ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BLOOD PRODUCTS ADVISORY COMMITTEE

63RD MEETING

VOLUME I

Thursday, June 17, 1999

8:00 a.m.

Double Tree Hotel
1750 Rockville Pike
Rockville, Maryland

PARTICIPANTS

Blaine F. Hollinger, M.D., Chairperson
Linda A. Smallwood, Ph.D., Executive Secretary

MEMBERS

John M. Boyle, Ph.D.
Richard J. Kagan, M.D.
Rima F. Khabbaz, M.D.
Marion A. Koerper, M.D.
Jeanne V. Linden, M.D.
Gail B. Macik, M.D.
Mark A. Mitchell, M.D.
Kenrad E. Nelson, M.D.
Kwaku Ohene‑Frempong, M.D.
David F. Stroncek, M.D.
Joel I. Verter, Ph.D.

NON‑VOTING CONSUMER REPRESENTATIVE

Katherine E. Knowles

NON‑VOTING INDUSTRY REPRESENTATIVE

Donald H. Buchholz, M.D.

TEMPORARY VOTING MEMBER

Paul R. McCurdy, M.D.

CONSULTANTS

Mary E. Chamberland, M.D.
Michael G. Fitzpatrick, Ph.D.

C O N T E N T S

PAGE

Statement of Conflict of Interest: 
Linda A. Smallwood, Ph.D.                     5

Welcome and Opening Remarks:
Blaine F. Hollinger, M.D.                     7

Committee Updates

Nucleic Acid Testing Implementation:
  Indira Hewlett, Ph.D.                       8

Human Parvovirus B19 Transmission from
SD Plasma:
  Thomas Lynch, Ph.D.                        26

Blood Safety and Availability Advisory 
Committee Meeting Summary:
  Stephen Nightingale, M.D.                  36

Transmissible Spongiform Encephalopathies
Advisory Committee Meeting Summary:
  Mary Elizabeth Jacobs, Ph.D.               46

Revised Guidance: CJD and nvCJD:
  Dorothy Scott, M.D.                        55

Schedule of OBRR Workshops:
  Linda A. Smallwood, Ph.D.                  71

I. Post‑Donation information Affecting Plasma Pools
for Fractionation (Inadvertent Contamination): Risk Issues

Overview:
Edward Tabor, M.D.                           74

Post‑Donation Information:
Sharon O'Callaghan                           85

cGMP Investigations:
Thomas Lynch, Ph.D.                          95

Open Public Hearing

Jason Bablak, IPPIA                         109

Committee Discussion 

C O N T E N T S(Continued)

PAGE

II. Strategies for Insuring Compliance
in the Plasma Fractionation Industry 

Steven A. Masiello                                    180

Open Public Hearing

     Jan Hamilton, Hemophilia Federation of America   196
     David Cavanaugh, Committee of Ten Thousand       199

Committee Discussion 

III. Supply and Demand of Plasma Derivatives

Introduction and Background:
Mark Weinstein, Ph.D.                       205

Perspective on Supply and Demand of Plasma Products:
Dennis Jackman                              213
Ron Demarines                               233

Background Considerations for the Estimation of
IGIV Demand:
Patrick Robert                              240

The Impact of Distribution on Supply and Availability:
Patrick Schmidt                             248
Allen R. Dunehew, R.Ph., M.P.A.             266

Is Demand Being Met?:
Patrick Collins                             277
Thomas Moran                                285

Open Public Hearing

Nancy Buelow, Alpha I National Association  292

Committee Discussion

P R O C E E D I N G S
Statement of Conflict of Interest
DR. SMALLWOOD:  Good morning and welcome to the 63rd Meeting of the Blood Products Advisory Committee.  I am Linda Smallwood, the Executive Secretary.  At this time, I will read to you the statement of conflict of interest that will apply to all proceedings of this meetings.
This announcement is made a part of the record at this meeting of the Blood Products Advisory Meeting on June 17th and 18th, 1999.  Pursuant to the authority granted under the Committee Charter, the Director of the FDA Center for Biologics Evaluation and Research has appointed Dr. Paul McCurdy as a temporary voting member for all committee discussions.
Based on the agenda made available and on relevant data reported by participating members and guests, it has been determined that all financial interest in firms regulated by the Center for Biologics Evaluation and Research that may be affected by the committee discussions have been considered.
In regard to FDA's invited guests, the agency has determined that the services of these guests are essential.  There are reported interests which are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the participants.
The interests are as follows.  Dr. Michael Busch is employed by Blood Center and is a member of Abbott's Advisory Committee.  Dr. Susan Stramer is employed by the American Red Cross, serves as a scientific adviser to Abbott Laboratories, and has financial interests in a firm that could be affected by the discussions.
In the event that the discuss involves specific products for firms not on the agenda, for which FDA's participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the public record.
Screenings were conducted to prevent any appearance, real or apparent, of conflict of interest in the committee discussions.  With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
Are there any declarations to be made at this time?
[No response.]
DR. SMALLWOOD:  Hearing none, I would like to introduce to you the members of the Blood Products Advisory Committee.  As I call your name, would you please raise your hand.
Dr. Blaine Hollinger, Chairperson.  Dr. Richard Kagan.  Dr. Marion Koerper.  Dr. John Boyle.  Dr. Mary Chamberland, who is a consultant to our committee.  Dr. Fitzpatrick, who is also a consultant.  Ms. Katherine Knowles.  Dr. Buchholz.  Dr. Paul McCurdy.  Dr. Joel Verter.  Dr. Jeanne Linden.  Dr. David Stroncek.  Dr. Rima Khabbaz.  Dr. Gail Macik.
There are other members that I anticipate will be here shortly.  They would be Dr. Mark Mitchell, Dr. Kenrad Nelson, Dr. Ohene‑Frempong, Mr. Corey Dubin.
May I ask, so that there will not be undue disruption of the deliberations, that all cell phones be cut off and if you must have them, have them very low, please.
Thank you.
At this time, I will turn over the proceedings of this meeting to our chairman, Dr. Hollinger.
Welcome and Opening Remarks
DR. HOLLINGER:  Thank you, Dr. Smallwood.
Welcome to the summer session of BPAC.  We have again as usual some most interesting topics today and tomorrow dealing with a variety of topics.  There will be some committee updates.
I do want to ask that anyone who is going to speak from the public, that when you come up to the microphone that you state your name and the organization, so we have it for the record.
With that in mind, I think we will try to keep on time today as usual, and we start with the committee updates on several topics.
The first one, Dr. Hewlett is going to tell us about where we are with nucleic acid testing implementation.
Dr.  Hewlett.
Committee Updates
Nucleic Acid Testing Implementation
Indira Hewlett, Ph.D.
DR. HEWLETT:  Thank you, Dr. Hollinger and good morning, everyone.
[Slide.]
I am going to be presenting an update on the implementation of NAT, or nucleic acid testing, for blood and plasma.
It is now well recognized that NAT is currently the most sensitive method for virus detection in the window period and that implementation of NAT could further reduce the window period for HCV, HIV, and HBV, resulting in enhanced viral safety of blood and blood products and in enhanced public health safety by providing early diagnosis and referral for medical treatment.
[Slide.]
Due to the complex and labor‑intensive nature of NAT, the approach of screening minipools or small pools of plasma rather than single donations has been considered to be more practical and feasible.
By 1997, some countries in Europe had initiated voluntary screening of donations by testing pooled donations of plasma using a nucleic acid‑based test method, and also a directive was issued by the European Union that HCV‑RNA testing would be required in Europe for all plasma for fractionation by July 1st, 1999, and that HIV‑1 testing of such plasma would be require at some unspecified later date.
This move created an impetus in the U.S. to implement such testing for blood and plasma, and this was made feasible by support from the NHLBI through contracts for developing such tests here in the U.S.
[Slide.]
A number of measures were taken in the U.S. to implement nucleic acid testing.  FDA viewed minipool testing as a form of donor screening, and this position was endorsed by the Blood Products Advisory Committee at the March 1997 meeting.
FDA developed guidance outlining regulatory approaches for implementing pool testing and discussed them briefly at the September 1997 BPAC meeting.
[Slide.]
FDA also developed and published draft guidance to industry for validation of nucleic acid tests.  In September 1998, we held a workshop to discuss NAT for HCV and other viruses.  At the last BPAC meeting, we discussed the issue of NAT implementation for whole blood and transfusable components under the IND mechanism.
FDA plans to hold a workshop in December 1999 to assess the status of NAT implementation under IND.
[Slide.]
Screening of source plasma for HCV and HIV‑1‑RNA was initiated in early 1998.  Pool sizes ranged from 96 to 1,200 donations.  At this time, virtually all source plasma in the U.S. is being screened for HCV and HIV‑1‑RNA by a nucleic acid‑based test.
A significant portion of the testing is performed by a central testing laboratory or testing service, and some manufacturers are also testing for HBV, although this is much more limited than HCV and HIV.
[Slide.]
Nationwide screening of whole blood donations was initiated under IND in early 1999.  Pool sizes ranged from 24 to 128 units, although sizes as small as 16 units have been proposed for future testing.
The ARC data, which was kindly provided to us by Susan Stramer, indicate actually that 2 out of 825,984‑‑and that is an update that I got from Sue yesterday, so this number is actually outdated at this point‑‑2 out of 825,984 donations tested were confirmed positive for HCV‑RNA in the absence of detectable antibody.
The ABC centers have reported that 3 out of 275,000 donations have been confirmed to be HCV‑RNA positive in the absence of antibody.  These are very recent numbers and apparently they have been reported or will be reported at the upcoming AABB meeting in November.
No confirmed HIV cases have been reported so far.  The false positive rate, interestingly, has been found to be similar to serologic tests.  This is during the Phase I testing of NAT.  At this time, more than 80 percent of donations are being tested by a NAT method, and it is anticipated that 100 percent testing will be achieved by the fall of this year.
[Slide.]
This slide just lists the IND PLA‑BLA requirements for test validation to give the committee a sense for the types of studies that are ongoing under the IND.  The test should be demonstrated to be manufactured consistently under GMP with appropriate quality assurance for components and kit performance.
The purity, identify, and functional activity of primers, probes, enzymes, and other components should be determined and specifications should be established.  Methods for collection of specimens, pooling, testing, et cetera, should be validated and conditions of specimen stability should be established.
There should be in place a validated mechanism for identification and retrieval of positive specimens in a pool, as well as the implicated donor.
[Slide.]
Instruments used in generating pools of to perform the tests and software used to calculate results should be appropriately validated, and the tests should meet the analytic sensitivity requirement of 100 copies per ml for the pool and 5,000 copies per ml for the original donation.
The clinical sensitivity, specificity, and reproducibility of the assay should be established through clinical and laboratory studies, and finally, the test would be subject to lot release requirements for licensing.  Compliance with analytical sensitivity requirements would be monitored using reference materials and lot release panels developed by the FDA.
[Slide.]
FDA has developed panels for HCV and HIV‑1 RNA.
At the present time, a WHO standard for HCV‑RNA is available.  It is a lyophilized antibody‑positive specimen from a single donor.  The CBER panel is an antibody‑negative specimen, genotype 1B.  One of the panel members has been calibrated against the WHO standard, so that one international unit equals 4 genome equivalence per ml.
[Slide.]
The WHO standard for HIV‑1 RNA, subtype B, is currently being established and the international unit is yet to be defined.  There are two FDA panels that are available.  One is an antibody‑negative plasma specimen, and two, is a cultured virus specimen spiked into HIV‑negative human plasma.  FDA will adopt the international unit for HCV at this time and for HIV when it is defined.
[Slide.]
The general study design for NAT validation involves screening of 300,000 to more than one million donations from at least 10,000 donors.  Screening for HCV is universal at this time, and a significant percent are also testing for HIV‑1.
Informed consent is obtained from donors who are recruited into follow‑up studies to confirm results and resolve status.  A validated supplemental NAT, that is, the same or another technology, is being used to confirm results.  This allows donors to be enrolled in early treatment studies and, of course, recipients, as well.
[Slide.]
Clinical sensitivity, analytical specificity, and reproducibility are also being evaluated under the IND.  Blood and plasma centers need IRB approval for NAT screening for donors.
Pre‑transfusion recipient concern is being managed by local IRBs of hospitals and transfusion centers.  Cost recovery has been permitted by the FDA under the IND due to the high cost of NAT testing and the national scale of studies.
[Slide.]
A number of issues have been identified regarding implementation under IND.  For example, NAT requires several days more than conventional tests due to logistics, that is, testing by centralized laboratories, and technology limitations.
Consequently, certain blood products, for example, platelets and some red cells, are expected to be released on the basis of serology during the initial phase of study, that is, Phase I.
This is necessary to prevent product shortages and harm caused due to lack of blood products.  This phase, however, which is expected to be of short duration, will be followed by a phase where all components are released on the basis of both NAT and serology, and this would be in Phase II.
[Slide.]
Other issues are that no product labeling or enhanced safety claims are permitted during the study phase, therefore, NAT screened and unscreened units would coexist during Phase I.  Other issues are that donors are counseled on the basis of confirmed investigational test results and deferred until status is resolved.  They are also indefinitely deferred from donating after they have undergone seroconversion.
In addition, lookback notification is required for recipients who receive NAT‑positive units prior to test results being obtained.
[Slide.]
Again, informed consent and IRB approvals are required for these studies.  Recipients are notified and counseled on the basis of serology during Phase I, and finally, there has been increasing concern about costs imposed on hospitals in particular by cost recovery.
[Slide.]
So, in summary, NAT is being implemented under the IND and at this time, more than 80 percent of whole blood and nearly all source plasma are being screened by a NAT method.
There are several implementation issues relating to donor, recipient, and product management that need to be monitored in the coming months and could be addressed in the workshop planned for December.
[Slide.]
At this time, there is universal product release based on NAT and serology, and is actually expected to occur in the very near future, so there is universal release based on serology, but release based on both NAT and serology is expected to occur in the very near future, and we have heard dates as immediate as July 1st, 1999, however, of course, we do have to watch the situation and see when this actually happens.
Other issues that are anticipated in the future are NAT for other viruses, for example, HBV, and the potential replacement of existing tests, such as HIV‑1 p24 antigen.  This last issue was actually discussed at the Blood Products Advisory Committee meeting last month, at the last meeting, which was in March of this year.
So, with that, I will conclude and thank you for your attention.
DR. HOLLINGER:  Thank you, Dr. Hewlett.  Any questions of Dr. Hewlett?  Yes, Dr. Stroncek.
DR. STRONCEK:  This NAT testing is progressing very quickly.  This is an unconventional way to introduce a new test for testing for blood.  In the past, they have all been licensed tests which have been readily available to all blood manufacturers and at low cost.
On the contrary, it is my understanding that this testing is expensive and available only at a handful of sites around the country.  Some of these centers have been very collaborative in that they have collaborated with other blood centers throughout the country.  Yet, because of the IND mechanism, each of these sites has to be very inflexible in how they collaborate with the other centers.
This has created a number of practical problems for both blood manufacturers all over the country and for transfusion services.  I guess I have a question as to the availability of the testing.
If this was available at a low cost and to all centers, then, I think it is reasonable to pursue the direction this is going, but the information I have is that this equipment and these reagents are just not widely available to all blood centers in the country.
Is there anyone from the manufacturers here that can address that issue?
DR. HOLLINGER:  Dr. Tabor.
DR. TABOR:  Ed Tabor from FDA.  Your question makes me think that perhaps you are really Rip Van Winkle because we have discussed all the issues you have raised at multiple meetings of BPAC, as well as at a workshop held in September of '98.
It is certainly an unusual regulatory process.  It has been driven by industry pressures that originate from regulatory pressures in Europe, but the FDA has been very closely observing and controlling the types of studies that are being done, and that is why the testing is being done under the IND process.
Furthermore, the reason it is being done universally under IND instead of being held up until a test is approved is the scientific community and the blood bank community and the regulatory community are in universal agreement that this kind of testing with what we know now about the tests that are being used, despite the fact that they are not fully validated, can only make the blood safer in the interim.
DR. STRONCEK:  I have no argument with any of that.  I agree with the IND process.  My question is, is do you all blood centers have access to the equipment and the reagents, so every blood center can apply for their own IND.
My information I have is that is not available and that is creating a number of competitive and practical problems for the collection and supply of blood in this nation.
I don't think it is appropriate for you to answer this question.  I think this is appropriate for the manufacturers, and because if it is not available, then, what you are doing has many important practical implications providing care to patients and to donors.
DR. TABOR:  As I said, the reason I am answering this question is because we have answered it and covered it many times before.
DR. STRONCEK:  I specifically asked for manufacturers to come forward today and to talk about this issue, and it's not on the agenda, so I don't think you have addressed this issue in a forthright manner.
DR. TABOR:  The last part of your question I think would be appropriate for the manufacturers to answer, and perhaps one of them would be glad to do that.
DR. HEWLETT:  Yes, I think we are aware of the ramifications of testing under IND, but the issue of supply and availability of reagents, and so on, although we are in dialogue with industry, I think it would be‑‑if there are members of the industry here, manufacturers of kits, perhaps we could hear from them, and if there are any comments about manufacturing and supply, this would be a good time for us t hear about.  I think they were invited to speak.
Is there anyone from GenProbe or from Roche?
DR. STRONCEK:  Frankly, I am appalled.  We have on the agenda later on many issues about the availability of plasma, and while I agree that safety is paramount in the blood, and I commend the FDA for the job they are doing on moving this testing quickly into the field, you can't ignore the issues of availability and supply or availability that is testing, and if you are not careful, it is going to impact, have important implications on the entire blood manufacturing.
I guess I have one more question for Dr. Alving.  Dr. Alving is here from the NHLBI.  You know, this testing would be helpful if it was available on an individual unit basis.  You mentioned the NHLBI has funded some contracting for this testing.  Are you funding more contracting to advance this testing, so we get beyond the fact where it is a very expensive assay and it's only available at a few places?
DR. HOLLINGER:  Does anyone want to respond to that?  Paul, do you have a comment about that in regards to the NHLBI?  Perhaps you could, and then we will come back to Jay.
DR. McCURDY:  I can't really speak officially at the present time since I am a consultant to the Institute and otherwise semi‑retired, but I believe that the contractor has made available to a number of laboratories the technology and the equipment and supplies to do mini‑ pool testing and will ultimately be moving toward individual donation testing.
I think if an individual blood bank wishes to insist on doing it themselves, there could be problems.  If blood banks are willing an interested in collaborating, then, I think there is plenty of availability of equipment and supplies, so that it can get done.
There are some logistic problems if you are in a small, rural area with poor transportation.  On the other hand, I learned of a small hospital blood bank that is arranging to get NAT testing done and is releasing products at the present time on the basis of NAT testing.
DR. HOLLINGER:  Thank you, Paul.
Dr. Epstein.
DR. EPSTEIN:  Well, I think, unfortunately, we are not prepared to answer Dr. Stroncek this morning, and that is the problem.  I would say this, just a couple of things.
First of all, in the IND phase, although we approved large‑scale studies, there was not the presumption that that led directly to 100 percent screening.  Certainly, that is a goal, and I think that Dr. Stroncek has done us a service by pointing out that there may be some barriers to access to NAT testing for I presume small institutions, mainly hospital based, and I think that we simply need to look into that and discuss with the manufacturers how they will ensure 100 percent availability as soon as is feasible.
So, I think it is sort of fruitless for us to try to dispute the facts here this morning because we don't have the information, but we certainly will take on the challenge.
DR. HOLLINGER:  Thank you.  I have just a couple other questions.  Dr. Chamberland.
DR. CHAMBERLAND:  Yes.  Has either the Red Cross or the ABC blood centers provided FDA with information about the results of no doubt early, but nonetheless, in‑progress, lookback investigations for recipients who may have received products from these NAT‑positive antibody‑negative donations?
DR. HEWLETT:  Not until the present, but obviously, that is something we would be asking them to provide us with.  Those investigations are going on.  It is my understanding that some of them are almost complete, but some of the others are still in progress.  There are a total of five cases at this point.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  I just have two questions.  The first one, you mentioned universal release as early as 1 July.  What percentage of the blood supply and whom do you think will be doing that?
The other one is on the statement that there is no product labeling or enhanced safety claims, is there any effort by the FDA to enforce that issue?
DR. HEWLETT:  In regard to the first question, it is an informal response, and I think I would like for Sue, who is in the audience, to comment about it.
We have heard statements being made that there is going to be a good‑faith effort to try to bring this on‑line even as soon as the 1st of July, and I will ask Sue to comment about it.
In regard to product labeling, there has been effort made at the FDA to enforce that.  We have, in fact, sent letters to manufacturers addressing that very specific issue, and it has been brought to our notice by several people in the field, and, yes, we are making an effort to pursue that in the form of correspondence back to the manufacturers who are engaged, if, at this point they are, in fact, engaged in promotion labeling, that has been addressed in terms of correspondence being sent back to them.
DR. HOLLINGER:  Dr. Stramer.
DR. STRAMER:  Sue Stramer from American Red Cross.
Firstly, I would like to comment on Mary Chamberland's question regarding efforts regarding lookback.
Two of the five cases of NAT, only serological negative units that were reported by Dr. Hewlett, we were able to control all products from those two units, so there were no products issued from those.
Regarding lookback, both were repeat donors whose previous donation was greater than 12 months prior to the NAT‑positive donation that we retrieved.  So, per our IND, we are only doing a 12‑month lookback for HCV according to current guidelines for HCV antibody.
Regarding the implementation phases, I can speak to the ARC issues and how we are moving forward.  We implemented NAT on 3‑3‑99, and in order to bring up 45 percent of the blood in the United States collected at 37 regions, it took us some time, because we wanted to do this carefully and not compromise availability, as Dr. Hewlett referenced, and compromise cGMP efforts to do this properly and within the context of the IND, we brought up our regions in phases, in five groups.
So, the final group of regions just began testing on June 7th, so now we are at 100 percent of Red Cross collections and any collections that Red Cross tests for are tested by NAT, but we do release under Phase I based on serology.
We are aggressively moving beginning in the July time frame, not necessarily corresponding with July 1st, although we would like that date to be true, but we are moving as aggressively as possible to now test very small pools, pools of 16, simultaneously with serology, such that all products may be released on the basis of NAT.
We are not there yet, but in the July, hopefully, not too much later into the August time frame, we will be at that point.
DR. FITZPATRICK:  So, that statement refers only to the Red Cross?
DR. HEWLETT:  Yes.
DR. FITZPATRICK:  Thank you.
DR. HEWLETT:  But I think the general anticipation is to move towards full implementation in July or by the fall of this year.
DR. STRAMER:  Today, at this meeting, I also represent the AABB, and the AABB has put together a NAT advisory task force to discuss the issues relevant to the implementation of NAT nationwide, and all blood centers involved in the nationwide INDs, who are part of the AABB task force, including Dr. Stroncek, have discussed actively rapid movement to Phase II, such that all products are released on the basis of NAT.
Many of the ABC centers are already doing that, so much of the blood and probably greater than 50 percent of the blood released by the ABC centers is already released on the basis of NAT, and those that are not are moving coincident with the ARC timeline, so by the end of the summer, latest early fall, we anticipate all ABC centers and all ARC centers to be releasing all products on the basis of serology and NAT, unless emergency conditions force release just based on serology, for example, for emergency platelets or fresh red cells, or whatever the need be, but it would only be based on emergency release.
DR. HOLLINGER:  Thank you, Dr. Stramer.  Thank you, Dr. Hewlett.
The next topic, Dr. Lynch is going to tell us about the human parvovirus B19 transmission in solvent detergent treated plasma.
Human Parvovirus B19 Transmission
from SD Plasma
Thomas Lynch, Ph.D.
DR. LYNCH:  Thank you, Dr. Hollinger.  Good morning.
[Slide.]
B19, as you recall, is a common non‑enveloped human virus about which you have some background information I think you should have received in the packets.  In the interests of time, I only want to make two points about human parvovirus.
First, in the majority of infections, the patient is asymptomatic or very mildly symptomatic, however, there are certain populations of patients who are at risk for significant clinical consequences of B19.
These are principally pregnant women, individuals suffering from hemolytic anemia, and immune‑compromised individuals.  In those cases, there can be serious consequences of the infection and therefore B19 is not to be taken overly lightly.
The second point I want to make is that in the ordinary course, an individual, once he or she is infected with B19, mounts a rapid and effective immune response, the antibodies neutralize the virus, and the individual is then immune from future infections with B19.
Most individuals, most adult individuals in this country and elsewhere in the world have been exposed to B19 at one time or another, and are resistant to it, and most individuals would test seropositive for anti‑B19 antibodies.
[Slide.]
Pooled plasma, solvent detergent treated, is a product that was licensed here in the U.S. a little over a year ago, and it has been in use in several countries in Europe for some time longer than that.
It is manufactured by taking units of recovered plasma from whole blood donations, pooling together as many as 2,500 donations, treating the pool with a mixture of a solvent and detergent to inactivate lipid envelope viruses.  This technique has proved highly effective at inactivating hepatitis B, hepatitis C, and HIV.  The solvent detergent is then removed from the plasma and the plasma is redistributed into individual units.
The purpose for this procedure is to reduce the residual risk associated with hepatitis B, C, and HIV that remains associated with single donations of FFP.  However, one of the considerations during the licensing review phase for this product was the question of whether the pooling process would increase the risk of exposing patients to non‑envelope viruses which would not be inactivated by the solvent detergent treatment.  Principally, hepatitis A and B19 were the viruses of concern.
Because the majority of people are, in fact, seropositive for anti‑B19 and hepatitis A, it was felt that the presence of neutralizing antibodies in these pools would be (a) consistent, and (b) effective at preventing transmission of these viruses to the recipients of this product.
This issue, as you recall, was taken up by this committee on at least two occasions in the past.  In the end, the decision was made to move forward with licensure, however, the sponsor of the product was asked to perform a Phase IV safety study, examining specifically the risk, if any, associated with the transmission of non‑envelope viruses, hepatitis A and B19.
[Slide.]
The study did not have to be terribly extensive in scope.  We calculate that the risk of viremia donation for B19 is anywhere from 1 in 3,000 to 1 in just under 40,000.  Therefore, given the size of the pools by which solvent detergent plasma is manufactured, the risk of an individual lot containing B19 would range anywhere from just under 10 percent to approximately 75 percent.
Therefore, if this virus was transmitted, it should be readily detected in a modest clinical trial.  Such a trial was designed and was initiated last year, and earlier this year, FDA received an interim report on the results of this trial.
[Slide.]
Jumping to the end, to date we have had 50 healthy normal volunteers who were initially seronegative for both hepatitis A and B19 enrolled in this trial.  There has been to date no evidence for hepatitis A transmission by the product, just to get that issue off the table.
However, initially, the sponsor reported that 9 out of, at the time, 41 individuals had shown evidence of seroconversion either via IgG or IgM assays, seroconversion to B19.  This phenomena was investigated by the use of PCR testing of the individual patient's plasma, which confirmed the presence in the seroconverting individuals of high titers of B19, suggesting that an active infection had in fact taken place.
[Slide.]
PCR testing was also applied to the lots of SD plasma that had been used in the trial.  All of the seroconversions had been associated with 2, the use of 2 of a total of 9 lots that had been used in the trial, and both of those lots had high titers of B19 DNA, approximately 10^7 genome equivalence per ml.
The 7 lots that did not exhibit any evidence of seroconversion for transmission of the virus had titers below 10^4 equivalence per ml.  In all, the lots that were tested, a very uniform level of anti‑B19 antibody was found, approximately 20 international units per ml.
At this point, the sponsor was asked to withdraw all lots that contained greater than or equal to 10^4 genome equivalence per ml of B19, and to test all lots manufactured to date by PCR for B19 DNA.
The upshot of this was recall in 3 separate cycles of 37 lots of SD plasma in April and May of this year, which is equivalent to approximately 25 percent of the production of this product.
[Slide.]
To address the observations made during this trial, the manufacturer has developed a release test for B19 DNA that will be applied to future releases of all lots of SD plasma, therefore, no future lots will be released if they have high titers of B19.
The sponsor is also developing a screening test for the incoming plasma in order to eliminate viremic units, high‑titered units before they are manufactured into SD plasma, and with suitable modifications, the clinical trial will resume using only low‑titered lots of SD plasma to confirm that the threshold that has been set for B19 DNA is in fact appropriate and will assure against future transmissions of the virus to recipients of this product.
Thank you.
DR. HOLLINGER:  Any questions of Dr. Lynch?  Yes, Dr. Stroncek.
DR. STRONCEK:  First of all, I heard about the recall via the FDA web page, and that is a nice service.  I have yet to appear about it through the manufacturer or our distributor of the product.  Maybe you could look into that to see if that has been recall appropriately.
Second, from what you have said, it is my understanding that this was a concern, parvovirus infection, about this blood product.  You know, we were told the neutralizing antibodies would take care of any parvovirus in the product and it shouldn't be an issue.
The product was released.  We have now found that that was wrong, that there was a problem with the product and some lots are released.  I am not an infectious disease expert, but from my point of view, it looks like there is still some concern whether or not the steps taken will ensure complete safety of this product.
You have listed three groups of people where this might be a concern.  Parvovirus infection, it doesn't sound like a lot, but quite honestly, immune‑compromised patients do represent a significant portion of people that currently get transfused.
I guess my question is why is this product still on the market, and shouldn't this be withdrawn from the market until it has been proved to be completely safe, and then be put back on the market.
DR. LYNCH:  Well, complete safety is an admirable ideal, and I think we all strive for it.  It is, in fact, difficult to achieve.  The concern over the individuals that you mentioned, the at‑risk populations, is considerable, significant, and is recognized, and the labeling for this product points out the risks to these patients, the potential risk resulting from a B19 infection.
Because the product offers alternative benefits with regard to transmitting envelope viruses, it was felt reasonable to leave the decision to treat a specific individual up to the discretion of the physician and to make the product available to those who wished to minimize the alternative risks that the solvent detergent procedure addresses.
We feel that the precautionary measures that have been implemented since this information came to light will, in fact, address the safety of this product adequately.  Are we absolutely sure of that?  No, that is why the Phase IV study will continue, and it will be scrutinized very carefully both by the participating investigators and by FDA.
In terms of the effectiveness of the recall, your point is well taken.  We did go through the exercise of recalling the product, but, in fact, although this procedure is not visible to the general public, our Office of Compliance has worked very closely with the manufacturer and the consignees of the product to assure the effectiveness of this withdrawal.
DR. STRONCEK:  I spoke with a medical director of one of the blood distribution centers handling this product, and this information that you have presented today was not being made available to them.  They informed me that their calls to the manufacturer are not being returned to them.
So, while I think there needs to be some‑‑if this product is going to stay on the market, the manufacturing distributor had better do a better job of communicating the benefits and risks of this product.
DR. LYNCH:  Thank you.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  I note in your slides you point out that there is well‑documented transmission by clotting factor concentrates, but no confirmed reports of transmission by IG, albumin, and so on.
Is there a part in the manufacturing process that you would identify as likely to be removing these non‑enveloped viruses like parvovirus?
DR. LYNCH:  Yes, the situation for the manufactured products, the plasma derivatives, is complex.  Parvovirus is physically very small, so it is difficult to filter out, and it is resistant to physical and chemical methods of inactivation that are commonly used.
However, it can be separated or partitioned away from one or another product, and it is somewhat sensitive to heat treatment.  So, for example, I would speculate that albumin, the absence of transmission by albumin might result from a combination of the partitioning during the fractionation of that product, and perhaps inactivation of some small residual virus during pasteurization of the product.
For immune globulin, the IGIV products all have different viral inactivation methods.  If it is solvent detergent, it wouldn't address the risk, nonetheless, these products don't transmit either, and I think my guess would be that this is an example of immune neutralization of the virus by the IgG itself.
IGIV, if you will recall, is the principal treatment for an acute or chronic B19 infection, and has proved highly effective in that regard.
DR. HOLLINGER:  Dr. Chamberland.
DR. CHAMBERLAND:  Although reporting of adverse events is really a passive system and hence subject to a lot of limitations, is FDA aware of any adverse events that could potentially be representative of infection with B19, acute infection among actual recipients of the product outside of these Phase IV trials?
DR. LYNCH:  Actually, yes.  I was informed this morning that the manufacturer had received one report.  It is the first report to my knowledge that an individual outside of the clinical trial had apparently seroconverted after using SD plasma.
The individual infected was a recipient of several of the lots of SD plasma that had been recalled, but I have no further particulars on that incident, and it hasn't been formally filed with our Medwatch system.
As you know, Mary, that is under a fairly tight timeline, so we should be getting a full report on that shortly.
DR. HOLLINGER:  But other than seroconversion, any clinical problem?
DR. LYNCH:  Not to my knowledge, no.  There is certainly nothing in Medwatch that is suggestive, and during the clinical trial, there was no evidence of seroconversions or certainly symptomatic infections.
DR. HOLLINGER:  Thank you, Dr. Lynch.
The next topic, Dr. Nightingale is going to give us a summary from the Blood Safety and Availability Advisory Committee meeting.
Blood Safety and Availability Advisory
Committee Meeting Summary
Stephen Nightingale, M.D.
DR. NIGHTINGALE:  In the interests of time, let me get started.  I can do this without the overheads if I have to.
Dr. Hollinger and Committee members:  the Advisory Committee on Blood Safety and Availability met on April 29th and 30th of this year to examine the reserve capacity of the United States blood supply and to recommend how it might be strengthened.
[Slide.]
By way of very brief introduction, as I believe the BPAC members know, the Advisory Committee was chartered on October 6th, 1995, to advise the Secretary and the Assistant Secretary for Health on a range of issues to include one of three:  the implications of blood safety and availability of various economic factors affecting blood product cost and supply; number two, definition of public health parameters around safety and availability of the blood supply; number three, broad public health ethical and legal issues related to blood safety, and our meeting was conducted under this rather broad mandate.
[Slide.]
I am sorry, I had shown this merely to show that Dr. Busch, Dr. Chamberland, Dr. Epstein, and Dr. McCurdy are members of the committee here in the room, and Major Fitzpatrick will be joining the committee on the 1st of July.
The second, which is up there, the charge to the Advisory Committee is listed up here, and I will read it because it is brief for the record, that it may be necessary at sometime in the future to defer at least temporarily some portion of the donor pool in order to maintain the integrity of the blood supply; that this action should be done in a way that would minimize the impact on those who depend on blood transfusions for their health and even for their lives, and finally, plans to utilize the reserve capacity of the blood supply should be established before and not after circumstances require use of this reserve.
Dr. Satcher further charged the Advisory Committee to do so before and not after circumstances might require use of this reserve capacity.  He concluded his charge by reminding the Advisory Committee that we should never be in the position, as some have suggested we may have been in the past, where we would feel obligated to release a unit of blood if we had any doubt whatever about its safety.
[Slide.]
Regarding the availability of blood supply, Ms. Marian Sullivan of the National Blood Data Resource Center, which is an affiliate of the American Association of Blood Banks, then described for us the current availability of our blood supply.
She stated that in 1997, about 12.6 million units of blood were collected and about 11.5 million units of red cells were transfused, 93 percent of the allogeneic units were transfused, 2 percent were discarded because of screening test results, 4 percent became outdated, and 1 percent were unaccounted for.
However, as shown on this slide, total blood collections decreased by 5.5 percent between 1994 and 1997, while the total number of whole blood and red cell transfusions increased by 3.7 percent during the same period.
Extrapolating from these current trends, Ms. Sullivan estimated an available blood supply in the year 2000 of 11.7 million units, and a total demand of 11.9 million units.
Three substantive comments were made in the discussion that followed this presentation.  First, most outdated units are group AB blood donations, which as everybody I believe in the room knows can only be transfused into group AB recipients.
Second, the fact that overall supply exceeded overall demand during 1997 does not mean that there were no local shortages during that year, as in fact there were.
Third, one factor contributing to the trend Ms. Sullivan described is the aging of the population since about half of all transfusion recipients are over 65.  As a result, as the population ages, there will be proportionately fewer donors and proportionately more recipients.
Dr. George Schreiber of Westat, Inc., and the National Heart, Lung, and Blood Institute sponsored a retroviral epidemiology donor study, then discussed how donor retention might influence the reserve capacity of the blood supply.
He began by noting that while almost half the adult population in the United States donated blood at sometime, only about 5 percent donate in a given year.  In 1995, about 32 percent of the roughly 8 million blood donors were first time donors.  Half of these new donors never returned, and two‑thirds of those that did, returned during the first year after the donation.
Dr. Schreiber estimated that if the rate at which first‑time donors returned for a second donation within one year could be increased by 15 percent, the blood supply could be increased by 10 percent.
The discussion that followed focused on the suitability of these donors that might be induced to return.  Dr. Schreiber had found that individuals who had donated only twice had no greater incident of HIV or hepatitis C than individuals who had donated more than twice.
A similar observation has been made about paid plasma donors.  Those who return only once regardless of the interval after their original donation appeared to be just as suitable as those who returned more often and more frequently.
Dr. Michael Busch of the Blood Centers of the Pacific then discuss differences in risk factors among blood donor groups.  Dr. Busch and others have found that the prevalence of deferable risk is 1.5 to 2 times higher for just about any given risk in first‑time donors than in repeat donors.
As a result, he concluded that a donor referral strategy that would increase the fraction of new donors in a donor pool would increase the risk of that pool, however, Dr. Busch did notice there was less difference between the incidence‑‑that means the new onset of deferrable risks‑‑in new and repeat donor population.
The consensus of the Advisory Committee emerged that the retention of more first‑time donors, as Dr. Schreiber suggested, was the strategy most likely to increase the capacity of the United States blood supply and least likely to increase its risk.
There was also consensus that it would cost a substantial amount of money and incentives, direct or indirect, to retain these first‑time donors, and that blood banks could not fund these additional costs from current revenues, however, no conclusions could be reached on what, if any, incentives up to and including paid donation would be effective, how much they would cost, or who would pay for them.
With this in mind, the Advisory Committee then addressed the issues of what, if anything, individuals with hemochromatosis or the blood substitute industry could contribute to the reserve capacity of the blood supply.
[Slide.]
After considering this issue, the Advisory Committee concluded the statement that I have, the third here, which is a complementary strategy in addition to increasing the retention of first‑time donors, would be to eliminated undue financial incentives for blood donation by individuals with hemochromatosis, and that such undue incentives are removed to create policies that eliminate barriers to the use of this resource.
The potential contribution of this resource is substantial, but uncertain, but again, there is no guarantee that this potential would be realized.
I would be glad to answer any questions.  I hope I have kept within my allotted time.
DR. HOLLINGER:  Any questions?  Ohene.
DR. OHENE‑FREMPONG:  Would you care to elaborate a little bit on the issue with those with hemochromatosis?
DR. NIGHTINGALE:  Yes.  What I think I would like to do by way of elaboration would be to read the exact statement that was passed unanimously by the Advisory Committee.  I think that that would probably be sufficient elaboration for purposes of opening the discussion.
That recommendation reads incompletely as follows.  The Advisory Committee recognizes that blood products obtained from persons with hemochromatosis carry no known increased risk to recipients attributable to hemochromatosis per se and therefore may be a valuable resource to augment the diminishing blood supply.
The Advisory Committee also recognizes that the obligate need for phlebotomy can constitute an undue incentive for blood donation due primarily to financial  considerations.
For this reason, the Department of Health and Human Services should create policies that eliminate incentives to seek donation for purposes of phlebotomy.  As such undue incentives are removed, the Department should create policies that eliminate barriers to using this resource.
Would you like to ask a follow‑up question or was that sufficient?
DR. OHENE‑FREMPONG:  What is the rough estimate of how much phlebotomy from patients with hemochromatosis would add to the blood supply?
DR. NIGHTINGALE:  The doctor asked the question why I glossed over it in my initial presentation.  Let me give you the slightly less short answer.
The estimates given to the Advisory Committee ranged from 300,000 units to 3 million units of whole blood and red cells that could be added to the blood supply.  There is some concern at least at the staff level, which I guess would be me, that the lower estimate might, in fact, be high.
Clearly, the frequency of the gene is known.  There would be roughly a million people in the United States with the gene.  At the same time, a quarter of those million people are under 21.  Half of those million people are female who, while they do express the gene, I think it is 88 percent, if I have got the right number, of the diagnosed cases of hemochromatosis are male.
We have the issue of expression of the gene even though it is a C282, the nucleotide is the same.  People are more complicated than that.  So, exactly how many people would come in is the first question.
The second question is how many of those people would meet the current AABB standards, for example, for hematocrit.  Clearly, because the phlebotomies are being done for therapeutic purposes, during the induction phase, the individual would be bled down below a hematocrit of 38.  I think they are bled down to I believe 31 is the number that is used at least in some centers.
So, how many of these units would be useful is a second question.  I think what folks came to would be a certain number we would like to think 180,000 seems like a reasonable estimate of how many units it would be.  That would be the number we would expect to see for new people entering the system.
The second even less well characterized part of the answer to your question is how many people with hemochromatosis are currently donating blood, and I don't think anybody has a good answer on that one.  I certainly don't.
DR. HOLLINGER:  But they are a continuous source since they are asked to donate at least three or four times a year after the iron had been removed from their system.
DR. NIGHTINGALE:  Yes.
DR. HOLLINGER:  Any other questions?  Yes, Dr. Stroncek.
DR. STRONCEK:  I would comment that I would be careful about assumptions about blood shortages because I think if a shortage occurs, many people will step forward and donate, so I am not sure that we will have a shortage and that we do need to change the policy on people with hemochromatosis.
The other comment is that it seems kind of schizophrenic to be recommending that one group here we have people with hemochromatosis donate, which I agree are probably no risk, on the other hand, we are going to talk, I think the next agenda item, on people traveling to England can't donate.  They don't seem consistent.
DR. NIGHTINGALE:  We would probably want to discuss privately the use of the term schizophrenic.
DR. HOLLINGER:  The next topic is going to be a summary of the Transmissible Spongiform Encephalopathies Advisory Committee, which was held June 2nd, in regard to new variant CJD.
Dr. Jacobs.
Transmissible Spongiform Encephalopathies Advisory
Committee Meeting Summary
Mary Elizabeth Jacobs, Ph.D.
DR. JACOBS:  Thank you, Dr. Hollinger.  Good morning, members of the Committee, ladies and gentlemen.
[Slide.]
At your March meeting you received an update on the December 1998 meeting of FDA's Transmissible Spongiform Encephalopathies Advisory Committee meeting, and that is an advisory committee which advises all parts of the FDA on TSE‑related questions.
We had brought to them the question of considering deferral of blood donors based on their foodborne exposure to the BSE agent through travel to BSE countries or residents there in order to reduce the theoretical risk of transmission of new variant CJD through blood.
At that December meeting, the Committee voted to recommend deferral, but asked for a survey of travel times in order better to estimate the impact on the blood supply.
In the June meeting, they took up that question again with the survey results, and again in order to have continuity with this committee, Dr. Hollinger served as a temporary voting member, as did Dr. Nelson, and we had other members who were there including Dr. Sayers and Dr. Leitman representing the blood banking community.
That transcript will soon be on our web site.
[Slide.]
In the agenda, we had first a consideration of the survey results by Dr. Williams, which I will give you in a second.  We then had two speakers on scientific aspects related to the time of the BSE epidemic and modeling of new variant epidemic‑‑excuse me, I shouldn't use new variant epidemic‑‑it's the BSE epidemic.
Dr. Donnelly is the head of the Statistics Unit at the University of Oxford, which has done all the modeling of the BSE epidemic, and they also have done modeling for new variant.
You can see her discussion on the web site, but in brief, the conclusions were that at the current time we cannot say how many cases of new variant CJD will occur.  The estimates go from under 500 to as high as 500,000, and the primary unknown is the time of incubation of new variant CJD.
The highest number, 500,000 cases, comes from using 40 years for the time of incubation.  It is possible that if the cases go down over the next two years, that better estimates will be available for that, but right now there are no estimates beyond this frame of under 500 to as high as 500,000.
Next, we had Mr. Philip Comer speak.  He was the primary person responsible for a risk assessment which was done under contract to the Department of Health in the UK, and they asked Det Norsk Veritas, which is a consulting firm, to look at estimates for infectivity and to potential transmission through blood.
That risk assessment has been peer reviewed and is now publicly available.  Again, although no definite scientific or good scientific data are available, in brief, we can state that there are more concerns with new variant, and these concerns include higher amounts of abnormal prions in the brain and also the potential role of B lymphocytes.
Next, we turned to questions of shortages because we asked the Committee to consider this in the light of potential shortages, and Dr. Nightingale, who just spoke, gave us a somewhat more detailed discussion of the BSE meeting.
Finally, we had a brief summary of Canadian discussions.  There was a meeting of their National Blood Safety Council, and they have had parallel discussions, because they also have fair numbers of their blood donors who travel to BSE countries, yet, they have had no indigenous cases of BSE.  They had one case in an imported animal.
[Slide.]
We at FDA feel very grateful to Dr. Williams, who is the principal investigator, and all those involved in this survey which was so quickly done between the meeting in December and having results available in June.
It was done through the American Red Cross ARCNET program with support from National Health, Lung, and Blood Institute REDS program, and in cooperation with the American Association of Blood Banks and America's Blood Centers.
It was a random sample, anonymous mail survey.  They had approximately 49 percent response at the time of the June 2nd meeting, and Dr. Williams presented data on 8,666 responses from a total of 19,067 that had been sent out.
Let me give you two of their results before we go to the main ones on which the decisions were made.  They found that there were a total of 22.6 percent of all blood donors who responded had been in either the United Kingdom or the Republic of Ireland between 1980 and 1996.
Just for those of us who have forgotten our sixth grade geography, the United Kingdom includes Great Britain, which is England, Scotland, and Wales, and then going into the United Kingdom, Northern Ireland, the Channel Islands, which are Guernsey and Jersey, and the Isle of Mann.  In addition, the Republic of Ireland was included.
So, in total, 22.6 percent had gone there, and as expected, more donors in older age groups had traveled there.
[Slide.]
Dr. Williams has given his okay to show his data today, and these are I think the heart of the matter.  They show, in the first column, the deferral criterion, in other words, greater than or equal to 5 years cumulative in the UK or Republic of Ireland between 1980 and 1996 and then following down greater than or equal to 1 year, 6 months, et cetera.
The next column shows you the percent of the U.S. blood supply which this travel represent, and the last one shows you the cumulative person‑days.
Now, one of the difficulties here is modeling the exposure which took place between 1980 and 1996, and the exposure method that was used here was linear exposure, in other words, to say 1 person who was there for 1 day is one person‑day, 1 person who was there for 100 days is 100.
So, if we look at this, you can see what percentage in the righthand column, what percentage of the risk, if it is modeled in a linear way, would be removed if we used the deferral criteria on the left side and what percentage of the U.S. blood supply would then be removed.
Let's go to the decision that was made by the PHS Committee.  We will then next go to the Committee vote, but then to focus on 6 months or greater residence would give a loss of 2.2 percent of the U.S. blood supply given our current donor profiles as represented in the survey, and would remove about 80 percent of the risk if it is calculated linearly.
[Slide.]
Following the deliberations of the Committee and the presentations, they voted, and for the record I will read in what the questions were and what their vote was.
Should FDA recommend new deferral criteria for donors of transfusible components to reduce the theoretical risk of transmitting nvCJD from transfusions based on donor exposure to BSE in the UK?
Their vote was 12 yes, 9 no, 0 abstained.
[Slide.]
Next, we asked the question, if so, what deferral criteria should FDA recommend, that is, time period, nature and length of exposure.
Rather than take a vote on one time period, the Committee took a poll, and the poll showed that 5 years or more was recommended by 3 members, 3 years or more by 1 member, 1 year or more by 5 members, 6 months or more by 7 members, and 4 months or more by 4 members.
[Slide.]
We did only one thing differently in asking the questions this time compared to December, and that was separating out the question of plasma donors compared to blood donors.
The second question asked the question for plasma donors.  Should FDA recommend new deferral criteria for donors of source plasma and recovered plasma for further manufacture into injectable products to reduce the theoretical risk of transmitting new variant CJD from plasma derivatives based on foodborne exposure to BSE in the UK?
Here, the vote was 12 yes, 8 no, 0 abstention.
[Slide.]
The next one.  Again, we asked, if so, what deferral criteria should FDA recommend, that is, time period, nature and length of exposure?  The Committee did not vote  on this question as written, but voted on keeping the criteria for question for 1b the same as the criteria for 2b.  19 yes, 0 no, 0 abstained.
[Slide.]
Now, what has been our follow‑up?  The Public Health Service has a committee called the Blood Safety Committee.  This is chaired by Dr. Satcher, who is both Surgeon General and Assistant Secretary for Health.
That committee, which includes FDA, CDC, NIH, HCFA, and the Department, met one week later.  There was a unanimous vote by the committee to Dr. Satcher to endorse the recommendations for deferral, and they recommended that the criteria be six months or more cumulative months of residence or travel.
They also recommended that FDA review the scientific data every six months, which underpin this decision, and here I will add that FDA has a standing committee across all of its centers and also one within CBER, which follows the scientific information on a routine basis.
This committee assigned to FDA for implementation through revised guidance, and Dr. Scott will talk about the guidance, and also the committee and Dr. Satcher pledged to work on donor recruitment and retention, and to monitor the impact on supply.
[Slide.]
This shows our proposed implementation plan.  FDA will call for blood establishments to implement this deferral as soon as feasible, but within 6 months of issuance of the guidance.
The FDA guidance will call for indefinite deferral from donations of blood or plasma of persons who lived in or traveled to the United Kingdom, England, Scotland, Wales, et cetera, for a cumulative time of 6 months or more between January 1980 and December 1996.
Thank you.
DR. HOLLINGER:  Any questions of Dr. Jacobs?  Yes, Dr. Buchholz.
DR. BUCHHOLZ:  I am sorry, I may have missed your very last statement.  What was the ending date?
DR. JACOBS:  1996.
DR. BUCHHOLZ:  And why was that taken as opposed to continuing for the foreseeable future?
DR. JACOBS:  I think the primary reason for that, although the committee did not explicitly vote on this, was the effect of the food bans and the displays of these which we seen in Dr. Donnelly's talk.
The remainder seems to be maternal‑to‑calf transmission within the UK, and therefore it is thought that these food bans are effective.
DR. HOLLINGER:  Dr. Mitchell.
DR. MITCHELL:  I guess I have more of a comment than a question.  I think that people have been hearing that travel to England is a deferrable criteria, and I am afraid that people will not go for blood donation because of that.
I was wondering if they considered saying that living in England instead of travel to may be from a perception point of view more accurate to define what the committee has planned to do.
Have they talked about saying living in the United Kingdom during that period of time?
DR. JACOBS:  I think that that is a very good question, and that has been discussed partially because sometimes people interpret those terms differently, did they actually live there or did they only travel there.
We are using the term "cumulative 6 months."  It is possible that people who travel there regularly for 2 or 3 weeks could possibly accumulate that amount of time there. So, I think Dr. Scott will be discussing the questions that are being considered, and we are trying to incorporate that aspect of it.
DR. MITCHELL:  I think the issue is one of semantics and what is getting out to the public.  If you say to the public, they lived, then, you can explain what lived actually means 6 months.
DR. JACOBS:  Yes.  Thank you.
DR. MITCHELL:  Thank you.
DR. HOLLINGER:  I think we will have Dr. Scott then tell us about the revised guidance for CJD and nvCJD.
Revised Guidance:  CJD and nvCJD
Dorothy Scott, M.D.
DR. SCOTT:  Good morning.  I am going to summarize the proposed revised guidance to reduce the possible risk of transmission of CJD and new variant CJD in blood and blood products.
[Slide.]
I believe you got a copy of this, this morning, but I am sure you haven't had time to read it in great detail.  What I would like to do is just summarize some of the main points in that new guidance for your consideration.
[Slide.]
Since December of 1996, we had a memorandum which did address deferral of donors and withdrawal of products for CJD.  Since that time, there have been a lot of ongoing advisory committee discussions, as well as new data that have come out, so as a result of all of these discussions and new data, which were taken into consideration, a recommendation was announced by Dr. Satcher late in the summer of 1998, and this was published on the internet by FDA.
That changed the previous recommendations, and I have put in bold the changes.  The changes were no longer to retrieve, quarantine or destroy plasma derivatives if the donor had CJD risk factors, and I will list those for you, or CJD, and this was based on evaluation of a large body of epidemiologic and laboratory evidence, which is summarized in the new document.
It was still recommended to defer donors that had CJD risk factors or CJD.  In addition, another new recommendation was made to retrieve, quarantine, and destroy materials if the donor had new variant CJD, and I am going to go into some of the details of that.
The TSE Advisory Committee on June 2, 1999, made the recommendations that Dr. Jacobs has summarized for you, and that was to defer donors based on exposure to bovine spongiform encephalopathy in the United Kingdom.
This recommendation was actually made in December of 1998 and reaffirmed in 1999, but with the time period criteria that you have seen, the majority did vote to defer donors who traveled to or lived in the United Kingdom for greater than or equal to six months, but as you saw, there was a spread of opinions for exactly what this time period should be.
This was endorsed by the PHS Blood Safety Committee on June 9th of 1999.
[Slide.]
So, the three points of the new proposed guidance that I am going to expand upon a little bit are the incorporation of new donor deferral criteria for the United Kingdom.  It also includes recommendations for products from donors with new variant CJD and suspicion of new variant CJD.  It also incorporates labeling recommendations for non‑implicated products which mention CJD as a theoretical risk.
First, I will just talk about the donor deferral recommendations which are still to defer all donors, of course, with CJD or new variant CJD, and also to defer donors with risk factors including family history of CJD in greater than or equal to one family member, and this has not changed.
In addition, we are asking for deferral of pituitary hormone recipients.  That is a slight change because before, we had specified human pituitary‑derived growth hormone.  Now, we are just saying pituitary growth hormone and gonadotropins since there are a few reports, mostly from Australia, that old gonadotropin preparations also transmitted CJD.
In addition, donors who have received dura mater grafts will be deferred as before.
The other new deferral is to defer donors with risk of exposure to new variant CJD, which you have just heard of.  I have written the wording of that which you have also essentially just heard, but this would be precisely the kinds of donors that we would recommend deferral for, donors who have spent greater than or equal to six months in the United Kingdom, Great Britain, Scotland, Northern Ireland, Isle of Mann, Channel Islands, cumulatively between January 1st, 1980, and December 31st, 1996, for the reasons that Dr. Jacobs has explained.
This, or course, encompasses the years when the BSE epidemic had peaked.
[Slide.]
I am going to move on to how new variant CJD is diagnosed.  Some of you have probably seen this before.  It became important to us because we realized that there could be cases of new variant CJD in the U.S. eventually if we are unlucky, and we need to certainly have a criteria for knowing that a patient has new variant CJD since this is going to result perhaps in large withdrawals if that person was a donor.
So, neuropathology is still currently required to make a definite diagnosis of new variant CJD, and I have listed for you the three neuropathological correlates that have been described by the United Kingdom groups.  These are the things they believe can give you a diagnosis of new variant CJD.
One is the presence of florid plaques, which is unusual in regular or classical CJD.  Spongiform change, particularly in certain places, the basal ganglia and the thalamus, but not the cerebral cortex, as well as immunohistochemistry, which shows a high‑density prion protein accumulation again which is unusual in regular CJD.
Potential new diagnostic indicators are being developed, but none of these have been validated, and those include tonsillar biopsy with immunohistochemical staining for prion proteins.  These are prion protein glycoforms which appear to be different for new variant CJD than for classical CJD, and also there may be an MRI criteria, which will be published soon by the United Kingdom group, which suggest that bilateral posterior thalamic signal of high intensity may be diagnostic for new variant cases.
However, it also seems possible that one could have a new variant case that doesn't have adequate neuropathology.  In fact, you can tell from those criteria for definite that you may actually want to look at a whole brain to determine the distribution of lesions.
So, it may be necessary to make the diagnosis of new variant CJD by clinical criteria.
[Slide.]
The CDC has a case definition for clinical criteria for new variant CJD in the United States, and we considered using this actually as a criteria for withdrawal in addition to neuropathological correlates of new variant CJD, but this CDC definition has to include all of the nine following qualities, and these again are mostly things that would distinguish a new variant CJD case from a classical CJD case.
First of all, the patients are typically young, age less than 55.  They present with painful sensory symptoms or psychiatric symptoms rather than movement disorders or even cognitive dysfunction.
They have a delayed development of neurologic symptoms after their initial presentation.  In most cases, this is for more than four months, but there have been exceptions.  They may have a normal or abnormal EEG, but not the EEG changes which are pseudoperiodic sharp waves that are seen in classical CJD, and they typically have a long duration of illness that is very drawn out compared to most, but not all, CJD cases.
It would be important for routine investigations to not suggest alternative non‑CJD diagnoses.  In the CDC criteria, they specify travel to a BSE country, which is the United Kingdom, but there are also other countries with low rates of BSE.
[Slide.]
We realized when we went over these criteria that it was quite possible that there would be cases which actually had new variant CJD which wouldn't meet all nine of these criteria, at least not right away.
For example, two of these criteria are based on the time course of the disease, either how prolonged it is or the development of symptoms in a certain order, and that time may not have elapsed to meet those criteria.
Furthermore, travel history and symptom history might not be available, and you can think of a few other cases in which all of those nine criteria have not been met, and that would actually be true of some of the UK patients who didn't have precise development of delayed neurologic symptoms by four months, and so forth.  So, we needed a lower threshold actually to be looking at cases which might have new variant CJD in the U.S.
[Slide.]
So, we proposed a threshold for investigation and consideration of quarantine and withdrawal of blood product for new variant CJD concerns, and that would be if the donor was less than 55 years old and if the donor had a physician's either clinical or pathological diagnosis of CJD, and because it's a young person, we would be concerned that this was actually a new variant case.
In the guidance, we are asking for immediate notification of FDA and CDC, and telephone numbers are provided.  It would then be planned to perform a rapid investigation of the case with CDC and FDA both involved and to make decisions about blood products on a case‑by‑case basis, and in fact, if it was ambiguous as to whether the donor had new variant CJD, if it couldn't be ruled out, then, it is likely that precautionary withdrawals would be recommended.
[Slide.]
I want to go on then to the proposed disposition of materials for all of these kinds of cases that I have discussed both for deferral and for new variant CJD case.  For CJD, CJD risk factors or new variant CJD exposure risk‑‑by that I mean travel to the United Kingdom for greater than or equal to six months, we would recommend withdrawal of components and unpooled plasma, but not withdrawal of derivatives.
If some of these components were to be used in non‑injectable products, we would suggest some labeling for those.  In the case of new variant CJD or precautionary withdrawals for cases that were suspicious might have new variant CJD, we would ask for withdrawal of components, derivatives, and that this material not be used for non‑injectable products, but we would permit it not to be destroyed but rather to be used in research on new variant CJD with appropriate labeling, which is also suggested in the document. 
[Slide.]
Finally, on the last topic, I want to go to proposed labeling of non‑implicated products, which has been discussed extensively within the FDA, and this is the statement that we have come up with in collaboration with the Office of Vaccines.
First of all, I just want to read out the statement that is also contained in the guidance, that no transmission of CJD or new variant CJD by human blood or plasma derivatives has ever been documented from human to human, however, as a precaution, FDA proposes that all blood component and plasma derived products include labeling to address the theoretical risk.
Now, this statement obviously covers more than CJD, but the statement is as follows.  Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Cretzfeldt‑Jakob disease agent.
Thank you very much.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  I have two questions.  One of the things, if I understood you correctly, is that some of the characteristics on biopsy or autopsy for new CJD are unusual, but sometimes present in classic CJD in the sense that you can't absolutely definitively tell between the two, is that correct?
DR. SCOTT:  Well, that is correct if you look at any one of those autopsy criteria alone, but taken together, the United Kingdom group feels that they are quite characteristic.  The other thing is, for example, in the case of some of these, the exceptions would be genetic cases which may have some of these feature, but, of course, those are easily ruled out with gene sequencing.
DR. BOYLE:  But in cases, for instance, of very young CJD cases identified in the United States recently where there has been a statement that on biopsy, definitively, they are not new variant CJD, that we can treat that as a definitive statement?
DR. SCOTT:  Well, there are a couple of things that happened with that biopsy or a couple of qualities that it had which really did appear to rule out new variant CJD, which as you know, was a considerable concern, and it still led to precautionary withdrawals.
The first is that that biopsy did not have florid plaques, and the second is that the prion protein glycoform was looked at, and it was either a Type I or a Type II, I can't remember, but it was a classical CJD form, not the Type IV that has been seen in every new variant case.
So, those two characteristics led us all to feel much better about this case.  It is my understanding now that the patient has died, but I don't really know where the brain got sent to.
DR. BOYLE:  The second question is your nine criteria that you require basically for a case to be new CJD if you don't have definitive lab results.  One of those criteria is under 55.  Yet, we also heard from the travel survey that your likelihood of spending a long time in England is much higher for older persons.
I understand it in terms of looking at new cases, but are you setting up something where older travelers to England are people who, because of their age, are going to be non‑CJD unless you have a lab diagnosis?
DR. SCOTT:  Well, I think there are a couple of answers to that question.  I think you are absolutely right.  Although no case has been seen greater than 55 years of age yet, including in the United Kingdom, it is entirely conceivable that such cases are going to occur.
I think that is why we decided ultimately that we, FDA, would not require the meeting of all nine of these criteria in order to effect a precautionary withdrawal.  So, we will use these qualities to help us evaluate that case, but we are not going to go ahead and do that.  I guess that is the answer I would like to give.
DR. HOLLINGER:  Dr. Koerper.
DR. KOERPER:  Identifying someone who has already donated blood as subsequently someone with CJD or new variant CJD depends on, as I understand it, a voluntary reporting by the physician, and I wondered.  It is my understanding that not every state right now lists CJD as a reportable disease.
DR. SCOTT:  That is correct.
DR. KOERPER:  What is the FDA working on in terms of trying to improve or increase the number of states that report CJD?
DR. SCOTT:  It is my understanding that the CDC is actually working on that very subject, however, there are several different routes by which we might find this information out.  One is, of course, through the blood banks or plasma collection establishments which receive post‑donation reports from relatives.
The second is, as you say, through the states to the CDC, as well.  The third is through neurologists who are part of working groups that are involved in more or less surveillance for new variant CJD.  But is the ascertainment perfect?  I agree with you that it is not, and I think we all wish that it were better and there is work ongoing to try to make this reportable.
Even all reportable cases aren't reported, and so it still wouldn't be perfect once that is achieved.
DR. HOLLINGER:  Dr. Epstein.
DR. EPSTEIN:  Yes, I just wanted to make two comments.  First, the draft guidance document that was provided to committee members is given to you confidentially and we are requesting your comments within the next two weeks.  That is to assist us in finalizing it before it can be made public.
Second, one point I wanted to make about the FDA plan regarding implementing the deferral for residence or travel to the UK, it is our current thinking that when we issue the guidance, we would call for implementation of that deferral as soon as feasible by blood collection establishments and plasma collection establishments, but within six months of issuance.
The reason that we are approaching it in that way or plan to is that we are highly mindful of the fact that the deferral may cause significant loss of blood or plasma in the supply, and we have a concurrent initiative to try to promote the retention and recruitment of donors to offset the losses that might be expected to occur.
We will try to monitor that situation very closely.  So, again, our expectation would be that when we issue the guidance, we would call for implementation, but no later than six months.
DR. HOLLINGER:  One of the issues I think, Jay, as you know, on the one chart that was spoken about earlier by Dr. Jacobs on the cumulative‑person days, and the real issue is whether that is a good marker because it may be that one person spending 100 days in the United Kingdom may have far greater risk than hundreds of people spending one day, which still gives you 100 person‑days, and that is an issue, and we don't know the confidence intervals around these numbers for choosing some sort of an exclusion.
Could you comment at all about that, Jay?
DR. EPSTEIN:  Of course, you are right.  That is one of the gaps in our knowledge, and there are some plans for animal experimentation to see what the cumulative effect is of subinfectious doses received multiply over time, one of the questions being how fast you clear exogenous exposure to abnormal prions, and it may be that they accumulate and you can reach an infectious dose from multiple exposure.
But this was discussed at the TSE Advisory Committee and it was felt that the best that one could do was apply the assumption of linearity, that risk is simply proportional to time spent on the theory that that correlates to the risk to a single or discrete infectious exposure.  No one knows if that is really true.
The other methodologic issue, which you didn't mention, is that there is some arbitrariness in assigning the exposure time as the midpoint of the interval that was queried in the history.
For example, if you were asked about exposure, say, between three and five years, exposure days were reckoned by calling that a four‑year exposure if the answer is yes, and it becomes very difficult when you consider the prolonged exposures because if you then treat, say, all exposures over five years, you know, in theory, that runs out into lifetime exposure.
In practice, we reckoned it back to the earliest epidemic of 1980 and called it a 17‑year interval, and then we chose the midpoint, but clearly, the contribution to capturing exposure time, if you apply those very long intervals, is disproportionate for the people who gave the histories of prolonged exposure.
In other words, on the linear assumption, you are assuming that those people contribute the greatest risk, and that may not, in fact, be true.  So, there are a lot of methodological limitations, and the bottom line is that we only had certain data available, and we had to make certain assumptions in order to deal with it, and that was the task that fell to the TSE Advisory Committee, and that was what they recommended that we do.
So, you know, you are right and I wish we had the data to answer that point, but we do not.
DR. HOLLINGER:  Dr. Khabbaz.
DR. KHABBAZ:  I have a couple of comments to make, to clarify for clarity, regarding the criteria for suspected new variant CJD, the CDC criteria.  These criteria are for, and the definition of suspected new variant CJD, is for surveillance purposes, and including of the young age, less than 55, I mean they are carefully crafted based on what we know of the new variant CJD cases reported in UK.
These criteria are likely to change with time as more information accumulates.  The age is not cast in stone.  There is some criteria may drop, may be added, and they are carefully reviewed, and so it is an ongoing process.  In no way did we think or suggest that these criteria ought to be the threshold for looking at it.
In fact, we encourage reporting of young cases.  I mean we use the same threshold of just young CJD to initiate investigation, and the investigation is for the purpose of if you don't have a pathologic diagnosis, then, we use those criteria to classify cases suspect new variant CJD for counting.
With regard to the reporting, we work with the Council of State and Territorial Epidemiologists for decision on what disease to include or not, but just to clarify that with regard to surveillance‑‑and there are some complicated issues‑‑making a disease nationally notifiable does not by the large assure reporting and results in better surveillance, and we have ample examples of conditions where we have better surveillance through other systems.
DR. HOLLINGER:  Thank you.
Thank you very much for this nice summary of that conference.
Dr. Smallwood wants to discuss the schedule of the OBRR Workshops coming up.  There is a number of very good workshops.
Schedule of OBRR Workshops
Linda A. Smallwood, Ph.D.
DR. SMALLWOOD:  In the interests of time, I am going to try to be very brief, however, on the table outside we have listed the proposed Office of Blood Research and Review workshops for 1999.  There are eight of them, and I will just read the titles briefly and give you the dates of those that have been scheduled.
The most imminent will be the Blood Donor Suitability Workshop ‑ History of Hepatitis.  That is scheduled for July 21st, 1999, and it will be held at the Natcher Auditorium located on the NIH campus.
The second is Bacterial Contamination of Platelets.  That will be held on September 24, 1999, at the Jack Masur Auditorium on the NIH campus.
The Blood Substitute Workshop is scheduled for one and a half days, September 27th and 28th, 1999, at the Natcher Conference Center located on the NIH campus.
There will be a Workshop on Plasticizers:  Safety Issues in Blood Collection and Storage scheduled for October 18th, 1999, at the Jack Masur Auditorium on the NIH campus.
A Workshop on Inactivation of Plasma Derivatives (Human Injectables) from Non‑Human Sources, scheduled for October 25th, 1999, Jack Masur Auditorium, NIH campus.
The Nucleic Acid Testing Implementation Workshop has been mentioned earlier.  It is scheduled for December the 7th, 1999, Jack Masur Auditorium.
A Donor Suitability Workshop is tentatively planned for October, the date subsequently, hopefully, to be determined.
Finally, a Workshop on Leukoreduction scheduled for December the 10th, 1999, at the Natcher Auditorium.
Information regarding these workshops may be found on the CBER web site page under What's New.  The web site address is as follows:  www.fda.gov/cber/whatsnew.htm.
DR. EPSTEIN:  It has been brought to our attention that the December 7th workshop date for the NAT workshop is in conflict with the American Society of Hematology meeting, and we have a request that we try to find an alternate date.  So, I think people shouldn't get too wedded to that date today.  We may change it.
DR. SMALLWOOD:  I would just like to follow up.  If you would keep abreast with respect to our web site, you will be notified of alternate dates and times.
Thank you.
DR. HOLLINGER:  We are going to move into the next session, actually, the first session for discussion.  This is going to be on the post‑donation information affecting plasma pools for fractionation (inadvertent contamination).  We discussed this at some length last time with an algorithm.  I made some suggestions which Dr. Tabor and their group have put together again for discussion.  I hope you all have had a chance to look at that, so we can move through on that.
Dr. Tabor, could you give us an overview, then, of the risk issues.
I.  Post‑Donation Information Affecting Plasma Pools
for Fractionation (Inadvertent Contamination): Risk Issues
Overview
Edward Tabor, M.D.
DR. TABOR:  Good morning.
[Slide.]
Inadvertent contamination is a subject that is a term that has been in use for more than 20 years, and since our discussions are new about this subject beginning in 1997, there has been a lot of interest, and I think some of it came from members of the Blood Products Advisory Committee although I don't know whether they are current members who brought this up, that the term "inadvertent contamination" is really not a very good name for this.
Nevertheless, after wracking our brains for a substitute term and coming up with nothing suitable, and also realizing that everybody knew what inadvertent contamination was even if no one liked the term, we continued to use it for a while, but now we are going to be calling post‑donation information.
As long as you recognize that these two terms are interchangeable, you should have no trouble following the discussion.
In June of 1997, we presented to BPAC information on inactivation procedures that are applied to plasma derivatives, inactivation and removal procedures, and the amounts of the viruses hepatitis B, hepatitis C, and HIV that were removed by these procedures in comparison with the amount that could be present in any pool.
So, we discussed that type of inadvertent contamination and really presented raw data in June of 1997.  In September of 1997, we discussed a different type of inadvertent contamination, which we were calling risk factor inadvertent contamination or now risk factor post‑donation information.
Basically, what we were talking about then was those donors who answered negatively or appropriately to all donor questions, whose serum or plasma was tested negative for all of the licensed tests for hepatitis B, hepatitis C, and HIV, but who nonetheless, after donation at some point provided post‑donation information that they, in fact, were a member of a risk group for one of those three viruses.
So, that was September of 1997.  Then, in December of 1998, we presented you with a draft algorithm for test‑positive cases of post‑donation information, that is, where you discover after collection and perhaps after pooling, perhaps after manufacture, that one of the units that had been reported as testing negative, in fact, tested positive.  That was in December of 1998.
At the last meeting, in March of 1999, we presented a revised algorithm which you voted to approve with some minor modifications, and a copy of that is in your information today, and it is not a subject for discussion unless you have something urgent to ask about it.
What we are going to talk about today is the algorithm for risk factor post‑donation information.  At the March 1999 BPAC, you were given a draft algorithm, and the committee had a number of concerns about the draft algorithm and asked us to go back and revise it.
I might add also that there were concerns raised from members of the audience regarding the large number of plasma pools and plasma derivatives that would be affected by post‑donation information related to risk factors, and so today we are going to discuss the revised algorithm for risk factor post‑donation information.
We are limiting our discussions in the BPAC meetings that I have listed for you and in this one to these three viruses:   hepatitis B, hepatitis C, and HIV.  We recognize that there are post‑donation information issues related to other viruses.  We recognize that there are post‑donation information issues related to viruses that have not yet been discovered, and perhaps we will muster the courage to bring those to you at a future BPAC, but right now we are talking about HBV, HCV, and HIV.
These are viruses for which we have tests to detect the viruses, and there are viruses for which inactivation methods or inactivation removal methods are available.  As I mentioned, there are test issues which we are not discussing today, and donor issues.
Donor issues or risk factor issues are really window period issues.  Today, with the tests that we have to detect infected individuals, when you ask someone if they are a member of a risk group for one of these viruses, you are really asking could you be in the window phase when you are infectious, but not detectable.
[Slide.]
I would like to just briefly go over recommendations that were made by BPAC in September 1997 when we discussed risk factor issues in post‑donation information.  You do not have to stick by your previous recommendations, but I think they will give you an idea of what the committee at that time felt, and I think probably at least half of you were members of the committee at that time.
The committee recommended that in cases of inadvertent contamination or post‑donation information of a pool consisting of units negative for HIV, HBV, and HCV markers containing a unit from a donor with a subsequently discovered risk factor, FDA should determine regulatory action based on an assessment of product risk.
I think what the committee was saying was we should evaluate how much virus could be in the pool if a window period unit happened to be included under these circumstances and what the effect of the inactivation rule procedures would be.
[Slide.]
The committee further recommended an assessment of product risk should consider the maximum level of contamination that could occur and the capability for virus removal and inactivation.
[Slide.]
Finally, the committee recommended again with regard to risk factor issues quarantine of distributed product cannot be dispensed with even if there has been a record of GMP compliance by the company.
What the committee meant was just because the company has had good GMP inspections at every regular inspection over the past so many years, doesn't mean you can ignore the fact that a unit with post‑donation information is in the pool, that is, that you have to look at GMPs again, and they recommended‑‑and this is important for our discussion today‑‑that a negative nucleic acid test on the donor or pool, or subsequent test‑negative donations by the donor, can obviate the need to destroy the product.
[Slide.]
Now, let's talk about the algorithm.  Let me just mention the algorithm has some footnotes.  For some of the footnotes, I will flash this to the footnote slides, for others I will just read you the footnote.  There are some footnotes in the footnote list that applied to the previous algorithm and may or may not appear here.
In the case of whole blood, which of course involves ultimately recovered plasma which can enter a pool, let's just say that a risk factor is discovered.  If the unit has not yet been transfused, you would destroy the unit of blood and plasma, and notify the consignee to destroy it if it had been shipped.
You would defer the donor, and there is footnote g, which I will read to you, which is the donor must be deferred.  In addition, if the donor can be located, all licensed tests for markers of HCV and HIV should be done on a newly obtained sample.
If any tests for HCV or HIV are positive or indeterminate, lookback should be conducted, and lookback here refers to both product retrieval and recipient notification, and prior collection should be quarantined.  Consignees of recovered plasma should be notified.
If the blood unit has been transfused, the blood unit recipient should be notified, the donor should be deferred with the provisions for possible lookback for HCV and HIV, as I just described.
Prior collections should be quarantined, and again the consignee of the recovered plasma should be notified.
[Slide.]
I recognize that this may be hard to read from a distance.  One of the objections that the committee had at the last meeting was that we talked about recognizing risk factors as having been discovered after the fact, and the committee was concerned that some risk factors were not as important as others.
So, we have changed the algorithm to say listed risk factors discovered with a footnote i, and I will show you that footnote in a minute.  The donor should be deferred with provisions for lookback if it involves HCV or HIV‑positive donor, and quarantine of prior collections because many of these donors will have given many times before.
[Slide.]
This footnote i lists the risk factors for HBV, HCV, and HIV to be used for post‑donation information algorithms.  This list was compiled based on reports to FDA concerning post‑donation information, and a little later you will hear a talk by Sharon O'Callaghan about those reports and the numbers we have received.
It was also modified based in part on scientific information about the relative importance of these risks, but I will just go through it now, and we can discuss it later.
The risks that would trigger this algorithm are needlestick or a transfusion within the past 12 months, having been tattooed within the past 12 months unless it was conducted in a presumed sterile situation, body piercing other than ear piercing within the past 12 months, ear piercing being considered to be performed in most cases in sterile situations nowadays, I.V. drug use ever, male to male sex within the past 12 months, sex with an I.V. drug user within the past 12 months, a sex partner who tests positive for current HBV infection or HIV infection, having exchanged sex for drugs or money within the past 12 months, a history of incarceration greater than for a period of 72 hours within the past 12 months, AIDS‑related signs or symptoms at the present time.
Some of these may seem a little unusual to be listing as risk factors, but you will hear from Sharon O'Callaghan that these are reports that we get in some numbers.  A female who had sex within the past 12 months with a male who had had sex with a male, any sexually transmitted disease within the past 12 months, and travel to or immigration from HIV Group O areas, which mainly involve the countries of the Cameroon and those countries bordering on the Cameroon.
Now, I will go back to the algorithm.
[Slide.]
One of the donors is discovered sometime after donation, despite having answered all the questions appropriately at the time of donation, to have one of these risk factors.  Either they forgot and called up and said, gee, I forgot I had had a tattoo or something like that, or they may have come in to donate again and answered yes to one of the questions that they had answered no to before.
I want to clarify footnote k, which I will just do verbally.  Footnote k is a post‑donation information typically is found to apply to multiple collections from a single donor.  So, we are talking here about any units from this donor that have not yet been pooled would be destroyed.
Any units that have been pooled, but not yet processed would be subject to quarantine of the pool, and we will discuss that further.  Units that have been pooled and processed, but not yet shipped, the products would be quarantined.  Any final products that had been shipped, you would notify the consignees to quarantine the products, and that is footnote j.
[Slide.]
I am going to turn to the footnote, so you can read it.  Footnote j says that quarantine is not necessary if additional testing is negative under a later part of the algorithm labeled point A‑‑and we will come to that‑‑or if comprehensive GMP evaluation is adequate under a later part of the algorithm labeled point B, and either of these is completed within 72 hours of the discovery that a unit in the pool came from a donor with a listed risk factor post‑donation information.
The choice of 72 hours we can discuss later.  It is somewhat arbitrary.  It is hoped that this whole process listed under footnote j will encourage manufacturers to keep better records and better computerized records, so that a GMP evaluation can be done rapidly and effectively.
Dr. Lynch later will discuss some of the problems involved in that.
[Slide.]
Just to go quickly through the remainder of the algorithm, in this situation, a company has 72 hours in which to do one of two things.  They can either take process a or process B.  Process A involves NAT testing, and process B involves a comprehensive GMP evaluation.
Under process A, a validated NAT test‑‑and, of course, right now we have no licensed NAT tests, but we are talking about a test that has been adequately validated under the INDs to the satisfaction of FDA, and we can discuss this further‑‑a validated NAT test for HBV, HCV, and HIV on the pool and the original sample would be done.
If the original sample is unavailable, all licensed tests, as well as a validated NAT for HBV, HCV, and HIV could be done on a subsequent sample from the donor.  What we are trying to do here is make sure that the donor was not in the window period at the time of the original donation.
If all of these tests are negative, the pool or the product could be released.  If any of these tests are positive, the pool obviously could be destroyed or the company could move to the GMP part of the algorithm, which they could have done in the first place if they wanted to avoid the testing, and a comprehensive GMP evaluation would be done.
[Slide.]
Under footnote d, a comprehensive GMP evaluation would be done by the fractionator to verify virus removal and inactivation.  GMP inspection, an actual inspection by FDA would be done as needed.  The fractionators would send reports to FDA listing all GMP evaluations conducted because of post‑donation information.
[Slide.]
So, if this GMP evaluation by the fractionator is conducted within 72 hours, and is found to be adequate with regard to those parts of the GMPs related to virus removal and inactivation.  We are not talking necessarily about a complete GMP evaluation, but just relevant portions regarding virus inactivation and removal.
If these are adequate, the pool or product could be released.  If they are not adequate, the fractionator would have to destroy the pool or product and issue a recall.  There is one exception to that situation is under footnote f, which states that in some cases, pools or products can be reprocessed if done so under an approved protocol.
I think at this point I would be glad to answer any brief questions, but some of your questions may be clarified by subsequent speakers.
Dr. Hollinger, do you want to move on to the next speaker?
DR. HOLLINGER:  Yes.
Post‑Donation Information
Sharon O'Callaghan
MS. O'CALLAGHAN:  Good morning.  I am Sharon O'Callaghan from the Office of Compliance.
[Slide.]
What we have done is looked at the error and accident reports that we have received in FY '98 and compiled information related to the post‑donation information report, so I am going to provide the background of how we got to the list of the risk factors.
[Slide.]
We will start off with the definition that we have come up with for post‑donation information, and that is, information that is provided by a donor or other source, and the other source could be either a donor spouse, friend, ex‑girlfriend, could be physician, state health department.  It could be even the police department given the information.
It is information that is provided at a subsequent donation or shortly after a donation.  About 70 percent of the post‑donation information is provided at a subsequent donation.  This information would defer the donor if that information had been known at the time of the previous donation, and the information could affect the safety, purity, or potency of the product.
[Slide.]
So the types of post‑donation information that we have seen reported to us have included "do not use my blood" where the donor calls back.  This is usually within a day or two and just says, "don't use my blood," and gives no other information.
It includes post‑donation illnesses that are not related to hepatitis or AIDS, such as measles, mumps, Lyme's disease is a big one lately.  It also includes post‑donation illnesses that are related to hepatitis and AIDS.  History of hepatitis or jaundice.  Sexually transmitted diseases, syphilis, gonorrhea, chlamydia.  Sex partner testing positive for hepatitis, AIDS, or sexually transmitted disease.
Male donor having sex with another male.  Female donor having sex with a male who has had sex with another male within the last 12 months.  I.V. drug users.  People having sex with I.V. drug users.  Travel or immigration to high‑risk areas, specifically, the Group O HIV risk areas.
[Slide.]
Exchanging sex for drugs or money within the last 12 months.  Receiving tattoo, body piercing, transfusion or needlestick within 12 months of the donation.  Non‑sexual exposure to hepatitis to AIDS.  This mostly includes household type exposure.
Travel to malarial endemic areas.  History of disease or cancer.  History of CJD or associated risk factors.  Either the donor had a family member that was diagnosed as CJD or received growth hormone.
Received vaccine or medication, such as Proscar or Tegison.  Donor was incarcerated for more than 72 hours within the last 12 months.  History of hepatitis A or exposure to hepatitis A.
High risk behavior that is not specified.  Frequently, a donor will call up or come back the next time and say, yeah, I am in one of these groups, one of these high risk groups, but not specify which group they are in or what type of behavior they have engaged in.  Also, information not specifically related to hepatitis or AIDS, such as non‑I.V. drug use.
Donors will frequently call up and ask for their test results.  The blood centers will defer them because they are thinking that they are donating to be tested, so without giving them any additional information.
We have had a couple of reports related to donors being mentally retarded or giving some indication that their history may be unreliable.  Also, we had one that the donor had a sex change operation, so the blood center decided to defer them for that.
[Slide.]
This table just gives you an idea of the number of reports that we have received.  The column on the right is the total number of error and accident reports received, and this is separated by the type of establishment reporting, the blood establishments versus the source plasma establishments.
Sixty percent of the total error and accident reports that we receive are related to post‑donation information, and that has been a consistent number for the last five to seven years.
The blood establishments, 59 percent of their reports are related to post‑donation, and 80 percent of the source plasma centers reporting involve post‑donation information.
[Slide.]
So, we took these types of post‑donation information that we receive and we identified the actual risk factors that are associated with specifically HBV, HCV, and HIV.
This is the actual number of reports for each type of risk factor.  I want to make a statement here that one report could represent multiple donations, just like Dr. Tabor had mentioned.  We have donors who will come in, plasma donors who have donated for several years, and a frequent donor, every three to five days or something like that, for several years, all of a sudden now says, oh, yeah, I had sex with another man.  Now, all of those donations could be affected.
So, the number of reports versus blood and plasma are depicted here, with the needlestick, transfusion, tattoos and body piercing all grouped as one category, 978 reports from the blood industry, and 183 from the plasma industry.
For I.V. drug use, the blood industry reported 274 and plasma was 114.  Male to male sex, 216 reports from blood, and 47 from plasma.
Sex with an I.V. drug user, 169 from blood, 25 from plasma.  Sex partner testing positive for hepatitis B or HIV infection, 414 from the blood industry, and 52 from the plasma industry.  Actually, when I looked at that this morning, I had to go back and double‑check that number because that seemed awfully high, but that's what we have.
Exchange sex for drugs or money is 40 from blood, and 18 from plasma.
[Slide.]
History of incarceration, only 26 from blood.  There is a lot more we get from the plasma industry, 161.
AIDS related signs or symptoms, blood reported 21, and plasma is 6.
Female having sex with a male who had sex with another male, 42 for blood, and 4 for plasma.
Sexually transmitted disease, 22 from blood, 2 from plasma.
Travel to or immigration from the HIV Group O risk area is 190 from blood, and 6 from plasma.
So, when you look at just these specific risk factors, that brings down the post‑donation totals to about 34 percent of the post‑donation reports fall into this group for blood establishments, and 70 percent, which is still a high number, for the source plasma industry fall into these risk factors.
Are there any questions about any of these specific risk factors or post‑donation?  Yes.
DR. BOYLE:  Of your first category, which merged transfusions and needlesticks and body piercing, what proportion does body piercing represent?
MS. O'CALLAGHAN:  We haven't separated those out, but as a good guess, probably about 20 to 25 percent.  It is a fair number.  It is also difficult sometimes with the way that the reports are presented, the donor is deferred for body/ear piercing.  So, it is difficult to tell whether it was one or the other.
DR. FITZPATRICK:  Did you exclude high risk  behavior ‑ not specified, or is that included in some of those others?
MS. O'CALLAGHAN:  We didn't include the high risk behavior ‑ not specified only because we were trying to look at the things that we knew really did affect, were related to hepatitis B, C, or HIV.
It is very nonspecific information.  I mean you could use the same argument with the "do not use my blood," you know, and the donors calling back, you know, for their test results.  It is the same kind of unspecified risk, but it is not directly related to HBV, HCV, or HIV.
DR. HOLLINGER:  Dr. Mitchell.
DR. MITCHELL:  Can you talk about the risk of being in prison?  Specifically, I am concerned, I want to know why 72 hours.
MS. O'CALLAGHAN:  Well, that was one of our guidance documents, and I don't recall the actual date of that one.  We had recommended deferral of donors that had been incarcerated for 72 hours because of potential high risk behaviors that could occur during that stay or any other kind of exposures that they may not know about.
DR. HOLLINGER:  Mark, I think it is primarily because a lot of people may be placed into prison overnight or a few hours, and things like this, and they wanted to remove that large number from the situation, so they had to choose a point, and they chose the fact that if somebody was in there three days, then, they would probably be in there longer.
DR. RUTA:  I am Martin Ruta.  That was exactly the concern that we had, where for the overnight, the 72 hours to capture people who might have been incarcerated over the weekend, but most of the data on incarceration relates to prisons where people are held for a longer period of time.  But you are right, Dr. Hollinger, that is the reason.
DR. MITCHELL:  I guess I am concerned about shorter periods of time.  It seems like a rather long‑‑we know that people who are in prison, that a large percentage of the rapes, for example, occur within the first 72 hours.
DR. TABOR:  Let me clarify something before we discuss that further.  First of all, I want to thank Sharon O'Callaghan for the really marvelous presentation of data that helps explain how we came up with this list in response to the committee's question at the last meeting.
What we tried to do, a group of us sat down and also I worked on it myself, as well, but a group of us sat down and tried to take the list that Compliance had of deferrable information and decide which of those factors would impact, as Sharon O'Callaghan said, on risk for HBV, HCV, and HIV.  So, obviously, the receipt of a vaccine recently has no impact on that.
We had to make some choices.  What we are dealing with here is a very low risk situation anyway.  You are dealing with people who are test‑negative, most of whom are not in the window period for any disease.
So, what you are trying to do is find the window period.  Now, the clarification I wanted to make with regard to your question about incarceration is we have two lists here.  The lists that Sharon O'Callaghan showed is a list based on guidance documents, such as the one Dr. Ruta was describing.
We are not in a position to change that list or the guidance documents, and they are really not a subject for discussion.  What is a subject for discussion is footnote i on the algorithm, and which should or should not be included there.
So, with regard to your question about incarceration, we said on footnote i, incarceration for greater than 72 hours.  You raised the question whether 72 hours is appropriate.  For footnote i, we can discuss should it be a shorter period of time.
Now, one of the problems we face is can we have criteria on footnote i for the use of this algorithm that is inconsistent with currently approved guidance documents.  You may hear arguments on both sides of that, and I think there are probably arguments on both sides.
So, your question is a very good one, but it should only apply to footnote i.
DR. HOLLINGER:  I think what I would like to do, if we could, I would like to maybe finish up the presentations, and then we will come back with me‑‑unless it is a question that really needs to be‑‑go ahead.
DR. OHENE‑FREMPONG:  It was just a quick question about what you define as "needlestick."
MS. O'CALLAGHAN:  Most of those involve like hospital workers that have drawn blood from a patient, and then stuck themselves with a needle without knowing whether or not the patient was actually hepatitis or HIV positive.
DR. OHENE‑FREMPONG:  So, you mean accidental.
MS. O'CALLAGHAN:  Accidental needlesticks, yes.
DR. OHENE‑FREMPONG:  I think it should be clarified.
MS. O'CALLAGHAN:  Sorry, didn't have quite enough room on the slide.
DR. HOLLINGER:  Thank you very much.
If we could then go to the final presentation in this section.  Dr. Lynch is going to talk about GMP Investigations.
cGMP Investigations
Thomas Lynch, Ph.D.
DR. LYNCH:  I should start out by saying that an investigation itself into adverse information regarding the manufacture of a product is part of GMPs itself.  Information can be received from a variety of sources.
[Slide.]
We are here concentrating today on information regarding the status of a donor with respect to a risk factor, but what I am about to say also applies to the case where a positive donation may be identified or if the information relates to the use of a product and an adverse event or suspected transmission associated with that use.
Finally, you should bear in mind that information can also come from within the manufacturing operation itself, such as where an audit reveals a heretofore undiscovered deviation in intended procedures or let's say a stability sample goes south at some point.
[Slide.]
In all cases, the information should flow into the part of the organization called Quality Assurance, and this component has several responsibilities in this process.  It certainly does collect the information, and it initiates and coordinates the investigation intended to assess that information.
In the first instance, it has to determine what the appropriate scope of the investigation is, that is, what products might be affected by whatever information has been received, and then once the investigation is completed, some sort of risk assessment has to be performed or health hazard evaluation, if you will, that will determine what, if any, risk there is to the recipients of the products that have been affected, and then based on that risk, appropriate action is identified and taken, and, if possible, corrective actions to prevent a recurrence are implemented.
Throughout the course of this, where appropriate, the appropriate regulatory authority, such as FDA, are informed of the situation.
[Slide.]
In the course of fulfilling these responsibilities, QA has to ask itself several threshold questions.  The first, whether or not the information does impact the transfusion‑associated risk is a given here.  Risk factors associated with the donor or donation, and relating to transfusion transmittable viruses are certainly relevant to plasma derivatives.
The second question, of course, is whether the manufacturing process addresses that risk, and that depends on the nature of the virus in question and the types of viral clearance procedures that are incorporated into the manufacturing process.
Here, we are talking about hepatitis B, C, and HIV, all lipid envelope viruses, and as we reviewed in 1997, are viruses for which clearance procedures have been incorporated into the vast majority of all plasma derivative manufacturing processes.
Then, finally, given the nature of the virus and the type of clearance procedures that have been adopted, does an adequate safety margin remain with respect to that product.
Again, we reviewed the risk factors associated with, for example, a window donation, and the effectiveness of the clearance procedures that are incorporated into manufacturing, which suggests that an adequate safety margin in most cases should exist.
[Slide.]
The adequacy of viral clearance is, if you recall, determined by taking whatever the production process step is and scaling it down into a laboratory model, and assessing its ability to remove or inactivate high titers of virus, which gives you a measure of its viral clearance capacity.
[Slide.]
So, this is the theoretical capability of a clearance process, however, for that process to be reliable, it has to be performed on a daily basis according to good manufacturing practices, which are a set of standards that encompass all aspects of the manufacture of plasma derivatives and particular in biologics and drugs in general, and they are designed to assure that the quality of these products remains consistent and to prevent manufacturing errors and contamination of these products.
[Slide.]
Rather than try to enumerate all aspects of good manufacturing practices, it is useful I think instead to consider what events would constitute breaches of good manufacturing practices that would impact the viral safety of any of these products.
I have listed a few of those here, for example, deviations from your established written procedures would constitute one such deviation, the nonconformance of a product with some predetermined specification that relates to viral clearance or the failure to properly maintain key equipment or to calibrate critical instruments that are used to control the process, or finally, anomalous laboratory results relevant to the clearance procedure that have not been adequately resolved.
All of these things could create uncertainty about the effectiveness of one or more viral clearance procedures in a manufacturing process.
[Slide.]
And because the risk that a recipient of a manufactured product confronts with respect to a donation that has a risk factor associated with it, that was used to manufacture that product, depends entirely, in my view, on the safety measures that are built into the manufacturing process, risk evaluation becomes largely a question of how closely good manufacturing practices have been adhered to during the production of that product.
[Slide.]
The effectiveness of a good manufacturing practice investigation in verifying that the products are safe from a viral perspective depends on four premises.
First of all, the manufacturing process is assumed to include effective clearance steps, and provided that those steps are properly performed, an adequate safety margin with respect to the virus is effected.
[Slide.]
While the overall quality of the product is determined by a global adherence to good manufacturing practices, we can identify particular steps in that process that are particularly germane to viral safety.  Those are the viral clearance steps themselves.
Therefore, the scope of a GMP investigation should focus on those particular steps.  However, the complexity of a GMP investigation is influenced by more than just this one factor.
[Slide.]
For example, a single donor with a particular donation history reports post‑donation information that feeds back into the collection center, for example, and thence to the manufacturer.
That donor may have contributed a number of donations over a span of relevant time, which have been incorporated into more than one manufacturing pool, each of which may have given rise to more than one product.
As you all know, a single plasma pool is the source material for multiple plasma derivatives.  Furthermore, in the course of manufacturing those products, intermediates in the process may become pooled together to form a single lot of a product, which therefore can be traced back through more than one plasma tree, if you will, or some products, such as a coagulation factor that is stabilized with albumin, can in fact be composed of more than one plasma derivative.
Therefore, the history of any of these products is complex when traced back through the donations from which they were made, and the history of any given donation with respect to the products that it gave rise to is also complex.
[Slide.]
Going back to the scope of the investigation, each lot of each of those products is associated with the voluminous record that documents its production from the source material down to packaging records and final testing.
This is a simple hypothetical example which might reflect the manufacture of an albumin since we have a terminal pasteurization step indicated here.  In this case, I would suggest that that step would certainly be one that would be included in a GMP investigation of post‑donation information.
However, the manufacturer may have also validated the effectiveness of one or more of the purification steps in reducing the viral burden, and if that is the case, then, those steps would also be included in a GMP investigation.
Finally, although this is rare, it does happen, some manufacturers perform final container testing on a product for one or more viruses, and if this is performed, the results of that testing and the testing itself, the testing methodology itself would also be included within a GMP investigation.
This entails a record review, and there are several possible outcomes to that review, and these are listed here.
[Slide.]
The most desired outcome is to find that your records for a particular lot are complete and accurate, and the manufacturing process proceeded according to plan with no deviations or discrepancies.  In that case, the concern is minimal, because the full assurance of viral safety that has been designed into the production process appears to have been achieved.
The worst case is to find that the records are incomplete or inaccurate or questionable in some way, and in that event, there is no possibility of assuring oneself that those safety measures were implemented as intended.  Therefore, the risk factor can't be evaluated and appropriate action, such as withdrawing a product, should be contemplated.
I should add parenthetically if such a deviation or discrepancy in the recordkeeping itself were found, even absent any other risk factors, because the assurance of viral safety has been compromised, similar precautionary measures should also take place.
Finally, somewhere in the middle, which may represent the most common outcome, is that the record review will reveal some deviation or discrepancy in the manufacturing process that may be relevant to viral safety.
These actually can take on a whole spectrum of characteristics.  First of all, the deviation and discrepancy may have been previously identified during routine review of the manufacturing records prior to the release of the product.  Those deviations and discrepancies may have been fully investigated and resolved as having no impact on the safety of the product.
In that case, we also have reasonable assurance that the safety measures built into the production process have taken place as intended.  However, the GMP investigation itself may reveal deviations and discrepancies that were not recognized at the time of the initial record review.
In that case, an investigation into those deviations must be conducted, and that is a time‑consuming process with an uncertain outcome.
[Slide.]
The severity or relevance of the deviations are also an issue that is germane to the subject.  First of all, deviations can occur that have absolutely no bearing on the viral clearance process itself.  I think these are not on the table for today's discussion.
There may be, however, a certain category of deviations that are related to the viral clearance procedures, but even there, they can be of greater or lesser import.  For example, a deviation may occur that is outside a manufacturer's written instructions, but well within the range that has been validated as being effective, nonetheless.
I will give you an example of this, a simple example relating to a temperature‑dependent inactivation process.
[Slide.]
During the course of the scaled‑down viral validation study, the manufacturer may have looked at a fairly broad range of temperature, in this case, 18 to 28 degrees.  However, because the manufacturing process is capable of controlling that process to a narrower range, and because the manufacturer wishes to afford himself a safety margin, the manufacturing instructions may actually call for controlling that process to within a tighter tolerance, 21 to 25, say.
If an excursion beyond this 21 to 25 degree range occurs, that is the deviation which gets recorded and documented in the manufacturing records, but if the excursion is still within the validated range, we can say that the viral clearance was still effective, nonetheless.
If, however, the deviation exceeds the validated range, we lose that assurance even though the true failure limits may be outside that range.  We don't have any knowledge of that, so we can only rely on what has been validated.
[Slide.]
So, in closing, there are several conditions under which a GMP investigation can be conducted and closed with no further action against products that have been distributed for use, the first of which is when everything occurred perfectly.  There were no manufacturing deviations whatsoever.
Another instance is when deviations may have occurred, but they were either irrelevant to the process or were within validated ranges for the viral clearance procedures themselves.
The third instance is where deviations may have occurred, but they were fully investigated, evaluated, and an informed decision to release the product was made.  Very often this involves referral to FDA and possibly a licensing action to cover the release of a product.  In these cases, a detailed risk assessment is performed.
Finally, there may be deviations for which a manufacturer has validated and approved procedures for repeating a step or remanufacturing the process in order to correct the deviation and maintain the assurance of viral safety.
I think I will stop there and take any questions if anyone has them.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  At the current time, you are doing this review of records to establish GMP for those things that were related to inactivation.
Is that something that involves the review of a database, or is it something that requires the review of physical records?
DR. LYNCH:  In most cases, these manufacturing records exist as discrete records, so you would go to an archive and pull out 6 feet worth of documents to review one lot of a product.  Six feet may be an exaggeration, but they are rather voluminous.
So, it would be under most recordkeeping practices, would be a record‑by‑record review.
DR. BOYLE:  If manufacturers understood that this was going to be a standard process and that they had 72 hours to comply, and that the records review were limited, you know, it is focused on the inactivation procedures, the things that you have described as the risk factors for a problem, if that type of material was routinely recorded in an automated database as opposed to having to go and pull out the ledger books, would that type of thing be viewed as a possible way of moving through this type of review, or do you feel that in every case, as opposed to an audit, that it really is important to look at the original entries in a hardcopy or whatever?
DR. LYNCH:  You raise a very interesting point.  My presentation obviously was focused in the context of a post‑hoc investigation.  You are suggesting that one can streamline that by organizing the data in a different way.
I see no reason why that would not be a perfectly acceptable way provided that all of the relevant data were captured.  Enhanced review up‑front may be another alternative to doing it in the crisis mode, if you will, where you are trying to meet a deadline and may have again, not just one record to review, but multiple products off a single pool and perhaps multiple pools captured by the investigation.
DR. TABOR:  I think Dr. Lynch also expanded on that at the last BPAC meeting in some more informal comments.  The very worst situation is where the records are very bad, where there are many, many donations from the same donor, and where intermixing of different pools has occurred prior to final manufacture.
As I said earlier, I think the existence of an algorithm of this type and the permission of 72 hours grace would encourage manufacturers to keep even better records.  With intermediate qualities of records, I think 72 hours is actually probably quite generous, and I realize I am not speaking from experience, but it would seem to me that if you had a choice of quarantining a large amount of product and putting your entire staff on a rush analysis of your records, that you could put everybody on a 24‑hour basis and get it done relatively quickly, even with hardcopy records if you had decent records.
DR. HOLLINGER:  I take it the people who use the investigator to go to look at these issues at the manufacturer, there are people who are familiar with all the various inactivation procedures and things like this in general, and I presume that all the material is usually supplied to them very quickly in terms of records and so on, in terms of pressures, and so on, to get the job done.
DR. LYNCH:  Yes to both parts of your question, we take some pride in the quality of our investigators now, especially under Team Biologics, and the training of those individuals includes a full orientation, rather exhaustive orientation into viral removal and inactivation techniques as they currently exist, and what standards one applies when evaluating those on an inspection.
So, that actually is something that we have addressed quite extensively.  Also, by the way, they frequently consult with the scientific staff at the center when they are out in the field doing an inspection, and those resources are readily available to them.
Finally, with respect to the cooperation of a manufacturer being inspected with regard to providing records, making information available, in my experience, that has always been good.
DR. HOLLINGER:  Thank you, Dr. Lynch.
What we are going to do, we will take a break until 11:15.  I have 10:53 now.  So, we will take a break until 11:15, we will come back, and open it with the open public hearing.  If there are any who wish to speak, let us know this at this time, and then we will go into the open committee discussion.
Thank you.
[Recess.]
Open Public Hearing
DR. HOLLINGER:  We have one speaker, Dr. Bablak, from the International Plasma Products Industry Association.
MR. BABLAK:  Good morning.  My name is Jason Bablak and I am Director of Regulatory Affairs for the International Plasma Products Industry Association.  Our members produce approximately 80 percent of the plasma derivatives for the U.S. market and approximately 60 percent worldwide.  I would like to briefly address the subject of inadvertent contamination and respond to the FDA's proposed algorithm.
The subject of inadvertent contamination has been discussed by this committee several times, including during the last two meetings.  Last March, the FDA presented a strategy for addressing instances when a fractionation pool contains a unit from a donor with a subsequently discovered risk factor that would have disqualified him as a donor had it been known at the time of donation.
These risk factors are determined from lifestyle or medical information about the donor which may indicate that there is an increased risk of viral exposure.  However, it should be noted that all these units are negative by all available serological tests and NAT testing that was done on that unit.  We will refer to these units from these donors as unsuitable units.
We raised several concerns with the proposal that was presented last March including its feasibility and our estimate of its significant impact on supply.  As we described then, all lots of plasma derivatives would be impacted during their shelf life by some type of PDI report, and thus require actions including quarantine and/or recall under this proposal.
This committee voted to delay further discussion of this topic and asked FDA and industry to work together to provide more specific information on several issues, including the length of time that a post‑donation report would require lookback analysis, whether "significant risk factors" could be defined, the role of NAT testing, and whether quarantining of released plasma derivatives was possible.
Today, we will provide a proposal that we believe addresses the potential safety issues that may be raised by PDI reports with respect to HIV, HCV, and HBV.  However, before we address these issues, we would like to focus on several points raised during the last meeting that will shed some light on our proposal.
First is the question raised by Dr. Epstein:  Are products any different because you happen to know that you pooled an unsuitable unit?  We believe the answer to this question is no, because statistically, we know that unsuitable units, including window period units or PDI units, enter fractionation pools, yet these products continue to be safe.
The second question follows from this:  In the case of learning additional information regarding a particular unit or donor, is it appropriate to take additional steps?
We would like to pose an answer to this question by reiterating another point raised by Dr. Epstein.  The most appropriate approach may be to put in place enhancements to existing systems that are feasible and probably ought to be done irrespective of PDI reports.
This point reflects the fact that plasma derivatives made from pools where we do not yet know of the post‑donation information are subject to the very same concerns as those made from units where we do know about post‑donation information.
Today, we propose an approach to be instituted for all lots of plasma derivatives that we believe will provide an additional layer of safety for these therapies.  Because the timing of post‑donation information receipt is unpredictable and as can be seen from the earlier presentation of the FDA, the type of information cannot easily be categorized as to risk, our proposal is that we treat all lots the same.
These measures that we are proposing will add to the current procedures already undertaken for every lot and will be performed up‑front on an ongoing basis regardless of post‑donation information received for any particular lot.
First, all unsuitable units at the collection center will not be shipped for therapeutic use and all unpooled units held in inventory by the fractionator will not be used for further manufacture into therapeutics.
Second, a maximum potential viral load for the viruses of concern will be established for each pool through the introduction of NAT testing of manufacturing pools and/or minipools through the FDA's IND process.
Third, an assessment of the theoretical risk will be performed for each plasma derivative to ensure that the potential viral burden below the limit of detection by NAT testing could be adequately removed or inactivated by the manufacturing process.
Fourth, an enhanced GMP review of critical viral elimination steps will be performed for each lot as part of the release criteria.
We believe this strategy will allow industry to address the concerns raised by the FDA regarding inadvertent contamination on a proactive, routine manner to help to ensure safety while not affecting product supply.
We would like to briefly expand on each of these points.  First, any unsuitable unit in custody will not be used for further manufacture.  This includes the initial unit if it is available and all other units held in inventory.  As you know, our industry has instituted a minimum 60‑day hold for all plasma units, and therefore, more units from this donor will be able to be removed from the pooling process.
Our members have also committed to implement NAT testing for HCV and HIV by the end of 1999, and HBV by the end of the year 2000.  These tests currently require an IND, and our members are following these requirements to introduce this technology and eventually obtain FDA licensure.
As these new tests are phased in, one critical element of this proposal will be established.  A maximum potential viral load for every pool will be established through minipool or manufacturing pool testing.
A risk assessment based on this scenario will be performed to demonstrate an adequate margin of safety for each lot manufactured from non‑reactive pools, minipools, or units.  Because the maximum viral bioburden will be established prior to release, PDI reports will not affect the original risk assessment, and therefore will not require additional action under this plan.
The second essential element of this proposal is the enhanced GMP review of critical viral elimination steps.  Rather than waiting for a PDI report to initiate action, our proposal is to proactively enhance the review already undertaken prior to lot release.
Our intention is to develop a list of critical viral inactivation and removal steps and identify their key parameters.  We will provide specialized, enhanced training to those individuals reviewing each of these steps, and provide them with the tools necessary to ensure proper performance.
We believe this approach addresses the issues raised by instances of inadvertent contamination:  what is the potential viral bioburden for the lot in question, and were the viral clearance processes performed as require to assure an adequate margin of safety?
When instituted for all lots, these enhancements reduce the need for a case‑by‑case algorithm by providing certain information before the lot is ever released.  Specifically, the maximum potential viral load of the pool is established through NAT testing results, and the enhanced review of viral inactivation procedures assures adequate GMP compliance for that particular lot.  By performing a one‑time risk assessment for that particular product, these measures will ensure adequate margins of safety for lots meeting these release criteria.
The benefit of proactively instituting these enhancements is two‑fold:  first, all plasma derivatives will be subject to the same enhancements regardless of whether or not post‑donation information was received; secondly, these actions will be taken up‑front, and therefore will obviate the need for quarantines, withdrawals, or recalls, thus minimizing any supply impact.  Most importantly, any potential safety issue will be addressed prior to release of that lot.
As stated earlier, our proposal is to institute these procedures for all plasma derivatives as a proactive method to continue to enhance the margin of safety for these therapies.  As with any new technology, it will take a little time to fully develop and implement an ongoing system for its use, and NAT testing is no different.
Our commitment is to institute NAT testing for HCV and HIV before the end of this year, and hepatitis B, by the end of the year 2000.  We believe that we will be able to implement the enhanced GMP review somewhat faster, and we are estimating that we can get this done during the fourth quarter of this year.
We would ask that the FDA provide a liaison to our working group on this issue, so that we can expedite the development of the specifics of this proposal.
Thank you for the time to address this important issue.  We believe this proposal is both feasible and valuable in terms of enhancing the margin of safety for plasma derivatives, while not affecting supply.
We would ask the committee to endorse this proposal, and we would be happy to report back in December on the progress we have made in implementing its elements.  I would be happy to answer any questions you might have at this time.
DR. HOLLINGER:  Are there questions of the committee for Mr. Bablak?  Yes, Dr. McCurdy.
DR. McCURDY:  What is the coverage of this proposal in the United States, in other words, this is presumably voluntary on the part of the IPPIA?  Are there non‑members who also distribute plasma derivatives in the United States, and what is the likelihood that they will be covered by it?
MR. BABLAK:  That is a point that we have not addressed at this point.  This is just for IPPIA members, but certainly if the committee were to endorse this, I am sure we would be able to have discussions with the non‑members to bring them up to speed on this issue.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  Does your proposal for the enhanced GMP review, which I understand is still ongoing and obviously is not set in stone, but are you saying that in point of fact, that you are going to be collecting and recording or establishing the information in such a way that it is complete for all cases, so that if there is a requirement to look at a case, that that data is there?
MR. BABLAK:  That could end up being the result of this, but really our proposal is to enhance the review that is already done, because as you are aware, through GMP, everybody reviews all of their procedures before a lot is ever released.
What we would do here is make a specific enhancement to part of the release criteria where we would develop a specialized section that would specifically at sections relating to viral inactivation, we would have additional training on these elements, perhaps develop a list for‑‑each manufacturer would have to do this obviously on their own‑‑but develop lists of their critical procedures and the critical parameters, have training that would expand the knowledge of the people performing those, so that they understood if it fell outside of a parameter, what the implications of that might be.
So, really we are talking about a significant enhancement to what is done, not that what is done isn't already adequate.  It is just that this is really a way to address up‑front the issues that were raised this morning, so that if there is a discovery of something, it is basically found before the lot is ever released.
That is really the critical element here, is that we can do this before a lot is released, and then if there is a problem, it is discovered before the product is out in the field and it can be resolved then rather than trying to do it within a 72‑hour time frame.
If I can just expand on this, one of the other things that was raised, if you looked at even the critical PDI areas that were listed today, we believe that even that is enough, that would really impact every single lot of product that is made.
In the end, what you would end up doing is going through and continually looking at these reports and then going forward and trying to trace those lots down and do your review.  Even if it's within 72 hours, it will become a continual process, and we discovered this really as we started to look at this after the last meeting.
It became clear that if you tried to determine what is really "higher" risk than others with regards to post‑donation information, even if you tried to limit that list, which is very difficult, it is still going to have an impact on all lots that are released.
So, we decided really what was the best thing to do was to try to put this up‑front as release criteria, because that allows us to have a regularized process where we can assure that all products meet this criteria.
DR. HOLLINGER:  The manufacturers of these plasma products get this post‑donor information almost on a weekly basis.  Does someone call in every week that provides some information on this?
MR. BABLAK:  What happens is, for instance, even if you look at the list that the FDA set, you may actually get three, four, or five a month, but the way that it follows is you get a report on a particular donor, but that donor has donated many times.
So, the donations from that donor are really what is important when you are looking at how this will implicate products.  So, if you have five reports over a month's time, that will reflect to basically affecting all of your product lots.
DR. HOLLINGER:  So, an inspection or evaluation or investigation might go on continuously.
MR. BABLAK:  It would basically be a continuous process.  So, what we have suggested is why don't we don that up‑front, if it is going to be a continuous process, let's do it before the product is released, and in that way we have assurances before the product is out the door.
DR. HOLLINGER:  And you are going to do that before it is released in what way?
MR. BABLAK:  All of these procedures that we are proposing here would be done before release, so as part of the release criteria, an enhanced GMP review would be part of that release criteria, so that if it didn't pass the GMP review, it would never be released.
DR. HOLLINGER:  And that would be a review by the manufacturers.
MR. BABLAK:  At this point, it would be a review by the manufacturer.  What we have asked is if we can have liaison from the FDA to sit with our working groups, so that we can define what the critical elements are and how that would be accomplished.
DR. HOLLINGER:  Dr. Epstein.
DR. EPSTEIN:  Thank you, Dr. Hollinger.
I think that there would be general agreement that if all deviations in manufacturing were adequately addressed prior to product release, that we would be in a much better situation regarding post‑donation information, and could conceivably waive further investigations and quarantines.
The problem is that we are not there right now, and I think that it needs to be understood that the algorithms that we have been talking about represent the agency's interim strategy.  In other words, until the industry gets to the point with regard to GMP controls, where what you are describing is in place, we do have a problem when incidents come to light.
I would say that the same applies to the issue of NAT.  Until we have the NAT tests validated and approved and fully in place, we still have a problem when the incidents arise.  So, for example, not all manufacturers are routinely testing the pool by NAT, and the NAT sensitivities haven't all been validated in relation to the viral inactivation and clearance capability of processing.
So, I would accept everything that you have said and endorse it as both correct and highly desirable, but I think that the committee needs to understand that what we are talking about is the current situation, which is we hope an interim situation that will go away someday.
MR. BABLAK:  I guess our response to that is we hope to make it go away before the end of this year.
DR. EPSTEIN:  Well, that would be nice, but it's the situation we have on our hands now and the one that we have been dealing with for a period of years.  We have been doing this.  It is just that we have been doing it without having formalized an algorithmic approach, and it has been done ad hoc case by case.
I would say that that problem won't go away overnight and that is why this issue has been in front of us.
DR. HOLLINGER:  On this same basis, what do you see as the problem with the algorithm from the industry standpoint, of the algorithm that was given by Dr. Tabor earlier?  What is the problem that you see from it, from an industry standpoint?
MR. BABLAK:  The problem is it creates a situation where you have to wait for a report to come in.  That report comes in.  You have to trace where those units from that particular donor have gone, and then you have to do your GMP review, because I think that is what we are talking about now since NAT testing has not been implemented for all the viruses, so really we are looking at that section.
Our commitment is to do it for all the viruses, but like I said, that won't be really until the end of next year.  So, what you are really doing is you are creating the work of looking at when the unit comes in, tracing it, and then finding those particular lots.  So, there is an additional amount of work that is done just to do that, when, in reality, we know it is going to affect all of the products at some point.
It may not be that it affects them all at the same time.  You may have one that comes in that affects a product lot in one month, and in that case, we can actually take those units out from our inventory hold.
But if you have something that comes in six months later, and some of those units have been pooled and may be in the manufacturing process.  If you get a report that comes in a year later, some of the product lot will actually be released, so you are waiting to get that information before you do your report.
What we are proposing is let's do it up‑front before it's released, and do it for everything as part of its release criteria.  To respond to Dr. Epstein, I think really, especially when you are talking about the post‑donation information reports, what is being done now is you get the information, you may trace where it goes, but there really isn't any additional review that is done, and that is how this has been handled in the past.
What we are saying is we are willing to go a step further and put in this enhanced GMP review.  If you look at the algorithm, I think the problem with that is if you are going to have to go back and do a review for every single lot within 72 hours, we are going to spend a lot of time doing this tracing and doing this review, where I think the better us of time is to fully implement this procedure that we have proposed, and then you will handle it for everything going forward.
I guess it's a matter if you are looking at the timing, over the next six months, can we spend the time and develop this proposal and institute it for all product lots, or do you want to continue to address it on a case‑by‑case basis ad hoc as they come in, because that is really I think what you are going to talk about.
If you are going to spend time reviewing these and tracing them, that is going to take away the time that you can spend instituting this on a regular procedure going forward for all product lots.
MR. JACKMAN:  My name is Dennis Jackman with IPPIA.  I just want to answer a question and make a clarification here.  Somebody alluded to this as being voluntary, I understand that this would be voluntary, and it is a voluntary proposal, but our association members have stated they are committed to implementing this, and would have no opposition to FDA making this mandatory because we would expect to have it in place in any case, so that is a possibility, and we just want to state that.
I mean that is a statement of the obvious in some ways, but we just want to make it clearer that we would have no opposition to that.
DR. HOLLINGER:  Thank you.
DR. EPSTEIN:  I would look at it from the FDA point of view this way.  We think that full resolution of deviations in manufacturing should be resolved before product release now, and that that is an existing GMP provision.  In other words, we don't really see it as something novel.
On the other hand, we recognize that the industry is not fully there in terms of compliance with GMP, and so we welcome an initiative to upgrade compliance, but we don't really think that the focus of debate is whether this is something new or something that requires a new policy or new requirement.
Resolution of deviations has always been part of GMP.  The problem that we have been faced with is that as we have investigated incidents, we have, unfortunately, found that there weren't full investigations.  For instance, we found deviations with respect to viral inactivation temperature that were outside the limits of the validation of the process.  That is a serious problem.
Such lots ought never have been distributed under GMP, but they were.  So, I think the way I see it is that it is an issue of compliance, it's not really a question of a new standard.  We want the industry to embrace the correction, and I think the notion of being able to come into full compliance on resolution of deviations before release of lots does go a long way to mitigating the problem.
I would agree with that point, but again I think it is a little bit miscast to describe it as something new requiring new policy or new requirement.  This is existing GMP thinking.
MR. BABLAK:  The only response I would have to that is what we are using to go back and look at those release criteria GMPs is a PDI report, and I guess what we are saying is that is probably not a very valuable way of looking at it because by the time you end up tracing that down, really, what you are talking about is all products and all lots.
So, I guess what we are saying is we are in agreement, it's just a matter of in that interim period before we develop this enhanced GMP section, is waiting to get a PDI report, which are inevitable and will happen, but also, at the same time, a very random occurrence which really tells us nothing about a lot that would separate it from an additional lot.  It that a good criteria to then go through and do this extra work, or is it better to develop going forward how we are going to develop the GMP element of this process.
I think that is really what we are coming down to is in the next five or six months, how is the time better spent.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  I don't understand why the two efforts are exclusive.  It seems to me that it makes good common business sense to do what you are proposing, so that if you get a PDI, then, you can immediately respond the FDA and say we have done the enhanced GMP review, and here is our results.
Now, you fit very well into the window, and you can allay them, assure their own compliance, and over time develop a track record to assure the FDA and us that you are now in compliance and eventually, by establishing that track record, perhaps you can do what you want to do, which is not have to react to the PDIs, but just show compliance on a continual basis.
So, I mean I don't see why the two are exclusive.
MR. BABLAK:  I guess the answer to that question is they are not exclusive, it's just the amount of time to trace and go through that extra process of relying on the PDI report takes away time that could be spent going forward.
In reality, the PDI report doesn't give us any additional information one way or the other about that particular lot, because we know that eventually, all lots will be associated with the PDI report, so by using that arbitrary criterion to go through and do this extra work really doesn't accomplish anything.
I think that is what we are trying to show here is going forward it would be better to do this for all lots.  If you are going to differentiate based on a PDI report, you are really not accomplishing anything except picking something out of the air perhaps and saying that this is what we are going to use to judge whether or not this lot needs an additional review.
DR. HOLLINGER:  Are you saying you wouldn't remove the samples or the units that came from this, that were generated from this PDI report basically?
MR. BABLAK:  But we do that already.  That is already done, so if a PDI report comes in, any unit that is held is already removed.  That is a point we wanted to make sure that everybody understood, that that is something that is being done and will continue to be done.
DR. HOLLINGER:  Okay.  Dr. Mitchell.
DR. MITCHELL:  But in your protocol, you don't say that the units will be destroyed, you say that the units will not be used for further manufacture into therapeutics.
What is your plan to do with the units?
MR. BABLAK:  This always raises a question.  The reason that that is said is the vast majority are actually destroyed.  Some have a value for diagnostics, for instance, units that are in the unit period, that you have a donor who has seroconverted, those units become valuable for diagnostic manufacturers, for test kits, and those types of things.  So, those units aren't technically destroyed.  They are not just not used for injectable therapeutic products.  But to be technically accurate, we have to say that they are not used for that, they are not destroyed, because not every single unit is destroyed.
DR. HOLLINGER:  Any other question from the committee?  Yes, Dr. Buchholz.
DR. BUCHHOLZ:  Just an issue to understand FDA's role versus manufacturers' roles.  When an issue like this comes up at present, is it the current policy that FDA visits the manufacturer and, in fact, documents this record review, or to what extend is the manufacturer allowed to do that and provide the documentation to FDA?
If this, in fact, is affecting every lot, it would seem like there could be a tremendous amount of effort here developed toward doing something, that I think this would seem to obviate much of that effort as proposed by IPPIA.
MR. MASIELLO:  Steve Masiello.  There really isn't the ability to go out and verify each and every one of these cases on site at the time that it occurs.  What we ordinarily do is there is certain communication back and forth on each and every issue.  Then, at the time of the inspections, these types of things are reviewed, but not at that moment.
DR. BUCHHOLZ:  So, in essence, right now FDA would be relying on the integrity of the manufacturer to, in fact, do that review and provide that information.  If that is the case, I begin to see very little difference between what is being proposed and what is currently going on.
There, indeed, may in fact be a small number of problems, but I am not clear as to how this proposal would differ from the current system which basically relies on the integrity of the manufacturer.
MR. MASIELLO:  I think the fact of the matter is we do spend quite a bit of time in the fractionators these days, so there is not a point‑by‑point verification in all cases, but there is quite a lot of inspectional coverage that is going on.
DR. HOLLINGER:  So, lots could be released from quarantine, and so on, just based upon the manufacturer's assessment before an investigation is done, is that correct?
MR. MASIELLO:  There probably is a verification via paper.  I mean there is a lot of communication that goes on, so that there might be a request for specific documents or copies of specific records to be submitted, so we may not be seeing them on site, but we are probably seeing them via review.
DR. HOLLINGER:  Thank you.
MR. BABLAK:  If I could just clarify from our perspective, that is not what is done for the PDI reports presently.  I think the change would be under the algorithm that there would be some additional element that would have to be satisfied before those lots could either be released from quarantine or released to be sold for use, whereas, the current practice is if a PDI report comes in, the manufacturer looks at that, traces that, understands what happened to that particular unit, and that is where it ends.
So, what we are proposing is an enhanced system, not necessarily based on PDI reports, but based on the output criteria basically, what will be released.
DR. HOLLINGER:  Dr. McCurdy.
DR. McCURDY:  It seems to me, and I think this has been stated by at least one other member of the committee, that one of the major results of this, which I think is very salutary, is that the review will go like greased lightning, and if it is already done, then, all you need to do is verify that it is already done, and that ought to be it, and take three hours or whatever.  I mean it should go very rapidly.
DR. HOLLINGER:  Ms. Knowles.
MS. KNOWLES:  I think the concern that I hear from the FDA staff is that if this proposal is adopted by this industry representative and their members, that nothing else will happen in that interim time, and I do think it is important that there still be some controls in place now until they are fully implemented.
DR. HOLLINGER:  Even afterwards, I personally would want to see that there is an evaluation done somewhere down the line regardless.
DR. BOYLE:  Jason, just for clarity's sake, I want to understand what happens now under the algorithm we have got here.  You have got apparently about 8,000 of these post‑donation reports per annum.
MR. BABLAK:  Let's just stick to the source plasma side, which is significantly smaller, but will still make the same point.
DR. BOYLE:  Fine.  Units not yet pooled, and you identify it as being a post‑donation problem, what happens right now?
MR. BABLAK:  If it is not pooled?
DR. BOYLE:  Yes.
MR. BABLAK:  The unit and all the units held in inventory from that donor are removed and not used for further manufacturing of therapeutic products.
DR. BOYLE:  So, no change then in the first box.
MR. BABLAK:  Exactly.
DR. BOYLE:  The second box.
MR. BABLAK:  It says "destroyed" here.
DR. BOYLE:  All right, destroyed versus not used for product.
The second thing is units pooled but not yet processed.  What happens now?
MR. BABLAK:  If the unit has been pooled, it has basically lost its individuality, and that is the end of the investigation.
DR. BOYLE:  So, under current process, it continues through the manufacturing process, and so here the FDA proposal does something new.
MR. BABLAK:  Exactly, and that is the same the rest of the way across.
DR. BOYLE:  Okay.
MR. BABLAK:  So, everything below that is new.  So, I guess the thing is we have been doing that all along.  What we are saying is we would like to implement something more, and the question is, over that time of implementation, say, the next five or six months, do we follow what the FDA has proposed, which will require a significant amount of time tracing lots and units based on a PDI report, which is a random event, or do we continue to go forward with a proposal that we can implement across the board for all lots as they are released.
DR. HOLLINGER:  So, you want to have some stability.
Dr. Koerper.
DR. KOERPER:  Your proposal would mean that you would not need to keep track of what pools individual donations went into because if the GMP were satisfactory, then, it wouldn't matter about getting these post‑donation information, because you have already done more than enough to kill any viruses that got in there, and this would then obviate the need to keep track of where the individual donations were going.
MR. BABLAK:  Exactly.
DR. HOLLINGER:  I see also if you have a consistency, reproducibility, and so on, and then you really don't have to find out where exactly it goes.
MR. JACKMAN:  We do track, it will be tracked going forward.  We just got clarification that they will be tracked and they would be tracked, so I want to give the correct answer.  I think there was just some confusion there.  Thank you.
DR. HOLLINGER:  Thank you.
Dr. Tabor.
DR. TABOR:  I would like to underline one of the points Dr. Epstein made, and I don't want to detract from what I think is generally an admirable proactive stance that the IPPIA has been taking over the past year or year and half, but at past BPAC meetings, one or two or three of the members of BPAC have raised concerns, and I recall Mr. Corey Dubin raising them, perhaps Dr. Mitchell, perhaps others, related to how well the GMPs are currently being carried out.
When we presented data showing that the currently applied mechanism for removal and inactivation of viruses are more than enough to kill any virus that is present, the question was raised by several BPAC members, yes, but there are so many GMP violations nationwide that we can't rely on that.
So, I would like to ask the question‑‑it doesn't have to be answered‑‑but at least rhetorically ask the question, your proposal would have to satisfy the critics who are concerned about the adequacy of GMPs, as Dr. Epstein alluded to, and what aspects of your proposal will satisfy those people.
MR. BABLAK:  I think if that is a question that is directed to me, basically, what we are proposing is to take the GMP review that has been put into the algorithm and just put that up‑front, and I think that is why we asked for an FDA liaison to our working group, so that we can be assured, and assure others, that what we are doing will meet the questions of those people who have raised those questions.
DR. HOLLINGER:  Dr. Chamberland.
DR. CHAMBERLAND:  I think, first, I would like a little clarification because I may very well have misunderstood this, but when Dr. Boyle just asked you to compare and contrast the proposed algorithm with what you are currently doing in practice, essentially, it started to differ very quickly after units became pooled, but I thought I understood Dr. Epstein to say that actually, this is what is happening currently, we have just never formalized it, and this just happens on an ad hoc basis.
That is my initial starting point is I am a little confused as to what is actually happening in practice.  What follows is if there really is a disparity between what is happening currently and what is being proposed, your comments about this looking back to multiple donations could possibly then really have significant implications for supply.
I think that is an important consideration if this, in fact, isn't currently happening, if it is implemented, are we going to face real significant acute shortages of products because essentially everything being quarantined or at least on an interim basis until it is resolved.
MR. BABLAK:  The answer to that is it is a possibility.  I don't know in the short term how that would work out with the numbers and things coming downstream.  I think our data has showed that over a time period, for a year, every lot would be affected, and so whether that would happen immediately, I can't say.  We don't have that data.
MR. MASIELLO:  Let me just clarify my earlier statement.  Ordinarily, the follow‑up that the FDA conducts is associated with releases by a plasma center or a blood bank of a unit that had a testing issue or a window period issue and those are the ones that the FDA is currently focusing on as opposed to these post‑donation calls where after a certain period of time, the unit would go into manufacture.
But we do, of course, look at the suppliers to make sure that those issues are being documented and are being tracked, and looking through our GMPs that the fractionators do receive information and take some steps.
DR. BUCHHOLZ:  I have a question with respect to the statement that FDA has made relative to compliance violations and citing examples where there is GMP violations to some extent.
I would presume that that GMP violation would lead to a correlation that there are many examples of disease transmission that have taken place and been documented in recipients that are related to those specific GMP violations.
My impression is that post‑plasma derivative infection except in a couple of instances where there is a very good explanation for that, is either nonexistent or exceedingly rare.  Could someone clarify that?
DR. EPSTEIN:  At previous advisory committee meetings where this issue was discussed, Dr. Tabor provided a complete historic review about HIV, HBV, HCV transmissions from plasma derivatives, and the bottom line is that with the exception of the isolated instance of transmission of hepatitis C from one manufacturer's intravenous immune globulin, which dated back to 1994 after the screening policies were changed, since 1987, there have been no reported transmissions of HIV, HBV, HCV by plasma derivatives, so we do believe on those grounds that the current procedures for manufacturing are adequate to eliminate the risk of transmission of those agents, however, it needs to be understood that the safety of the products is dependent on the manufacturing processes.
We know for a fact that window period units will contaminate fractionation pools.  We know it statistically, and we know it from the occasional instances where a documented window period unit was pooled.
We also are operating right now in an environment where there has not been rigorous validation of the inactivating or clearance capability of the processes with regard to the viral loads that might enter the pool.  Mainly the problem is that the viral loads in the pools haven't been directly measured.
So, we know the end products have not transmitted.  We know that the processes are very robust, and we have reviewed all that data at previous meetings, but we still have this concern at two levels.
One, that we would like to tighten the data set on validation, we would like to really know what tests are in place to ensure upper limits to contamination that may occur, and how many logs overkill or clearance there is in the process.  We really need to firm that up, and I think you are calling for that data to be made available and we applaud that.
The second is that we do know that since the safety directly depends upon the accurate and reliable accomplishment of the inactivation and purification in the course of manufacturing, that deviations are important to investigate, and not all deviations are equal.
There are going to be deviations that raise significant questions, and we gave examples at previous meetings.  For example, when there was a report of an HIV antibody‑positive plasma pool that was based on pool testing for antibody performed in the UK of products that have been distributed under license by U.S. fractionator, and with the knowledge that an HIV antibody‑positive unit must have entered the pool, we then felt that we needed to investigate the adequacy of the HIV viral inactivation and manufacturing, and lo and behold, we found deviations that had not been investigated and resolved, and that the deviations were outside the validation range of the manufacturing process.
We have ancillary data that suggested to us that the processes would be nonetheless robust, but the actual validation data didn't deal with the range of the deviation, and on that basis, there were quarantines of products put into place, particularly for factor IX.
I think the problem is not trivial although I would agree with you that the safety record of the end products since 1987, with the one exception related to Gamma Gard, is excellent, but what we are trying to do is ensure that, in other words, we want to shift it from retrospective observation to prospective assurance, and that is what this is all about.
I think that in a certain respect, we are getting hung up on the wrong issue.  Everyone would endorse the concept that if there is up‑front resolution of all deviations if manufacturing based on sound validation data, and before product release, that we can mitigate concerns over investigating specific incidents.
The problem is what do we do today before the doctor comes.  I would accept the observation that has been made that what we have described in the algorithm does go somewhat beyond current practice, because current practice has been to do investigations either when there has been pooling of test‑positive units or the finding of a test‑positive result on a pool, or a reported case of transmission even though none of those has ever been proven.  We do get reports.
Those have been the triggers for the investigation, however, as we have discussed the concern over post‑donation information and the theoretical possibility of contamination, it has become clear that we should have as much or greater concern about window period units as about test‑positive units.  Why?  Because the viral titers can be higher.
So, that is why we have broadened the scope of concern to try to define the instances where risk histories ought to worry us about window period, and this committee itself suggested to us that we not create an arbitrary distinction between risk history and window period, those being essentially the same thing.
Now, they are not the same thing in terms of frequency, because most cases of a post‑donation information report about risk won't correlate with the donor being in the window, whereas, there is some small subset where we know that the donor was in the window, and the best example of that was a case that we did present as a case study at a previous meeting, where a donor subsequently gave whole blood donation, his units transmitted HIV to red cell and platelet recipients, and the plasma had been fractionated, and that was a test‑negative donor.
So, we had absolute proof that the donor was in the window period, and we went ahead and investigated the soundness of the viral inactivation and manufacturing record for the derivatives, and we think that is completely rational.
That is a little bit different than a case where you have a risk history and you don't know what is true, but again the committee advised us to lump them, so we have lumped them, but that is an extension of what we currently do, in other words, we have currently investigated only, if you will, the better established cases of a risk where we knew it was a donation in the window or where we knew that there was inadvertent pooling of a test‑positive unit.
It would be a broadening of our scope of concern to also consider these same procedures simply based on risk history without further information, and that is correct, and that has been highlighted by a number of the committee members, and that is very important, and I think that it leads to where should the debate focus.
The debate should focus on whether the set of triggers, as outlined by Dr. Tabor, are the right ones, and I think what you are hearing the industry say is, look, we can't live with that, it is going to implicate essentially all our products.
That is a legitimate response.  I mean that is one of the problems.  So, I would rather see the focus shift on discussing the triggers and recognizing that this is an interim policy proposal than debate whether it is in conflict or not with the industry proposal to do up‑front resolution of deviations, which I think we should applaud, you know, it is the right answer, and could it in the long run obviate case‑specific investigation, I am prepared to say yes, but only at the point where we are assured that there is full resolution of deviations before products are released, and unfortunately, that has not been the compliance history of the firms to date, and that is where the problem lies.
So, I think we need a strategy in the interim, and I think that it is red herring to pose it as an alternative to up‑front investigation, and I think that where we really need to focus our attention is what the triggers for quarantines and investigations ought to be, recognizing industry's point of view that it might be too broad as construed or as proposed.
DR. BUCHHOLZ:  Could I ask a question in terms of the issues here, there seem to be potentially two issues with the industry proposal in terms of the six‑month or whatever that time period is, five to six months to get fully implemented.
It seems that part of that proposal involves some NAT testing of pooled or final product, and obviously, that isn't something that can necessarily be turned on overnight, but I would wonder if the questions that FDA is concerned about, that is, documentation of good manufacturing practice, aren't, in fact, resolvable in a much shorter period of time, and have the potential to be addressed very rapidly even though NAT testing of pools may not take place for two, three, four months.
MR. JACKMAN:  May I comment because it was addressed as a comment we were going to make.  I think some of the issue here is on timing and how quickly this could be implemented, and we are confident that we could work to accelerate our proposal especially with the cooperation and input of the agency on this, and we think that would be beneficial, so we think we could accelerate that from the date we even talked about by the end of this year and make it even sooner, and that might address some of the question of whether or not you need an intermediate step.
The other thing is in discussing the algorithm, the intermediate steps, we have to be aware that if those are implemented, we could be seeing significant amounts of quarantine effect.  As it is constructed, we think that most of our products would wind up in quarantine.  That is going to take quite a bit of time and have a major impact on supply, so we do favor an up‑front check all the time.
This is not new authority, but it is an enhanced method of assuring compliance with GMP on viral inactivation in the most important areas.  We can accelerate it, we can have a real impact on this issue here, and with cooperation we think we can get this done.  I don't think we really see the need for an intermediate step.
DR. EPSTEIN:  I would comment for Mr. Bablak, that I would have put the timing the other way around, because I think that we have created a very significant feature that would expedite investigation and resolution by permitting retesting of the unit or the donor and/or the pool by current licensed tests and NAT as a strategy to avert the need for quarantine and GMP investigation.
Perhaps it is worth showing the algorithm again to point that out, because we do think that that is feasible now, and we do know that the industry has the capability.  It is simply a question of showing FDA data on the sensitivity and reproducibility of the NAT tests, and my instinct in the matter is that it will take longer to convince the agency that there is adequate up‑front investigation of deviations and resolution before lot release, because the cases that we have dealt with have simply taken many, many months to resolve.  I mean some of them are going on years, and they are still not resolved.
So, I have a little bit less confidence that that is going to be in place in five or six months, although I would be very pleased if that were true, but again, the algorithm does provide for an alternate strategy to resolve things rapidly, and I see that as quite feasible today.
DR. HOLLINGER:  I just wanted to ask one question.  Jay, on the same one, from what Dr. Tabor said initially, we are talking about HBV, HIV, and HCV, for which there are tests available, and what you are saying I think as an alternative is really if you had the donor there, you actually could obviate all of this if you went back and retested that donor with NAT or with other things, and found them to be negative.  Basically, then, you really don't have to move forward for that particular situation. 
Is that what I am hearing you say?
DR. EPSTEIN:  I think that what is under discussion here, and perhaps Dr. Tabor wants to just highlight it, we are talking about point A in the algorithm where there is concern about the product and you can avert the comprehensive GMP evaluation if you have a validated NAT for HBV, HCV, and HIV on the pool, and the original sample or a fresh sample from the donor.
If you do not have an original sample, such as a segment, and we accept the comment that these units and their segments are traceable, that is, in fact, the norm in the industry, if you don't have the segment, you can retest the donor, but then you should do all the screening tests also to look for seroconversion.
What we are saying is that if you can accomplish that in 72 hours, you don't have to do the quarantine.  If you can't accomplish that in 72 hours, you do need to do the quarantine, but you can stili avert the comprehensive GMP evaluation just by getting negative additional tests.
We think that that is a very important alternative that mitigates the impact of otherwise calling for these investigations, and again, I would agree with the comments that have been made by the panel members, particularly Dr. Fitzpatrick, that this is not in conflict with the parallel strategy to put in place up‑front GMP resolution of deviations as a strategy to have the answers in place.  I think they are fully compatible.
That is the importance of what was highlighted as Note A.
MR. BABLAK:  I think there are two concerns with that strategy.  One, very rarely will we have the samples, so then you would have to go back to the donor. If you are able to get a sample from the donor, the time of doing that, running the tests, and getting the results will most likely fall outside of the 72 hours, and therefore you have the quarantine which, from our point of view, is the most difficult part of this whole process is putting products out on the market on quarantine, quarantine products that are in‑house, those types of issues.
Obviously, we are all anticipating putting PCR testing in place, and we are in the process of doing that under the procedures that the FDA has asked us to do.  Trying to I think circumvent that and go forward with testing either individual pools or individual donors on an ad hoc basis is not as simple I think as is being proposed, and certainly not as timely.
DR. JACKMAN:  May I clarify something?  I just want to point out that only one manufacturer has HBV NAT testing at this point, and the other manufacturer for the other viruses, there are INDs that are in place, that are applications, but we are not there yet, so we are not able to do some of the parts that are envisioned in the algorithm.
DR. HOLLINGER:  Dr. Verter has been very patient here and has a question and then I think we ought to move into closing the public hearing the get into the questions, so Dr. Verter.
DR. VERTER:  Part of the training of a statistician is to be patient.  I am confused, so being patient was probably good, but let me see if I can summarize what I think I have heard and then I have a suggestion which can be blown out of the water.
I think what I heard this morning is the following.  One, that the risk of transmission of HBV, HCV, and HIV, since 1987, is essentially zero.  There have been no known cases in the United States.
DR. TABOR:  Transmission by plasma derivatives made in the United States.
DR. VERTER:  Correct.  Thank you.
This committee in the years that I have been on it has struggled often with the issue of safety versus supply, and almost unanimously, I think, we have come down on safety with maybe one or two small exceptions, but we always worry about supply, and whether that is or isn't an issue I can't speak to because I am not in the business, and I don't know how accurate any of the data or the suppositions made here this morning are, but it is a concern and we can't ignore it.
The other thing is based on Dr. Tabor' algorithm and what we heard this morning, it seems to me that what the industry is proposing to do, if fully implemented, and if all the GMPs are adhered to completely, goes beyond the algorithm.  It actually kind of brings A up to the top and says everything will be NAT tested.
DR. TABOR:  No, I don't think you understood them correctly.  What they said was that by the end of the year 2000, everything would be NAT tested.  The entire procedure, A under the algorithm would not be in place until the end of the year 2000.  What they are proposing now is to do procedure B on everything regardless of post‑donation information.
DR. VERTER:  You are right, I forgot about the 2000, but other than that, I agree with that statement.
Then, we heard some presentations by the FDA about which post‑donation issues, or at least some distribution of the reasons for post‑donation notification of problems.
So, we are trying to balance risk and supply, safety and supply.  Why not investigate which of those factors resulted in the‑‑well, kind of the hierarchical analysis, which of the factors resulted in the most recalls or taking product off the market.
Maybe only three or four of those actually resulted in having to take product off, so quarantine everything based on any PDI, you know, probably doesn't seem practical or realistic, well, maybe it shouldn't even be considered.
So, my suggestion is to go back and look at all those factors and see if you can narrow it down in the interim, number one.  Number two, I would strongly suggest that the FDA and the industry and whoever else can get involved do whatever they can to implement these testing procedures earlier.
DR. TABOR:  Well, first of all the procedure B, which was discussed also in March, that is, the comprehensive GMP evaluation, was an attempt to allow the industry not to have to quarantine product.
Secondly, I think the process to get NAT testing on the market is moving forward at such breakneck speed that it could not possibly, even with special resources, it could not possibly be going faster than it is in this country and elsewhere.
Parenthetically, HBV is being done last because it is expected to have the smallest benefit in terms of this short a window period compare to the other viruses.
There is a question for the committee, as you know, related to this, and before reading that, let me just say that I think it is important for you to follow up on Dr. Epstein's comment.  If you do approve the algorithm, you need to‑‑perhaps without going one by one through all the items in footnote i‑‑at least decide whether that list is going to impose an undue burden on the industry in the supply.
I would like to also emphasize what Dr. Epstein said, and that is that NAT testing, when it is in place and licensed, will change the whole algorithm and that this is an interim measure.
DR. HOLLINGER:  Before we go on here, is there any other further comment from the public regarding this?  If not, I am going to close the public hearing.
MR. BABLAK:  Could I make one last statement summarizing?
DR. HOLLINGER:  Yes, please.
MR. BABLAK:  I think Dr. Epstein has sort of focused you on what he thinks are important.  I would like to at least give my two cents on that.
First of all, I think while the number of PDI reports, there are a lot of them, and they end up affecting all product lots, the actual number of window period units, which is really what we are concerned about, is exceedingly small, so you are using, if I can, the shotgun approach to try and determine whether or not you can look for a particular lot that is released going backwards instead of forwards.
I think that has been done in the past has been for PDI reports, they haven't been seen to be of a significant risk that we would have to go in and do something once the unit has been pooled, and we are saying for the interim, for the next several months, until we get this GMP review, we can continue on that path based on the safety record that we have had with these products since 1987, and then going forward we will enhance what is already being done to add an additional margin of safety to these products which are already very safe.
I think I would like to just leave you with that statement.
DR. HOLLINGER:  Thank you, Mr. Bablak, appreciate that.
We are going to close the open public hearing.
Go ahead, Dr. Buchholz.
DR. BUCHHOLZ:  As I listen to this conversation, i am getting more and more confused here.  It seems to me there are two separate issues that are being discussed.  One relates to NAT testing, which is in the process, but not yet there, and the second relates to documentation of validation of good manufacturing practices, and it seems to me we are blurring NAT testing and documentation of good manufacturing processes into this six‑month window.
FDA, I have heard it said a couple of times this morning that the current manufacturing processes are safe and, in fact, are very robust, have excess capacity to inactivate, so I think it is important for us to understand whether we are talking about validation of GMP at the manufacturer level or if we are talking about implementation of NAT.
My presumption is that one of these, the validation of good manufacturing process could proceed as a significantly more rapid pace than implementation of NAT testing.  If, in fact, there is general agreement that the current manufacturing processes, if followed, are more than adequate to inactivate the viruses of concern, it would seen to me that the industry proposal might be a very valid one and especially enhance the safety in that all lots, not just one that happens to come up for examination, are questioned.
Committee Discussion
DR. HOLLINGER:  Thank you.
Any other comments?  Maybe we should put up the question what you want us to deal with here, and then we can ask some more questions at that point, at least maybe see the question.
DR. TABOR:  The question is very straightforward.   It really just asks you whether the algorithm is okay.  It is actually the same as Question No. 2 from the March meeting.  I would actually like to ask Dr. Hollinger if he could officially designate post‑donation information as the wording of choice in place of inadvertent contamination in the question.
For post‑donation information regarding plasma in which the contaminating unit was found to have come from a donor who, despite having answered in the negative all questions about risk factors for infectious disease and to have had negative assays for HBV, HCV, and HIV at the time of the donations, was later found to have answered the donor questionnaire incorrectly or otherwise to be at risk, does the committee agree that the algorithm provides suitable responses for FDA to take?
DR. HOLLINGER:  There have been some very good comments here, I think, about what is at stake in this.  On the one hand, where there should be at last an evaluation by the FDA of what is going on or whether there should be GMP in place in the first place as validation, I think the key issue is what has been mentioned.  We do have a safe product.  We should not ignore that issue.
The question is to make sure that there is no breaks, I guess, in GMP down the line because if the product is prepared in the proper way, then, we shouldn't have to worry about it.  I mean there is nothing to worry about.
The issue is clearly, as I think Dr. Epstein has mentioned, is whether or not one can be certain under these circumstances that you don't have some breakdown which would allow a unit to be contaminated and transmit.
Dr. Nelson.
DR. NELSON:  We have been told by the FDA that there have been breaks in GMP.  The issue that I am interested in is that there is a lot of donor screening, and there is a huge list of possible markers for the window period.  Most of them vary, still quite unlikely that the person is in the window period.  So, I don't think the system has been really put to a good test.
I don't have a good sense as to  what have been the breaks in good manufacturing process and how risky have they been, and how frequently does a really high risk break occur.  If some really high risk problems have occurred in retrospect, that were only identified because of a problem donor, then, you know, there is still a theoretical problem.
What I am getting at is I don't think the fact that we haven't had transmissions, although probably when the huge pools, there probably have been donors in the window period, yet, I am not thoroughly convinced that the system has really been highly tested, you know, that we would have detected transmissions for sure.
But if they are all minor breaks, I mean GMP is very complicated.  It is a summation of a complex series of procedures.  I don't understand what the level of problems with GMP have been that have been discovered so far.
DR. HOLLINGER:  Maybe on that same issue about the risk, and so on, of the blood, maybe we should just discuss just for a minute the risk factors that they pointed out here.  I think Dr. Tabor wanted you to look at that list under I, Section I, to see if these are the ones that should be used in terms of those which place the product at greatest risk, and if anyone has any comments about those.
Dr. Boyle.
DR. BOYLE:  I just have a point of clarification because part of what has been discussed here is timing, that the industry says NAT will be in effect by the year 2000 or sometime in the year 2000.  What I am not clear on is if we go ahead and vote in favor of this today, the FDA would still have to go through a Notice of Proposed Rulemaking or Advanced Notice of Proposed Rulemaking, and my question is if we today said this is a great idea, go for it, how long would it take before this was actually implemented?
DR. HOLLINGER:  Dr. Tabor.
DR. TABOR:  If you approve this today, we will begin doing it today.  It is essentially a codification of what‑‑it is not that far from what we are doing anyway.  We do not propose to issue a Notice of Availability, and so forth, initially.  We are going to wait until the NAT tests are approved because the algorithm will have to be changed completely at that time.
The same goes for the algorithm that you approved at the last meeting.  So, these will be for FDA use.  Whether they can be made available stamped Draft or not, I don't know, but so far they have generally not been.
DR. KAGAN:  Is there an issue of whether or not we are considering whether an algorithm is needed before we discuss the contents of such an algorithm, or is there an algorithm in place already, and it's just a question of do we want to modify that algorithm?  I am unclear on that.
DR. HOLLINGER:  It is my impression they are asking about the algorithm that was presented here under the risk factor plasma primarily, and then I think probably they could ask about what are some of the issues within the algorithm.
DR. KAGAN:  So, there is currently no such algorithm in place, is that correct?
DR. EPSTEIN:  Well, FDA has been involved with this set of evaluations since the 1980s.  We have done most of the investigations or mandated them ad hoc.  We have developed in the past some matrices that were used as guidance for reviewers, and those were presented at previous meetings of the BPAC.
There was a sense that we needed to move from that ill‑defined position to codifying our current thinking on the subject, and that is what led to the development of algorithms which have been vetted publicly because one of the complaints of the industry has been that there was lack of clarity what FDA's expectations were for further investigation or mitigating circumstances or the triggers, et cetera.
So, it is not that there has been no effort to codify internally what we are doing.  It is just that we have moved from some internal exercise to having a public discussion about what should be the expectation, what should be the trigger, and what should be the mechanism of resolution.
So, I would say that again we have presented in the past, and perhaps you weren't on the committee at the time, the current state of play as it existed within the agency, and what has changed is that we have elevated it to the level of public debate and advice from the committee, and that is why you are looking at algorithms.
DR. HOLLINGER:  Dr. Verter.
DR. VERTER:  I know I am not going to get the data today, but at some point it would seem to me that‑‑well, that is not being facetious, I just know that it hasn't been done probably‑‑but Ms. O'Callaghan's report I think to me is one of the more important things in my reasoning, and that is, in Fiscal Year '98, you reported 3,200 and some‑odd PDIs.
Of those 3,200, I just kind of looked at the distribution pretty quickly, and 60 percent are due to three things:  the needle category, I.V. drug use, and who is a sex partner.  What I don't know from here is of those 3,200 or those 60 percent, how many resulted in destruction of units or recall of units or sending it out to a user and saying, "Quick, get to your doctor, there is a big problem," was it zero, was it 10 percent, was it 100 percent?
The answer to that question to me personally would sway how I vote on something like this.  In light of not having that, you know, i am pretty sure I know how I am going to vote, but that is a key element it seems to me.
DR. EPSTEIN:  Historically, there have been no plasma derivative withdrawals on the basis of these risk factors.  That is what Mr. Masiello was stating a little bit earlier.
One of the questions here is whether there should be.  With respect to individual unit recalls, however, there have been many, but that is not really the point of contention here.  I mean no one is arguing that we shouldn't retrieve and destroy unpooled units, whether for further manufacturing or for transfusion.
So, really, the issue does focus on implications for plasma derivatives.
DR. VERTER:  Maybe I didn't state it right, Dr. Epstein.  What I am trying to get at is‑‑and I think I know the answer based on the data you and others have provided‑‑whether anything got out there because of this, from the FDA perspective, I guess, lack of a complete algorithm that affected any individual adversely.
DR. EPSTEIN:  Well, none that we know, but you get into the question of how adequate is surveillance.  I think that we can state on statistical grounds that there must have been derivatives distributed that contained units that were fractionated, that were obtained from persons who get post‑donation information on risk history.
That must be true, and it has been true for years.  There are no validated reports of transmission of hepatitis B or C or HIV from any plasma derivative with the exception of the Gamma Gard incident, which had unrelated causes.
So, I think it is fair to say that there are no validated reports of transmission in the face of the fact that such unsuitable units must have been fractionated over the years.
DR. HOLLINGER:  Also, Jay, in addition to the fact that there hasn't been any more GMP validation requirements up to this point other than what is being currently done.
DR. EPSTEIN:  The GMP requirements have not changed, but the agency has become aware of breaches of GMP which do lie in the domain of either validation of the purification or viral clearance and inactivation steps or in the adequacy of investigation of deviations in manufacturing, and it is those observations that have driven this concern, and I would be inclined to agree with Mr. Bablak, that if we were all assured that there was complete and adequate resolution of manufacturing deviations against a background of full validation of the processes, that this problem would go away.  It is just that it is my contention that we are not there yet.
DR. HOLLINGER:  Dr. Khabbaz.
DR. KHABBAZ:  In looking back and forth, I am looking at this algorithm, and I am struck that despite all the complexities, it is quite simple and it really relies on comprehensive GMP evaluation.  If you go down A, and you have a sample and you can test, then, the test is positive.  Then, you go to B, and there is a comprehensive GMP evaluation is adequate, then, the pool or the product is released.
So, basically, this algorithm and the proposal are one and the same.  What this does is require a fractionator to send reports to FDA of the GMP evaluation for those pools where you have a risk factor.  So, it is kind of a first step towards No. 2.  I just wanted to comment on that.
DR. EPSTEIN:  I think the debate is over the up‑front quarantine.  What the industry is saying is that if the triggers are as broad as proposed, that a very large number of product lots would become subject to quarantine, and I think that that is a legitimate observation by the industry and very important for the committee to focus on.
DR. KHABBAZ:  But if you had a comprehensive GMP evaluation ahead of time, and that was sent to FDA, and it clears a product, and quarantine is really limited.  Would you have to quarantine if you can do it within 24 hours?
DR. EPSTEIN:  Again, we asked the committee that question at a previous meeting, and I don't remember if it was September or March, whether an adequate GMP status in all manufacturing steps which could impact on product safety could obviate a recall of the product or withdrawal of the product, and FDA's proposed view was yes, it should, and the committee concurred.
What we are really just debating is when and how that happens
DR. HOLLINGER:  Dr. Stroncek.
DR. STRONCEK:  I think this protocol is straightforward and clear.  I think that it is realistic to expect the FDA to confirm that cGMP was done.  There is just no way that they cannot do that.  It is like saying a center swears to abide by all the rules and they won't be inspected annually.
Concerning what the industry, about this pooling quarantine issue, they have not been very clear with what they wanted, and I would recommend the committee vote in favor of this protocol and get on with it, and if there is a problem, they can come back to us.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  I just need to ask two points for clarification.  On A, when we talk about a validated NAT, does that mean that there is the possibility of using a non‑IND‑approved NAT?
The other is, is the FDA going to go back through the IND approved NATs now because there is a least one that I know of that prohibits retesting of the pool?
DR. HOLLINGER:  Does anybody from FDA want to respond to that?  Dr. Tabor.
DR. TABOR:  I think we are going to get into an issue of semantics unfortunately, because really, none of the NATs are fully validated yet because they are not licensed.
I think what we are talking about is an NAT for which the information filed in the IND satisfies FDA as to its sensitivity, specificity, and reproducibility.
DR. FITZPATRICK:  Wouldn't it be simpler just to say IND approved?
DR. TABOR:  I am sorry, i can't hear you.
DR. FITZPATRICK:  Wouldn't it be simpler to just say IND approved?
DR. TABOR:  Well, IND approved has too much ambiguity.  We can take out the word validated if you like and say FDA sanctioned or‑‑I mean the point being that you can't just take a homebrew test that hasn't been seen by FDA and test it.  I don't know of a better word, but I agree that there are weaknesses in the word validated.
DR. FITZPATRICK:  Are you going to review current?
DR. TABOR:  You can't ask a manufacturer to test in conflict with the approved IND.
DR. FITZPATRICK:  The FDA staff who reviewed the INDs are very familiar at least with what has been submitted to FDA regarding validation before the clinical trials of the NAT tests begin.  So, for us to obtain the answer to the question is this an adequate NAT test to use for this algorithm is quite easy.
DR. HOLLINGER:  So, you could say either an NAT done under IND or a licensed NAT.
DR. TABOR:  Well, if there were a licensed NAT, yes.  I think that answer to your question is yes.
DR. HOLLINGER:  Dr. Chamberland.
DR. CHAMBERLAND:  A couple of things.  There have been several FDA comments, and I would concur that I think there is a need for some interim strategy or rearticulation of what currently is being done, but I am sort of following along the same path that Dr. Verter is, which is if I have interpreted Ms. O'Callaghan's data correctly, in Fiscal Year '98, there were 618 instances in which post‑donation information that is in sync with footnote i were reported, so that we overnight would be going from a situation in which industry is moving from zero to, in a given year, potentially 600 instances in which they have to proceed along this algorithm of which the largest impact seems to be quarantine.
We have heard from industry that in their view at least at this point in time, not a lot of these would be resolvable in 72 hours.  I am trying to balance that also with what I view the items in footnote i are again, as has been stated previously, are very insensitive predictors of window period.
So, I am struggling with is there any sort of compromise along the way in which I think FDA is wanting to move from just acting on test data, as Dr. Epstein explained, the current triggers are really based on test information, you know, a donor testing positive or a pool testing positive to acting on post‑donation information reports, which again, as BPAC members have really had some concerns that that is not currently really being done, but I have to say I have a concern of moving so quickly from nothing to a fairly comprehensive albeit insensitive list of triggers and worrying where we might be with respect to product supply and keeping that flowing, because we know for certain products at least we are already in a shortage situation.
I don't know if the committee feels there is any point discussing how this current list of triggers might be modified, if that is even doable.
DR. HOLLINGER:  Dr. Mitchell.
DR. MITCHELL:  I, in fact, do like the list of triggers that are listed there, but I understand and I agree that there has to be some kind of an implementation period, and I would expect that FDA would come up with some kind of a date.  If we are only talking about reassuring that GMP is being followed correctly, it seems to me that that should be able to be done in less than six months, and I hear industry saying that it might be able to be done in less than six months.  However, I think it would be unreasonable to say that by tomorrow that we would expect this to be done.
I think there has to be some kind of implementation period, and I think that it should be up to FDA to sort of judge what that should be.
The only thing that I would change, like I said, in the algorithm, is I would adopt the industry's term of under the first one, instead of destroying units, that the units be removed from use for therapeutics.
DR. HOLLINGER:  I think we will go ahead and vote on the question, and then if there is issues that have to do with the algorithm, if that is what is voted, then, we can deal with those, but I think we first ought to find out if everyone on the committee agrees with the question for the committee, which is whether or not the algorithm provides suitable responses for the FDA to take as such.
Dr. Tabor has already read the question.  A yes vote would mean that you agree that this algorithm should be adopted, and then we can discuss about the algorithm itself, and a no vote would be no, that you do not agree with that, and people have to go back to the drawing board again.
Dr. Smallwood wants to indicate who is going to be voting.
DR. SMALLWOOD:  I would just like to clarify for the voting process that our advisers, Drs. Chamberland and Fitzpatrick, will not be voting.  Neither will our non‑voting consumer and industry representatives.
DR. HOLLINGER:  Dr. Boyle wanted a question.  I meant to call on him.  I am sorry I didn't.  So, this will be the final.
DR. BOYLE:  The only issue I have is in some sense, the relationship of the two questions.  I want to sort of basically agree with Dr. Chamberland's comments.  Number one, we believe that the product is safe only because good manufacturing practices are followed, if they aren't, it is not going to stay a safe product.  So, that is very important.
It is not good when people say that the data doesn't exist to be able to verify whether good manufacturing products have been done, and it is appropriate to have as a trigger to investigate that, things that appear to be greater risks.
On the other hand, if there are 600 and some of these cases which may involve half of all the products shipped, that 600, given the absence of NAT, these 600 immediately have to go through these good manufacturing practice investigations.  That is an average of two a day across the industry.
So, if we go forward with voting in favor of it, you know, my concern is we are running the risk of basically shutting down availability or dramatically reducing it.  On the other hand, I think the basic algorithm is a good idea, and if we went forward with, for instance, the category AIDS related signs or symptoms, of which there were six reported cases last year, or something on that order, then, you have an opportunity to see how well it works before moving to the next step.
If I were, as I am going to be asked to vote, if I were asked to vote on a very limited scale where we were taking one or two of these items and seeing how the process worked, how long it took to do these things, what the burden to the industry was, how many quarantines occurred, and then had that reported at the next session, I could vote in favor of that.
If, on the other hand, we are voting across the board on implementing a process that basically could shut down product availability or dramatically reduce it, then, I would have to vote against it.
So, that is why the order of these two questions becomes of some significance.
DR. HOLLINGER:  The order of the algorithm versus?
DR. BOYLE:  What is in the algorithm, what the triggers are.
DR. HOLLINGER:  I will give an issue, if anybody has any comments about that where they think that is an issue.
Dr. Stroncek.
DR. STRONCEK:  It is my opinion it doesn't do any good to have product out there that is not any good.  I would be appalled if half the products in the country didn't meet good cGMP.  I think that would be a disaster in itself.
DR. HOLLINGER:  I am going to call for the question.
All those in favor of the question, agree that the algorithm provides suitable responses for the FDA to take as such, please signify by raising your hand.
[Show of hands.]
DR. HOLLINGER:  All those opposed?
[Show of hands.]
DR. HOLLINGER:  Abstaining?
[One hand raised.]
DR. SMALLWOOD:  According to my count, it doesn't come out right, so I am going to need you to vote again.   We are one short.
DR. HOLLINGER:  I voted yes.  Sorry.
DR. SMALLWOOD:  The Chairperson explained to me that he is voting with the yes votes.  All right.
The result of voting.  There were 7 yes votes, 5 no votes, 1 abstention.  There are 13 members here who are eligible to vote.
DR. HOLLINGER:  Dr. Buchholz, you were going to comment how you‑‑
DR. BUCHHOLZ:  I would vote no.
DR. HOLLINGER:  Ms. Knowles?
MS. KNOWLES:  I am going to abstain.
DR. HOLLINGER:  Are there any questions, then, in regards to the algorithm then or the contents of the algorithm?  Yes, Dr. Verter.
DR. VERTER:  I will just quickly reiterate what I said before, and also comment again on what Dr. Chamberland said.  I think someone needs to go through the items in i and rank them in some order, both in the numerical reports, as well as what happened when they investigated those reports.
I am concerned, as Dr. Boyle indicated, of the balance between risk and supply.  I mean this is a good example of where we might have a problem.
DR. HOLLINGER:  Dr. Ohene‑Frempong.
DR. OHENE‑FREMPONG:  My concern was also with the list.  I imagine that the list was compiled based on some scientific data or maybe the best suppositions that could be made, but I see some inconsistencies in them, and unless there is some full explanations for some of the broad sweeps, it is hard for me to, for instance, see whether there is a difference between a risk of incarcerated females and female prisoners versus incarcerated men in male prisons, and whether somebody incarcerated for contempt of court in a minimum security prison is different from somebody in the maximum security prison.
I think there are some issues and some brushes have been cast very wide, and maybe there are data to support them.
DR. TABOR:  May I answer that question?  The way it was compiled was with the data presented by Sharon O'Callaghan.  A small committee of us went through that list and tried to eliminate the things on the compliance list that we thought were of minimal significance.
Obviously, we are willing to modify that list further, and we welcome your suggestions.  In answer to Dr. Verter's comment, you said to rank them.  Do you really mean to rank them or do you mean to reduce the list to a smaller list?
DR. VERTER:  I meant to rank them based on data which may not be possible to get.  In other words, if you could‑‑I forget how many items‑‑say there were 8 items, and you could start by ranking them in the frequency that they occurred, but more importantly it seems to me, what percentage of those resulted‑‑I mean was the result of every one of those PDIs that something was brought back and destroyed?
DR. TABOR:  I am not the one to answer that, but my question about the ranking is if we rank them, do you want us to drop the ones that are low ranked?
DR. VERTER:  My suggestion was that in the ranking and the further investigation, if you could determine that some of those PDIs resulted in no action, that it was not worthwhile doing a recall, that those would be dropped, yes.
DR. HOLLINGER:  I think it is important.  This is a very close vote here.  Obviously, there is a lot of concern about the algorithm and what it might mean both for the industry and otherwise in a product that is fairly safe.
Does anyone want to respond?  We know why the yes votes are there, but does anyone want to respond who voted no or abstained, because I think the FDA needs‑‑I think they have heard this anyway under comments, but I think they probably need to find out what the real issues are here with the other major group.
Yes, Dr. Nelson.
DR. NELSON:  The reason I abstained was I was confused.  One of the things that I was confused about is that I guess this algorithm for inadvertent contamination or post‑donation information has not been used, but there has been used the test result, and I didn't see any data presented about how the review of GMP practices on the test results has affected the industry and how many units have ended up being quarantined or not used.
Therefore, even though there are a lot of instances, maybe half of the pools, I couldn't really tell whether or not these could, in 90 percent, be resolved within 72 hours with no problem or if two‑thirds of them would be quarantined for six months.
Therefore, I didn't have the data to project what would be the impact of this even on the short term.  I don't know if there is any answer to that question.  I mean since it hasn't been used in this number before, you maybe don't know, but there is some experience with the test results.
Can anybody enlighten me about this?
DR. EPSTEIN:  Well, first of all, in terms of frequency, it has only been a handful in any given year, like two or three.  Second of all, the resolutions of the GMP concerns have ranged from resolving the matter of hours to days to remain unresolved after years.
So, there has been no consistency.  I would say that it is also sorted out differently by product, that most of the time when there has been potentially affected albumin, for example, the validation records on heating in the liquid state have been adequate, and there hasn't been a problem, that with some of the more recently introduced practices related to solvent detergent processing or column purifications, there has been a wider spectrum as to the adequacy of the validation data as it could bear on interpreting the significance of the deviation, and it has just been much harder.
So, there really has not been a consistent experience.  It has simply varied from manufacturer to manufacturer, and product to product.  But I would say that the majority of cases have been resolved within weeks.  It has been rare to resolve it within the course of a day or two, and there have been some outliers that have been extreme.
MR. BAKER:  Don Baker, Baxter Health Care.  I would like to give the committee a couple of pieces of information that I think is relevant to some of the numbers that we have heard.
With respect to the inadvertent contamination for source plasma units, roughly two‑thirds to 75 percent of the proximal units are interdicted in the 60‑day period.  So, by that I mean of that 610 that we heard thrown out, roughly two‑thirds to three‑quarters of them, of the proximal unit to the report, will be caught in our 60‑day period.  That is our industry experience.
However, I should say of the remainder that aren't caught, and of those ones that are caught, on average, a source plasma donor gives something in the neighborhood of  10 to 14 units a year.  So, of the nonproximal units, there is a significant multiplier.  So, the number doesn't come  out to 600 in terms of these post‑donation information reports, and I think that is what you have to understand.  That is what is driving the industry concern.
I also want to point out Baxter Health Care manufactures for the American Red Cross, and I am sorry there was no Red Cross spokesman here, but for those of you that are looking at the numbers, you should, of course, keep in mind that there is a difference in the volume of donation by a source plasma donor versus recovered plasma donor, i.e., it's about a quarter.
So, there are four times as many units roughly in a liter of recovered plasma versus a liter of source plasma. This algorithm will have a disproportionate effect on products manufactured from recovered plasma in terms of the number of PDI reports that are going to have to be reviewed, and you saw that there was, I think 8,000‑odd in the recovered plasma side.  The American Red Cross accounts for about 50 percent of the plasma collected, so you can say just for the American Red Cross manufactured product, there is going to be some 4,000‑odd PDI reports.
So, when you start thinking about the workload, that is what is driving the industry concern.
DR. HOLLINGER:  Dr. Tabor.
DR. TABOR:  I think it is worth emphasizing we are dealing with a low risk situation here.  We are dealing with units that are test‑negative, donors who are in risk groups, most of whom are not in the window period, and with products that despite some of these problems that have occurred over the years have not been known to transmit these viruses since 1987.
But we are also dealing with a society that expects zero risk from things made from blood, and I would say that some of what we are doing today is driven by the fear or anxiety that at some point, a window period donation will get into a pool, and due to GMP failures, will infect a large number of people, and then there will be a lot of fur flying.
I think this concern was very vehemently raised at previous BPAC meetings by BPAC members.  If all GMPs could be met, it would be a different situation.
DR. HOLLINGER:  If there are no other comments, we are behind, but I think it is important that these issues be discussed.  We had a lot of important issues this morning.
We are going take an hour break.  We are going to come back at 2 o'clock for the session this afternoon.
Thank you.
[Whereupon, at 1:00 p.m., the proceedings were recessed, to be resumed at 2:00 p.m.]

AFTERNOON PROCEEDINGS
[2:00 p.m.]
DR. HOLLINGER:  The first session this afternoon is on strategies for insuring compliance in the plasma fractionation industry.
Mr. Masiello, Director of the Office of Compliance and Biologics Quality is going to talk to us about it.
II.  Strategies for Insuring Compliance in the
Plasma Fractionation Industry
Steven Masiello
MR. MASIELLO:  Thank you.
[Slide.]
We have a little bit of a change of pace from this morning's discussion.  The purpose of this particular presentation is really to give you some insights into how we are regulating the fractionation industry in terms of GMPs, and we are going to talk mostly about the injunctions and consent decrees that we have in place and what the elements of are.
There will be a few things before we get there.
[Slide.]
I would like to thank Larry Fenner for, first of all, creating or making up the slides and then for helping me out here today.
We are talking about inspectional frequency is one of the things that is a manner in which you might provide mechanisms for insuring the compliance with GMPs.  Enhanced training of investigators is another thing we will mention.  Communications, really talking about communications with the industry, and post‑inspectional issues, and that is when we will really talk about the consent decrees.
[Slide.]
In terms of inspectional frequency, right now we are conducting annual inspections.  I put down here that there is an exception for pulling back a little bit from the frequency of the inspections if you have certain conditions that exist.
The fact of the matter is we are really not at that position at this time.  I think we would be willing to consider doing that, but certain conditions have to exist first, namely, have NAI, which is no action indicated, or VAI, which so voluntary action indicated conditions.  The VAI is a broader category, and you may have some flexibility in there.
In terms of "as needed" basis, we certainly do conduct inspections to follow up on complaints, recalls, and to verify corrective actions under certain circumstances.
[Slide.]
In terms of investigator training, Dr. Lynch covered a little bit this morning in terms of the specific comprehensive training that some of our ORA investigators undergo before they go out to the fractionation industry.
A few words of explanation.  The Team Biologics, that is a whole lecture in itself talking about Team Biologics, but the Team Biologics is made up of core team members and the cadre.
The core team are those individuals‑‑and there are about 12 to 15 ORA investigators that receive specific training for each of the product areas that they will be inspecting‑‑fractionation is one of those, IVDs, allergenics, and in October, the vaccines will be going over to the Team Biologics investigators.
So, they receive this training and as Tom mentioned, there are product specialists, which are those CBER personnel that have expertise in the product, in the process, that will either accompany the Team Biologics inspectors, or be available in some other capacity, either by phone or however.
So, that is the core team.  The blood cadre are the inspectors, the ORA investigators who do the blood and plasma inspections.  At one time I believe there were somewhere in the area of 200‑plus individuals who at one point or another during the year or during the cycle might do an inspection of a blood or plasma center.
When Team Biologics was developed, the idea was to reduce that number, so that we could enhance consistency in terms of inspections.  I believe now‑‑I don't know whether there is anyone from ORA here or not‑‑there are approximately 125 FDA investigators that will be doing blood and plasma.
I think that is really all I need to say on the investigator training.
[Slide.]
Communications.  I will just mention very briefly that meetings, such as this, provide hopefully opportunities to communicate on key and important issues, public meetings, such as the one noted that dealt with plasma product withdrawals and recalls, and liaison meetings that occur with industry are ways that we can and do communicate current issues.
[Slide.]
In terms of post‑inspectional issues, I really want to talk about just two here, and that is warning letters and consent decrees.  Just to briefly mention the warning letters, in the next chart we will have a view of the warning letters that have been issued over the last couple of years.
[Slide.]
What I want to be careful here is not to mislead you as data can sometimes do in terms of the slope of this change.  There were, of course, a peak number of warning letters that were issued in '97 following some fairly intensive inspections conducted in '96 and '97, and there are, as you can see, fewer warning letters that have been issued since that time.
This is not meant to imply that the industry is fully complying with GMPs, but I think you can look at this and see that there has been some progress and that we are not in the same situation perhaps that we were in, in Fiscal Year '97.
[Slide.]
In terms of the consent decrees, it is certainly not any secret that there are two primary manufacturers in the fractionation area that are under consent decree at the moment, Centeon and Alpha, and just to mention that Parkdale Pharmaceuticals, which is owned by King Pharmaceuticals, is also under injunction that was initially a Warner Lambert/Parke‑Davis facility, that also might in the future make blood products.
[Slide.]
What Larry has done for us here is identified a number of the elements of the consent decrees that would be useful for you to see what kinds of things are being addressed in the consent decrees.
On top on that list, of course, is the reworking, reprocessing of returned and rejected products, and this is an area that over the years there have been some different interpretations that have taken place, and consistent with current GMP, these are being addressed and identified for follow‑up.
We also as part of the consent decree, in all consent decrees, there is an element for expert consultants, and really the purpose here is to assure that manufacturers develop the systems in conjunction with experts in the area that will not therefore be reliant on FDA to find problems.  The consultants working with the industry will develop the audit systems, quality assurance programs, what have you, where they will have the ability, the capacity to find and correct problems independently.
Management and personnel controls, these are areas where the agency always stresses the importance of having strong management and control over the various kinds of personnel, how they operate, and the type of people that are in place, whether they are appropriately trained for that position.
Quality assurance and quality control programs.  We certainly always insist on a consent decree that the firm develop and have in place quality assurance and quality control programs.
[Slide.]
As I mentioned, training is obviously an important element in all consent decrees, and there is a high degree of emphasis in that area.  Internal audits, again, it is important for us to have that level of assurance that the company, as it works through its problems, is also developing sufficient expertise, so that they will be able to identify the problems, and not rely on FDA.
Production and process controls.  It is obviously important to have these in place, laboratory controls, and building and facilities have to be adequate, and these areas have to be addressed, and there may be sufficient attention on that, and a fair sum of money that would be spent.
[Slide.]
Equipment, of course, you have to have the appropriate equipment in place, records and reports.  I think there is a great deal of emphasis on assuring that the manufacturers have in place adequate records and reports, so that they can make the appropriate decisions.
I think this morning there was some discussion about out of spec findings, inadequate investigations, and I think it is in that area and others that we would expect to see the records complete, so that they can make adequate decisions and that we can verify those.
Recall procedures have to be in place at the manufacturer, so that should there be a need, those can be implemented, and post‑compliance audits and reports.  Ordinarily, what we are asking for from firms is periodic reports to the FDA, so that we can measure their progress in certain areas.
[Slide.]
In addition, there are certainly specific procedures in most of the consent decrees that deal with issues where there may have to be a revision or a modification of any reports, so if we get reports and in conjunction with either inspectional information or other reports, find that these are inadequate for us to assure compliance, then, these can be modified in some way to assure that.
At anytime, additional information can be requested and reports requested for submission to the agency, and, of course, if there are findings where it is apparent that a change has been made or changes need to be made or an existing condition is not acceptable, then, you may have to require the submission of supplements to the license.
[Slide.]
In addition, the agency can, and does, often look at the facility and make a determination that there are sufficient problems that manufacturing needs to cease or processing or any aspect of manufacturing may come into question, and the agency has the power and the authority to require that the manufacturing or any of those areas cease.
That is something that perhaps doesn't come across clearly if you look at a consent decree and you see the titles of management controls and records, and things like that.  This is a very important and powerful tool for the agency in terms of bringing firms into compliance.
The agency can also order specific recalls under the consent decree, so if there is evidence that points to problems with a particular lot or lots, the agency can order a recall.
Now, of course, all of these issues can be challenged by the firm in court, so if there is a belief that the agency is acting arbitrarily or capriciously, the firm can go to the court and request relief from that, but that has not occurred yet.
Lastly, the agency essentially can take any action, can request or order any other corrective action that is appropriate to the situation.
[Slide.]
Just a listing pretty much of the kinds of things that, in fact, we have done over the last couple of years.  You probably are well aware that the agency has ordered manufacturers to cease manufacture and distribution of products based on inspectional findings, based on noted examples of contamination, and things of that sort.
We have ordered recall of products, requalification of products via inspections, and additional testing, so that if there is a situation where there is a need to essentially enhance our level of assurance that these products are safe, we can ask or require that additional testing be done.
FDA has also requested the submission of data for us to review prior to the release.  This, of course, is above and beyond lot release provisions where there is a set protocol for what comes into the agency and what the agency would do.  There may be instances where we need to go beyond that.
[Slide.]
We have certainly had issues of validation and requested that firms cease reprocessing until the system that is currently in place has been validated, and a lot of that, as you can imagine, goes back a number of years.
There is the request for third‑party reports in terms of lot release issues or lot release requests, so that in addition to the specific testing that was done, these particular circumstances, there was a review conducted by a third party and then that review was submitted to the agency with the lot release.
Again, that goes back to the concept of the firm developing the procedures and the capability of making these kinds of reports and findings without the FDA having to go out on site and conduct inspections.
There have been requests for submission of things such as environmental reports and requests for increased frequency of media fills.
[Slide.]
I bring this up on insofar as it impacts on the fractionator industry.  There are of course, as we mentioned this morning, the suppliers of plasma, source plasma and recovery plasma.  Insofar as a fractionator uses material from the American Red Cross or Blood Systems or New York Blood Center, there are things that are done in the consent decrees that exist with these firms that have what we believe is a positive impact.
[Slide.]
There is a similarity here.  You can see that in the consent decrees with the blood banks, we have requirements for management control, quality assurance, quality control programs.
A few different items here that are unique to the supply side, or course, are the computer systems and the databases.  If there is a problem with deferrals and things of that sort, they are going to usually be associated with the databases.
Records management, part of that, and, of course, making sure that establishments have the systems in place for reporting errors and accidents, adverse reactions, lookback cases, et cetera.
[Slide.]
Also, we have again the need for internal audit systems, employee training and education, donor suitability determinations, and the testing areas.  There is a great deal of time that is spent on assuring that these particular establishments have these systems in place and have the capability of auditing their own systems and making sure that they carry through with that.
There are in these particular consent decrees also provisions similar to the ones in the fractionation consent decrees which really allow the government to pursue whatever else really needs to be done if there is a finding of problems in terms of GMPs or testing, what have you.
I believe that is it.  If there are any questions, I would be glad to address them.
DR. HOLLINGER:  Questions?  Yes, Dr. Mitchell.
DR. MITCHELL:  You had mentioned OSRs, I believe.
MR. MASIELLO:  OSRs.  Tell me what I meant by OSRs.
DR. MITCHELL:  You said that the groups that were doing the inspections‑‑maybe I had the initials wrong.
MR. MASIELLO:  There is the core group‑‑the ORA, sorry about that, the Office of Regional Affairs.  These are the field investigators.
DR. MITCHELL:  Also, on the orders issued, you had said something about monthly environmental reports and increased frequency of media fills.  What does that mean?
MR. MASIELLO:  In terms of the manufacturing process, the manufacturers generally have in place procedures for monitoring the environment.
DR. MITCHELL:  The outside environment?  I don't understand.
MR. MASIELLO:  No, the manufacturing environment, I am sorry.  Those areas within the manufacturing suite where it makes a difference what the quality of the air is, so that it prevents contamination, and so we may ask for additional monitoring or media fills, which are a way in which a manufacturer essentially tests their aseptic processing abilities to make sure that they can manufacture material in an aseptic way.  I am sure Dr. Lynch or others can say that so much better.
DR. HOLLINGER:  Dr. Koerper.
DR. KOERPER:  What are NAI and VAI?
MR. MASIELLO:  The NAI is No Action Indicated and the VAI is the Voluntary Action indicated, so that if a firm has had an inspection that we classified as NAI, essentially, that is either a no 483 or very minimal 483 that has been issued to them, the list of observations.
The VAI is a little broader.  You may have issues that come up during the inspection that a firm can address and fix without a need for the agency to take any action, and that is a voluntary action.
DR. KOERPER:  So, if they have two of these consecutive inspections, you then will only go to see them every other year?
MR. MASIELLO:  Well, there is under consideration right now a decision that we need to‑‑again, we have 12 to 15 Team Biologics core investigators, and they are doing all of the biologics, fractionator work, IVD work, allergenics, and they will be doing the vaccines.
So, the resources are somewhat limited, and what we will do is insofar as we can do that, we will cut back in areas that have demonstrated ability to be in compliance.  We are really not there yet, but hopefully, we are approaching that.
DR. KAGAN:  In this particular industry, is there any other monitor of compliance other than FDA?  Are there any organizational accrediting bodies, voluntary accrediting bodies, or are you the only level of monitoring for this particular type of industry?
MR. MASIELLO:  Well, certainly we are the last ones.  Of course, all the firms that I am aware of have internal procedures, and I think the vast majority, if not all, have outside consultants that conduct audits of their facilities.  I would defer to someone in the industry to answer if there are other bodies that are inspecting.
Certainly, there might be states or other government agencies.  I am not hearing that there are others out there.
DR. LYNCH:  I am not sure that you would consider it relevant, but many of these firms have licenses in other countries and inspectional authorities from Europe, for example, will also be performing similar, but not identical investigations.
DR. HOLLINGER:  Do they share information?  Let's say they inspected and they found something wrong, do they share it with you?
DR. LYNCH:  It may not be routine, but in exceptional circumstances, yes, we communicate with each other.
MS. WAYS:  This is Judy Ways from Centeon.  Actually, Dr. Lynch said exactly what I was going to say.  Many of us have European licenses, and we are inspected by the regulatory authorities of those countries, for example, the Paul Erhlich Institute in Germany, Medicine and Control  Agency in the UK.
DR. HOLLINGER:  Thank you.
Dr. Mitchell.
DR. MITCHELL:  Can you tell me what percentage of the products from the fractionators is currently under consent decree?
MR. MASIELLO:  I am sorry, I missed the first part.
DR. MITCHELL:  I am trying to figure out what percentage of the fractionators or what percentage of the market is currently under consent decree.
MR. MASIELLO:  Domestically, what is generally viewed as the Big 4, I guess there are two, so that would be about 50 percent of the larger facilities.
DR. HOLLINGER:  I am sorry, there are four fractionators?
MR. MASIELLO:  No, four large, considered generally large.
DR. HOLLINGER:  How many fractionators would come under all this‑‑
MR. MASIELLO:  There is somewhere in the area of 24.
DR. HOLLINGER:  Twenty‑four.
MR. MASIELLO:  Yes, because I think some have discontinued manufacture, but internationally, 24 or so.
DR. HOLLINGER:  Thank you.
There were two individuals who asked to speak on this topic in this session, and I will call on them to do so now under the Open Public Hearing.  The first is Jan Hamilton from the Hemophilia Foundation.
Open Public Hearing
MS. HAMILTON:  I am Jan Hamilton with the Hemophilia Federation of America.  I want to thank you once again for allowing me to address you with some of our concerns regarding consent decrees.
We would like to pose a few questions about them and their effects upon industry, product shortages, and other results.
First of all, it is our understanding, and now we know for sure, that there are a set of standards generally referred to as general manufacturing practices and that each manufacturer has access to these standards.
We would like to know how they are regulated, are they viewed on a regular basis similar to the way hospitals go through JAACO accreditation?  I understand that it is annually by the FDA.  Is the only monitoring done by the FDA?  Somebody else just asked that question.  If so, is it on a regular basis or just when a problem occurs?
We appreciate the plethora of information that we have received this morning regarding GMP, but we had a few additional questions, many of which were just answered by Mr. Masiello, but I will go ahead and review them anyway.
We wanted to know who conducts the GMP review, how long does it take to do an entire facility, and is everything in the facility covered, such as records and procedures and equipment and products, the whole nine yards?
What is the structure of such a review, is it conducted by just one person or a multidisciplinary team or what is the makeup of it, and what are the checks and balances?
Can consumer groups get results of these reviews?
We are now getting supply reports through IPPIA.  We would also like to get the GMP reports.
In the same light, if each of the manufacturers have those standards, and they know they must adhere to them or face a consent decree, which must prove to be costly for everyone, then, to use a borrowed phrase, this is a puzzlement.
Why would a manufacturer slip out of compliance?  Why wouldn't good working quality improvement, quality assurance practices prevent a situation that would result in a consent decree?
In the last couple of years, as we saw in the chart a few minutes ago, there have been several consent decrees issues.  In a couple of situations, the companies voluntarily closed facilities to correct a problem.
We hear about the consent decrees being issued.  Perhaps there are others who, like our group, would like to see reports on the correction along with what plans have been made to prevent recurrences of these situations.
Are there levels of severity of consent decrees?  What is the cutoff between a consent decree and suspension or removal of licensure?  What if the reasons for the issuance of a consent decree are of a repetitive nature, same cause, same company?
If there is a suspension or removal of licensure, then, is there a formula to determine the length of that suspension or removal, and what must be done to accomplish reinstatement?
We have been observing shortages in supply over the last several months, and how much of these shortages result from plants being under consent decrees versus other problems?
We have been pleased to see the increase of information from industry regarding recalls and/or withdrawals through the IPPIA and the establishment and operation of the patient notification system through IPPIA and the National Notification Center.
In addition, we appreciate the efforts of IPPIA as presented this morning by Jason Bablak, but we have some concerns similar to those already stated here today, and would hope for a solution that would allow forward progress without leaving any gaps in surveillance.
We would like to see similar data to the recall withdrawal information made available surrounding consent decrees and other sanctions.
Those of use who lives depend on obtaining safe, reliable products to keep us healthy, safe, and leading productive lives are concerned about the effects of consent decrees upon the supply of quality products and wonder what are the reasons a company would allow themselves to create a situation that would call for these measures.
Once again, we thank you for the opportunity to express our concerns.
DR. HOLLINGER:  Thank you.
I next want to call on David Cavanaugh for the Committee of Ten Thousand.
MR. CAVANAUGH:  Thank you, Dr. Hollinger.
We also are very pleased to have this presentation when two of the four producers of the products we consume are under legal sanction for some years, and no further feedback is available on the results of that process, if you will.  It is scary and it makes us wonder how the product is doing in terms of becoming improved, algorithm or no algorithm, if you will, if I can borrow from the earlier presentation on a different matter.
There were 16 warning letters in the last half decade, and I don't know if those covered whole blood as well as fractionators alone, but although it is a large and important industry to us and the four fractionators that are the largest make up a huge piece of industry, and the 24 being on there, perhaps another if you do add whole blood, that seems like not so many in terms of warning letters.
Obviously, when you move to legal decrees, your scope vastly increases in terms of the enforceability of various provisions and the kinds of provisions you can impose, but it looks almost like you write a few letters and then you slam the industry under legal control, and then you don't say anything about how it is going with it.
We are confused.  We don't know how it is going with obtaining GMP.  In Mr. Masiello's comments on the overview and insuring compliance, he talked about frequency of visits and some of it is an ad hoc basis and training.  Sometimes the CBER people go along and sometimes they don't in terms of expertise on site.
He talked about communication at BPAC meetings and at special meetings with industry.  I would like to add consumers into your thinking, so that there is more‑‑I grant you these meetings are open, but they are for the members of the committee, and general reporting on consequences of legal actions would be appreciated by this regulatory agency's consumers, if you will.
Two of the four have been under for 18 months.  I mean we are curious about progress.  When you listed the issue of initiatives that can be reviewed, records and reports and recalls were items 11 and 12 out of a 15‑item list.  We are down quite a ways, and yet the whole algorithm really talked about this morning really requires going in and rapidly reviewing records and being able to‑‑you know, the ability to generate a fast GMP review requires a good database, if you will, and Dr. Tabor was very clear about trying to bring people up to the speed where that is attainable, but it really highlights that tracking and records, which would seem to be rather basic management functions in a large‑scale manufacturing process, need to be highlighted and need to be focused on.
It is easy to give reports on how that is going to public groups, even if it is to the BPAC in closed session.  That hasn't been done.  You heard Corey Dubin, our president, talk at some length, as a sitting member of this committee, about the need to FOIA, file Freedom of Information Act requests in order to see these consent decrees on the industry, you know, of which he is a consumer of the product, and, you know, having seen them, further questions get generated.
What about the reports that are required?  Have the consultants been hired?  Are the reports coming in satisfactorily?  What, if not?  What is the sanction for a fractionator that is not in compliance with a consent decree, is the judge monitoring, is the judge educated to monitor, or it only an FDA process?
At what level in the FDA is a decision made about compliance with a consent decree that is ongoing?  When you have Red Cross for six years, and it is one‑half of the whole blood collection, how is it going?
I read newspaper articles about their new computer system, but what is the official report on the progress of the consent decree?  I guess one thing you could say is are these permanent or are they to be expected?  Would we be more likely to expect the other two of the four fractionators to go under consent decrees or for these two to come out?
I am not trying to be glib, I am just trying to say what is the hoped for status and what is the trend line in terms of attaining it, and I think a little bit more public disclosure would really be helpful in helping us see clearly the answers.
Thank you.
DR. HOLLINGER:  Thank you, David.
Does someone from the FDA want to respond?  Is there a public disclosure of what is happening with these consent decrees and reports produced that is available?
MR. MASIELLO:  In most of the consent decrees, there are‑‑let me rephrase that‑‑certainly in the blood consent decrees, there were time frames for reports, and there generally ended up being lots of communication on issues, but if the reports that are required are not satisfactorily completed, then, that would elevate the issue perhaps back to the court.
The question came up what is the recourse if people don't follow the consent decree.  I am not a lawyer, but I can tell you that contempt would be one of the things that you would back to the court with, probably civil contempt initially, and it went beyond that, you might actually go to a criminal contempt action.
So, these reports‑‑I guess there is an element there that you raise that is a good point, and that is, how can we communicate to you that these issues are being resolved, and it is something for us to take back and give some thought to how we can do that, because I think it is a good idea.
As we speak now, when an element in a consent decree is met by the firm, that information is not shared with the public directly.  It may be available under FOI, but there are no affirmative statements that I am aware of that the FDA takes to explain that, and that is something we can look into.
DR. HOLLINGER:  Thank you.
Yes, Dr. Koerper.
DR. KOERPER:  I have another question for you.  Maybe you could explain to some of us who don't quite understand this.  Consent decrees, are they time‑limited or are they open‑ended?  Do they end after a certain lapse of time or do they end after certain specified requirements are met?
MR. MASIELLO:  Yes, almost any of those can be the case.  There are several kinds of injunctions.  There are prohibitory injunctions where a firm might actually be closed down until all the corrections are made, and they are not allowed to open and ship products again until they are absolutely 100 percent.
Then, there are mandatory injunctions, which is pretty much the biologics area where you really can't afford to do that, because you are doing more harm by removing all the product from the market than closing them down.
So, you have established goals that they have to meet and you have time frames for that.  Most of the current consent decrees have a sunset provision, I think of four or five years.  That is not to say that in four or five years they are necessarily over. They are not over, Yogi, until they are over.
The Red Cross consent decree had a sunset provision of five years.  As someone mentioned, it is in year six, and we are not at that point yet.
DR. HOLLINGER:  Any other comments in regard to this particular item?  Ms. Knowles.
MS. KNOWLES:  I am wondering if it might be possible for this gentleman to maybe give us more information at a future meeting relating to the other issues surrounding the other injunctions for other blood facilities, just in terms of numbers, how many are still in that process, et cetera.
DR. HOLLINGER:  Okay.
I am going to close the open public hearing and just to see at this point if there is anything in regards to the committee discussion and comments.  Does anybody have an issues that have not been dealt with?
Okay.  I think we are going to move on to the next item, which is supply and demand of plasma derivatives, a most important issue.  Dr. Weinstein is going to give us an introduction and background to this issue.
III.  Supply and Demand of Plasma Derivatives
Introduction and Background
Mark Weinstein, Ph.D.
[Slide.]
DR. WEINSTEIN:  Better ways are needed to estimate the demand for plasma derivative products.  The need for this assessment has come about because of the shortage of certain plasma derivatives, particularly IGIV, and our difficulty in determining whether our efforts to alleviate shortages are working.
An accurate estimate of demand can also help FDA to prioritize activities to reduce shortages or to devote energies to other projects.  The major objective of this session is to examine ways that demand can be estimated from the perspectives of manufacturers, marketing research expert distributors, and the patient community.
By way of background, severe shortages of plasma derivatives, particularly IGIV, began in 1997.  Sporadic reports of IGIV shortages were received early in 1997, and FDA addressed requests for information from patients and physicians about product availability primarily by calling manufacturers to find out how much material they had in inventory and informing the requester about potential sources of product.
By November of 1997, however, it became clear that the availability of IGIV to patients was severely limited.  In that month, FDA received hundreds of telephone calls about difficulties obtaining sufficient supplies of IGIV.  The phone calls were from many different sources including individual patients and patient groups, physicians, distributors, and major treatment centers.
FDA inquiries to manufacturers, large distributors, and group purchasing organizations revealed that nationwide there was little product in inventory or available on the market.
Major reasons for the shortage included decreased production related to achieving compliance with good manufacturing practices throughout the plasma fractionation industry, withdrawals because of CJD, insufficient manufacturing capacity, and an increase in demand for products both for FDA‑approved and for off‑label uses.
It is agency policy to attempt to prevent or alleviate shortages of medically necessary products as best we can given our legal authorities.  We are committed to assisting and marketing and making sure there is an adequate supply available of product meeting high quality standards.
Each FDA center has a drug shortage officer who is responsible for investigating shortage reports to determine the extent and urgency of the reported shortage.  The centers evaluate potential drug and biologics shortage problems, assess the potential public health impact, and propose steps to resolve such shortage issue.
FDA's primary means of identifying whether or not the shortage actually exists is to monitor and number and persistence of inquiries from consumers, manufacturers, and distributors.
Another potential aid in estimating whether demand is being met is to determine whether the distribution of product is changing or remaining the same.  Data about product distribution in the United States is supplied to the FDA on a monthly basis by manufacturers as part of the reporting requirement regulations found in the CFR.
Although these data do not give us real‑time information or an accurate assessment of product availability in the marketplace, the data do provide information about whether the amount of product is tending to increase, decrease, or remain the same.
The next few slides will give you an idea of the nature of this data and its limitations in giving us a sense of whether sufficient supplies are available to meet demand.
[Slide.]
The data presented here show IGIV distribution data on a company‑by‑company and month‑by‑month basis in 1998.  Each box represents the distribution of a single manufacturer.  Although actual distribution figures for individual companies have been modified to preserve confidentiality, the overall trends in aggregate monthly totals are correct as represented.
The monthly distribution pattern varied widely depending on the manufacturer.
Some manufacturers of IGIV maintain a fairly steady state of distribution throughout the year, and you can see that in this white box, while others had reduced or had no distribution for a portion of the year, for example, this manufacturer stopped producing or releasing product at this point in time.
Other manufacturers tended to have a relatively low level of production during a portion of the year and then increased distribution considerably.
Therefore, the inability to meet demand for a particular manufacturer's product may not be reflected in the aggregate data for a total distribution of a given product class.
Reports of a shortage may reflect the inability of a customer to get a particular product brand.  The shortage of a specific product brand may have effects beyond being merely a inconvenience, but have medical consequences, such as allergic reactions to alternative products.
Answering the question of whether demand is being met must take into account the degree to which product brands can be interchanged, as well as whether the product class overall is in short supply.
[Slide.]
Aggregate distribution data for factor VIII is presented in this slide.  In contrast to IGIV distribution which varied greatly month by month, the distribution of factor VIII varied relatively little except for some spikes as you see here.
The distribution pathway for these two products are also very different.  IGIV is distributed mainly to hospitals, while factor VIII is distributed through home care companies and hemophilia treatment centers, thus, ways of assessing supply and demand and acquiring information about product distribution outside of the manufacturers' control are highly product‑specific, and any sentinel system to monitor these products must be done on a case‑by‑case basis.
I have made estimates of demand for IGIV and factor VIII by extrapolating data from years when there was an adequate supply of product.  Here you see an example of this estimate of projected demand.
For IGIV, I took the distribution data from 1996 and compounded that by an estimated annual growth rate of 10 percent.  For factor VIII, I have taken the distribution data from 1997 and multiplied that by 6 percent, the average annual growth in distribution from the previous four years.
From these estimates, the shortfall in IGIV distribution was 25 to 30 percent for 1998, while distribution should have met demand for factor VIII.  Yet, in fact, representatives of the factor VIII patient community reported to the PHS Advisory Committee on Blood Safety and Availability in August 1998 that factor VIII was in short supply even though there was virtually no change in the overall aggregate distribution.
[Slide.]
At present, the demand for IGIV appears to be lessening somewhat based on the reduced number of requests that FDA has received for information about product availability even though the distribution data shows relatively little overall change, that is, they are still well below this projected level of demand.
This may be the result of a feedback effect of supply on demand whereby the high cost and past unavailability of IG reduced off‑label use and inhibited the development of protocols for new uses.
Thus, in one sense and by one measure, demand has been reduced, but this clearly does not mean that the desire for IGIV has been met or that the health needs of the American public are being adequately addressed.
Exploring how demand should be measured is one of the reasons for placing this topic on the BPAC agenda.  Also, the PHS Advisory Committee on Blood Safety and Availability directed its staff to develop options to be presented to the Blood Safety director for the creation of a sentinel system to monitor production, demand, and utilization of good products, and to create projections for future demand.  Our efforts at this meeting will help to examine the feasibility of creating such a sentinel system.
Dennis Jackman and Ron Demarines, representatives from the International Plasma Products Industry Association, and Georgetown Economic Services, respectively, will speak about legal restraints that manufacturers have in sharing information about supply and demand publicly, as well as ways that they can assist us in addressing the problem of estimating demand.
Patrick Robert from the Marketing Research Bureau will talk about methods he uses to estimate short and long term demand, particularly of IGIV.
Patrick Schmidt of FFF Enterprises, an organization that manages the distribution of plasma derivatives, and Allan Dunehew from Premier Purchasing Partners, a group purchasing organization, will present their perspectives on the demand for plasma derivatives and potential indicators of demand.
Finally, Patrick Collins and Tom Moran, representatives from the patient user community, will talk about product shortages particularly the differences between needs and wants, and the ways the user community may help us estimate demand.
Are there any questions?
[No response.]
Perspective on Supply and Demand of Plasma Products
Dennis Jackman
MR. JACKMAN:  Good afternoon, everyone.  My name is Dennis Jackman.  I talked earlier.
[Slide.]
I am from IPPIA, International Plasma Products Industry Association, and our members include Alpha Therapeutics, Bayer, Baxter, and Centeon, and we are happy to be here to talk about understanding a little bit about supply and demand to provide some perspective on that.  That is what we were asked to do.
[Slide.]
First of all, we understand that stakeholders have a strong desire to really understand supply and demand for a variety of reasons, and we understand the need for information, the desire for information.  In fact, the Association provides what we think is useful monthly data on U.S. distribution, and I will talk about what that means in terms of demand.
We also, as manufacturers, are very interested in trying to meet supply.  That is the goal of manufacturers, to meet supply and meet patient needs.
[Slide.]
I think some of you have seen this data before.  This is data that is provided monthly.  It is in a tabular form, as well, but I am providing the summary charts here.  It shows U.S. distribution versus inventory over time.  This is for IVIG.
What you are seeing, these are monthly data, we are well below one, which indicates that our average inventory over time is well below one, which means we have well less than a month's supply.  The last month, in fact, for instance, was about three‑tenths of a month's supply on average.
It is not an absolute predictor of demand, but to use an FDA type of word, it is sort of a surrogate endpoint.  It sort of shows that over time, that we keep being at a relatively low level of inventory over distribution over time, which indicates there is tight supply situation.  It is not a perfect estimation of demand, but it's an estimation.
We want people to recognize that we are providing information that could be useful, and we distribute that widely.  That is one thing.
[Slide.]
I talked about the monthly trend data.  We also have, in terms of supply, some people have asked whether we can project supply as an association, and the answer is we really can't.  We got a legal opinion from outside counsel, one of the top antitrust firms in Washington, that made it very clear that it is illegal for an association in any way to facilitate the exchange of information on projecting supply or for us to project supply.
Saying that, again, we are trying to collaborate in any way we can and cooperate by providing our monthly data, but we can talk about what impacts future supply, and we do think that future supply is heavily impacted, of course, by our investment in plant capacity and new processes, and that is how we are trying to meet the supply demand, but also regulatory actions.
Regulatory actions have a major impact, actions like, for instance, today, the post‑donation information decision will have an impact on supply.  There are other regulatory actions, as well, product and process of plant approvals, how rapid will those be, when will they occur.  That will have an impact on supply.
Compliance actions, those will have impacts on supply.  Those are very hard to predict with any accuracy, but that gives you some idea of the factors that affect supply in the long term.
[Slide.]
Turning to demand, first of all, as I mentioned, we produce this distribution data.  I want to make it clear that it is consumption data in a sense.  It is distribution.  It is not demand.  Demand and consumption are two different things.
There may be pent‑up demand or unmet demand in the marketplace, and there are many indications that that may exist.  So, what we have is distribution data.
The trend data does give you some ideas, as I described earlier, on predicting demand, because you can sort of see if you are on balance meeting that consumption.  If your distribution or your inventory is not building up, you are probably just meeting demand or undermeeting demand.
There are a number of demand measurement challenges I would like to talk about, as well, and I think other people are going to address those.  First of all, demand of our products is affected by a multitude of variables, it is prescribing, it is usage, it is reimbursement, as well.
If you have a demand for a product and the reimbursement isn't there, that demand may not be met.  So, a demand curve is always based on a given amount of demand at a given price, given certain amounts of reimbursement, and if reimbursement doesn't exist at a certain level, then, it can affect the demand.
Those are hard to measure, and they are challenges.  Costs are another thing that could impact demand, as well, cost of the products, and of course price of the products.
So, I think we have some reliability issues in trying to project demand.  At a macro level, having some general ideas of where our demand might be going could be useful, but I think everybody has to be aware of what the limitations are in terms of reliability and its usefulness as a predictor or certainly we think there are several limitations on that type of thing and predicting regulatory action or in any way trying to target regulatory action toward where they feel there is an imbalance of supply and demand.
We think there are so many limitations with the data that that may not be the best way to go.
[Slide.]
The summary is our goal really is to meet patient provider needs and demand.  We feel that estimating future demand does not ensure that the demand will be met, and that is stating the obvious.  It may provide some useful information, but we want to do things that really would try to help us to meet demand.
Individual companies and members of our association are all robust competitors.  They are going to seek to meet demand.  Every textbook model, we have all had our Economics 101, every textbook model shows that given a certain amount of revenue possibilities, certain costs, the competitors will seek to meet demand, and they will succeed in meeting that demand officially.
There is no more efficient market than the U.S. market.  Any type of proposal with the try and tune, and match up supply and demand at a federal level and then try to pick federal actions on that basis, I think probably are not going to be that successful over time.
I think that most fruitful would be policies that would optimize our ability to meet that demand, and that means reimbursement, again, hopefully, we will have reimbursement policies that are in place that will allow patients to have their demand met, if the physician prescribes a product, that they can obtain it, because we have adequate reimbursement.
Secondly, an improved cGMP environment.  That means that we are working with the agency.  We just had a GMP workshop in May to try to improve our common understanding of GMP requirements and take those back to our plants, and continue to enhance our training and our investment, and trying to meet GMP, and that will help us to meet supply and demand.
Also, product and process approvals.  If there is anything that we could do, and again, I think this is a group and team effort, all the stakeholders have to be involved, but to improve the product and process approval requirements, clinical trial requirements, review requirements, and achieve that balance, the optimal balance between cost‑benefit, that will help us to meet demand, as well.
Thank you very much.
DR. HOLLINGER:  Thank you.
DR. EPSTEIN:  I did have one question for Mr. Jackman.  As you well know, the FDA does not have authority to control exports.
We treat export of products the same way we treat interstate commerce under our laws, and yet it is a fact that only about half of the plasma collected for fractionation is utilized to satisfy the U.S. demand for plasma derivatives.  The other half is presumably exported and used in other countries, and also some portion of the finished products of manufacturing by U.S. fractionators ends up in export.
I would just like to ask you, and recognizing that the majority of large U.S. licensed fractionators are in fact not U.S. owned, I would like to ask you how does your industry look at the issue of whether there is some moral obligation, not a legal obligation, but a moral obligation to satisfy the U.S. need from the donations that are obtained in the U.S.?  In other words, recognizing that there is a twofold excess of collection relative to the U.S. need for endproducts, why are we ever in a situation of inability to supply the U.S. need?
I would just ask how do you look at that issue?
MR. JACKMAN:  I would be happy to answer that question.  First of all, we are, in terms of IVIG because we are talking about IVIG here very heavily, there was testimony given, I think it was last year, that showed that about 80 percent of the IVIG stays in the U.S. market, and about 20 percent of it is exported.
We also are importing about 20 percent, as well, so there seems to be pretty much a balance there.  I think anybody would indicate that the most efficient way for world to work is to have mobility of goods and mobility of therapies, because where the needs are greatest at one point may change over another point.
We may at some point need a European manufactured product to satisfy some of our need.  As a matter of fact, there are products that are available in Europe, in fact, some of them, we have their applications pending at the agency.
I think a perfect example of helping to meet supply would be Endobulin.  There is a product that is produced by one of our companies, Baxter, that was mentioned at an HHS hearing about nine months ago.  It is being sold in Germany and a number of countries, and the company would like to bring that in the United States.  So, there is as an example where if we could act promptly on that kind of an application and get that product here, we could bring it right into the country, and that would really benefit our supply situation.  It shows that mobility of goods both ways can be very beneficial.
In terms of other products like recombinant factor, those type of things, there is every indication, I have seen some data out there that show that the U.S. population is getting‑‑if you did it on a strictly proportional basis‑‑the U.S. population gets more than a proportional basis of the products, way more, and we could take about some of those data, but I have seen some data to indicate that.
So, I don't believe that the U.S. is being disadvantaged, in fact, I think that on the recombinant factor side, for instance, you want to make it so that it is beneficial for us to both manufacture here and distribute here, and meet the demand here, and we are trying to do that, and there is indications that we are doing that.
At the same time, if there is demand that has to be met overseas, you are going to try to meet that, as well, because after all, some of those patients have no other choices for therapies.  So, that is a moral obligation, too.  We consider it a moral obligation to supply patients throughout the world, and I think that is a moral obligation.
DR EPSTEIN:  I appreciate those remarks.  I think there is perhaps opportunity for some misunderstanding in that the products that you are calling imported are still fractionated from U.S. donations.  These are, for example, the recovered plasmas.
MR. JACKMAN:  I am talking about finished products.
DR. EPSTEIN:  I know, but the ones that are imported into the U.S. by U.S. licensed manufacturers abroad are still fractionating U.S. plasma.
MR. JACKMAN:  But Jay, actually, the situation is we don't have right now at this point, the United States does not have a shortage of plasma in terms of producing what we could do, our plants could run at capacity with the plasma we have, where if there were a shortage of plasma, that might be an issue, but it is not an issue.  We are running at full capacity.
Actually, if we could let our plants run fully and get them up to full production with a predictable environment in terms of compliance and all those, if we could optimize that situation, we would help to alleviate the supply situation in a great way, and if we could get more rapid product approvals on some of the process‑‑in fact, for instance, there was a process approval application, there are several others in there that could increase yields of plasma by up to 40 percent.
So, rather than worry about if the plasma is moving to other places, when the U.S. demand has already been met, or U.S. manufacturing needs have already been met, let's think about how we can get greater yield out of a liter of plasma.  That would be I think the most fruitful discussion.
DR. MITCHELL:  I still don't understand what you are saying.  On the one hand, we are saying that there is a shortage of IVIG in the U.S., but you are saying that there is full capacity of the manufacturing plants, and therefore there is no problem.  Is that what you are saying?
MR. JACKMAN:  No.  What I was saying was in terms of plasma, the question was about exporting plasma, whether or not plasma is being exported, we don't have a problem in the manufacturing side in getting the plasma we need to produce the IVIG we need.
What we have is that there is some temporary production interferences or interruptions as a result of some of the activities in terms of trying to achieve full compliance with GMPs.  So, that is the situation there, but we have to make sure we are talking about, you know, it's apples and oranges.
DR. MITCHELL:  So, you are saying that you are not exporting IVIG or producing IVIG from U.S. donations that are being sent to elsewhere in the world?
MR. JACKMAN:  No, I am not saying that.  I am saying that we are producing IVIG that is being exported, but at the same time we are bringing back in product that is a net sum, zero sum gain, but the issue isn't plasma, the issue is enough product coming out of the plants.
DR. MITCHELL:  You agree that there is an IVIG shortage in the U.S.
MR. JACKMAN:  There is an indication that we‑‑yes, there is an indication that we are on‑‑there is not much inventory in the pipeline versus supply, and that there is probably demand that goes beyond that.  I think that IDF will talk about that in more detail, that there probably is additional demand that is out there.
But we are manufacturing basically all that we can right now given current limitations.  We are exporting some and importing some.  If you were somehow to say let's not export that small amount that we are exporting or that amount that we are exporting, then, what would happen to those imports?
DR. MITCHELL:  So, you are saying that the amount that we are importing from blood sources in Europe or from blood donors in Europe is equivalent‑‑
MR. JACKMAN:  Again, the point of the matter is that the amount of finished product being made available in the United States, when you compare our exports to our imports, is basically a net sum gain, whatever the source of the plasma is.  To me, the issue isn't the source of the plasma because we don't have a shortage of plasma right now.
The point is that we are importing as much finished product roughly as we are exporting.  So, in terms of the actual finished product that is available to consumers that are in there, that is a net sum zero.
DR. HOLLINGER:  But if you wouldn't export that amount, you would then have enough for inventory.
MR. JACKMAN:  You know, there is a market situation here.  If we try to limit that in some way, what would happen then to that manufacturer who is now currently selling and exporting to the United States, if all of a sudden, we then say, all of us, we are not going to send any of that overseas to sell to some of those customers and markets overseas‑‑and some of those are Canada, by the way, I think there is some agreements with Canada and requirements that some contractors have, and there is an obligation because they don't fractionate there‑‑but what would happen then?
I mean would that mean that all of a sudden‑‑I can't predict this because we haven't had that conversation, but you have to think about some possible unforeseen consequences.  In that situation, that manufacturer may say well, that supply is now remaining in the United States, now there is a gap over here, I will just sell it over here.
I mean the world works that way.  Where there is demand, manufacturers will try to meet that demand, and to try to sit here, either as a committee or an agency, and try to carefully plan where a product goes and where it doesn't go, it hasn't seemed to work very well in many centralized planned economies.
I wouldn't recommend we got that direction.  I think what you wind up doing over time is you wind up discouraging potentially investment in the United States.  If the demand is overseas at some point, you just basically are saying why don't you just invest in other places, if you can't have the free mobility of your goods.
You are encouraging, you are basically discouraging investment in the United States.  So, there are a lot of consequences to those kind of behaviors.  In fact, Secretary Shalala, in a letter in response to the Advisory Committee on Blood Safety and Availability, in response to a question about whether there should be any kind of limitations on exports said as much as I understand the desire to supply the U.S. population, she did not feel that the idea of in any way limiting exports was a wise idea because it has so many unforeseen consequences.
It has been tried the past, it hasn't worked, and you probably will wind up doing more harm than any good.  So, what I would like to turn back to is let's look at the regulatory policies that we can implement that would help us to meet the demand as manufacturers.
Let competitors try to meet the demand by improving the regulatory environment by accelerating approvals, by looking at surrogate endpoints, by looking at clinical trial requirements.  There are processes out there that could greatly increase the amount of supply if they were acted on as quickly as possible, we would see no problem with supply, and supply and demand would be met, and we wouldn't be worrying about exports.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  Is the average price per gram for IVIG in Europe higher or lower than the United States?
MR. JACKMAN:  I don't have data on the pricing in every single country, but I have asked people what is the marketplace out there a little bit.  It varies country by country.  In some cases, the European price might be higher, in some cases the country price might be lower.
The U.S. is not always the highest, and sometimes not the lowest.  The interesting thing is we have had some complaints from European patient organizations that are starting to say, gee, we don't even want you to export the product you are sending, we don't want to see European product going to the United States for a higher price.  That has actually been said.
So, we have people over there, other advisory committees and other advisory groups trying to say, look, why don't we try to hold back here.  That is all we need in the world is to have a number of committees sitting here trying to say let's hold everything here, let us control the market, we are smarter than the marketplace.  I don't think that is going to work.
DR. MITCHELL:  So, is there a shortage in Europe also, and is there a sense that it is the same magnitude?
MR. JACKMAN:  I don't have a sense of the supply and demand balance in Europe.  I have heard, I think at a recent symposium, the representative of one of the patient groups there that uses IVIG indicated that he felt there was a tight supply in Europe, as well, but I can't give you an absolute accurate assessment of that situation.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  At the last meeting we discussed clinical trial design and how that could be used to speed up and help alleviate the shortage.  Has there been any progress?  It has been three months.  That was supposed to be a more rapid way of looking at this?
MR. JACKMAN:  We would like to see progress in that.  I am sure people may want to comment on that, but we think that there is room for progress clearly.  I know that they are working on trying to come up with some clinical trial requirements, new clinical trial requirements for new IGIV product, for instance.
At the same time, we have had applications pending out there.  I don't want to comment on the particular merit of the application.  That is open to discussion, but when it is taking a certain amount of time to do that, you just have to look at it and say are there any ways we could accelerate that.
Are there ways, for instance, we could harmonize applications between Europe and the United States that might help us to accelerate that when you are trying to bring a product in from Europe, that we could have that kind of harmonization.
Are there ways to develop surrogate endpoints?  I know that is being looked at by the agency for IGIV.  When you have a new process for a product, does that require a large clinical trial, treating it as if it is a brand‑new product, when, in fact, it is still IGIV, does that require a full‑blown, large‑scale clinical trial, or can it be done with surrogate endpoints and with a smaller n?  All of those kind of things.
By the way, all the manufacturers in the association play user fees, so under PDUFA, the User Fee Act, there are supposed to be timelines as to when things get acted upon.  When an application takes place, there is a clock that starts ticking, so trying to adhere to that PDUFA timeline would be helpful, as well, on a number of applications.
DR. GOLDING:  Could I just comment in relation to the previous question and some of the comment that Mr. Jackman made earlier?  My name is Basil Golding.  I am from the FDA.
The question of foreign suppliers sending in applications to the United States and asking for approval for use of their IGIV, this is being looked at by the agency in a manner at to try and expedite those reviews as quickly as possible, and there have been multiple meetings and a lot of time and effort devoted to that, and I think you are probably aware of it, plus the trial design issue has been a major discussion point between the agency and the IDF and manufacturers, and this is an ongoing process.
I think many steps have been taken in the right direction which will speed up the trials and the approvals, so I think as far as from our perspective, I think it is fair to say that everything is being done or much is being done to try and approve more IGIV as quickly as possible and to make sure that the FDA's part in this equation is to optimize the process.
MR. JACKMAN:  That is great to hear.  As I mentioned, I know that some actions are being taken.  I think in response to the question, a review of everything possible that could be done, and including a review of FDAMA, the FDA Modernization Act, and its application to our products would be useful, accelerated approvals.  Those are envisioned for biologics.  In a supply shortage situation, it is clearly envisioned under FDAMA as one of the areas we should be focusing on for accelerated approvals.
It is not just the AIDS drugs and protease inhibitors.  It is where we have a population that could use the product.  FDAMA clearly applies, and i would be happy to share more of that information.
So, if we could work and maybe have a symposium where we could explore what the possibilities are, and make sure we are doing everything possible to optimize the approval and review environment, we would welcome that.
I know that has been talked about a little bit and it is something that we would envision being happy to do, and I think that could have some positive results.  It won't be immediate, but in some cases, some of these product applications would be an immediate impact.
DR. HOLLINGER:  Dr. Ohene‑Frempong.
DR. OHENE‑FREMPONG:  Are you suggesting that if the approval regulations were streamlined somehow, that it would be easier than to import finished product from Europe to meet the demand in the U.S.?
MR. JACKMAN:  That is one side of it.  I am not just talking about the European imports, but I know for a fact that there are some applications or at least an application, and I mentioned one product Endobulin, that is being sold in a number of European countries.  The application is pending, and if that were approved‑‑and there may be reasons why it hasn't been approved yet, I know they are working on it‑‑but the fact of the matter is there is a timeline.
This was talked about nine months ago, so the sooner that gets approved, every month that goes by, that Endobulin is not in the marketplace, and that Endobulin will have a significant kick to the IVIG supply, and the manufacturer is anxious to import it and anxious to sell it to meet demand.
So, we are talking about projecting demand and trying to estimate, well, we know that the demand is there, it is a matter of let's get the product in.  So, that would help there.
Secondly, it is not just that.  There are process applications and things like that are being talked about, that if those process applications were approved, and every month it takes‑‑let's put it this way‑‑every month longer it takes to approve that, we don't get the benefit of that new process, and one process would increase the yield from a liter of plasma by well over 30 percent.
So, think about what the implications are of that process if it gets reviewed rapidly and approved on the IVIG supply situation.  I think that is where the most fruitful focus would be, and we are willing to engage in this in every way possible, make constructive suggestions and work with government, the decisionmakers.
DR. HOLLINGER:  Mr. Demarines.
Ron Demarines
MR. DEMARINES:  Thank you very much.  My name is Ron Demarines.  I am with Georgetown Economic Services.
Let me give you a little background on Georgetown Economic Services, GES.  It is a research firm that designs and implements market research, both domestic and foreign.
We provide market analysis for a variety of clients including trade associations, industry coalitions, lobbying groups, and corporate clients in a variety of industrial, consumer, and agribusiness products.
GES has years of experience in conducting surveys to evaluate the overall health of an industry by tracking economic indicators, such as shipments, consumer and industrial demand, profit levels, employment capacity, cost of goods sold, a number of a variety of other indicators.
We also provide analytical suppose for industry groups in their dealings with government regulators.  In this capacity, GES provides analysis of the economic impact of government regulations including environmental, trade, and worker safety regulations.
I was asked her to come here to describe the process that we envision to measure demand for several blood derivative products, especially IGIV and factor VIII.  I have to tell you that I am not an expert in this industry.  We are certainly expert in measuring demand.
As I understand the current market situation, the rate of demand growth for IGIV and factor VIII has led to periodic shortages in the two products.  In some way, the blood derivative market is very much like a traditional commodity market that we dealt with at GES.
There are several layers of distribution between the producer and the end user.  There is a spot market operating alongside a long‑term contract market, and the uses of the products, new uses are constantly being developed, creating a new demand for the product.
But unlike most commodity markets, applications of some of the products in this industry, in the blood derivative industry, may be expanding at a far greater rate than could be envisioned just a few years ago.
Predicting current and future demand for these products is a challenging task.  The obstacles include unpredictable, long‑term applications of the product, especially in off‑label applications, and the lack of a comprehensive and centralized body of data on current usage.
In addition, the demand for these products is highly inelastic, and that is, there is very little correlation between the quantity of products purchased and the price of the product, and there are also very few substitutes for these products.
Therefore, traditional indicators of demand don't come into play here to the degree that they would in some traditional commodity‑driven market.  Some of these indicators would be days of supply in the pipeline, order backlog, and spot versus contract price.  So, these would not be able to be used effectively as an indicator of demand in this industry.
In arriving at the level of current demand for these two products and projecting future demand, an understanding of the market dynamics is needed.  In this respect, the most valuable source of demand data would come from the distribution channels.
To calculate demand, hard data must be gathered from the distributors, other middle men, and the health care providers.
[Slide.]
Most of you probably cannot see this, but this is the various levels in the distribution channel for these products.  As I said, I am not an expert.  You will notice that I have mislabeled IVIG.  I put IVIG.  We didn't catch it, but it's IGIV.  Sorry about that.
The group purchasing organization, because as much as 80 percent of IGIV sales are made to group purchasing organizations, GPOs, this group of companies will play a key role in demand calculation.
I envision a survey designed to gather the level of purchases and sales over at least the past eight quarters.  Data on sales intended for FDA‑approved usage, and off‑label usage should also be captured from the GPOs to the extent that they can provide that information on this subject.
Questions regarding pricing to the next level of distribution should also be gathered in this process.
The next group is the wholesalers.  Because the wholesalers are positioned between the GPOs and the next level of distribution, their insight should provide a valuable information on the demand for these products.
Since wholesalers distribute as much as 80 percent of all prescription drugs, as I understand from the research that I read recently, this group of companies should provide further information on the trends in sales for FDA‑approved usage and off‑label usage.
This group should also be a source of information for future demand for the blood derivative products because they tend to be further down the supply chain.
Data provided by dealers, the next level, will provide still further awareness of the current and future demands in the marketplace.  Because this groups serves the spot market, the level of sales gathered from the dealers should provide an additional level of data for calculating current and future demand.
Finally, in the distribution chain, the home health care segment.  They report a 20 to 25 percent of IGIV and more than 70 percent of the clotting factors.  This group is perhaps closest to the end user and should be a valuable source of information on the demand and current and future of the blood derivatives.
In addition to the research surveys and interviews in the distribution channel, we would further suggest doing a series of interviews with medical researchers from, for example, the National Institutes of Health and other appropriate agencies, as well, selected biotech firms, also researchers and scientists employed by IPPIA could provide additional information and background material on new uses for the target products.
Other sources of information include the Immune Deficiency Foundation and the International Patient organization for Primary Immmunodeficiencies or the National Hemophilia Foundation.
The objective of these one‑on‑one interviews is to probe into the most recent research on off‑label usage for these products and to assemble some degree of consensus as to the future demand for the application.
[Slide.]
Based partially on this information that I have just described, we will suggest putting together a demand scenario for a one‑year, three‑year, and five‑year period.
What I have up here is basically a table that describes how we are going to take the data, how we would envision taking the data from the information we have gathered, and putting it into a demand formula.
The demand calculation will be further shaped through projections of usage for both FDA‑approved applications and off‑label applications.  For example, an analysis of the immune deficiencies requiring FDA‑approved IGIV or factor VIII treatment should be undertaken to determine the percent of the population with these deficiencies.
This analysis will likely be based on survey results, one‑on‑one interviews, and a review of the published medical research.  One‑year, three‑year, and five‑year projections of demand should be constructed by examining U.S. population growth, the projections for this population growth relative to the level of individuals with immune deficiencies, the average annual per‑patient amount of IGIV or factor VIII given as treatment for each of these types of deficiencies should also be factored into the calculation.
Of course, other factors enter into this calculation, such as duration of the treatment and the age of the patients, et cetera.  The same procedure should be utilized for off‑label applications and the same types of projections would be based on these types of calculations.
I was told to keep the comments brief, so I did, and if you have questions, I will be glad to try and answer them.
DR. HOLLINGER:  Thank you.
The next discussion is going to talk about background considerations for the estimation of IGIV demand.  Mr. Patrick Robert, president of the Marketing Research Bureau, Inc.
Background Considerations for the Estimation
of IGIV Demand
Patrick Robert
MR. ROBERT:  Good afternoon.  My name is Patrick Robert, Marketing Research Bureau.  Our firm has been involved in collecting data for the blood industry a few decades.
[Slide.]
On the first overhead is a presentation of the sales of IVIG since 1981, shown in 2.5 grams units, so as you can see, it has been fairly steady growth.  It's about 8 to 10 percent growth per year except for 1997, where it started decreasing following the events which we have been talking about today.  I believe that you have heard about 1998 and 1999 where the growth has been negative again.
So, this is a reflection of the very great success of polyvalent IVIG or IGIV, as you prefer in this country as well as in other countries, as well.
In 1995, our company undertook a forecast study to attempt to determine what would be the demand for IVIG in 2000.  I apologize if there is some overlap with the previous speaker, but many people are interested in knowing the same thing obviously.
This study was completed.  Obviously, it was done four years ago, so it is somewhat out of date, but back then in late 1995, we predicted the market to be about 18 metric tons by 2000.  If I am not mistaken, in 1998, approximately 15.5 metric tons were used in this country, so the growth, the demand is still growing.
[Slide.]
Now, our methodology is strictly going from the bottom up, and we first went to the medical literature to see what medical indications were used, for which medical indication IVIG was prescribed, and this is just the beginning of one updated list of such indications, which were used for an update of the study, which we will begin soon for completion by the end of this year.
The way we do is to ask the end users, that is, the prescribers, the physicians, and also ask them questions about alternative therapies, possible changes in dosage, what is the impact of cost and reimbursement, and, of course, the impact of access to the product, and we combined this with all kinds of demographic and economic and social data.
So, we hope to be able to update and come up with more reliable figure for a forecast of the demand for IGIV in this country by 2004, whatever, 2005, three‑year horizon.  So, this is what we do in this country, and we do similar work in other countries, and that is pretty much all I have to say today.
Thank you very much.
DR. HOLLINGER:  I am not sure I understand how you got your figures.  I mean of 14 metric tons in 1997, and so on, where did that come from?
MR. ROBERT:  This is rather complex methodology, which I don't know if I have time to explain here, but we go to the number of patients which received the product by medical indication.  We apply a dosage or we know the dosage which translates into grams.
DR. HOLLINGER:  Where do you get the number of patients, for example?
MR. ROBERT:  The number of patients is actually provided by a supplier of data, which I understand uses some government data to start with, number of patients hospitalized with certain medical conditions.  I think there is national health surveys, and these type of data.
DR. HOLLINGER:  Dr. Boyle.
DR. BOYLE:  I would like to follow up.  The health interview survey doesn't include some of the things that are up here.  Did you use that or did you go to physicians and other providers to identify the various conditions you are talking about?
MR. ROBERT:  I mentioned the national health survey.  This is probably not the right term, but there are all kinds of databases supplied by the government, but, in fact, I did not use these data directly, but these data as processed by another supplier, which I updated and reformulated the figures, and completed the figures for my purpose.
DR. BOYLE:  There is good news and bad news here.  The good news is that your figures are widely quoted, and they have been quoted in a number of the projections about demand and supply and demand.  For that reason, I think we are all very interested in a fairly detailed understanding of how you got to where you got.
Did you interview a national sample of providers to estimate what they were doing?  Tell us what you did.
MR. ROBERT:  As I said, I don't know if we have time to go into detail, but yes.  I interviewed a number of opinion leaders and a number being about 25 back then, which is not many, but that is the number, and we also undertook a mail survey among several hundred physicians who prescribe IVIG, so as to balance the responses from both groups.
DR. BOYLE:  Do you mean you received several hundred questionnaires back from those who were treating?
MR. ROBERT:  I sent out several hundred.  I did not have a very good response, I must confess.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  I would like to go back to a previous question.  Could you give us an idea of what the supply issues are in Europe, and is there a shortage in Europe similar to what we see here in the U.S., and is the monthly supply, is there less than a month's worth of supply available in Europe, or is the supply in Europe different?
MR. ROBERT:  I am sorry, I don't have monthly supply data on Europe.
DR. HOLLINGER:  Dr. Verter.
DR. VERTER:  If I can follow up on where I think Dr. Boyle was heading.  Is there anyone in the room who knows, one, how much is manufactured in the United States in 1998, what the total manufacturing was?  If you know that, is there anybody who knows how much was sold to intermediaries?  The last question, which I am sure no one knows is how much was actually used by the individuals?
I think we have heard in previous reports of this committee that it is very difficult to get good data because even the doctors who service these patients don't often know how frequently they use it, how much they use it, so it is self‑regulated by the patients from I think what Dr. Boyle and others have told us in previous meetings.
I don't have any concept other than what I hear constantly that there is a shortage.  I don't know how to quantitate that shortage, and I have never heard any data that gives me an insight on how to quantitate it.
MR. JACKMAN:  I will try and answer that question.  In 1998, it was approximately 15,000 kilograms of IVIG manufactured and distributed in the United States.  Most of that goes through intermediaries in some way, shape, or form.  In the broad sense of the word, intermediaries, home health care companies, a number of people like that, that would distribute it.  It does not go directly to consumer.
DR. MACIK:  I am listening to a lot of talk about demand, but do we really have any idea of what the demand is?  It seems like we are using a lot of formulas about how much you sent to distributors and what was happening, but I mean can't we go to an individual hospital or‑‑I mean somebody wrote a prescription for that patient to get IVIG.  How many prescriptions were written in a year?
There should be some way that we can tabulate what is happening to know what is going on here, because it doesn't seem to add up between where product goes, and yet the end user saying they can't get product.
I realize that marketing is a very complex process for a poor clinician to understand, but somewhere, somebody prescribed a drug, and the patient is using the drug, and somebody is bringing to his home, we can't get an idea of who much is actually being used.
DR. KOERPER:  Usage does not equal demand.  I think that is part of the issue here.  We may write prescriptions for 25 grams of IVIG, but there may only be 20 grams available, and that is what the patient gets that month, or the patient may skip a month or the patient may have to go for five weeks instead of four weeks.
So, simply tabulating the prescriptions or what was actually administered doesn't capture what it is that physicians would like to have given under optimal circumstances.  That is the intangible that we are having trouble getting ahold of.
DR. MACIK:  I understand that.  In fact, that actually was my point.  I mean do we really know what the demand is because we don't even know how much we are giving out.  Nobody can even tell us how many prescriptions we have written, whether or not they were met.  Even if we assumed that they were all met, we don't even know how much that is.
Then, it comes to the second point, which is what you are saying, is do we know how much of that was actually given.  At some point, you know, in hemophilia, we have our patients keep a log of how many units of factor did they infuse.  You add up all the logs, and you get some idea of what was used, and then you can go back and say how often did you not give yourself an injection when you thought you might have.
There seems to be something kind of lacking between trying to get some information about what is out there and what true demand is.
DR. KOERPER:  I think the endpoints aren't quite as finite with the use of IVIG as they are with hemophilia.  In hemophilia, patients bleeding now, he knows if he needs a dose now, he knows if the bleeding stopped if he gave himself enough or it didn't stop and he has to give a second dose, he knows right away, whereas, with IVIG, the intangible is did the patient more or less infections over the course of a month, and it's a little hard to have an immediate cause and effect, the way you can in hemophilia.
DR. HOLLINGER:  So, we know basically, if we take the numbers that were listed here, we know how much is manufactured, but what you are saying is that actually, the prescriptions might have been written for 25,000, and only 15,000 is available to use.  That is the issue that we don't know.
Does anyone here know how much is used off‑label, the percentage that is used off‑label, do we have any approximations?
DR. GOLDING:  I don't think there are accurate figures for this, but many leaders in the field from large medical centers that were asked this question said in the region of at least 50 percent of the use was off‑label.  I think the IDF also believes that this is the ballpark area of off‑label use.
DR. HOLLINGER:  Thank you.
DR. KAGAN:  I just want to make one brief comment.  At our university hospital, our Pharmacy and Therapeutics Committee has come to those of us who use it off‑label, and said you are out, you wouldn't even possibly go on the list at this point for consideration.  So, orders from our hospital are really being limited to those where there are true indications, and the off‑label people aren't even getting the chance to write the prescriptions or write the orders for the patients to have it in the first place because it's such a low priority given this apparent shortage.
DR. HOLLINGER:  Thank you.
The next discussion is on The Impact of Distribution on Supply and Availability:  A Premier Model.  The first discussant will be Patrick Schmidt, CEO of FFF Enterprises, Inc.
The Impact of Distribution on Supply
and Availability:  A Premier Model
Patrick Schmidt
MR. SCHMIDT:  Thank you very much.  It is a pleasure to be here.
[Slide.]
Listening to the last few minutes of conversation, I was struck by the observation that we have had over the last several years, that this is an industry that is starving for data.  It is very difficult to come by, and I don't know if we can answer some of those questions, but we are certainly going to give it a try.
[Slide.]
A little bit about FFF.  You have probably never heard of us, but our corporate mission statement is called "Helping Health Care Care."  There are a lot of abuses that take place at the blood products distribution market.  I may have time to touch on those for a minute, but that is our corporate vision.
[Slide.]
Our corporate mission statement, I will just focus on really the key words.  Everything that our company gets involved in has to do with availability, affordability, and safety of crucial products, and we try and create innovative distribution systems, and those innovations have come from our customers.
We consider our customers the manufacturers of these products, as well as the end users, and every innovation that we have been credited with has been a customer‑driven innovation.
[Slide.]
FFF was started in 1988, a little more than 10 years ago.  I had no idea that I would be here today.  I was a former football player.  I didn't even know what blood products were.  A company named National Medical Care, when I was trying to sell them some latex gloves, said, "We won't buy your gloves."  I said, "What would you buy if we had it?"  They said, "We would buy some albumin."  I said, "What is albumin?"
That is how we got into the business, and I have learned, and I was again struck by the comments here.  I have learned, and our company has learned and maintained that same mission, to ask the customer.  They have a lot of answers, and I think that is one thing that we are very good at.
After 11 years, we have nationwide distribution of especially pharmaceuticals, 80,000 square feet, 88 people, and I am very proud of the picture there, because we built that two years ago, but I also put this up for one reason.  FFF houses the Federal Repository for Intramuscular Immune Globulin.  We keep a reserve there that is not accessed unless we collaborate with the CDC, and there has been a shortage of IMIG over the last several years, and we have come up with some innovative situations to make sure that that product is available.  So, that is the National Federal Repository for Intramuscular Immune Globulin.
[Slide.]
About our role in the marketplace, this year we will distribute close to 5 million grams of IVIG and 5 million equivalent units of albumin.  We also administer some of the emergency allocation programs, the IDF Safety Net program, and the products that we distribute through the IDF in collaboration with the IDF Safety Net program, the American Red Cross product, Baxter, Centeon, and we also do the emergency screening for Alpha Therapeutics emergency allocation program, so we have a lot of data, we have a lot of close contact with the physician and the patients.
[Slide.]
Those 5 million grams and 5 million equivalent units of albumin are distributed among the top 10 group purchasing organizations in the country.  This is a list of the top 11.  I think there is 9 bars that we have contracts with.
This is the market share that I think has been unprecedented in terms of a single company rising to, and it is not because we do anything better than anybody else, but we have listened to the needs of our customers, and we think we have responded accordingly.
[Slide.]
Our presentation is called A Premier Model.  I wanted to emphasize the impact and the influence that a group purchasing organization has.  Nearly every health care entity in the U.S. has some group purchasing affiliation, whether it be a hospital, a home care company, or a physician office, and when you combine those together, it is referred to as the latest acronym, the Integrated Health Network, but group purchasing organizations have a tremendous amount of influence, and it is a tremendous amount of data that we can gather from that influence.
[Slide.]
When we bring on a new customer, a new contract customer, a new group purchasing organization, it presents to us a significant opportunity that we think has not been taken advantage of in the past.  It is a data mining opportunity for us.  We survey the demand for therapeutic plasma fractions.
We don't send out a survey and hope it gets mailed back.  We exhaustively survey.  We go out and ask the customer again what their needs are, what the demand is.  We believe we have some of the most accurate usage data in the country.
We use that data to refine our contracting strategy, because for us to be successful, we have to meet the needs of our customers, and our customers are the hospitals, physician offices, home care companies, that are the members of the group purchasing organizations.
In a time of a shortage, a very labor‑intensive effort that we put forth is what we call "interactive allocation system."  Instead of putting a lot of product into a single location where one hospital may have 7,000 grams on hand, another hospital may have zero, we interactively allocate product to make sure that we are meeting the moment of use demand.
Again, it is a very labor‑intensive process, and i believe we are the only people in the country that do that.  From that, from our sophisticated database systems, we monitor usage by GPO, by entity.  You said this is what your demand was, you are over that demand, help us understand why.
We have got a new oncologist, we lost an oncologist, he has transferred to another facility, so we track usage by GPO, by entity.
Then, in the future‑‑this may be considered a paid political announcement‑‑but we have from talking to our customers, there is a need to track blood products to the end user.  FFF has designed over the last two years a proprietary software product that can track blood products to the end user.  It integrates easily with every hospital, home care, physician, or blood bank system.
It is very inexpensive, and it will provide for the first time we believe moment of use data.  At the last Advisory Committee on Blood Safety that I was at, someone asked could we track product by patient, and to track patient movement when you have a shortage and you have an allocation, can you track that patient movement.
One of the characteristics of this last shortage‑‑I feel like I am talking fast, because somebody said I only had 15 minutes, and we are from California anyways, we talk fast out there‑‑but someone said could you track, could you track the patient movement, and our Lot Track system will allow us to do that, because one of the characteristics of the last shortage that I believe has been dreadful is patients have had to migrate from provider to provider based on who had the product, and we would like to see an end come to that.
But the hallmark of the notification system is we can provide instant notification in the event of the first hint of product compromise.  We believe anybody can distribute products.  This distribution business is not a very exclusive club, believe me.  I got in it.  It is not a very exclusive club.  [Laughter.]
Anybody can distribute product.  It takes a company that really wants to help health care care get them back at the first moment of compromise, and that is really what our mission is.  We are very good at tracking lot products.  We endeavor to be the best in the world at it.
[Slide.]
I was reading the other day and I came across this quote.  "To acquire knowledge, one must study, but to acquire wisdom, one must observe."  Our observations over the past decade in this business have led to some of these, what we hope to be changes in the business.
One of my best buddies, who I think is one of the top guys in the fractionation business, this was a quote that he used, and when we present our program to group purchasing organizations, I always lead with this.  The plasma fractionation market is characterized by steady, increasing demand met by inconsistent manufacturing.  The risk of something happening is 100 percent.
I took his name off to protect the innocent.
[Slide.]
In thinking about the presentation, and when we talk to pharmacists around the country, over the last year, we have probably spoken to 1,000 pharmacists in settings just like this.  This is probably the most important slide of our whole presentation because there is so little knowledge out there in the prescriber community as to the relationships between these products.
When I see this, I think of a three‑legged stool, and in that three‑legged stool, two of the legs are getting shorter.  It creates a very unstable place to sit on.  You have decreasing demand for albumin, you have decreasing demand for plasma‑dried factor products, and you have got a burgeoning demand, unmet demand for IGIV.  We have a very unstable situation here.
I believe we are at a crossroads here in this industry.  Yogi Bear once said when you come to a Y in the road, take it.  I don't think that is what we are talking about here.
[Slide.]
I am not an expert is fractionation.  I don't even want to say we are an expert in distribution.  We are trying to learn it.  But very simply put, the plasma manufacturing costs‑‑and I didn't consult with anybody on these, I just picked what I thought would be the big ones‑‑research and development, regulatory compliance, overhead, and yes, they do make a profit.  People have to make a profit.
The reason that I think there is softness right now in the IVIG shortage is because the end user, the end user, the health care entity cannot make any money, and that is why there is a little bit of softness in the IVIG market right now.
It almost always comes down to economics, but if you think to the previous slide, I don't think these costs are coming down, first of all, and if they are, if somebody would correct it, I appreciate it.  If these costs are coming down, manufacturers that do very well spread those costs over several different plasma fractions, hyperimmune globulins, the antihemophilic clotting facts, IGIV, and albumin is the one that I am really concerned about.
If the albumin prices go down or eliminated, or the plasma‑dried factor products, I asked pharmacists what do you think will happen to the rest of the products, and someone says, "I think they are going to go up," I always agree with them, I do, too.
[Slide.]
This is not an indictment of manufacturing business practices, I want to make that very clear.  I have had the privilege the last month or so‑‑and I think Dr. Goldsmith is in the room‑‑to follow him in a few presentations, and I think when he presents his company's perspective on the fractionation business, I think he uses the number 210 days from the time of collection of plasma to maybe the finished goods lot release.
So, that is a long time.  It's somebody else's math, but I think it is seven months.  So, that's an awful long time.  So, if we donated plasma today for fractionation, that product would be part of the new millennium.
But my point here is prior to that, when manufacturers finally get product released, they fulfill their contractual obligations to group purchasing organizations.  If there is any left, they sell products to biological distributors at a higher price.
They deplete their inventory because it is a very capital‑intensive business, and then they have very little or no reserve capability.  Chris Lamb‑‑I hope he is not in here‑‑the vice president of a plasma operation for the National Red Cross, in the April 12, 1998, pink sheet, said we have a three‑ or four‑day supply on hand.  It does not promote good patient safety and patient availability, and it is because it is a very capital‑intensive business.
[Slide.]
I am going to go through this quickly and talk a little bit faster if I possibly could.
The traditional contracting model had been for a group purchasing organization to contract with one or two manufacturers, and invariably new manufacturer would have a better price.  I am using albumin as a model here.  You could plug in any product.
So, the health care entity, it may be a hospital, whoever has the best price, most of us would buy that because of health economics.  So, the manufacturer who has the higher bid price may end up with some unrealized, not in the case of IVIG lately, but in the past has been true, may end up with some unrealized contract inventory, so the contractee would not buy their product, and then the manufacturer would sell it to a secondary distributor at a higher price, because they have to move the inventory.
What would happen is we would have maybe a manufacturing delay, a regulatory action, and whoever had been buying from their primary contractee in the past would turn to the secondary awardee.
Then, what would happen is that product wouldn't be there because it has been sold to biological distributors.  Then, the biological distributors turn around and sell it back to the hospital at a higher price.
It is probably the same product, but it turns around, coming back to them at a premium of 100 or 200, in some cases 400 percent.
We thought there is a better way.
[Slide.]
This is a bad word, and this is the things that I think have extracted a huge toll on our business.  This bundling.  This is not bundling that the manufacturers bundle.  What this is, is a biological distributor will by product, IGIV and human serum albumin.
They will look at it as $114 for the investment in both products.  Then, they will take that product to two different entities.  They will sell IGIV, use $112.  In the past, you could have plugged just about any number in there.
Then, they will sell the albumin for $45.  On that $114 investment, they made $157, $43 profit, 27 percent.  Somebody mentioned wholesalers, and somebody mentioned‑‑I don't think anybody mentioned FFF, I think I did.  Those are not the margins we work on.  I wish they were, but they are not.
[Slide.]
Another example that is taking place now is something called swapping, that you don't hear a lot about.  A hospital may have, because biological distributors will call hospitals, do you have any excess IVIG.  Maybe they ordered some products for a patient, the patient got transferred, didn't show up, we have got 150 grams of IVIG.  We paid $45 for it.  The hospital's investment in it is $6750.  The broker, out of the goodness of their heart, will say, well, we have some albumin, you may need some of that.  We paid $54 for it.  We will just swap it straight out, and we will take an apparent $1,300 loss.
They turn around, sell the 150 grams at $112 a gram to some unsuspecting other hospital or health care entity that absolutely has to have the product, and the original investment of $8100, that is a profit of $8700.  This is stuff that I don't believe is good for health care.
[Slide.]
Because of that, we have tried to develop innovative situations and solutions to counteract some of those things.  We are trying to provide, our company is trying to provide the most stable platform for the availability and affordability of plasma products.
Our primary, secondary program creates a primary level of pricing, as well as a secondary level of pricing, at near as possible guarantee of availability, albumin pricing index, to make sure that all manufacturers that are participating in the contract have pulled through, we average our price, and we create an albumin price index, again providing stability to the pricing of the products.
Our interactive allocation system we talked about again and Lot Track.  We believe the technology is here.  We have successfully beta‑tested the product at children's hospitals around the country, because we like to go where children are first, and the product works extremely well.
We have been using it internally now for a year, and it has cut our response time from the moment of withdrawal or recall to notification into seconds.
[Slide.]
The current market for IVIG.  This is based on the observations we spoke about earlier.  Nearly every institution in the country has implemented IVIG utilization guidelines.  Those guidelines are usually a function of availability and affordability.
Right now I believe that the U.S. IVIG market, the demand has been suppressed while supply remains fairly constant.  The demand is down.  Our inventory build‑up at FFF, it makes me chuckle because when I first spoke with Dr. Weinstein on the phone, he said, "How is the inventory level?"  I said, "Hang on, I will go out back and look."  I said, "It looks pretty good right now."
We also monitor the spot market.  There has been a dramatic decrease in spot market pricing.  I think we can touch on that now.
[Slide.]
Here is how we view the marketplace.  There is a primary contract rate.  These are averages, we didn't put up exact numbers, but the primary contract rate in the U.S. has risen to about $39 per gram.  Somebody was asking about Europe.  There is a preponderance of companies trying to get product into the U.S.  It is for one reason ‑ higher average selling price.  It is very simple.  I always believed‑‑I would like to believe that they were coming in here to address the human situation.  I think it is to get the highest ASP humanly possible.
The secondary contract, as part of our primary secondary program, it is hovering around $50.  The emergency allocation programs that have provided great relief and I think a great sense of security for a lot of patients and practitioners in the U.S., and have a tremendous amount of value, range between $50 and $65.
The spot market is $70 approximately right now, but you hear outliers, the highest that I had heard over the last 12 months is $300 per gram.  That is‑‑I don't want to say what I think it is.
[Slide.]
Responding to Mark's question, how is the inventory build‑up at FFF, we trend these on a daily basis.  We believe the group purchasing organizations hire us to manage us the blood products market.  It is a dynamic, it's a fast‑moving market, and it changes.  It changes on a moment's notice.
So, we have been trending here, and on a linear trend, the blue line is sales, the green line is our inventory, and we see a widening in‑between our sales and our inventory, we are having an inventory build‑up.  This is temporary.  The availability today in the U.S. of IVIG is better than it has been in the past six months.  We believe it is temporary, and it is because of those utilization guidelines.
Those utilization guidelines are in place, and I will address those a little bit more later.
[Slide.]
We talked about our data mining opportunity.  We have surveyed 3,079 of the 6,056 hospitals in the U.S.  Again, it is not a mail‑out survey.  It is talking to the practitioners, it is talking to the pharmacists who are the gatekeepers, and I think we have a pharmacist who is going to come on later, but those are the gatekeepers of the product.
From our extrapolation on the ones we did not survey yet, we believe the demand in the U.S. for albumin is 11,482,000 equivalent units.  The albumin market is not operating at that level right now.  It is falling far short of that.  It is because of the utilization guidelines that have been in place.  There is an economic reason for that.
[Slide.]
I think the IGIV numbers, which probably this crowd is more interested in, was 18 1/2 million grams.  I was thinking back as I was listening to the first conversation before I got here, I was thinking back.  In the last two weeks I have sat with executives from the plasma fractionation market, one said the demand is 21 million, the one said it was 25 million.  So, we don't actually know.
I am not saying we know either, but we are asking our customers.
[Slide.]
I think the good news is that there is a change in business practices that are taking place because of some of the toll that has been extracted on the health care community by the biological distributors.  There is a change in business practices, and it is for the positive.
Alpha has a direct contract only, not selling to biological distributors only.  Baxter is doing exactly the same thing.  Bayer has implemented a sales price cap, so those excesses, those are very positive moves.  For the first time, we are seeing those take place, and we support that, and Novartis has a semi‑closed distribution system.  I look at that as very positive.
[Slide.]
If we could be so bold to make some recommendation.  We believe that through GPOs and our Premier Model, there is an opportunity to communicate supply information to the practitioners.
There are two types of shortages, I believe.  There is a shortage when you absolutely cannot get the product and it is not available.  That is definitely a shortage.  Then, there is a shortage that I think we are in right now where patients are not aware of availability and are being denied care.
To us as a distributor, that one is a little bit more simple.  If you don't have the product, that is certainly understandable, but if it is there and it is not a responsible distribution channel, those are the things we have to change, and the utilization guidelines must be dynamic to protect all patients.  Typically, they are not.
We layer over a utilization guideline, and I refer to it as "shutting the faucet off."  We tell all practitioners it is just not available.  Someone was talking about off‑label demand right before I came up, and for those folks, the faucet has been turned off.
There is no mechanism in the U.S. heretofore where you can turn the faucet back on, and prescribing patterns often continue to follow the last set of guidelines, and I believe again there is an opportunity here to mandate the tracking of blood products to the end user.
You will increase the safety of blood products, and it will also remove the mystery from supply and demand, because when you have an industry where the middlemen or the distributors make more than the major stakeholders, the manufacturers in some cases, then, that is characterizing the biological distribution market, it is characterizing the home care, you have a problem, and we are seeking to change that.
[Slide.]
Our marketing strategy is listening to the needs of the customer, and I appreciate your time listening to us.
Thank you very much.
DR. HOLLINGER:  Thank you.
The next speaker is Allen Dunehew, Director of Managed Care Contracting and Fractionated Blood Products, Premier Purchasing Partners.
Allen R. Dunehew, R.Ph., M.P.A.
[Slide.]
MR. DUNEHEW:  I work with Premier Purchasing Partners.  We have several offices across the country including one office in Washington here.  Our primary job is to advocate for our members.  I will show you some slides to give you an idea of the impact of Premier throughout the health care industry in the country.
We are wholly‑owned by our members.  We have about 220 shareholders.  So, our total focus is really to meet their needs and to advocate for them, and to work for them.
[Slide.]
This will give you an indication of our penetration into the country, and I have another graphical of high demonstration that gives you a better idea, too, but we are really well represented throughout the continuum of care, which is an important issue certainly as we talk about these products, blood products.
We have worked with FFF to put together what we think is a fairly unique program and is working well for our members today in a very tight market, although that changes daily, as you know.
Again, roughly about one‑third of the health care in the country belongs to Premier.
[Slide.]
This is just to show you the different types of organizations.  We have both small rural hospitals, as well as medical centers that belong to us, individual and physician group practices, hospitals, home health, home infusion, as well as HMOs.
[Slide.]
This represents in the GPO world, group purchasing organization world, our penetration into the market.  Again, it is about roughly one‑third.  On any given day, some of these numbers change based upon who robbed the last member from them and joined their group.
[Slide.]
To give you just a little bit of a background on the history of this program and why we put it together.  We started on this probably about a year and a half ago, and as  you know, at that time, albumin was still a little bit of a problem, but IVIG was beginning to be a significant problem, and certainly it has gotten worse since then, and we had a serious issue with the way the program worked before under the contracts.
We had only three manufacturers under contract through manufacturers or suppliers, if you will, and we felt that there was a need really to significantly increase that, and the availability of product, so we extended that out to essentially all of the manufacturers or suppliers within the country.
One of the problems we had before was that the distribution channel and the selection distributors was actually designated by the manufacturer, and so the problem that created for us, particularly in a tight market was because of a chargeback system, and if you really want some information on distribution, I can give you that at another time or off line, but there were some incentives in the distribution system, in the standard distribution system in this country, and they still exist today, although not in our program, because of a practice called chargeback mechanism, whereby an item would be purchased at a list price, if you will, and when it was sold under contract it would be sold at a lower price, and that distributor or wholesaler would go back and charge back to the manufacturer the difference between the contract price and the selling price.
If that distributor chose not to sell it under contract, but to sell it to anybody else, they could do that freely.  They were allowed to do that.  So, we did not have control over the product to make sure that what we had under contract actually went to our members.
Really, Novartis worked with us in the very beginning of putting this together, and actually pushed us to start the program a little bit before we were ready, because they realized the same issue because the majority of their product was distributed through the typical pharmacy wholesaler under the chargeback mechanism.
Today, we have one distributor, and we had RFQs from I believe it was eight or nine specialty products distributors across the country, and based upon what Patrick and his organization could offer to us, we made the award to them for an exclusive agreement.
Today, we have complete audit capability on the total product that is supposed to go to Premier members.  I know monthly how much is supposed to come in to the program, and I know every sale that occurs to our members, and I total that up and check that every month to make sure it only goes to our members because that is what we are doing, we are advocating for them.  It is very important.
Even with that, we still have not been able to get enough, certainly enough IVIG to meet their needs.
Another thing that we did was the last bullet point on that last slide, which I think is important, and we treated all members as equals.  I can tell you when we set this program up July 1st, I had hundreds of calls a day from our facilities complaining because it was a significant change in the way they do business.
Again, I am not trying to slam manufacturers, I wouldn't do that because they are important business partners for us, but their alignment of goals and decisions are different based upon how they do things and which facility, which hospital, or home infusion company might give more product because they are looking at it as how it relates to the total product line that that facility buys from them.
I can remember one comment from a teaching facility, and they said, you know, "We should IVIG because our patients are more important," and my response back to them was, "Well, you know, if I had a child and I lived in a rural area, and they were treated at a 45‑bed medical center, and they needed IVIG, I would have a hard time believing your stance on that."
So, what we tried to do is really put this uniformity in the system and accountability on all partners.
[Slide.]
You have wanted some numbers, so we have got some numbers for you, and these are facts, and we track this monthly.
DR. HOLLINGER:  Mr. Dunehew, I am sorry.  I have seen equivalent units.  You have used it several times.  Just tell me what that is.
MR. DUNEHEW:  Equivalent units on albumin is a 12.5 gram equivalent unit.  That is the way we measure it.
DR. HOLLINGER:  12.5 grams?
MR. DUNEHEW:  12.5 gram equivalent unit, right.  We don't use equivalent units on IVIG.  We use grams because it is easier to follow.
We did a survey back in January of 98, so this data really is supported by two surveys of our members and again of about 1700 or 1800 facilities.  In January, we came up with about 3.2 million grams, and that was a very small return on that.  We were very dissatisfied particularly when you look at the problems in the market at that time, but actually when we put the program together in June of '98 and FFF assisted us and actually went out and talked to all of our facilities in setting up our allocation program, that was confirmed that really these numbers were accurate.
So, albumin and IVIG were both at a demand of about 3.2 million units and grams respectively, and not much has been mentioned about albumin today, because I realize that is not a shortage issue, but I have to tell you I am a little bit concerned about our ability to continue to get IVIG because albumin has become a soft market and that is a factor that I think really needs to be considered, as well.
So, in spite of that 3.2 million amount that we needed, with albumin we are okay, we were able to get everything we needed and actually we had a little bit of excess, but when you look over here at IVIG, we could only get 1.8 million grams, and that was a significant decrease from what we had had in the previous year, in '96 and early '97, for that matter.
So, we had really a shortfall of about 1.2 million grams.  Shortly after we went into this in July, as you know, one of the manufacturers that we were depending on stopped shipping product, but our other manufacturers were actually very good to us and stepped up to the plate and really supported the program, and we were actually able to make up for that difference and get a little bit more here, so we were able to get about 2 million grams over this past year.
Now, we are very happy about this.  Through a lot of finagling and discussions and different angles, we were able to increase the amount of IVIG.  The next slide will tell you some of the reasons why we were able to do that, but we still have an unmet need of about 0.3 million grams, but if you look here, we have only got about 2.1 million of albumin under agreement now, it is actually a little bit higher than that.
That is at our request because the albumin need has decreased so significantly, and as a practicing pharmacist, I get pressure sometimes to try to promote the use of albumin, but I can tell you, if you can use an 80‑cent liter bag of saline instead of albumin, that is a good move if the patient outcome is the same.
I would stress that when you try to look at those decisions, as well as it relates to off‑label use of IVIG, that doesn't necessarily mean that is bad.  Really, what should be considered is what effect does that have on the patient in terms of outcome, is there an improved outcome from the use of that product, and if it is, it is appropriate even though it might be off‑label.
But in fact, there are a number of protocols out there, and we have them in our own institutions where they say you cannot use it for off‑label use if our supply stock falls below a certain safety level, like 200 grams on the shelf, and those are out there and in place today.
[Slide.]
Reasons for the two‑year increase.  I don't want to make you think that the shortage of IVIG is over because I don't think it is.  I think that there is still certainly a need for more, and anything that can be done to increase that supply is very important.
It is also very important because as you well know, the supply status of a given company from day to day or week to week, as we experienced a couple of weeks ago or a week ago, changes overnight, and it can dramatically change the market.  So, I think the effort should really be to increase the supply.
Again, some amount of production increases from our contract with manufacturers, negotiations with the business partners, substantial price increases.  We have had substantial price increases.  One company that I won't name has increased prices from the price we had in '98, before the program, about 100 percent going into the first year, and we just experienced about another 30 percent increase, so price increases are out there, and they are happening, and I could talk with you more about that later.
And then the success of the dedicated distribution program, and I think the manufacturers today understand that this has worked well for them, as well.
[Slide.]
Measurement of availability.  Just some suggestions from my perspective that I think would be of some assistance.  That is, groups, such as Premier could be used as a reference on a monthly or quarterly basis.  What are we receiving into the program, and what is being ordered, is there any excess supply, you know, even to the point where if there was a need for a survey, perhaps there could be some assistance put together for that.
I think this is a good measure.  IVIG, if you are looking at it, just monitor the spot market price.  If it is $130 a gram, you know, there is a significant shortage because they are able to sell it at that price.  Spot marketers, sometimes I refer to them as privateers or pirateers I guess.
The other part of it, too, is if it gets down to $50 or $60 a gram, supply is pretty good.  You can get it for most needs.  Availability of product under the Emergency Supply programs‑‑and this changes, too, based upon availability‑‑and then there maybe is an opportunity for an FDA web site through something you already have created, that is specific to this issue, and we could even help publicize that with our members and get that information out that if there are supply problems on a patient level basis or whatever, then, we could help get that information.
[Slide.]
Some general suggestions.  Communicate supply status to physicians or changes in supply status to physicians and health care practitioners.  I think this is important, if, in fact, the IVIG market does soften up a little bit, because those facilities that have protocols in place, probably need to decrease the enforcement of those protocols, and we try to keep our members up to date on where we are.
Recommend flexibility in the application protocols.  Continue to work to increase the overall supply, as I mentioned before.  I do think that that is important.  Again, I am concerned about albumin, because it is going to have an impact.  I am not sure what it is, but it is going to have an impact on IVIG availability one way or the other, and again, the off‑label use is not necessarily bad use, it is what impact does it have on the patient outcome for that indication.
Thank you.
DR. HOLLINGER:  Thank you.
We have got two more discussants and someone who has asked to speak in the open public hearing plus anything that anyone wants to say.  What I would like to do is maybe just take a 15‑minute break.
It is 4:33, so let's say around quarter until 5:00 we will break.
[Recess.]
DR. HOLLINGER:  We will go on here.
I think this is also a critical discussion, is demand being met.  This is important because now we are going to have a perspective from the user community, and the first speaker will be Mr. Patrick Collins from the National Hemophilia Foundation.
Is Demand Being Met?
Patrick Collins
MR. COLLINS:  Thank you, Dr. Hollinger, and good afternoon, everybody, or should I say good evening by now.
My name is Patrick Collins and I am Director of Government Relations at the National Hemophilia Foundation.  Presenting with me will be Thomas Moran, President of the Immune Deficiency Foundation.
We would like to discuss the current demand for product and whether or not that demand is being met.  I will speak about the current demand for clotting factors, immune globulins, and alpha‑1 proteinase inhibitors.  Tom will then discuss the greater concerns and demands for plasma derivatives as a whole and conclude with some suggestions on what the plasma manufacturers, public health service, and consumer groups can do to remedy the supply and demand issue.
I think clearly today we have seen a difference between those who are experts in the field of methodology and those who are experts in the field of disease, and I hope that after our presentation today, that difference will be cemented.
I would like to start with the most glaring example of a product that is in great demand, yet is not anywhere close to having that demand met.  Individuals with alpha‑1 antitrypsin deficiency depend on the alpha‑1 proteinase inhibitor to prevent lung damage from infections that cause the loss of lung function, disability, and ultimately death.
The demand for this product is great, yet there is only one available licensed product within the United States, that being Prolastin by Bayer.  Unfortunately, Prolastin is being rationed at 50 percent of historic purchasing levels for distributors and care providers.
There are approximately 5,000 individuals who realize that they are antitrypsin deficient in the United States, and they cannot get product.  These 5,000 individuals are basically held at the whim of the Bayer Corporation.
A unilateral reduction of product by 50 percent has made this community the most glaring example of individuals who are in desperate need of product, yet, they cannot get it.  Obviously, Bayer has not met the demand for this product in the antitrypsin deficient community.
Regretfully, the Alpha I Foundation states that this situation will in all likelihood continue until two other products, which are in Phase III trials currently, are licensed are leased onto the market.
What is a community to do when this demand for product is not met?  Comes before this advisory committee, as well as others, time and again.  Let's hope that one day the demand for alpha‑1 proteinase inhibitor is met, because right now it is not, and unfortunately, people's lives are at stake.
I would now like to take a couple of minutes to review whether demands for coagulation factors VIII and IX, inhibitor products and von Willebrand factor have been met.
With regard to factor VIII, NHF has appeared before both this committee and the Blood Safety and Availability Committee to discuss the shortage of factor VIII, specifically, recombinant factor VIII.
The situation was rather dire at one point until October 1998 when Baxter Health Care received FDA licensure of their recombinant plant in Thousand Oaks, California.  Baxter's product release has helped to significantly ease the shortage.  Supply data that the IPPIA makes available indicate that the distribution of factor VIII, specifically recombinant, has begun to increase as a result of this influx of product.
For the last available month in the IPPIA supply data, at least the data that I receive, March 1999, over 103,000 international units of recombinant factor VIII were in inventory.  This is the largest inventory in almost one year.
In our informal polling of the hemophilia treatment centers, there is some difficulty in having supply met based on which manufacturer the center may have a contract with, but product now does seem to be available.  Some work and creativity may be required to obtain this product, but it can be obtained.
I would just like to comment briefly on an overhead that Mark Weinstein had on the overhead about an hour or so ago with regard to the distribution of factor VIII.  Mark claims that the distribution has been pretty constant, and I wouldn't necessarily disagree with him, however, I think it is incontrovertible to argue that both Bayer and Baxter at one point were on allocation.
So, while factor VIII distribution may have been more or less constant, recombinant factor VIII, of which approximately 70 percent of the population was on, that distribution was not constant.
As a result of that, people had to switch in some cases, and quite a few cases, to high purity plasma‑derived product, and the IPPIA data does reflect that for the summer months of 1998 specifically.  Some had to switch to medium purity product, basically, any product they could get from all the way down to Joe's backyard sludge factor plant, but while the distribution may be constant, the quality of that product was nowhere near constant.
The hemophilia treatment center polling that we did does indicate an underlying concern.  Although recombinant factor VIII is obtainable, it is not readily available.  As a result of the HTCs report‑‑and this is informal data, basically me getting on a phone calling every HTC‑‑but they state that while getting product in some cases was difficult, but they were more or less able to get it, that some treatments, such as elective surgeries on numerous occasions, as well as immune tolerance and prophylaxis treatment was deferred.
These procedures are treatments are part of the demand that the bleeding disorders community has for product.  Surgeries, such as joint replacement, while classified as elective, are a major need for many individuals who have to deal with chronic pain as a result of hemophilic joint destruction.
Moreover, immune tolerance treatment is a universally recognized method to eliminate inhibitors, and prophylaxis is recognized as a good method to prevent bleeding disorders.  By having this treatment deferred, a person, in most cases a child, does risk life‑threatening bleeding episodes.
Having access to immune tolerance treatment, prophylaxis treatment, and elective surgery is one desire, in fact, it is a demand, of the bleeding disorders community.  Unfortunately, there is not enough available product to meet this demand.
Factor IX deficient patients are in a far worse situation, unfortunately.  While the recombinant factor IX benefits is readily available, there is a percentage of the community that either cannot afford the product or have had a negative reaction when using the product.  Hence, these individuals are relying on plasma‑derived factor IX products.
Unfortunately, the plasma‑derived products are in incredibly short supply, factor IX specifically.  The IPPIA supply data states that for March 1999, only 3478 international units were in inventory.  In our informal polling of the HTCs, more than half of those responded cited difficulty in acquiring plasma‑derived factor IX product even for routine use.  I think that is an obvious case of demand not being met.
The same holds true for inhibitor bypassing products.  The HTCs overwhelmingly reported difficulty in acquiring such products.
Lastly, for von Willebrand factor products, there is just presently not enough data to judge.  Many factor products are use off label in treating bleeding episodes in von Willebrand patients, and just recently the FDA for this indication approved human AP.  Yet, the availability of this product, as well as other factor VIII concentrates that have been successfully used to treat von Willebrand disease have been dangerously limited.
Will the licensing of human AP ease the situation?  We can only hope so.
The bleeding disorder community views as necessary having enough product, so that a normal life can be lived without the fear of a bleeding episode, having enough product available for elective surgeries, such as joint replacement, and having enough product available for preventive treatment, such as the elimination of inhibitors and prophylaxis treatment.
These are the needs of the bleeding disorder community, and they are currently not being met.
Lastly, with regard to immune globulin, I think it is fair to say that we are aware that demand for this product is not being met.  The Shays Committee had a hearing last summer, which I am sure we are all well aware of, as well as 60 Minutes, which profiled the situation in detail last summer.
In 1996, 17,000 kilograms of IGIV were consumed in the U.S. marketplace.  In 1998, 15,200 kilograms were released to the U.S. market, which is a reduction of over 10 percent from the 1996 levels.
Projecting IPPIA data on IGIV released through April 1999, it appears that 1999 IGIV levels will be very close to those in 1998.  In prior BPAC meetings, the Immune Deficiency Foundation has reported on the significant negative health consequences of the IVIG shortage to its members during 1998.
I would like to now turn it over to Tom Moran, who will speak in more detail on IGIV specifically, as well as discussing action steps required for industry and regulators in light of this dynamic situation.
Thank you.
Thomas L. Moran
MR. MORAN:  I have got about a five‑minute presentation, Mr. Chairman, so I will get through quickly.
[Slide.]
I just wanted to comment on an earlier point that was raised related to someone asked a question about the FDA's‑‑since the last BPAC meeting‑‑the FDA's efforts with respect to licensing new products and the issues of surrogate markers, and so forth.
Dr. Golding responded on behalf of FDA, and I just wanted to add my confirmation that IDF is working with three companies now with the cooperation and the assistance of FDA, and I think there is progress being made with respect to moving some product approvals through the system, and I think that perhaps by the next BPAC meeting, there may well be some very tangible evidence of that.
As Patrick Collins has just pointed out, there are serious personal consequences when patients are unable to obtain or afford their therapies.  The testimony at previous BPAC meetings of the Alpha I Foundation and the Immune Deficiency Foundation, and others, have reported serious adverse health consequences within our communities resulting from shortages of plasma derivatives.
It might be useful to revisit one piece of data from the IDF Physician Surveys conducted in April and August of 1998.  This data captures how physicians and the pharmacists who order for them adjust to market shortages and how this might affect personal health.
[Slide.]
Many of the strategies listed on this chart result in a reduced use of IGIV.  One could call it reduced demand.  For example, when physicians postpone scheduled infusions, switch to different IGIV brands, increase the interval between infusions, reduce the dosage, or eliminate therapy altogether.
Basically, what happens is you have a diminished demand for a short period of time, but this raises questions about the quality of health care that the patients are receiving.
[Slide.]
In response to the IVIG shortage and in response to the health care related problems our patients were having, the IDF, in cooperation with the IGIV brandowners, listed here, and FFF Enterprises, established the Safety Net program to provide IGIV on an emergency basis to physicians, stipulating a need for product based on medical necessity.
[Slide.]
To date, 368 physicians have enrolled in this program, 132 immunologists, 236 physicians from other specialties.
[Slide.]
Between January 1, when the program began, and May 31st of 1999, 76,000 grams of IGIV have been shipped at the request of IDF through the Safety Net program.
[Slide.]
1,224 patients in 43 states have benefitted from Safety Net.
[Slide.]
Sixty‑eight percent of those patients, or 826, have diagnoses of primary immunodeficiency disease.  I would just like to point out very quickly that IDF does not limit the distribution of IVIG to primary immunodeficient patients, but rather distributes it based on the representation from physicians of medical necessity, and this is an issue that was discussed earlier.
A comment that I have made in previous meetings is that on‑label and off‑label is not necessarily the same discussion as medically necessary or non‑medically necessary.
[Slide.]
We have trends although we are dealing with a much smaller quantity of product than Patrick discussed earlier, and as you can see, these are three of the products that we distribute through Safety Net, and what these graphs represent are really a velocity or product moving into the IDF Safety Net program and off, so the data points are how quickly that product is exhausted.
As you can see, the trend from March through May in all three products was slightly up.  I will say, however, that we, too, have noticed in the last several weeks a subtle softening, if you want to call it that, and perhaps if we had June data, it may show a similar kind of down trend to what Patrick has shown.
However, I think another explanation for the apparent discrepancy between the FFF data and the Safety Net trend lies in the fact that we are seeking out spot shortages as distinct from the spot market.
We are seeking out places that cannot get IGIV that might be outside of the general purchasing organizations, and these kinds of spot shortages come to our attention, so that may help explain the trend if, in fact, there is a softening in the general market.
I would, however, caution FDA and the committee to avoid over‑interpretation of short‑term trends in a market where we know we are still 10 percent below historical supply levels.
This leads me to the main point that plasma consumers would like to make.  Well, just one other comment before I make the main point.
[Slide.]
The IGIV supply in the United States, April 30th of 1999, as estimated by IPPIA at 10 days in '98, 11 days, so I am not quite as sanguine as some of the other presenters today about the shortage may be over.
One can imagine any number of scenarios including a strike by UPS, for example, that could well‑‑10 days is not a big safety margin.
[Slide.]
The point, however, that we want to make is that as product shortages persist, the market adjusts to the current supply reality, a kind of equilibrium occurs, and what happens in the marketplace are things like the rationing protocols that Allen Dunehew mentioned, where hospitals are in effect rationing IGIV.
Alternative therapies are employed where possible, maybe not equivalent therapies, but alternative therapies.  Some therapy, as we saw in the first slide, can be eliminated.  Patients migrate to different sites.  If they can't get it from their home care company, they may well get it from the hospital.
[Slide.]
As a result of these adjustments to supply, the public health consequences of these adjustments must be understood in order to develop appropriate public policy responses.  The question of the current theoretical upper limits of demand is an interesting question and probably important to corporate planning for investment purposes, but the more relevant question for consumer groups, and we believe for agencies mandated with public health responsibilities, like FDA and CDC, is what are the health consequences to patients of different levels of product supply.
What I am suggesting is we may be stuck at a situation where demand equals supply at 15 million grams, for example, of IGIV, where people are being undertreated or not being treated, and there may, in fact, if pharmacists and physicians and others get used to this availability, this level of supply, we can have a persistent situation where less than optimum health care is being delivered.
[Slide.]
Expressed differently, in markets like IGIV, A1PI, and certain clotting factors, where there is 100 percent consumption of existing product, are we failing to meet the therapeutic needs of patients with accompanying adverse health consequences?
I would like to assert that in my opinion this is probably the case today.  What the consumer organizations are recommending, and following on to I think what was implicit in a lot of the presentations today, is that I think we need to find out what the facts are.
[Slide.]
I guess the difference in our perspective is we would take it from a health point of view rather than a supply and demand point of view, but I think a collaborative effort that involved consumer groups, medical societies, pharmacists, distributors, general purchasing organizations, manufacturers, U.S. Public Health entities like FDA and CDC, I think we need to get together and find out are we stuck in second gear and are people getting sick as a result of that, or are the consequences of the shortage from a public health perspective not quite as significant as perhaps we believe.
[Slide.]
The kind of data that we look at is how are these products used by diagnosis.  If you take IGIV as an example how much of the product is being used on‑label, off‑label, how much is being used in medically necessary areas, maybe how much of it is reaching areas that are generally agreed not to be medically necessary.
How are products, for example, like clotting factors being used with respect to prophylactic treatments versus acute care, is there product enough to provide prophylaxis.  Stage of disease that these products are being used at in the A1PI community, the Alpha I Antitrypsin community, is it simply people that are in late stages of disease, or is there enough product to get patients in early stages of disease on product.
Finally, are patients having to migrate from one treatment setting to another in order to get their drug.
The distinction we are making is between levels of care based on emergency supply versus optimal care based on accepted medical standards.  We think that the discussion and research, data collection, data analysis needs to take into account the health consequences at each level of supply, at each level of these products.
I don't think this has to be an extraordinarily complex undertaking although I know it is not easy.  I think FDA notice could well get a lot of cooperation from all elements of the industry including the consumer group to accomplish this, and I think that is where we need to go.
Thanks.
DR. HOLLINGER:  Thank you.
Any questions for these last two speakers?
[No response.]
DR. HOLLINGER:  If not, one person asked to speak in the open public hearings, and that is Nancy Buelow, who represents Alpha I National Association.
Open Public Hearing
MS. BUELOW:  Good afternoon.  My name is Nancy Buelow and I am here today to represent the Alpha I National Association.
We have only one manufacturer, and that manufacturer cannot meet demand for the people who have alpha‑1 antitrypsin deficiency.  We are currently under a 60 percent allocation based on patient population that was in 1997.  We are diagnosing a new alpha every day, and they can't be treated because of lack of product.
We have patients of long standing that suddenly have no product at all.  Unfortunately, this usually starts in the VA, and a lot of these are Viet Nam veterans.
I am one of those people that you have referred to today, the other people, and we live in constant fear, wondering when we will get our next product, where it is going to come from, and if we are going to have it.
Without product, we are very vulnerable to lung infections.  When we get a lung infection, we can lose quite a bit of lung function at a very fast rate.  I am just recovering from a lung infection.  I have 36 percent lung function, which I can do pretty well with, and I would like to keep it.
We are hearing that full production will not ever meet our demand.  We need more product and a safe product for this life‑sustaining drug.  I would like to thank you for the supply and demand continued discussions.  I would also like to thank Mr. Collins and Mr. Moran for their perspective.
Our community needs to know what can be done to help us, and, please, ask the industry to address when we can expect to again get our full prescription dosage at our weekly intervals.
Thanks for the opportunity to address these concerns and holding this committee.
DR. HOLLINGER:  Thank you.
Anyone else from the public wish to make a statement?
[No response.]
Committee Discussion
DR. HOLLINGER:  If not, we will close that portion and then just see if there is any issues that should be dealt with here by the committee.  A lot of this was information about where I think we stand at the present time with many of the products.
Is there anyone that has any issues that they would like to discuss?  Yes, Dr. Ohene‑Frempong.
DR. OHENE‑FREMPONG:  I have a question about the alpha‑1 proteinase inhibitor production.  Is there anybody here representing‑‑is it Bayer?  Is there any reason that anybody can give for why there are only 50, 60 percent of demand?  Is this something very difficult to produce?
MS. HUXSOLL:  My name is Jean Huxsoll, and I am from Bayer.  It is not a decrease in production.  It has been an increase in demand.  We recognize that if the increase in demand continued, there would be a shortage as there was with IGIV, so the 60 percent limitation was set so that we would not end up with some consumers not having any product at all.
DR. HOLLINGER:  I am sorry.  So, product was mostly a decision made to produce Prolastin as well as well as IGIV, is that what you are saying?
MS. HUXSOLL:  No.  The Prolastin production has not changed.  The demand has increased.  So, in order not to have a shortage the same as we did about a year ago with the IGIV, the 60 percent limitation was put on, so that there would be product available.
DR. HOLLINGER:  Why do you think the demand has changed?
MS. HUXSOLL:  I am sorry, I can't answer that.  I don't know.
DR. KOERPER:  I think there is more people being diagnosed with this.
DR. HOLLINGER:  Anyone else?  Yes, please.
DR. MITCHELL:  How long do you expect that the demand will stay at high levels, and are you planning on being able to meet those demands?
MS. HUXSOLL:  I can't answer the question about the demand, but I can tell you that one of the things that we are trying to do right now, the product has a very low yield and comes from an intermediate fractionation product.  We are presently processing all of that material that we have in house, but we are looking at establishing contracts with the other manufacturers, so we can buy that intermediate from them and increase the production.
DR. MITCHELL:  Do you have a time frame on that?
MS. HUXSOLL:  I know that a present contract is being negotiated as we speak, and we expect to get material in the next month or two.
DR. HOLLINGER:  Are there other manufacturers of this product?
DR. EPSTEIN:  There are IND holders.
DR. HOLLINGER:  Yes, please.
MS. MARA:  My name is Judy Mara and I am President of the Alpha I Association.  I just wanted to clarify a little bit.  Even though we are on 60 percent allocation, because of distribution inequities, we have many people not getting product at all, so that that is a real big problem for us.
Also, anyone newly diagnosed for the last year has not been able to get product.
DR. EPSTEIN:  I just wanted to ask Judy Mara, could you just state for purpose of clarity whether Bayer is at full production in all its facilities or not?  The previous speaker I am asking.  I am sorry, Jean Huxsoll.  I am sorry, I asked the wrong person, my fault.
MS. HUXSOLL:  Yes, it is my understanding that we are at full production.
DR. HOLLINGER:  That is the only manufacturer of that product available, is that correct?
DR. EPSTEIN:  Again, there are some IND products, but there is only one licensed product.
DR. HOLLINGER:  One licensed product at the present time, some in IND.  Okay.
Dr. Boyle.
DR. BOYLE:  I would just like to point out that we have been in the IVIG shortage for some time, and I am encouraged today because we have learned some new things that we didn't know a year ago, but we are faced at this committee with a lot of decisions and a lot of decisions we have to make with fairly limited information.
Now, one of the things we learned today was the 10 percent estimate about demand turns out to be based on qualitative research.  I don't blame the people who do the qualitative research.  I have done the focus groups and seen the people in the back room say three of the people like my product, that is a 30 percent market share, but it is very important to recognize that that data really doesn't tell us what we need to know.
It is also important to note that because the FDA at least currently does not produce and distribute gamma globulin, the likelihood that continued calls to them will represent the unmet demand, it just isn't going to happen.  If they call and you can't help them, they are not going to call you back.
What is very important for us to understand in the future is to get true measures of demand.  I think it is important that some of the things that were suggested sort of towards the end, that there needs to be some improved information collection and that because of the different parties involved, government, industry, and consumer groups, there has to be some effort made to try to bring them together to get that better information.
DR. HOLLINGER:  I was impressed with listening to some of the presentations today, at least that the distribution seems to be getting in hand a little bit, so you don't have these areas where there is no product and some product at least, as well as a control on the cost, which seems to be was a critical problem at one point of who could get it, and then if that person could get it, how much it costs.
That, at least in the marketplace, seems to be working toward smoothing that out a little bit, and I think that was very encouraging over the past few months.
Anybody else with a comment?
[No response.]
DR. HOLLINGER:  I appreciate everybody's responses today and discussion.  We will start tomorrow morning at 8 o'clock.
[Whereupon, at 5:20 p.m., the proceedings were recessed, to resume at 8:00 a.m., Friday, June 18, 1999.]
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