly HTLV-I and II because of the white

 17   cell transmission, and then core has been omitted

 18   because of the desire to have hepatitis antibodies

 19   in the plasma.

 20             DR. NELSON:  Are there any issues beyond

 21   the infectious disease issues related to the

 22   storage, that might make recovered plasma different

 23   in terms of whatever it might be made into, would

 24   the storage affect its suitability?

 25             DR. SIMON:  My understanding is, because 

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  1   of the short supply, then, the manufacturer would

  2   set the storage requirements, isn't that correct?

  3             MS. O'CALLAGHAN:  Yes, that is what the

  4   short supply agreement would lay out with the

  5   manufacturer that they would be sending the

  6   recovered plasma to.

  7             DR. SIMON:  In my mind, the advantages of

  8   moving to standards would be to eliminate the short

  9   supply and have a very well established set of

 10   standards that would apply, that everybody would

 11   understand, would be uniform.

 12             DR. DiMICHELE:  Given that you brought

 13   that up, I was just wondering, for some of the

 14   newcomers who don't understand this very well, is

 15   there any reason for us to understand the short

 16   supply agreement a little bit better than certainly

 17   people like me do?

 18             MS. O'CALLAGHAN:  Elizabeth, do you want

 19   to explain that?  You are probably in a better

 20   position to do that.

 21             MS. CALLAGHAN:  Short supply has been a

 22   major boondoggle since I have been at the FDA.

 23   What it says essentially is that the consignee of

 24   the product that is in short supply, and if you

 25   want to consider recovered plasma in short supply, 

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  1   sets the standards that the manufacturer of the

  2   product will adhere to, so that he can sell the

  3   product to the consignee.

  4             The short supply agreement should outline

  5   how the product is processed, how it is stored, how

  6   it is shipped, and the consignee oversees this to

  7   make sure that the manufacturer of the recovered

  8   plasma is making the product according to the

  9   specifications.

 10             FDA has no control over any of these, and

 11   a lot of times does not even see the short supply

 12   agreements.  That is why we are concerned about

 13   shipping and storage temperatures and lack of

 14   consistency because whatever the manufacturer and

 15   the consignee agree to is whatever they want to do.

 16             Does that make it any easier?

 17             DR. DiMICHELE:  Why has this product been

 18   considered in short supply just from a historical

 19   perspective?

 20             MS. CALLAGHAN:  Because that was the only

 21   way we could get a nonlicensed product to be

 22   shipped in interstate commerce.

 23             DR. SIMON:  Just to clarify, so that if we

 24   set standards, then, that would allow you to have

 25   the product licensed, is that correct? 

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  1             MS. CALLAGHAN:  Well, we could either just

  2   set standards and keep with the short supply

  3   agreement, or we could, in fact, make it a licensed

  4   product, in which case the short supply agreements

  5   would disappear.

  6             DR. SIMON:  I mean, for example, at one

  7   time, there was a fair market for so-called room

  8   temperature plasma, and you didn't have to have the

  9   plasma frozen.  I think that may have disappeared,

 10   but there was a lot of concern about the

 11   microbiological impact of that, so it has been

 12   something that hasn't had the same stringent

 13   requirements in terms of things like storage,

 14   temperature.

 15             MS. CALLAGHAN:  Right, hence, the lack of

 16   consistency.

 17             DR. SIMON:  Right, and that has been the

 18   case with source plasma, because it's a license

 19   product, so it has been there.

 20             DR. KLEIN:  But I don't think anybody

 21   knows, Toby, as to whether it has gone away or it

 22   hasn't gone way, because those are agreements

 23   between institutions and their fractionater.

 24             DR. ALLEN:  Two other questions that come

 25   up.  When a blood center collects recovered plasma 

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  1   and ships it to a fractionater for processing, I

  2   have always been under the assumption that it has

  3   all been mixed in together in huge lots, that the

  4   lot will contain both recovered and source plasma.

  5             Is that correct?

  6             MS. CALLAGHAN:  That is my understanding,

  7   too, but perhaps the fractionaters could answer

  8   that question better.  Do you mix source plasma and

  9   recovered plasma together?

 10             DR. WHITAKER:  In general, they are not

 11   mixed.

 12             MS. CALLAGHAN:  Okay.

 13             DR. ALLEN:  That is interesting.  The

 14   second, with recovered plasma, if a unit of blood,

 15   let's say is found to be core antibody positive,

 16   the cellular components obviously would be

 17   discarded.

 18             Is the plasma still then acceptable for

 19   recovered?

 20             MS. CALLAGHAN:  Yes, it is.

 21             DR. ALLEN:  I had just always made the

 22   assumption that the whole unit was discarded, but

 23   the components still might meet one criteria, but

 24   not the other?

 25             MS. CALLAGHAN:  Right. 

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  1             DR. NELSON:  But the processing and viral

  2   inactivation procedures are the same for recovered

  3   and source plasma, if they are kept separate?

  4             MS. CALLAGHAN:  Yes, they are.

  5             DR. NELSON:  They undergo the same

  6   process.

  7             Kay Lewis is next, FDA.

  8             MS. LEWIS:  Good morning.  I am Kay Lewis

  9   with the Office of Compliance in CBER.

 10             I am the branch chief for Blood and Tissue

 11   Compliance.  Within my branch, we also handle

 12   recalls, which is considered a voluntary compliance

 13   action.

 14             I just want to give you a few numbers

 15   today on recalls and recovered plasma.

 16             [Slide.]

 17             The slide that I have here shows the

 18   number of recalls for FY 2000 and FY 2001,

 19   specifically for recovered plasma, the Class II's

 20   and Class III's.

 21             Now, the Class II's are the aqua color,

 22   and the Class III's are the dark blue.

 23             As you can see, there have been a greater

 24   number of Class II's than Class III's, and the

 25   intervening between FY 2000 and 2001, the number of 

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  1   Class II's has increased slightly.  That is

  2   probably due to the overall number of increase in

  3   recalls, and has no real effect on recovered plasma

  4   per se.

  5             The only other thing that I want to say

  6   about the recovered plasma is that for Class II's,

  7   we currently audit those here at CBER rather than

  8   have the field audit those, and basically, by

  9   "auditing," what I mean is that the fractionaters

 10   send us information regarding lot numbers and

 11   products that the recovered plasma has been

 12   manufactured into, and we review that data, the

 13   viral inactivation steps, et cetera, to make sure

 14   that the product is still safe for its intended

 15   use.

 16             That is basically all I have on recalls

 17   and recovered plasma.  Are there any questions?

 18             DR. NELSON:  Could you describe the

 19   difference between Class II and Class III?

 20             MS. LEWIS:  The difference is in the

 21   health hazard evaluation, and that is done by our

 22   product officers.  Without going into my recall

 23   talk, basically, when we receive a recall

 24   recommendation, we ask our product officers what is

 25   the hazard involved with whatever is wrong with the 

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  1   product, whatever it is being recalled for.

  2             They come back with whether or not it is a

  3   danger to health or whether it is a remote

  4   possibility of adverse health consequences, whether

  5   it is medically reversible, or whether it is not

  6   likely to have a hazard.

  7             Based on that information, we will

  8   classify it as Class I, Class II, or Class III.

  9   So, Class II's are either a remote possibility of

 10   adverse health consequences or medically reversible

 11   health consequences, and Class II is not likely to

 12   produce any adverse health consequences.

 13             DR. DiMICHELE:  Do you repeat that one

 14   more time?  Which is worse?

 15             MS. LEWIS:  Class II is worse than Class

 16   III.  Class I is the most egregious.  That is the

 17   danger to health.  Class II is either a remote

 18   possibility of adverse health consequences or the

 19   consequences are medically reversible.  Class III,

 20   there is not likely to be adverse health

 21   consequences.

 22             DR. FITZGERALD:  The numbers that you are

 23   reporting then are, by FDA definition, and by FDA

 24   guidance documents and requirements, recalls based

 25   on requirements for the product versus the things 

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  1   we heard about in the talk like--

  2             MS. LEWIS:  Postdonation information?

  3             DR. FITZGERALD:  --the red cell unit was

  4   recalled, so they recalled the plasma, too.

  5             MS. LEWIS:  That is a lot of what we see

  6   if the transfusable products are recalled, then,

  7   the recovered plasma is also recalled.

  8             DR. FITZGERALD:  So, that would be

  9   included in these numbers also?

 10             MS. LEWIS:  No, these are only recovered

 11   plasma products.  It does not include transfusable

 12   products.

 13             DR. FITZGERALD:  No, but was the plasma

 14   that was recalled, but is included in these

 15   numbers, recalled because the transfusable product

 16   was recalled?

 17             MS. LEWIS:  Yes.

 18             DR. FITZGERALD:  Okay.  So, these numbers

 19   include all the units that were recalled regardless

 20   of whether you think it was a valid recall or not?

 21             MS. LEWIS:  By "valid recall," what

 22   exactly are you alluding to?

 23             DR. FITZGERALD:  Okay.  They recalled the

 24   red cell, there really wasn't a reason to recall

 25   the plasma, but they did.  Malaria. 

                                                               138

  1             MS. LEWIS:  In the case of malaria, no, we

  2   would classify that as a market withdrawal rather

  3   than a recall, because there is no hazard to having

  4   recovered plasma out there because of malaria

  5   reasons.

  6             DR. FITZGERALD:  That is what I am trying

  7   to get to.  Have you screened out of these numbers,

  8   those units that were the manufacturer instituted a

  9   recall, but the reason for the recall may not have

 10   been because of an FDA requirement?

 11             MS. LEWIS:  Yes, we have.  The only

 12   numbers that I have here are recalls of recovered

 13   plasma where the reason for recall was valid to

 14   include the recovered plasma.

 15             DR. HOLLINGER:  Also, on the left of the

 16   screen, are those in units or lots or what?

 17             MS. LEWIS:  Those are actual number of

 18   recall events.

 19             DR. HOLLINGER:  Recalls, but it could be

 20   multiple units.

 21             MS. LEWIS:  Yes, it could be.

 22             DR. HOLLINGER:  Do you know how many units

 23   that represents?

 24             MS. LEWIS:  Not offhand, no.

 25             DR. LEW:  Just to get a better 

                                                               139

  1   understanding of this increase, do you have like

  2   the percentage for overall use?  We already saw

  3   data of increased use for IVIG products, you know,

  4   other types of products.  Could this just reflect

  5   increased production and use, but the same

  6   percentage is being recalled?

  7             MS. LEWIS:  No, because our overall recall

  8   percentage increased from FY 2000 to FY 2001.

  9   There was an overall increase in the number of

 10   recalls that we processed.

 11             DR. LEW:  What I am trying to get at, is

 12   it a reflection of because there is more production

 13   now, it is still--I am going to make this up--5

 14   percent are recalled, 5 percent were recalled in

 15   2000, 5 percent were recall in 2001, and do we have

 16   any sense of--

 17             MS. LEWIS:  No, I don't.

 18             DR. CHAMBERLAND:  What you are looking for

 19   is the denominator.  Is there an appropriate

 20   denominator to affix with this numerator?  I don't

 21   know if there is or not, but I think that is what

 22   you are looking for.

 23             MS. LEWIS:  I don't know there is an

 24   appropriate denominator.  We haven't evaluated the

 25   number of recalls or the increase to determine 

                                                               140

  1   whether or not it was due to a specific reason or a

  2   specific number of reasons.  We haven't evaluated

  3   that data.

  4             DR. NELSON:  Where would you put CJD,

  5   would that be a Class II or Class III, because

  6   clearly, you know, I mean somebody traveling to--

  7             MS. LEWIS:  I am sorry, I can't answer

  8   that question.  We would have to ask our product

  9   officers, Office of Blood or--

 10             DR. EPSTEIN:  We treat postdonation

 11   information for BSE exposure as a voluntary market

 12   withdrawal, and we do not classify it as a recall

 13   because there has been no proven transmission.

 14             DR. HOLLINGER:  Do the blood banks send

 15   off individual units of plasma to the plasma

 16   manufacturer or do they pool it and send it off?

 17             MS. LEWIS:  As far as what we have seen,

 18   it has been individual unit numbers is what we see.

 19             DR. FALLAT:  Can you get an estimate of

 20   the denominator from the source plasma industry as

 21   to what percentage of the source plasma is, in

 22   fact, or what percentage of the plasma that is used

 23   by the source plasma people is recovered plasma?

 24             MS. LEWIS:  No, I don't have that.

 25             DR. FALLAT:  Is that information at all 

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  1   available from the industry?

  2             MS. LEWIS:  At least not through the

  3   recall process.

  4             DR. SIMON:  Well, there has been estimates

  5   that it is approximately 80-20, I believe, yes,

  6   approximately 80-20, approximately 80 percent

  7   source plasma production, approximately 20 percent

  8   in the American market is recovered.

  9             DR. FALLAT:  That would give you some idea

 10   of the denominator then.

 11             DR. SIMON:  Well, the denominator here, I

 12   was just going to say we know that the amount of

 13   blood drawn in the United States has not increased

 14   substantially, so it is about the same in 2000 and

 15   2001, so I think your denominator would be about

 16   the same in those two years.

 17             DR. ALLEN:  What is the length of time

 18   between the donation and the recall on average or

 19   what is the range?  The corollary to that is are

 20   some of these recalls actually of manufactured

 21   product, so what we are seeing is not a unit being

 22   called back for disposal, but actually manufactured

 23   product that is being recalled.

 24             MS. LEWIS:  The majority of the recovered

 25   plasma recalls are of actual manufactured product, 

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  1   which is why we actually review the lot number

  2   information and the products that it was

  3   manufactured into from the fractionaters for the

  4   Class II's, because by the time whatever violation

  5   has occurred or the actual blood bank acknowledges

  6   that that violation exists and does the recall,

  7   many times the product has already been

  8   manufactured into product.

  9             DR. DiMICHELE:  You may have alluded to

 10   this before, but let's say if you look at the

 11   number of recalls in 2000 and 2001 for source

 12   plasma, how does it compare or can you compare it?

 13             MS. LEWIS:  I probably could compare it,

 14   but I don't have that data with me, but I could

 15   make that comparison.  I could look at all the

 16   source plasma that was recalled in those two FY's,

 17   and do an actual comparison.  I could do that and

 18   maybe get it to the exec sec.

 19             DR. DiMICHELE:  Okay.  Thank you.

 20             DR. FALLAT:  I would like to return to

 21   that question about the difference between

 22   autologous and non-autologous.  Do you have any

 23   data as to how many of these recalled ones were

 24   autologous versus not?

 25             MS. LEWIS:  No. 

                                                               143

  1             DR. FALLAT:  That would be the one area

  2   where some of the source information is deficient,

  3   and therefore, wouldn't be just a processing

  4   problem.

  5             MS. LEWIS:  Exactly.  The blood banks and

  6   people that manufacture recovered plasma don't send

  7   the information in to us that way.  It is just

  8   labeled as recovered plasma.

  9             DR. SIMON:  I don't believe autologous is

 10   being used.  I get the right signs back there yes.

 11   I think this is a non-issue.  Autologous plasma is

 12   not being used, this is allogeneic for further

 13   manufacture.

 14             DR. NELSON:  Yes, I think he is saying

 15   they throw this out or if they don't use it, the

 16   autologous.

 17             DR. SIMON:  A lot of it is kept as whole

 18   blood for the patient who is supposed to receive

 19   it.  Also, autologous is going down substantially

 20   in the United States right now, the so-called pre-deposit.

 21             DR. LEW:  Actually, I had a question for

 22   Dr. Simon because he seemed to have these answers.

 23   You said that the rate of blood donation is the

 24   same, but the other question would be, if there is 

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  1   a rising demand for these type of blood products

  2   recalled, do you know if industry or various places

  3   are increasing their production of recalled

  4   product, because again that might affect the

  5   denominator.

  6             Is there a great need?

  7             DR. SIMON:  I think the amount of product,

  8   as we saw in the first presentation, is being

  9   increased, the production of product, but the

 10   amount of actually recovered plasma has not I don't

 11   believe increased significantly in that time frame.

 12             DR. FITZGERALD:  I don't know if we can

 13   say that, Toby, because the market has changed and

 14   the price has gone up, and there is a difference

 15   between what you get for injectable versus non-injectable,

 16   so there may be more recovered plasma

 17   being produced and sold than there was.

 18             DR. NELSON:  Thank you.

 19             MS. CALLAGHAN:  I have some overheads that

 20   might help clear up some of your questions.

 21             [Slide.]

 22             As far as testing requirements, the

 23   differences between source plasma and recovered

 24   plasma donors, source plasma donors are not tested

 25   for anti-core, they are not tested for anti-HTLV I 

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  1   or II.

  2             There is no deferral for travel to

  3   malarious areas for source plasma donors, and the

  4   VCJD deferral for five years in Europe is not

  5   required for source plasma donors. All of these

  6   things are required for recovered plasma donors.

  7             [Slide.]

  8             As far as syphilis testing goes, source

  9   plasma donors are tested every four months for

 10   syphilis, initially, every four months for

 11   syphilis, where recovered plasma is tested on every

 12   unit.

 13             [Slide.]

 14             Some of the differences between source

 15   plasma and recovered plasma donors.  Source plasma

 16   donors have an annual physical, recovered plasma

 17   donors do not.  They have a little, mini-physical,

 18   if you want to call it that, at every donation, but

 19   they do not have an actual physical by a physician

 20   every year.

 21             Source plasma donors have a total protein

 22   done at every donation, recovered plasma donors

 23   don't.  Source plasma donors have a serum protein

 24   electrophoresis performed every four months, and

 25   recovered plasma donors don't. 

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  1             Source plasma donors can donate twice a

  2   week as long as the donations are 48 hours apart,

  3   and recovered plasma donors donate every 56 days.

  4             Does this help any, I hope?

  5             DR. NELSON:  Are there any specifics

  6   mandated on the physical exam?  I mean what does it

  7   conclude?

  8             MS. CALLAGHAN:  The physicals are like an

  9   annual, like a physical you would have at a

 10   physician's office.  They do everything that a

 11   physician would do.

 12             DR. NELSON:  My physician probably

 13   wouldn't look for tattoos.

 14             MS. CALLAGHAN:  He might if they were

 15   infected.

 16             DR. NELSON:  I guess they map out tattoos

 17   that were there previously, because tattoo donation

 18   is one year for both source plasma and recovered?

 19             MS. CALLAGHAN:  Right.  What the physician

 20   does at an annual physical, they note on a chart,

 21   on a little diagram of a person where the tattoos

 22   are or the body piercings, and if a new one shows

 23   up that is not on the little diagram, they will

 24   question the donor as to when they got it.

 25             DR. NELSON:  But as far as the FDA is 

                                                               147

  1   concerned, if the plasmapheresis center said we did

  2   a physical, that would be it, it is not like the

  3   donor questionnaire saying you have to ask this

  4   question this way, right?

  5             MS. CALLAGHAN:  No, it's an actual

  6   physical.

  7             DR. NELSON:  Yes, it is an actual

  8   physical, but it is not mandated as what is

  9   recorded or is it?  Does the FDA mandate what

 10   should be in the physical?

 11             MS. CALLAGHAN:  Oh, yes, it has to be part

 12   of the donor's chart, and everything that is found

 13   or in the physical is on there.

 14             DR. NELSON:  But the content.

 15             DR. SIMON:  Yes, there are certain

 16   requirements.

 17             MS. CALLAGHAN:  There are requirements.

 18             DR. SIMON:  Like, for example,

 19   auscultation of the heart and lungs, palpation of

 20   the abdomen, at least some neurological exam, so

 21   there are certain features that are required, and

 22   then FDA inspectors routinely sit in on one or more

 23   physicals when they come to do the inspection.

 24             DR. NELSON:  As an aside, the first AIDS

 25   patient I saw had a physical exam, and he was a 

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  1   transsexual who had had surgery, and it was

  2   reported that this patient had normal female pelvic

  3   exam, but when we went back, it was not done very

  4   well or very completely.

  5             So, a physical is a physical, you know, it

  6   can differ.

  7             DR. SIMON:  Plasma donor centers don't do

  8   pelvic exams.

  9             DR. KLEIN:  There are also storage

 10   differences or potential storage differences

 11   between recovered plasma and source plasma, is that

 12   not correct?

 13             DR. SIMON:  It is correct, but you may

 14   want to elaborate on that.

 15             MS. CALLAGHAN:  Source plasma, when it is

 16   collected, must, according to the CFR, must be

 17   frozen immediately.  There are no storage

 18   requirements at all for recovered plasma.  So, it

 19   is whatever the consignee and the manufacturer of

 20   the recovered plasma agree upon.

 21             DR. LEW:  Just for my education, what is

 22   the purpose of the electrophoresis that you require

 23   for the source?

 24             MS. CALLAGHAN:  To make sure that the

 25   donor is not being overpheresed so that their 

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  1   protein levels become abnormal.

  2             DR. EPSTEIN:  I just want to comment.  The

  3   FDA permits both source plasma and recovered plasma

  4   to be fractionated.  There are issues in two

  5   different directions on the table.  I think to a

  6   certain extent we have got the committee confused

  7   whether what we are worrying about are the

  8   infectious disease control issues or the donor

  9   safeguards.  Those are really not the issues.

 10             The issue that we are concerned about is

 11   the quality of the plasma as a raw material for

 12   fractionation. On the one side, you have source

 13   plasma where the conditions of preparation and

 14   storage and labeling are rigorously defined.  It's

 15   a licensed product, it meets well-defined

 16   standards.

 17             On the other side, with recovered plasma,

 18   although we go about the donor safeguards and the

 19   donor screening in a different way, the issue at

 20   hand is that that product is not a well-defined

 21   product.  It is not subject to product standards

 22   defined by the FDA in regulations or guidance.

 23             It has variable storage conditions related

 24   to temperature and time.  It does not otherwise

 25   meet any standards related to protein content.  It 

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  1   is entirely governed by these agreements with the

  2   fractionater.

  3             Let me just say that the short supply is

  4   based on the concept of short supply of the end

  5   product, not short supply of the raw plasma

  6   material.  In other words, it isn't because the

  7   plasma is in short supply, it is because the

  8   derivative is in short supply.  We permit the

  9   fractionater to engage in short supply agreements

 10   for raw materials.

 11             So, the issue is really thinking of the

 12   plasma and what should be the specifications as a

 13   substrate for fractionation.

 14             Now, what is on the table from the FDA

 15   side is the FDA is of a mind-set that we really

 16   ought to be substituting product standards for the

 17   short supply agreements and define this material

 18   similar to the way we define source plasma, but you

 19   are going to be hearing that there is a whole other

 20   set of issues from the side of the industry.

 21             The industry would like the FDA to relax

 22   the conditions under which a plasma by-product can

 23   become salable, because even though the

 24   specification on the product for recovered plasma

 25   is not well defined, there are some limitations 

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  1   that are troublesome to the industry.

  2             For example, if you are doing a

  3   cytapheresis, you can only sell surplus plasma,

  4   say, for making platelets, as expired fresh-frozen

  5   plasma.  You can't just directly take the plasma

  6   and sell it as recovered plasma.  Industry would

  7   like us to relax that condition.  Then, there are

  8   others that you will hear.

  9             So, I think part of the problem is that

 10   the committee has not yet heard the full spectrum

 11   of presentations, but the issue of stringency is

 12   should we raise recovered plasma to a processing

 13   standard and a labeling standard that makes it

 14   pretty much the same thing as source plasma except

 15   for the nature of how it got collected, and then

 16   conversely, should we relax stringency. The

 17   industry will be asking should the FDA relax

 18   stringency, so that there are more ways to get to a

 19   recovered plasma as a salable product.

 20             Let me just say that there is an issue

 21   there which has to do with intent of collection.

 22   One of the differences that we have not

 23   highlighted, source plasma is intended knowingly

 24   and deliberately to be used solely for

 25   fractionation.  It is dated and sealed.  It is for 

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  1   the manufacture and use, period, full stop.

  2             The concept with recovered plasma is that

  3   the blood or component that was collected, was

  4   collected with the intention of transfusion, not

  5   with the intention of further manufacturing, and

  6   that, therefore, the plasma that may arise is a by-product,

  7   not deliberately made.

  8             Again, what the industry would like us to

  9   do is to try to relax or even erase that

 10   distinction, such that you could willfully generate

 11   recovered plasma when you know you are going to be

 12   creating excess plasma from other collections, or

 13   you could simply capitalize on the opportunity.

 14             So, if you know you are going to make

 15   platelets, can you knowingly make a surplus plasma

 16   and then just sell it upfront, why do you have to

 17   go through the drill of freezing it as FFP and

 18   waiting for it to expire, for example.

 19             But the nuance there is deliberate

 20   collection of something that the FDA has legally

 21   regarded as an accidental or incidental by-product.

 22   So, the whole mind-set on recovered plasma

 23   historically and in the regulations and in the

 24   guidances is that it was an unintended by-product

 25   which became useful, whereas, the concept for 

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  1   source plasma was that it was a deliberately

  2   collected raw material for further manufacturing,

  3   and that is one of the distinctions that we are

  4   being asked to modify.

  5             So, the issues on the table are should we

  6   have a product standard like source plasma

  7   applicable to plasma obtained from whole blood

  8   collection, should we relax the standards on

  9   recovered plasma, so that there are more varieties

 10   that are salable and so that the collections can be

 11   done knowingly upfront.  Those are the real issues.

 12             I think the other background on how these

 13   things are distinguished is useful and its matters

 14   of fact, but it is taking us away from the question

 15   and why it is on the table.

 16             I think a lot of this will become clearer

 17   after the industry presentations.

 18             DR. NELSON:  Thanks for the clarification,

 19   Jay.

 20             Barbara.

 21                      Industry Presentations

 22                               PPTA

 23             DR. WHITAKER:  Good afternoon.  I am

 24   Barbee Whitaker with the Plasma Protein

 25   Therapeutics Association. 

                                                               154

  1             PPTA is the global trade association and

  2   standards-setting organization for the world's

  3   major producers of plasma derived and recombinant

  4   analog therapies.  Our members provide 60 percent

  5   of the world's needs for source plasma and protein

  6   therapies.

  7             These include clotting therapies for

  8   individuals with bleeding disorders,

  9   immunoglobulins to treat complex diseases in

 10   persons with immune deficiencies, and individuals

 11   with alpha-1 anti-trypsin deficiency which

 12   typically manifests as adult onset emphysema and

 13   substantially limits life expectancy.

 14             PPTA members are committed to assuring the

 15   safety and availability of these medically needed

 16   life-sustaining therapies.

 17             Over the past two years, PPTA and its

 18   predecessor ABRA, have been engaged in dialogue

 19   with the whole blood industry about the possible

 20   establishment of specific criteria uniquely

 21   applicable to so-called "recovered plasma."

 22             This dialogue was born out of an

 23   acknowledgment of the important public health

 24   benefits to be gained through utilization of high

 25   quality recovered plasma for the production of 

                                                               155

  1   plasma-derived medicinal products.

  2             While recovered plasma is currently used

  3   in the production of safe, high quality plasma

  4   therapies, the major producers of plasma

  5   therapeutics sought to harmonize starting material

  6   requirements between recovered plasma and source

  7   plasma to the greatest extent practicable.

  8             This ongoing dialogue has proved valuable.

  9   Following initial meetings, representatives of the

 10   American Association of Blood Banks, the American

 11   Red Cross, American's Blood Centers, Blood Centers

 12   of America, and PPTA, with participation by an FDA

 13   representative, continued to meet over the 2000-2001 time

 14   period.

 15             Although consensus among all participants

 16   was not attained, much common ground was

 17   identified.  Areas with the greatest potential for

 18   harmonization include donor documentation criteria,

 19   quality assurance practices, the National Donor

 20   Deferral Registry, among others.

 21             This initiative grows out of a PPTA

 22   identified need for harmonized standards for plasma

 23   for fractionation, whether derived from whole blood

 24   or apheresis.  Further, such standards for

 25   recovered plasma are consistent with PPTA's other 

                                                               156

  1   quality programs: the International Quality Plasma

  2   Program (IQPP) for Source Plasma and the Quality

  3   Standards for Excellence Assurance and Leadership

  4   (QSEAL)  program, launched in 2000 for plasma

  5   fractionation.

  6             PPTA is committed to continuous quality

  7   through programs like IQPP, QSEAL, and now,

  8   recovered plasma standards.  Other quality

  9   initiatives under development include criteria for

 10   plasma fraction intermediates and harmonized

 11   guidelines for NAT testing laboratories.

 12             Once again, PPTA is encouraged by the

 13   productive dialogue regarding recovered plasma that

 14   has taken place to date.  We anticipate that a

 15   workable set of standards and criteria can be

 16   achieved by January 2004.

 17             It is worthwhile to note that this same

 18   exercise is underway in Europe.  A gap analysis of

 19   recovered plasma practices in Europe has just been

 20   completed.  We look forward dot  continuing this

 21   dialogue and moving ahead toward the implementation

 22   of appropriate criteria for recovered plasma on a

 23   global basis.

 24             Thank you for the opportunity to present

 25   this information.  The objective of establishing 

                                                               157

  1   high standards for plasma therapies is clear - to

  2   assure a consistent supply of safe, high quality

  3   human plasma for the use in the manufacture of

  4   plasma-derived medicinal products.

  5             Thank you.

  6             DR. NELSON:  Thank you.

  7             Questions?  Mary.

  8             DR. CHAMBERLAND:  Can you briefly tell us

  9   what some of the areas were that you were not able

 10   to reach a common understanding?

 11             DR. WHITAKER:  Some of the IQPP standards

 12   that are applied to source plasma include the

 13   qualified donor, drug testing.  Those were the

 14   major issues.

 15             DR. FITZGERALD:  You mentioned from the

 16   floor that lots of source plasma and recovered

 17   plasma are kept separate.  Is there a difference in

 18   the quality of the products or the efficiency of

 19   manufacturer from those two different products?

 20             DR. WHITAKER:  I can't really address

 21   that.

 22             DR. HARVATH:  I was curious as to whether

 23   there is a difference in the consent for an

 24   individual donating for source plasma as compared

 25   to those who would come to a blood bank, donate for 

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  1   a cellular component, and that would be used for

  2   recovered plasma.

  3             Is there any difference in the donor

  4   consent for those two types of products?

  5             DR. WHITAKER:  I believe there are

  6   differences in the donor consents.  Every

  7   collection company has its own informed consent,

  8   but our consent includes the possibility of being

  9   registered in the National Donor Deferral Registry

 10   among other things, and, of course, the intended

 11   use of the product.

 12             DR. NELSON:  But aren't both types of

 13   donors registered?  This is if they have an I.D.

 14   marker?

 15             DR. WHITAKER:  Yes.  Currently, that's in

 16   use by the source plasma industry, but it has not

 17   been expanded to include the whole blood industry,

 18   and that is one of the areas that we are undergoing

 19   dialogue about as a part of this process.

 20             DR. NELSON:  I am surprised.

 21             DR. KLEIN:  There is no National Registry

 22   is what she is saying for volunteer donors.

 23             DR. SIMON:  Just in Dr. Fitzpatrick's

 24   question, conventionally, in the literature, in

 25   general, factor VIII levels are higher in source 

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  1   plasma donors and albumin levels are higher in

  2   recovered plasma and possibly gamma globulins, so

  3   there is some difference in the starting product

  4   from that point of view.

  5             But I was going to ask Barbee, would the

  6   answer to this question, the FDA as opposed to us,

  7   and the creation of standards by the FDA, would you

  8   look at that as supporting your volunteer efforts,

  9   or would you prefer to move voluntarily instead?

 10             DR. WHITAKER:  We feel that our standards

 11   are in addition to the criteria set forth by the

 12   FDA, and to this point we have not gotten into

 13   specific criteria for the production of recovered

 14   plasma.  However, those things are still in the

 15   process of discussions.

 16             DR. FINLAYSON:  John Finlayson, FDA.

 17             I would like to go back to Dr.

 18   Fitzgerald's question and amend that which Dr.

 19   Simon said.

 20             If one reads the literature of the late

 21   1970s, and I strongly suspect that I am the only

 22   person in this room that does such a bizarre thing,

 23   one sees reports of a number of differences in

 24   products made from recovered or source plasma.

 25             If one looks at a workshop that was held 

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  1   in 1977, and which was followed by one which was

  2   held in 1978, one would see that the tendency for

  3   elevated levels of a pre-kallikrein activator in

  4   plasma protein fraction was considerably more

  5   common in plasma protein fraction made from

  6   recovered plasma than in that made from source

  7   plasma.

  8             That is not to say that source plasma

  9   could never be the starting material for a plasma

 10   protein fraction that had elevated levels of a pre-

 11   kallikrein activator, but it was a rarer event.

 12             If one moves to 1978 to a paper on

 13   stability of immunoglobulins, and modesty forbids

 14   my mentioning of all the authors, one sees that the

 15   likelihood of fragmentation during storage was

 16   greater in the case of immune globulins made from

 17   recovered plasma than that made from source plasma.

 18   Again, it was not absolute.

 19             If one continues into 1979, there were

 20   some elegant studies by Dr. James McIver [ph] of

 21   the Massachusetts Department of Public Health,

 22   which showed exactly the same thing.

 23             Now, if one knows these things, there are

 24   steps that one can take to circumvent them, but

 25   this was certainly the case as it existed in the 

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  1   1970s, when the storage of recovered plasma was at

  2   best heterogeneous and was rarely equivalent to

  3   that of source plasma, which as has already been

  4   said, is collected by plasmapheresis and

  5   immediately frozen and is stored at minus 18

  6   degrees Celsius or colder.

  7             Now, the question large devolves then to

  8   the one that has been discussed here, but which, as

  9   Dr. Klein said, we really don't have an answer to,

 10   is what is the usual storage condition of recovered

 11   plasma at present and how soon does it get into

 12   that storage condition.

 13             DR. ALLEN:  In your studies, were you able

 14   to look at the differences in the units and apply

 15   any differential based on length of storage or

 16   freezing and thawing, and so on?

 17             DR. FINLAYSON:  As somebody's analogy was,

 18   it's not like using a shotgun, it's like using a

 19   rifle at a shooting gallery.  You have to pick

 20   ducks off one at a time.

 21             One has to look at specifically what it is

 22   one is worried about.  If one is worried about

 23   elevation of plasma kallikrein activator--again

 24   this is a generalization--pre-kallikrein activator

 25   is one of the components of the--I am not saying 

                                                               162

  1   this for your benefit because you know, but for the

  2   benefit of the audience--is one of the components

  3   of the contact activation system.

  4             Mother Nature has been very, very good in

  5   supplying plasma with a number of protein

  6   proteinase inhibitors, which are very good at

  7   inactivating the active forms of the contact

  8   activation system, however, these things work very

  9   well at the temperature that Mother Nature intended

 10   it to be, which is 37 degrees Celsius or slightly

 11   below, whereas, if one puts it in the refrigerator,

 12   the association constants between the protein

 13   proteinase inhibitors and those proteinases, which

 14   is the things that we are talking about, these

 15   inactivated enzymes of the contact activation

 16   system, those association constants become

 17   considerably lower.

 18             So, a great deal of activation can take

 19   place of factor XII to pre-kallikrein activator

 20   upon storage in the cold, and, of course, the

 21   longer one stores in the cold, the more this can

 22   happen.

 23             Now, on the other hand, if one moves over

 24   to considering stability of immune globulins, what

 25   one there is concerned about is related to, but 

                                                               163

  1   expanded upon, that of the activation of the

  2   contact activation system.

  3             What one is ultimately worried about for

  4   the fragmentation of immune globulins, other words,

  5   IgG, is the presence of plasmin, but that can

  6   happen in a variety of fashions.  One is that the

  7   plasminogen gets activated to plasmin while the

  8   plasma is still plasma, and then the plasma, which

  9   rides along with the final product, chews at the

 10   IgG, and what one is there concerned about is how

 11   long is the immune globulin stored.

 12             Now, the activation of plasminogen to

 13   plasmin proceeds very nicely at room temperature,

 14   and in the old days, there certainly used to be

 15   room temperature storage of the liquid recovered

 16   plasma.  It occurs more slowly, considerably more

 17   slowly in the cold.

 18             On the other hand, kallikrein, which is

 19   the result of the action of pre-kallikrein

 20   activator on pre-kallikrein, which is also in

 21   plasma, kallikrein can convert plasminogen to

 22   plasmin.

 23             If you ask the people who are contact

 24   activationologists, if there is such a word, they

 25   will tell you that kallikrein is a terrible 

                                                               164

  1   activator of plasminogen, and that is certainly

  2   true, but these people do enzyme experiments that

  3   take an hour or two hours or three hours.

  4             When you are storing the final product,

  5   you are storing it for years, and so if it turns

  6   out that plasminogen gets into the final product,

  7   that is, the IgG-containing product, and there is a

  8   little bit of kallikrein, it can gradually activate

  9   the plasminogen to plasmin, which will chew on the

 10   IgG.

 11             So, it is a very heterogeneous mix.  You

 12   first sentence again, have you studied, yes, we

 13   have studied, but we have not gotten to the point

 14   where one can give you a nice short answer, which

 15   is what you were looking for.

 16             DR. NELSON:  Thanks, John.

 17             Are there other questions for Dr.

 18   Whitaker?

 19             Thank you.

 20             The next presentation is Kay Gregory of

 21   American Association of Blood Banks.

 22                               AABB

 23             MS. GREGORY:  Thank you.  My name is Kay

 24   Gregory and I am representing the American

 25   Association of Blood Banks, which is the 

                                                               165

  1   professional society for over 8,000 individuals

  2   involved in blood banking and transfusion medicine

  3   and represents approximately 2,000 institutional

  4   members, including blood collection centers,

  5   hospital-based blood banks, and transfusion

  6   services as they collect, process, distribute, and

  7   transfuse blood and blood components and

  8   hematopoietic stem cells.

  9             Our members are responsible for virtually

 10   all of the blood collected and more than 80 percent

 11   of the blood transfused in this country.  For over

 12   50 years, the AABB's highest priority has been to

 13   maintain and enhance the safety and availability of

 14   the nation's blood supply.

 15             The AABB agrees that the FDA should

 16   reevaluate its requirements for recovered plasma.

 17   Disease facto regulation, through the requirement

 18   for a short supply agreement that sets the

 19   requirements for this product, is not an

 20   appropriate method of control, and FDA should set

 21   standards for licensing recovered plasma.

 22             The AABB specifically included recovered

 23   plasma in its 21st edition of Standards for Blood

 24   Banks and Transfusion Services.  These BBTS

 25   Standards were implemented by our members effective 

                                                               166

  1   May 1st, 2002.  However, in setting these

  2   standards, the AABB worked within the constraints

  3   of the FDA requirements and identified concerns

  4   that we now know need further consideration.

  5             While we will continue to use the term

  6   recovered plasma in these comments, it is probable

  7   that new terminology should be adopted to describe

  8   the various kinds of plasma licensed by the FDA.

  9             The AABB's first concern is the definition

 10   of recovered plasma.  Currently, this term is

 11   applied to plasma that is removed from whole blood.

 12   Source plasma is defined as plasma that is

 13   collected by plasmapheresis and is intended for

 14   further manufacture.

 15             The primary distinction in definition

 16   appears to be the intent of the collection and the

 17   method of collection.  These definitions are no

 18   longer appropriate and should be revised or

 19   discarded.  Use of intent as a criterion severely

 20   limits the flexibility needed to maximize the

 21   utilization of collected blood.

 22             New technology now permits collection of

 23   plasma concurrent with other blood components that

 24   are intended for transfusion, for example,

 25   plateletpheresis or red cells by apheresis.  This 

                                                               167

  1   plasma is collected for fresh frozen plasma that is

  2   intended to be transfused.

  3             However, this plasma is also suitable for

  4   use in further manufacturing and could be converted

  5   to that use at a later date if the need for the

  6   fresh frozen plasma in inventory no longer exists.

  7             Currently, that is not possible because

  8   the plasma does not meet the existing definition of

  9   recovered plasma, i.e., it was not collected with

 10   the intent of being used for further manufacture,

 11   nor was it obtained from whole blood.

 12             Alternatively, concurrent plasma, that is,

 13   plasma collected concurrently with other blood

 14   components, can also be collected and used for

 15   further manufacture, but this can only be done if

 16   the facility has a license to collect source

 17   plasma.

 18             Because source plasma donors may donate

 19   much more frequently than whole blood donors, FDA

 20   has established additional requirements to protect

 21   the donor's health.  These requirements include

 22   physician examination prior to the first donation

 23   and at subsequent intervals of not more than one

 24   year, and determination of total serum or plasma

 25   protein and a plasma or serum protein 

                                                               168

  1   electrophoresis or an equivalent test to determine

  2   immunoglobulin composition of the plasma or serum

  3   at least every four months.

  4             FDA has issued guidance stating that

  5   infrequent plateletpheresis donors may donate every

  6   four weeks, including concurrent plasma donations,

  7   without any requirements other than those applied

  8   to whole blood donors.

  9             Because most blood collection facilities

 10   utilize only infrequent plateletpheresis protocols,

 11   there is no need for them to obtain a source plasma

 12   license.  Note, however, that if blood collection

 13   centers do permit plateletpheresis donors to donate

 14   more frequently than every four weeks, then, they

 15   must meet the same requirements as for source

 16   plasma donors.

 17             The AABB believes that FDA should permit

 18   the use of concurrent plasma for further

 19   manufacturing without requiring a source plasma

 20   license, when the concurrent plasma is collected

 21   using an infrequent donation protocol. Further,

 22   such plasma should be acceptable  even if it was

 23   originally labeled and intended for use as FFP.

 24             Following this same logic, it should be

 25   acceptable to convert plasma that is derived from 

                                                               169

  1   whole blood donors that was originally collected

  2   and labeled as FFP to plasma for further

  3   manufacture.  The current requirements permit this

  4   only after the FFP reaches the expiration date, and

  5   for FFP, this is one year after collection.

  6   However, plasma fractionaters  will not accept

  7   year-old plasma, so the FFP is wasted.

  8             A second concern relates to the confusion

  9   about record retention requirements.  Because

 10   recovered plasma is not a licensed product, it does

 11   not have an established expiration date.  Blood

 12   banks are now required to keep records indefinitely

 13   for any product without an expiration date.  All

 14   licensed blood components have defined expiration

 15   dates and these dates determine the record

 16   retention requirements.  Recovered plasma should be

 17   assigned an expiration date.

 18             Third, the AABB believes that there is no

 19   need to distinguish between recovered plasma and

 20   source plasma based on donor suitability.

 21   Recovered plasma donors have established donor

 22   suitability requirements, as they must meet the

 23   same criteria as whole blood donors.  These same

 24   requirements apply to plateletpheresis and

 25   concurrent plasma donation. 

                                                               170

  1             As you will hear later today, the plasma

  2   industry has worked closely with the whole blood

  3   community to develop a new donor history

  4   questionnaire.  The proposed new questionnaires

  5   will simplify the questions and make them more

  6   readily understandable.

  7             There will remain some differences in that

  8   questions that are applicable to components

  9   containing red cells are not always applicable to

 10   donations of plasma, but the donor questions are

 11   comparable, and the distinction between recovered

 12   plasma and source plasma is no longer necessary.

 13             Likewise, requirements for testing for

 14   infectious disease agents for both recovered plasma

 15   and source plasma are comparable.  FDA may wish to

 16   continue the requirements for testing designed to

 17   protect the health of frequent plasma donors, and

 18   the AABB would support that approach.

 19             Finally, the AABB points out that

 20   facilities collecting recovered plasma are subject

 21   to stringent voluntary standards, including

 22   standards for quality assurance.

 23             The AABB has been setting voluntary

 24   standards for blood banks and transfusion services

 25   for more than 50 years.  Our standards include 

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  1   quality management concepts with the quality

  2   management system providing the framework for the

  3   organization of the standards.

  4             The general quality standards appear at

  5   the beginning of each of the 10 chapters followed

  6   by more specific requirements that address the

  7   elements of the facilities' day-to-day operations.

  8             The technical standards are based on

  9   current scientific and medical data when available,

 10   and are developed using an evidence-based decision

 11   making process when possible.  The BBTS Standards

 12   are updated on a regular basis based on input from

 13   AABB members, the public, and recognized experts in

 14   blood banking and transfusion medicine.

 15             Therefore, recovered plasma is subject to

 16   the same standards as whole blood.  Other products

 17   such as FFP have been licensed by the FDA and

 18   recovered plasma should also be eligible for

 19   licensure.  The AABB does note that the Plasma

 20   Protein Therapeutics Association has implemented

 21   standards for source plasma collection.  Therefore,

 22   source plasma also meets stringent standards.

 23             The AABB appreciates this opportunity to

 24   present our thoughts on standards for recovered

 25   plasma.  We are prepared to cooperate with the FDA 

                                                               172

  1   and others in developing comprehensive up-to-date

  2   standards for this valuable resource.

  3             Thank you.

  4             DR. NELSON:  Thank you, Kay.

  5             Questions?  Yes, Judy.

  6             DR. LEW:  Has the AABB started studies to

  7   look at the difference between recovered plasma and

  8   source plasma?

  9             MS. GREGORY:  I think, as you heard from

 10   Dr. Whitaker, we have been in a dialogue

 11   considering some of these issues for about 18

 12   months, I think, and we are still continuing that

 13   dialogue.

 14             DR. LEW:  But not studies have been done,

 15   you are just talking about it.

 16             MS. GREGORY:  We are just talking.  We are

 17   not going to do scientific studies.  We may

 18   identify studies that need to be done, but this

 19   particular group is not a group that would do

 20   actual studies.

 21             DR. LEW:  I guess the follow up to that,

 22   though, is that clearly, there may be differences,

 23   and you are recommending FDA set up some standards

 24   without good studies to guide them, unless they

 25   have been done and it just needs to be looked at. 

                                                               173

  1             What are these standards going to be

  2   without scientific evidence to back them up?

  3             DR. SIMON:  I think there are studies that

  4   characterize the two types of plasma in the old

  5   literature. I don't want to imply that I am back

  6   into it as much as Dr. Finlayson, but I believe

  7   that there are a fair number of studies back there,

  8   are there not, that compare the two of them?

  9             DR. FINLAYSON:  Step over to the

 10   blackboard, please.  The answer is yes, but my take

 11   for the modern era would be that the fractionaters

 12   would prefer to have material regardless of what

 13   name was put on it and, as we just heard, maybe we

 14   have to use some name other than recovered plasma

 15   because maybe it implies that it was sick once and

 16   just got better.

 17             But if it were frozen soon after

 18   collection and maintained in a frozen state, and

 19   let's say for the sake of consistency, maintained

 20   below minus 18 degrees Celsius, I would be

 21   surprised if one would be able to find any

 22   differences between products made from it and made

 23   from source plasma.

 24             So, the answer to your original question

 25   is yes, there are studies and there are data 

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  1   available, but they resulted from this

  2   heterogeneous array of storage conditions of the

  3   plasma itself, and I suspect that one could solve

  4   the problem largely by circumventing it today and

  5   just going rapidly to a frozen state.

  6             DR. NELSON:  What proportion of recovered

  7   plasma is fresh frozen plasma because that, it

  8   seems to me, would be quite comparable in storage

  9   conditions to source plasma, right?

 10             DR. FINLAYSON:  Are you directing that

 11   question to me?

 12             DR. NELSON:  Anybody.

 13             DR. FINLAYSON:  I certainly don't know the

 14   answer and, at the risk of plagiarizing, it is

 15   really Dr. Klein's question revisited.

 16             DR. KLEIN:  I can say with great

 17   confidence I don't know the answer either, John.

 18   There are some other slight differences that may

 19   not be physiologically important, and that is that

 20   there is a difference in the volume of

 21   anticoagulant, so there is a dilution difference,

 22   and in the nature of the anticoagulant, as well,

 23   between plasmapheresis, plasma, and plasma that is

 24   removed from whole blood.

 25             DR. NELSON:  As has been pointed out, 

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  1   there may be some differences in the donors, but I

  2   guess the implication was that that wouldn't have a

  3   major effect on the end product.

  4             DR. DiMICHELE:  Thank you, by the way.

  5   This clears up a lot of the questions that we had,

  6   but you sure presented a catch-22 here, because,

  7   you know, at one point I am thinking that there is

  8   a lot of recovered plasma that is being sent to

  9   manufacturers.  At this point, I am beginning to

 10   feel that you are hardly collecting anything

 11   because of the catch-22 that you presented.

 12             In other words, a lot of what you would

 13   recover from whole blood that meets the standards,

 14   you can't really sell to manufacturers because they

 15   don't want year-old plasma.

 16             MS. GREGORY:  Well, that is only if we

 17   have originally labeled it as fresh frozen plasma.

 18   If, when we collect the whole blood, we don't make

 19   fresh frozen plasma, we can make that into

 20   recovered plasma.

 21             DR. DiMICHELE:  I see.  Okay.

 22             MS. GREGORY:  So, I am looking for ways to

 23   augment the supply.

 24             DR. NELSON:  But if it was frozen, it

 25   would be labeled fresh frozen plasma. 

                                                               176

  1             MS. GREGORY:  Yes, if it was frozen.

  2             DR. NELSON:  So, if it was collected and

  3   stored the same way that source plasma would be,

  4   then, it couldn't be used because it would be

  5   expired.  It's crazy.

  6             DR. DiMICHELE:  My second question then is

  7   applicable.  What percent of the potential

  8   additional plasma that blood banks could collect is

  9   actually being collected as recovered plasma, or,

 10   in other words, the corollary is, is how much

 11   additional plasma would be collectable if these two

 12   catch-22 issues that you referred to, the two major

 13   ones, are no longer issues?

 14             MS. GREGORY:  I think there is a potential

 15   for concurrent plasma, that is, plasma that is

 16   collected along with another product that is

 17   intended for transfusion.  I think there is a fair

 18   amount of potential in that area.

 19             There is probably less potential in what

 20   we collect now as fresh frozen plasma and then to

 21   find perhaps we don't need it for that, but the

 22   concurrent plasma, I believe there is a huge

 23   potential for.

 24             DR. DiMICHELE:  Do you have a sense of how

 25   much additional plasma that would provide compared 

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  1   to what you can now?

  2             MS. GREGORY:  I don't know if anyone in

  3   the audience might have a feel for that, but I

  4   don't.

  5             DR. ALLEN:  Two questions.  Just going

  6   back to the issue of the fresh frozen plasma versus

  7   recovered plasma, I am assuming that if a unit of

  8   plasma is not labeled immediately as fresh frozen

  9   plasma, that the blood centers can't go back, I

 10   mean if they then need more fresh frozen plasma,

 11   they can't go back subsequently.

 12             MS. GREGORY:  That's correct.

 13             DR. ALLEN:  That really does present a

 14   catch-22, and I guess I would like to know--and I

 15   am not asking for an answer, I am sort of stating a

 16   question--why is it an issue that one can't take

 17   fresh frozen plasma at some point X number of

 18   months, but less than 12 months, and reconvert it

 19   back to recovered plasma?

 20             The second question then is with the

 21   increasing use of red cell pheresis and double-unit

 22   collections, my understanding is that one of the

 23   tradeoffs with being able to take off two units of

 24   red cells is that the plasma is reinfused into the

 25   patient, is that correct? 

                                                               178

  1             MS. GREGORY:  I believe that is usually

  2   the case.

  3             DR. ALLEN:  I am just wondering if one

  4   wanted then to collect more plasma, can that be

  5   done at the same time during the double-unit red

  6   cell pheresis, or is that a physiologic tradeoff

  7   that the donor gets the plasma back. Maybe that

  8   needs to be addressed to somebody else, but it

  9   seemed to be pertinent to this discussion.

 10             DR. KLEIN:  Jim, you can't do that, but

 11   with many of the new instruments coming out, you

 12   can collect red cells in plasma, red cells,

 13   platelets in plasma, you can do a variety of

 14   different things that will allow you to collect

 15   plasma concurrently, and clearly, this is a growing

 16   area with the new instrumentation by different

 17   manufacturers, so that it is probably important to

 18   define what that plasma is and certainly not to

 19   lose it.

 20             DR. SCHMIDT:  The AABB seems to be the big

 21   objector to the name, and what name do you suggest,

 22   and what can you suggest instead of concurrent

 23   plasma while you are at it, by the way, because

 24   that is a loser?

 25             MS. GREGORY:  Yes, we think that's a lousy 

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  1   name.  We actually don't have a suggestion.  We

  2   just think that maybe because there is so much

  3   confusion surrounding recovered plasma, that

  4   somebody could come up with a better name, and we

  5   are willing to think about it, but we don't have a

  6   suggestion to make right now.

  7             DR. SCHMIDT:  Not here.

  8             MS. GREGORY:  No.

  9             DR. SIMON:  What about just plasma?

 10             [Laughter.]

 11             MS. GREGORY:  Well, I have to be honest.

 12   The whole definition of the various kinds of plasma

 13   is extremely confusing.

 14             DR. HOLLINGER:  Kay, just a couple of

 15   questions. The recovered plasma that is obtained, I

 16   mean when a person donates whole blood, very few

 17   people are using whole blood for transfusions, so

 18   it is separated into its components.

 19             Is the recovered plasma invariably frozen

 20   at that point anyway, or is it kept, and if it is

 21   kept at refrigerated temperatures, why is it kept

 22   at refrigerated temperatures, what is its purpose

 23   at that point if it's not freshly frozen?  That's

 24   the first question.

 25             MS. GREGORY:  I don't know.  I think most 

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  1   of it is frozen pretty quickly, but it depends on

  2   what is in your short supply agreement and what

  3   your manufacturer tells you they want you to do.

  4             DR. HOLLINGER:  But it could be used as

  5   fresh frozen plasma if the components are separated

  6   and it's frozen down immediately.

  7             MS. GREGORY:  Not if it isn't frozen under

  8   the conditions that you are required to use for

  9   making fresh frozen plasma and labeled as fresh

 10   frozen plasma.  So, I think what you are asking is

 11   could I have a product and call it source plasma,

 12   and then convert it into fresh frozen plasma, and

 13   right now, no, you couldn't do that.

 14             DR. HOLLINGER:  And the plasma that is

 15   collected, the standards are, what, that it has

 16   been to be frozen at a certain temperature, but it

 17   also has to be frozen how soon after collection?

 18             MS. GREGORY:  That depends on the method

 19   of collection, so there is no one answer, but there

 20   are defined standards that it must be frozen and

 21   what temperatures and within what amount of time.

 22             DR. HOLLINGER:  As I read sort of the

 23   things that you have mentioned here, you have

 24   several things that you would like to see perhaps

 25   done.  One is you just mentioned about concurrent 

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  1   plasma, you could use it as further manufacturing

  2   as source plasma, and I think the issue about

  3   whether it is called fresh frozen plasma and it is

  4   used later, that is another issue.

  5             I take it fresh frozen plasma, if it is

  6   stored for a year, you said the manufacturers will

  7   not take it.

  8             MS. GREGORY:  Yes.

  9             DR. HOLLINGER:  And is the reason they

 10   won't take it, is there something in the standards

 11   that they have, that says they can't take it after

 12   a year?

 13             MS. GREGORY:  I can't answer that

 14   question, I don't know.

 15             DR. HOLLINGER:  You also felt that the

 16   recovered plasma should be assigned an expiration

 17   date.

 18             MS. GREGORY:  Yes.

 19             DR. HOLLINGER:  Do you have any thoughts

 20   about what expiration date?

 21             MS. GREGORY:  No, we just want there to be

 22   an expiration date.

 23             DR. HOLLINGER:  As Dr. Klein said, it

 24   depends on how it is stored.

 25             DR. NELSON:  They want to get rid of the 

                                                               182

  1   room full of records that they have, I guess.

  2             MS. GREGORY:  The warehouse is full of

  3   records.

  4             DR. NELSON:  Mike.

  5             DR. BUSCH:  A few clarifications.  FFP

  6   needs to be frozen within 8 hours.  FFP outdates in

  7   a year, so it is a fairly stable product, and blood

  8   centers are always able to sustain their required

  9   inventories of FFP, and everything else is

 10   maximized for recovered plasma, to sell it.

 11             So, most recovered plasma is also frozen

 12   quickly.  The only time it is frozen on a delayed

 13   basis, within 24 hours or slightly longer, is if

 14   there is a logistical issue, and you get less money

 15   for plasma that is not frozen at 8 hours versus 24.

 16   So, the whole system is maximized to be able to

 17   utilize the by-product recovered plasma, but there

 18   are these nuances, the FFP outdated product and the

 19   move toward concurrent plasma that do need I think

 20   the fixes you are discussing.

 21             DR. DiMICHELE:  Excuse me, can I ask you a

 22   question?  So then basically, if you have a blood

 23   bank and you are sort of looking at your

 24   projections and your collections through the year,

 25   and you say, okay, a certain amount of our plasma 

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  1   has to go into FFP because this is what our

  2   requirements are, the rest will go into recovered

  3   plasma for sale.

  4             DR. BUSCH:  Absolutely.

  5             MS. GREGORY:  Yes.

  6             DR. DiMICHELE:  So, the intent is not for

  7   transfusion.

  8             DR. BUSCH:  No, it will be specifically

  9   labeled as recovered plasma, so as you are hearing,

 10   you cannot label for FFP and then convert, so we

 11   will maximize the collection and the processing to

 12   maximize the amount of recovered plasma derivative.

 13             DR. DiMICHELE:  What I am saying is that

 14   the initial intent is to do just that.

 15             DR. BUSCH:  Of course.

 16             DR. KLEIN:  But the unit of blood is

 17   collected for transfusion, and so therefore,

 18   because of the intent, it is not source plasma that

 19   is recovered.

 20             DR. SCHMIDT:  I think it used to be your

 21   FFP after one year, you could change the label and

 22   call it frozen plasma, and then it had a five-year

 23   date.  This would be in the hospital setting, so

 24   you would use that for your other patients.

 25             Does that still exist, and does that enter 

                                                               184

  1   into this discussion?

  2             MS. GREGORY:  I believe it still exists.

  3   I can't tell you whether or not that product is

  4   actually used in hospitals.

  5             DR. SCHMIDT:  It might be an avenue to get

  6   it into recovered, but you are looking for less

  7   avenues rather than more.

  8             MS. GREGORY:  Yes.

  9             DR. HOLLINGER:  John, just a question.

 10   Were you saying that with the kallikrein and other

 11   things which might cause some activation,

 12   fragmentation of immune globulin, is that going on

 13   in the frozen state also?

 14             DR. FINLAYSON:  No.

 15             DR. HOLLINGER:  Thank you.

 16             DR. NELSON:  You didn't cite any old

 17   literature.

 18             DR. FINLAYSON:  Well, as a matter of fact,

 19   there have been studies done on both ends, both on

 20   plasma that was stored frozen and the made into

 21   product, and looking for pre-kallikrein activator,

 22   and there have been studies of the immune globulin

 23   stored out of its intended temperature range,

 24   namely, stored frozen, so that one could do a

 25   controlled experiment with immune globulin frozen 

                                                               185

  1   at the normal refrigerator temperature, which would

  2   be within its labeled range of 2 to 8 degrees

  3   Celsius, compared with that frozen, compared with

  4   that stored at room temperature, compared with that

  5   stored at elevated temperature.

  6             For all practical purposes, one does not

  7   get any fragmentation whatsoever in the material

  8   that is stored in the frozen state even if that

  9   which is stored at higher temperatures shows

 10   fragmentation.

 11             DR. KLEINMAN:  Steve Kleinman.  Maybe I am

 12   missing something here but both recovered and

 13   source plasma ultimately get made into plasma

 14   derivatives.  Each plasma derivative presumably has

 15   to meet some kind of lot release specification.

 16   So, ultimately, whether or not you use studies on

 17   the starting material, you need to at least reduce

 18   a final material that meets FDA qualifications for

 19   release.

 20             So, I think while it is interesting to

 21   speculate about whether these things are equivalent

 22   or not, we do have some quality in place, and that

 23   is the final released product.  I am not arguing

 24   against standards for storage, but I think we are

 25   missing the boat when we think that we are not 

                                                               186

  1   assaying these things because I think we are down

  2   at the end, which is important.

  3             Now, maybe the efficiencies are different

  4   from the starting material, but we do have end

  5   products that meet minimal requirements.

  6             DR. NELSON:  But I understand that

  7   currently, plasma that is collected as recovered

  8   plasma, some of it is discarded based on current

  9   regulations.

 10             DR. SIMON:  They brought up some issues

 11   where they haven't been able to optimally use it,

 12   but it is not regulation, it is the manufacturer's

 13   requirement, it is not FDA that won't let them

 14   relabel it, it is the manufacturer that won't take

 15   it at one year, and that is just the manufacturer's

 16   requirements.

 17             DR. NELSON:  Celso Bianco from America's

 18   Blood Centers.

 19             Celso, you have changed.

 20                               ABC

 21             MS. DARIOTIS:  Thank you.  My name is

 22   Jeanne Dariotis.  I am the president of America's

 23   Blood Centers.  We had an error in who was going to

 24   speak today.

 25             In my other life or my paid life, I am the 

                                                               187

  1   CEO of a community blood center, Southeastern

  2   Community Blood Center in Tallahassee, Florida, so

  3   I am a little nervous to say that I know probably

  4   quite a bit about making recovered plasma because

  5   it is a lot of what our blood centers do.

  6             America's Blood Centers, or ABC, is a

  7   national network of locally-controlled, non-profit

  8   community blood centers that provide half of the

  9   U.S. blood supply from volunteer donors.

 10   Collectively, we operate in 45 states and serve

 11   more than half of the nation's 6,000 hospitals.

 12             America's Blood Centers' total blood

 13   collections exceeded 7 million donations in 2001,

 14   and we shipped over 1 million liters of recovered

 15   plasma from volunteer donors for manufacture into

 16   plasma therapeutics..  These shipments that we make

 17   are made either through ABC, through Blood Centers

 18   of America, through plasma brokers, or are shipped

 19   directly to pharmaceutical manufacturers.

 20             American's Blood Centers thanks the FDA

 21   for the opportunity to participate in this public

 22   discussion about recovered plasma.  Recovered

 23   plasma is the only blood component manufactured by

 24   FDA licensed blood establishments that does not

 25   have direct FDA oversight.  Instead, recovered 

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  1   plasma is regulated through "short supply

  2   agreements" signed between the supplier of the

  3   recovered plasma and the pharmaceutical

  4   manufacturer or plasma therapeutics.

  5             The specifications in these agreements are

  6   part of a product master file maintained by the

  7   pharmaceutical manufacturer.  The concept of

  8   regulation by short supply agreements was created

  9   many years ago when plasma was literally recovered

 10   from expired whole blood and manufactured into

 11   albumin and other plasma products.

 12             This indirect mode of regulation is out of

 13   pace with FDA's more recent and extensive

 14   application of drug cGMPs to blood establishments.

 15   It is also inconsistent with the strict regulation

 16   of source plasma.

 17             Today's recovered plasma is the plasma

 18   retrieved from whole blood collections remaining

 19   after the blood center has fulfilled its patient

 20   needs for plasma for transfusion.  Plasma for

 21   transfusion produced under FDA license constitutes

 22   about 20 percent of all the plasma produced by

 23   blood centers.

 24             Although the name recovered plasma implies

 25   a lower value, in fact, as a starting material for 

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  1   manufacture into plasma therapeutics, recovered

  2   plasma generally has higher protein content and

  3   higher levels of IgG than source plasma.

  4             Until the early 1990s, the traditional

  5   view of recovered plasma as a waste product, the

  6   lack of FDA oversight, and the low reimbursement

  7   received from brokers and manufacturers provided

  8   very little incentive for blood centers to give

  9   this product the same attention as blood components

 10   for transfusion.  In the 1990s, two factors

 11   radically changed the traditional view of recovered

 12   plasma.

 13             Shortages of plasma in the world market

 14   caused by increased demand, new donor deferrals,

 15   and the vigorous enforcement of cGMPs by FDA.

 16             As a result, plasma therapeutics

 17   manufacturers improved their quality systems, short

 18   supply agreements became far more detailed and

 19   manufacturers initiated vendor qualification

 20   programs that included inspections of the

 21   collecting facilities.

 22             Blood centers also made substantial

 23   investments in quality systems, software and

 24   facilities applied to all blood components,

 25   including recovered plasma.  Finally, AABB has 

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  1   included recovered plasma into its recently

  2   published 21st edition of its Standards for Blood

  3   Banks and Transfusion Services, and blood banking

  4   organizations and the Plasma Protein Therapeutics

  5   Association have been working together on voluntary

  6   standards for recovered plasma.

  7             Despite the many improvements made by the

  8   private sector, ABC members believe that recovered

  9   plasma must be subjected to the same regulatory

 10   scrutiny and licensure requirements as plasma for

 11   transfusion, in order to assure the highest quality

 12   for plasma therapeutics.  ABC also believes that

 13   this can be achieved through simple changes in

 14   current regulations, and we have a few suggestions.

 15             First, we think that FDA regulations

 16   should be modified to require that all plasma

 17   shipped for manufacture into plasma therapeutics be

 18   licensed by FDA.  The new regulations would also

 19   specify that such licensed products could be either

 20   source plasma or plasma for transfusion derived

 21   from whole blood or apheresis collections.

 22             We request that FDA provide a mechanism to

 23   allow the shipment for further manufacture of

 24   certain plasmas that do not qualify for transfusion

 25   in order to meet the manufacturers' requirements 

                                                               191

  1   and increase the plasma availability.

  2             For instance, plasma derived from whole

  3   blood that is reactive for antibodies to the core

  4   antigen of hepatitis B is needed to guarantee

  5   minimum levels of antibodies to ensure product

  6   safety.  Also, plasma from individuals who traveled

  7   to a malarial area can be safely transfused for

  8   further manufacture because the parasite does not

  9   survive fractionation.

 10             In order to protect blood donors, the new

 11   regulation allowing shipment of plasma for

 12   transfusion for further manufacture would only

 13   apply to infrequent whole blood and plasma

 14   collections currently licensed by FDA.  FDA should

 15   continue to require source plasma licenses for

 16   establishments that perform frequent

 17   plasmapheresis.

 18             The product name "recovered plasma" would

 19   disappear and short supply agreements would merge

 20   into plasma therapeutics manufacturers' product

 21   specifications for source material.

 22             ABC members believe that these changes

 23   would increase the availability of high quality

 24   plasma for further manufacture, would extend FDA

 25   oversight to all products manufactured by a 

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  1   collection facility and would not interfere with

  2   voluntary standards such as those developed  by

  3   AABB and by PPTA.

  4             We also believe that the change would

  5   facilitate the handling and processing of our

  6   plasma by derivatives manufacturers and relieve

  7   them, at least partially, of some of their

  8   regulatory burden.

  9             Thank you very much for the opportunity to

 10   present our point of view.  One statement that I

 11   wanted to reiterate, blood centers generally, all

 12   of our collections are driven by our need to

 13   collect whole blood or red blood cells, and so we

 14   do not normally set out to recruit more recovered

 15   plasma donors.  What we are out to do is recruit

 16   more blood donors, and in the process, we end up

 17   with more plasma.

 18             Thank you.

 19             DR. NELSON:  Thank you, Jeanne.

 20             Mary.

 21             DR. CHAMBERLAND:  I just wanted to follow

 22   up with a question to you regarding Suggestion No.

 23   2, your example that plasma derived from whole

 24   blood that is reactive to core antibodies would be

 25   allowed to be used for further manufacturing into 

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  1   derivatives.

  2             You also give the malaria example.  It

  3   relates because one of the questions that we are

  4   going to be asked to ultimately vote on has to do,

  5   the way it is phrased currently is should standards

  6   for recovered plasma include negative screening

  7   tests for anti-core and anti-HTLV.

  8             MS. DARIOTIS:  I am not an expert in the

  9   field, but currently we provide the core-positive

 10   units for the manufacturer's benefit to have more

 11   antibody present, so that question is not something

 12   I--

 13             DR. CHAMBERLAND:  I understand that.  I

 14   guess the question I actually had for you is what

 15   is your sense of blood collection centers' ability

 16   to kind of address some additional complexities,

 17   namely, that you would have blood donors that

 18   would--how do I put this--would you almost in a

 19   sense have two kinds of blood donors, those that,

 20   for example, if they travel to malarial areas, they

 21   would not qualify as a blood donor, but would be

 22   deferred, or if they tested positive for core

 23   antibody, they would be deferred.

 24             Are you proposing that, in some instances--

 25             MS. DARIOTIS:  An explanation to that is 

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  1   we end up, we draw donors, and at the end of the

  2   testing, we find that some of our donors are core-positive,

  3   we would like the ability, we think that

  4   the ability should still be there to ship those, I

  5   call them "accidentally found" core units.

  6             If you were going to set out to draw core-positive

  7   donors, I think you would then be talking

  8   about a source plasma license.

  9             DR. CHAMBERLAND:  I understand that.  The

 10   malaria travel--

 11             MS. DARIOTIS:  Again, it would be the same

 12   thing, that if your blood center had the ability to

 13   control your products adequately, that you could

 14   assure that you were destroying the products that

 15   would be a risk with the malaria, then, you would

 16   have the option to supply the plasma.  I think that

 17   gets back to the blood centers' ability to control,

 18   if your blood centers' systems and processes would

 19   not allow it to do that with a fair amount of

 20   confidence, then, I would think the blood center

 21   would choose not to provide those products.  Some

 22   could do it, some could not.

 23             DR. SCHMIDT:  Jeanne, your statement says

 24   that recovered plasma generally has a higher 

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  1   protein content and higher levels of IgG than

  2   source plasma, and my recollection is the whole

  3   idea of measuring protein levels and IgG levels

  4   when plasmapheresis got started was an idea that

  5   was based on no data, that this was an important

  6   thing to do.

  7             I am wondering, maybe I should have asked

  8   the PPTA how functional is this with the source

  9   plasma people, are there donors who are frequently

 10   pheresed, whose total protein or IgG drops, and was

 11   that a good idea or could that whole thing be

 12   thrown out to make these two more equivalent?

 13             MS. DARIOTIS:  Dr. Schmidt, I think I will

 14   let Dr. Bianco comment, too, but I believe that the

 15   statement comes from the people that we are

 16   providing our products to, tell us that recovered

 17   plasma is more valuable to them for those issues,

 18   and I would leave it to them to establish that.

 19             DR. WHITAKER:  We have done some studies

 20   with frequent donors that have been published in

 21   Transfusion, and found that while regular frequent

 22   plasmapheresis donors sometimes have slightly lower

 23   total proteins and individual proteins, that they

 24   are within the allowed range by the regulations.

 25   Then, of course, if they are not, then they are 

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  1   deferred a certain amount of time.

  2             DR. SCHMIDT:  Is it something that

  3   happens, is it worthwhile doing these tests on your

  4   donors?

  5             DR. WHITAKER:  I think that there are

  6   times when donors do or I know there are times when

  7   donors do have total proteins lower than the

  8   required levels, and they should be deferred.

  9             DR. SCHMIDT:  Thank you.

 10             DR. KLEINMAN:  I wanted to follow up on

 11   Mary's question about the anti-core content of

 12   recovered plasma. It is really a question to FDA.

 13             I think the requirement is in place or the

 14   procedure in 1987, when anti-core testing was first

 15   done was to say if we don't ship these anti-core

 16   positive units, we will take all the anti-HBS out

 17   of the donor pool and that will give less

 18   protection for our plasma products.

 19             But I wonder, 15 years later, now that

 20   more people are getting vaccinated for hepatitis B,

 21   whether we still need that requirement to ship

 22   anti-core positive units and whether we would have

 23   sufficient anti-HBS in a pool of products that no

 24   longer contained anti-core positive units just from

 25   vaccine-induced immunity, which, of course, 

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  1   everybody knows those people will come up negative

  2   on anti-core.

  3             So, has anybody looked at this?  Are there

  4   any plans to reexamine that requirement or do

  5   studies?  I mean it really should be very

  6   straightforward just doing anti-HBS levels in

  7   recovered plasma units and assaying a few pools and

  8   seeing that they meet the FDA requirements.

  9             Celso says what about source plasma.  I

 10   think you could do the same thing for source

 11   plasma.  So, I guess, as long as this is being

 12   opened up into looking at plasma requirements in

 13   general, you know, I would put this on the agenda

 14   as something that ought to be looked at.

 15             DR. HOLLINGER:  Steve, just in comment, as

 16   you know, most of the vaccine is going into

 17   infants, so you are talking about a couple of

 18   decades down the line, you know, as one point.  The

 19   other point is since there is no boostering of this

 20   antibody, it is going to be a fairly low

 21   concentration in my opinion by the time an infant

 22   gets to an adult age and they become a donor.

 23             DR. KLEIN:  Blaine, I certainly think you

 24   would have to look at it to know the answer, but

 25   just a couple of comments.  Certainly, medical 

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  1   health care workers who comprise several percent of

  2   donors, most of them have been vaccinated and

  3   within the last decade.  So, I think that there may

  4   be a source of vaccinated donors, and now

  5   adolescents are being or school age children are

  6   being vaccinated, not infants.

  7             So, I think that conceivably, there is

  8   more anti-HBS titer in the donor pools than you

  9   might think, and we just need to look at it.  I

 10   don't know how it would come out, I am just

 11   suggesting that we have a possible change in the

 12   anti-HBS content of donor pools that we could study

 13   if somebody wanted to fund that.

 14             DR. FINLAYSON:  First, I would like to ask

 15   is there a representative from Bayer that would

 16   like to address that question.  I guess not.  The

 17   reason I asked that question is because at a

 18   meeting of the Blood Products Advisory Committee in

 19   1989, I believe it was October 31st if memory

 20   serves, a representative from Bayer did so.

 21             There were very nice data presented that

 22   dealt with several aspects of collection, one of

 23   which was that at the time when AIDS was on the

 24   rise and there was no specific tests for what today

 25   we call HIV, people were trying a large number of 

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  1   surrogate tests.

  2             One of those that the corporation

  3   introduced was that for anti-HBC, and the result

  4   was that the plasma pool, and consequently the

  5   immune globulin intravenous, ended up with very low

  6   levels of anti-HBS, which is what had been alluded

  7   to here.

  8             When that information was made public, it

  9   was also accompanied by a fair amount of data

 10   showing that as other tests had been introduced,

 11   there was sometimes also a concomitant decrease in

 12   the level of anti-HBS.

 13             The result was it was considered not only

 14   desirable, but actually necessary to include a

 15   certain number of vaccinated, that is, vaccinated

 16   for hepatitis B donors in the donor population that

 17   would be used for the pools.  So, the experiment

 18   has already been done.

 19             DR. SIMON:  I just wanted to clarify.  It

 20   is strictly optional to the blood center whether

 21   they ship core-positive or not units, is that not

 22   correct?

 23             MS. DARIOTIS:  That is correct.  Usually,

 24   your short supply agreement will request that you

 25   ship them, but the blood center can elect not to if 

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  1   they can't properly control the process.

  2             DR. FINLAYSON:  I would like to

  3   corroborate that. What the FDA recommendation is,

  4   is that it not be withheld from the pools, and that

  5   one need not label it if one is shipping it for the

  6   manufacturer, but there is not an FDA requirement

  7   to include such plasma in the fractionation pools.

  8             DR. SIMON:  The only other thing I wanted

  9   to clarify from the industry point of view, there

 10   are donors who are specifically collected as source

 11   plasma donors for their high titers, hepatitis B

 12   surface antibody, and the presumption is--some of

 13   this is proprietary information--but that that can

 14   be added to the IVIG product to raise the levels or

 15   IMIG product.

 16             DR. NELSON:  Thank you.

 17             From the American Red Cross, Don Fipps.  I

 18   think after this one, we will break for lunch.  I

 19   am told that in 20 minutes, lunch will no longer

 20   meet FDA requirements for consumption.

 21                               ARC

 22             MR. FIPPS:  Good afternoon.

 23             The American Red Cross is pleased to have

 24   the invitation to speak regarding recovered plasma

 25   standards to the Food and Drug Administration's 

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  1   Blood Products Advisory Committee.

  2             The American Red Cross collects more than

  3   6 million units of blood from volunteers each year

  4   in the United States.  The donated blood is also

  5   fractionated into plasma derivatives.  I am Don

  6   Fipps, Vice President, Quality Assurance Blood and

  7   Plasma Operations in Biomedical Headquarters, and I

  8   am responsible for the quality of blood and plasma

  9   distributed by the American Red Cross.

 10             The American Red Cross agrees that there

 11   should be standards for recovered plasma.  We

 12   recommend that the FDA use the standards of whole

 13   blood collections for that of recovered plasma.  We

 14   believe that these standards can and should be

 15   different from that of source plasma.

 16             Source plasma and recovered plasma are

 17   collected from two different sources of donors

 18   using different collection and frequency standards.

 19   As these processes are different, so should the

 20   standards associated with the resulting products to

 21   ensure a safe material for further manufacturing

 22   into licensed plasma derived products.

 23             We believe the current high standards for

 24   whole blood collection, testing, and processing

 25   results in very safe transfusionable blood and 

                                                               202

  1   blood products.  Recovered plasma benefits from

  2   these high levels of safety requirements.  The

  3   product comes from a volunteer donor as frequently

  4   as once every 56 days.

  5             The donor is qualified through a health

  6   history and mini-exam.  Within the ARC, the

  7   confidential unit exclusion is also used as an

  8   additional check on the motive of the donor.

  9   Safety testing currently includes testing for HIV-1

 10   by both nucleic acid testing and antibody HIV-2

 11   antibody, hepatitis C by both nucleic acid testing

 12   and antibody.

 13             Only whole blood donors are also tested

 14   for antibody to hepatitis B core, the antigen to

 15   hepatitis B and for other retroviruses, HTLV-I and

 16   II antibody.  Additionally, all whole blood donors

 17   are also currently tested at each donation for

 18   syphilis and unexpected red cell antibody.

 19             We believe that the current processes used

 20   in the industry to attract, medically screen

 21   donors, and using very sensitive tests makes

 22   recovered plasma a very safe product. Accepting

 23   donations from volunteers provides a level of

 24   assurance that donors will not provide anything

 25   other than accurate answers to the health history 

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  1   questions.

  2             As stewards of the gracious donation of

  3   volunteer whole blood from our donors, we use the

  4   plasma recovered from manufacturing to make

  5   critical and life-saving plasma-derived products.

  6   The American Red Cross currently manufactures

  7   recovered plasma through contracts with Baxter

  8   BioScience and ZLB Bioplasma, AG, into albumin,

  9   immune globulin and antihemophilic factor.

 10             Specifications for starting materials

 11   among all the manufacturers of plasma derivatives

 12   are highly variable nationally and worldwide.  For

 13   example, recovered plasma, the Red Cross processes

 14   with Baxter BioScience follows a specification in

 15   which only plasma frozen within 24 hours after

 16   collection may be used, whereas, ZLB Bioplasma, AG,

 17   has a different specification that allows for

 18   plasma to be frozen greater than 24 hours but less

 19   than 120 hours after collection.

 20             The Red Cross supplies intermediate

 21   products, Fraction IV-1 paste, to Bayer, and again

 22   we have detailed and extensive requirements for

 23   that starting material, as well.

 24             Storage temperatures for recovered plasma

 25   are also varied in that, for plasma from which 

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  1   antihemophilic factor will be produced, the storage

  2   temperatures must be maintained at minus 20 degrees

  3   or colder versus a specification as warm as minus 5

  4   degrees Centigrade when plasma is intended for

  5   albumin and immune globulin.

  6             Temperature variations also occur between

  7   what is expected in the U.S. at minus 18 degrees,

  8   and what is accepted in Europe at minus 20 degrees.

  9   The age of the recovered plasma used by the

 10   manufacturer is set by the specifications for the

 11   product being manufactured by the manufacturer.

 12             Through existing standards of whole blood

 13   collection, testing and processing, and

 14   specifications from plasma derivative

 15   manufacturers, which are different between each

 16   manufacturer and product, we believe that there is

 17   no need for further regulatory guidance at this

 18   time.

 19             If action is deemed necessary, the

 20   American Red Cross proposes that recovered plasma

 21   use, as an appropriate standard, that of whole

 22   blood collections.

 23             I would like to thank the FDA for the

 24   opportunity to present our statement to the Blood

 25   Products Advisory Committee.  The American Red 

                                                               205

  1   Cross is willing to work with the government and

  2   industry on recovered plasma.

  3             I would like to thank you for allowing me

  4   to do this today.  There are a couple of issues

  5   that I would like to define for the American Red

  6   Cross.  The American Red Cross does have a national

  7   donor deferral registry where we collect all of our

  8   deferred donors in, however, that is not shared

  9   with other blood agencies in the United States or

 10   with PPTA at this time.

 11             Also, there was a question about

 12   concurrent plasma.  When the American Red Cross

 13   implements concurrent plasma collections in our

 14   system, we estimate that we will collect an

 15   additional 50,000 units annually from that.

 16             So, those are a couple of questions that I

 17   would like to clarify.  That is the end of my

 18   statement.

 19             DR. NELSON:  Thank you.

 20             DR. HOLLINGER:  Not necessarily a question

 21   here, but this is always very confusing to me, and

 22   I guess for the record, I will bring it up.

 23             That is, we have organizations that are

 24   seemingly speaking for each other, but then we see

 25   different questions raised.  The AABB apparently 

                                                               206

  1   supposedly speaks, initially, gave the impression

  2   that it was speaking for the American Red Cross and

  3   America's Blood Centers.  Then, we see America's

  4   Blood Centers have an issue they talk about, and

  5   the American Red Cross then has an issue, which is

  6   different from what we just heard from the AABB.

  7             I think this is very confusing.  We see it

  8   almost every meeting that comes here.  I think that

  9   is confusing to have those different viewpoints

 10   when one seems to be speaking for the same

 11   organization.

 12             I understand the American Red Cross is

 13   part of the AABB, is that correct?

 14             MR. FIPPS:  That is correct.

 15             DR. HOLLINGER:  America's Blood Centers

 16   are, too, and then at the same time, you have

 17   different proposals basically.  You don't feel that

 18   there should be any new regulations, whereas, that

 19   is not what I heard from the other presentations.

 20             MR. FIPPS:  Well, we just represent a

 21   portion of the AABB, so we don't represent a

 22   majority vote in that organization.  We agree with

 23   a lot of what Kay stated in her statement about the

 24   need to make other plasma products available for us

 25   to turn into recovered plasma for further 

                                                               207

  1   manufacturing.  We don't disagree with that one in

  2   the least.

  3             We agree with their quality standards and

  4   their regulations as far as the AABB goes.  The

  5   position of the Red Cross at this time is we don't--because

  6   we sell our recovered plasma to these

  7   manufacturers, we didn't think that their

  8   particularly additional regulatory guidance needs

  9   to come out now.  We will continue to work with

 10   industry to develop, on a voluntary basis, the

 11   standards, and we are working with them on that.

 12   But I appreciate your statement.

 13             DR. FITZGERALD:  Don, I just had one.

 14   From the time of making the recovered plasma until

 15   you ship it to the manufacturer, do you have any

 16   idea how long it is in storage at your facility

 17   before you ship it?

 18             MR. FIPPS:  Well, in our storage it is not

 19   very long.  It could be within one of our regions

 20   for a couple of days, and then we ship it through a

 21   third party, to Baxter, within a week.  Primarily,

 22   that is most of our products.

 23             The stuff going to Europe takes longer

 24   because it has to be containerized before it is

 25   sent overseas on a ship to Switzerland. 

                                                               208

  1             DR. FITZGERALD:  But less than a month?

  2             MR. FIPPS:  It could extend longer than

  3   that.  I don't think I have an average off the top

  4   of my head how long that is.  It is not a year, but

  5   it is usually within six months.

  6             DR. FITZGERALD:  In the second paragraph,

  7   you say, "We recommend FDA use the standards of the

  8   whole blood collections," but then you say you

  9   don't want more regulation.

 10             Are you saying that if you do have

 11   regulation, you would like it to be--

 12             MR. FIPPS:  Absolutely.  We think it is

 13   sufficient at this time.  If the decision is that

 14   regulations are needed, then, we propose that of

 15   whole blood be used for recovered plasma instead of

 16   overlaying source plasma requirements for that of

 17   recovered plasma, because there are different

 18   sources of material and different frequencies.

 19             So, that is our position on that.

 20             DR. CHAMBERLAND:  I guess I have to admit

 21   to a certain level of confusion, as well, on a

 22   different issue, and I am not sure it you are

 23   perhaps the right person to address it.

 24             What you have outlined here, the various

 25   agreements that you have with these various 

                                                               209

  1   manufacturers, there is a lot of variability, and I

  2   guess my understanding with that, FDA has

  3   regulatory requirements related to processing for

  4   the source plasma industry.

  5             Not to use this in a negative term, but in

  6   point of fact and reality, do those represent a

  7   certain kind of a minimum level of standards, and

  8   then the source plasma folks, with their agreements

  9   with various manufacturers, do they have to do

 10   something different depending on what the ultimate

 11   product is going to be?  Is this heterogeneity

 12   present in the source plasma industry, as well?

 13             DR. WHITAKER:  Would you repeat your

 14   question, please?

 15             DR. CHAMBERLAND:  I was just noting with

 16   interest that the Red Cross outlines, they have

 17   variable requirements related to various processing

 18   steps, time to be frozen, et cetera, depending on

 19   the individual agreement with the manufacturer and

 20   I guess the ultimate product at the end, and I was

 21   curious, in the source plasma industry, do you face

 22   these requirements, as well.

 23             I guess I had maybe an oversimplified view

 24   that the current FDA requirements for source plasma

 25   were kind of uniform, and it didn't matter based on 

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  1   the plasma-derived product at the end, that they

  2   weren't different.

  3             This suggests that there is actually a lot

  4   of different requirements and that maybe FDA's

  5   requirements sort of are some sort of kind of

  6   minimum requirement, but that you might be required

  7   to meet different specifications depending on who

  8   you are selling to and what the ultimate end

  9   product is.

 10             DR. WHITAKER:  Every customer has its own

 11   set of criteria, so sometimes those criteria are

 12   met by the FDA source plasma regulations, and

 13   sometimes there are requirements for additional

 14   temperature and storage characteristics.

 15             DR. CHAMBERLAND:  They go above and

 16   beyond.

 17             DR. WHITAKER:  Right.

 18             MR. FIPPS:  As I understand it, these

 19   requirements are all built into their plasma master

 20   file for each of these products that the

 21   manufacturers have to maintain and keep.

 22             MR. BULT:  My name is Jan Bult.  I am the

 23   president of PPTA.  I would like to add to Dr.

 24   Whitaker.  In this case, source plasma has to be

 25   frozen within 24 hours anyway, so I think that 

                                                               211

  1   answers the question.

  2             DR. BIANCO:  Celso Bianco, America's Blood

  3   Centers.

  4             Those differences are not critical

  5   differences about infectious disease testing or

  6   things, but what they are is, for instance, for the

  7   manufacturer, those people that manufacture solvent

  8   detergent treated plasma want plasma that was

  9   frozen within 8 hours.  That is the FFP standard,

 10   or frozen within 15 hours.

 11             Other manufacturers will accept plasma

 12   that is frozen within 24 hours, and many will want

 13   plasma that was removed from the red cell that

 14   actually is a new European standard being discussed

 15   that was removed from the red cells within 72

 16   hours.  Those are the variations that you see, or

 17   how it is shipped, what kind of units will go into

 18   a container, and how long it will be stored before

 19   it gets to the manufacturer, and things like that.

 20             DR. NELSON:  Other questions or comments?

 21             If not, it is lunch break.  There is also

 22   some other testimony.  I thought that if went

 23   through that, we wouldn't have lunch.

 24             Come back at 2:30, please.

 25             [Whereupon, at 1:25 p.m., the proceedings 

                                                               212

  1   were recessed, to be resumed at 2:30 p.m.]

  2                              - - - 

                                                               213

  1             A F T E R N O O N  P R O C E E D I N G S

  2                                                    [2:30 p.m.]

  3                       Open Public Hearing

  4             DR. NELSON:  Blood Centers of America.

  5   Laura McDonald.

  6             MS. McDONALD:  Thank you and good

  7   afternoon.

  8             My name is Laura McDonald and I am the

  9   director of Scientific Programs for Blood Centers

 10   of America.

 11             The statement today represents Blood

 12   Centers of America and its subsidiary, hemerica,

 13   and the 30 blood collection organizations in the

 14   United States that we provide services to.

 15             These organizations conduct over 3.7

 16   million whole blood and apheresis procedures each

 17   year.  They produce 525,000 liters of recovered

 18   plasma annually, from which almost 20 million grams

 19   of therapeutic proteins are derived. Many of these

 20   blood collection organizations also distribute the

 21   therapeutic derivatives that are manufactured from

 22   the plasma.

 23             The purpose of this statement today is to

 24   make certain points about the potential to license

 25   or to have standards for recovered plasma, and to 

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  1   encourage that any rulemaking take into

  2   consideration the practicalities of how blood is

  3   collected and processed by community blood centers.

  4             Specifically, we believe that plasma

  5   collected concurrently with apheresis procedures

  6   should be more easily directed for further

  7   manufacture into therapeutic proteins.

  8             Blood centers currently collect blood

  9   using two diverse technologies.  The first is the

 10   use of the plastic bag with integrated satellite

 11   pouches which permit the sterile separation of

 12   blood components in high speed centrifuges.

 13             The second is the use of cell separators

 14   which permit the separation of blood components in

 15   the centrifugal field while still connected to the

 16   donor.  Known as apheresis technology, this became

 17   prevalent in the early seventies for the production

 18   of platelets and is rapidly expanding today, with

 19   multiple component capacity from individual donors.

 20             Historically, plasma derived from whole

 21   blood not required for transfusion has been sold to

 22   pharmaceutical companies that can separate the

 23   therapeutic proteins from the plasma.  These

 24   transactions occur under the short supply agreement

 25   mechanism, which permits the shipment of unlicensed 

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  1   products for further manufacture.

  2             As apheresis technology improved and

  3   additional products could be produced concurrently

  4   with target products, the question of how

  5   concurrent plasma could be used was raised.

  6             Traditionally, the FDA has ruled that

  7   plasma derived as a concurrent product from an

  8   apheresis procedure must be used as a transfusion

  9   product if it is drawn under the whole blood rules.

 10   Only if source plasma rules are used in the

 11   selection of the donor and a source plasma license

 12   is in place can the concurrent plasma be used for

 13   further manufacture.

 14             The centers affiliated with us conducted

 15   over 350,000 apheresis procedures in 2001.  This

 16   represents an incredible potential to produce

 17   concurrent plasma for further manufacture.

 18             The current situation with dual

 19   requirements force the operator to make an

 20   either/or decision and since the primary purpose of

 21   the apheresis procedure is to produce a transfusion

 22   product, it is seldom that a concurrent plasma is

 23   even collected for further manufacture.

 24             Our donors have made it clear they wish us

 25   to create the maximum therapeutic benefit from 

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  1   their donation and given the therapeutic value that

  2   proteins derived from plasma can provide, it is

  3   unfortunate we can't easily divert plasma derived

  4   from apheresis procedures for further manufacture.

  5             This is doubly unfortunate given the

  6   periodic market shortages of plasma proteins, such

  7   as IVIG.

  8             We would like to strongly encourage the

  9   Blood Products Advisory Committee and the FDA to

 10   consider recovered plasma and concurrent plasma as

 11   products with identical properties when considering

 12   standards or licensure, and would further encourage

 13   that blood centers be allowed to process concurrent

 14   plasma under the whole blood rules and divert this

 15   for further manufacture when not necessary for

 16   transfusion.

 17             Thank you.

 18             DR. NELSON:  Thank you very much.

 19             Questions?

 20             Thank you.

 21             Next is Carolyn Jones for AdvaMed.

 22             MS. JONES:  Good afternoon.  Thank you for

 23   the opportunity to speak on behalf of AdvaMed, the

 24   Advanced Medical Technology Association.

 25             AdvaMed represents more than 800 

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  1   innovators and manufacturers of medical devices,

  2   diagnostic products, and medical information

  3   systems.  Our members produce nearly 90 percent of

  4   the health care technology products consumed

  5   annually in the United States, and 50 percent of

  6   the products purchased around the world.

  7             Some of our members manufacture products

  8   that contribute to the national effort to improve

  9   the safety and availability of blood and blood

 10   products in the U.S.

 11             As the committee considers standards for

 12   recovered plasma, AdvaMed would like to take this

 13   opportunity to propose to the committee a means of

 14   meeting the increasing demand for plasma without

 15   compromising donor or product safety.

 16             Today, licensed facilities collecting

 17   whole blood and preparing fresh frozen plasma may,

 18   at any time, relabel the product "recovered plasma"

 19   and ship for further manufacturing use.  No

 20   separate license is required.

 21             Facilities license to collect FFP as a by-product

 22   of red blood cells or platelets collected

 23   by apheresis, however, do not have this option.

 24   Currently, a separate license is required to ship

 25   for further manufacturing use, plasma collected as 

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  1   a by-product of cytapheresis.  The plasma by-products are

  2   treated the same as plasmapheresis

  3   products, that is, source plasma, despite the fact

  4   that these products are not collected by pheresis

  5   as stipulated in 21 CFR 640.60.

  6             The products are further distinguished

  7   from plasmapheresis products in that due to

  8   restrictions on the frequency of red cell and

  9   platelet donations, the products are collected from

 10   infrequent donors.

 11             As you are well aware, the agency, the

 12   blood community, and industry are looking for ways

 13   to address the continuing blood shortage problems

 14   in the U.S.  Increasingly, blood centers are moving

 15   towards apheresis as one means of addressing the

 16   country's blood supply problem.

 17             Current FDA policy requiring an

 18   establishment to obtain a source plasma license in

 19   order to ship the plasma by-products of

 20   cytapheresis for further manufacturing use

 21   represents a substantial barrier to volunteer donor

 22   centers that are already licensed for apheresis

 23   collections.

 24             We propose that FDA allow plasma by-products of

 25   infrequent cytapheresis procedures, 

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  1   that is, red cell or platelet apheresis

  2   collections, to be labeled as recovered plasma.

  3             Because these products are not collected

  4   by plasmapheresis, a formal change to the

  5   regulation is not required.

  6             The short supply provisions of 21 CFR

  7   601.22, which are applicable to plasma by-products

  8   of whole blood collection, can be applied to plasma

  9   by-products of infrequent cytapheresis procedures.

 10             This would reduce the burden on the blood

 11   community and on FDA reviewers, and would increase

 12   the availability of plasma products for

 13   fractionation into therapeutic derivatives.  The

 14   policy change should permit fractionaters

 15   simultaneously to amend contractual agreements to

 16   permit this change in source material definition

 17   and labeling.

 18             We ask that the committee seriously

 19   consider this proposal and recommend this policy

 20   change to FDA.

 21             Thank you for your consideration.

 22             DR. NELSON:  Thank you.

 23             Are there questions or comments?  Jay.

 24             DR. EPSTEIN:  Just one comment, Carolyn,

 25   thank you. 

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  1             I just want to clarify to the committee

  2   that we don't have a legal opinion within FDA

  3   whether we would or would not have to change the

  4   regulation, because what is being presented here is

  5   an interpretation of existing regulation.

  6             So, I would just suggest that the proposal

  7   that FDA allow plasma by-products of infrequent

  8   cytapheresis procedures to be labeled as recovered

  9   plasma or otherwise sold in a similar way is the

 10   essence of it, and that the mechanism is a

 11   separable issue which we don't have to really

 12   resolve today.

 13             DR. NELSON:  Thank you.

 14             DR. HOLLINGER:  Can I ask Jay another

 15   question?  It could be labeled as recovered plasma,

 16   but it could also be labeled as fresh frozen

 17   plasma, as well.  The reason is, is because that is

 18   what is usually ordered.  I mean from a physician's

 19   standpoint, if they want something, they order as

 20   fresh frozen plasma, not as recovered plasma, and

 21   so that issue is going to be very important I think

 22   in our deliberations here.

 23             DR. EPSTEIN:  Recovered plasma is not a

 24   product suitable for transfusion.  Fresh frozen

 25   plasma, which meets standards in the regulations, 

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  1   is a component suitable for transfusion.  Centers

  2   that prepare a fresh frozen plasma product may not

  3   relabel it and sell it as recovered plasma until it

  4   reaches its expiration date.  It can only become

  5   recovered plasma after expiration.

  6             DR. HOLLINGER:  And that is a legal

  7   statement in doing that, when you say it could not

  8   be changed to a recovered plasma, is that a legal

  9   issue?

 10             DR. EPSTEIN:  Well, the issue being raised

 11   here is how much flexibility exists for

 12   interpretation of the existing regulations.  The

 13   problem is that the regulations speak about

 14   recovered plasma as a product of the whole blood

 15   collection, and then they speak about

 16   plasmapheresis as the source material for source

 17   plasma when, and only when intended solely for

 18   further manufacturing use.

 19             The problem is that we now have a practice

 20   of generating transfusable components by apheresis,

 21   and it is a question what is the legal status of

 22   the plasma, but the agency has not previously

 23   recognized the plasma as a by-product of generating

 24   a transfusable component to be recovered plasma.

 25             The way we have looked at the regulations 

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  1   is that that is a whole blood donation, and

  2   therefore, you are making only transfusable

  3   components.  But what this reflects is a mind-set

  4   that goes back several decades, which was to

  5   discourage deliberate collection of a product

  6   intended solely for further manufacturing on the

  7   pretense of collecting products for transfusion.

  8             That is why the regs distinguished it by

  9   intent. The idea was that if someone donate to make

 10   transfusion products, that is what they are for,

 11   and it is only under very restricted circumstances

 12   that anything else would be done with them.

 13             What we are really being asked is to erase

 14   that distinction and say that products that meet a

 15   certain quality standard, for example, based on how

 16   rapidly they were frozen and what temperature they

 17   were stored and how long they were stored are

 18   equally suitable for further use to manufacture

 19   injectables or non-injectables, and that it should

 20   no longer matter what the intent was at the time of

 21   collection.  It should only matter what process was

 22   followed to make that plasma.  That is the essence

 23   of what is going on.

 24             DR. NELSON:  The infrequent blood donor

 25   who donates the red cells or other components of 

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  1   that donation could be transfused and now it's just

  2   not permissible that any component or any portion

  3   of it be used for further manufacture, right?  So,

  4   it is not violating really the agreement with the

  5   donor.  I mean you still would transfuse the red

  6   cells.

  7             DR. EPSTEIN:  Okay.  I mean that is one of

  8   the arguments is that there is not pretense if you

  9   are, in fact, collecting the blood component for

 10   transfusion, then, that is what you do with it, and

 11   then the fact that there is the surplus plasma is

 12   not problematic.  I mean that is one possible

 13   position that could be taken.

 14             But the situation has arisen because of

 15   the fact that we now can generate deliberately a

 16   surplus plasma product, and the question is should

 17   we allow the collection industry to do this.

 18             DR. FITZGERALD:  If a rule change were

 19   made that allowed you to convert fresh frozen

 20   plasma to recovered plasma at any point in its

 21   lifetime, that would resolve one issue, but it

 22   wouldn't resolve what seems to be more of an

 23   ethical issue within the agency of intent, even

 24   though you can draw a unit of whole blood, make the

 25   decision immediately after collection to make that 

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  1   plasma recovered plasma, and there is no issue.

  2             DR. EPSTEIN:  I think you have got it

  3   right.  There is the practical question should we

  4   simply allow FFP that was generated with the full

  5   intention of being FFP, to be at any point in its

  6   storage life, converted to recovered plasma through

  7   relabeling and/or should we allow deliberate

  8   collection of a plasma product for further

  9   manufacturing use concomitant with collection of

 10   components for transfusion, thereby erasing the

 11   issue of intent.

 12             I think that those are sort of the

 13   fundamental issue in this decision.

 14             DR. NELSON:  I fail to see the ethical

 15   issue.  I think if you are giving to patients who

 16   need it, you know, and not feeding it to the hogs

 17   or something like that, the person who donated the

 18   unit is helping somebody.

 19             DR. EPSTEIN:  Well, you are presuming the

 20   only reason that the donation happened was to make

 21   a concomitant transfusion component, but I can tell

 22   you that in other parts of the world, what happens

 23   is that there is donation under false pretense.

 24   The goal is to make the plasma because it is

 25   profitable to sell it. 

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  1             DR. NELSON:  I understand that, that is

  2   true.

  3             DR. EPSTEIN:  But we haven't had that

  4   problem because we distinguished, in the 1970s, the

  5   product is based on the intent of collection.  So,

  6   what is at issue is are we going to cause the

  7   problem that we never had in this country by

  8   allowing it now, or do we think that the system we

  9   have of altruistic donation to make transfusion

 10   products is not going to become such a bonanza in

 11   surplus plasma as to create pressures on use of the

 12   donors.

 13             I think that is the ethical side of the

 14   issue.  I don't know better than you whether that

 15   is material in our system or not, but there is a

 16   reason that we separated the product streams.

 17             DR. NELSON:  The recent situation in

 18   China, I guess, is an example of a problem, a real

 19   ethical problem.

 20             DR. SCHMIDT:  I caucused with John

 21   Finlayson, and this concept of plasma in short

 22   supply, and in shuffling it off to the

 23   manufacturers, it predates FDA, and to my

 24   recollection, we were using this in 1954, plasma

 25   was in short supply and NIH let the manufacturers 

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  1   decide, and it is obviously time for a change.

  2   That is 48 years that I am aware of it.

  3             DR. CUNNINGHAM-RUNDLES:  Can I just ask

  4   because I don't know, volunteer donors who give the

  5   red cells, fine, the red cells are given, but what

  6   happens to the plasma if it is not used then, it is

  7   thrown away?  If it is not used for FFP in that

  8   year's window, it is discarded?

  9             DR. SIMON:  I think that we were told that

 10   the FDA allows it to be relabeled at the end of the

 11   year, but we were also told that manufacturers,

 12   that the blood centers are unable to find

 13   manufacturers who will take it at that time.

 14             DR. FITZGERALD:  Or it can be provided to

 15   a manufacturer for a non-injectable.  Recovered

 16   plasma is also used for non-injectable products

 17   like controls and antibodies, and that kind of

 18   thing, but some is thrown away.

 19             DR. BIANCO:  I think I can help a little

 20   bit.  It is either/or in paper, but what the blood

 21   centers do, they manage the process.  You know that

 22   about 20 percent of your collections, that plasma

 23   is going to be needed for transfusion.  So, what

 24   blood centers do, they try to focus those on their

 25   needs, and they focus, since the plasma has to be 

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  1   removed from the red cells within 8 hours of the

  2   insertion of the needle, so they will manage

  3   actually the time that they arrive in the

  4   component's lab from the drive step that runs

  5   closest to the blood center that is going to

  6   process it, and those are the units that will

  7   become fresh frozen plasma.

  8             When they fulfill the needs, from then on,

  9   they are going to put the product as recovered

 10   plasma.  So, the amount that is wasted as fresh

 11   frozen plasma is limited.  It will be some units of

 12   plasma Type A or something like that, that is in

 13   larger supply, and you are always looking for

 14   plasma of Type AB that is what you really need.

 15             So, the process is managed.  The waste is

 16   not going to be the issue.  It is that from the

 17   point of view of current good manufacturing

 18   practices, as we work today, not like Dr. Paul

 19   Schmidt, I was born in '54, Dr. Schmidt, but I was

 20   not in blood banking.

 21             At that time, it made sense, and as Dr.

 22   Epstein presented it very well, it made sense

 23   ethically.  There was a lot of discussion of what

 24   is ethical in terms of a blood donor, how do you

 25   collect, what do you collect.  The entire country 

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  1   was on paid donations as a source of whole blood.

  2             New York had 100 blood banks on the Bowery

  3   that was providing blood to the hospitals, and at

  4   the same time, 25 percent of the patients that

  5   received multiple transfusions had overt hepatitis.

  6   That is what caused the changes of the system in

  7   the seventies.

  8             Today, what we are looking is from a

  9   different perspective, is the quality of the

 10   product, and the quality of the product is the

 11   same.  So, it doesn't make sense now, because of

 12   the issues of intent.  I understand the concerns

 13   the Dr. Epstein, could we just go in a crazy market

 14   pressure or something.  No, the reimbursement for

 15   the recovered plasma is very small.  It is not the

 16   major source of revenue of blood centers, and this

 17   is not going to change substantially.

 18             The thing is that it hurts us to see that

 19   product that is so valuable not being used for a

 20   very good purpose.

 21             DR. HOLLINGER:  Celso, before you leave,

 22   in general, what percentage of the revenues in a

 23   blood center, and I will ask that also of the

 24   American Red Cross and any others about it, what

 25   percentage of the revenues come from recovered 

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  1   plasma at this point, and has it been increasing

  2   over the time?

  3             DR. BIANCO:  I can give you a percent off

  4   just my head, that it is maybe 4 to 5 percent of

  5   the revenue.  I can tell you what the reimbursement

  6   is.  The reimbursement is on the order today, and

  7   that increased in the last year, year and a half

  8   with more requirements with introduction of NAT and

  9   all those things, is around in the 80s for a liter

 10   of plasma that will require from four to five

 11   donations depending on the value of plasma that is

 12   obtained.

 13             So, it is in the order of maybe less than

 14   $20 a unit.

 15             MR. FIPPS:  You had asked about our

 16   revenues or percent.  We, for the most part, our

 17   recovered plasma, we make into our own products and

 18   then resell them, so it is not necessarily the same

 19   analogy, but out of $2 billion annual revenues in

 20   the Red Cross, plasma sales or derivative sales

 21   represent $360 million of that.

 22             I can't do the math right now in my head,

 23   but anyway--what's that--18 percent, okay, but that

 24   is as finished products, as plasma-derived

 25   products. 

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  1             DR. ALLEN:  Mr. Chairman, I would like to

  2   just ask a general question, if there is somebody

  3   in the audience or on the committee or from the FDA

  4   staff that could provide information.

  5             It seems to me that I have heard from

  6   other sources at other times that sometimes the

  7   plasma industry requirements for recovered plasma,

  8   you know, we have already heard today that they

  9   differ somewhat, I just wonder are there other

 10   issues between the requirements of the plasma

 11   manufacturers and the recovered plasma providers

 12   that are going to get in the way or that would be

 13   impacted by possible recommendations.

 14             I want to make sure that we have got all

 15   the information on the table.

 16             DR. NELSON:  Does anybody want to answer?

 17             DR. BIANCO:  From our point of view, we

 18   would like to see it licensed like all the other

 19   products that we distribute, and considering the

 20   short supply agreements that we have signed with

 21   many manufacturers, not many, some, because the

 22   number of manufacturers that today utilize

 23   recovered plasma is limited, most use source

 24   plasma, the specifications are not going to change.

 25             That is their intent in general is to get 

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  1   as much of fresh frozen early plasma as possible,

  2   that increases the yields.  They can speak more,

  3   but my sense is that when the driver as factor VIII

  4   production or manufacture, then, it was more

  5   important the immediate 8 hour or 15-hour

  6   collection, today, the driving force appears to be

  7   IVIG that is a little bit different, because there

  8   is less time pressure.

  9             DR. EPSTEIN:  I think there is another

 10   large impact, which may be a bit subtle.

 11   Currently, if you are a registered unlicensed

 12   establishment because you operate intrastate, you

 13   still can sell recovered plasma to a fractionater,

 14   however, if recovered plasma becomes a licensed

 15   product, then, establishments that are currently

 16   registered, but want to sell recovered plasma,

 17   would have to hold licenses for recovered plasma.

 18             Now, there are about 2,500 of those

 19   establishments.  Now, they don't contribute a large

 20   fraction of the components for transfusion.  I mean

 21   all together, they probably contribute no more than

 22   10 percent of all the products, the 90 percent

 23   coming from the current licensees, but I don't know

 24   what proportion of recovered plasma they currently

 25   contribute. 

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  1             I only know that is the recovered plasma

  2   is licensed, they will have to be licensed.

  3             DR. SIMON:  Well, their only

  4   representative here I guess is AABB.  Do you know

  5   how the hospitals feel--these are typically

  6   hospital blood banks I think.

  7             DR. BUSCH:  I don't know about that.

  8             MS. GREGORY:  I really don't have any

  9   information on how they would feel.

 10             DR. BUSCH:  Your question about other

 11   implications, I think a licensed FFP would sort of

 12   define the standards required for safe plasma

 13   derived from a recovered source.  There has been

 14   this allusion to this discussion over the last few

 15   years between the recovered and source industry

 16   about uniform standards.

 17             We have seen enormous progress on the

 18   source plasma side with inventory hold and

 19   registered applicant donor discrimination, and

 20   obviously drug testing and a national registry,

 21   these are appropriate and have proven to be very

 22   effective safeguards that have I think brought

 23   source plasma donations into the same safety level

 24   that recovered plasma has had for a long time

 25   because of volunteer sector sourcing. 

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  1             The GAO report several years ago concluded

  2   that there is really equivalence now with all of

  3   the enhanced safety standard that the source

  4   industry has brought forward.

  5             But, nonetheless, there is an effort by

  6   the source industry to impose some of these

  7   standards on the recovered side, and many of these

  8   things just don't make sense.  I mean if you only

  9   use repeat donor plasma for recovered plasma, that

 10   says you have to use all your first-time donor for

 11   FFP, so you are transfusing unprocessed, you know,

 12   non-virally inactivated product from the less safe

 13   whole blood collection pool, the first time donors,

 14   in order to meet the recovered plasma requirement

 15   that it be from repeat donors.

 16             That doesn't make any sense.  The whole

 17   issues of drug testing, et cetera, to me don't make

 18   sense, and if FDA, if this was a licensed product

 19   with clear public regulatory guidance on what is an

 20   appropriate standard, then, this behind-the-scenes,

 21   you know, debate and negotiation that is going on,

 22   that I think should be taking place in this forum,

 23   would be hopefully superseded by clear regulatory

 24   authority.

 25             MR. BULT:  My name is Jan Bult.  I am the 

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  1   president of PPTA.

  2             This issue about standard setting in the

  3   industry has been discussed many times, and I have

  4   the feeling that at this moment, we are talking

  5   about two different issues.  I think the issue at

  6   stake is the question of FDA, whether there should

  7   be a system that allows you to make use and to get

  8   more plasma, and have an efficient use of

  9   resources.  That is one issue.

 10             The second issue is even in this sector

 11   like PPTA, has a set of voluntary standards that

 12   includes, for source plasma, the standards that

 13   were explained by Dr. Whitaker. We, as an industry,

 14   feel it is extremely important that we have a

 15   single set of standards and that we do not use dual

 16   quality in our fractionation.

 17             For that reason, or board of directors has

 18   made a decision to develop a standard for recovered

 19   plasma that indeed includes drug screening.  The

 20   target date for implementation is January 2004, but

 21   I want to remind you it is a voluntary program.

 22   That means every supplier, every fractionater is

 23   free to participate in the program.

 24             It is also open for public comment, and as

 25   you have heard several times today, we are 

                                                               235

  1   negotiating what we can do, and we have made a lot

  2   of progress, but there are some issues that still

  3   need some further discussion.

  4             I just would like to reiterate it's a

  5   voluntary program.  Nobody is forced or obliged to

  6   do so.  That would be a clear violation of the

  7   legal framework in which we have to operate, and it

  8   is up to the individual fractionater to determine

  9   the criteria that they deem necessary for the

 10   manufacture of the products.

 11             DR. NELSON:  We are getting pretty late.

 12             Steve, a short comment.

 13             DR. KLEINMAN:  Just a comment, just for

 14   perspective of the committee.  You know, it is

 15   useful to look at the NAT testing paradigm because

 16   since fractionated products come from two sources,

 17   and recovered plasma comes from whole blood donors,

 18   I think everybody should recognize that because of

 19   safety concerns in the source plasma industry, the

 20   whole blood industry has implemented a series of

 21   tests, some of which would have been implemented

 22   anyway, like HCV and HIV NAT perhaps, but others of

 23   which, like parvovirus B19 and HAV NAT, which we

 24   now in discussion, probably have no value for blood

 25   donors and probably no value for the final 

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  1   products, although that is debatable on the

  2   fractionated products, but basically, what I am

  3   trying to say is that what the source plasma

  4   industry does sets a standard out there some way,

  5   and it actually influences what the whole blood

  6   industry does, and in a sense, while it may not be

  7   regulatory, we have to recognize that in the

  8   current environment, in a way that has trumped FDA

  9   regulation in a variety of fashions here.

 10             The reality is people who collect whole

 11   blood are having to do things that don't make sense

 12   in the whole blood sector, and do make sense in the

 13   source plasma sector, and it may be because they

 14   want to be competitive in the market for their

 15   fractionated product, so there is a lot of complex

 16   forces, and I guess I just offer this by way of

 17   perspective.

 18             The last person that wanted to speak was

 19   Sue Stramer who has moved temporarily to Chiron,

 20   but she said she is going to be moving back to the

 21   American Red Cross after this talk.

 22             DR. STRAMER:  I have moved nowhere except

 23   out of my seat fortunately.

 24             I am going to change gears a little bit

 25   and the focus of this morning's and early 

                                                               237

  1   afternoon's discussion has been on recovered

  2   plasma, but I am going to discuss kind of a new

  3   topic - infrequent volunteer source plasma.

  4             So, whether we are discussing recovered or

  5   infrequent volunteer source plasma, both are plasma

  6   donations, at least in the context that I will be

  7   discussing from volunteer donors and consistency

  8   between recovered and infrequent volunteer source

  9   plasma testing standards should exist.

 10             [Slide.]

 11             First, I want to define what is IVSP.

 12   Starting with source plasma, it is the fluid

 13   portion of human blood collected by plasmapheresis

 14   and intended as source material for further

 15   manufacturing use.

 16             Volunteer donor is a person who does not

 17   receive monetary payment for a blood donation.

 18             Infrequent plasma may be collected from

 19   healthy, non-immunized individuals who donate every

 20   four weeks or less frequently.  All other

 21   collection requirements are the same as donors of

 22   whole blood other than donation frequency or

 23   minimum weight.

 24             [Slide.]

 25             The main difference between frequent, that 

                                                               238

  1   is, collections that shall not occur less than two

  2   days apart or more frequently than twice in a

  3   seven-day period, and infrequent, is that

  4   manufacturers must perform physical examinations

  5   and tests for total serum or total plasma protein

  6   on frequent donors.

  7             Frequent donors may also be part of an

  8   immunization program.

  9             [Slide.]

 10             On February 27th, 2002, the Chiron

 11   Procleix HIV-1, HCV NAT assay was licensed with the

 12   following intended use - as a test for HIV and/or

 13   HCV in human plasma from donations of whole blood

 14   and blood components for transfusion.

 15             So, donations from IVSP donors qualified

 16   as part of the clinical trial, but not included in

 17   the licensed PI, but were not included in the

 18   licensed package insert.  The reasons are unknown,

 19   but I will discuss further.

 20             Now, IVSP donations represented

 21   approximately 0.3 percent of the collections in the

 22   manufacturer's pivotal trial, as well as

 23   collections in the Red Cross' IND for pools of 16

 24   using, at that time, the unlicensed test since

 25   September 8th, 1999, which represents over 21 

                                                               239

  1   million total donations.

  2             [Slide.]

  3             Infrequent volunteer source plasma is also

  4   not specifically mentioned in either FDA draft

  5   guidance document on NAT, and there are two

  6   documents that I have referenced here.  Without

  7   inclusion in the licensed NAT package insert,

  8   testing under IND will continue because we have no

  9   mechanism to test these donations.

 10             [Slide.]

 11             Now, other options that exist under the

 12   current regulations, one would assume would be that

 13   we would have to identify these samples from whole

 14   blood donations versus those from infrequent

 15   volunteer source plasma donations and segregate

 16   those during processing.

 17             So, once they are segregated, potentially,

 18   then, we would have to submit them to a different

 19   pooling algorithm and send them to the manufacturer

 20   who is licensed for source plasma NAT, which is

 21   National Genetics.

 22             So, for a very small percent of our

 23   collections, we would have to implement two very

 24   unique processes.  So, our comments to the draft

 25   guidance were provided to FDA. 

                                                               240

  1             [Slide.]

  2             Why would an IVSP be included in the

  3   package insert?  There are three potential reasons

  4   or three potential issues why they haven't been.

  5             One, the manufacturer, Gen-Probe, and the

  6   FDA were unaware that these donations were included

  7   in the clinical trial and the IND data, so that no

  8   claim could be provided.

  9             A second potential reason is questions

 10   regarding the method of sample collection, that is,

 11   is the process for IVSP different than routine

 12   whole blood collections, and thirdly, are the

 13   demographics of these donations different than

 14   whole blood donors, and therefore, no claim could

 15   be provided.

 16             In the few minutes that I have, I am going

 17   to review those three issues.

 18             [Slide.]

 19             Firstly, the collection process.  Samples

 20   from both whole blood and IVSP donors are collected

 21   as whole blood samples, and they are not diluted in

 22   anticoagulant, and they are obtained directly from

 23   the donor into a plasma preparation tube, which is

 24   an EDTA spray-coated plastic tube qualified for

 25   NAT. 

                                                               241

  1             Our plasma is collected using seven

  2   different qualified apheresis instruments.  We

  3   collect plasmapheresis, plateletpheresis,

  4   aretsoapheresis [ph], and we collect either FFP or

  5   IVSP.

  6             All samples are obtained prior to the

  7   start of the collection, and again, no

  8   anticoagulant or saline dilutes the test samples,

  9   so basically, the test samples from whole blood and

 10   pheresis donors are identical.

 11             [Slide.]

 12             I have just here listed, which I won't go

 13   through, but the seven licensed methods that we use

 14   for collection.

 15             [Slide.]

 16             To go through the specific data for the

 17   IVSP collections, the period covered for NAT on

 18   pools of 16 includes from 9-8-99 through the end of

 19   the year 2001, which includes greater than 16

 20   million allogenic donations.  In that period of

 21   time, there were 67 HCV and 5 HIV seronegative

 22   yield donations identified.

 23             None of those were from infrequent

 24   volunteer source plasma donors, but what were from

 25   IVSP donations were 50,669 donations from 10,673 

                                                               242

  1   donors which included anywhere from 1 donation per

  2   source plasma donor to 28 separate donations.  One

  3   donor, in fact, donated once monthly during this

  4   time period.

  5             [Slide.]

  6             The collections occurred at 15

  7   geographically distinct sites, and the inclusion

  8   criteria for the analysis included collections from

  9   any region in which greater than 100 IVSP

 10   collections were obtained.

 11             Seven reagent lots of product were used,

 12   and data were analyzed for all collection from

 13   which NAT and serology were complete, and FDA

 14   licensed methods were, of course, used for HIV and

 15   HCV.

 16             [Slide.]

 17             This slide shows you the 15 regions that

 18   were included in the analysis, obviously,

 19   widespread through the United States and varying

 20   numbers of source plasma collections.

 21             [Slide.]

 22             This graph shows you the frequency of

 23   donations per donor.  So, the column closest to me

 24   represents the number of donors only donating once

 25   per this period of time versus donors on the far 

                                                               243

  1   left that would have donated up to 28 times.

  2             [Slide.]

  3             As I mentioned, the NAT testing is

  4   performed in pools of 16, so this slide shows you

  5   the number of IVSP donations that were contained in

  6   pools of 16, anywhere from one donation, that were

  7   contained in 26,191 pools to 11 IVSP donations

  8   contained in only one pool during this time.

  9             [Slide.]

 10             Of the 50,669 IVSP donations, 50,586

 11   donations were tested, and 35,951 pools containing

 12   between 1 and 11 IVSP donations; 83 were tested

 13   individually, that is, never pooled.  Of 35,951

 14   pools tested containing IVSP's, 99.3 percent were

 15   NAT nonreactive, and 0.7 percent, or 244, were NAT-reactive.

 16   That included 336 IVSP donations, and

 17   the remainder, whole blood samples.

 18             Of the 83 IVSP donations screened by NAT

 19   individually, 76 were NAT and serology nonreactive,

 20   and 7 additional samples were NAT nonreactive, but

 21   were repeat reactive by serological testing.

 22             [Slide.]

 23             To go through the data in composite, of

 24   the 50,669 IVSP donations, 336, those were the ones

 25   that were tested in pools, resolved to 2 NAT 

                                                               244

  1   reactive samples, neither of which were

  2   discriminatory HIV or HCV NAT reactive, and neither

  3   were HIV or HCV seroreactive.

  4             So, the NAT positivity in this study out

  5   of IVSP was zero percent.  To compare that with

  6   what we obtained in whole blood, the frequency is

  7   0.004 percent.  There is a zero point missing on

  8   this slide, but the bottom line is there was no

  9   significant difference between these two.

 10             Next point.  Of the 50,669 IVSPs, they

 11   contained 15 or 0.03 percent anti-HIV reactive

 12   samples, none of which confirmed.  So, again, that

 13   is the HIV positivity rate for antibody of zero

 14   percent, which again is statistically non-different

 15   from whole blood donors at 0.003 percent.

 16             For HCV, of the 50,669 IVSPs, there were 8

 17   anti-HCV repeat reactive samples, 2 confirmed.

 18   Now, both of these had weak RIBA banding patterns

 19   suggestive of resolved infection.  So, the anti-HCV

 20   positivity of IVSP in this case was 0.004 percent

 21   versus whole blood at 0.18 percent, and those two

 22   were significantly different.

 23             So, bottom line is marker rates were

 24   comparable or lower when you consider NAT and

 25   serology from IVSP donations than from whole blood 

                                                               245

  1   donations.

  2             [Slide.]

  3             This slide just shows the breakout by pool

  4   testing the 336 reactive pools, of which resolved

  5   to 2 individual donations, neither of which were

  6   NAT reactive.  This shows the composite for all of

  7   the serological data.  There were the 15 HIV

  8   antibody reactives, and the 8 HCV antibody

  9   reactives, again only 2 being RIBA confirmed

 10   positive, both of which were NAT negative.

 11             [Slide.]

 12             To look at the population distributions of

 13   the IVSP donations tested, the population means for

 14   the NAT nonreactive pools was 0.225 versus whole

 15   blood, which is what is in the package insert or

 16   actually whole blood with a mixture of some low

 17   percentage of IVSP of 0.21.  These are not

 18   significantly different.

 19             The same thing for the NAT nonreactive

 20   individual donation samples tested, a population

 21   mean of IVSP of 0.225 versus the whole blood, what

 22   is in the package insert at 0.17.  Again, not

 23   statistically different.

 24             [Slide.]

 25             This slide shows you the distribution of 

                                                               246

  1   NAT nonreactivity or the S to CO values for NAT

  2   nonreactive pools and samples for IVSP donations,

  3   and again not significantly different than whole

  4   blood.

  5             [Slide.]

  6             In conclusion, donation samples from IVSP

  7   donors are collected by the same processes as

  8   routine whole blood donations.  Donations from IVSP

  9   donors have similar or lower marker rates than

 10   those from whole blood donors.

 11             IVSP donations have been qualified as part

 12   of the IND process for HIV-1, HCV NAT.  These data

 13   have not been excluded from the Chiron Procleix

 14   package insert data, however, they did require a

 15   separate data analysis since they are not included

 16   in the current package inserts.

 17             [Slide.]

 18             Since data for IVSP and whole blood

 19   donations are comparable, and both have been

 20   qualified, both should be included in the intended

 21   use statement of the Chiron Procleix HIV-1/HCV

 22   assay.

 23             The American Red Cross has provided these

 24   data to Gen-Probe, that is, the manufacturer or

 25   license holder on May 13th, 2002, for FDA 

                                                               247

  1   submission as a BLA supplement labeled transmittal

  2   to their current package insert.

  3             Thank you.

  4             DR. NELSON:  Thank you.

  5             Questions?  Jay.

  6             DR. EPSTEIN:  Susan, how does this relate

  7   to the topic at hand?

  8             DR. STRAMER:  Actually, it doesn't.  It

  9   really doesn't deal with recovered plasma per se,

 10   but if we are talking about standards, and

 11   certainly testing is a standard and we are talking

 12   about all the collections from volunteer donors, be

 13   they recovered plasma or be they infrequent

 14   volunteer source, they should all be tested using

 15   the same testing algorithms, and not have to be

 16   separated in our operational processes.

 17             DR. EPSTEIN:  Are you then arguing that

 18   since you have data on unpaid source plasma donors

 19   collected under whole blood standards for

 20   infrequent apheresis, that therefore, the license

 21   for the NAT tests should extend to all source

 22   plasma donors?

 23             DR. STRAMER:  No, not to all source plasma

 24   donors, to those source plasma donors that have

 25   been qualified as part of the clinical trial for 

                                                               248

  1   the assay, which include volunteer source plasma

  2   donors.

  3             DR. EPSTEIN:  I don't know that we needed

  4   to do this in front of the committee because you

  5   are basically asking the FDA whether your data

  6   validated an extension of label, and we are not

  7   going to decide that here today.

  8             DR. STRAMER:  I understand that, but it

  9   was a request from Chiron and Gen-Probe to make

 10   these data public, so since we were the keepers of

 11   the data, I honored their request.

 12             DR. EPSTEIN:  All right.  We hear what the

 13   implicit request to the FDA is, and I think we will

 14   discuss it at another time and place.

 15             DR. STRAMER:  Okay.  Thank you.

 16             DR. NELSON:  I think we will move to the

 17   questions for the committee.

 18             DR. HOLLINGER:  Could I just ask Dr.

 19   Fitzpatrick just a minute, we never heard anything

 20   about the military.  Is this an issue for the

 21   military at all?

 22             DR. FITZGERALD:  Not really.  Our donor

 23   centers collect and prepared recovered plasma with

 24   short supply agreements just like other centers, so

 25   we function under the same constraints as the 

                                                               249

  1   industry is functioning, and we will go along with

  2   the regulation if it appears or continue to work

  3   under the short supply agreement, but we don't

  4   supply large amounts of recovered plasma.

  5             DR. NELSON:  I guess we are looking for

  6   the questions.  If you can't find them, we could

  7   just read them theoretically.

  8             MS. CALLAGHAN:  I think we finally

  9   arrived.

 10                    Open Committee Discussion

 11                   Questions for the Committee

 12             MS. CALLAGHAN:  The first question to the

 13   committee.  Should FDA develop specific product

 14   standards for recovered plasma?

 15             DR. SIMON:  I think the way the

 16   presentations went, it might not have been apparent

 17   but I really do think there is a consensus from

 18   industry that standards would be appropriate.  I

 19   think there is a difference on what exactly they

 20   should be, but I do believe that substituting for

 21   the short supply agreements and eliminating that

 22   ambiguity and the difficulty with standardization

 23   that exists, and substituting some standards for

 24   things like storage conditions and dating periods

 25   would be a step forward. 

                                                               250

  1             I think we recognize it's an international

  2   industry.  A lot of things are governed by the

  3   manufacturer, and there may be requirements in

  4   excess of what we said or what is set by FDA, but I

  5   think it would be appropriate to move ahead with

  6   standards.

  7             It sounds like that comes out of most of

  8   the presentations.  Then, this would allow, under

  9   the third question, it would allow the FDA to go

 10   ahead and consider some of these specific examples

 11   like the apheresis and include them as it develops

 12   those standards.

 13             So, I would certainly favor a yes vote on

 14   No. 1.

 15             DR. FITZGERALD:  In going back to Jay's

 16   first comments and the fact that one major player

 17   that collects almost 50 percent said they didn't

 18   want regulation, I am not sure I agree totally, but

 19   I think industry appeared to be asking for the

 20   flexibility to use FFP as recovered plasma as one

 21   issue.  That would take a change in a rule to do

 22   that, so that piece of regulation would be a piece

 23   that would be required.

 24             When we look at all the other items

 25   impacted by the general statement, should there be 

                                                               251

  1   specific standards for recovered plasma, I think it

  2   gets complicated, and we have a lot of unanswered

  3   questions.

  4             We have the major proponent of source

  5   plasma is paid donors, the major proponent of

  6   recovered plasma is volunteer donors, two

  7   distinctly different donor populations.  The

  8   voluntary standards that have been established by

  9   PPTA have been put into effect to assure the safety

 10   of their donor population, which is a different

 11   donor population, and to assuage some of the

 12   concern and perception of the public that those

 13   paid donors are less desirable than volunteer

 14   donors.

 15             So, I am not sure the voluntary

 16   application of all the standards that PPTA is

 17   advocating for their donors would be applicable or

 18   should be applied to volunteer whole blood donors.

 19             The other questions that we have is you

 20   usually regulate something because there is an

 21   issue of safety or efficacy of the product on the

 22   other end.  I didn't hear any data or information

 23   to imply that there is a problem with safety or

 24   efficacy of the concentrates that are being

 25   manufactured from either source plasma or recovered 

                                                               252

  1   plasma.

  2             The recall information seemed to imply

  3   that there were implications of increased recalls

  4   because of postdonor information, but when we asked

  5   specific questions about the numbers of units, the

  6   percentage of units, and if there was a change,

  7   that information wasn't available, and that data is

  8   very hard to interpret and is incomplete.

  9             Storage conditions do seem to vary between

 10   suppliers and could be an issue on the safety and

 11   efficacy of the end product, but we don't know the

 12   answer to that question.

 13             Records was brought up, but records brings

 14   up another implication, because whenever FDA or

 15   anyone has set standards including AABB regarding

 16   retention or records, usually, there is a clause in

 17   there that says records should be retained until

 18   the expiration of the product or a period past the

 19   expiration of the in-date product.

 20             Recovered plasma would be used to prepare

 21   an injectable in-dated product.  So, now you have

 22   to give a requirement for the donor centers as to

 23   how long after the infusion of the concentrate that

 24   was prepared from the plasma should be kept.  That

 25   might be less time than indefinite probably, but 

                                                               253

  1   that needs to be arrived at also if you are going

  2   to talk about record retention.

  3             So, given all those indications, and the

  4   fact that there isn't an overwhelming indication to

  5   me from the industry that there is a problem with

  6   the end product, it seems like the indications are

  7   standardization of storage and a rule changed maybe

  8   to allow changing the labeling of FFP to recovered

  9   plasma at any point.

 10             I take into consideration Jay's comments

 11   about other countries where donors were recruited

 12   under perhaps false pretenses to get plasma.  We

 13   have never had the problem in this country of

 14   having excess red cells.  If we got to that point,

 15   I guess we could address that, but it would be a

 16   pleasure to get to that point.

 17             So, I don't see that there is an initial

 18   problem with recruiting thousands of volunteer

 19   donors for the sake of getting another unit of

 20   recovered plasma that you can sell for 20 to $25,

 21   which will come nowhere near covering the cost of

 22   the red cells.

 23             I understand the ethical implication and

 24   what was done years ago because of other

 25   considerations.  I am no sure it impacts where we 

                                                               254

  1   are right now.

  2             If we consider regulation, I would suggest

  3   to the FDA the regulation that at first be limited

  4   to allow relabeling of FFP, perhaps address storage

  5   conditions, but that the other items, especially

  6   with the need for hepatitis B antibody in the end

  7   product, that that would require a lot more data

  8   and information to make any determination on the

  9   other questions.

 10             DR. NELSON:  The limited changes that you

 11   recommended would require a yes, that there would

 12   be then specific standards or no?  There would be a

 13   change in the current regulations.

 14             DR. FITZGERALD:  To me, relabeling isn't

 15   changing --well, I guess it is, changing of product

 16   standard.  It would be yes to the first.

 17             DR. DiMICHELE:  I would just like to add

 18   to what has been said already.  I guess I would say

 19   yes upfront.  I think I agree, there appears to be

 20   a need.  I agree with what Dr. Fitzpatrick said,

 21   that there truly aren't any safety or efficacy

 22   issues that have been identified today.

 23             I would also agree with you that I think

 24   standards should be instituted where standards are

 25   needed, and I think you iterated very well what 

                                                               255

  1   those problem areas were, but I do think, in my

  2   opinion, that standards are required because it

  3   appears to me that there is a precious resource out

  4   there that is going to waste because of certain

  5   ambiguities and lack of standardization, and I

  6   think that in itself creates a mandate for

  7   standards that would resolve that issue.

  8             However, I just would like to say that I

  9   think, you know, I am a little embarrassed as a

 10   hematologist who has been working in this field for

 11   a while, that I had to learn a whole lot about a

 12   field that I thought I knew a lot about because I

 13   am a hemophilia treater and I give these plasma-derived

 14   products all the time, and it is amazing

 15   what one doesn't know.

 16             I believe there is an issue of disclosure

 17   here and I believe that the disclosure, I hope that

 18   standardization, if the FDA does develop standards,

 19   includes standardization of disclosure, disclosure

 20   to the patient, who is coming in as a volunteer,

 21   and from whom there is a paid product, a product

 22   that is being sold.  This person is donating a

 23   commodity.  I think that person needs to know.

 24             I think that there needs to be disclosure

 25   from the plasma fractionation industry as to what 

                                                               256

  1   exactly is in plasma-derived products, what

  2   components, what mixes, and I think that some of

  3   these issues, there needs to be--you know we

  4   understand this voluntary versus paid, but I am not

  5   sure that we have understood the full implications

  6   of this, and I think there needs to be better

  7   disclosure even to the physicians using this

  8   product.

  9             I also, if I can just be a patient

 10   advocate for a moment, I believe that I can speak,

 11   and maybe Charlotte can actually speak for her

 12   population, but I will speak on behalf of any of

 13   those patients who are using fractionation

 14   products, that regardless of what happens, that

 15   patients and the medical system cannot bear an

 16   increase in the cost of fractionated products,

 17   whether they be IVIG or clotting factor

 18   concentrates.

 19             This has maxed out and those of us who are

 20   dealing with this on the front lines would like to

 21   just make that point.

 22             DR. NELSON:  Thank you.

 23             Jim.

 24             DR. ALLEN:  I concur with the comments

 25   that have been made.  I personally would come down 

                                                               257

  1   on the side of that it is time to move towards the

  2   development of standards.  I was going to raise

  3   also the point that Donna just raised at the end,

  4   and that is, I know that cost is not a primary

  5   consideration.  It has not really been addressed

  6   here in terms of what the impact on collectors

  7   might be of standards and licenses with the

  8   exception of Jay's statement about the very small

  9   intrastate collectors.

 10             I think the implication was that it would

 11   be extremely costly to them to have to go through

 12   the licensure and regulatory process, which they

 13   don't currently.

 14             With that aside, I think that there is a

 15   cogent argument for moving ahead and addressing

 16   some of the issues that have been laid before us

 17   today.

 18             DR. NELSON:  Any other comments?

 19             Do you want to vote on this?  I guess it

 20   is yes or no.

 21             DR. SMALLWOOD:  Voting will take place by

 22   roll call.  There are 14 eligible voters.  So, as I

 23   call your name, would you please indicate your

 24   preference by yes, no, or abstaining.

 25             Question No. 1 stated as read.  Should FDA 

                                                               258

  1   develop specific product standards for recovered

  2   plasma?

  3             Dr. Allen?

  4             DR. ALLEN:  Yes.

  5             DR. SMALLWOOD:  Dr. Chamberland.

  6             DR. CHAMBERLAND:  Yes.

  7             DR. SMALLWOOD:  Dr. Cunningham-Rundles.

  8             DR. CUNNINGHAM-RUNDLES:  Yes.

  9             DR. SMALLWOOD:  Dr. DiMichele.

 10             DR. DiMICHELE:  Yes.

 11             DR. SMALLWOOD:  Dr. Fitzpatrick.

 12             DR. FITZGERALD:  Yes.

 13             DR. SMALLWOOD:  Dr. Klein.

 14             [No response.]

 15             DR. SMALLWOOD:  He is absent, I think.

 16             Dr. Lew.

 17             DR. LEW:  Yes.

 18             DR. SMALLWOOD:  Dr. McGee.

 19             DR. McGEE:  Yes.

 20             DR. SMALLWOOD:  Mr. Rice.

 21             MR. RICE:  Yes.

 22             DR. SMALLWOOD:  Dr. Schmidt.

 23             DR. SCHMIDT:  Yes.

 24             DR. SMALLWOOD:  Dr. Fallat.

 25             DR. FALLAT:  Yes. 

                                                               259

  1             DR. SMALLWOOD:  Dr. Harvath.

  2             DR. HARVATH:  Yes.

  3             DR. SMALLWOOD:  Dr. Hollinger.

  4             DR. HOLLINGER:  Yes.

  5             DR. SMALLWOOD:  Dr. Nelson.

  6             DR. NELSON:  Yes.

  7             DR. SMALLWOOD:  Dr. Stuver.

  8             DR. STUVER:  Yes.

  9             DR. SMALLWOOD:  Dr. Simon, how would you

 10   have voted if you could?

 11             DR. SIMON:  Yes.

 12             DR. SMALLWOOD:  It takes a little longer

 13   to add up these, but I think that they are

 14   unanimous.  Unanimous yes votes.

 15             DR. NELSON:  The second question.

 16             MS. CALLAGHAN:  Yes, unfortunately, you

 17   are not getting away that easy.

 18             If yes, should the standards for recovered

 19   plasma include:

 20             (a)  Negative screening tests for anti-core and

 21   anti-HTLV I/II?

 22             DR. SIMON:  I think it is difficult

 23   because if the other components are collected, and

 24   I presume those tests would be required although

 25   plasma could be pulled out, but I am of the 

                                                               260

  1   opinion, scientifically and medically, to answer no

  2   to that, I don't believe that that contributes to

  3   the safety or efficacy of the final product.

  4             We have talked about the need for the

  5   hepatitis antibody in plasma preparations.  The

  6   HTLV I/II, I believe is pretty well substantiated

  7   not to be transmitted by plasma.  So, I think we

  8   should answer no to that question.

  9             DR. NELSON:  Except that remember that red

 10   cells are being collected.

 11             DR. SIMON:  You still would have to have

 12   it for these other components.  They would have to

 13   have it for all those other components.

 14             DR. CHAMBERLAND:  Also, my understanding

 15   is, if I heard correctly, I believe it was from the

 16   ABC statement, was that currently, if the screening

 17   test came up with a positive anti-core, blood

 18   collectors were presently sending those, the

 19   recovered plasma, for manufacture, and discarding

 20   obviously the other components.

 21             The other half of that, though, is would

 22   the person be deferred from further donation in

 23   accordance with the current FDA guidance since they

 24   would not qualify, if you will, as a whole blood

 25   donor. 

                                                               261

  1             DR. BIANCO:  That is correct.  So, it is

  2   only for the donations.  It will be one or actually

  3   two donations.

  4             DR. EPSTEIN:  I just want to comment.  FDA

  5   has been of a divided mind over this, between anti-core and

  6   HTLV.  In the case of anti-core, as has

  7   been explained by Dr. Finlayson and others, we do

  8   permit, indeed encourage, continued use of the

  9   anti-core positive unit in the fractionation pool,

 10   and so we allow the use of the unit collected from

 11   the donor, who would become deferred from whole

 12   blood collection, to be sold and fractionated.

 13             However, for HTLV, we took the opposite

 14   tack, which is that we discouraged use of the

 15   marker-positive plasma.  It is not in the

 16   regulations, it is in the guidance, and the reason

 17   was that we were concerned that if we allowed the

 18   product streams to go two ways under different

 19   standards, we might increase the error of use of

 20   the transfusable component, which is the point that

 21   Dr. Nelson I believe was trying to make.

 22             So, you know, the FDA, I guess sits on the

 23   fence because we have done it one way in one

 24   setting and the other way in the other setting, but

 25   the underlying issue of concern is the 

                                                               262

  1   inappropriate use of the transfusable component.

  2             We agree with Dr. Simon that we are not

  3   actually worried about the derivative as the end

  4   product because we do know that the  derivatives

  5   don't transmit HTLV.  So, it is really a question

  6   about how worried are we about things getting mixed

  7   up at the blood center is really what that question

  8   comes down to.

  9             In other words, we know we exclude the

 10   unit for use for transfusion, should we be

 11   permissive about continued use for fractionation.

 12             DR. NELSON:  And given the fact that

 13   medical error, et cetera, is a substantial, perhaps

 14   one of the major contributions to significant

 15   errors.  I think this is really an issue, yes.

 16             DR. ALLEN:  It is an important issue.  On

 17   the other hand, the person has already donated the

 18   unit of blood, and it was the lab test, not the

 19   donor history screening, that disqualified the

 20   transfusable units.

 21             In many instances, I assume that by the

 22   time the lab testing is completed, that the

 23   separation of the components has already occurred,

 24   and they are all in the system, and you have got to

 25   identify and recover and make a determination of 

                                                               263

  1   all of those components anyhow.

  2             I think, depending on the system that it's

  3   in place in a given blood bank, one could make an

  4   argument that if there is not a safety i.e., an

  5   infection risk to allowing that unit to go into the

  6   recoverable plasma process, that that could be as

  7   easily done as discarding the unit.

  8             They have to have a process for

  9   identifying the ultimate disposition of each of the

 10   components that were created anyhow.

 11             I certainly wouldn't want the donor coming

 12   back in a second time.  I think there could be an

 13   argument that as long as it is already in the

 14   system, it could be handled safely one way as the

 15   other.

 16             DR. NELSON:  Are you ready to vote on

 17   this?

 18             DR. LEW:  If I could just add one comment

 19   to that, though, it seems like we shouldn't be

 20   finding a lot of patients, I suspect, who are going

 21   to come up positive for the antibody, so that is a

 22   rare event.  So, we are not going to lose a whole

 23   lot.

 24             Even though it is a rare event that they

 25   might make a mistake, that would be a very bad 

                                                               264

  1   mistake.

  2             DR. FITZGERALD:  This is actually one of

  3   the most problematic tests we do.  It has a high

  4   false positive rate, and you confirm the initial

  5   positive by putting the donor on surveillance.

  6   They come back in the second time, and are deferred

  7   after the second positive result.

  8             So, the core antibody test is problematic

  9   in and of itself.  On the next three questions, I

 10   would be inclined to abstain, because I don't think

 11   we have data to make a definitive recommendation to

 12   FDA one way or the other, and I would assume--

 13             DR. NELSON:  Are you talking about the

 14   core or the anti-HTLV?

 15             DR. FITZGERALD:  Core.

 16             DR. NELSON:  I think you were talking

 17   about the HTLV.

 18             DR. FITZGERALD:  I am sorry, I thought you

 19   were talking about core.  I would assume that now

 20   that you have the recommendation to set standards,

 21   you would work on a guidance document and producing

 22   standards for comment, and we would have the

 23   opportunity to look at more data and do those sorts

 24   of things.

 25             DR. NELSON:  Do you want to vote on this, 

                                                               265

  1   and you can abstain if you think that there is not

  2   sufficient data. The guidance document, whatever

  3   the regulations or standards the FDA eventually

  4   comes up with may be different than what we say

  5   here, but they have asked us to comment or to vote

  6   on this.

  7             DR. CHAMBERLAND:  I just have a request

  8   for one further clarification from Jay just to make

  9   sure I understand it.  Currently, what is allowed

 10   is, in the instance of recovered plasma, would be

 11   to allow a positive core, recovered plasma go

 12   forward for further manufacture, but a positive

 13   anti-HTLV, no, the guidance would suggest that it

 14   not go forward.

 15             So, that is the current system.  Do you

 16   have evidence or data that you can bring for us to

 17   consider in a more quantitative way, this important

 18   concern about mix-ups occurring vis-a-vis

 19   inappropriate release and whatever, because if I

 20   understand it correctly if we vote yes, then, we

 21   are making a change from the current practice.  If

 22   we vote no, then, the current practice would not

 23   change or at least that would be our

 24   recommendation.

 25             DR. NELSON:  At the same time, we would 

                                                               266

  1   put this recovered plasma standards with regard to

  2   this issue similar to the current source plasma.

  3             No, if we say yes, it will be the same as

  4   the current practice.

  5             DR. SMALLWOOD:  No, if you say no.  No

  6   will be the same as the current source plasma.

  7             DR. CHAMBERLAND:  No would be the same.

  8             DR. NELSON:  Right, that's what I meant.

  9             DR. FITZGERALD:  No would be a change

 10   because you are saying that you would allow a

 11   positive anti-HTLV to go forward or a positive core

 12   unit to go forward.  If you vote yes, you are

 13   making a change because you are saying a negative

 14   HTLV--either way, you are making a change.

 15             DR. CHAMBERLAND:  It is because you

 16   coupled these in one question when you consider

 17   them currently separately.

 18             DR. EPSTEIN:  This is correct, but the

 19   reason we framed it this way is what we are really

 20   asking is whether it should conform to the current

 21   source plasma standard.  That is what we are really

 22   saying.  You don't screen source plasma either for

 23   anti-core or for HTLV, so what we are saying is if

 24   you have done it on a whole blood donor, should we

 25   care. 

                                                               267

  1             So, the question really is should we

  2   harmonize the standard with source plasma.

  3             DR. CHAMBERLAND:  If you agree that you

  4   should harmonize, then the answer is--

  5             DR. EPSTEIN:  The answer would be no.  The

  6   answer would be no because you do not have a

  7   requirement to the negative test.  2(a), the answer

  8   would be no.

  9             But let's come back to the question.  What

 10   do we know about errors?

 11             MS. O'CALLAGHAN:  Based on the BPD data,

 12   there are very few, if any, deviations related to

 13   the inappropriate release of units that tested

 14   positive for HTLV I.  We see very few reports of

 15   those.  That is just not something that has

 16   occurred.

 17             DR. HOLLINGER:  How about for anti-HBC?

 18             MS. O'CALLAGHAN:  For core?  Well, because

 19   we have allowed to be released, the recovered

 20   plasma, we wouldn't see that as a deviation because

 21   it's okay to do that.  It's not considered a

 22   deviation.

 23             DR. NELSON:  Unless the red cells were--

 24             MS. O'CALLAGHAN:  That is what I was going

 25   to say, that for recovered plasma, we haven't seen 

                                                               268

  1   that.  For red cells, again, even that is very few,

  2   a handful maybe.

  3             DR. HOLLINGER:  And fresh frozen plasma

  4   would never be made from this anyway, is that

  5   correct?

  6             MS. O'CALLAGHAN:  That's right.

  7             DR. NELSON:  Okay.  Let's vote.

  8             DR. SMALLWOOD:  A vote is being taken on

  9   Question 2(a) as stated.  Should the standards for

 10   recovered plasma include:

 11             (a)  Negative screening tests results for

 12   anti-HBC and anti-HTLV I/II?

 13             Dr. Allen.

 14             DR. ALLEN:  Qualified no.

 15             DR. SMALLWOOD:  Dr. Chamberland.

 16             DR. CHAMBERLAND:  No.

 17             DR. SMALLWOOD:  Dr. Cunningham-Rundles.

 18             DR. CUNNINGHAM-RUNDLES:  Not enough

 19   information.  I am going to abstain.

 20             DR. SMALLWOOD:  Dr. DiMichele.

 21             DR. DiMICHELE:  I would agree with Dr.

 22   Cunningham-Rundles.  I have to abstain.  Same

 23   reason.

 24             DR. SMALLWOOD:  Dr. Fitzpatrick.

 25             DR. FITZGERALD:  Abstain. 

                                                               269

  1             DR. SMALLWOOD:  Dr. Lew.

  2             DR. LEW:  Abstain.

  3             DR. SMALLWOOD:  Dr. McGee.

  4             DR. McGEE:  Abstain.

  5             DR. SMALLWOOD:  Mr. Rice.

  6             MR. RICE:  Abstain.

  7             DR. SMALLWOOD:  Dr. Schmidt.

  8             DR. SCHMIDT:  Abstain.

  9             DR. SMALLWOOD:  Dr. Stuver.

 10             DR. STUVER:  No.

 11             DR. SMALLWOOD:  Dr. Fallat.

 12             DR. FALLAT:  Abstain.

 13             DR. SMALLWOOD:  Dr. Harvath.

 14             DR. HARVATH:  No.

 15             DR. SMALLWOOD:  Dr. Hollinger.

 16             DR. HOLLINGER:  Abstain.

 17             DR. SMALLWOOD:  Dr. Nelson.

 18             DR. NELSON:  No.

 19             DR. SMALLWOOD:  Dr. Simon, your opinion.

 20             DR. SIMON:  No.

 21             DR. SMALLWOOD:  I believe I counted 5 no

 22   votes and 9 abstentions.

 23             DR. NELSON:  Okay.  2(b).

 24             MS. CALLAGHAN:  Should the standards for

 25   recovered plasma include: 

                                                               270

  1             (b)  Specifications for allowable storage

  2   conditions and dating periods?

  3             DR. SIMON:  I would think everything has

  4   directed us to a yes on this.  This would

  5   presumably be the reason for doing it.  This would

  6   allow them to allow fresh frozen to be converted,

  7   for example, before a year, and so on, and so

  8   forth.

  9             DR. NELSON:  Do you want to vote?

 10             DR. SMALLWOOD:  Vote on Question 2(b).  I

 11   can make this easy.  If everyone is in agreement, I

 12   can call it unanimous.

 13             DR. NELSON:  Can you do a show of hands?

 14             DR. SMALLWOOD:  I will do it the right

 15   way.  I will call each name.

 16             That is the question I asked.  Are there

 17   any opposing votes?  Are there any abstentions?

 18   There is a unanimous yes by all voting members.

 19   Dr. Simon, you agree. Thank you.

 20             DR. NELSON:  2(c).

 21             MS. CALLAGHAN:  Should the standards for

 22   recovered plasma include:

 23             (c)  Labeling requirements similar to

 24   source plasma to distinguish appropriate use for

 25   manufacturing of injectables versus non-injectables 

                                                               271

  1   based on the preparation and storage conditions?

  2             DR. SIMON:  I would have probably not

  3   thought so until I heard Dr. Fitzpatrick's

  4   comments.  I didn't realize it was common within

  5   the blood centers to label things for non-injectable use,

  6   and I would think if that is going

  7   on, that we would need labeling requirements

  8   because we certainly wouldn't want anything that

  9   was unsuitable for injectable to be able to be so

 10   labeled.

 11             So, I would think here also it would be

 12   something we would want, so it would be yes.

 13             DR. NELSON:  Vote.

 14             [Vote.]

 15             DR. SMALLWOOD:  I just want it to be clear

 16   for the record.  I am supposed to call the roll,

 17   however, if we have unanimous votes.  All right.

 18             Are there any opposing votes at all?

 19             [No response.]

 20             DR. SMALLWOOD:  Any abstentions?

 21             [No response.]

 22             DR. SMALLWOOD:  Then, it is a unanimous

 23   yes for No. 2(c).

 24             Dr. Simon.

 25             DR. SIMON:  Yes. 

                                                               272

  1             DR. SMALLWOOD:  Thank you.

  2             DR. NELSON:  Question 3.

  3             MS. CALLAGHAN:  The last question, and you

  4   are not getting away this easy on this one.

  5             Do committee members have additional

  6   suggestions regard product standards for recovered

  7   plasma?

  8             DR. NELSON:  This one is yes, no and

  9   maybe.

 10             DR. ALLEN:  I think we have already heard

 11   a number of suggestions, and I have written down a

 12   few things, and I would just like to offer four

 13   brief statements, and then we could see what we

 14   want to do with this.

 15             I would recommend that:

 16             1.  The issue of "donation intent" not be

 17   a fundamental principle in the standards.

 18             2.  Concurrent plasma collection, or

 19   whatever term is used, during apheresis procedures

 20   be allowed.

 21             3.  Relabeling fresh frozen plasma for use

 22   as recovered plasma at any time prior to the

 23   outdating be allowed.

 24             4.  The impact on small intrastate blood

 25   collectors of standards and licensure for recovered 

                                                               273

  1   plasma be studied and appropriate accommodations

  2   for these collectors be considered as part of the

  3   proposed standards.

  4             DR. FITZGERALD:  I just wanted to get

  5   again on the record retention, it is going to be

  6   problematic, so you are going to have to address

  7   whether you have to retain the donor records for

  8   the life of the manufactured product, as well as

  9   the plasma product.

 10             DR. SIMON:  I think on that one, though,

 11   they have addressed it for source plasma, if I am

 12   correct.  It's 10 plus 1.  I think source plasma

 13   has a 10-year.

 14             MS. CALLAGHAN:  Plus 6 months.

 15             DR. SIMON:  Plus 6 months.  So, it has

 16   been addressed for source plasma, so I assume they

 17   could address it the same way for this new plasma.

 18             DR. HOLLINGER:  Jim, I guess I would agree

 19   with most of the things you mentioned about things

 20   to take into account.  I am not sure that I would

 21   want to see it to be a different regulation for the

 22   group that are just doing intrastate processing

 23   even though--I mean there may be some hardships

 24   here, but I don't see how you can have a different

 25   standard. 

                                                               274

  1             DR. ALLEN:  I basically agree with you.  I

  2   think the issue ought to be addressed, however, and

  3   that some of them ought to be brought into the

  4   process and asked for comments and impact.  I agree

  5   that to the extent that you can avoid any

  6   difference at all, it ought to be done, but

  7   accommodations might be considered at least.

  8             DR. DiMICHELE:  The only other question I

  9   would have is whether if more recovered plasma is

 10   used in the fractionation industry, and the ratios

 11   of source to whatever we are going to call the

 12   recovered plasma change, I think there has been

 13   some debate or certainly some old data, but not any

 14   new data, that standardization, for instance, if it

 15   is going to be used for factor VIII, what are the

 16   factor VIII levels in recovered plasma versus

 17   source plasma.

 18             I am not sure.  You know, I just don't

 19   know about this, but I am just bringing forward

 20   that maybe there needs to be, for whatever that

 21   plasma is going to be used, that there needs to be

 22   good standards, so that understand if there is a

 23   mix and a change in the mix, what that means

 24   relative to the particular product that physician

 25   or patients may have an interest in. 

                                                               275

  1             DR. FALLAT:  I would second what you just

  2   said, and since I think I heard from industry that

  3   they do treat the source plasma differently and

  4   process it, they don't lump it together, is that

  5   right?  It's the derivatives that are derived from

  6   one or the other.

  7             I think it becomes an important issue to

  8   know what the standards are of that derived product

  9   when it comes from two different sources.

 10             DR. NELSON:  Presumably, this change, if

 11   the FDA adopted any of these regulations, they may

 12   not be in the future separate, but it would be of

 13   some advantage probably to keep them separate just

 14   because of the way they are collected and processed

 15   are different and were a problem to develop

 16   relating to that difference in processing, storage

 17   handling, or population, it might be easier to

 18   identify what the problem was if they were kept

 19   separate as they are now.

 20             DR. SIMON:  I believe the majority of the

 21   recovered plasma product in the United States is

 22   American Red Cross, so at least that portion is

 23   clearly identified, and is all from volunteer

 24   donors.  So, we have experience with that being in

 25   use. 

                                                               276

  1             At least with factor VIII, it is measured

  2   by the end product in terms of the factor VIII

  3   assay.  Now, with things like IVIG, where there is

  4   no standardization, then--I shouldn't say no, but

  5   where there isn't this type of standardization in

  6   terms of antibody levels to each of the various

  7   organisms, there could be some differences, and it

  8   would be interesting to study that.

  9             DR. DiMICHELE:  I would just like to add,

 10   though, that factor VIII is not factor VIII, is not

 11   factor VIII, and I think that there may be

 12   differences with processing differences in terms of

 13   the final biochemical product.

 14             I just think that, you know, if there is

 15   going to be a really substantial difference in the

 16   plasma, in the fractionation mix, that we have to

 17   understand what that looks like.

 18             I guess I would just encourage the FDA to

 19   request that.

 20             DR. HOLLINGER:  It seems to me that the

 21   most important thing that I have heard here so far

 22   has to do with storage.  I mean that is really the

 23   critical thing, and it sounds like the Red Cross is

 24   doing a lot of that, I mean with their short supply

 25   agreements, that there are some really finite time 

                                                               277

  1   periods in which they have to freeze samples down,

  2   I think that is really critical.

  3             If you are going to call it fresh frozen

  4   plasma, that is done very nicely, and then the

  5   question is how much further out should one go

  6   before allowing this to be used as recovered

  7   plasma, I think there needs to be a real finite

  8   level whether it is three days, four days, five

  9   days, or what.

 10             DR. NELSON:  I think the FDA probably

 11   should look at some of the short supply agreements

 12   or whatever, and take some of the requirements and

 13   criteria that seem to be applicable or useful if

 14   they are going to make it into standards, and there

 15   need to be some standards.

 16             I think we could just vote yes, that there

 17   need to be some standards.

 18             DR. SCHMIDT:  Come up with a new name for

 19   recovered plasma.

 20             MS. CALLAGHAN:  Any suggestions?

 21             DR. NELSON:  Jay, is this discussion

 22   sufficient?

 23             DR. EPSTEIN:  I appreciate the patience

 24   and endurance of the committee, and I think we have

 25   had the discussion we need. 

                                                               278

  1             MS. CALLAGHAN:  Thank you.

  2             DR. NELSON:  Let's move on to the final

  3   item.

  4             We are now going to discuss the Uniform

  5   Donor History Questionnaire.

  6             Alan.

  7             II.  Uniform Donor History Questionnaire

  8                   Introduction and Background

  9             DR. WILLIAMS:  Just to establish some

 10   context, what we are going to discuss in this

 11   session is basically reviewing the product of a

 12   task force that has been looking at the donor

 13   screening instruments and has produced its final

 14   report in addition to providing cognitive studies

 15   really for the first time on a questionnaire that

 16   is used over 13 million times a year for donors of

 17   whole blood and blood components.

 18             A really very important issue and I think

 19   some very impressive progress in tightening up the

 20   donor qualification procedure.

 21             Because some members of the committee are

 22   new, I want to very briefly give a little bit of

 23   introduction and then introduce the topic.

 24             [Slide.]

 25             Why is accurate donor qualification 

                                                               279

  1   important? Obviously, the first reason is to

  2   maximize blood safety with respect to known agents

  3   where laboratory screens are in place, these

  4   screens are very sensitive, they there are still

  5   very rare errors associated with window periods,

  6   associated with infections, testing errors, and

  7   produce release errors.

  8             Also important, however, are unknown

  9   threats to the blood supply when there is no

 10   laboratory screening test available.  In some

 11   cases, donor questioning may be our only protection

 12   for the blood supply in deferring donors who may be

 13   carrying a transmissible agent.

 14             The second reason is to minimize donor

 15   loss due to inappropriate deferral.  There is a

 16   tendency to add questions every time we are

 17   concerned about something that might threaten blood

 18   safety, and as we all are aware, sometimes these

 19   questions are nonspecific to the point that we are

 20   losing donors that we shouldn't be losing simply

 21   due to inaccuracy in the screening process, the

 22   questionnaire  process.

 23             There is a lot of operational impact

 24   associate with donor qualification.  If you get an

 25   incorrect answer, and this becomes known later, 

                                                               280

  1   there is what is known as postdonation information

  2   that, at the highest level, could result in product

  3   recalls, which have major impact.

  4             Fourth, and often isn't mentioned, is the

  5   fact to minimize staff exposure to infectious

  6   donations, these bloods are drawn, processed in the

  7   laboratory, and it is simply better not to have the

  8   unit of blood drawn at all if there is a risk.

  9             [Slide.]

 10             There are various stages of donor

 11   qualification. The first is exclusion of risk

 12   populations.  Protections that have been in place

 13   for some time are the exclusion of prisoners and

 14   the requirement for special labeling for paid

 15   donors of whole blood.

 16             There are self-deferral where the

 17   potential donor sees educational information prior

 18   to donation, and simply concludes that they are not

 19   appropriate for a donation and doesn't appear.

 20   Similarly, that same process can happen at the

 21   blood site before the interview is actually done

 22   with a staff member.

 23             There can be deferral by staff during the

 24   interview process.  This is really the focus of

 25   today's discussion, however, some of these prior 

                                                               281

  1   factors are really much larger in magnitude than

  2   the actual deferral due to staff interview.

  3             Then, there is postdonation information

  4   already commented on.

  5             [Slide.]

  6             Current donor qualification.  There are

  7   certainly successes.  We know by comparison with

  8   general population studies that blood donors coming

  9   in for the first time have lower prevalence levels

 10   than the general population, and this is certainly

 11   an impact of the education and screening process.

 12             We know there are some failures.  When a

 13   donor is found positive for an infectious marker,

 14   particularly HIV or HCV, often by interview, we can

 15   identify that this donor had  a risk factor that

 16   should have prevented donation, and there are

 17   certainly hurdles to providing an accurate donor

 18   qualification - limitations in having donors read

 19   materials and apply that information to their own

 20   situation, concerns about validity assessments both

 21   for the criteria used for the deferral process,

 22   whether they are scientifically accurate, and also

 23   the methodology of the screening process, whether

 24   that is optimized to the greatest extent.

 25             Behavior science has made great progress, 

                                                               282

  1   but it is still certainly considered a softer

  2   science than, for instance, the development of

  3   laboratory tests, and this has had an impact on the

  4   donor qualification process, as well, in that it is

  5   not regulated as tightly as it infectious disease

  6   testing, the science isn't quite as well defined,

  7   and the financial drivers that are there for the

  8   laboratory tests simply don't exist for the donor

  9   screening process, so the progress has been a

 10   little slower.

 11             [Slide.]

 12             There have been some major research

 13   advances particularly associated with defining AIDS

 14   risk factors in the general population.  One of

 15   these includes the use of a computer self-assisted

 16   questionnaire with audio components.

 17             This is probably the future of donor

 18   screening, but it is not quite there yet.  There

 19   are some sites that are using some very preliminary

 20   version of this type of screening, and as

 21   mentioned, there are now available some cognitive

 22   studies of the donor screening questionnaire.

 23             This was first done at the Red Cross

 24   through the use of focus group studies by Dr.

 25   Orton, et al., and most recently through the 

                                                               283

  1   National Center for Health Statistics, which we

  2   will be speaking about their studies today.

  3             [Slide.]

  4             I wanted to mention briefly that there is

  5   a draft guidance in the field right now for

  6   comment.  It is entitled "Streamlining the Donor

  7   Interview Process: Recommendations for Self-Administered

  8   Questionnaires."

  9             One particular component of this, which

 10   think you will hear discussed a little bit in the

 11   other presentations, is that this draft guidance

 12   contains FDA current thinking that self-administered

 13   questionnaire processes should not be

 14   used for brand-new blood donors at a blood center

 15   with the exception of audio, computer self-administered

 16   interview.

 17             This is for a couple of reasons.  Number

 18   one, the studies mentioned earlier by Joe Catana

 19   and Turner, and others, have shown that an audio

 20   component is important to getting individuals to

 21   recognize the content of the question.

 22             There are also concerns about literacy,

 23   not the basic levels of whether someone reads or

 24   not, but somewhat different levels of functional

 25   illiteracy and scientific illiteracy.  I think it 

                                                               284

  1   is a fair assumption that not every donor, reading

  2   every question, understands the full content of

  3   that question.

  4             Also included in the guidance are a

  5   recommendation for secondary measures at the blood

  6   collection centers to assure donor understanding,

  7   provision of adequate instruction assistance and

  8   quality assurance assessment related to the

  9   qualification process, that new or modified

 10   questions which come along should, in fact, be

 11   highlighted in some way or else administered by

 12   staff interviews, so that repeat donors who have

 13   seen this questionnaire many times have new

 14   questions pointed to them, so that they can look at

 15   them with special attention.

 16             There are special preventions in the

 17   guidance for audio, visual, and CASI technology as

 18   it grows and it harmonizes with the new final

 19   guidance for deferrals related to potential variant

 20   CJD exposure.

 21             [Slide.]

 22             The draft guidance was announced in the

 23   Federal Register in April and comments are due June

 24   21st, 2002, and we look forward to receiving those

 25   comments. 

                                                               285

  1             [Slide.]

  2             With respect to today's topic, the Uniform

  3   Donor History Task Force has been organized by the

  4   American Association of Blood Banks, but contains

  5   members from numerous industry and agency

  6   representatives.

  7             Within the FDA, Judy Ciaraldi has really

  8   been I think the primary representative from the

  9   regulatory side. Robin Biswas and John Lee

 10   participated early on in the task force

 11   discussions, and Sharyn Orton and I were also

 12   members of the task force until we joined FDA and

 13   when we became liaisons to the task force.

 14             [Slide.]

 15             The subject was discussed just about a

 16   year ago at the Blood Products Advisory Committee,

 17   and this was kind of an interim discussion, no

 18   questions, related to the approach that was being

 19   taken by the task force and the way that the FDA

 20   would review the product of the task force.

 21             The committee made comments about the

 22   cognitive s studies proposed, the questions

 23   proposed for elimination, the transfer of some

 24   questions out of the questionnaire itself to the

 25   written educational information. 

                                                               286

  1             The committee also commented on some

  2   elements of the redesigned questionnaire, and the

  3   questions were somewhat varied, but very helpful,

  4   but overall, the support for the UDHQ Task Force

  5   effort was quite strong.

  6             Importantly, the committee strongly

  7   discussed and recognized the need for funding

  8   related to this program, and fortunately, the

  9   National Heart, Lung, and Blood Institute

 10   generously provided some funding, so that the

 11   National Center for Health Statistics could

 12   participate in the cognitive studies.  I think this

 13   really helped provide definition to this whole

 14   project.

 15             [Slide.]

 16             The speakers for this subject, next will

 17   be Dr. Joy Fridey, who is in fact the chairman of

 18   the task force and the senior vice president for

 19   Medical Affairs at the Blood Bank of San

 20   Bernardino.

 21             Following Joy will be cognitive studies

 22   presented by Dr. Paul Beatty at the National Center

 23   for Health Statistics.  FDA's own Judy Ciaraldi

 24   will be providing an FDA perspective on the review

 25   of the document submitted by the task force or the 

                                                               287

  1   current status and some of the thoughts, and then

  2   finally, I will come back with a couple of

  3   questions for the committee, which I will just

  4   introduce right now.

  5             1.  Does the committee believe that the

  6   revised Uniform Donor History Questionnaire

  7   proposed by the task force is suitable to screen

  8   donors of allogeneic whole blood and blood

  9   components for transfusion?

 10             2.  What additional comments does the

 11   committee have on:  (a)  The validation process of

 12   the UDHQ, and (b) the specific content of the UDHQ

 13   questions.

 14             As you consider these questions, I just

 15   want to present very clearly that these questions

 16   presented are designed for the whole blood and

 17   blood component donors, and not the source plasma

 18   donors.  As you will hear from PPTA, that is a

 19   somewhat different process.  It overlaps quite a

 20   bit with the current proposed questions, but will

 21   differ a little bit, so we are primarily talking

 22   about whole blood donation with respect to these

 23   questions.

 24             Thank you.

 25             DR. NELSON:  Thank you, Alan. 

                                                               288

  1             Joy Fridey.

  2             Overview of AABB Task Force UDHQ Project

  3             DR. FRIDEY:  I would like to thank Dr.

  4   Smallwood, Dr. Epstein, CBER, and the Blood

  5   Products Advisory Committee for the opportunity to

  6   be here today.

  7             Almost exactly one year ago today, it was

  8   June 14th, I stood before this committee to present

  9   a proposal for modifying the Blood Donor Screening

 10   Questionnaire, and, in fact, by that time we

 11   already had a working draft of the revised

 12   questions that were submitted to the BPAC.

 13             At that time, you provided insight and

 14   ultimately endorsed our approach, and today, I am

 15   here to give you a final report on the work that

 16   has been done over the past year and to ask for

 17   your input on the new donor screening materials.

 18             [Slide.]

 19             Briefly, I will give you an introduction

 20   and background of why we launched this project at

 21   all, what our redesign goals were, the task force

 22   members and resources, I think it is important for

 23   you to know who these people were, who are making

 24   these kinds of decisions; the new documents, there

 25   is not just one, there are actually several that we 

                                                               289

  1   have submitted to the FDA for review and that you

  2   all have copies of; and then the efforts that we

  3   undertook to communicate with the various

  4   stakeholders and obtain their buy-in.

  5             [Slide.]

  6             This has truly been an exceptional

  7   project.  The FDA came to the AABB, recognizing

  8   that there were problems with the questionnaire,

  9   and asked the AABB to head up a project to redesign

 10   the questionnaires.

 11             There has been extensive collaboration by

 12   numerous stakeholders.  We basically pulled in

 13   everyone that we thought should be at the table.

 14   There has been a tremendous commitment on the part

 15   of the task force.  This has been a two-year

 16   project.  People have stayed with it, stayed

 17   involved.

 18             We have used a groundbreaking approach to

 19   redesigning and designing the blood donor screening

 20   questionnaire.  It is not groundbreaking from a

 21   survey design perspective because this is what is

 22   done all the time, and we have simply taken those

 23   principles and applied them to the donor screening

 24   context, and we believe that we have obtained

 25   support and buy-in from the constituents. 

                                                               290

  1             [Slide.]

  2             Dr. Williams has already discussed the

  3   importance of screening blood donors through

  4   questioning.  The first nationwide questionnaire

  5   was advocated by the American Association of Blood

  6   Banks in 1953.

  7             Since that time, many questions have been

  8   added, and by the early nineties, it literally was

  9   a mishmash of non-chronological questions, quite

 10   confusing to donors, and the Blood Centers of

 11   California developed a model questionnaire that had

 12   been simplified and questions put in more

 13   appropriate order.

 14             This was picked up by the AABB, which then

 15   requested FDA input and approval, and it became

 16   known as the AABB Uniform Donor History

 17   Questionnaire, and the BPAC members have copies of

 18   that very interesting document, which hopefully

 19   will go the way of the dinosaurs in their packet.

 20             [Slide.]

 21             Now, some evidence that there have been

 22   problems with the questionnaire, we find in the FDA

 23   blood product deviation reports.  In 2001, nearly

 24   80 percent of deviation reports related to errors

 25   in the donor qualification process.  Also, the 

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  1   American Association of Blood Banks surveyed many

  2   blood centers around the country in 2000 to find

  3   out what they were doing in terms of screening.

  4             Now, everyone was complying with the AABB

  5   and FDA guidelines, but there was considerable

  6   variation in the format, methods of administration,

  7   and the education materials that were used.

  8             [Slide.]

  9             Currently, the problems that donors, blood

 10   centers, the FDA, all of us agree on, is that the

 11   questionnaire is very long, extremely complex--and

 12   I will talk about that in second--uses medical and

 13   scientific jargon, which frankly, most people can't

 14   relate to or understand, it uses non-chronological

 15   time frames, repeatedly questions donors about

 16   events that could never have been repeated if they

 17   had once already said no to them, and there has not

 18   been an abbreviated version for frequent donors

 19   with the exception of one blood center in the

 20   Midwest.

 21             [Slide.]

 22             The questionnaire has more than 70

 23   informational items.  Some of them are a single

 24   item question, but half of the questions are either

 25   compound questions or contain multiple items.  Now, 

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  1   this does not include the demographic information.

  2   That is another information set that we ask of

  3   donors.

  4             [Slide.]

  5             This is an example of compound, multi-item

  6   question.  It is one of the worst ones.  "In the

  7   past 12 months, have you had a tattoo applied," et

  8   cetera.  You can read it for yourself.  A donor has

  9   to sit down and wade through this and come up with

 10   an appropriate answer.

 11             [Slide.]

 12             Another complex question, "Female Donors:

 13   In the past 12 months --", et cetera.  You can read

 14   it.  This is a very complicated question, and not

 15   every question is this bad, but this is just to

 16   give you a flavor of what donors are dealing with.

 17             [Slide.]

 18             From a scientific perspective, however,

 19   the most fundamental problems are there has not

 20   been input from survey design experts in the

 21   designing questions.  Questions do not even follow

 22   the basic rules of survey design.  There are too

 23   many items in them, and they are too complicated,

 24   and there, by and large, has not been any kind of

 25   evaluation for comprehension and usability. 

                                                               293

  1             [Slide.]

  2             So, we have to ask, how accurate and

  3   complete is the information provided by donors, and

  4   is there a safety issue.  Now, I am not at all

  5   dismissing the questions we have been asking for

  6   years in terms of their ability to provide

  7   safeguards.

  8             What I am saying is that I think that we

  9   can do it better and enhance at least safety and we

 10   have to ask do the complexity and length serve as

 11   disincentives to donors.  This could raise supply

 12   issues.

 13             [Slide.]

 14             As a result, the project was launched at

 15   the initiation of the FDA in June of 2000, two

 16   years ago, and off we went.

 17             [Slide.]

 18             Now, a couple of months after that, in

 19   October of 2000, there was a joint AABB and FDA

 20   workshop to help provide suggestions on how the

 21   task force might attack this project.  These were

 22   recurring themes of that conference.

 23             One, there had to be a balance between

 24   safety and availability, something I have already

 25   alluded to.  The questionnaire and the questions 

                                                               294

  1   had to be simplified.  There needed to be a renewed

  2   emphasis on donor education because this is such a

  3   complicated process.

  4             The actual mechanics of drawing a unit of

  5   blood are not complicated, but the screening

  6   process has.  Validation or at least evaluation for

  7   comprehension of any questions that are asked of

  8   donors, an abbreviated version for repeat donors,

  9   and the need for blood centers to move towards CAI,

 10   computer assisted interviewing.  Software right now

 11   is out there, it us undergoing refinement.  A few

 12   blood centers have used it, but by and large, the

 13   majority of blood center will continue for the next

 14   few years at least to use the manual approach that

 15   is in place.

 16             [Slide.]

 17             So, we have five overall goals, and these

 18   are what they are.

 19             1.  To simplify the wording and questions

 20   mainly to improve donor comprehension, but also to

 21   enable self-administration by the donor.

 22             2.  To evaluate changes using accepted and

 23   appropriate research methodologies, which I will

 24   discuss in more detail.

 25             [Slide.] 

                                                               295

  1             3.  To reformat the questionnaire, make it

  2   easier for the donors to follow and answer to.

  3             4.  Develop an abbreviated questionnaire

  4   for frequent donors, and define what a frequent

  5   donor is.

  6             5.  To standardize the donor educational

  7   materials.

  8             [Slide.]

  9             Our objectives in selecting the task force

 10   members were twofold:

 11             1.  We wanted to represent, we wanted to

 12   throw out a wide net and represent as many

 13   constituents as possible from government, from

 14   industry, which would be blood centers, plasma

 15   centers, and the public, which would be blood

 16   donors and recipients.

 17             2.  Obtain the appropriate methodological

 18   expertise.  We felt this was crucial to deliver a

 19   product that was scientifically sound.

 20             [Slide.]

 21             I am not going to read all of these, but

 22   we clearly had included the FDA and the CDC, the

 23   Department of Defense, the industry organizations -

 24   AABB, America's Blood Centers, which they are

 25   independent of the Red Cross and collect about half 

                                                               296

  1   the nation's  blood, Plasma Protein Therapeutics

  2   Association.

  3             We also had two research survey design

  4   specialists, one, in fact, who was a BPAC member

  5   last year, and the other one was from the National

  6   Center for Health Statistics, Paul Beatty.  We will

  7   hear from him today.

  8             There also was someone to represent the

  9   consumer, a public member.  This professor is an

 10   ethicist.  We had a statistician, and our neighbors

 11   to the north, who struggle with the same kinds of

 12   issues that we do, also were represented.

 13             [Slide.]

 14             This was work that was done predominantly

 15   on a volunteer basis.  We did it through literally

 16   dozens of conference calls, hundreds of e-mails,

 17   three, face-to-face meetings.  The members who

 18   participated volunteered their time and their

 19   talents.  There were several pro bono projects that

 20   were done.  Jerome Holland Laboratories sponsored

 21   the focus groups, Dr. Sharyn Orton did those.

 22             We needed some data tabulated.  John

 23   Boyle, the former BPAC member, his company

 24   tabulated those data, and the AABB provided

 25   administrative support and funded travel for the 

                                                               297

  1   members.  We didn't go to Tahiti or some place like

  2   that, we came here to this area.

  3             NHLBI provided funding for the NCHS

  4   Cognitive Evaluations.  This was through Dr. George

  5   Nemo's efforts and also Dr. Barbara Alving.  But I

  6   want to make a strong point here, that funding was

  7   not available for any other aspects of this project

  8   from government agencies or other entities.

  9             [Slide.]

 10             Now, I am going to focus on the new

 11   screening materials.  You heard about these last

 12   year, but I want to tell you what we have done and

 13   where we are now with them - the full-length

 14   questionnaire, the abbreviated questionnaire for

 15   frequent donors, the pre-screening educational

 16   materials, and the user brochures.

 17             [Slide.]

 18             The full-length questionnaire is a

 19   questionnaire for first time and infrequent donors.

 20   It contains all of the FDA-recommended items and

 21   AABB-required items.

 22             [Slide.]

 23             The goals of revision are to simplify and

 24   to re-format.

 25             [Slide.] 

                                                               298

  1             We basically took a very simple approach

  2   to simplifying.  Taking into consideration patient

  3   safety and donor safety, we asked two questions:

  4   what is the target information of the question that

  5   we are evaluating and working on, and what is the

  6   simplest way that a question can be stated?

  7             [Slide.]

  8             We wanted to avoid rarified phraseology.

  9   We wanted to break down most of the compound

 10   questions and multi-item questions.  We wanted to

 11   find a better way to get at the medications that

 12   the donors are taking, specifically those that are

 13   FDA-deferrable medications, and focus on the most

 14   germane of health conditions.

 15             [Slide.]

 16             Our thinking was that if we have better

 17   donor comprehension that there will be more

 18   relevant information and accurate information

 19   provided by the donor, there will be fewer errors

 20   and better information capture, and hopefully,

 21   improved safety.

 22             [Slide.]

 23             This is probably the most important slide

 24   of the entire handout because it shows the very

 25   iterative approach that we used. 

                                                               299

  1             First, we took the full-length Uniform

  2   Donor History Questionnaire, the AABB one which the

  3   committee members have.  We divvied it up into

  4   major sections - donor safety issues, patient

  5   safety issues, infectious diseases, and a survey

  6   design expert, Dr. Boyle, worked with the

  7   subcommittees who looked at each question and asked

  8   those two fundamental things, what is the point of

  9   asking this question, what is the target

 10   information, what is the simplest way we can ask

 11   it.

 12             When this was done, the entire task force

 13   reviewed that material and made some further

 14   adjustments.  At this point in time, we had a

 15   working draft and felt that it was important for

 16   the FDA to see what we were up to and to provide us

 17   with input.

 18             So, we sent a letter to CBER in May of

 19   last year, which contained the suggested revisions.

 20   At the same time, the focus group evaluation

 21   started, the task force refined the questions

 22   further based on that input.  Then, cognitive

 23   evaluation was done by the NCHES.

 24             We looked at that information, it was a

 25   40-some page document that we considered when we 

                                                               300

  1   were making our final revisions, and finally came

  2   up with final wording and questions.

  3             Along about September, CBER provided us

  4   with a very detailed and helpful letter, which

  5   expressed concerns and insights and suggestions for

  6   our proposed draft of the questions, and we

  7   integrated those comments in our final products.

  8             [Slide.]

  9             Just a few words about the focus groups.

 10   The focus group methodology was based on a

 11   methodology that was used for a published peer

 12   review article that appeared in Transfusion,

 13   written by Drs. Orton and Virvos in 2000, but there

 14   were four groups convened specifically for task

 15   force research purposes.  There was a nice

 16   demographic mix.

 17             The participants were eligible non-donors.

 18   These are people who had never donated blood

 19   before, but would qualify to donate blood, virgins,

 20   if you will.  They were presented with the

 21   questions that had been reworked and asked for

 22   feedback and alternative wording.

 23             [Slide.]

 24             The National Center for Health Statistics

 25   then performed cognitive evaluations.  I am going 

                                                               301

  1   to let Paul Beatty go through these, but the

  2   questionnaires, the medication deferral lists, the

  3   donor educational materials were evaluated by these

  4   individuals, and the questions were probed in a

  5   one-on-one laboratory setting with a trained

  6   interviewer to determine whether or not the

  7   questions were understandable and what revisions

  8   should be made.

  9             [Slide.]

 10             Now, I am not going to go through every

 11   single change that was made to every single

 12   question because we will be here until 10 o'clock

 13   tonight if we do that.  I know that we enjoy each

 14   other's company, but perhaps not that much.  But

 15   the committee members do have copies of all the

 16   questions, the revisions that were made, and the

 17   rationale for each one.

 18             So, I am going to go over some basic

 19   features, some key features of the full-length

 20   questionnaire.

 21             First of all, the questions all start out

 22   with a time-bounded approach.  This gives the donor

 23   a frame of reference.  "In the past [however long]

 24   have you done this or that?"  "Between the years of

 25   X and Y, have you done this or that?" 

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  1             The time frames we put into chronological

  2   order.  In the current questionnaire, they are not,

  3   they are all over the map and requires basically

  4   the donors to engage in what I like to refer to as

  5   "mental time travel," which can be very confusing.

  6   So, the questions now are in chronological order

  7   from the most recent, which is 48 hours for aspirin

  8   use or something that has aspirin in it, to have

  9   you ever.

 10             [Slide.]

 11             We also used something called "capture

 12   questions." You might also refer to these as wide

 13   net or umbrella questions which have already been

 14   used for many years to screen donors, and it is a

 15   standard screening tool.

 16             You want to throw out a wide net, so that

 17   you can identify donors to which that information

 18   applies, but also to which it doesn't apply.  If

 19   the information doesn't apply, the donors can move

 20   on.  It's a nice streamlining tool.  If the donor

 21   says yes to a capture question, then, there are a

 22   series of additional questions that have to be

 23   asked to find out what part of that information

 24   applies.

 25             It is very useful for a number of things - 

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  1   medications, travel, and so forth.

  2             The user brochure, which I will be

  3   discussing shortly, contains suggested follow-up

  4   questions for those instances in which a donor

  5   replies yes to a capture question, and the specific

  6   follow-up questions, though, could be spelled out

  7   individually by blood centers in their standard

  8   operating procedures.

  9             [Slide.]

 10             Here are two capture questions that are

 11   already in use.  No. 14 on the AABB questionnaire.

 12   We have used this for many years.  "In the past 3

 13   years have you been outside the United States or

 14   Canada?"  The purpose of this question is to

 15   identify individuals who might have traveled in an

 16   area where they could have been exposed to malaria.

 17             We felt this was a great question.  We

 18   couldn't think of a better way to reword it.  We

 19   kept it.

 20             Question 30A.  This is to identify people

 21   who may have been exposed to HIV Group O.  This is

 22   how it currently reads, but we felt we really want

 23   to know if they have been in Africa.  That is the

 24   capture information.  So, we asked them, and we

 25   have changed this, we will ask them:  "Have you 

                                                               304

  1   ever been in Africa?"

  2             If they say no, it takes care of travel,

  3   it takes care of residence.  You can move on to the

  4   next item.  But if they say yes, then, they are

  5   asked, "Did you travel there, did you live there?"

  6             So, this is just an example of capture

  7   questions and how they are used.

  8             [Slide.]

  9             We have also embedded within the full-length

 10   questionnaire, some quality assurance tools.

 11   The purpose of these are to assess if the donor is

 12   paying attention, what I call are so-called

 13   surprise questions.  The donor really is expecting

 14   to answer "no" to a lot of these, but if you have

 15   something in there where they have to say "yes,"

 16   perhaps if they answer "no" to it inappropriately,

 17   then, the staff can pick up on that and probe with

 18   them further on, is it truly relevant information

 19   that they are trying to give or were they not

 20   paying attention.

 21             Another kind of quality assurance tool is

 22   that the gender-based questions require specific

 23   responses from a member of the opposite sex, to

 24   there are at least three questions in the full-length

 25   questionnaire that are gender specific.  It 

                                                               305

  1   starts out "Female donors, have you X, Y, Z," and

  2   there is a little set of instructions in

  3   parentheses that say "male donors check no."

  4             They are not allowed to leave it blank,

  5   they are not allowed to write "not applicable."  If

  6   they do those things, we have to ask, one, were

  7   they not following instructions, or, two, weren't

  8   they paying attention.

  9             So, these are the kinds of things that are

 10   in the questionnaire for determining if the donor

 11   is with it, if you will, or with us.

 12             [Slide.]

 13             Now, there are many medications listed on

 14   the medication list, specific medications, most of

 15   which are FDA-deferrable medications.  This has

 16   cluttered the questionnaire and also made it more

 17   difficult as questions need to be asked for blood

 18   center to incorporate that information.

 19             [Slide.]

 20             Question No. 10 actually is the question

 21   that deals with medications.  I have just

 22   abbreviated them for you.  They are actually full-length

 23   questions, a proper question with a noun and

 24   verb.

 25             What we have determined is another 

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  1   approach may be to simply say to the donor, "Please

  2   read the Medication Deferral List," which I will

  3   show you in a second.  "Have you ever taken any

  4   medications on the Medication Deferral List?"

  5             [Slide.]

  6             Again, the committee has a copy of this,

  7   but this is what the Medical Deferral looks like,

  8   and the donor is expected to go down and look at

  9   each of these items.  If they haven't taken any of

 10   them, they say "no," the screener moves on.  If

 11   they say "yes," which medication, when did you take

 12   it?

 13             If it is clear that the donor is not

 14   giving the medication list its due, the donor

 15   glances at it, says "no," it is up to the screener

 16   to give the list back to the donor and ask them to

 17   review it carefully.  This is not something we want

 18   them to blow off.

 19             So, that is the full-length questionnaire.

 20   We did not set out with a specific number of

 21   questions what we wanted it to have.  It turns out

 22   that it has 48 questions, which actually is a

 23   little more than the number of numbered questions

 24   on the current questionnaire, but as you look at

 25   the full-length questionnaire, I think you can 

                                                               307

  1   appreciate and compared to the AABB, the current

  2   version, that is much simpler and the wording is

  3   much easier to understand.

  4             [Slide.]

  5             I would like to say a few words now about

  6   the abbreviated questionnaire for frequent donors.

  7             Currently, a donor has to answer every

  8   question at every donation including things that

  9   never could have been repeated, for instance, if

 10   they had ever taken Human Derived Growth Hormone.

 11   Well, that product was not available after the

 12   early 1980s.  Why do you have to keep asking that

 13   question of a donor every time they donate when, if

 14   they have said no, and it was an accurate answer,

 15   it's over, it's done.

 16             I would like to go to the next slide and

 17   then come back to this one, if I could, please.

 18             [Slide.]

 19             What the abbreviated questionnaire does is

 20   that it integrates the FDA parameters.  Elizabeth

 21   Callaghan has given a number of very helpful talks

 22   on what the FDA expectations were for an

 23   abbreviated questionnaire, things like what do you

 24   do if a blood center accidentally administers an

 25   abbreviation questionnaire to a donor who should 

                                                               308

  1   have had the full-length questionnaire, how do you

  2   handle new questions.  These are examples of some

  3   of the issues that the FDA wanted us to address and

  4   we have.  The committee has that.

  5             Also, to define a frequent donor, and this

  6   is someone who has donated at least twice.  One of

  7   those donations had to have been within the past

  8   six months, and both donations, at least two

  9   donations, the donor had to have been screened

 10   using the full-length questionnaire.

 11             We chose twice because we feel that

 12   screening is an educational process.  If they have

 13   been through the full-length questionnaire at least

 14   twice--and I can tell you there are millions of

 15   donors out there who have been through the full-length

 16   questionnaire now many, many, many times--if

 17   they have been through it at least twice, they have

 18   gotten the gist of the kind of information that we

 19   are seeking.

 20             Now, if we could go back.  Thank you.

 21             [Slide.]

 22             So, what the abbreviated questionnaire

 23   does is it eliminates the non-repeatable event

 24   questions, and it identifies recent changes, that

 25   is, since their last donation, which could not have 

                                                               309

  1   been any longer than six months ago, in their

  2   health, travel, and behavior, and this is where we

  3   are able to pare out a number of the questions that

  4   appear on the full-length questionnaire.

  5             It obviously retains questions about risk-

  6   associated activities that are relevant, it uses

  7   capture questions, it is in a time-bounded format.

  8             Basically, the abbreviated questionnaire

  9   now has 27 questions on it, and this is a

 10   significant difference from the full-length

 11   questionnaire with its 48 questions on it.

 12             [Slide.]

 13             The pre-screening donor educational

 14   materials.  The idea of providing donors with

 15   materials before they donate originated in 1984

 16   because there was not an HIV assay available, so

 17   donors were given written materials that contained

 18   the HIV signs and symptoms, and risk information.

 19             The goal was to get the donor to self-defer or at

 20   least get them to ask the blood center

 21   staff about these things, so they would know

 22   whether or not to be deferred.

 23             The educational materials in use by blood

 24   donors currently include all of this information

 25   plus information about new and potential risks, and 

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  1   information about the donation process, but we had

  2   some concerns about the educational materials.

  3             First of all, they are not uniform within

  4   the U.S. Now, blood centers do include the FDA

  5   required information on the educational materials,

  6   but there is a great deal of variability.  We felt

  7   that there needed to be more emphasis on accuracy

  8   and honesty in the donor, so the second paragraph

  9   in the educational materials hits them with that

 10   please provide us with information that is honest

 11   and accurate as possible.

 12             We tried to answer questions for donors,

 13   what is sex.  Now, we will get to that in a second.

 14             [Slide.]

 15             Therefore, we have a new emphasis on

 16   accuracy and honesty, an emphasis on encouraging

 17   donors to ask questions. We feel this has to be a

 18   two-way interactive process, that we needed to

 19   define sexual contact, because in about 20 percent

 20   of the questions, there is a question about sexual

 21   contact or sex, and we know from the survey of

 22   design literature or survey literature, that people

 23   have very differing views of what constitutes sex.

 24             For instance, in a 1998 JAMA article

 25   published by Sanders, et al., there was clearly 50 

                                                               311

  1   percent of donors or of respondees did not think

  2   that oral sex constituted sex. We know that poses a

  3   risk for transmission of a number of agents.

  4             A fifth of the respondents did not think

  5   that anal sex was sex, and there are a number of

  6   other studies out there that we looked at, and, of

  7   course, our former president, Bill Clinton, I think

  8   helps to drive home this point.  So, we do have

  9   definitions of sex listed.

 10             We decided to go with medical jargon.  To

 11   try to use street terms, we thought just would be

 12   really pushing the envelope especially with the

 13   blood drives to high schools where there are 17-

 14   and 18-year-olds although they probably know a lot

 15   more than the rest of us.

 16             We are also recommending that the

 17   educational materials be standardized, that the

 18   blood centers can add to them, but they cannot

 19   rearrange the current format, and they cannot

 20   delete anything.

 21             [Slide.]

 22             The user brochures.  These are brochures

 23   that have been designed to help blood centers and

 24   donor screeners learn how to use the new materials.

 25   There is one for the full-length questionnaire and 

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  1   one for the abbreviated version.

  2             It explains the concept of capture

  3   questions, which I think many blood centers already

  4   understand because they have been using them for

  5   years, but for a new screener, this is helpful

  6   information, and it offers suggested follow-up

  7   questions to any affirmative answers for capture

  8   questions.

  9             [Slide.]

 10             In terms of administration around the

 11   U.S., currently there is significant variation.

 12   The American Red Cross, with FDA approval in 1998,

 13   began to use the self-administered questionnaire.

 14   There was one question at the end asked by staff in

 15   order to ascertain whether the donor had any

 16   questions or there was anything they didn't

 17   understand.

 18             In some centers, the donor uses the pencil

 19   or the pen and paper approach, answers the

 20   questions, answers the questions, and blood bank

 21   staff will either ask all of the questions again or

 22   just selected questions.  In some blood centers,

 23   they just ask questions orally of donors.  So,

 24   there is a fairly significant degree of variation.

 25             [Slide.] 

                                                               313

  1             We are recommending that the full-length

  2   and abbreviated screening questionnaires be self-

  3   administered by blood donors for the following

  4   reasons.

  5             [Slide.]

  6             1.  Survey literature shows that people

  7   are less likely to disclose personal information in

  8   a face-to-face interview versus a self-administered

  9   questionnaire.

 10             2.  The NCHS cognitive evaluations and the

 11   entire process was geared toward a self-administered

 12   questionnaire with the input and buy-in of our survey design

 13   experts, so we are

 14   recommending a self-administered questionnaire.

 15             [Slide.]

 16             Now, one of the issues that we grappled

 17   with was how we get the word out to our

 18   constituents, blood centers, and donor screeners

 19   about what we are doing, and how do we know that

 20   they support this process.

 21             First of all, we included what we felt

 22   were the key people, and we have discussed that

 23   already, but starting with the FDA.  Alan actually

 24   has done this, so I won't reiterate the FDA

 25   involvement, but there were two representatives 

                                                               314

  1   ultimately who communicated informally with CBER.

  2   This was presented to the BPAC last year, and then

  3   we incorporated the input that CBER provided last

  4   fall.

  5             [Slide.]

  6             America's Blood Centers, the American Red

  7   Cross, American Association of Blood Banks had

  8   numerous meetings, conference calls, web postings,

  9   publications in which the task force activity was

 10   well chronicled, and in all of those, there were

 11   requests for feedback, which was provided.

 12             [Slide.]

 13             American Association of Blood Banks

 14   especially was very proactive in doing this.

 15             [Slide.]

 16             As Chair of the task force, I got to

 17   travel and see interesting and unusual places to

 18   take the gospel, if you will, of the task force, or

 19   mantra at least--gospel is probably not a good

 20   word--but our mantra at multiple national meetings,

 21   meetings in California.  California is important

 22   because it collects 8 percent of the blood, and it

 23   was the Blood Centers of California that developed

 24   the first Uniform Donor Screen Questionnaire, so

 25   thereby and in particular we felt it was important. 

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  1             The goal of my presentation was, first of

  2   all, to discuss our activities, but also to use the

  3   bully pulpit to get feedback about what we were

  4   doing.

  5             [Slide.]

  6             Finally, we also went to the blood

  7   screeners themselves.  It was a small study, but

  8   yielded very important information.  We went to

  9   five different blood centers and had 13 screeners

 10   evaluate the new materials for their usability,

 11   user friendliness, comprehension, and because these

 12   are the people who are on the front line

 13   interviewing donors, to try to get an idea from

 14   them how they felt the donors would respond to the

 15   materials.

 16             We provided the data to CBER, and the

 17   ratings indicated a very, very positive response to

 18   the new materials, very high ratings, and most of

 19   the screeners who looked at these materials felt

 20   that they were a significant improvement over what

 21   they were currently using.

 22             [Slide.]

 23             In terms of how we are going to get the

 24   word out after the FDA, with the input of BPAC,

 25   publishes its guidance or endorsement, or however 

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  1   it will communicate, puts its imprimatur on the

  2   products, the AABB will use its publications and

  3   web site to inform members about the final

  4   products, will make the materials available, will

  5   use the resources at its disposal to work with

  6   blood centers in implementing the new products.

  7             [Slide.]

  8             Blood centers will be responsible for

  9   obtaining and familiarizing themselves with the new

 10   materials, for developing their standard operating

 11   procedures to go with the new questionnaires, for

 12   training their staff, and assessing competency, for

 13   educating blood donors about the new approach,

 14   because this is very, very new, and have staff

 15   available to assist donors.

 16             These are our thoughts about how the

 17   implementation should proceed.

 18             [Slide.]

 19             So, just to kind of wrap up, the documents

 20   that were submitted to the FDA, and which the

 21   committee now has before it, are the full-length

 22   questionnaire, the Medication Deferral List, which

 23   is the companion document to the full-length

 24   questionnaire, an abbreviated version for frequent

 25   donors, the donor educational materials, and the 

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  1   user brochures for the questionnaires.

  2             [Slide.]

  3             I just want to once again emphasize the

  4   task force really was breaking new ground here in

  5   terms of donor screening.  This is really the first

  6   time that appropriate approaches for evaluating the

  7   questions, on writing them had ever been used, and

  8   we hope that this is an approach that will continue

  9   to be used by the FDA and the AABB as they develop

 10   new questions, and that considering that questions

 11   that went into the original AABB questionnaire had

 12   not undergone field testing, did not, by and large,

 13   have the input of survey design expertise, that

 14   what the task force is putting before you today

 15   represents a significant and major improvement.

 16             [Slide.]

 17             I would like to thank the many task force

 18   members and after two years of hard work, I think

 19   they deserve to have their names read out loud, and

 20   I will do it in microwave version - Paul Beatty,

 21   John Boyle, Mary Chamberland, Linda Chambers,

 22   JoAnne Chiavetta, Judy Ciaraldi, Ken Clark, Kay

 23   Gregory, Jan Hamilton, Debbie Kessler, Steve

 24   Kleinman, Trish Landry, Sharyn Orton, Terry Perlin,

 25   Mary Townsend, Steve Vamvakas, Donna Whittaker, 

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  1   Alan Williams, and Anita Winters.

  2             Special thanks I would like to give to Dr.

  3   Sharyn Orton, who conducted the focus groups,

  4   George Nemo, who made the funding possible for the

  5   cognitive evaluation, Paul Beatty and John Boyle,

  6   who were our survey design experts, and to Kay

  7   Gregory and Anita Winters, who provided all the

  8   administrative and logistical support and hand-holding to

  9   get us through this project.

 10             I would like to thank the committee for

 11   their interest, for their attention, and this

 12   concludes my presentation.  Thank you.

 13             [Applause.]

 14             DR. NELSON:  Thank you.  It sounds like

 15   you did a lot of work on this.

 16             Questions or comments?

 17             DR. ALLEN:  One comment, one question.

 18   This is fabulous, long overdue.  I really applaud

 19   the process that was used and the way in which you

 20   have approached it. Fortunately, we got the

 21   materials enough in advance that we had a chance to

 22   look through, read, and review them, and I think

 23   they are fabulous.

 24             My question.  Was anything off limits?

 25             DR. FRIDEY:  Well, we would all love a 

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  1   questionnaire that only had five questions on it,

  2   but the question is which ones do you eliminate.

  3   We did go to the FDA and ask if there were any

  4   specific items that we could drop, and the FDA felt

  5   that at this point in time, that we should retain

  6   all the FDA-recommended or required items, so we

  7   did, we did retain those.

  8             DR. ALLEN:  In the exact format or were

  9   you allowed to recommend changes?

 10             DR. FRIDEY:  Oh, no, we absolutely had the

 11   FDA buy in to revise those questions, to reword

 12   them, yes, absolutely.

 13             DR. NELSON:  I hate to bring up specific

 14   questions, but I have one, which is No. 46, had

 15   sexual contact with anyone who was born in or lived

 16   in Africa, and there is something about travel to

 17   Africa.

 18             If that relates to Subgroup O, I thought

 19   the FDA had required that screening tests be

 20   sensitive to Subgroup O, and I wondered why that's

 21   in there.

 22             DR. FRIDEY:  I will let Jay answer that.

 23             DR. EPSTEIN:  We have not yet approved an

 24   HIV screening test with validated sensitivity for

 25   Group O.  We have encouraged manufacturers to 

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  1   submit supplements or new tests, new original

  2   submissions, but that process has been slow.  There

  3   are such tests in the pipeline, but we are not

  4   there yet.

  5             DR. NELSON:  So we can drop that question

  6   as soon as you license it.

  7             DR. EPSTEIN:  Well, that has been our

  8   thinking.

  9             DR. NELSON:  Maybe you could drop it now.

 10             DR. EPSTEIN:  Well, we could revisit that.

 11   I mean when we took the position that the screens

 12   should be sensitive to Group O, it was based on the

 13   perception that there might be an expanding new

 14   epidemic, it was after the first two cases were

 15   identified in the U.S.

 16             It is my understanding that there have not

 17   been any subsequent cases identified in the U.S.,

 18   but it is also the case that surveillance may not

 19   have been kept at the same level.  So, I mean we

 20   could revisit that question, but I think it is fair

 21   to--

 22             DR. NELSON:  If the tests aren't sensitive

 23   or if the tests that are being used are not, then,

 24   I certainly agree with the question, but it was my

 25   understanding that they were sensitive. 

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  1             DR. EPSTEIN:  The existing tests are

  2   incompletely sensitive, and they do vary.

  3             DR. NELSON:  Yes.

  4             DR. LEW:  I don't know if you are the one

  5   to ask this question, but if you could clarify.  In

  6   the information in our packet, it did mention the

  7   studies that suggested a one-on-one interview was

  8   better to look at HIV risk factors, and I also

  9   understand though, indeed, that under the privacy

 10   of looking at questions yourself, that other

 11   studies have shown that you are more likely to tell

 12   the truth.

 13             It wasn't very clear to me, though, how

 14   you all decided in the end to go with the studies

 15   just saying it is better to do it in privacy rather

 16   than looking again at the issue of doing it one-on-one, when

 17   those studies did clearly say it seemed

 18   to be more helpful.

 19             DR. FRIDEY:  First of all, I want to thank

 20   you for reading the materials, it is clear that you

 21   did.  That's great.  This is a study that was done

 22   at a blood center by a blood banker.  It was

 23   published 10 years ago.  With all respect to the

 24   author, those kinds of findings have not been

 25   reproduced in general survey literature. 

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  1             It was observed in that study that, in

  2   general, first-time donors, people who donate that

  3   frequently were more likely than frequent donors to

  4   pay attention to a self-administered questionnaire,

  5   so the authors of that paper did, in fact, make

  6   that comment.

  7             There was another study that was later

  8   done and felt that even though there was face-to-face

  9   interviewing, that they did not observe that

 10   the overall decline in HIV seroprevalence was

 11   significant, and said, in fact, that the decrease

 12   in HIV seroprevalence was likely not attributable

 13   even to direct questioning.

 14             So, given the fact that there is a very,

 15   vary large body of literature, survey design

 16   literature, which we gave some references from

 17   directly and, in fact, cited in the project, and

 18   the fact that none of these have substantiated the

 19   10-year-old study out of a blood center, we felt

 20   that it was appropriate to recommend a self-administered

 21   questionnaire.

 22             DR. NELSON:  I understand that the CASI,

 23   the questionnaire is read, I mean there is oral

 24   administration of the question and then computer

 25   answers, might be better than a personal interview, 

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  1   but how do you deal with the issue of literacy

  2   among the donor population where somebody might

  3   check answers yes or no, but really not actually be

  4   able to read the questionnaire, and marginal

  5   literacy is perhaps more frequent in U.S.

  6   populations than is thought?

  7             DR. FRIDEY:  Well, we could hold up a sign

  8   that says, "Can you read this?"

  9             DR. NELSON:  If somebody said, "Yes" --

 10             DR. FRIDEY:  I am being a little tongue in

 11   cheek there.  That was a joke.  My father used to

 12   say, "There are always two floor shows, one to tell

 13   it and one to explain it."

 14             That is an issue that I think we have to

 15   struggle with.  I think that when eventually blood

 16   centers get to computer-assisted interviewing,

 17   there will be an audio portion.  The video portion

 18   will be terrific for donors who are hearing

 19   impaired.  There will be the capability for

 20   multiple languages.  That's a long way to say I

 21   think that is probably an issue that has to be

 22   worked out, and our feeling is at this point that

 23   the blood centers should develop an approach for

 24   determining whether someone can really sit down and

 25   go through the questionnaire and answer it 

                                                               324

  1   themselves based on their literacy level or whether

  2   or not the blood center should administer it.

  3             DR. NELSON:  This questionnaire will be in

  4   a couple of languages, certainly Spanish and maybe

  5   Chinese?

  6             DR. FRIDEY:  The task force members are

  7   all looking forward to a long retirement somewhere

  8   in the South Pacific, but there already are

  9   approaches out there, and many blood centers have

 10   translated their current materials into Spanish and

 11   have used validation approaches for that, so we

 12   would just suggest that blood centers do the same

 13   for this.

 14             MS. KESSLER:  Debbie Kessler, New York

 15   Blood Center.  I was on the task force.

 16             About the literacy question, Joy was

 17   describing how you could pick up on problems a

 18   person would have in answering the questions based

 19   on the answer patterns, and you could always

 20   administer it orally if you did have somebody who

 21   couldn't read the questionnaire.

 22             DR. FITZGERALD:  Joy, this is really

 23   great.  I just had one question on the disclaimer

 24   on what happens to your donation.  How do we

 25   address the AABB standard that we have to inform 

                                                               325

  1   the donor that their blood sample may not be

  2   tested, is that done at the local level or is that

  3   going to be included?

  4             DR. FRIDEY:  That would be at the local

  5   level, and that actually is an issue that the

  6   Standards Committee is going to take up because it

  7   has continued to be a troubling one.

  8             DR. HOLLINGER:  Excellent, and I am glad

  9   we had all this information given to us to read.

 10             One thing that wasn't on there, though, is

 11   the educational material, the pre-screening, if you

 12   will.  Was there something on there?  I guess I

 13   didn't see the pre-screening educational material.

 14   Sorry about that.  That is one thing I didn't see,

 15   because I think that is really critical because

 16   there is where a lot of the perhaps self-referrals.

 17             I see a reasonable number of patients who

 18   have had hepatitis, for example, hepatitis C, who

 19   are found to be positive and obviously when we talk

 20   to them, have histories of injection drug use, and

 21   so on, that obviously have not responded to the

 22   question.

 23             A lot of that is because this concern

 24   about putting an X or having an X put in a box,

 25   that is going to be there for a long period of time 

                                                               326

  1   on a record about this, have you ever had sex with

  2   a prostitute or a variety of other things.  I mean

  3   people don't like to see that.  It is one thing

  4   they don't like to have on there even though they

  5   might answer it otherwise.

  6             We often have to just tell many of them

  7   who come in, look, I don't have to put it in your

  8   chart, I am not going to put it there, but it's

  9   important for us in terms of talking to you about a

 10   variety of other things, at which time many of them

 11   will say, well, okay, you know, and then they will

 12   give that piece of information.

 13             I have been impressed with that particular

 14   difficulty in answering these kind of behavioral

 15   questions. Sometimes you could get that out in the

 16   educational material, which really explains why

 17   these questions are important about even once, and

 18   things like this, so they could self-defer ahead of

 19   time.

 20             But that is the only concern I have with

 21   some of the questions is that they do have some

 22   powerful things that keep people from answering, I

 23   think, honestly.

 24             DR. FRIDEY:  I agree, and the survey

 25   literature does, in fact, support that, and if you 

                                                               327

  1   are talking about methods of administration, that

  2   is something that the donor sits down and does

  3   themselves, they are more likely to answer

  4   truthfully than if it's in a face-to-face format.

  5             We do try to assure donors that the

  6   information is confidential.  That is getting to be

  7   a tougher sell, I think, these days, but blood

  8   centers have to have systems that are secure and

  9   do, and communicate that to blood donors, so that

 10   they will feel more comfortable answering these

 11   kinds of questions.

 12             DR. NELSON:  Thank you.

 13             DR. FRIDEY:  Thank you very much.

 14             DR. NELSON:  Paul Beatty.

 15                      UDHQ Cognitive Studies

 16             DR. BEATTY:  I sort of walked into this

 17   process kind of like in the middle of the session,

 18   so I think it was really nice to have the

 19   introduction that Alan and Joy provided.

 20             I am actually going to now talk about

 21   something a lot smaller than the whole scope of

 22   things that they talked about, a pretty small part

 23   of the process although an intensive one, and only

 24   about one major product really.  The questionnaire

 25   itself is what I am going to spend most of my time 

                                                               328

  1   talking about.

  2             You will also notice as I go through this

  3   that I will be talking more about what we found

  4   that wasn't so great rather than what was good, and

  5   that is not because that was the overwhelming stuff

  6   that we found.  Actually, we found that the

  7   evidence was very positive about this instrument

  8   and about the questionnaire.

  9             The idea behind cognitive testing is

 10   really to poke and prod and push this thing until

 11   we find out what goes wrong with it and where it

 12   breaks, so that is going to be more what I am going

 13   to be talking about.

 14             Fortunately, the things that we found are

 15   generally pretty fixable.

 16             [Slide.]

 17             The task force, at the point that I came

 18   in on this had already revised the questionnaire

 19   based on a review of regulations, principles, the

 20   questionnaire design, information from focus

 21   groups, and all that, but the evaluation stage that

 22   we came in had to address some remaining questions,

 23   and we had to figure out, well, what is the best

 24   way to evaluate, how easy this thing is to

 25   understand, what is the quality of material that it 

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  1   generates, what is the validity of the responses,

  2   and all that, and what the task force decided to do

  3   was employ cognitive interviewing.

  4             At the National Center for Health

  5   Statistics, this is what our group does full time,

  6   evaluate survey questionnaires primarily to find

  7   out the strengths and weaknesses of each of them,

  8   but what is cognitive interviewing?

  9             [Slide.]

 10             It is a process that has been developed

 11   about 15 years ago where questionnaire design

 12   specialists conduct one-on-one interviews with

 13   people who are typical respondents of a

 14   questionnaire.

 15             They administer the questionnaire as it

 16   originally appears, so mode is an important factor

 17   there.  This was given as self-administered

 18   instrument, so we had the people that participated

 19   in our study fill it out by themselves first.

 20             Then, the investigative part is where we

 21   probe the interpretation of the answers and what

 22   they think questions mean.  That helps to explore

 23   various things - comprehension problems, difficulty

 24   of what they are trying to recall, various response

 25   biases, inappropriate answer categories although 

                                                               330

  1   that wasn't so much of a concern with this one

  2   because the answer categories were basically yes

  3   and no, so they seemed to work pretty well.

  4             It is not the only technique that is used

  5   to develop questionnaires and to evaluate their

  6   quality.  Focus groups have been mentioned, and

  7   they can play an important role.  Actually field

  8   pre-tests of questionnaires that are exactly the

  9   same as someone going through the process without

 10   this intensive probing can also be important.

 11             But this technique seems to work best when

 12   you are at sort of middle point, where you have the

 13   basic content figured out, but there are still some

 14   tweaking of the actual wording that needs to be

 15   developed.  So, it's sort of something that falls

 16   in the middle.

 17             [Slide.]

 18             Let's make it a little more specific.

 19   This is one of the questions that we looked at.

 20   "In the past 12 months, have you had sexual contact

 21   with a person who has had hepatitis?"

 22             They would answer that question by

 23   themselves first.  Then, we would use probes to

 24   explore several possible things, like how do people

 25   interpret what we mean by sexual contact.  We would 

                                                               331

  1   use probes to explore whether they know anyone who

  2   has hepatitis, what sort of contact did they have

  3   with this person, what time frame they are thinking

  4   about while they are answering, to basically take

  5   their answer that they give us, which is a short

  6   yes or no, and then get a more expanded, long-term

  7   answer that we use to evaluate the validity.

  8             So, when we get either a yes or a no, this

  9   longer and extended narrative is what we use to

 10   evaluate the quality of what they have given us.

 11             The interviews are tape recorded, they are

 12   very textually rich, transcribed, and they are

 13   analyzed largely qualitatively, although some

 14   quantitative techniques can be used with certain

 15   caveats that I will get to in a minute.

 16             [Slide.]

 17             These interviews are pretty labor-intensive.  We

 18   worked on this for about six months

 19   of actually interviewing and analyzing these data

 20   with a fairly small sample.  We only talked with 35

 21   people, which is about the same or maybe slightly

 22   larger than most of the studies that we do.

 23             Now, the participants are selected, so

 24   that they are relevant to the topic of interest,

 25   but you shouldn't take that to mean that we are 

                                                               332

  1   considering this to be a representative sample in

  2   any sense.

  3             We are not trying to infer the exact

  4   extent of a problem in some population.  What we

  5   are trying to do, instead, is to understand what is

  6   likely to be a problem and then to develop a basis

  7   for understanding why that is likely to be a

  8   problem.

  9             The extent is something that you really

 10   have to go somewhere else to figure out, but we can

 11   usually, when we do this properly, figure out what

 12   it is exactly that is going on in people's minds,

 13   and then point that back to something that is wrong

 14   with the question itself.

 15             [Slide.]

 16             The people we talk to in this study, we

 17   did it in three rounds where we had a chance to

 18   actually conduct about 12 interviews per round, and

 19   then regroup, rethink what we learned, and then

 20   talked to some different people.

 21             The first round, we decided to go for

 22   people who had never donated blood, but were

 23   eligible to do so as far as they knew.  Hopefully,

 24   that group is representative--representative is a

 25   funny word--but those people are common of the type 

                                                               333

  1   of people who would be first-time users of this

  2   questionnaire, they have no experience with it,

  3   they are relatively naive.

  4             Some of these terms, concepts, and ideas,

  5   they have never seen before.  The whole process

  6   might seem alien to them.  So, we want to get them

  7   really kind of on the ground floor.  The problem

  8   with that is that it misses a lot of things.  In an

  9   evaluation of this type, we get a lot of people who

 10   answer the questions "no," because a lot of the

 11   things we are asking about are quite rare.

 12             We want to get also people who answer the

 13   questions "yes," because if you only are evaluating

 14   the veracity of "no" responses, you are really

 15   missing a big part of the puzzle.  So, that is kind

 16   of what the second round is all about.

 17             We looked for people who had been actually

 18   deferred from donating whole blood on at least one

 19   occasion.

 20             Then, the third category after that was

 21   sort of a catch-all to fill in the gaps.  We has

 22   some evidence or some reasons to believe that

 23   younger participants might be interpreting some of

 24   the questions differently.  We weren't sure that we

 25   had really adequately hit people how had lower 

                                                               334

  1   education levels, so we wanted to fill in some gaps

  2   there, and we also used the third round to address

  3   the quality of the abbreviated version of the

  4   questionnaire.

  5             [Slide.]

  6             Thirty-five total interviews came out 12,

  7   12, and 11 per round, and what did we learn?

  8             [Slide.]

  9             One of the real challenges of this

 10   instrument, I think, is that it has to balance

 11   thoroughness and simplicity.  On the one hand, you

 12   need the questions to be not so simple that they

 13   are open to misinterpretation because that way,

 14   they could fail to stimulate memories, but

 15   questions that are overly thorough, even though

 16   they might address all these sources of ambiguity,

 17   could be tedious and may reduce the overall

 18   motivation.  What do you do to balance that out?

 19             [Slide.]

 20             Well, it is important to keep in mind that

 21   many of the nuances that questions are really

 22   designed to get at, like hitting a definition

 23   really hard to make sure they understand exactly

 24   what it means, for example, clotting factor

 25   concentrates only apply to a very small number of 

                                                               335

  1   people, so if you are making a question that is for

  2   the, I don't know, let's just say 1 percent that

  3   that applies to, you are really forcing everyone

  4   else to be dragged through this process that can be

  5   quite long and involving.

  6             One alternative that you have is you have

  7   to remember that this questionnaire is unlike a

  8   survey questionnaire in a lot of ways.  It doesn't

  9   have to stand entirely by itself.  It can be

 10   supplemented by the pre-screening materials, the

 11   educational stuff, and also are guidelines for

 12   people who ask questions that there can be

 13   additional information to help them clarify, like,

 14   well, I might have had clotting factor

 15   concentrates, but I am not sure.  If you provide

 16   staff at centers with definitional guidance, that

 17   is perhaps way and a more efficient way to help

 18   them clarify what they are getting at.

 19             [Slide.]

 20             Burden is something that a lot of survey

 21   questionnaire designers completely fail to think

 22   about, and it was actually a very serious concern

 23   in all the deliberations of this task force, which

 24   is I think really to their credit.

 25             [Slide.] 

                                                               336

  1             Sometimes we found that there were

  2   attempts to make the questions a little too

  3   compact, that had actual larger ramifications.  One

  4   example was feeling well as opposed to a question

  5   that said feeling healthy and well. Well, that

  6   seems like that is basically the same thing, but

  7   when you interview people in depth, you find that

  8   when you just say "well," a lot of them think you

  9   are talking about a more holistic sense of their

 10   mental and possibly physical well-being, but they

 11   don't always focus in on what you are really

 12   thinking about.

 13             Now, I am not sure that that actually

 14   means that someone would say if they had the flu,

 15   that they are feeling well, because they are in a

 16   good state of mind, but it opened up a little

 17   ambiguity that didn't really need to be there.

 18   Just by adding the word "healthy," you could make a

 19   lot of that go away.  So, this sort of minor

 20   tweaking really helped to make a difference.

 21             Another issue, terms "even once," there

 22   was talk about taking them out.  A lot of people

 23   said, well, you know, the question was clear

 24   enough, I didn't need that to clarify it for me,

 25   you know, it was kind of insulting, and so on.  

                                                               337

  1   Actually, though, "even once" can be important for

  2   a small group of people because that is sort of an

  3   out that people take.

  4             You know, I might have done this sort of

  5   thing at one time, but that is not what I am

  6   anymore, that is not what I am all about, that is

  7   not the way I think, that is not the way I am, and

  8   therefore, they think that is the larger truth, and

  9   they can use that as a basis to justify their

 10   answer of no, I never did that, because admitting

 11   that you did it once, that would be kind of not

 12   really indicative of what they are all about.

 13             So, it really doesn't make a lot of sense

 14   to take that out.  The burden that it creates is

 15   really not significant.  Keeping it in there

 16   actually can make a definite improvement.  We have

 17   seen plenty of evidence in the social sciences that

 18   people do make such inferences about what they can

 19   get away with because it doesn't really apply to

 20   them.

 21             So, the principle, dropping a few words

 22   sometimes doesn't significantly reduce the burden,

 23   but can create complications.  There are times when

 24   that is not the right approach.

 25             [Slide.] 

                                                               338

  1             Other examples of minor tweaking of

  2   wording.  This was one example where just a few

  3   minor changes, I mean the question was basically

  4   all right, but a simple fix could have a little bit

  5   of an impact.

  6             "In the past four weeks, have you had any

  7   shots or vaccinations?"  It is not that it is not

  8   clear, but sometimes it seemed like people thought

  9   too much about vaccination and really failed to

 10   think about other things that could qualify as

 11   shots.

 12             One person was very remarkable in this

 13   case.  They had actually had a shot of cortisone in

 14   their foot on the way to the interview where we

 15   talked to them, and answered the question "no," and

 16   only in probing in depth, well, wait a minute, you

 17   mentioned that you just had a shot, and that was

 18   this morning, doesn't that count?  And they are

 19   like, oh, my gosh, I was thinking totally about

 20   vaccinations, which you can see sort of why that

 21   would happen.  It talks about shots or

 22   vaccinations.  That kind of looms large in the

 23   brain, overwhelms potentially other interpretations

 24   that you might have of that.

 25             Again, maybe these are not huge things to 

                                                               339

  1   have lost, but you never know, and it is easy to

  2   solve this problem.  The principle that you invoke

  3   to fix it is that you say, well, "vaccinations or"

  4   and then you give this other half of it more

  5   weight, "any other kind of shot," emphasizing that

  6   there are really multiple ways this could come into

  7   play.  It is a simple fix, it really costs you

  8   nothing, and it has the potential to solve a

  9   definitely identified error.

 10             [Slide.]

 11             Some of the questions that were originally

 12   on the instrument were quite compounded, linking

 13   many, many things, and so all the questions that we

 14   dealt with were much shorter that we actually

 15   tested, but some of them still had some compounded

 16   things that didn't make a whole lot of sense.

 17             "Had an ear or skin piercing including

 18   acupuncture."  When you are trying to get a

 19   question that is easy for people to answer and has

 20   a really appropriate frame of reference that you

 21   don't have to scan their entire memories, but can

 22   think about something quite specific to come up

 23   with an answer, this is a little too much.

 24             I mean a tongue piercing and acupuncture

 25   are not in the same universe of activities, and 

                                                               340

  1   people pointed that out to us.  Even more so in the

  2   next question that we have. "Had an accidental

  3   needlestick or come into contact with someone

  4   else's blood."  One participant remarked, you know,

  5   "Oh, my God, you are talking about cleaning my

  6   granddaughter's knee and stepping on a hypodermic

  7   needle in the same question," like what's that all

  8   about.

  9             Are the consequences of doing this really

 10   severe?  Probably not for a large group of people,

 11   but it can seem strange, and strangeness has

 12   another problem, as well, because it really has

 13   sort of a subtle and insidious impact on how

 14   seriously they take the whole process.

 15             If you are asking questions that are just

 16   absurd, they think you don't really know what you

 17   are talking about, and they don't take you as

 18   seriously.  You can also get them from a purely

 19   cognitive standpoint to have their attention

 20   gravitate towards one aspect or the other.  So,

 21   they hear skin piercing, they don't hear

 22   acupuncture.

 23             Again, maybe acupuncture is not that

 24   important, but if it is, you might as well separate

 25   it out.  The same thing with accidental 

                                                               341

  1   needlestick, coming into contact with someone

  2   else's blood, we thought was probably worth a

  3   question of its own.

  4             DR. NELSON:  Just as an aside, we took out

  5   acupuncture at the last meeting.

  6             DR. BEATTY:  But you get the principle

  7   anyway.

  8             DR. NELSON:  We have simplified the

  9   question.

 10             DR. BEATTY:  Good principle, good thing to

 11   do.

 12             By the way, these are all minor things.

 13             This is kind of some good news.  False

 14   positives are really much more common that false

 15   negatives, which is really in the direction that

 16   you would hope to find things. All the pushing and

 17   prodding and trying to find mistakes that we could

 18   come up with generated a few false positives and

 19   very few false negatives.

 20             The false positives that we did come up

 21   with really fell into two categories, one, more

 22   conceptual, and the other involving time frame and

 23   dating.

 24             An example of a conceptual false positive

 25   is, "Have you taken aspirin or anything that has 

                                                               342

  1   aspirin in it." We had a lot of reports of people

  2   bringing in ibuprofen, acetaminophen, things that

  3   if you have a follow-up with them at all are not

  4   that difficult to find out that that is what they

  5   are talking about.

  6             In the time frame example, it is more

  7   about a process called "forward telescoping" where

  8   something that actually occurred longer ago than

  9   the reference period you are talking about, somehow

 10   gets imported into the time frame you are talking

 11   about.

 12             So, say, for example, 14 months ago this

 13   happened. You say "yes" to the question.  Why does

 14   that happen?  Well, it is really the same thing for

 15   both.  When you have people think through this

 16   question and what it is getting at, they scan their

 17   memory for anything that seems to be relevant and

 18   anything that could possibly apply to it, and

 19   things that are close, but not quite there can get

 20   tagged.  They don't literally go back in time until

 21   they hit the 12 months period and then say, oh,

 22   that's enough, I am going to stop. They think for

 23   events usually first and then try to date them.  If

 24   they are close, they get stuck in the memory and

 25   sometimes get reported. 

                                                               343

  1             The same thing for the conceptual stuff.

  2   Did I have anything?  Well, they probably think

  3   medications first and pain relievers, oh, yeah I

  4   did have one of those, it was acetaminophen.

  5   Again, with even a minuscule amount of follow-up,

  6   that's not that difficult to find that that sort of

  7   thing is happening, and much more common than the

  8   alternative, which is what we would like.

  9             [Slide.]

 10             Sometimes in spite of our best efforts, it

 11   is not really a problem with the question, but

 12   people just have incomplete knowledge.  "Have you

 13   come into contact with the blood or saliva of a

 14   person who has hepatitis?"

 15             Well, the thought process that someone

 16   might go through to answer a question such as that

 17   is, first, to think broadly, do I know anybody who

 18   has hepatitis, and they might say "no" at that

 19   point and then that is simple, they don't really

 20   worry about the other nuances of the question,

 21   that's enough for them to make the judgment

 22   necessary to answer, or maybe they do, and they

 23   don't think they have had that type of contact, and

 24   that is where they have to kind of work through the

 25   implications of the exact wording a little bit 

                                                               344

  1   more.

  2             But sometimes they just don't know.  I

  3   mean, well, yeah, I do have a friend with

  4   hepatitis.  Did we have any saliva contact?  Well,

  5   I mean they are over at my house a lot.  We have

  6   parties.  We share wine glasses perhaps.  It is

  7   just hard to tell, so they make the best estimated

  8   guess that they can.

  9             One thing they do is they bring in a sort

 10   of an assessment of potential risk, and they think,

 11   well, what is the real chance that this could have

 12   happened.

 13             Another example is had sex with a male who

 14   has ever had sex with another male.  They can make

 15   general assumptions about what they think their

 16   partner is like. Like one person said, oh, I am

 17   sure that he had never had sex with another male,

 18   he is the most homophobe person of all, but

 19   sometimes that doesn't tell you necessarily

 20   anything.

 21             So, you have to realize realistically what

 22   you are getting.  You are getting reasonable

 23   inferences about what is likely to have been the

 24   case, not a total 100 percent accurate screening of

 25   everything that could have ever happened to them. 

                                                               345

  1             [Slide.]

  2             Some concepts we found were just

  3   inherently difficult.  Joy invoked the name of Bill

  4   Clinton on this one, and many of our participants

  5   did also.  When you talk about sex, what does it

  6   mean, intercourse or other activities such as oral

  7   sex?

  8             It was very clear in talking to people

  9   that their definitions of what "have sex" included

 10   varies quite a bit. Some included things other than

 11   intercourse, and some people didn't, but the

 12   tendency, and it was probably more so this way than

 13   we expected, was for people to be inclusive.

 14             The reason that they did is because they

 15   thought, well, pragmatically, I know what you are

 16   trying to find out, you are trying to find out

 17   about risk.  I recognize that this is a screening

 18   instrument, and if there is any doubt, it should be

 19   included in there.

 20             There were exceptions, some of which we

 21   saw for sure happening and others that we just

 22   realized could happen.  It could be that young

 23   people think differently, and there are also some

 24   people who would reject that whole argument I just

 25   made because they would say that oral sex is not 

                                                               346

  1   risky, to therefore, it is not of any concern to

  2   you, it is not of any concern to this question.

  3   So, there is some potential room for error there.

  4             Note, though, that most people don't have

  5   to go through that big debate with themselves about

  6   what the meaning of "have sex" is.  A lot of people

  7   we talked to said, "I didn't even think about it, I

  8   haven't had any sexual contact with anyone in over

  9   a year."

 10             Other people said, "Well, I have been

 11   married for 20 years, and I am pretty confident we

 12   have both been faithful, so I didn't even really

 13   think about it.  Whether oral sex counts or not is

 14   totally irrelevant to me."  There is a more global

 15   sort of judgment that is invoked instead, but for

 16   some people that is not the case, and you have to

 17   sort of work with them.

 18             [Slide.]

 19             Sometimes the problems are not entirely

 20   with the wording of the question, but can do it the

 21   way they are presented visually.  We didn't use

 22   what was in any sense a final version of the way

 23   this instrument should look.  We did a mock-up of

 24   it ourselves, and sometimes the way that we mocked

 25   it up had some problems. 

                                                               347

  1             For example, the time frame was often

  2   forgotten.  We had people answer questions that

  3   were in a long series invoking things that happened

  4   in the last 12 months, like had a tattoo applied,

  5   and they would answer yes, not because they had had

  6   a tattoo in the past 12 months, but because they

  7   had had one 10 years ago.

  8             The point there is that you can have

  9   perfect questions, but there is still another step.

 10   You have to make sure it looks appropriate and in a

 11   way that is easy for them to make sense of.  They

 12   are going to use the organization of it physically

 13   and visually to make sense of it and understand the

 14   details.  So, that is an important step that

 15   shouldn't be ignored.

 16             [Slide.]

 17             I mentioned that one of the things we were

 18   trying to do was get people who answer both yes and

 19   no to some questions.  That is hard to do.  You

 20   can't really ask people these questions in advance

 21   to screen them or you have kind of blown the

 22   question before they even get into the room.

 23             You have to have people who are hearing

 24   the question kind of for the first time.  That is

 25   largely what the point of this thing is.  On the 

                                                               348

  1   other hand, it is hard to get people to get enough

  2   variety in all these answers.

  3             So, what can we do?  To do a really high

  4   end, ultimate gold standard validity test, what you

  5   would do is find people that you knew from some

  6   other source for sure fill in some of these

  7   categories, like you know that they have Chagas'

  8   disease, but they don't know that you know that, so

  9   that way you get them.

 10             You know in advance they should answer

 11   yes, and then you can evaluate the quality of their

 12   answer.  In most cases, that is simply not feasible

 13   to do.  That would be extremely expensive,

 14   extremely time-consuming.

 15             At some point, it would be great if people

 16   actually did that.  In lieu of that, we have

 17   devised a sort of towards the end of the study,

 18   something that might help a little bit, the use of

 19   vignettes that sort of artificially expand the

 20   variety of experiences that people have to think

 21   about while answering.

 22             Here is one example.  Kim has a boyfriend

 23   who has used a needle to inject illegal drugs at

 24   least once.  They have not had sexual intercourse,

 25   although they have had oral sex together.  I am 

                                                               349

  1   trying to paint a picture of someone that is kind

  2   of on the cusp, playing on their ambiguities, maybe

  3   this should be a yes, maybe this should be a no,

  4   what do you think.  It might help us understand

  5   more about the way people are interpreting

  6   questions for situations that there is extremely

  7   little chance that we would actually pick up in a

  8   sample of 35 people.

  9             [Slide.]

 10             That is not an ideal test.  I mean it is

 11   still hypothetical and it doesn't rely on their own

 12   autobiographical memory, but it does at least

 13   require them to go through their thought processes

 14   of answering the question.  It requires them to

 15   absorb the words that we are asking them to think

 16   through a situation and apply this text of this

 17   question to this situation, and at least it's close

 18   than a totally hypothetical do you think this

 19   should count, do you think this definition includes

 20   this.

 21             The vignette responses tended to echo what

 22   we had already found, that they were very

 23   conservative in their answers.  They included

 24   things that--I say conservative--what I really mean

 25   is that their interpretations were very broad.  If 

                                                               350

  1   there was any doubt at all they should be included,

  2   they tended to stick it in.

  3             Is that a perfect test?  No, it is not,

  4   but it does tend to indicate that there is a sort

  5   of pragmatic component to question interpretation,

  6   that they are trying to figure out what it is that

  7   you want and why you want it, which also does come

  8   back to the issue of the educational materials, and

  9   their importance is not only as a pre-screener to

 10   tell them the order of the major things that you

 11   should be looking out for, but to give them more of

 12   an input into what the process is all about, why

 13   this matters, why you should care, why you need to

 14   think about these things and answer them

 15   accurately, because that is an important component

 16   of how they make sense of what you are asking them.

 17             [Slide.]

 18             So, to wrap up, the questionnaire that we

 19   tested was very much on target in terms of

 20   balancing simplicity and thoroughness.  It made

 21   things about as simple as you reasonably could with

 22   maintaining the integrity of the information that

 23   it needed to capture.

 24             The lion's share of errors that we found,

 25   and we tried hard to find errors, were false 

                                                               351

  1   positives, much more common than false negatives.

  2   The things that we did find were minor, really fell

  3   into three categories of ways that you could solve

  4   them.

  5             One is by supplemental materials, either

  6   definitions provided afterwards for that small

  7   group that might have questions or doubts about

  8   what something means, minor wording changes which

  9   we recommended, and the splitting of questions

 10   occasionally where it must made a little more sense

 11   to separate concepts that were linked and might

 12   have been a little confusing that way.

 13             DR. NELSON:  Thank you very much.  It was

 14   a very clear presentation.

 15             DR. ALLEN:  You obviously addressed well,

 16   I think, the question basically of aspirin.  Did

 17   you get a sense as you asked people about other

 18   products that contained aspirin, I mean are they

 19   aware that the standard cold medications, you know,

 20   these sort of wastebasket medications that are over

 21   the counter often contain aspirin products?  Was

 22   there that degree of sophistication or is there a

 23   potential problem with missing some of these?

 24             DR. BEATTY:  It was varied, but I think it

 25   was clear that not everyone knew whether all 

                                                               352

  1   medications that they had, had aspirin in them at

  2   some time.  We found people that said things that

  3   probably did have aspirin in them and didn't report

  4   them.  Most people answer in a more global level,

  5   that, you know, I haven't had anything that could

  6   possibly apply, medicine of any type, I don't take

  7   it, I don't like it, I try to avoid it.

  8             I think, if I am remembering, the time

  9   frame for that was pretty recent, as well.  We

 10   weren't thinking about even 30 days, we are talking

 11   about a couple days, so most people could be ruled

 12   out on that basis.

 13             That is another good example, though, of

 14   what do you do about it.  You would find that there

 15   are potentially some mistakes.  You could provide a

 16   huge list of anything that could include it, but is

 17   that really worth it?

 18             I mean the answer is that if someone has

 19   any doubts, you encourage them to talk about their

 20   doubts if they have them, and you have a list

 21   available if they need them, that might contain

 22   some examples, and you sort of prompt that way.

 23             The question itself is probably as good as

 24   it could possibly be.

 25             DR. FITZGERALD:  In your survey, it was 

                                                               353

  1   Question  31 and on the card it is Question 30, and

  2   the response to one of the individuals brought out

  3   something I am not sure we thought about or the

  4   task force may not have thought about.

  5             Question 30 says, "Were you a member of

  6   the U.S. military or civilian military employee or

  7   dependent of a member of the U.S. military and then

  8   in 31, one of your respondents was the spouse of a

  9   civilian employee on a base, and added up her time

 10   on the base because she lived on the economy and it

 11   didn't add up to six months.

 12             But what we are losing there is that the

 13   importance of that question is the availability of

 14   purchasing beef from the commissary and eating it

 15   during that period of time, and civilian employees

 16   on DoD installations overseas have access to the

 17   commissary, so we are missing a group of dependents

 18   of people in that question.

 19             So, I just needed you all to go back and

 20   look at that aspect of that question because it

 21   doesn't matter how long she was on the base because

 22   she probably went to the commissary and bought

 23   groceries on those brief periods that she was

 24   there.

 25             DR. FRIDEY:  If I could just briefly 

                                                               354

  1   address that, that kind of discussion did take

  2   place with the task force members, like a

  3   contractor, somebody who comes onto the base to do

  4   some work and might eat there, how do you deal with

  5   that.

  6             We did actually recommend ultimately some

  7   different wording to the FDA because about this

  8   time that all this was going on, there were some

  9   new variant CJD questions that were being floated,

 10   there was a draft guidance out there, so we did

 11   make this recommendation that the wording be such

 12   that it does capture that kind of information.

 13             I think the FDA did choose in the guidance

 14   that's the final guidance to retain their original

 15   wording, but it was something that was discussed.

 16             DR. KLEINMAN:  That was very nice, Paul.

 17   I just thought of something even though I was

 18   involved during this process, I hadn't thought of,

 19   and that is, we tended to say that we wanted to

 20   make the questionnaire simpler and more

 21   comprehensible to persons, to interviewees, and in

 22   the way we equated those two terms in our mind,

 23   simpler and more easily comprehended, but I don't

 24   think those two are the same, because I think

 25   actually what we found in the process--and you can 

                                                               355

  1   correct me if I am wrong--is that our real goal was

  2   to make it more easily comprehended, so that people

  3   really  understood what the questions were.

  4             I am not sure that resulted in the

  5   questionnaire necessarily being simpler, i.e.,

  6   being shorter, but hopefully, it is less ambiguous.

  7   I think if we use the word "simpler" we are using a

  8   word that is subject to a lot of interpretation,

  9   and I think it might be easier to think of this as

 10   trying to make a questionnaire where the intent of

 11   the questions would be clearer to the people who

 12   are reading it, because I am not sure that we wound

 13   up with a document that is any simpler.

 14             DR. BEATTY:  Yes, I think that is

 15   absolutely right, and that was something that I

 16   tried to kind of put forth there.  Sometimes

 17   simpler is less comprehensible because it doesn't

 18   give you enough information to make sense of what

 19   you have.

 20             DR. FRIDEY:  Actually, when we launched

 21   this project, I gave a number of talks at AABB

 22   meetings, and I tried to prepare the membership for

 23   the fact--membership being blood banks--that we

 24   were not necessarily going to end up with a

 25   questionnaire that was shorter with every question 

                                                               356

  1   very brief, and so I was trying to introduce that

  2   concept to the membership that you cannot

  3   necessarily have simple and comprehensive together

  4   in the same thing.

  5             Actually, I thought of them as more kind

  6   of mutually exclusive terms, so actually, with all

  7   respect to Dr. Kleinman, it was a concept that was

  8   introduced early on to AABB members, so that they

  9   would understand that the final product was not, in

 10   fact, going to be a five-question document, and

 11   clearly, we tried to balance things out, so that we

 12   could get at the information, but in a way that the

 13   person being screened would know what we were

 14   trying to get at.

 15             DR. KLEIN:  I guess this just illustrates

 16   how difficult it is to do things, because I think I

 17   don't qualify as an illiterate person, I mean I

 18   obviously can understand concepts, and yet I

 19   somehow went through this process thinking that

 20   although we were trying to make it more--obviously,

 21   we weren't going to do a five-question

 22   questionnaire, I think we knew that, but that

 23   somehow it seemed there was some sort of equation

 24   between more comprehensive and simpler, and there

 25   is to some extent, but I think, as the cognitive 

                                                               357

  1   studies pointed out, you can oversimplify and then

  2   lose the comprehension.

  3             I think Paul said it much better than I

  4   did, that there is a balance between the two, but I

  5   think ultimately, you don't necessarily wind up

  6   with a document that if you now bring it out to

  7   people, that people will say, gee, I thought your

  8   purpose was to simplify this, this doesn't seem any

  9   simpler to me than it was before.

 10             I think you may get that reaction even

 11   despite the fact that you have tried to prepare

 12   people for that.

 13             DR. NELSON:  One comment back there.

 14             DR. LUCY:  I am Dr. Charles Lucy.  I am an

 15   occupational environmental medicine doctor.  I

 16   wanted to echo one comment and then make another

 17   comment.  I have had a lot of experience with

 18   screening tests.

 19             With truckdriver physicals, I have found

 20   in many years of practice that many of the drivers

 21   do not spend enough time answering the questions

 22   that are meant to screen them for the Department of

 23   Transportation's required physical exams and

 24   questionnaires.

 25             Only upon questioning by a physician do 

                                                               358

  1   they admit that they have been hospitalized or they

  2   have had problems or things like that, so I think

  3   with any questionnaire you still have a problem of

  4   checking the data.  How can you do that?

  5             I think one area that has been explored by

  6   other people for informed consent is the use of

  7   interactive media laboratories that allow a process

  8   that is interactive and can be tailored at the

  9   patient level depending on their education and what

 10   their concerns are.

 11             So, I think this is an excellent approach

 12   to a questionnaire.  I think in the future, as you

 13   do move into a computer-assisted device, it gives

 14   you the opportunity perhaps to design an instrument

 15   that is educational, as you say, that is tailored

 16   to help the person understand what the questions

 17   mean, that perhaps can be changed, so that

 18   questions are programmed to be asked if a positive

 19   is received at a screening or a grab bag level, et

 20   cetera.

 21             I might just make that suggestion that

 22   interactive media is one way to get the person

 23   involved and may help clarify some of the things

 24   you are looking at, and may allow you to do such

 25   things as self-verification, so you know the person 

                                                               359

  1   understands the instrument and you know the person

  2   has attempted to answer truthfully, for instance.

  3             DR. NELSON:  Thank you.

  4             Judy Ciaraldi from the FDA.

  5           FDA Status of Review of AABB Task Force UDHQ

  6             MS. CIARALDI:  Good evening, everyone, and

  7   thank you so much for staying on.  I have to start

  8   out with letting you know that I was going to tease

  9   Alan Williams, my division director, about his

 10   effect on a crowd and his ability to clear a room

 11   when I noticed that as soon as he got up, everybody

 12   left, just about everybody.  The most important

 13   people are here.

 14             [Slide.]

 15             I am going to give you a brief overview of

 16   how we are conducting the review of the AABB

 17   Uniform Donor History Questionnaire.  I am going to

 18   follow with some review comments, comments from the

 19   preliminary review.  Now, we haven't completed

 20   analyzing all of the documents and going over all

 21   of the comments, so these will only be preliminary

 22   comments and it will not be complete.

 23             I will also list the proposed mechanisms

 24   that we are discussing for implementing the donor

 25   history questionnaire.  Before I get any further, I 

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  1   want to remind you that I am only talking about the

  2   review of the questionnaire used to screen whole

  3   blood donors and plateletpheresis, plasmapheresis

  4   donors, the donors for transfusable blood

  5   components.

  6             As you know after today's talk, these

  7   donors also donate recovered plasma.  We are going

  8   to use the same general review process for the

  9   donor history questionnaire that is submitted by

 10   the source plasma industry, but we don't have that

 11   yet, and we will use this particular review process

 12   when it is submitted.

 13             [Slide.]

 14             The process stated by assembling a work

 15   group that identified the scope of the review and

 16   selected a cadre of reviewers with a variety of

 17   backgrounds and expertise.  The reviewers were

 18   given three weeks to complete the review, and they

 19   were to have their comments in to me by the end of

 20   May, and everyone that provided comments back did

 21   have that.

 22             We are currently compiling the reviewers'

 23   comments and we are going to be evaluating them.

 24   When that is done, we will prepare a written

 25   response and send it back to the AABB Task Force 

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  1   informing them of our findings.

  2             The working group facilitating the review

  3   process consists of Dr. Williams, Dr. Orton,

  4   Elizabeth Callaghan, Jennifer Thomas, who is the

  5   Associate Director for Policy for the Office of

  6   Compliance and Biologics Quality, and me.

  7             Because Drs. Williams and Orton and I were

  8   all on the task force, we could not be on the

  9   reviewer cadre.  Ms. Thomas and Ms. Callaghan were

 10   both part of the review cadre.

 11             [Slide.]

 12             This is a list of the documents that were

 13   sent to each of the reviewers.  I am not going to

 14   go over it because Dr. Fridey already did, but I

 15   will show you what they got.

 16             So, it was a yeoman's job and our hats

 17   went off to them.

 18             [Slide.]

 19             We asked the reviewers to keep in mind the

 20   following questions, so that they could focus their

 21   review.  Is the content of the questions and the

 22   accompanying documents consistent with our

 23   regulations and our recommendations?  Is the

 24   rationale for the revisions appropriate?  Is the

 25   proposed format for the questionnaire acceptable? 

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  1             So the user brochures provide adequate

  2   instructions for donor screening personnel, and are

  3   there any other issues that still need to be

  4   addressed, any concerns that they want us to let

  5   the task force know about?

  6             [Slide.]

  7             These are the hard-working reviewer cadre,

  8   the individuals that are on the reviewer cadre who

  9   kindly agreed to participate in this project.

 10             On the lefthand side, we have reviewers

 11   from within the FDA.  They represent the Division

 12   of Blood Applications, Division of Emerging

 13   Transfusion Transmitted Diseases, and the immediate

 14   Office of the Director for the Office of Blood

 15   Research and Review.

 16             We also have the Office Compliance and

 17   Biologics Quality represented, as well as the

 18   Office of Regulatory Affairs.

 19             On the right side are consultant reviewers

 20   that we had representing the interest of industry

 21   both from the donor center side and the patient

 22   side.  These people provided personal opinions,

 23   their ideas and their concerns on the guidance

 24   document.

 25             I think you will recognize the names of 

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  1   current and ex-BPAC members, but their

  2   participation were as experts in the industry, and

  3   not as BPAC members.  Of the 12 reviewers, 10 have

  4   submitted comments, one that submitted no comments

  5   at all, she didn't have any comments, and there was

  6   one that has not turned in their comments to me

  7   yet, and you know who you are.  I also know where

  8   you live, so I will come and get those soon.

  9             [Slide.]

 10             We are still compiling the comments, but

 11   in general, the reviewers thought that the

 12   questions were consistent with the FDA regulations

 13   and recommendation, the rationale for the revisions

 14   and the studies were appropriate.  The proposed

 15   format was acceptable, the accompanying documents

 16   were simple, and I am sorry to use that word now,

 17   but that was their word, but they captured the

 18   important issues.

 19             The abbreviated questionnaire seems to be

 20   acceptable for repeat donors and possibly even a

 21   desirable option, and they felt that the documents

 22   will improve the donor interviews and streamline

 23   the interview process.

 24             Before I go any further, I want to say

 25   that these opinions and the opinions on the next 

                                                               364

  1   two slides are those of the cadre of the reviewers,

  2   and not my opinions or the opinions of the FDA.

  3             [Slide.]

  4             Now, the reviewers still had some ideas

  5   that they felt still needed to be addressed.  They

  6   felt that there were some limitations in the

  7   cognitive studies.  A few examples of these were

  8   that the individuals in the focus groups and in the

  9   cognitive study groups do not represent all the

 10   minorities especially those for whom English was a

 11   second language.  They didn't see that that

 12   evidence was there in the report.

 13             Also, they observed that the testing was

 14   done on individual questions, and not on the

 15   format, the whole tool of the Uniform Donor History

 16   Questionnaire.  They felt that terms needed to be

 17   defined and written in a language that the donors

 18   will understand.

 19             They felt that there was a little too much

 20   medical terminology, specifically phrases like

 21   "prescribed by a physician" and "apheresis device."

 22             They felt that the user brochure needed to

 23   explain when accompanying documents should be used.

 24   For example, they weren't sure if the educational

 25   material sheet should be used for abbreviated 

                                                               365

  1   questionnaires.

  2             They also felt that the user brochures

  3   need to contain more information about what to do

  4   with donor responses.  The user brochures do not

  5   describe how to document follow-up responses in a

  6   standardized manner.

  7             In addition, the users are referred to

  8   their own SOP for whether or not a donor is

  9   acceptable depending on the responses they give,

 10   and the reviewers felt that properly the user

 11   brochure said make some of those decisions.

 12             Lastly, it wasn't clear from the user

 13   brochure if the donor was to complete the whole

 14   questionnaire even if they were deferred on a

 15   question early in the questionnaire.

 16             [Slide.]

 17             They also felt that there were some

 18   limitations on the Medication Deferral List.  For

 19   instance, they felt that donors will provide

 20   information only on the medications that are on the

 21   list while there may be other medications that

 22   donors are taking that may defer them.

 23             They also felt that the donors may be

 24   taking the medications for the conditions that are

 25   different than the conditions that are listed on 

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  1   the Medical Deferral List, and therefore, not

  2   volunteer that they are taking that specific

  3   medication.

  4             They also felt that the educational

  5   material was difficult to read.  They felt it was

  6   hard to get through all the different fonts and the

  7   organization of the material, and one reviewer

  8   recommended that the educational material sheet be

  9   revised in plain language.

 10             They also noticed that the information on

 11   the educational sheet was not exactly in the same

 12   order as the information provided in the

 13   questionnaires, and they felt that if the donors

 14   were to read it and then to go to the

 15   questionnaire, they might get confused.

 16             Now, in the rationale, one of the

 17   questions that asked for contact with saliva by

 18   kissing, explained in the rationale that this was

 19   due because of exposure to hepatitis, this was to

 20   detect somebody who had been exposed for hepatitis.

 21             The reviewer felt that this wasn't an

 22   adequate question to detect all incidents of

 23   hepatitis because there are other ways of getting

 24   exposed, such as the fecal-oral route.  So, this is

 25   one of the responses that we will have to look at 

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  1   closely because this is one that we recommended to

  2   the task force in our letter last year be included

  3   in the questionnaire, so our working group will

  4   look hard at this to decide which way we go on it.

  5             Also, in the rationale, they stated that

  6   they eliminated the question off the questionnaire

  7   about asking the donor if they understood the

  8   questions and if they had any other--the questions

  9   that were asked to them and the information that

 10   was presented, and had all their questions been

 11   answered or did they have any other questions.

 12             They stated that they removed this because

 13   it was part of the donor consent statement, and the

 14   reviewers felt that they could not make this

 15   judgment, they didn't know whether to agree with it

 16   or not, because there weren't any donor consent

 17   statements that were included in the review packet

 18   for the FDA.

 19             Lastly, they were concerned a little bit

 20   about the abbreviated questionnaire.  The user

 21   brochure states that the abbreviated questionnaire

 22   will be used only after the donors have been

 23   screened with the full-length questionnaire two

 24   times.

 25             Some of the biological product deviation 

                                                               368

  1   reports that have come in to FDA has shown that

  2   there are considerable numbers of postdonation

  3   information reports that come in to CBER, that are

  4   due to information that is gathered on the third

  5   donation or even later, and if those questions are

  6   eliminated from the abbreviated questionnaire,

  7   there may be a group of donors that are missed.

  8             They weren't sure if the abbreviated

  9   questionnaire would be given to current repeat

 10   donors in the donor center once the whole tool is

 11   implemented in a blood center or would once the

 12   whole tool is implemented, would repeat donors

 13   start getting the new questionnaire and then

 14   eventually step down to the abbreviated.  That

 15   information wasn't explained.

 16             [Slide.]

 17             Previously, we reviewed the UDHQ from AABB

 18   when it was sent in, and we provided comments back

 19   to them, however, we did not review a final

 20   document, but the AABB published the new

 21   questionnaire as being FDA approved.

 22             Our Chief Counsels have informed us that

 23   we can no longer do it this way, so we are

 24   evaluating some alternative mechanisms for

 25   implementing the donor history questionnaire, the 

                                                               369

  1   new revised one.

  2             One mechanism that we are looking at is to

  3   have a prior approval supplement submitted by a

  4   licensed applicant that we would review and

  5   approve.

  6             Another possible mechanism is to prepare

  7   our own questions and list them in a guidance,

  8   similar to what we did with the '93 HIV guidance.

  9             Another possibility is to adopt the

 10   industry standard, in other words, the AABB

 11   questionnaire, in a guidance document, similar to

 12   what we did with the ISBT-128, uniform labeling

 13   guidelines.

 14             I am not going to go into any detail in

 15   any of these because they are still being discussed

 16   internally, and in the end, we may even decide to

 17   do something that is not listed on this slide.

 18             [Slide.]

 19             To conclude, this is where we are going.

 20   We are going to complete compiling the reviewers'

 21   comments, and we hope to have this done sometime in

 22   July.  Then, we will prepare a written response to

 23   send back to the AABB Task Force, and we hope to

 24   have that out the month after.

 25             After AABB has addressed our comments and 

                                                               370

  1   have sent them in to us, we will give them back to

  2   the reviewers. I have informed the cadre that their

  3   job is not over yet, so they will get the response

  4   back, and they will determine if all of the

  5   concerns have been addressed.

  6             Of course, we don't know this date,

  7   because it will be on AABB's timeline.  In the

  8   meantime, we will determine which mechanism we will

  9   use to implement the questionnaire, and if it is

 10   determined that we need to publish guidance

 11   document, we hope to have that out by September.

 12             Thank you very much for your attention.

 13             DR. NELSON:  Thank you, Judy.

 14             Questions?  Yes, Mary.

 15             DR. CHAMBERLAND:  Judy, thanks for your

 16   comments.

 17             Just a question for my education here,

 18   too, in terms of the feedback that is going to be

 19   given to AABB, I guess I have to say I am just not

 20   familiar with sort of the format that that might

 21   take.

 22             For example, will it include every

 23   reviewer's comments on filtered, so you get their

 24   raw data, so to speak.  Then, I have to imagine

 25   there must be some intermediary step where FDA 

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  1   staff, some of whom are on the Review Committee,

  2   but supplemented by additional folks who have all

  3   the regulatory and all that information, that they

  4   provide, if you will, sort of like a comment on the

  5   comments, and some sort of final summary of what it

  6   is that you need to do either that would be

  7   required to be done, would be recommended but not

  8   required.

  9             Could you speak to that a little bit,

 10   about what to expect for feedback and its format?

 11             MS. CIARALDI:  Sure.  What we will do, and

 12   it will be the working group of the five or six

 13   individuals I had up on an earlier slide, with

 14   input from our General Counsel and Dr. Epstein and

 15   his group, as well.

 16             We are going to look over the comments.

 17   Some of the comments were given to us, I didn't

 18   include them in here.  For instance, one reviewer

 19   wanted us to recompound all the questions, which is

 20   something that we know because some of us are

 21   reviewers and some of us were on the task force, is

 22   not optimal, it is not desirable.

 23             So, that would be a comment that our

 24   working group would decide that we probably would

 25   not forward on to the AABB Task Force as a valid 

                                                               372

  1   comment.  So, basically, we are looking for ones

  2   that are comments that really need to be addressed,

  3   that we feel are--I don't want to use the word

  4   valid, but do raise concerns where revisions are

  5   needed or issues need to be brought up.

  6             So, we are not judging the right or wrong

  7   of the comments because all the comments were made

  8   in good faith, but there are some cases where some

  9   of the comments were probably made outside of some

 10   additional knowledge.

 11             DR. CHAMBERLAND:  So, will there be a set

 12   of recommendations or requirements?  I guess I am

 13   just not sure.  I mean this could go on

 14   indefinitely, and Joy said the task force is

 15   waiting for its vacation on some exotic isle.

 16             You make it very clear.  I mean there are

 17   some things that probably will be not negotiable,

 18   but there might be others that would be.  As I

 19   said, we could continue to exchange drafts ad

 20   infinitum.  How do we put some closure to this?

 21             MS. CIARALDI:  It is our desire not to go

 22   back and forth.  What we will do will be similar to

 23   what we do with what we call a complete response

 24   letter.  In it, we address what we call, in the

 25   case of a review, it is called a deficiency, in 

                                                               373

  1   here it will be called an observation, things that

  2   we have picked up during our review.

  3             Then, we will go ahead and come back and

  4   say something like FDA recommends you do this or

  5   please give us some additional information, so we

  6   can make a determination if this is valid.

  7             So, in some cases, we may ask for

  8   additional information, and in some cases, we may

  9   ask for revision.  It may be a combination of both,

 10   but we definitely will give them some guidance on

 11   how they should address it.

 12             Alan, I saw that you were up, I am sorry.

 13             DR. WILLIAMS:  You answered most of it,

 14   Judy.  I guess the one comment I have, the one new

 15   word I learned since joining the agency, is

 16   vetting.  What we do is discuss everything

 17   internally.  I suspect what goes back will be a

 18   unified opinion from the agency, incorporating what

 19   we feel are the most relevant comments, and

 20   certainly would not want to hinder progress in this

 21   area.

 22             DR. NELSON:  Thank you.

 23             I would like to move to the Open Public

 24   Hearing.

 25             Celso Bianco from America's Blood Centers. 

                                                               374

  1   Hopefully, we can have some brief statements at

  2   this point.

  3             DR. BIANCO:  The committee has received

  4   the statement, the audience, too, so I would like

  5   to read only the last paragraph of the statement

  6   from America's Blood Centers.

  7             I am Celso Bianco.  I am with America's

  8   Blood Centers.

  9             ABC urges this committee to support the

 10   task force recommendation that all new donor

 11   screening questions undergo vigorous validation

 12   procedures to assure that they are both sensitive

 13   and specific to the transfusion risk they are

 14   intended to address.

 15             The donor screening document being used

 16   today is a hodgepodge of questions that have

 17   evolved over time.  These questions have not been

 18   evaluated for efficacy or efficiency.  The result

 19   is a screening tool that includes many complex

 20   multi-part questions that are confusing to donors

 21   and screening personnel alike.

 22             Prime examples are the recently

 23   promulgated questions to identify persons at risk

 24   of CJD because of international travel and

 25   questions now under consideration by FDA to 

                                                               375

  1   identify donors at risk for exposure of zono via

  2   xenotransplantation.

  3             ABC urges FDA and this committee to

  4   require validation of all new questions and to

  5   submit them to a forum, such as the Interagency

  6   Task Force to redesign the blood donor screening

  7   questionnaire.

  8             Thank you.

  9             DR. NELSON:  Thank you, Celso.

 10             Dr. Rita Reik from the American Red Cross.

 11             DR. REIK:  Good evening.  I am Rita Reik,

 12   Senior Medical Officer at the American Red Cross.

 13   I would like to thank you for the opportunity to

 14   speak to the committee regarding the Uniform Donor

 15   History Questionnaire.

 16             I am somewhat of a cognitive quality

 17   control check for those of you who are staying

 18   paying attention because some of you probably

 19   realize that I am not the Red Cross representative

 20   on the task force.  Dr. Linda Chambers actually

 21   represented the Red Cross, but she was unable to

 22   make it, so I am here in her stead.

 23             I would be very happy to read this very

 24   brief statement into the record.

 25             In late March, AABB submitted their 

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  1   recommendations for a revised Uniform Donor History

  2   Questionnaire to the FDA.  This submission was, as

  3   you know, the culmination of a two-year effort by

  4   AABB and the Uniform Donor History Questionnaire

  5   Task Force to examine all possibilities for

  6   strengthening the questionnaire.

  7             The American Red Cross is currently

  8   evaluating the Uniform Donor History Questionnaire

  9   and its operational implications, and we are

 10   pleased to have the opportunity to emphasize our

 11   support of both the AABB submission today and the

 12   process used in the redesign of the Uniform Donor

 13   History Questionnaire.

 14             Those of us in the blood industry have

 15   received considerable feedback from our donors over

 16   the years regarding the design of our donor history

 17   questionnaire. They tell us they find the questions

 18   to be confusing, time consuming, and too numerous.

 19   In addition, frequent donors object to the need to

 20   answer the same questions repeatedly at each

 21   donation.

 22             So, we believe that this is a very

 23   important first step in improving the Health

 24   History Questionnaire, and we call it a first step

 25   because the Red Cross also believes that ongoing 

                                                               377

  1   evaluation of the questionnaire will be an integral

  2   part of the process.

  3             FDA and the blood industry will continue

  4   to encounter new or potential threats to the safety

  5   of the blood supply.  When these threats become

  6   known, the first consideration will be determining

  7   whether a donor might have been exposed.

  8   Traditionally, a primary method used to make that

  9   determination has been to add a new question to the

 10   Health History Questionnaire.

 11             The donation process is becoming

 12   increasingly more complex.  For example, donor

 13   deferral policies have expanded as we have become

 14   aware of the potential for transmission of emerging

 15   diseases.  As a result, there are more questions

 16   than ever.

 17             In addition, the nation's demographics are

 18   changing, and we now recruit donors from a

 19   multitude of different cultures for which English

 20   is a second language. While it is feasible to offer

 21   translations of the donor questionnaire, we must

 22   keep in mind that a translation is more likely to

 23   result in an accurate answer if we start with the

 24   simplest English version possible.

 25             Also, having the briefest, simplest 

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  1   questionnaire is desirable in that donors are more

  2   likely to return if we  minimize their time

  3   investment relative to donation.

  4             In conclusion, the ARC believes that BPAC,

  5   FDA, and the industry have a unique opportunity

  6   here to advance the collection process to a new

  7   level.  With the approval of the improved

  8   questionnaire would also come the opportunity to

  9   institute a process for ensuring the value-added of

 10   future questions.

 11             Therefore, we urge BPAC, FDA, and the

 12   blood industry to adopt the following as guiding

 13   principles for the process of crafting the donor

 14   questionnaire:  simplicity, uniformity,

 15   effectiveness and efficiency.  To that end, when

 16   determining whether to add or revise donor

 17   questions, the FDA should:

 18             1.  Ensure that the questions are

 19   understandable and effective prior to including

 20   them in the final FDA regulations or guidances.  Of

 21   course, it seems best to do this by piloting the

 22   questions on persons who have characteristics

 23   similar to our donors.

 24             2.  Recognize that ensuring clarity of the

 25   questions optimizes the chance for accuracy in 

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  1   responses and that is just as important as ensuring

  2   accuracy in any other part of the blood product

  3   manufacturing process.

  4             3.  Adopt new questions only after

  5   determining that the existing questions cannot

  6   provide the answers and cannot be modified to do

  7   so.

  8             4.  Add new questions only after

  9   determining that they will not negative affect the

 10   ability to obtain precise answers to previously

 11   existing questions.

 12             We look forward to continuing working on a

 13   process that we hope will establish an important

 14   set of guiding principles for future revisions.

 15             Thank you for your attention.

 16             DR. NELSON:  Thank you very much.

 17             Jan Hamilton.

 18             DR. HAMILTON:  This statement has already

 19   been provided to the committee.  I am Jan Hamilton.

 20   I am with ZLB Plasma Services, and I am speaking on

 21   behalf of PPTA Source.

 22             It is a relatively long statement, I would

 23   say, but I am going to read the whole thing.

 24             DR. NELSON:  Is there a way you could

 25   summarize it given that it will be included in the 

                                                               380

  1   record?

  2             DR. HAMILTON:  No, but I will shorten it,

  3   which is a bit different.

  4             When you are given five minutes, it's

  5   pretty concise, to begin with, so I will just start

  6   a couple paragraphs down.

  7             The source plasma industry supports the

  8   overall task force objective of simplifying the

  9   current questionnaire.  The proposed questionnaire

 10   and supporting documents are intended to enhance

 11   blood and source plasma safety by making the

 12   screening process more effective in capturing

 13   relevant donor qualifying information.

 14             Due to differences in the collection

 15   practices for the blood and source plasma, a

 16   subcommittee of the task force was organized by

 17   PPTA to revise the screening documents for source

 18   plasma donors.  Although the majority of source

 19   plasma questions are identical to the blood

 20   industry questions, specific revisions were made to

 21   conform to source plasma screening requirements.  A

 22   separate source plasma screening system proposal,

 23   including specifically tailored donor screening

 24   documents, will be submitted for review and

 25   approval by the FDA. 

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  1             The source plasma screening documents

  2   include both the full-length questionnaire and

  3   abbreviated questionnaire. The abbreviated

  4   questionnaire is proposed for use with donors who

  5   have previously been questioned using the full-length

  6   questionnaire and donate frequently, as

  7   defined as at least once in a 30-day period.

  8             The full-length questionnaire will be

  9   administered each year at the time of the donor's

 10   annual physical examination, which is not a

 11   requirement for blood donors.

 12             The source plasma abbreviated

 13   questionnaire and high-risk poster were tested in

 14   cognitive interview studies by the National Center

 15   for Health Statistics.  In addition, the questions

 16   that were revised to meet plasma sourcing

 17   requirements were also tested.

 18             To this end, the source plasma screening

 19   documents have been tested for donor comprehension.

 20   Currently, the results of the research study are

 21   under review and the appropriate revisions are

 22   being completed on the proposed screening

 23   documents.  PPTA plans to submit the source plasma

 24   proposal to FDA in July 2002.

 25             PPTA appreciates the opportunity to 

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  1   participate in this important industrywide effort

  2   to improve the donor screening process.  We look

  3   forward to continued participation with the FDA and

  4   the blood industry on this and other initiatives.

  5             DR. NELSON:  Thank you very much.

  6             The next speaker, Dr. Paul Cumming.

  7             DR. CUMMING:  I am Paul Cumming.  I am

  8   president of Talisman, Limited.  We are a

  9   manufacturer of software, multimedia, audio/video

 10   donor interviewing software financed, in

 11   significant part recent by the National Heart,

 12   Lung, and Blood Institute, and George Nemo, guiding

 13   it.

 14             I did not come here prepared to make

 15   remarks, but was convinced I should do so.  First,

 16   I would like to compliment the committee.  I think

 17   they did superb work given the conditions under

 18   which they were doing it, and their limits on

 19   resources and everything else.  It is very

 20   expensive work to do, speaking as someone who has

 21   done it for a long time, and I have nothing but

 22   compliments for the committee.

 23             Talking to people here, many people are

 24   unaware of what it is we are doing and the fact

 25   that it is an FDA priority, part of the five point 

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  1   plan, and it was financed by NIH, so we should be

  2   aware of it.  Our effort has gone into the software

  3   and into publications.

  4             The work, I will refer to as just other

  5   places that can find more information as opposed to

  6   going into it and generally what it is.  First, the

  7   information is presented in terms of the first

  8   study, was presented to this committee back in

  9   1999.  It was done in conjunction with the Hoxworth

 10   Blood Center, and was a pilot study.

 11             It was presented more recently in the

 12   December 2001 issue of Transfusion.  Again, it was

 13   Dr. Zuck.  We had about 400 donors.  It was largely

 14   donor satisfaction information.

 15             Since then, the technology has been

 16   expanded, and we have learned our lessons.  It is

 17   now applied in the Mississippi Valley Regional

 18   Blood Center out in Davenport, Iowa, running in

 19   eight or nine centers, and we are looking at

 20   extending applications there, and another large

 21   Midwestern blood center.

 22             The technology is officially known as

 23   Audio/Video Computer-Assisted Self-Interviewing.

 24   It runs on computers and has an audio portion

 25   through earphones for privacy.  It uses Touch 

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  1   Screen to avoid donor problems with keyboards and

  2   keyboard kinds of errors that go in with some other

  3   kinds of CASI technology, and it uses extensively

  4   color.  It has a color picture to explain or try to

  5   explain the question, as well as the audio and the

  6   text on screen.

  7             The results, which are on our web site,

  8   the newer work at Mississippi Valley, and I think

  9   we have interviewed something like 10,000,

 10   something in excess of 10,000 donors now, and we

 11   have repeated the studies at Hoxworth plus extended

 12   them to other things, and that is available in the

 13   form of presentations we have made to the AABB and

 14   the FDA, and it is on the web site.

 15             The system is known as the Quality Donor

 16   System. The people who have done most of the data

 17   collection and presentation are Dr. Louis Katz from

 18   Mississippi Valley and Lauri Rozinski.

 19             The studies in general show that donors

 20   prefer the Audio/Video Computer-Assisted Technology

 21   by a factor of at least 4 to 1, and that over face-to-face

 22   interviewing.  They say, among other

 23   things, that the screening questions are clearer,

 24   they can understand them better, that they will be

 25   honest in their responses, and they are more likely 

                                                               385

  1   to donate again.

  2             Staff studies we have done of staff

  3   satisfaction show similar kinds of things where the

  4   staff prefer them and believe the donors will be

  5   more honest with the technologies than they will be

  6   with face-to-face interviewing.

  7             Staff savings in times is in the range of

  8   four or five minutes per donation.  An omissions

  9   and error study that Katz and Rozinski did showed a

 10   60 percent decline in those factors.

 11             The information can all be found on our

 12   web site, which talismanlimited.com, all spelled

 13   out, and I can give people more complete

 14   information afterward, more precise reference.  I

 15   thought it was important to communicate that.

 16             Thank you.

 17             DR. NELSON:  Thank you.

 18             Are we ready to discuss the questions,

 19   Alan?

 20            Questions for the Committee and Committee

 21   Discussion

 22             DR. WILLIAMS:  Question 1.  Does the

 23   committee believe that the revised Uniform Donor

 24   History Questionnaire proposed by the Task Force is

 25   suitable to screen donors of allogeneic whole blood 

                                                               386

  1   and blood components for transfusion?

  2             DR. NELSON:  Discussion or let's vote.

  3             DR. DiMICHELE:  I just wanted to ask,

  4   initially, when you asked that question, I thought

  5   we were kind of voting on the final version, but

  6   this isn't obviously the final version, so exactly

  7   how do you want us to comment on that?

  8             DR. WILLIAMS:  I think given that it's an

  9   ongoing process with some interaction still to be

 10   conducted between the Task Force and the FDA, it

 11   would be probably most relevant to use the concept

 12   that we do arrive at a final FDA--I hesitate which

 13   word to use, but FDA-compatible version of the

 14   questionnaire, and that is what we are addressing

 15   the question to.

 16             I think given the content, you might also

 17   separately consider issues, such as self-administration and

 18   other factors on which you might

 19   want to comment separately, but what we are looking

 20   for is conceptually whether the field can make the

 21   change from the existing documents, which are non-

 22   standardized to what we hope would be a

 23   standardized document as shown here today.

 24             DR. NELSON:  Your idea was that once a

 25   final document was arrived at, this would be a 

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  1   mandated questionnaire by the FDA?  As I understand

  2   it, the content of what is asked is mandated, but

  3   how they ask it, blood centers are able to come up

  4   with any sort of way to do this.

  5             DR. WILLIAMS:  I think "mandated" probably

  6   isn't the right term.  For instance, if a guidance

  7   is a mechanism, it would be recommended, and

  8   centers are free to use alternate approaches.  If

  9   those approaches are less restrictive or otherwise

 10   substantially different than what is contained in

 11   the guidance, they would have to apply under a

 12   prior approval supplement for changes to their

 13   license, but that wouldn't necessarily mean that

 14   everyone has to use this questionnaire.  There are

 15   avenues for variations.

 16             I would add to that, that if there are

 17   changes proposed, that particularly changes in

 18   wording and content of the questionnaire, that it

 19   would be reasonable to expect that cognitive

 20   studies, at least up to the quality of those

 21   discussed so far, would be part of that process.

 22             DR. STUVER:  So, if this version or

 23   something close to it, it becomes recommended or

 24   not necessarily required by the FDA, will the

 25   expectation be that it is going to be a self-administered 

                                                               388

  1   instrument, or will there be

  2   flexibility as to whether it could be given orally

  3   or depending upon the literacy of the donor?

  4             DR. WILLIAMS:  There has been discussion

  5   about the relative merits of self-administration

  6   versus audio CASI versus face-to-face.  I think I

  7   would take the position that that scientific debate

  8   has yet to be fully held.

  9             There are literature which support

 10   arguments in both directions.  The studies which

 11   actually have been conducted on the blood donor

 12   population are few with small numbers, and mostly

 13   they are extrapolations from other studies that

 14   have been done either in high risk populations or

 15   the general population.

 16             As I mentioned in the introduction, there

 17   is a guidance document in the field for comments,

 18   and we expect that there will be arguments

 19   addressing that, supported by the scientific

 20   literature, and we, in fact, cited some in the

 21   guidance document itself, defining a similar

 22   position.

 23             So, I think that discussion still needs to

 24   be held in depth.

 25             DR. NELSON:  Through the REDS study, you 

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  1   and colleagues have done a lot of case control,

  2   calling back of donors, and tried to get an

  3   understanding, particularly of donors who turn out

  4   to have markers as to whether or not the issue was

  5   that they didn't understand the question, or the

  6   issue was that they did understand the question,

  7   but didn't give the information candidly.

  8             Can you assess what the proportion of the

  9   problem was with those who turn up to have markers

 10   that should have been screened out as to how much

 11   is misunderstanding and how much is actually not

 12   being candid?

 13             DR. WILLIAMS:  There are some data to

 14   address that particularly with the CDC-sponsored

 15   studies of HIV seropositive donors, the reasons for

 16   their screening responses really are across the

 17   board.

 18             I would say that process has a validation

 19   concern of its own, and that being face to face

 20   with an individual, it is very difficult for

 21   someone, you know, obviously faced with some sort

 22   of misrepresentation to say, well, yes, I lied.  It

 23   is a lot easier to say that I didn't understand the

 24   question thoroughly.

 25             So, the data are out there.  It is a 

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  1   proportion.  I hesitate to give that proportion.

  2             DR. NELSON:  At least it is some of the

  3   problem.

  4             DR. ALLEN:  Going back to the issue of

  5   implementation once the process on developing the

  6   questionnaire is completed, is it FDA's

  7   anticipation that licensed blood centers will come

  8   back and work out a mechanism through perhaps

  9   changes to their standard operating procedure for

 10   implementing this?

 11             DR. WILLIAMS:  That will, in fact, be a

 12   critical component.  It wasn't discussed

 13   explicitly, but portions of the questionnaire use

 14   capture questions to identify a certain population

 15   which will be subject to more detailed questions,

 16   and some of that will have to be contained in the

 17   center's SOP, correct.

 18             DR. NELSON:  Theoretically, the REDS study

 19   will continue, which as I recall the REDS study has

 20   like a 10 percent resample or something of donors,

 21   isn't that right?

 22             DR. WILLIAMS:  It depends which component

 23   is being referred.  There is a survey component

 24   which has captured data with respect to behavioral

 25   risk, and then there are other components, some of 

                                                               391

  1   which capture the entire database for markers and

  2   donor demographics, and so forth.

  3             Probably the most relevant aspect is the

  4   survey component and which we can actually assess

  5   behavioral information.  Ideally, the best way to

  6   test something like this is in a pre/post sort of

  7   study with a phased implementation, and you could

  8   survey a pre/post population or comparable parallel

  9   populations, and get some idea of what is going on.

 10             But because the outcomes are very rare,

 11   those type of data are very difficult to measure.

 12             DR. HOLLINGER:  Alan, once this gets to

 13   the point where it could be implemented, since it

 14   has gone through all the organizations, and so on,

 15   do you perceive that there would be a problem of

 16   having what you started out to have, which is a

 17   universal uniform at least donor history from all

 18   the blood banks and blood organizations, that there

 19   would be then slight changes that would go on

 20   there, and if so, where do you perceive these

 21   occurring?  What do you see these as a problem?

 22             So, when a donor goes into a blood bank,

 23   no matter where they go, at least this portion here

 24   would be identical.

 25             DR. WILLIAMS:  I think that is the goal, 

                                                               392

  1   to have the major components of the questionnaire,

  2   certainly the FDA recommended and required elements

  3   be standardized.  I think because transfusion

  4   medicine is medical practice, there will always be

  5   a wish for some local options, and those will be

  6   always part of the process submitted to FDA for

  7   review.

  8             So, I suspect there will be some variation

  9   center to center.  What you have to be careful of

 10   is that things aren't tagged onto the questionnaire

 11   that actually begin to compromise what has been

 12   tested as a unified package.  That is the down side

 13   to making changes.

 14             Whether or not sites will use it as is

 15   without changes remains to be seen, but we have

 16   already seen with the source plasma components,

 17   that they have split off, and I think

 18   appropriately, looked at areas that are more

 19   relevant to their donors and which they would like

 20   to define different areas of emphasis or methods.

 21             DR. DiMICHELE:  I just wanted to ask

 22   regarding this issue of self-administration versus

 23   not, on the committee was an ethicist.  I know we

 24   have talked a lot about which way to do it vis-a-vis getting

 25   the most effective history, but was 

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  1   there sort of an ethical response to this in terms

  2   of patient rights and sort of the ethics of

  3   administering very personal questionnaires, and how

  4   they are best done, was there any opinion there?

  5             I just bring this to the group, was there

  6   any opinion that was rendered by the ethicist on

  7   the panel?

  8             DR. WILLIAMS:  I prefer to defer to Joy on

  9   that question.

 10             DR. FRIDEY:  I think the issue of asking

 11   personal questions is one that has been discussed

 12   for a number of years.  The HIV questions dealing

 13   with males having sex with other males, or people

 14   who may have had sex with someone has been a topic

 15   of discussion for a number of years.

 16             Those questions were issued in 1992, and

 17   there has been ongoing concern about that, but on

 18   the other hand, we are trying to identify people

 19   who may have these risk factors, and how do you get

 20   at that without just out and out saying it.

 21             The ethicist on the committee did not

 22   render an opinion about the fact that we are asking

 23   such personal questions, because I think there is a

 24   general recognition that we really need to.

 25             DR. DiMICHELE:  My question is not so much 

                                                               394

  1   that we are asking them, because, of course, we

  2   have to ask them, but just in terms of the way it

  3   is done.  I mean the ethicist rendered no opinion

  4   in terms of one way or the other, is that correct?

  5             DR. FRIDEY:  When you say "the way it is

  6   done"--

  7             DR. DiMICHELE:  Like, in other words,

  8   self-administered or interview-administered.  I

  9   mean that is probably the biggest difference.

 10             DR. NELSON:  At one point, I remember they

 11   had--before there were specific questions--the

 12   person was given a card with a list of deferred

 13   conditions, and the person could then--the question

 14   would be, "Do you fit into any of these

 15   categories," and the person, theoretically, they

 16   could say guess without identifying that they were

 17   a drug user or that they had sex with another man.

 18             I don't know if that is still part of the

 19   scenario.

 20             DR. FRIDEY:  To directly address your

 21   question, yes, that is on the educational

 22   materials.  Except for the FDA liaisons, the Task

 23   Force was unanimous in its opinion that it should

 24   be a self-administered questionnaire, and that

 25   included the ethicist that was on the task force. 

                                                               395

  1             DR. DiMICHELE:  Thank you.

  2             DR. CHAMBERLAND:  Joy, but always with the

  3   understanding that if the donor preferred an oral

  4   administration--

  5             DR. FRIDEY:  Right, there was always that

  6   option, absolutely.

  7             DR. CHAMBERLAND:  So, it would never be

  8   denied.

  9             DR. FRIDEY:  That's correct, if someone

 10   wanted an oral one, they could.

 11             DR. NELSON:  Are we ready to vote on this

 12   first question?  I guess it's a yes or no.  We are

 13   voting on when the final Uniform Donor History

 14   Questionnaire is agreed upon and developed, is it

 15   or will it not be suitable, and it will probably be

 16   very similar to what we have.

 17             DR. SMALLWOOD:  Are there any oppositions

 18   to this question?

 19             [No response.]

 20             DR. SMALLWOOD:  Are there any abstentions?

 21             [No response.]

 22             DR. SMALLWOOD:  Then, it would be a

 23   unanimous yes. Thank you.

 24             DR. WILLIAMS:  The second question.  What

 25   additional comments does the committee have on:  

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  1   (a) the validation process of the Uniform Donor

  2   History Questionnaire as revised; and (b) the

  3   specific content of the Uniform Donor History

  4   Questionnaire questions?

  5             DR. DiMICHELE:  I would just say that I

  6   think I would echo some of the comments that were

  7   made in the open hearing regarding the ongoing

  8   validation of whatever instrument is used, that it

  9   needs to have an ongoing evaluation process in the

 10   field.

 11             DR. HOLLINGER:  I have some questions, if

 12   I could, and they probably are answered, and there

 13   are probably answers to them, but I wanted to just

 14   run through them as I saw them, if I might have the

 15   opportunity.

 16             The question about aspirin or aspirin

 17   product.  Of course, that can be a real problem

 18   anymore because so many people are taking aspirin

 19   for cardiovascular events, et cetera, so a lot of

 20   people are on aspirin, but it doesn't include the

 21   other nonsteroidals - ibuprofen, Advil, Relafen,

 22   Motrin, et cetera, which also equally can cause

 23   platelet dysfunction.

 24             It is a question we have to ask all of our

 25   patients before we are going to do a biopsy on 

                                                               397

  1   them.  We also ask them not to take them for at

  2   least seven to 10 days before we do a biopsy for

  3   that reason, because we do bleeding times on most

  4   of them.  Invariably, their bleeding time--not

  5   invariably--but sometimes their bleeding times will

  6   be elevated, and they are on Motrin or ibuprofen,

  7   and so on.

  8             This also goes over to Celebrex and Vioxx,

  9   but not anywhere into the same realm as you find

 10   with the other nonsteroidals.

 11             I know the question is asked primarily I

 12   guess because of its effect on the platelets--and

 13   correct me if I am wrong, Toby--or are we talking

 14   about because when they draw the blood, they are

 15   worried about bruising and things like this, which

 16   is it?

 17             DR. SIMON:  It is the effect on the

 18   platelets because if the person has been on

 19   aspirin, they can still donate, you just cannot use

 20   them as an exclusive source of platelets.  So,

 21   their platelets can still be used in a pool, and it

 22   relates to the irreversible effect of aspirin

 23   versus the other drugs that you are talking about

 24   that have a reversible effect.

 25             So, it has been consensus of scientific 

                                                               398

  1   medical opinion that it is not necessary to exclude

  2   platelets as a single source, platelets from those

  3   who are on these other drugs.

  4             DR. HOLLINGER:  So, they could actually be

  5   a plateletpheresis donor also if they were on these

  6   other drugs, if that is what they were coming in

  7   for?

  8             DR. SIMON:  Well, I believe that is the

  9   case.  I think some centers may have individualized

 10   rules on that, but at least it is my understanding

 11   that AABB, FDA, up until now, you could be.

 12             DR. FRIDEY:  Many blood centers, and

 13   actually if there is anyone here to whom this does

 14   not apply, have very extensive lists of aspirin-containing

 15   comments.  I know that our blood center

 16   does, I know the American Red Cross does, the DoD

 17   does, so that if a donor says, gee, I did take

 18   something yesterday, and I am not sure if it had

 19   aspirin in it or not, we can help them out because

 20   we have a list.

 21             So, that is one way to address the concern

 22   that you have.  At our blood center also, we do

 23   have a separate question that we ask donors,

 24   plateletapheresis donors, to try to find out if

 25   they have taken a nonsteroidal anti-inflammatory 

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  1   because at our center, we don't want that person to

  2   be a plateletapheresis donor.

  3             I can't speak for other organizations, so

  4   I would have to ask my colleagues in the American

  5   Red Cross and ABC to get up and address that.

  6             DR. SIMON:  There isn't good literature on

  7   it actually, even under the aspirin, the old

  8   studies done in the seventies, I think upon which

  9   things were based, showed that after 72 hours, you

 10   couldn't tell a difference.

 11             DR. HOLLINGER:  And this would include

 12   Ticlid and Plavix and the other things which cause

 13   an irreversible change to those platelets, as well.

 14             DR. SIMON:  I don't think they have been

 15   studied.

 16             DR. HOLLINGER:  Oh, they have been

 17   studied.

 18             DR. SIMON:  But not as plateletapheresis

 19   donors, to my knowledge.

 20             DR. HOLLINGER:  That, I don't know.

 21             DR. BIANCO:  Maybe this will help a little

 22   bit.  After the explanation that Toby gave, the

 23   only donor that is important to defer is the

 24   apheresis donors, because that is a full platelet

 25   donor. 

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  1             The apheresis donor is recruited in a

  2   different way, is a scheduled donor, and so that

  3   donor is recruited by telemarketing or has already

  4   made an appointment, is a donor that has already

  5   donated red cells.

  6             Nobody puts on a machine a donor that

  7   didn't have at least some experience in the

  8   donation, and that is the first thing that the

  9   person that is talking with the donor will say,

 10   "Remember, for the next couple of days or in the

 11   next three days, you are not going to take any

 12   aspirin before you come to the appointment to make

 13   your donation."

 14             So, it is rare that an apheresis donor

 15   will say yes to any of those questions because it's

 16   a different population, is recruited with a lot of

 17   care.  The donor is going to sit on a chair for a

 18   couple of hours for the process, and you want a

 19   full platelet dose to do well.

 20             DR. HOLLINGER:  There is a couple other

 21   questions. I found the Questions 34 and 19 to be

 22   confusing about this, where it says, "Males, check

 23   no," or "Females, check no."  I understand one is

 24   asking about male donors, the other asking about

 25   female donors, but it is that parenthesis which 

                                                               401

  1   says males, check no, and females, and I don't

  2   understand the reason.  The "no" doesn't fit with

  3   the question.

  4             If I were reading this, and it was in

  5   capital letters, where it said female donors or

  6   male donors, it would be clear to me that is not

  7   for me to answer if it said female donors, but then

  8   when I read on, it says, "Males, check no," it just

  9   doesn't make sense.

 10             DR. FRIDEY:  This falls into the category

 11   of the quality assurance questions or tools, if you

 12   will, that we wanted to embed into the

 13   questionnaire.  Now, granted, it is not perfect, it

 14   doesn't make exactly perfect sense to tell males to

 15   say check no to a question that applies to females,

 16   we recognize that, but we have those little

 17   parenthetical phrases in there as one means of

 18   trying to determine whether or not the donor really

 19   is paying attention and is following instructions.

 20             So, while I understand your concern, when

 21   we had that concern also with that, what overrode

 22   that was the fact that we felt we needed to have

 23   something in there to make sure that the donors

 24   were paying attention when they were going through

 25   the questionnaire, and following directions. 

                                                               402

  1             It is also part of the auditing function,

  2   as well, when blood centers review the

  3   questionnaires afterwards, and that part of the

  4   questionnaire was also evaluated in the NCHS

  5   cognitive evaluations, and did not seem to pose a

  6   significant problem.

  7             DR. HOLLINGER:  The other question has to

  8   do under the section says, "Have you ever."  I know

  9   you used this once before when you have added the

 10   word "even once."  I felt that at least in 36, even

 11   though you say, "Have you ever," to me it would be

 12   better if that sentence said, "Have you ever used

 13   needles even once to take drugs, steroids, or

 14   anything."

 15             It is one of those added words there that

 16   I think is important for people who take injection

 17   drugs, it just doesn't seem to come across often

 18   even once--that if they had just done it once, you

 19   know, it is okay.  So, oh, yeah, I only did it

 20   once.  That is often the answers I get back, and I

 21   would like to see at least that be put in there

 22   somewhere on that question or at least considered.

 23             DR. NELSON:  Do people share needles when

 24   they use steroids?

 25             DR. ALLEN:  High school students certainly 

                                                               403

  1   can, and I assume college.

  2             DR. FRIDEY:  The reason we took "even

  3   once" out of that, and several other questions, is

  4   that the focus groups that were conducted or in the

  5   focus groups, the participants indicated that this

  6   was really redundant and unnecessary.

  7             If we put it into one question, like we

  8   did put it back into Question--for males who have

  9   had sex with other males, we have it in there--it's

 10   Question No. 34.  It was in a number of other

 11   questions, and looking at all the questions that

 12   had that in there, the input from the focus groups

 13   was this really did add some excessive verbiage,

 14   and we felt that the question in itself was clear

 15   enough that it justified removing the "even once."

 16             DR. NELSON:  I am not sure I agree.  I

 17   think I agree with Blaine because when we find

 18   donors who test positive for hepatitis C, they have

 19   injected drugs maybe once or a few times, often

 20   years ago, and they have a chronic infection, and

 21   this question, they would not answer it the way it

 22   is, and I am not sure your focus group has specific

 23   expertise to tease out this question.  I think

 24   Blaine probably agrees.

 25             DR. HOLLINGER:  I agree.  This a very 

                                                               404

  1   important question, the needle question, as well as

  2   the other question that you had where you put it

  3   in, and maybe even once.  I mean those are

  4   important questions.  At least I would like that to

  5   be considered as a possibility--

  6             DR. FRIDEY:  And it will be.

  7             DR. HOLLINGER:  --for other comments, and

  8   see what you think about that.

  9             DR. FRIDEY:  Okay.  It will be.

 10             DR. HOLLINGER:  The other thing is the

 11   issue about have you had hepatitis, and you have

 12   probably resolved this, but at one point we took it

 13   out.  I think we said if you had hepatitis before

 14   the age of 11, that that wouldn't be considered as

 15   an exclusion, but then I noticed that that is not

 16   in here about have you had hepatitis after the age

 17   of 11.  Did you feel that that created more of a

 18   problem than not?

 19             DR. FRIDEY:  It is essentially we are

 20   using it as a capture question.  If they say yes, I

 21   have had it, then, we would ask how old were you

 22   when you had it, and we will try to determine if

 23   they had it before the age of 11.  If they say yes,

 24   then, obviously, they can go on to donate; if they

 25   say I have had it after 11, then, they cannot 

                                                               405

  1   donate. So that information will be captured in a

  2   follow-up format.

  3             DR. HOLLINGER:  The final question--I am

  4   sure this may be a problem in the blood bank--about

  5   had any problems with your heart or lungs.  The

  6   lungs, I guess could be a real problem.  It sounds

  7   like a lot of people with asthma and other things,

  8   and I take it that is not an exclusion for anybody

  9   there, but that seems like that creates a real

 10   problem on the question about lungs.

 11             DR. FRIDEY:  We talked about actually

 12   including specific pulmonary conditions on that,

 13   such as asthma, but felt that we ran the risk of

 14   donors focusing on that to the exclusion of other

 15   conditions that they may have.

 16             So, this was one question that was

 17   extensively discussed by the Task Force and in the

 18   cognitive evaluations where we felt we should ask a

 19   very broad question.

 20             DR. HOLLINGER:  What was the question

 21   there, Joy, that was because of tuberculosis

 22   before, or what was the real reason that question

 23   has been asked?

 24             DR. FRIDEY:  It was in the CFR, acute

 25   pulmonary disease, and that originated in the CFR 

                                                               406

  1   many, many years ago when TB was a concern.

  2             DR. HOLLINGER:  So, if you took that out,

  3   one could ask the question of have you had TB, or

  4   if you don't ask that, is there any other lung

  5   condition that creates a problem, then, in terms of

  6   blood donation either for the safety of the donor

  7   or--

  8             DR. FRIDEY:  There are a number, but in

  9   infectious conditions, such as pneumonia, for

 10   example, or a cold, we feel that we capture that by

 11   three questions.  We ask donors if they are feeling

 12   healthy and well today.  We ask if they are on an

 13   antibiotic or if they are taking any other

 14   medication for an infection.  So, that is how we

 15   try to get at that.

 16             DR. HOLLINGER:  I guess the final question

 17   that I have, you took the question out about

 18   intranasal cocaine?

 19             DR. FRIDEY:  That was never an FDA

 20   required question.  There was an article published

 21   after the original one that raised concerns that

 22   essentially refuted the concept that that was an

 23   independent risk factor for HCV infection.

 24             DR. HOLLINGER:  But you ask you about

 25   kissing and saliva for hepatitis B.  On the one 

                                                               407

  1   hand, I mean the CDC and others talk about, well,

  2   you don't have to worry about that kind of casual

  3   contact being transmissible, and I agree with that

  4   in there, and I can agree with the saliva since

  5   most of the studies in chimps, at least that they

  6   did with chimps, one study in which they took 18

  7   chimps, 13 of them were given it orally.  None of

  8   them came down--this was an infectious saliva--none

  9   of them came down with hepatitis B. Five of them

 10   that were given it parenterally all came down with

 11   hepatitis B, and that has sort of been--

 12             DR. SIMON:  I think they are looking for A

 13   there, for acute A, is that what you were looking

 14   for primarily on that question?

 15             DR. NELSON:  Even with A, and they don't

 16   mention stool, have you changed a diaper or have

 17   you, you know, whatever.

 18             DR. SIMON:  That's the critique that Judy

 19   was talking about.

 20             DR. FRIDEY:  If I could just make a

 21   comment about that, in our subsequent discussions

 22   with the FDA about that, the FDA explicitly stated

 23   their concern, which was that we did not ask about

 24   specific risk factors for hepatitis A.

 25             Now, intuitively, perhaps that is 

                                                               408

  1   something that we should do, but this would

  2   basically represent a policy change, and it was the

  3   Task Force's position, in fact, they are charged

  4   from the AABB Board that we basically should not be

  5   tackling policy issues, and we felt that the

  6   questionnaire perhaps was not the most appropriate

  7   vehicle for introducing a policy change.

  8             So, what we did do was ask the FDA if they

  9   are concerned specifically about hepatitis A, that

 10   should be the usual channels for communicating that

 11   and getting public comment, and so forth, should be

 12   followed rather than implementing a policy by way

 13   of the questionnaire.

 14             DR. NELSON:  Was the FDA concerned about

 15   the transmission of hepatitis A by saliva, or B?

 16             DR. FRIDEY:  No, that was the fecal/oral

 17   comment. Hepatitis B was the concern that we were

 18   trying to address by having the saliva question.

 19             DR. NELSON:  It was B.

 20             DR. SIMON:  But there was, Joy, a classic

 21   old question about close contact with hepatitis.

 22             DR. FRIDEY:  Right, and the concern has

 23   been for hepatitis B and C, so that is why we broke

 24   that question out to ask if they had kissed someone

 25   or come in contact with someone who had Hepatitis 

                                                               409

  1   B.

  2             DR. HOLLINGER:  Who has hepatitis, I think

  3   is the word in here.  I guess if I were looking at

  4   that, I would consider the risk factors for

  5   intranasal cocaine use far exceeds that of the

  6   kissing on there, which is a question you have.

  7             DR. FRIDEY:  That was a hep-B concern.

  8   That was trying to capture hep-B.

  9             DR. HOLLINGER:  Those are the major

 10   concerns that I have.

 11             DR. STUVER:  Joy, I just wanted to follow

 12   up on Blaine's comment about the gender-specific

 13   questions, because I guess I have doubts as to

 14   their quality control value.  Is there data that

 15   they do provide a quality control?

 16             DR. FRIDEY:  To the extent that they were

 17   evaluated by the participants in the cognitive

 18   interviews, there is information about that.  The

 19   people who were involved in those interviews

 20   understood the purpose of the questions there.

 21             No, there is not.  Do we have data to

 22   demonstrate there won't be changes in sensitivity

 23   or specificity or predictive value, if we implement

 24   this version, no, that would require a large, long,

 25   expensive study, but given the tools that were 

                                                               410

  1   available for assessing donor attentiveness, this

  2   was one.  Again, this was done with the input and

  3   at the suggestion of our survey design specialists.

  4             So, we had to rely on that.

  5             MS. KESSLER:  I just want to mention, in

  6   addition, that one of the reasons why that was put

  7   there, probably of equal weight, was that after a

  8   donor has donated one or two times, somebody is

  9   auditing that form, and you can't really leave an

 10   empty spot.

 11             Usually, there is a pattern of answers

 12   that you expect to see, and if you see a blank,

 13   then, you are putting it in some clerk's hand or

 14   some nurse's hand, or somebody's hand, who is doing

 15   a million of these, to look at the question, see

 16   whether it was a male or a female, and so we wanted

 17   to be able to make the process run smoothly, be

 18   able to be consistent with the later audit, which

 19   is not part of the donor history discussion between

 20   the health historian and the donor, but for the

 21   later audit not to be compromised.

 22             So, that was part of it, and it was also

 23   being able to perhaps capture somebody who was not

 24   paying attention.

 25             DR. STUVER:  So, that wouldn't happen 

                                                               411

  1   right away, that they would look through it and

  2   then they would see that they have a blank, and if

  3   they have a blank, then, are all the questions

  4   administered orally with the assumption that the

  5   person hasn't paid attention?  I guess I am just

  6   not clear about the quality control aspect of it.

  7             I mean is it just for later use?  Do you

  8   see my point?

  9             MS. KESSLER:  The committee didn't make

 10   any recommendation of whether or not the whole

 11   questionnaire would be re-administered.  That was

 12   left to local decision of what their quality

 13   control SOPs were in the blood centers where they

 14   implement it, but there is separately from the

 15   donor historian reading over the answers and making

 16   sure everything is cool and the donor should

 17   proceed to donation, there is an audit function,

 18   which is just kind of a clerical audit, making sure

 19   that everything was filled out properly, that this

 20   person really is eligible to donate, and the

 21   product should be used.

 22             DR. NELSON:  One other option would be

 23   instead of a "No," to have a Not Applicable answer

 24   to those two questions.

 25             DR. HOLLINGER:  I think actually, if it 

                                                               412

  1   were left blank, to me, if it were left blank, and

  2   it was a male, they left the female one blank, that

  3   would be a better audit than if they had a no.

  4   That would show that at least, if that is the one

  5   that they had, and a female, if they left that

  6   blank when the question is for the male donors,

  7   that would to me be a much stronger audit than if

  8   you put a no in there.

  9             DR. FRIDEY:  I really appreciate the

 10   comments and the concern and that everyone who is

 11   involved in this process is asking these kinds of

 12   questions.  The reason we had two survey design

 13   experts on the task force, so that they would lend

 14   their expertise, and their input was that this was

 15   the best way to try to assess donor attentiveness.

 16             As our resident experts/consultants, we

 17   felt that it was appropriate to follow their advice

 18   is really what it comes down to.

 19             DR. LEW:  I guess what I am kind of

 20   hearing, though, maybe it is because it's on my

 21   mind, is this whole idea of getting some

 22   validation.  I think, in general, we have all said,

 23   in general, this type of question is a good thing,

 24   they have tried to do their best in validating it,

 25   but we all know with focus groups, they have lot a 

                                                               413

  1   lot of political campaigns with the wrong focus

  2   group, and we are a different focus group, and we

  3   are coming up with different ideas.

  4             I think before it actually goes out, it

  5   need to have some sort of validation with the

  6   population you are after, and particularly the

  7   target populations, because I can see just with

  8   this question, you may not capture necessarily who

  9   is not paying attention, you are just capturing

 10   people who misunderstand that question.

 11             DR. FRIDEY:  The cognitive evaluations

 12   were not focus groups.  They were a much different

 13   and scientifically very well accepted approach to

 14   evaluating this information.

 15             Now, in the real world--

 16             DR. LEW:  But that is still the population

 17   that you gave it to, and it is a limited number of

 18   people who--

 19             DR. FRIDEY:  One of the slides that I

 20   showed when I was talking about the Task Force and

 21   its resources had, as a last bullet item, in gold

 22   letters, the comment that there was not funding

 23   available aside from that provided by the NHLBI.

 24   That was an $80,000 interagency funds transfer

 25   agreement.  There was no other money made 

                                                               414

  1   available.

  2             We would have loved to have had much more

  3   money to evaluate a larger group and a broader

  4   spectrum.  The reality was the FDA, other

  5   governmental agencies, other entities were not able

  6   to provide funding, so basically, we did the best

  7   with what we had, and, yes, as Dr. Beatty said, it

  8   would have been important and useful to try to

  9   capture some of the other groups, and from the

 10   comments that Judy Ciaraldi made, but we were very

 11   limited in terms of what we could do, so we made

 12   the best use of the funds that were available.

 13             DR. LEW:  And I appreciate that, and I

 14   think you all did a fabulous job, many of you

 15   unpaid for all the work that you all did, but it

 16   seems to me that such an important questionnaire,

 17   you know, maybe someone needs to cough up the money

 18   to do the appropriate validation.

 19             DR. FRIDEY:  The validation was the

 20   cognitive interviews.  That was the validation.  We

 21   were looking for comprehension, we were looking for

 22   usability.  That was the validation.

 23             DR. CHAMBERLAND:  Judy, can you maybe

 24   amplify a little bit more, or Sherri, a little bit

 25   more when you use the term "validate the 

                                                               415

  1   questionnaire," what you are thinking of?  What

  2   would, in your mind, constitute a more adequate or

  3   comprehensive validation?

  4             DR. LEW:  Maybe that's not the right word.

  5             DR. CHAMBERLAND:  I don't know if Paul

  6   Beatty or anybody else wants to make any comments

  7   about this.

  8             DR. LEW:  It has been mentioned by several

  9   people it would be good to have people who actually

 10   are going to be the donors, but not just in general

 11   the donors, take this questionnaire and see how

 12   they feel about it, and if it really helps for

 13   them.

 14             But also, in a sense, because you are

 15   trying to capture those people who have these risk

 16   factors, to me, those are a critical group, to read

 17   the questionnaire, and that, in their best ability

 18   to answer it, and that you know that they are

 19   understanding the questions, and whether they

 20   honestly or not, but at least they are given the

 21   opportunity and urge to.

 22             When I looked at the different focus

 23   groups that actually--there were four, I think,

 24   different focus groups, and one of them was

 25   elicited from a group of people who went to church, 

                                                               416

  1   and then they mentioned some were just others, and

  2   I asked myself, well, are these representative of

  3   people who actually go to donate at the blood bank.

  4             Again, they only had a limited amount of

  5   money and I understand that, a limited amount of

  6   time, but I still have that concern that if this

  7   major questionnaire that is going to go out to all

  8   these people, and we are going to say this is the

  9   best, shouldn't we put a little more effort into

 10   it.

 11             DR. NELSON:  I think a group that could be

 12   surveyed, and that is what essentially Dr. Williams

 13   is doing today, is people who have had a lot of

 14   experience dealing with blood donors, and

 15   particularly blood donors who later are found to

 16   have risk factors that weren't captured in a

 17   questionnaire, and that is why I think the issue of

 18   adding the "even once" to the drug use or steroid

 19   injection is maybe redundant, and maybe the focus

 20   groups didn't like it, but I think it is important.

 21             DR. CHAMBERLAND:  Paul, I know you are at

 22   the mike, and I guess one other thing I would ask

 23   you is, I don't know, this questionnaire may be the

 24   most frequently administered questionnaire in

 25   America when you consider it, and I was just 

                                                               417

  1   wondering if it would help if you could tell us,

  2   for example, what kind of pre-administration

  3   evaluation is done for a questionnaire that goes

  4   to, not certainly the same size, but a very large

  5   population.

  6             I am thinking perhaps of the census,

  7   although I don't think CDC would be involved in the

  8   census.

  9             DR. NELSON:  IRS forms.

 10             DR. CHAMBERLAND:  But I am thinking of the

 11   Health Interview Surveys, and things like that.

 12   Would that be helpful if you can tell us--because I

 13   think you said in your comments that usually

 14   cognitive interview, cognitive testing really does

 15   usually involve a small number of interviewees, and

 16   it's complementary to focus groups.

 17             I mean there is no one way to do it and

 18   make sure you have got it right.

 19             DR. BEATTY:  It is different than focus

 20   groups in a lot of ways.  Focus groups really do

 21   put the person that you are talking to in the role

 22   of the expert.  You are asking them to evaluate

 23   something without actually using it the way that a

 24   user actually does.

 25             As for the kind of larger issue of whether 

                                                               418

  1   this is a validation or not and whether it is

  2   typical of what is done in other surveys, it is not

  3   a true validation and we know that, and we are

  4   pretty upfront about what it is and what it isn't.

  5             It is probably the best that can

  6   reasonably be done given the resources that are

  7   available a lot of the time.  Certainly, studies

  8   like the HIS, the Health Interview Survey, are put

  9   through multiple types of quality control.

 10             Cognitive interviewing, I think, is

 11   probably the best of those layers in terms of

 12   figuring out which specific wordings are working

 13   and what exactly are the problems, not just what

 14   the problems are, but how you can identify what it

 15   is about the question that is creating them in the

 16   first place.

 17             Generally, it is true that a lot of those

 18   questions are not tested as thoroughly as these

 19   were.  This was a pretty thorough type of

 20   evaluation.  We don't usually put questionnaires

 21   through as much intense scrutiny as this one was

 22   through, and then it also--it wasn't just us, I

 23   mean we brought recommendations back to the Task

 24   Force and discussed them at great length.

 25             I also don't want to create any appearance 

                                                               419

  1   of inconsistency among ourselves and the Task

  2   Force, but I will just kind of touch on one thing

  3   briefly about the males and females Check No box.

  4   That wasn't what we actually tested. The version

  5   you can see in the questionnaire itself says--it

  6   had something slightly different like "males, check

  7   here," or something like that.  It is actually in

  8   the materials that we had.

  9             The recommendation that that could be used

 10   as a quality control, we did say that, but it

 11   didn't come up exactly as a part of the cognitive

 12   testing, because you really can't say whether

 13   something worked or not if you didn't actually ask

 14   it that way.

 15             We were just thinking that it didn't make

 16   sense really the way that it was in there, and what

 17   could we do differently.  That seemed like one

 18   alternative that might have some quality control

 19   aspects.  I think we have to be a little more

 20   agnostic as to whether we think that is really a

 21   great way to do it.

 22             I certainly didn't strongly advocate that

 23   as a great way to insert some quality control

 24   measures.  It might work, might not.  We didn't

 25   really look at it, and there might be better ways 

                                                               420

  1   to ask it.

  2             The one comment about whether it would be

  3   better to have a box that said, "Males, please

  4   check here," is a better way of paying attention.

  5   That might very well be.  We really didn't spend

  6   enough time to tell for sure.

  7             DR. DiMICHELE:  Actually, I could ask you,

  8   Dr. Beatty, or just certainly I just bring it up to

  9   everyone for historical perspective, you know, we

 10   do have a tool that has been out there.  It is

 11   being used over and over again.

 12             DR. BEATTY:  No, we don't.  We have lots

 13   of different tools.

 14             DR. DiMICHELE:  Well, in any case, you

 15   have lots of different tools, okay, that are out

 16   there, but it sounds like you are still going to

 17   have lots of different tools because this one isn't

 18   going to be mandated either.

 19             But the thing is it seems like it has been

 20   working pretty well?  Not well, terribly.  I guess

 21   my point is, is that--anyway, maybe there is no

 22   points--but I guess what I am trying to say is that

 23   this tool is undergoing more validation than the

 24   previous basic tool that everyone has adapted and

 25   used, and if it's working reasonably well, what 

                                                               421

  1   might end up having to happen is that you might end

  2   up having to go with your best, and put it out in

  3   the field, and then figure out how you can validate

  4   it, because it may not really be validatable until

  5   you kind of get it out in the field and really use

  6   it and see if it's turning up some very glaring

  7   omissions, et cetera.

  8             Just to that point, I just wanted to say

  9   that the question then if we are going to do that,

 10   or we are going to do that in the blood banking

 11   industry, how much of a routine SOP should we be

 12   mandating, because otherwise you main not be able

 13   to validate it out in the field, because I think

 14   that is what is going to end up being most

 15   important anyway, and eventually, you have just got

 16   to take it and run with it, I guess.  That is all I

 17   was going to say.

 18             DR. SIMON:  I will follow up on that

 19   point.  There is an old quote that the best is the

 20   enemy of the good, and I think that for those of us

 21   who have been in the field, I think we recognize

 22   what you have just said, these many different

 23   instruments do, in fact, work in terms of donor

 24   safety, but there are all the other problems that

 25   have been brought up about turning donors off, and 

                                                               422

  1   that sort of thing.

  2             When you look at what this committee has

  3   done and put together, it is so far superior to

  4   what we have that I would hate to see anything

  5   prevented from going forward.  I think putting in

  6   our best comments and suggestions and

  7   recommendations is appropriate, but I would just

  8   like to put in a plug for the process and for the

  9   movement.

 10             The one thing I would differ, I think from

 11   what Dr. Williams said, my interpretation is when

 12   FDA goes out with a guidance with this, any center

 13   that chooses to use a different one, would have to

 14   prove that theirs has more validation.

 15             So, my belief is that this would be, in

 16   fact, out there as the single prevalent blood

 17   screening device, and I think it would be a great

 18   improvement over the status quo.

 19             DR. STUVER:  I would agree with what Toby

 20   said.  I mean certainly what has gone on to develop

 21   this questionnaire, the process is excellent and

 22   much better than anything that has happened before.

 23             I think as far as like doing validation

 24   studies, I mean I don't really see how you could do

 25   a formal kind of validation because there is not 

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  1   really a gold standard that you could say, well,

  2   this is the truth, and does the questionnaire

  3   capture the truth.

  4             I don't really see how you could do that

  5   unless you had medical record data or some other

  6   source that had the truth in it.  But I think there

  7   are things that you could to get a better sense,

  8   like you were saying, of how it is going to

  9   actually work in the place in which it would be

 10   used.

 11             I mean you could do some kind of pilot

 12   testing of the instrument in a blood donation

 13   facility and see how people answer it.  If they are

 14   male, do they leave that female question blank?

 15   Then, you would know right off, well, okay,

 16   everybody is going to leave it blank or a large

 17   portion are going to leave it blank, maybe we

 18   should redo something like that.

 19             I think another thing that could be done

 20   potentially would be to do repeat questioning with

 21   it, so you give it some blood donors and then when

 22   they come back a month or several months later,

 23   give it to them again and see if they answer in the

 24   same way, barring whatever time changes, actual

 25   real changes have happened. 

                                                               424

  1             So, little things like that, it is not

  2   validation per se, but I think it would give you a

  3   sense, a more true field sense of how it is going

  4   to work.

  5             DR. KLEINMAN:  I think people are getting

  6   hung up on the term "validation."  I think Paul has

  7   made that point, and I just want to make it again,

  8   might be better off if we talked about evaluations

  9   of the questionnaire because I think that is what

 10   was done.

 11             I think the intent of the evaluations, the

 12   panel should understand the intent of the

 13   evaluations, and they were really at not whether

 14   this questionnaire gets to the truth, because

 15   obviously, for low risk behaviors that happen 1 in

 16   1,000 times, you cannot evaluate that in 35

 17   responses or four focus groups of five people each.

 18             So, the sense of the evaluation was can we

 19   get wordings of questions that people appear to

 20   understand better than the current wordings that we

 21   are using, can we present it in a way, so can we

 22   evaluate comprehension, not can we evaluate the

 23   accuracy of response.

 24             I appreciate that it would be nice to be

 25   able to evaluate the accuracy of response, and I 

                                                               425

  1   think in the cognitive studies, there was some, you

  2   know, create a scenario and see if you can do that,

  3   but it was really more towards comprehension.

  4             The second point I wanted to make was that

  5   you can't really pilot this in a blood donor

  6   setting because the screening process is part of an

  7   FDA license, and so you can't just say I am going

  8   to change my process for a month and put in this

  9   new questionnaire.

 10             I mean you can't give it in addition to

 11   the questionnaire that you use, it wouldn't make

 12   sense, and you can't substitute it because you

 13   would have to change all your SOPs and get FDA

 14   approval that you could use this new thing.

 15             So, you can't really, unless somebody can

 16   come up with a creative mechanism, sort of pilot

 17   this out for a month and say, gee, I want to make

 18   these changes.  So, you are really, I think, left

 19   with postimplementation evaluations.  You put the

 20   best thing you can out there and then I think it

 21   would be important as this would be used within a

 22   month, in a million people, if you had the right

 23   network, quickly try to tabulate some information

 24   and get some feedback, and do another iteration of

 25   this relatively quickly. 

                                                               426

  1             So, I think that may have to be the

  2   approach.

  3             DR. BIANCO:  I don't want to prolong this,

  4   but a true evaluation, the objective of a medical

  5   history is to prevent collection of blood from

  6   people that should not be donating.  We ask the

  7   questions, we ask "even once," but we find people

  8   with hepatitis C.  The "even once" didn't help.

  9   Finally, we got a group of people that worked day

 10   and night, and they found a way to ask better

 11   questions.

 12             There are many ways by which we will

 13   evaluate the true impact of that, but we are

 14   improving comprehension, we are improving the

 15   process, and it is the first time in history, and

 16   we have been using medical history for over 60

 17   years, that we are being able to do something that

 18   is more rational that what is currently done.  What

 19   is currently done is not good.

 20             DR. HOLLINGER:  I appreciate that, but

 21   also you don't know how many you picked up because

 22   you asked the question "even once."  It is true

 23   that you might have even missed some when you asked

 24   "even once," but you really don't know how many you

 25   picked up because you asked "even once." 

                                                               427

  1             DR. NELSON:  You don't know how many you

  2   are going to drop by dropping the "even once."

  3             DR. BIANCO:  I understand your point, Ken,

  4   but I think that this is a rational way.  The

  5   medical history is the first step, is the first

  6   layer of selection.  We know  that our prevalence

  7   is several fold lower than the prevalence of the

  8   general population for any of those infectious

  9   disease's marker.

 10             So, we have to say that there are several

 11   processes - donor education, the populations that

 12   are recruited to donate blood, they are susceptible

 13   to recruitment to donate blood, and the medical

 14   history made that reduction, and I hope that

 15   improving the process will make it even better.  We

 16   can measure prevalence, and we can measure surveys,

 17   as Alan proposed a few minutes ago, so help us.

 18             DR. LEW:  Just one last comment because I

 19   want to go on the record that I would agree that it

 20   sounds like this particular revision is so much

 21   better than what we have now, and I agree with that

 22   and I would rather have good than best if that is

 23   all we can have.

 24             On the other hand, I just feel we have an

 25   opportunity now to do some additional looking at 

                                                               428

  1   it, that may not be tremendously expensive, just to

  2   see if the people can use it who are really going

  3   to be the ones will be answering these questions

  4   out in the field.

  5             I feel sad that it sounds like we won't be

  6   able to do that unless we go with what one of the

  7   speakers suggested, just go ahead and just mass use

  8   it, and then within a few months, try to gather

  9   some data and make some corrections.  It seems such

 10   a shame to have to do that if you could do a pilot

 11   first.

 12             I think the validation work should be left

 13   out, because that was the question, but rather than

 14   evaluation.

 15             DR. NELSON:  I think it could be evaluated

 16   after it was implemented, very soon there

 17   afterwards and see what happened without a pilot,

 18   if you will.

 19             DR. HAMILTON:  I would like to point out

 20   that there is a lot of informal evaluation of this

 21   questionnaire that took place over the two years

 22   that it was being developed.  People who are on

 23   that committee took that questionnaire back to

 24   various centers and said please administer this

 25   questionnaire to donors and see how it works. 

                                                               429

  1             While we didn't administer to 10,000

  2   people, we didn't make this questionnaire in a

  3   vacuum.  We did take it back.  Every iteration went

  4   back to the centers informally to centers that we

  5   worked with directly, and "What do you think about

  6   this, can you give us feedback, is this making

  7   sense to people," so it didn't rely just on the

  8   cognitive interviews.  There was a lot of informal

  9   testing going on, so it hasn't taken place outside

 10   the context of a blood or a plasma collection

 11   facility.

 12             DR. NELSON:  Thank you.

 13             DR. ALLEN:  I think these are very

 14   important comments that have been made.  This has

 15   been looked at far more carefully than any other

 16   donor screening in the past.

 17             I have been a blood donor for 37 years in

 18   a variety of settings.  This is so much better than

 19   anything that has ever been administered to me

 20   before.  It is much clearer, it is much more

 21   precise, it gets the information out in a variety

 22   of ways.  It is not going to be implemented in a

 23   single way in blood centers across the United

 24   States.

 25             We do need to have follow-up evaluation 

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  1   and comparison to see how, you know, what ways seem

  2   to work better.  It does need to be refined.

  3             I think what concerns me the most is that

  4   given all the concern about blood safety over the

  5   last  15, 20 years, that there is no budget for

  6   this, and I would hope that this committee tomorrow

  7   morning would consider a question or a motion to

  8   urge the FDA and the CDC and the NIH to really put

  9   in a budget item for evaluation monies for this

 10   sort of thing, because I think we are going to make

 11   a huge step forward, it needs to be implemented

 12   rapidly, and then we need to refine it and follow

 13   up in the future.

 14             DR. HOLLINGER:  I think this is tomorrow

 15   morning, isn't it, Jim?

 16             DR. NELSON:  Dr. Williams, I hope the

 17   detailed discussion of the committee will answer

 18   the final question.

 19             DR. WILLIAMS:  I think we have the

 20   information we need, and I thank you all for your

 21   insightful comments. Certainly, if there is funding

 22   available, the studies can become more elegant and

 23   the process can become further refined.

 24             DR. NELSON:  See you tomorrow morning at 8

 25   o'clock. 

                                                               431

  1             DR. SMALLWOOD:  I just have to make a

  2   statement for the record on the question that the

  3   committee voted on. There was a unanimous yes vote,

  4   but I have to indicate that there were 11

  5   individuals that participated in that voting, and

  6   there was a written and signed note from Dr.

  7   Harvath that she would have voted yes, which I did

  8   not count, but I read it I want it to be known into

  9   the record.

 10             Thank you.

 11             [Whereupon, at 7:00 p.m., the proceedings

 12   were recessed, to be resumed on June 14, 2002, at

 13   8:00 a.m.]

 14                              - - -