1

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

                      FOOD AND DRUG ADMINISTRATION

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

                   BLOOD PRODUCTS ADVISORY COMMITTEE

                              73rd MEETING

                         Friday, June 14, 2002

                               8:00 a.m.

                        Holiday Inn Gaithersburg
                     Two Montgomery Village Avenue
                         Gaithersburg, Maryland 

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

                                                                 2

                              PARTICIPANTS

         Kenrad E. Nelson, M.D., Chairman

         Linda A. Smallwood, Ph.D., Executive Secretary

         MEMBERS

         James R. Allen, M.D.

         Mary E. Chamberland, M.D.

         Donna DiMichele, M.D.

         Judy F. Lew, M.D.

         Daniel L. McGee, Ph.D.

         Terry V. Rice

         Paul J. Schmidt, M.D.

         Sherri O. Stuver, Sc.D.

         CONSUMER REPRESENTATIVE

         Robert J. Fallat, M.D.

         NON-VOTING INDUSTRY REPRESENTATIVE

         Toby L. Simon, M.D.

         TEMPORARY VOTING MEMBERS

         Liana Harvath, Ph.D.

         Blaine F. Hollinger, M.D. 

                                                                 3

                            C O N T E N T S

         Committee Updates:

         Summary of FDA/PPTA Workshop on Comparability

         of Plasma Derivatives, Andrew Chang, Ph.D.              5

         Summary on AABB Conference on Oxygen

         Therapeutics and Transfusion Alternatives

           Toby A. Silverman, M.D.                              15

         Public Presentation:

         Hereditary Angioedema Association

           Anthony Castaldo                                     24

         Requirements for Premarket Submission: In vitro

         Diagnostic Software and Instruments

           Diane Gubernot                                       36

           Sheryl Kochman                                       44

           James Callaghan                                      50

         Reported Association of Six Percent Hetastarch

         with Excess Bleeding in Open-heart Surgery:

         Introduction and Background

           Laurence Landow, M.D.                                56

         Presentation, Charles C. Canver, M.D.                  62

         Presentation, Gary R. Haynes, M.D., Ph.D.              83

         Open Public Hearing:

           John Spoden, B. Braun Medical                       154

           T.J. Gan, M.D., Duke University Medical Center      161

           Thomas Shaughnessy, M.D.,

             University of California                          192

           Lewis Kaplan, M.D.                                  202

           David Moskowitz, M.D.                               212

           Keith Berman, M.D.                                  221

         Committee Discussion and Recommendations              227 

                                                                 4

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

  2             DR. SMALLWOOD:  Good morning and welcome

  3   to the second day's session of the 73rd Meeting of

  4   the Blood Products Advisory Committee.  I am Linda

  5   Smallwood, the Executive Secretary.  Yesterday, I

  6   read the statement of conflict of interest that

  7   pertains to this meeting.  It is available for

  8   anyone's review if you so desire.

  9             At this time, I would like to ask if there

 10   are any declarations to be made regarding conflict

 11   of interest on the topics to be discussed this

 12   morning.  If there are none, then I would just like

 13   to announce that we have a very tight schedule

 14   today with a complex subject.  We would ask that

 15   all speakers please adhere to the time frame

 16   allotted so that we can complete the agenda for

 17   today.

 18             I would also ask, as far as protocol is

 19   concerned, when speaking at the mike, please give

 20   your name and your affiliation and please speak

 21   into the mike since we are having the proceedings

 22   recorded.

 23             At this time, I will turn the meeting over

 24   to the Chairperson, Dr. Kenrad Nelson.

 25             DR. NELSON:  Thank you, Dr. Smallwood.  

                                                                 5

  1   The first items are some committee updates.  The

  2   first is the Summary of the FDA/PPTA Workshop on

  3   Comparability of Plasma Derivatives.  Dr. Chang?

  4                        Committee Updates

  5          Summary of FDA/PPTA Workshop on Comparability

  6                      of Plasma Derivatives

  7             DR. CHANG:  Thank you, Mr. Chairman.  Good

  8   morning, everyone.

  9             [Slide]

 10             My name is Andrew Chang.  I am a special

 11   assistant to the director, Division of Hematology

 12   in the Office of Blood Research and Review, CBER,

 13   FDA.  In the next 15 minutes I am going to give the

 14   committee an update on the FDA/PPTA co-sponsored

 15   workshop, entitled Comparability Studies for Human

 16   Plasma-Derived Therapeutics.  This one and a half

 17   day meeting was held in the Doubletree Hotel, in

 18   Rockville, on May 30 and 31.

 19             [Slide]

 20             The objectives of this workshop include to

 21   evaluate the implementation of the FDA

 22   comparability policy to plasma-derived

 23   therapeutics; obtain better understanding of the

 24   FDA's and industry's concerns and expectations; and

 25   improve comparability approaches for plasma-derived 

                                                                 6

  1   therapeutics.

  2             [Slide]

  3             For the benefit of this audience, I will

  4   give a brief introduction to FDA's comparability

  5   guidance as it is related to the discussion during

  6   this workshop, followed by the agency's experience

  7   and the results of the workshop.  Also in the

  8   interest of time, I will not be able to cover all

  9   the topics that were discussed in the workshop.  I

 10   have chosen issues that might be of interest to

 11   this audience.

 12             [Slide]

 13             In April, 1996 FDA published a guidance

 14   entitled, FDA guidance concerning demonstration of

 15   comparability of human biological products,

 16   including therapeutic biotechnology-derived

 17   products.  As you know, plasma derivatives is one

 18   type of biologic product so this guidance actually

 19   covers plasma-derived products.

 20             [Slide]

 21             The comparability policy has resulted from

 22   a desire to reduce the regulatory burden for

 23   manufacture changes.  It is stated in the guidance

 24   that the FDA may determine that two products are

 25   comparable if the results of comparability testing 

                                                                 7

  1   demonstrate that the manufacturing change does not

  2   affect safety, identity, purity or potency.  This

  3   policy allows for changes in the product

  4   characteristics if they have no adverse effect.

  5             [Slide]

  6             As referenced, this slide illustrates our

  7   idea of what comparability is.  Comparable stays in

  8   between identical and different.

  9             [Slide]

 10             In the guidance, the 1996 comparability

 11   guidance, the following testing strategy for

 12   demonstrating comparability is stated:  There are

 13   three levels.  The first level includes in vitro,

 14   and sometimes in vivo, analytical functional

 15   studies.  These could be chemical, physical,

 16   immunological or bioassays.

 17             The next level, the second level is a

 18   preclinical study, such as animal pharmacokinetic,

 19   animal pharmacodynamic study and a toxicity study.

 20             The last level, which is the third level,

 21   is a clinical study.  This could be clinical

 22   pharmacokinetic, immunogenicity and clinical safety

 23   and efficacy studies.

 24             The one thing I want to emphasize here is

 25   that the comparability testing is not necessarily a 

                                                                 8

  1   hierarchical system where one result leads to

  2   another level of testing.  Sometimes this system is

  3   complementary.  For example, if the testing at a

  4   preclinical study finds some differences, that may

  5   trigger some additional in vitro analytical

  6   studies.

  7             [Slide]

  8              So, what is FDA's experience since 1996,

  9   when we published the comparability guidance,

 10   related to the plasma derivatives?

 11             [Slide]

 12             I have just a quick review of what plasma

 13   derivative products have been licensed by the FDA.

 14   Basically, there are four different categories of

 15   plasma derivatives.  The first is the coagulation

 16   factors, including antihemophilic factor, including

 17   von Willebrand Factor complex.

 18             I am not going to go through this list; I

 19   will just point out some categories.  The next one

 20   is albumin and plasma protein fraction.  We also

 21   have a group of protease inhibitors, such as alpha

 22   1 protease inhibitors which you are all familiar

 23   with and, lastly, the family of immunoglobulin

 24   products.  This list may not be a complete list but

 25   I just put this here to give you a review of what 

                                                                 9

  1   products we are dealing with.

  2             [Slide]

  3             In addition to the plasma derivatives, we

  4   also have five licensed recombinant coagulation

  5   factors, such as the BeneFix, which is recombinant

  6   Factor IV; ReFacto, and so forth and so on,

  7   Kogenate and Recombinate.  We also have one drug

  8   substance, recombinant antihemophilia factor for

  9   further manufacturing.

 10             [Slide]

 11             In the past five years FDA has received 70

 12   to 100 prior approval supplements.  For those of

 13   you that are not familiar with the term "prior

 14   approval supplement" I want to briefly say that a

 15   prior approval supplement is a supplement that is

 16   used to support a specific manufacturing change.

 17   We deem this type of change as significant, and the

 18   product made after the change cannot be released to

 19   the market for distribution until the agency

 20   approves it.

 21             The number of supplements, as you can see

 22   here, remained relatively steady during 1997 to

 23   2001.  The 2002 data is up to May of this year.

 24   Another thing I want to point out to you on this

 25   slide is that at the top of the slide there are 

                                                                10

  1   some numbers.  These numbers indicate the number of

  2   the major supplements that required clinical data

  3   to support the approval.  Totally, we have six such

  4   major supplements with clinical data, and three of

  5   them actually are efficacy supplements for new

  6   indications.  The other three involve manufacturing

  7   changes such as formulation changes and major

  8   process changes.  So, roughly we have about 1.31

  9   percent major supplements that require clinical

 10   data to support a change.  If you take out the

 11   three efficacy supplements, we only have roughly

 12   about 0.7 percent of the supplements requiring

 13   clinical data.

 14             [Slide]

 15             So, what is our regulatory approach?  I

 16   want to emphasize here that up till now we have

 17   regulated major manufacturing changes on a case by

 18   case basis.  The following three factors are

 19   important in terms of determining what type of data

 20   will be required.  First, we have to deal with so

 21   many different types of products.  Product is

 22   important.  Also, the type of manufacture changes

 23   and, lastly, the risk analysis and assessment that

 24   the agency makes for that particular manufacturing

 25   change. 

                                                                11

  1             [Slide]

  2             For the benefit of this audience, I

  3   include two general examples to illustrate the

  4   scope of change and the regulatory requirements.

  5   This example includes the type of changes, such as

  6   a new facility with no change in in-process

  7   control, no change in specification, and

  8   demonstration of in vitro comparability.

  9             A second type of change includes new

 10   assay, new standard for quality control and lot

 11   release.  Lastly, we have quite often received a

 12   one-time exception supplement.  For those of you

 13   who do not know what a "one-time exception

 14   supplement" is, basically it is a company that

 15   sends in a request to the agency for release of

 16   some of the lots that were manufactured with minor,

 17   or sometimes major, deviations from their license.

 18             To handle this type of manufacturing

 19   change, the review mechanism that we have is under

 20   the prescription user fee program, for which we

 21   have a four-month review time.  For some of the

 22   applications, such as a new facility, we also

 23   require a pre-approval inspection.

 24             [Slide]

 25             Another type of manufacturing change which 

                                                                12

  1   we consider very major manufacturing change is a

  2   new facility with alternate process; changes in

  3   specifications for drug substance and drug product;

  4   demonstration of comparability, and this

  5   demonstration includes three tiers of analysis

  6   which I mentioned earlier.  Under PDUFA 2 we have

  7   ten months review time and data supporting this

  8   kind of manufacturing change includes in vitro

  9   biochemical/biophysical characterization,

 10   preclinical studies, bridging clinical studies, and

 11   normally involve human pharmacokinetic data and

 12   sometimes will require safety and efficacy clinical

 13   data.  Pre-approval inspections are always required

 14   for this kind of manufacturing change and in some

 15   cases, and very often, a new proprietary name is

 16   used.  A company normally voluntarily phases out

 17   their old process but the agency has no requirement

 18   to make a commitment of time for this transition.

 19             [Slide]

 20             In conclusion, comparability approaches

 21   apply to both plasma- and biotech-derived

 22   biologics.  In our experience, clinical data have

 23   seldom been required to support manufacturing

 24   changes, however, major concerns remain.

 25             [Slide] 

                                                                13

  1             Concerns related to plasma protein

  2   therapeutics are the following, which may not be a

  3   complete list but I have pointed out some major

  4   things:  Poorly defined starting material.  We have

  5   source plasma versus recovered plasma that we had

  6   extensive discussion yesterday about.  We have

  7   different pool sizes used for the manufacturing.

  8   Lack of robustness of the manufacturing process,

  9   minor changes with major impact.  We have learned

 10   this lesson a long time ago and this is still the

 11   case.  Introduction of a vasoactive substance, such

 12   as PKA that Dr. John Finlayson mentioned for some

 13   of the cases yesterday.  Low purity;

 14   neoatigenicity.  Impurities, as I quoted here, may

 15   be active and may affect activity or absorption.

 16   Often this type of product is highly complex; and

 17   heterogeneous proteins; history of viral

 18   transmission.

 19             [Slide]

 20             Lastly, I want to give you some of the

 21   major results that came out from this workshop.

 22             [Slide]

 23             It is the agency's impression that the

 24   plasma derivatives industry welcomed the agency's

 25   comparability policy.  Comparability approaches 

                                                                14

  1   have been successfully used to expedite the

  2   implementation and approval of manufacturing

  3   changes.

  4             [Slide]

  5             Due to the complexity of the products and

  6   processes, it is unlikely, in the near future, to

  7   have a formula to decide what is comparable.

  8   Judgments will always be needed.  Up till now, as I

  9   mentioned earlier, we still use a case by case

 10   approach.  Due to the complexity and the reasons I

 11   mentioned earlier, there are many specific concerns

 12   for this type of product.

 13             [Slide]

 14             In conclusion, this workshop has fostered

 15   a better understand between the FDA and industry on

 16   the various topics related to the demonstration of

 17   comparability of human plasma-derived therapeutics.

 18   This workshop has also prepared both parties for

 19   more focused discussions to advance the goal of

 20   providing consumers with safe, pure, potent

 21   products in the most expeditious manner.  I thank

 22   you for your attention.

 23             DR. NELSON:  Thank you, Dr. Chang.  Are

 24   there any questions?

 25             [No response] 

                                                                15

  1             The next item is a summary of the AABB

  2   Conference on Oxygen Therapeutics, Toby Silverman.

  3              AABB Conference on Oxygen Therapeutics

  4                   and Transfusion Alternatives

  5             DR. SILVERMAN:  Thank you, Mr. Chairman.

  6   I attended the AABB Conference on Oxygen

  7   Therapeutics and Transfusion Alternatives on May

  8   30th to 31st of this year, and I am going to give

  9   you a brief summary of the discussions that

 10   occurred at that meeting.

 11             [Slide]

 12             AABB convened a conference to discuss a

 13   variety of topics, to include red cell transfusion,

 14   transfusion risks, perceptions of transfusion

 15   risks, alternatives to allogeneic red blood cell

 16   transfusion, and future directions for a class of

 17   products known as oxygen therapeutics, as well as

 18   other transfusion alternatives.

 19             [Slide]

 20             The meeting structure was essentially as

 21   follows.  I have rearranged some of the order of

 22   the talks to organize them into subject groups.

 23   There was an introduction and outline of the issues

 24   by the conference chairs.  There was a discussion

 25   of the impact of red blood cell alternatives; 

                                                                16

  1   logistical and control issues; and then a number of

  2   scientific discussions to include cancer and cancer

  3   treatment related anemia, the efficacy of

  4   transfusion, and the ethics of so-called bloodless

  5   medicine.  There was a discussion of the military

  6   needs for oxygen therapeutics.  There were a number

  7   of manufacturer presentations, and then the meeting

  8   concluded with my presentation.

  9             [Slide]

 10             The impact of oxygen therapeutics on the

 11   current transfusion environment, there is and

 12   remains a public perception that allogeneic

 13   transfusions are not safe for a number of reasons.

 14   First, known infectious risk; a concern about

 15   emerging infectious risks; and then further, a

 16   concern about the noninfectious hazards of

 17   transfusions, affectionately known as NISHOTS.

 18   There is a desire for alternatives to be used to

 19   reduce or eliminate the risks of blood

 20   transfusions.

 21             [Slide]

 22             Here are a number of transfusion

 23   alternatives that were mentioned or discussed at

 24   the meeting:  Predeposit autologous transfusion;

 25   hemodilution; intraoperative autologous donation; 

                                                                17

  1   pharmacologic therapeutics; apheresis to reduce

  2   donor exposure; viral inactivation of a variety of

  3   transfusion products; and, finally, oxygen

  4   therapeutics.

  5             [Slide]

  6             There are a number of competing

  7   technologies for oxygen delivery that were

  8   identified in discussions at this meeting.  These

  9   include intravenous allosteric modifiers of

 10   hemoglobin function; hemoglobin from transgenic

 11   animals and pathogen-reduced red blood cells.  One

 12   that was new to me was in vitro red blood cell

 13   culture, and a number of others.

 14             [Slide]

 15             What is the impact of transfusion

 16   alternatives?  You see a number of question marks

 17   for everything here on the slide.  What is the

 18   demand for allogeneic blood donors for the

 19   manufacture of such products?  Unknown.  Whether

 20   there will be an improved outcome in trauma is

 21   unknown.  Whether there will be an impact on the

 22   volunteer blood donor pool is unknown.  There are

 23   many implementation questions that remain.  The

 24   first is where will such products be stocked.

 25   Pharmacy or will they be controlled through the 

                                                                18

  1   blood bank?  What will happen in terms of

  2   collection of source red blood cells for such

  3   products?  How will such products be reimbursed?

  4   Then, what choice of agents to stock either in the

  5   blood bank or in the pharmacy?

  6             [Slide]

  7             How and where will oxygen therapeutics be

  8   used?  First how, will they be used for initial

  9   resuscitation?  Will they be used as a bridge to

 10   transfusion?  Will they be used as adjunctive

 11   therapy for, for example, radiation treatments to

 12   enhance oxygen delivery to tumors?  Will they be

 13   used as a transfusion alternative?  Will they be

 14   used as an oxygen therapeutic?

 15             Where and by whom will such products be

 16   used?  Will they be used on the battlefield?  Will

 17   they be used at the accident scene?  Will they be

 18   used in the transport vehicle, such as an

 19   ambulance?  Will they be used in the hospital and,

 20   if in the hospital, where?  In the OR, in the

 21   emergency room, in the cath lab?  Will they be used

 22   by oncologists?  Will they be used in physicians'

 23   offices?

 24             [Slide]

 25             Who will control and how will control of 

                                                                19

  1   products be maintained?  First, who will control?

  2   Will it be the pharmacy?  Will it be the blood

  3   bank?  Will it be both?  Will it be neither?

  4             What control and oversight issues remain?

  5   What will be the initial and then what will be the

  6   total dose of such products to be used?  How will

  7   use of the product be monitored?  Will there be a

  8   utilization review committee?  What will happen in

  9   terms of the clinical laboratory and how will the

 10   clinical lab handle the interference that

 11   invariably is associated with the use of a colored

 12   product in terms of the readouts for some of the

 13   clinical chemistry laboratory tests?  Who will

 14   control and how will quality control be maintained?

 15   Finally, who will have oversight or who will

 16   evaluate transfusion or infusion reactions?

 17             [Slide]

 18             The scientific discussions.  The first was

 19   a discussion of cancer and treatment-related

 20   anemia.  High dose hemotherapy and autologous stem

 21   cell transplantation can be performed without the

 22   use of blood or platelet transfusion.  We heard

 23   that stem cells are cryopreserved with albumin;

 24   that pre-transplant use of erythropoietin and

 25   intravenous iron help reduce the need for red cell 

                                                                20

  1   transplantation; that there is no mortality when

  2   high-dose chemotherapy is delayed until the total

  3   hemoglobin level is at least 11 g/dL.  There is a

  4   question as to whether high-dose chemotherapy

  5   should be delayed until platelet recovery has

  6   occurred.  Thrombocytopenia can be managed with

  7   antifibrinolytic agents.  And, there was no

  8   significant bleeding with platelet counts above

  9   5000.

 10             [Slide]

 11             Efficacy of transfusion, there are a

 12   number of considerations:  What is the level of

 13   anemia that adversely affects outcome?  What is the

 14   level of anemia at which transfusion has been

 15   demonstrated to reverse poor outcome?  I think what

 16   you can gather from this is that there are an awful

 17   lot of questions and not an awful lot of answers.

 18             [Slide]

 19             The efficacy of transfusion, there is one

 20   adequately powered trial in the world literature

 21   that suggests that total hemoglobin of 7 g/dL as a

 22   threshold is safe in ICU patients, but the data may

 23   not be generalizable overall.  There are

 24   observational data in patients with cardiovascular

 25   disease that suggest that a higher total hemoglobin 

                                                                21

  1   level may be needed in such patients.

  2             One of the conclusions was that it is

  3   likely that the most important factor related to

  4   outcome is whether or not the patient has had

  5   outstanding medical care or less than outstanding

  6   medical care.  Then, there is a question as to

  7   whether to use alternative treatment when there is

  8   increased risk and transfusions have improved

  9   outcome.

 10             [Slide]

 11             There was a discussion of the ethics of

 12   bloodless medicine.  The standard of practice was

 13   described.  Blood transfusions are indicated when

 14   specified conditions pertain, however red blood

 15   cells are a scarce resource.  Patients may refuse

 16   transfusion.  There was a discussion of the use of

 17   informed consent and decisional capacitation and

 18   also a discussion of the outcomes of clinical

 19   research on bloodless techniques.  There is a range

 20   of practices that are the product of accumulated

 21   medical experience but, as you have seen, there are

 22   very few clinical trials.

 23             [Slide]

 24             Decisional capacity, there are four

 25   conditions that pertain in order to determine 

                                                                22

  1   whether a patient is decisionally capacitated.  The

  2   patient must be able to understand his or her

  3   medical condition.  They must be able to understand

  4   the medical alternatives which include no treatment

  5   at all.  The patient must be able to understand the

  6   risks and benefits of each alternative and express

  7   a choice about those alternatives.  For refusal of

  8   a high benefit and low-burden treatment, the

  9   patient should have a stable set of personal values

 10   that can be ascertained, and must have the ability

 11   to apply those values to the clinical situation.

 12             [Slide]

 13             Finally, the last two talks for the

 14   conference included military blood use.  For the

 15   military, delivery of blood or transfusion products

 16   is logistically difficult and it is very difficult

 17   to position appropriate products where they are

 18   needed.  Not all products are available where they

 19   are needed.  For example, platelets cannot be

 20   shipped because of the time lag between the date of

 21   notification of need and the date of arrival at the

 22   scene, which can be as long, if I recall correctly,

 23   as 10 or 11 days.  Therefore, untested whole blood

 24   is collected for platelet transfusion in the combat

 25   arena.  Finally, the frozen blood inventory is 

                                                                23

  1   reaching its 10-year storage limit.

  2             [Slide]

  3             There were a number of manufacturer

  4   presentations which I will not summarize here.  We

  5   were updated by Alliance Pharmaceutical

  6   Corporation, Amgen, Biopure, Hemosol and Northfield

  7   Laboratories.

  8             [Slide]

  9             A very brief overview of the talk that I

 10   gave, there are some considerations when looking at

 11   clinical trials for oxygen therapeutics.  Whether

 12   one should look at trials as urgent versus elective

 13   use; trauma versus surgery versus medical use; or

 14   whether blood is available as opposed to blood not

 15   being available.

 16             [Slide]

 17             We made a number of recommendations, that

 18   studies in both trauma and elective surgery are

 19   probably needed for best initial understanding of

 20   the benefits and risks of oxygen therapeutics in

 21   the broadest spectrum of situations where and when

 22   such products might be used, generally as

 23   alternatives to red cell transfusion.  An

 24   indication for use where and when blood is not

 25   available is best supported by studies in both 

                                                                24

  1   elective surgery and in trauma.  Safety evaluation

  2   should be performed in stable elective surgical

  3   settings before using a product in unstable or

  4   traumatized patients.  Finally, the FDA may accept

  5   applications for elective surgical indications

  6   alone.

  7             In general, the discussion at the meeting

  8   suggested that there might be other places for use

  9   of oxygen therapeutics, particularly as adjunctive

 10   therapy or for medical indications or indications

 11   other than surgery or trauma.  That seems to be the

 12   new message coming out of this particular meeting.

 13   Thank you very much.

 14             DR. NELSON:  Thank you, Toby.  Questions?

 15   No?  We had a request for a brief presentation from

 16   Anthony Castaldo, from the Hereditary Angioedema

 17   Association.

 18                       Public Presentation

 19                Hereditary Angioedema Association

 20             MR. CASTALDO:  Thank you, Mr. Chairman.

 21   Good morning.  My name is Anthony Castaldo, and I

 22   am here today to briefly discuss issues associated

 23   with gaining FDA approval for plasma-derived

 24   purified C1 inhibitor concentrate.  This drug is

 25   the only treatment available for acute attacks of 

                                                                25

  1   hereditary angioedema, HAE, and has been used

  2   safely and effectively in Europe and other parts of

  3   the world for over a decade.

  4             Although I am a board member of the

  5   association that represents patients with this

  6   severe, debilitating, and life-threatening disease,

  7   it is important that I mention up front that

  8   statutes governing the ethical conduct of

  9   government employees preclude me from representing

 10   the HAE Association during today's proceedings.

 11   Accordingly, to ensure strict compliance with

 12   federal statutes that prohibit a government

 13   employee from representing a third party before any

 14   governmental entity, I would like to state for the

 15   record that technically I am not appearing on

 16   behalf of the association or in my capacity as a

 17   board member.  I appear today as an advocate for

 18   the severely affected HAE patients in my immediate

 19   family.  That takes care of 18 USC 205.

 20             HAE patients were recently informed that

 21   the results of a Phase III clinical trial of Baxter

 22   International's C1 inhibitor concentrate product

 23   were not favorable enough to obtain FDA approval.

 24   Patients suffering from HAE are once again left

 25   with little near-term hope for an acute attack 

                                                                26

  1   therapy.  This outcome is tragic in light of the

  2   unanimous view among participating investigators

  3   who are convinced that Baxter's C1 inhibitor

  4   concentrate is an effective and safe acute attack

  5   therapy.

  6             By way of background, HAE is a rare

  7   condition in which a genetic defect causes a

  8   deficiency in the plasma protein C1 inhibitor.

  9   Dysfunctional C1 inhibitor protein permits

 10   production of vasoactive peptides that alter

 11   vascular permeability and cause edema.

 12   Accordingly, the disease is characterized by

 13   episodic swelling of the extremities, face, bowel

 14   wall, and upper airway.  Studies of affected

 15   kindreds have reported mortality rates of over 30

 16   percent, with death most frequently caused by

 17   asphyxiation due to airway closure.

 18             We are constantly reminded of the inherent

 19   danger posed by hereditary angioedema.  Over the

 20   past 18 months, I have received information

 21   regarding the untimely deaths of three patients who

 22   were active participants in an informal email

 23   support group for HAE patients.  Two of these

 24   patients, by the way, were enrolled in the Baxter

 25   clinical trial and were unable to get to the trial 

                                                                27

  1   site in time for treatment.

  2             The fact that the Baxter C1 inhibitor

  3   product will not be licensed in the United States

  4   is shocking for many reasons.  Foremost among them

  5   is the fact that this product boasts a decade-long

  6   track record of safe and effective use outside the

  7   United States.  Moreover, the same product was

  8   proven safe and effective in a well-designed

  9   NIH-funded study conducted by three respected

 10   scientists who published their results in a 1996

 11   paper that appeared in The New England Journal of

 12   Medicine.  It is, indeed, ironic that the day

 13   Baxter notified us of the trial failure marked the

 14   one-year anniversary of a study out of Europe in

 15   the Archives of Internal Medicine that assessed 193

 16   cases of HAE-related laryngeal edema, all

 17   successfully treated with C1 inhibitor concentrate.

 18             In light of the foregoing, there looms an

 19   obvious yet quintessential question, how could a

 20   demonstrably life-saving therapy, with a proven

 21   track record of efficacy and safety, be judged a

 22   failure?  Investigators who participated in the

 23   trial immediately knew the answer, and it continues

 24   to haunt the HAE patient community.  To meet the

 25   mandated primary clinical endpoint, the trial had 

                                                                28

  1   to demonstrate that C1 inhibitor concentrate was

  2   effective within one hour from commencement of an

  3   infusion.  In contrast, studies that garnered C1

  4   inhibitor concentrate approval in Europe assessed

  5   efficacy within a four-hour window.

  6             Perhaps the most compelling evidence of

  7   the C1 inhibitor clinical trial design deficiencies

  8   was articulated in an email from Dr. Andrew Grant,

  9   a trial investigator from the University of Texas

 10   at Galveston.  I quote, my patient, TA, with HAE

 11   was admitted to this hospital with complete

 12   obstruction of his airway.  He survived the day

 13   only because he has a permanent tracheostomy which

 14   he could open.  Within 20 minutes of starting his

 15   C1 inhibitor infusion he noticed some improvement,

 16   which continued over the next four hours to the

 17   point of near resolution.  But until one hour, his

 18   course was not at all clear.  Thus, he probably

 19   would have been judged and listed by me as a trial

 20   failure at one hour, thus, another proof that the

 21   study design was hopelessly flawed, closed quote.

 22             Additional analysis performed by one of

 23   the study's principal investigators shows just how

 24   close we were to getting approval for this vital

 25   and critically needed therapy.  This scientist 

                                                                29

  1   evaluated the clinical trial data set using 80

  2   minutes instead of 60 minutes as the endpoint.

  3   Even this relatively small additional time

  4   increment produced a striking difference in the

  5   number of treatments that would have been reported

  6   as a positive response, and likely would have

  7   altered the study's final result.

  8             In conclusion, the only treatment shown

  9   effective for abating dangerous and painful acute

 10   attacks of hereditary angioedema is replacement

 11   therapy using plasma-derived purified human C1

 12   inhibitor concentrate.  The human suffering that

 13   will result from the lost opportunity to gain

 14   approval of C1 inhibitor concentrate motivates HAE

 15   patients to pick up the pieces and try again.  This

 16   has become more complicated since the trial failure

 17   appears to have prompted Baxter International's

 18   decision to cease worldwide production of its C1

 19   inhibitor product.

 20             At this juncture, HAE patients are left

 21   without any near-term hope for an acute attack

 22   therapy.  However, HAE patients are working

 23   feverishly to interest another company in

 24   conducting a clinical trial with their C1 inhibitor

 25   product.  I urge the FDA staff to work with the HAE 

                                                                30

  1   investigator community to establish a more rational

  2   and fair C1 inhibitor concentrate clinical trial

  3   design.  To be sure, this is a crucial factor that

  4   will influence drug company decisions on whether

  5   another C1 inhibitor concentrate clinical trial

  6   will be conducted in the United States.  Thank you

  7   for your time, and I would be happy to answer any

  8   questions.

  9             DR. NELSON:  Thank you.  Toby?

 10             DR. SIMON:  Is the plasma useful--we

 11   realize it has a lot of disadvantage to a

 12   concentrate in view of the volume, but how useful

 13   is it in treatment?

 14             MR. CASTALDO:  FFP, there is just not

 15   enough inhibitor.  I can give you an example of my

 16   daughter before we got access to the factor.  We

 17   actually got compassionate use of it because of the

 18   severity of my daughter's disease.  We literally

 19   used gallons of FFP and it just doesn't work

 20   effectively at all.  Some patients report some

 21   efficacy but, generally speaking, because of the

 22   other substrates that are in plasma and the

 23   possibility of attack exacerbation, it is not an

 24   effective therapy.  Furthermore, it is a 24-hour

 25   resolution at best, and generally it is not 

                                                                31

  1   considered an effective therapy for this

  2   indication.

  3             DR. HOLLINGER:  Is it found in

  4   cryoprecipitate?

  5             MR. CASTALDO:  I am sorry?

  6             DR. HOLLINGER:  Is the factor found in

  7   cryoprecipitate of this inhibitor?

  8             MR. CASTALDO:  I don't believe so.

  9             DR. NELSON:  Yes, it sounds like it is a

 10   fairly complex problem.  As I put it together from

 11   your presentation, it appears that the trial was

 12   designed with a certain endpoint which wasn't met

 13   but still there was a benefit.  Then, the FDA, I

 14   think, required the manufacturer to satisfactorily

 15   meet the endpoint and they met another endpoint

 16   and, therefore, it wasn't licensed and the company

 17   decided not to proceed.  So, it is a very difficult

 18   situation.  I don't think the committee can do

 19   much, except we are very thankful for the

 20   information.

 21             MR. CASTALDO:  Well, we note that the

 22   staff is here--

 23             DR. NELSON:  And we are hoping, if there

 24   is any progress or change on this, that maybe we

 25   could discuss it at a future meeting. 

                                                                32

  1             DR. EPSTEIN:  Just a few things.  First of

  2   all, I appreciate your remarks.  On the other hand,

  3   this was not a topic on the agenda and we didn't

  4   come prepared to really deliberate it.

  5             MR. CASTALDO:  Right.

  6             DR. EPSTEIN:  But that said, the first

  7   point is that the product does remain available for

  8   compassionate use so the patients have not entirely

  9   been abandoned either by the company which makes it

 10   available, or by the FDA that permits the

 11   compassionate use.

 12             The second point I would make is that, you

 13   know, it is a fundamental error in clinical trial

 14   assessment to take a failed trial and to draw a

 15   circle about an observation and to say that you

 16   have now validated the new endpoint.  This is a

 17   heresy; it violates all statistical principles.  I

 18   am sure Dr. McGee would agree with me.  You simply

 19   can't go about it that way.  When that happens what

 20   has actually occurred is that you have generated a

 21   new hypothesis which you then should test

 22   prospectively.  That is the only way to know

 23   whether you have committed an error of logic.

 24             So, the normal response, and true in this

 25   case, would be to say to the company, well, it 

                                                                33

  1   looks as if it might have efficacy with this other

  2   endpoint which would appear to have clinical

  3   benefit if shown true, and you need to redo the

  4   trial prospectively with that endpoint in mind, or

  5   the new target.  You can't just draw a circle

  6   around a result and say that was our target; we met

  7   it.  You have to have the target and then do the

  8   study.

  9             So, you know, it falls to the company to

 10   decide whether to pursue a trial with a different

 11   endpoint and, of course, to convince people that

 12   this different endpoint is also a clinically

 13   meaningful endpoint.  I would just submit that most

 14   of the enlightening exercise needs to be directed

 15   towards the company to address patient need.

 16             MR. CASTALDO:  Yes, and we agree.  In

 17   fact, that is what this testimony basically says

 18   today, that we just hope that staff would be

 19   willing to work with our physician investigator

 20   community that is going to work, hopefully, with

 21   another company to design a trial that would be

 22   more in accordance with what we observed to be the

 23   response, the pathophysiological response to the

 24   therapeutic.

 25             But I agree with the reasoning that you 

                                                                34

  1   have posited here.  One of the things that we have

  2   heard anecdotally from our discussions with various

  3   individuals who represent different companies which

  4   make this factor is that if there were some notion

  5   that there could be an endpoint that would be more

  6   in accordance with what the European trials have

  7   done, then a company would be more willing to come

  8   into the market.  That is basically what we are

  9   looking for.  In the next trial, hopefully, the

 10   design will be a little different than the one we

 11   currently have.

 12             DR. HOLLINGER:  In terms of numbers, how

 13   many people in this country do you know of that

 14   have this deficiency in terms of powering of

 15   studies, and how often do they have a problem?

 16   Once a year?  Once a week?

 17             MR. CASTALDO:  Yes, one of the things

 18   about this disease is that the presentation is

 19   highly variable among patients.  The

 20   epidemiological data on the disease is not very

 21   good.  There is a very wide spread.  It is between

 22   1 in 10,000, which would give you a patient

 23   population of 28,000, to 1 in 50,000, which would

 24   make around 5500.

 25             You know, there is an association of 

                                                                35

  1   patients and I can tell you that that association

  2   generated upwards of 2000 letters to the Baxter

  3   chairman, in response to their decision to exit

  4   this market, to see if we couldn't change his mind

  5   and have him come back and do another trial and try

  6   to go for a different endpoint.

  7             Again, as I mentioned before I looked at

  8   the time requirement and I crossed a few things out

  9   of my statement today, but the current available

 10   therapy is anabolic steroids, 17-alpha alkylated

 11   androgens, and they do provide prophylaxis in some

 12   patients but most of those patients, in my

 13   experience, still have what we call breakthrough

 14   attacks.  Moreover, trauma is a big part of this

 15   disease.  Many attacks are induced by any form of

 16   trauma.  As a result, if you are going to have oral

 17   surgery or any other kind of surgery, in Europe it

 18   is customary to have a prophylaxis dose of C1

 19   inhibitor concentrate to ensure you don't have

 20   associated edema with that.  But most patients, I

 21   would say roughly speaking maybe on the more

 22   severely affected side of the continuum would

 23   probably have attacks anywhere from once a month to

 24   once every two weeks, not withstanding androgen

 25   therapy.  That excludes a whole other tragic 

                                                                36

  1   population of children, and there are a lot of very

  2   severely affected children out there, for whom, of

  3   course, anabolic steroid therapy is

  4   contraindicated.

  5             DR. NELSON:  Thank you.  The next item is

  6   requirements for premarket submissions:  in vitro

  7   diagnostic software and instruments, Diane

  8   Gubernot.

  9             Requirements for Premarket Submissions:

 10           In vitro Diagnostic Software and Instruments

 11             MS. GUBERNOT:  Thank you.  Good morning.

 12             [Slide]

 13             There will be three of us presenting on

 14   this topic this morning, and we will also have John

 15   Murray, who is a software expert from CDRH, in the

 16   audience, if there are questions.

 17             I am Diane Gubernot.  I am a reviewer in

 18   the Division of Emerging and Transfusion

 19   Transmitted Diseases.  The presentation is on the

 20   requirements for premarket submissions for in vitro

 21   diagnostic instrumentation and software related to

 22   donor screening and all HIV diagnostic assay

 23   systems.

 24             [Slide]

 25             The issue is that software/instruments are 

                                                                37

  1   becoming increasingly complex due to the

  2   development of automated platforms for testing and,

  3   therefore, the applications are becoming more

  4   complex.  Some manufacturers have expressed

  5   confusion regarding premarket submission

  6   requirements for software related to blood typing,

  7   donor screening and HIV diagnostic assay systems.

  8             [Slide]

  9             The objectives of this presentation are,

 10   one, to summarize the regulations and guidance

 11   documents applicable to the software systems for

 12   premarket applications; two, to provide specific

 13   information to the manufacturers on the content of

 14   submissions to expedite the review process.

 15             [Slide]

 16             Three, to inform manufacturers of the

 17   standards for level of concern determination which

 18   apply to CBER-regulated donor screening and HIV

 19   diagnostic assay systems.

 20             [Slide]

 21             For software development, manufacturers

 22   must follow the quality system requirements, the

 23   QSR, found in 21 CFR 820.  The general principles

 24   of software validation is a guidance for industry

 25   which should also be followed.  It describes how 

                                                                38

  1   certain provisions in the QSR apply to software.

  2   It is a very useful document.  This is true for

  3   device applications that are submitted to CDRH and

  4   to CBER.

  5             [Slide]

  6             When submitting software and instrument

  7   applications to CBER, or applications that contain

  8   a software component or an instrument of an assay,

  9   manufacturers should follow the guidance for

 10   content of premarket submissions for software

 11   contained in medical devices.  This is a CDRH

 12   guidance document available on our website.  By

 13   following this, this will expedite the review

 14   process.

 15             In addition, manufacturers of blood bank

 16   software should follow reviewer guidance for a

 17   premarket notification submission for establishment

 18   computer software, which we refer to as BECS.  This

 19   guidance is specific for 510(k)s for BECS.

 20             [Slide]

 21             The applications may be premarket

 22   notifications, which are 510(k)s.  These are for

 23   substantially equivalent devices.  Premarket

 24   approval applications, PMAs, are usually submitted

 25   for diagnostics.  Biologic license applications, 

                                                                39

  1   BLAs, are for donor blood testing.  If you are

  2   confused, please contact us prior to submitting.

  3             [Slide]

  4             Blood bank and HIV diagnostic instrument

  5   and software devices may be stand-alone software,

  6   such as blood establishment computer software.  It

  7   could be software that is used in conjunction with

  8   automated instruments.  It could be software that

  9   controls an instrument or software that collects

 10   data and results from an instrument.  Or, it could

 11   be automated and semi-automated instruments

 12   containing firmware, which is embedded software.

 13   Although people may not perceive instruments to be

 14   software, they do contain software and, therefore,

 15   the guidance applies.  An example would be an

 16   automated pipetter or an analyzer.  Also,

 17   accessories, such as barcode scanners, should be

 18   part of the application.  I mention barcode

 19   scanners, they are important data input and part of

 20   the system for sample traceability and unit

 21   traceability.

 22             [Slide]

 23             The CDRH guidance for premarket submission

 24   includes definitions for major, moderate and minor

 25   level of concern; a flowchart for determining the 

                                                                40

  1   level of concern for your device; and required

  2   documents to be submitted based on the level of

  3   concern determination.

  4             [Slide]

  5             The level of concern is a term used by FDA

  6   and industry to determine which software design

  7   documents are required to be submitted in an

  8   application.  Therefore, it determines the depth of

  9   the review.  The required verification, validation

 10   and testing activities performed by a manufacturer

 11   are not limited to the scope of the application

 12   submission.  Therefore, the application should be a

 13   xeroxing exercise.

 14             [Slide]

 15             Major level of concern is defined as

 16   operation of the software associated with device

 17   function directly affects the patient so that

 18   failures or latent flaws could result in death or

 19   serious injury, or indirectly affects the patient

 20   such that incorrect of delayed information could

 21   result in death or serious injury of the patient

 22   and/or operator.

 23             [Slide]

 24             Moderate level, operation of the software

 25   associated with device function directly affects 

                                                                41

  1   the patient so that failures or latent flaws could

  2   result in noon-serious injury, or indirectly

  3   affects the patient such that incorrect or delayed

  4   information could result in non-serious injury of

  5   the patient and/or operator.

  6             [Slide]

  7             Minor level, failures or latent design

  8   flaws would not be expected to result in any injury

  9   to the patient and/or operator.

 10             [Slide]

 11             This is a flowchart from the CDRH

 12   guidance.  It is a little difficult to read, but

 13   note the arrows for the boxes.  Those are the

 14   decisions that I will be going over, the questions

 15   that bring us to the level of concern.

 16             [Slide]

 17             The first box, does the software control a

 18   life-supporting or sustaining device?   The answer

 19   is yes for blood establishment computer systems,

 20   blood screening systems, blood typing systems

 21   because blood is life supporting and sustaining.

 22   Sheryl Kotchman will be talking more about that.

 23   That would be a yes and that brings us over here.

 24             [Slide]

 25             Then for HIV diagnostics, these would be 

                                                                42

  1   no until we get to box number two.  Does the

  2   software provide diagnostic information as a basis

  3   for treatment or therapy?  And the answer is yes.

  4   So, that bring us over here.

  5             [Slide]

  6             That brings us down to box number three,

  7   prior to mitigation could a software failure result

  8   in death or serious injury?  The answer is yes, so

  9   that brings us here to major level of concern.

 10   That is a recap with the numbered boxes.

 11             [Slide]

 12             HIV diagnostic instruments and software,

 13   FDA has determined these to be a major level of

 14   concern.  Products that aid in diagnosis, monitor,

 15   such as the viral load assays, or genotype HIV, the

 16   resistance assays, meet the 21 CFR 809.3 definition

 17   of an in vitro diagnostic device.  Incorrect test

 18   results from use of the devices could mislead

 19   physicians regarding treatment decisions, resulting

 20   in serious injury.

 21             [Slide]

 22             This is directly out of the CFR definition

 23   for in vitro diagnostic devices.  in vitro

 24   diagnostic products are those reagents, instruments

 25   and systems intended for use in the diagnosis of 

                                                                43

  1   disease or other conditions, including a

  2   determination of the state of health in order to

  3   cure, mitigate, treat or prevent disease.

  4             [Slide]

  5             In summary, all software and instrument

  6   systems, regardless of the determined level of

  7   concern, must follow the QSR for system

  8   development.  General principles of validation

  9   guidance document should also be referenced.  The

 10   guidance for the content of premarket submissions

 11   for software contained in medical devices should be

 12   followed to expedite the review process.  Seek

 13   guidance from CBER prior to submitting an

 14   application.  Again, the application should be a

 15   xeroxing exercise.  FDA expects complete and

 16   organized submissions, and we strongly encourage

 17   early interactions prior to the submissions so that

 18   we can go through the guidance documents and

 19   discuss the data that should be submitted.

 20             These are CBER software contacts.  I work

 21   in the Division of Emerging and Transfusion

 22   Transmitted Diseases.  My phone number is

 23   301-827-3624.  Sheryl Kochman, who will be

 24   presenting next, is in the Division of Blood

 25   Applications.  Her phone number is 301-827-3524 and 

                                                                44

  1   Richard Potter, in the Division of Hematology,

  2   301-496-2577.  If you are unsure whom to call, you

  3   may call any of us and we will send you in the

  4   right direction.  Thank you.

  5             DR. NELSON:  Thank you.  Next is Sheryl

  6   Kochman.

  7             MS. KOCHMAN:  My presentation,

  8   considerations for premarket submissions for

  9   automated blood grouping systems and blood

 10   establishment computer software, is just a summary

 11   of how we have been doing business, and to put

 12   things in perspective for the things that Diane

 13   just went over.

 14             [Slide]

 15             I am Sheryl Kochman.  I am chief of the

 16   Devices Review Branch.  My branch covers those

 17   devices that are used in tracking donor

 18   information, which would be the BECS, and also the

 19   devices and reagents that are used in blood typing

 20   for transfusable products.

 21             [Slide]

 22             The objectives of my presentation are to

 23   confirm that the information just presented by

 24   Diane also applies to automated blood grouping

 25   systems and blood establishment computer software, 

                                                                45

  1   and it is also to remind manufacturers of

  2   additional existing guidance that we have.

  3             [Slide]

  4             First, for automated blood grouping

  5   systems, the existing FDA guidance for reviewers,

  6   premarket notification submissions for automated

  7   testing instruments used in blood establishments,

  8   which is a draft guidance available on the CBER

  9   website, is something that you can refer to.  It is

 10   still a draft and it states FDA's current thinking

 11   on reviewing these devices.  It should also be

 12   pointed out that this document, while labeled as

 13   being a reviewer guidance, also applies to

 14   manufacturers.

 15             [Slide]

 16             We also have some other information, that

 17   has been around for a while, that indicates our

 18   thinking on what we expect these devices to do.

 19   So, we also would like to refer people to a

 20   memorandum to all licensed blood establishments.

 21   The title is changes in equipment for processing

 22   blood donor samples, issued by CBER July 21, 1992.

 23   This document was initially intended for device

 24   users but it provides useful information to

 25   manufacturers of automated blood group systems as 

                                                                46

  1   it describes some of the expectations we have for

  2   what a user is supposed to do to validate and

  3   install the system.

  4             [Slide]

  5             We also have a points to consider

  6   document, design and implementation of field trials

  7   for blood grouping reagents and anti-human

  8   globulin, docket number 91N-0467.  It is a 1992

  9   draft.  The notice of availability for this

 10   document was published in May of '92 and it is 57

 11   FR, 18885.  This document is also still a draft but

 12   it states FDA's current thinking on performance of

 13   field trials.  This document was intended for

 14   manufacturers of reagents but provides useful

 15   information to manufacturers or automated blood

 16   grouping systems as well.

 17             I also want to reaffirm that the guidance

 18   for content of premarket submissions for software

 19   containing medical devices, May 29, 1998, is also

 20   applicable to this group of devices.  As Diane

 21   indicated, it is applicable to devices.  Again, the

 22   general principles of software validation, final

 23   guidance for industry and FDA staff is also

 24   applicable.  Both of these are available on the

 25   CDRH website. 

                                                                47

  1             [Slide]

  2             I also want to reiterate that the level of

  3   concern for automated blood grouping systems is a

  4   major level of concern since the affected end

  5   product, which would be human blood, is

  6   life-sustaining and a defect in the software could

  7   result in the transfusion of an incompatible

  8   product causing death or serious injury.

  9             [Slide]

 10             For blood establishment computer software,

 11   and I will call it BECS for the rest of the

 12   presentation, we have a guidance that has been

 13   published, reviewer guidance for premarket

 14   notification submission for blood establishment

 15   computer software.  The final was published in

 16   January of 1997, and this document is available on

 17   the CBER website.  There are some things that we

 18   found that are not quite clear in this document,

 19   and if people have questions about intent or a

 20   description of what we are looking for, they should

 21   feel free to give us a call and we will help you

 22   work it through.

 23             [Slide]

 24             In addition, BECS manufacturers might find

 25   some other information that would be useful to them 

                                                                48

  1   in a memorandum to all licensed blood

  2   establishments.  Again, this was recommendations

  3   for implementation of computerization in blood

  4   establishments.  It is a CBER, April, 1998

  5   document.  This was initially intended for blood

  6   establishment personnel but provides useful

  7   information to manufacturers of BECS.  It describes

  8   some of the things we expect the software to be

  9   used in blood banks to be capable of doing.

 10             [Slide]

 11             Again, another memorandum to all licensed

 12   blood establishments, requirements for

 13   computerization in blood establishments, from CBER,

 14   September, 1989.  It was initially intended for

 15   blood establishment personnel but also provides

 16   useful information to manufacturers of BECS in that

 17   it describes what we expect the software to be

 18   capable of doing.

 19             [Slide]

 20             Just another reaffirmation that the two

 21   CDRH guidance documents are applicable to BECS, as

 22   well as the CBER guidances that are available.

 23             [Slide]

 24             Again, confirmation that the level of

 25   concern for BECS is a major level of concern since 

                                                                49

  1   the human blood is life-sustaining and a defect in

  2   the software could result in the transfusion of an

  3   incompatible or unsuitable product causing death or

  4   serious injury.

  5             [Slide]

  6             Some of these documents that I have

  7   referenced here are so old that they are not

  8   available on the web so I wanted to give people

  9   some help in finding some of the older documents.

 10   If there is no website address, you can contact our

 11   Office of Communications, Training and Manufacturer

 12   Assistance.  I have the email, the phone number and

 13   the fax number for those people.  You can also send

 14   a letter to that same office if you need additional

 15   help.  They should be able to refer you to any

 16   other help you might need.  Thank you.

 17             DR. NELSON:  Thank you, Sheryl.  Questions

 18   or comments?  You talked about testing, and so

 19   forth, but does FDA require a patient registry,

 20   computerized patient registry?  The reason I ask

 21   this is because I have done a lot of work in

 22   international settings and when you go to even a

 23   large international blood bank you find that they

 24   still have paper records, and it becomes just an

 25   impossible situation.  My feeling is that all blood 

                                                                50

  1   banks in the U.S. are computerized with regard to

  2   patient demographics and previous test results,

  3   etc., but is that an FDA requirement?

  4             MS. KOCHMAN:  No, it is not, not that it

  5   be electronic.

  6             DR. NELSON:  Because if it isn't

  7   electronic it is kind of useless.  Thank you.  Jim

  8   Callaghan?

  9             MR. CALLAGHAN:  Good morning.

 10             [Slide]

 11             I am Jim Callaghan.  I am from CDRH.  I

 12   work in the Office of Device Evaluation, the

 13   Division of Clinical Laboratory Devices.  I am here

 14   to talk about CDRH classification policy for

 15   laboratory automation.  This includes automated

 16   clinical laboratory analyzers, reagents and

 17   automated laboratory test systems.

 18             [Slide]

 19             These test systems may be considered

 20   combination devices.  This was discussed in a

 21   guidance document, a blue book memo, back in 1986.

 22   It was in a premarket notification review program

 23   guidance.

 24             [Slide]

 25             Specifically, when any of these analyzers 

                                                                51

  1   are regulated as a combination device, the analyzer

  2   accessory is classified in the highest of the

  3   predicate device classifications of this system

  4   combination.  There has been confusion on this, and

  5   this is why I am bringing that up.

  6             [Slide]

  7             Prior to FDAMA, automated clinical

  8   laboratory analyzers were not exempt from premarket

  9   notification.  Now, since they are class I devices,

 10   these analyzers are exempt from 510(k).  However,

 11   they are not exempt when an analytical claim is

 12   made for class I reserved devices, by virtue of the

 13   limitations to exemptions under 862, 864 and 866.9,

 14   or a class II device.  If there is a claim made for

 15   a class III device, it would be regulated under the

 16   PMA process.

 17             [Slide]

 18             In January, 2000 there was a Federal

 19   Register notice exempting class I devices from

 20   premarket notification.  In this Federal Register

 21   notice there were several class I devices reserved

 22   from this exemption.  In particular, blood banking

 23   supplies, vacuum-assisted blood collection systems,

 24   blood measuring devices and blood weighing devices.

 25   Additionally, quality control materials were 

                                                                52

  1   exempted--there are class I devices that were

  2   exempted from premarket notification, but they are

  3   reserved if they are assay control material or

  4   controls that are unassayed, used for blood

  5   banking.

  6             [Slide]

  7             The limitations to the exemptions are

  8   under 862, 864 and 866.9.  They all have the same

  9   language.  The limitations to exemptions refer to

 10   any class I device.  They would not be allowed to

 11   be exempt from premarket notification if the

 12   modified device operates under new technology, such

 13   as an in vitro diagnostic device that measures

 14   infectious agents by using a DNA probe or nucleic

 15   acid hybridization technology, or if it is used for

 16   screening purposes, diagnosis or monitoring of

 17   life-threatening diseases, such as AIDS or

 18   hepatitis.

 19             [Slide]

 20             Additionally, there are other indications

 21   that limit in vitro diagnostics from the

 22   exemptions, and those would be for use in diabetes

 23   management and risk of cardiovascular diseases.

 24             [Slide]

 25             We have covered the analyzer and reagents, 

                                                                53

  1   now we need to talk a little bit about laboratory

  2   automation systems.  When there is a link to the

  3   automation system to the analyzer, there is also a

  4   link to the reagents and the laboratory automation

  5   system would be classified according to this

  6   classification of the reagent when we go beyond the

  7   transmission of data to and from the analyzer, and

  8   the automated laboratory system starts taking over

  9   the functions of the analyzers.  Then we would

 10   require premarket notification.  There is a really

 11   grey area as to when this kicks in, and we would

 12   ask that you call and discuss it with our CDRH

 13   people for CDRH, and for blood banking you would

 14   have to do the premarket notification.

 15             [Slide]

 16             I want to talk about a policy that is

 17   different.  It is unique to DCLD.  It is not used

 18   in CDRH and it doesn't apply to CBER.  The reason I

 19   want to talk about it is to just show you that we

 20   are different and the centers are different because

 21   of specific issues.

 22             The policy that we use is replacement

 23   reagent policy.  It is based on a guidance issued

 24   in 1996.  The guidance is for data for

 25   commercialization of original equipment 

                                                                54

  1   manufacturers, secondary generic reagents for

  2   automated analyzers.

  3             [Slide]

  4             This policy is meant for

  5   well-characterized clinical laboratory testing

  6   systems intended for use by clinical laboratory

  7   professionals.

  8             [Slide]

  9             It is only meant for instruments or

 10   reagents that have been previously cleared, and

 11   when there is a claim made for a new test system

 12   reagent combination.  It is also used for the

 13   introduction of new instrument family members of

 14   previously cleared families.

 15             [Slide]

 16             DCLD feels that there are sufficient

 17   controls for these types of claims and test system

 18   modifications when there is an acceptable test

 19   system validation protocol in place.

 20             [Slide]

 21             We are using an add-to-the-file process to

 22   notify the FDA in place of our traditional 510(k).

 23   What this policy did for us, because of the numbers

 24   of different combinations that would come in--we

 25   have thousands of 510(k)s and it would tie up our 

                                                                55

  1   resources, so we put this policy in place for DCLD

  2   only to address those concerns.  We are not

  3   recommending that CBER follow this at all.  In

  4   fact, when the policy was written, it applies to

  5   devices intended in support of blood banking

  6   practices for class III devices, over-the-counter

  7   devices or for exempt general purpose reagents.

  8             [Slide]

  9             In summary, while there are some

 10   differences between the centers, we are on the same

 11   page.  We review devices based on health risks,

 12   established guidance and policy and regulations.

 13   Thank you for your attention.

 14             DR. NELSON:  Thank you.  Questions?  Dr.

 15   Landow is not here?  Are you ready?  We could take

 16   a break now.  Maybe we should, and maybe come back

 17   at about 9:45.

 18             [Brief recess]

 19             DR. NELSON:  The next item on the agenda

 20   is reported association of six percent Hetastarch

 21   with excess bleeding in open-heart surgery.  The

 22   topic will be introduced by Dr. Laurence Landow,

 23   from FDA.

 24          Reported Association of Six Percent Hetastarch

 25            with Excess Bleeding in Open-heart Surgery 

                                                                56

  1                   Introduction and Background

  2             DR. LANDOW:  Good morning, everyone.  Here

  3   is our agenda for this part of the meeting.  I am

  4   going to give a few introductory comments about

  5   cardiopulmonary bypass and hetastarch, then Dr.

  6   Canver will present the argument that hetastarch

  7   does not increase the risk of bleeding.  He will be

  8   followed by Gary Haynes, who will make the opposing

  9   argument.  Then I will make some closing comments

 10   about non-randomized trials and then we will have a

 11   discussion of the questions by the committee.

 12             [Slide]

 13             The first question for the committee is,

 14   is the evidence for excessive bleeding in cardiac

 15   surgery patients who receive six percent hetastarch

 16   strong enough to warrant a warning statement in the

 17   hetastarch labeling?

 18             The second question is if there is

 19   insufficient evidence for a labeling change, should

 20   a randomized, controlled trial or trials be

 21   conducted to answer this question?  If a trial is

 22   warranted, please comment on the inclusion and

 23   exclusion criteria; what endpoints and differences

 24   are clinically meaningful; and what are the major

 25   predictors of blood loss. 

                                                                57

  1             [Slide]

  2             Hetastarch was approved in the early

  3   1970s.  If you look on the label, in terms of this

  4   meeting, the indication is for the treatment of

  5   hypovolemia when plasma volume expansion is

  6   desired.

  7             [Slide]

  8             In the dosage and administration section

  9   you will find the following, the amount of six

 10   percent hetastarch, usually administered is 500 to

 11   1000 mL.  Doses of more than 1500 mL per day for

 12   the typical 70 kg patient are usually not required,

 13   although higher doses have been reported in

 14   postoperative and trauma patients when severe blood

 15   loss has occurred.

 16             [Slide]

 17             The warnings on the labeling include this,

 18   large volumes of hetastarch may transiently alter

 19   the coagulation mechanism due to hemodilution and a

 20   mild inhibitory action on Factor VIII, and may

 21   result in transient prolongation of prothrombin and

 22   activated partial thromboplastin, clotting and

 23   bleeding times.

 24             But it also says, and this is the only

 25   citation in the warning section, in randomized, 

                                                                58

  1   controlled, comparative studies of hetastarch

  2   injection and albumin in surgical patients, no

  3   patient had a bleeding complication and no

  4   significant difference was found in the amount of

  5   blood loss between the treatment groups.  That is

  6   it.

  7             [Slide]

  8             This is a cartoon of a cardiopulmonary

  9   bypass circuit.  The circuit goes like this, blood

 10   leaves the body on the venous side and is pumped by

 11   a roller pump into the oxygenator; leaves the

 12   oxygenator and then goes through a microfilter, and

 13   then returns to the patient through the arterial

 14   line.

 15             Before you can put a patient on bypass,

 16   the perfusionist has to prime the pump.  Here is

 17   the pump.  The prime is usually colloid that is

 18   albumin and then more likely hetastarch.  The

 19   reason they do this is to get rid of any air

 20   because, obviously, if air enters this circuit it

 21   will go into the patient.  Likewise, you could have

 22   what is called an air block where an air bubble in

 23   this circuit stops flow entirely and that is a

 24   catastrophe because most likely the patient will

 25   die. 

                                                                59

  1             The second step is to insert canulas into

  2   the right atrium and the aorta so that venous blood

  3   can leave the right atrium, as I discussed a second

  4   ago, and then return back to the arch of the aorta.

  5             The final stage, once the blood is

  6   circulating like this into the body, is to stop the

  7   heart with cardioplegia solution.  The surgeon now

  8   has what is called a quiet field and he or she can

  9   do whatever needs to be done in terms of vessels,

 10   valves, or both.

 11             [Slide]

 12             This is a photograph of a cardiopulmonary

 13   bypass machine.  I don't know if you can see, but

 14   this dark tubing here is coming from the patient.

 15   The patient is over here.  The venous tubing is

 16   here, in dark red.  The arterial filter is over

 17   here, this little object and I don't think you will

 18   be able to see it too well.  The roller pump is

 19   down here, and here is the perfusionist's hand.  He

 20   is turning the knob here to increase or decrease

 21   the flow as the rate of blood return increases or

 22   decreases during the procedure.  Then, the blood

 23   returns to the patient.  I don't know if you can

 24   see that but it goes up here, like this, back into

 25   the aorta.  So, you have a complete circuit.  The 

                                                                60

  1   perfusionist has to change this constantly.  He is

  2   constantly watching the patient.

  3             [Slide]

  4             Included in the background package that

  5   the FDA sent out to you were five articles.  They

  6   are all retrospective.  Three of them are chart

  7   reviews; one was a case-control epidemiology study

  8   and one was a meta-analysis.

  9             [Slide]

 10             The first article, by Canver and Nichols,

 11   was a chart review of 887 patients, and one of

 12   their conclusions or their main conclusion was that

 13   use of hetastarch in primary cardiopulmonary bypass

 14   circuitry is devoid of any added hemorrhagic risk

 15   after coronary bypass.  In other words, they added

 16   hetastarch into the circuit, into the pump circuit

 17   that I showed you before.  This is not always done

 18   in studies that I am going to talk about in a

 19   second.  Sometimes the hetastarch is given before

 20   the patient goes on the pump; sometimes it is given

 21   after, including in the ICY; and sometimes it is

 22   given in the pump as well.  So, you have various

 23   combinations of when hetastarch can be

 24   administered.

 25             [Slide] 

                                                                61

  1             Knutson et al. studied 445 patients, and

  2   they concluded that use of hetastarch may increase

  3   bleeding and transfusion requirements in patients

  4   undergoing upon heart surgery.

  5             [Slide]

  6             Cope et al. looked at 189 patients and

  7   concluded hetastarch infusion produces a clinically

  8   important impairment in post-cardiac surgical

  9   hemostasis.

 10             [Slide]

 11             Herwaldt conducted a case-control

 12   epidemiology study and they divided the subjects

 13   into two groups.  Cases were predefined.  There was

 14   a prespecified criterion for what bleeding was.

 15   They divided their cases into those that had

 16   excessive bleeding and the controls who did not

 17   have excessive bleeding.  What they concluded was

 18   that patient age and hetastarch are risk factors

 19   for hemorrhage in patients undergoing open-heart

 20   surgery.

 21             [Slide]

 22             Finally, Wilkes et al. conducted a

 23   meta-analysis.  He looked at 653 patients, and I

 24   think it was around 13 clinical trials.  His

 25   conclusion was that postoperative blood loss is 

                                                                62

  1   lower in patients exposed to albumin than to 6

  2   percent hetastarch.

  3             Now I would like to hand the microphone

  4   over to Dr. Canver, who will be the first speaker

  5   who will speak on this topic, and he will be

  6   arguing that hetastarch does not lead to increased

  7   bleeding.

  8                           Presentation

  9             DR. CANVER:  Good morning.  I have never

 10   been at an FDA-related panel discussion like this

 11   so I am very grateful that Dr. Landow asked me to

 12   be here.

 13             [Slide]

 14             I am an ordinary cardiac surgeon and I

 15   have no connection with Hespan, albumin or any

 16   commercial companies at all.  The reason that we

 17   did that study was for scientific curiosity and to

 18   reduce blood product utilization.  I am also

 19   director of the Heart Institute and head of the

 20   Department of Cardiothoracic Surgery.  Of course, I

 21   do the training.

 22             [Slide]

 23             I think that Dr. Landow summarized the

 24   background better than I would do it.  As you know,

 25   we perform 250,000 open-heart surgical procedures 

                                                                63

  1   in the United States every year, and there is an

  2   increased interest in doing these operations

  3   so-called off-pump, meaning doing them without that

  4   machine that Dr. Landow showed us earlier.  But

  5   still, the majority of the operations require the

  6   cardiopulmonary bypass machine, in lay terms the

  7   heart-lung machine.  The patients are placed on

  8   this device while the surgeon quickly treats the

  9   disease, blockage, valve repair or whatever, also

 10   during heart replacement, such as heart

 11   transplantation.

 12             The other thing that is an issue is that

 13   we don't have enough blood.  The donor pool is very

 14   short.  Blood is very expensive.  Last year alone

 15   we paid about five million dollars for blood

 16   products at Albany Medical Center, the biggest

 17   expense for us.  Of course, just imagine the

 18   societal issues, nobody wants to get blood products

 19   because of HIV, hepatitis and all the societal

 20   issues attached to that.

 21             So, I think we have an obligation

 22   economically and also societally.  Therefore, there

 23   are many strategies that surgeons and all

 24   care-givers have developed over the years.  I think

 25   there are many of them, but I think we will focus 

                                                                64

  1   today just on hetastarch and colloid administration

  2   during cardiac surgery.  This is one of the many

  3   strategies that we have.

  4             [Slide]

  5             Again, hydroxyethyl starch is a starch.

  6   The technical term is amylopectin.  It is

  7   essentially derived from corn.  I think there is

  8   some technical information that normally it is

  9   degraded or destroyed in the body off-amylase, an

 10   enzyme, and to reduce that degradation is attached

 11   second or sixth carbon atoms.  The molecular weight

 12   of the substance is important, and the one we are

 13   actually going to discuss, Hespan which is the most

 14   commercially available, is 480 kD weight.  Low

 15   molecular weight, 70 kD, is not available in the

 16   United States.

 17             [Slide]

 18             Again, commercially there are two

 19   solutions available.  One of them is Hespan,

 20   constituted in normal saline.  Also, it is

 21   available as Hextend in lactated Ringer's solution.

 22             [Slide]

 23             The characteristics of Hespan are similar

 24   to albumin.  I guess I have to say that the

 25   argument--you may just say what's the big deal of 

                                                                65

  1   albumin versus Hespan?  The basic thing actually is

  2   the cost.  Surgeons and physicians who get involved

  3   in this issue primarily are paying less amount of

  4   money and providing the same care.  With respect to

  5   all the properties, Hespan has similar effects to

  6   albumin, which expands the vascular volume, meaning

  7   that it increases the intravascular space;

  8   increases the blood pressure; increases the

  9   perfusion, and so forth.  It does stay in the

 10   system for a long time as well.

 11             There is no antigenicity.  I mean, there

 12   is no rejection of allergic reactions, or whatever.

 13   There are some case reports, but in general it is

 14   kind of a neutral agent.

 15             Adverse effects are taken actually from

 16   the PDR.  These are some reports that have been

 17   mentioned.  It doesn't mean that it is going to

 18   happen all the time but I think it has been

 19   reported.  When you read it, of course, it is kind

 20   of scary that you are going to have salivary gland

 21   enlargement, edema and sometimes anaphylactic

 22   shock, which is true for everything so this should

 23   not really be scaring you that much.

 24             [Slide]

 25             Again, Hespan has been associated with 

                                                                66

  1   bleeding abnormalities.  If you look in the

  2   literature, you are going to find a lot of

  3   experimental studies.  There are some dog studies

  4   and pig studies and they say that the bleeding is

  5   higher compared to other agents.  Practically, PT

  6   and PTT are the clinical measures we have to

  7   measure the bleeding state or coagulation state of

  8   the individual and this is slightly increased.

  9   Also, platelets, those little, clumpy cells--when

 10   you cut yourself these cells go to the cut surface

 11   and with spongy areas and essentially stop

 12   bleeding.  Of course, after you have major

 13   open-heart surgery you want these cells to stop

 14   bleeding.  Again, Hespan is associated with some

 15   platelet dysfunction, but also it is well

 16   established in the literature that if you reduce

 17   the dose, if you limit the dose of Hespan to

 18   500-1000 mL any of these issues or concerns we have

 19   are not apparent in a real clinical setting.

 20             [Slide]

 21             Again, I also want to tell you these are

 22   the components of Hespan that affect blood

 23   coagulation, molecular weight, the lower the

 24   molecular weight, the less likely it is that it

 25   will interfere with the blood system.  Again, let 

                                                                67

  1   me say that low molecular weight is not available

  2   in the United States.  It may be that that is going

  3   to be one of the strategies that we need to

  4   explore.

  5             Substitution ratio, that deals with how

  6   many of this hydroxyethyl--those funny shaped

  7   chemical things that I have a hard time

  8   understanding myself, but the number of those, the

  9   groups are attaching to glucose or sugar molecules.

 10   That is what they are talking about.  This also

 11   affects their influence on the clotting system.

 12   Again, attachment to the C-2 ring, carbon-2 ring,

 13   is less likely to have clotting disorders.  Again,

 14   concentration, like six percent versus ten percent,

 15   of course, will have an influence.

 16             So, we can make some changes in any of

 17   these components and we can anticipate some

 18   effects.  But the problem is very complex.  As you

 19   know, in open-heart surgery there are many, many

 20   factors involved.  First of all, the person having

 21   surgery is not the same thing.  I may be doing

 22   heart transplantation or I may just be doing

 23   bypass, putting new vessels on the heart, or maybe

 24   repairing a leaky valve.  They are all different

 25   people and different disease entities. 

                                                                68

  1             As Dr. Landow demonstrated earlier,

  2   cardiopulmonary bypass or the heart-lung machine

  3   itself has negative effects or adverse effects on

  4   the clotting system in general.  It does promote

  5   platelet degradation and essentially makes the

  6   platelets rupture and burst, because of the

  7   swelling, and then they are dysfunctional, meaning

  8   that they no longer can hold onto each other and

  9   make big clots to stop bleeding and they are

 10   malfunctional.  Some of these clotting factors, and

 11   I am sure you know that there are 13, 14 clotting

 12   factors like hemophilia bleeding disorders, those

 13   similar clotting factors, mainly in the liver, are

 14   used, meaning there is not enough in the body to

 15   help the clotting.  Again, the fibrinolysis is one

 16   of the factors needed for the finalized shape of

 17   the clot and it is utilized and not available in

 18   the environment.

 19             [Slide]

 20             Again, cardiopulmonary bypass heart-lung

 21   machine is not a normal thing.  You are putting

 22   bigger than your finger size pipes inside the

 23   aorta, inside the right side of the chamber of the

 24   heart, and you are taking the blood and you are

 25   shuffling about five to six liters per minute.  

                                                                69

  1   Then, this blood is not used to going through these

  2   rigid tubes.  From the sheer force, as the blood is

  3   trying to go through these narrow channels, it hits

  4   the walls and everything, and all the cells get

  5   destroyed.  All these destroyed cells will burst

  6   and then inside a lot of enzymes, a lot of chemical

  7   elements inside the cells will be distributed

  8   through the system.  That will essentially be our

  9   enemy later one.

 10             Again, despite all the bad things we are

 11   talking about, most of them are self-limited,

 12   meaning that after a successful repair or surgical

 13   treatment within 48 hours all these abnormal values

 14   return to normal.  Therefore, traditionally we put

 15   in about three to four chest tubes.  I am sure some

 16   of you have relatives, or whatever, and you have

 17   seen that in open-heart surgical patients with

 18   finger size hoses, big hoses.  So, we anticipate

 19   that up to two days there may be some oozing or

 20   bleeding and within two days everything is pretty

 21   much back to normal.  Again, that low platelet

 22   count will be normalized within two to three days.

 23             [Slide]

 24             I will try to summarize what we did, and I

 25   think Dr. Landow did a beautiful job.  It was 

                                                                70

  1   published in the journal Chest, in 2000.

  2             [Slide]

  3             It was a chart review, essentially a

  4   retrospective study, but it did have a lot of

  5   patients, 887 patients, and we mainly wanted to

  6   focus on isolated CABG, meaning that if the patient

  7   had aortic valve replacement or the patient had

  8   mitral valve surgery or redone bypass, we excluded

  9   all of those because we wanted to know purely

 10   whether Hespan makes any difference because you

 11   can't look at a multifactorial group of patients

 12   and expect to get meaningful results.

 13             [Slide]

 14             This how the stratification was done.  Of

 15   course, this could have been a better

 16   stratification if this was prospective but

 17   unfortunately it wasn't.  We had four groups.  The

 18   first group had crystalloid, which is a traditional

 19   balanced-salt solution and we gave a half liter,

 20   and there are only 11 patients.  Then we had

 21   albumin.  Albumin was supposed to be better or

 22   superior to the Hespan.  We had about 217 patients.

 23   Hespan was given to 298 patients.  Also, we had

 24   another group where albumin and Hespan were used

 25   together in 161 patients. 

                                                                71

  1             [Slide]

  2             I don't think I need to explain everything

  3   to this group but the purpose of this slide is

  4   simply to tell you if you look at the patient

  5   characteristics, like the person's age and

  6   patient's size, patient's ejection fraction,

  7   meaning the contraction ability of the heart, and

  8   their red blood cell count and their platelet count

  9   of clumpy cells, and their overall blood count and

 10   also kidney function, they are all identical.  So,

 11   for practical purposes, I think all these four

 12   groups had similar patients with similar

 13   characteristics.

 14             [Slide]

 15             Again, as far as what happened in the

 16   operating room, those operative events can

 17   influence the bleeding rate afterwards as well.

 18   Perfusion time, that is, the duration of

 19   cardiopulmonary bypass time, how long we kept the

 20   patient on the heart-lung machine.  The longer you

 21   keep the patient, the more likely you are to have

 22   bleeding problems because the damage of the machine

 23   will be higher on the cells.  Again, among those

 24   four groups there is no significant difference.

 25             As you know, when we do this operation, we 

                                                                72

  1   put a little metal clamp on the aorta.  The aorta

  2   is a big pipe that comes from the left side of the

  3   heart and carries the red blood, clean blood, and

  4   you cannot operate on a beating, moving heart,

  5   particularly if you are doing valve repair and so

  6   forth.  So, we put this metal clamp there and

  7   exclude the heart from the body while it is being

  8   perfused by this heart-lung machine, and we go in

  9   and quickly do the job.  We put some ice to stop

 10   the heart.  Then, as soon as we are done whatever

 11   we are doing, we start warming and we give a little

 12   jolt of electricity and the heart starts beating

 13   again.  So, the cross-clamp time is also, of

 14   course, important but there is no difference among

 15   any of the groups.

 16             Again, we did only bypass surgery on these

 17   cases, and then the number of the bypasses were

 18   essentially similar.  Again, the number of arterial

 19   grafts was the same.

 20             [Slide]

 21             If you look at the amount of

 22   heparin--heparin is the medication we use before we

 23   put the patient on the heart-lung machine to

 24   prevent any clotting.  This simply essentially

 25   stops any clotting in the system.  At the end of 

                                                                73

  1   the operation we reverse that with another

  2   medication.  Overall, the patients' length of stay

  3   in the intensive care unit hasn't changed, and

  4   their hospital stay was essentially identical.  The

  5   re-exploration rate, meaning that the patients had

  6   significant bleeding from those tubes, the hoses,

  7   and we had to take them back to surgery, in all

  8   those groups they were identical.

  9             [Slide]

 10             This is actually I think the most

 11   important part because we were very interested in

 12   the economics mostly.  So, we thought that our

 13   utilization of blood and blood products are not any

 14   different.  If you look at the packed red blood

 15   cells, this the bank blood you get from the Red

 16   Cross, essentially all the groups are pretty much

 17   the same.  So, it doesn't matter what combination

 18   you use, they are identical.  Platelets, those

 19   clumpy cells making clots, were similar in all

 20   groups.  Statistically there was no difference.

 21   Fresh-frozen plasma, this is taken from humans and

 22   then is essentially rich in clotting factors, and

 23   the use of this plasma is similar in all groups.

 24             [Slide]

 25             We also had access to the database and we 

                                                                74

  1   had the results after ten years because we were

  2   able to track what happened to these patients.  You

  3   can actually see all those four groups.  In the

  4   left column is the Kaplan-Meier survival, and years

  5   after operation on the bottom, and all those groups

  6   essentially overlap each other and there is

  7   survival advantage or disadvantage among the

  8   groups.  Essentially, what that means is whether

  9   you use Hespan during surgery or not, it doesn't

 10   alter anything up to ten years.

 11             [Slide]

 12             These are essentially our conclusions for

 13   the review, and there was no hemorrhagic risk after

 14   primary CABG.  We also said that the type of prime

 15   solution, whether albumin, colloid or crystalloid,

 16   has nothing to do with the early outcome or late

 17   survival.

 18             [Slide]

 19             I actually wanted to bring some issues.  I

 20   am not here to really sell you anything.  I mean, I

 21   am not here to say Hespan is good or Hespan is bad.

 22   I think the issues are more about the facts.  These

 23   are that Hespan and albumin are volume expanders.

 24   They increase blood pressure; useful in traumatic

 25   shock or some heavily injured people.  I think it 

                                                                75

  1   is a good solution.  It is much better than

  2   crystalloid.  So, I don't think we would have too

  3   much argument there.

  4             There is also I think universal acceptance

  5   that Hespan is cheaper, significantly cheaper.  In

  6   our hospital, for the last two years we monitored

  7   the use of albumin as a criterion for quality

  8   improvement, meaning that we don't want to use

  9   albumin unless it is necessary because you deplete

 10   your bottom line.  It is rather expensive.

 11             Again, Dr. Landow summarized all these

 12   observation studies, and they did suggest that

 13   there is some association with excessive

 14   postoperative bleeding.  But, again, if you read

 15   those study articles, I think they are available,

 16   you will find these studies are similar to ours.  A

 17   doctor was interested and he said I want to write a

 18   paper.  So, he went and looked at it.  I think one

 19   of the papers, in the Palo Alto VA hospital, in

 20   California, said they had an outbreak of bleeding.

 21   Well, again, we have no idea what the operation

 22   was; who was the surgeon; what was going on.  You

 23   don't get outbreaks of this kind just because of

 24   the solutions but that was the conclusion.

 25             [Slide] 

                                                                76

  1             Again, I guess the reason I was invited

  2   here is because our work suggested that there was

  3   no association.  I have to admit that I did look

  4   around the last five years at what has been

  5   published, and we are in the minority.  The only

  6   advice or I guess opinion I can give you is that in

  7   my personal opinion, based on what we did and what

  8   I practice, I don't think that Hespan prime during

  9   bypass circuitry has any side effects.  But I find

 10   that whether you use it before surgery, during and

 11   after, the studies are inadequate.  I think that

 12   one needs to focus on the questions, which I think

 13   are very valid that Dr. Landow is raising, and I am

 14   not certain about the warning label.  That is not

 15   my expertise.  But I am now motivated myself, when

 16   I go back to Albany, to try to see if we can do

 17   some prospective, randomized studies addressing

 18   each issue.

 19             I will stop there.  Again, thank you so

 20   much for the opportunity to talk here today.

 21             DR. NELSON:  Thank you very much.  I have

 22   one question.  In table 2 in your paper, where you

 23   compare the four groups and you talked about the

 24   time on the pump or cross-clamping time in this

 25   table, you said that the groups were comparable.  

                                                                77

  1   But, in fact, group one was on for 84 minutes;

  2   group two for 103; group three, which was the

  3   hetastarch group, for 79, plus/minus 2; and group

  4   four for 127.  Those numbers sound different to me.

  5             DR. CANVER:  Well, I agree with you.  I am

  6   not a biostatistician and our biostatistician

  7   reviewed this commonly called cross covalence test.

  8   I don't even know how you do that, but it is

  9   essentially based on the numbers--

 10             DR. NELSON:  No, no, no.

 11             DR. MCGEE:  You know, the rule of thumb is

 12   if you just calculate the 95 percent confidence

 13   interval and they don't overlap, things are

 14   significant.  They are not even close.

 15             DR. NELSON:  This could affect the

 16   bleeding because, in fact, the group that received

 17   hetastarch was on for a significantly shorter

 18   period of time.  So, it seems to me that would

 19   affect the comparison.

 20             DR. MCGEE:  That is also true in table 3

 21   for the platelets.

 22             DR. NELSON:  Right.  You know, I think it

 23   is valuable as a preliminary to do a retrospective

 24   review, but you need to do a correction, or have

 25   comparable patients in order to be sure that, in 

                                                                78

  1   fact, there is no effect.

  2             DR. HOLLINGER:  These were all done by you

  3   in one hospital?  Is that correct?

  4             DR. CANVER:  Correct, yes.

  5             DR. HOLLINGER:  I know they weren't

  6   randomized, but how were they selected for each

  7   group?  You have almost an equal number in every

  8   group, so how were they actually selected?

  9             DR. CANVER:  It was actually arbitrary.

 10   That I think is the drawback with all retrospective

 11   studies.  The chief perfusionist in the hospital

 12   was the driving force behind this, and he was

 13   essentially just using one of these combinations

 14   without letting us know because we are a teaching

 15   hospital and, including myself, none of us really

 16   knew what kind of combination the patient had to

 17   reduce the bias.  But essentially those were

 18   arbitrarily chosen by the chief perfusionist.

 19             DR. SIMON:  I have two questions.  I think

 20   you pointed to the concerns with the retrospective

 21   versus doing an appropriate prospective, but there

 22   are two questions and they relate to your data.

 23   One is, if albumin were cheaper than Hespan, would

 24   you use albumin instead of Hespan?  Number two, you

 25   dismissed crystalloid but you had a whole group of 

                                                                79

  1   people who did just as well with crystalloid which

  2   is even cheaper.  Is there a consensus among

  3   cardiac surgeons that crystalloid should not be

  4   used?  Have you stopped using it?

  5             DR. CANVER:  I think crystalloid is not

  6   utilized in general because it increases the

  7   postoperative edema and swelling.  Patients gain

  8   more weight.  It actually makes the patient's

  9   respiratory status worse and the patients stay in

 10   intensive care longer.  So, I think that

 11   crystalloid is pretty much out in cardiac surgery.

 12             DR. SIMON:  That is not what your data

 13   show.

 14             DR. CANVER:  Exactly.  Well, this data

 15   goes all the way to 1995, but I think that albumin,

 16   if it is cheaper, yes, we probably would use

 17   albumin.  I mean, that is probably the right

 18   assumption.

 19             DR. MCGEE:  I have one more question.

 20   Your cases go across nine years.  Was the mix of,

 21   say, albumin and Hespan the same over those nine

 22   years, or in the early years was it more albumin

 23   than in the later years?

 24             DR. CANVER:  It is the same concentration

 25   and the same chemical properties, to my knowledge. 

                                                                80

  1             DR. NELSON:  No, the same distribution of

  2   patients in the four groups over the years?  In

  3   other words, could there be a temporal effect on

  4   other things, other care that might affect the

  5   measures of blood loss?

  6             DR. CANVER:  Well, I mean I share that

  7   concern.  You cannot control like that.  In the

  8   1990s the people operated on are different than

  9   what we are doing now, and in the same thing in the

 10   1980s, it was a completely different set of people.

 11   We change our behavior, practice patterns based on

 12   what we have done in the past.  So, you go back and

 13   you look at them and you make some assumptions.

 14             DR. NELSON:  These are difficult issues to

 15   control but there are methods for adjustment of

 16   data where the groups aren't comparable.  It is

 17   unclear about the comparability of the groups I

 18   think.

 19             DR. LEW:  One thing that you did mention

 20   is that when you use a lot of Hespan there have

 21   been noted to be potential problems.  I wasn't

 22   sure, do you know how much each patient received?

 23             DR. CANVER:  We only used priming in the

 24   circuitry, like 500 cc.  We did not use it

 25   postoperatively and we did not use it as a volume 

                                                                81

  1   expander later on.

  2             DR. LEW:  So, it is just a limited amount.

  3             DR. CANVER:  We extrapolated from the

  4   experience that trauma surgeons had during shock,

  5   and they have used two to three liters of Hespan

  6   and they did report increased bleeding problems.

  7   But we never really used more than what is

  8   recommended.

  9             DR. NELSON:  The volume of the pump is

 10   500?

 11             DR. CANVER:  Yes, 500.

 12             DR. LEW:  But I do think it is worthwhile

 13   if you take even this data back to your

 14   statistician because it is remarkable that the

 15   least perfusion time, the least clamping time for

 16   Hespan but they used the most platelets, the most

 17   FFP.  It just might be worth taking another look at

 18   it.

 19             DR. DIMICHELE:  As a follow-up to Dr.

 20   Lew's question, I was just going to ask do you

 21   routinely use thromboelastograms during your

 22   procedures to monitor coagulation?

 23             DR. CANVER:  Yes, we do.  We use ACT,

 24   activated clotting time, throughout the pump.

 25             DR. DIMICHELE:  Just the ACT? 

                                                                82

  1             DR. CANVER:  ACT only.

  2             DR. DIMICHELE:  And were you able to look

  3   at the ACT data?  That is recorded, right, in

  4   general?

  5             DR. CANVER:  Yes.

  6             DR. DIMICHELE:  Is there any way that you

  7   could have looked at the ACT data during the

  8   procedure?

  9             DR. CANVER:  It is available but in this

 10   set we didn't look at it because ACT is generally

 11   when you are on pump during bypass, and you like to

 12   give 400 measure.  That is pretty much standard.

 13   So, it wouldn't give us that much of an answer, and

 14   at the end of the procedure we used protamine to

 15   reverse the heparin and we would like to see the

 16   ACT level constant at less than 150.  But in my

 17   mind, and practically, I don't think it would give

 18   us too much information because as soon as the

 19   patient goes to the intensive care unit he will end

 20   up with platelet count and PT and PPT, the more

 21   traditional parameters, and also the rate of

 22   bleeding from the chest tubes.  Those would pretty

 23   much assess the effect.

 24             DR. NELSON:  Any other questions?  Thank

 25   you.  The next discussant is Dr. Gary Haynes. 

                                                                83

  1                           Presentation

  2             DR. HAYNES:  Good morning.  I hope you can

  3   all hear me.

  4             [Slide]

  5             My name is Gary Haynes, and I am an

  6   associate professor of anesthesia at the Medical

  7   University of South Carolina, in Charleston, South

  8   Carolina.

  9             I would like to thank the committee, first

 10   of all, for the opportunity to speak today about

 11   this issue because this is what I have been

 12   interested in for some time.

 13             Let me tell you at the outset my interest

 14   in this originally started out of a concern with

 15   some of the recent marketing that has been

 16   conducted for hetastarch solution, suggesting the

 17   aggressive use of hetastarch, because I grew up in

 18   an environment where I was taught, as our two

 19   previous speakers have already pointed out, that

 20   the appropriate dose of a hetastarch solution

 21   should be 10-15 mg/kg or 20 mg/kg body weight to a

 22   total maximum dose of about 1500 cc on any one day.

 23   So, that is what prompted some of my concerns about

 24   this.

 25             Then, as I looked into this issue more and 

                                                                84

  1   more, I thought it is very appropriate to look at

  2   what has been going on and to take a look at the

  3   use of hetastarch solutions in a very select group

  4   of surgical patients, and it is the cardiac

  5   patients we are talking about today.  So, I have a

  6   concern about using hetastarch in all surgical

  7   patients.  I mention that briefly, but to stick to

  8   the point of today, we are looking at this issue in

  9   a very select group of patients, those having

 10   cardiac surgery for some very particular reasons

 11   that I will go over in just a minute.

 12             [Slide]

 13             Just to give you a little idea of who I am

 14   and why I am standing here, talking to you about

 15   this, I am a clinical anesthesiologist in an

 16   academic practice, taking care of cardiac patients

 17   with major transplant surgery, liver transplant

 18   surgery, or the anesthesia for those cases at our

 19   hospital.  We do a lot of them.  We are in the top

 20   20 programs in the liver transplant business these

 21   days.  Consequently, I am one of those guys in the

 22   trenches using up an awful lot of blood and blood

 23   products.

 24             I am also the chairman of our medical

 25   center's blood and tissue utilization review 

                                                                85

  1   committee.  So, I help try to establish our local

  2   guidelines and work with our blood bankers and our

  3   clinical pathologists in dealing with the issues of

  4   what is appropriate and inappropriate use of these

  5   products, and the availability, and working out all

  6   the other headaches associated with this at our

  7   hospital.

  8             I also sit on the transfusion committee,

  9   as a member of that committee of the American

 10   Society of Anesthesiologists, and I have had

 11   research interest in this for a number of years,

 12   which goes back to medical school.  I guess that is

 13   where my interest really started because my Ph.D.

 14   was in pathology and one of my teachers was a

 15   hematologist, Oscar Ratnoff, who was the fellow who

 16   proposed the cascade mechanism for coagulation.

 17   So, I have had this interest for a number of years.

 18             [Slide]

 19             Without belaboring the point, I would just

 20   like to reiterate a couple of things that Dr.

 21   Landow and Dr. Canver have already mentioned, and

 22   that is a little bit of what hydroxyethyl starch

 23   is.  It is something that has been around for close

 24   to 40 years, one time as an experimental and now a

 25   therapeutic modality.  In fact, I know the guy who 

                                                                86

  1   did a lot of the basic research, a guy who was in

  2   Charleston at what was then the medical college of

  3   South Carolina, a guy names Lay Thompson, who was a

  4   graduate student back introduction he early '60s

  5   investigating this as a volume expander, a plasma

  6   volume expansion agent.

  7             As Dr. Canver mentioned, most

  8   anesthesiologists and surgeons tend to like to use

  9   colloidal substances to replenish intravascular

 10   volume, simply because it stays in the

 11   intravascular space for a longer period of time and

 12   we know that if somebody is hypotensive you can

 13   fill them up with crystalloid solutions to

 14   reestablish blood pressure but you can do the same

 15   thing with colloids, but a smaller volume, and they

 16   work a little bit more efficiently because they

 17   tend to stay in the intravascular space longer.

 18   That is why we like to use them.

 19             So, hetastarch is really an amylopectin

 20   but what that really means is it is just branching

 21   chains of polymeric glucose, just a bunch of

 22   glucose molecules strung together.  Hetastarch as

 23   hydroxyethyl starch groups substituted on the those

 24   glucose rings just to retard the metabolism of

 25   this.  As was mentioned, amylase is what breaks it 

                                                                87

  1   down.  It is also sequestered in the reticular

  2   endothelial system and tends to stay in the

  3   circulation for a long period of time.

  4             But when we are using a hetastarch

  5   solution clinically, we get it in a plastic bag.

  6   It comes in a 500 cc bag, and when we get a bag of

  7   this stuff it is a six percent solution of

  8   polydispersed substance, which means these branch

  9   chains of this hetastarch compound are not all

 10   uniform.  They vary in molecular size from around

 11   10 kD all the way up to 480 kD or maybe even

 12   higher.  When it is infused the small stuff, of

 13   molecular weight of around 60,000 or less, gets

 14   filtered out by the kidneys pretty quickly.  So, it

 15   is that size and above that stays in the

 16   circulation.  What is available in the United

 17   States for us in clinical use is two forms of this,

 18   Hespan, which is six percent hetastarch in normal

 19   saline, which has been around for a number of

 20   years, and more recently, Hextend, which is the

 21   same thing, six percent hetastarch in a lactated

 22   electrolyte solution.  I think it has been on the

 23   market for a couple of years now.

 24             [Slide]

 25             In contrast to albumin, which has been 

                                                                88

  1   mentioned and it is going to be compared to albumin

  2   frequently because that is the other colloidal

  3   substance that we have for routine clinical use,

  4   albumin is monodispersed and one albumin molecule

  5   is just like another so they are all the same, with

  6   a molecular weight of about 70 kD.

  7             [Slide]

  8             I think one thing that is important when

  9   you look at worldwide literature is to make sure

 10   that you are dealing with the same substance

 11   because, as was again previously mentioned, in

 12   Europe and in Canada there are different hetastarch

 13   solutions available that are of smaller molecular

 14   weights.  Some consider 200 kD medium and some

 15   consider it low molecular weight, but those

 16   preparations have been used over there, and they

 17   also have a different substitution ratio of

 18   hydroxyethyl groups to glucose for every 10 glucose

 19   units.  I don't know if that substitution ratio

 20   really has much, if any, effect on the coagulation

 21   mechanism or not, but Hespan and Hextend, which are

 22   in clinical use in the United States now, are the

 23   high molecular weight and that is the type of

 24   hetastarch that seems to be associated with

 25   bleeding problems.  I will show you a study from 

                                                                89

  1   Europe in a minute which illustrates that fact.

  2             [Slide]

  3             One important clarification to make is to

  4   make a distinction between some abnormal laboratory

  5   test with either of these substances, and make a

  6   distinction between that and what is a clinically

  7   significant bleeding problem because there are a

  8   lot of things we do to patients out of necessity.

  9   They are not always the ideal, and they all have

 10   some fallout, some risk or some unwanted side

 11   effect but we can live with it if the benefit is

 12   much greater.

 13             In terms of the laboratory test variation

 14   that occurs when patients receive a hetastarch, it

 15   has been nailed down for years--in fact, Lay

 16   Thompson published, in 1964, a report of giving

 17   hetastarch to dogs and showing that fibrinogen

 18   levels went down and bleeding times went up.  So,

 19   we have known this for a number of years.  A number

 20   of investigators have also documented exactly why

 21   this happens, and it is because von Willebrand

 22   factor decreases.  Consequently, Factor VIII

 23   activity decreases and you can get a

 24   hypofibrinogenemia.  So, it shouldn't come as any

 25   surprise that there is a prolongation of the 

                                                                90

  1   prothrombin time or the partial thromboplastin

  2   time.  Bleeding times, of course, really aren't

  3   used that much clinically anymore but that is an

  4   old that too has been shown to increase in these.

  5             I want to emphasize this point because in

  6   a few minutes I am going to show you some data from

  7   one of the papers which shows that there are small

  8   increases that can be documented in prothrombin

  9   times that may be statistically significant but you

 10   kind of wonder whether clinically that has a real

 11   impact.

 12             I want you to be aware that that happens,

 13   but there are also other effects, that Dr. Canver

 14   also mentioned, on platelets that we don't fully

 15   understand.  But, apparently, there may be more

 16   than one molecular mechanism for why hetastarch

 17   impairs platelet function, but one is that it

 18   probably coats the surface of platelets and

 19   interferes with the receptor ligand interaction of

 20   platelets for their different receptors.  Of

 21   course, platelet function is extremely important.

 22   It is the thing that forms the primary hemostatic

 23   plug and that is why we tend to stop bleeding in

 24   the first place.

 25             The unfortunate thing is that clinically 

                                                                91

  1   we can measure platelet counts and get those

  2   results almost in real time; that is not the

  3   problem.  The problem is we don't have any good

  4   test for clinical use of platelet function.  So, a

  5   lot of times we know that this is happening but we

  6   can't measure it or deal with it clinically when we

  7   are dealing with patients.

  8             That is the laboratory side.  What about

  9   the clinical outcomes?  The question needs to be

 10   asked does hetastarch or anything else really

 11   contribute to bleeding?  As I mentioned, we have

 12   some concerns about this in other groups of

 13   surgical patients as well.  We will focus on this

 14   issue in cardiac surgery patients and as one

 15   example of that one problem that comes up is when

 16   you are dealing with stroke patients and

 17   neurosurgical patients.  If a patient has an

 18   intracranial aneurysm that bleeds, they are going

 19   to have a stroke.  The problem in that situation is

 20   not just the bleeding but the vasospasm that occurs

 21   in blood vessels around that area of bleeding, and

 22   the one therapy that seems to work is to load these

 23   patients up with volume to expand their

 24   intravascular volume to retard that vasospasm.

 25             Neurosurgeons have looked at this.  In one 

                                                                92

  1   study that is reported here by Trumble, they used

  2   large volumes of hetastarch but it was over a

  3   period of several days because these patients are

  4   in ICUs.  Some of the patients developed

  5   coagulopathies and some had worsening subarachnoid

  6   hemorrhages, and even problems like epidermal

  7   hematomas that required surgical intervention.  So,

  8   there are some subsets of surgical patients where

  9   we just don't use hetastarch at all.  Neurosurgery

 10   is one area; liver transplant surgery; any place

 11   where you know the patient has a severe

 12   coagulopathy to begin with.

 13             [Slide]

 14             Both previous speakers did a very nice

 15   introduction about what cardiopulmonary bypass is

 16   all about.  I would just like to add a couple of

 17   points about this.  One is that when you think

 18   about the volume of these priming solutions and the

 19   cardiopulmonary bypass, you have to realize--I

 20   think the smallest is about 1.7 L and generally

 21   when we prime one of those cardiopulmonary pumps we

 22   are talking about a volume of about 2 L, a little

 23   bit more than 2 L.  Most of us, as we sit here, we

 24   probably have an effective blood volume of about

 25   5-6 L.  So, when you hook one of these pumps into a 

                                                                93

  1   patient and you mix these circulations, the

  2   effective circulating volume for that patient

  3   effectively becomes 6-8 L, of which about a fourth

  4   is whatever was priming that bypass pump.

  5             Now, when it is determined that a patient

  6   needs some kind of heart surgery, they are brought

  7   to the operating room.  The anesthesiologist

  8   induces anesthesia.  Once they have the patient

  9   asleep, intubated, put in the different lines,

 10   arterial lines to monitor arterial pressure which

 11   allows us to sample arterial blood whenever we

 12   want, and large vascular access so we can put in

 13   pulmonary-artery catheters, watch heart function

 14   and infuse large volumes as needed into the venous

 15   side of the circulation and sample venous blood as

 16   we need, in the first part of the surgery what is

 17   going on is the sternotomy is made, the chest is

 18   opened, there is potential for bleeding because of

 19   direct surgical trauma to the chest, and the

 20   surgeon is dissecting out, in the case of a

 21   coronary-artery bypass surgery, something like a

 22   saphenous vein or internal mammary artery or other

 23   artery to graft in and bypass stenotic vessels

 24   because you are there to try to prevent myocardial

 25   ischemia. 

                                                                94

  1             So, there can be some surgical bleeding in

  2   that first part of the case but, at some point, you

  3   have to stop the heart and work on it.  So, in

  4   order to manage that we place patients on

  5   cardiopulmonary bypass and prior to that either the

  6   anesthesiologist or the surgeon injects heparin to

  7   anticoagulate the patient because you obviously

  8   don't want catastrophic thrombosis going on in the

  9   pump.  So, we are using a huge blocking dose of

 10   heparin, on the order of 300 units/kilogram.  Of

 11   course, it is given as an IV bolus and has a pretty

 12   immediate effect.

 13             The surgeon places the cannulas, as was

 14   described, so we can support the patient's

 15   circulation.  The cardiopulmonary bypass pump can

 16   cool and warm the solution so we start cooling

 17   patients down.  We cool patients in order to reduce

 18   the metabolic demand of tissues as some assurance

 19   that the patient is not going to have hypoxic

 20   injury to any tissue, and also because with that we

 21   can circulate blood in the pump at a lower rate.

 22   You know, we are circulating our blood right now at

 23   5-6 L a minute.  With a bypass pump you are going

 24   to do it at about 2.2 or 2.4 so there is less

 25   trauma to the blood. 

                                                                95

  1             The surgery on the heart is going to be

  2   done.  After it is completed, you separate from the

  3   bypass.  If there is any residual heparin effect

  4   around, that is reversed with protamine.  So, in

  5   that middle part of the surgery you have four

  6   reasons why you have bleeding in these patients,

  7   circulating the blood through the pump; the

  8   heparin; the cooling; the protamine that can

  9   interfere with coagulation.

 10             So, typically when you see bleeding in

 11   these patients it tends to be in this latter part

 12   of the case.  The important reason for focusing on

 13   the intraoperative use of hetastarch in this group

 14   in particular is because what we do here is going

 15   to have an immediate effect, as would be very

 16   reasonable to think, in the immediate period in the

 17   intensive care unit.  It is important to look at

 18   this group because in this group of patients we

 19   have limited options if they start bleeding in the

 20   intensive care unit.  Yes, you can infuse some more

 21   blood and if the patient is stable you may get away

 22   with that.  But the problem is you can't let

 23   somebody bleed in their chest.  If they become

 24   hypotensive or if they are losing oxygen-carrying

 25   capacity, the surgeon has to make a decision to go 

                                                                96

  1   back to the operating room.  That isn't the case

  2   necessarily with all the other surgical procedures

  3   we have.  Sometimes they are a little more

  4   forgiving but in this group, if they have to come

  5   back to the operating room, you are dealing with

  6   patients who are at risk for increased morbidity,

  7   mortality, longer ICU stay, longer hospitalization

  8   stay, greater stress on the surgical and hospital

  9   systems and much greater cost, as you can imagine.

 10             [Slide]

 11             So, when we look again at why this is an

 12   important group, sometimes these patients are on

 13   drugs before surgery but those can be minimized.

 14             [Slide]

 15             You see that once the patient is off the

 16   bypass, in the intensive care unit, many of the

 17   issues, like running circulating blood through the

 18   bypass pump, heparinization and hypothermia all

 19   start to resolve as variables.  Heparin, you know,

 20   is a pretty short-acting drug.  Its half-life is

 21   two or three hours.  So, it is not going to

 22   normalize immediately but many of these variables

 23   can start to diminish when we get into the

 24   intensive care unit.

 25             [Slide] 

                                                                97

  1             What I would like to do is to start to

  2   discuss a few pieces of literature.  I have divided

  3   this into the issue of some patients from earlier

  4   studies that have received Hespan or hetastarch

  5   preparations postoperatively, and then some early

  6   studies where patients received hetastarch

  7   intraoperatively and what their results were, and

  8   then the more recent papers, all published since

  9   1997 or 1998, on intraoperative use of hetastarch.

 10             If we look at these first papers, these

 11   are in cardiac patients back in 1982.  These are

 12   all small studies.  They had two groups of

 13   patients, about 30 each.  It was a younger age

 14   group.  As it was mentioned a little while ago, our

 15   patient population is changing over time.  Older

 16   patients tend to have these operations whereas

 17   before it was a younger patient group.  We have

 18   more patients that are reoperated on, having a

 19   second or third coronary bypass surgery.

 20             Diehl looked at this, and in this case

 21   patients received only hetastarch postoperatively,

 22   and found--and also in the Kirklin study as

 23   well--this trend towards a higher blood loss in

 24   patients who had received hetastarch as opposed to

 25   albumin.  Maggio compared albumin to Hespan for 

                                                                98

  1   volume expansion in the postoperative period.  From

  2   reading his paper, I am not sure at what point it

  3   was given, if it was given first day, second or

  4   even third day.  So, I am not quite clear what the

  5   details were on that.  But they also gave fairly

  6   small volumes of both of these substances.

  7             Either way, it looks like with hetastarch

  8   solutions there was more bleeding in two of the

  9   three studies here.  Because there is no

 10   statistical significance here, there is no reason

 11   to think that giving patients hetastarch after the

 12   surgery is necessarily contraindicated.

 13             [Slide]

 14             If we switch to some early studies on

 15   intraoperative used of hetastarch, the first one

 16   was in 1983 by Saunders.  Again, it was a very

 17   small study.  This was a study where patients

 18   received either hetastarch or 25 percent albumin as

 19   a priming solution.  It was what was going into the

 20   pump.  Again, a bit of a trend there, not

 21   statistically significant but there was more

 22   bleeding in the hetastarch group.  But they did see

 23   that the patients who received hetastarch required

 24   actually significantly more blood than those who

 25   received albumin. 

                                                                99

  1             Bob Sade and Fred Crawford, at my hospital

  2   back in 1985, studied hetastarch and compared it

  3   to, I think, 25 percent albumin in prime solution.

  4   Again, a little bit younger patient population.

  5   These were all adults but both of those surgeons do

  6   a lot of pediatric surgery so I think some of those

  7   were redo pediatric patients.  But, again, they

  8   couldn't find any distinct difference between the

  9   hetastarch and albumin group, although it looked

 10   like there was a little higher blood loss in the

 11   hetastarch-treated group.  Again, as pointed out

 12   earlier, this was a study conducted just to see if

 13   there was a way of reducing cost because at that

 14   time albumin was much more costly than hetastarch.

 15             Boldt did a study in Europe, published in

 16   1993.  It was a prospective study where they

 17   infused different colloid solutions at the

 18   beginning of surgery.

 19             [Slide]

 20             They looked at actually four different

 21   colloid solutions, one gelatin which I didn't

 22   include on this slide.  Once the anesthesiologist

 23   had the patient induced, they just looked at the

 24   pulmonary-artery pressures to see if they were low,

 25   which would be an indication that the patient was 

                                                               100

  1   intravascularly depleted.  They just infused one of

  2   these different colloid solutions to just double

  3   the pulmonary-artery pressure.  The ones they used,

  4   high and low molecular weight Hespan or albumin,

  5   they found that with the high molecular weight

  6   Hespan there was significantly more bleeding

  7   postoperatively in those patients.  As you would

  8   expect, that group also received more blood

  9   products on the first postoperative day.

 10             [Slide]

 11             Switching to another study, a more recent

 12   one by Cope at the University of Virginia, in 1997,

 13   Cope looked at the intraoperative or postoperative

 14   use of hetastarch for volume replacement.  They did

 15   a retrospective review.

 16             [Slide]

 17             There was a wonderful review by Warren and

 18   Durieux in Anesthesia and Analgesia, addressing the

 19   issue of hydroxyethyl starch and whether it is safe

 20   or not.  They made the point--since a statistical

 21   discussion occurred a moment ago--of what was

 22   needed to have an appropriate study.  From that

 23   review they quoted an important point, that is, to

 24   have a type 1 error of only 0.5 and a type 2 error

 25   of 0.1 or 90 percent power, these studies require 

                                                               101

  1   200 patients or more.

  2             [Slide]

  3             Coming up to Cope here, in 1997, not quite

  4   200 patients but 189.  He looked at consecutive

  5   patients having coronary-artery bypass surgery.

  6   Even though it was a retrospective review, it is

  7   useful because it is kind of a crossover.  Albumin

  8   became in short supply so they had to switch to

  9   hetastarch.  Subjectively, they observed that there

 10   was more bleeding once that occurred.

 11             They eventually went back to albumin and

 12   eliminated the use of hetastarch, and they went

 13   back and looked at the patients four months prior

 14   to this period of time when they used hetastarch

 15   and four months after to come up with a comparison.

 16   They found what they believe is a significant

 17   increase in blood loss and the use of hemostatic

 18   agents associated with hetastarch use in the OR.

 19             [Slide]

 20             These are their values.  When patients

 21   went out of the OR into the ICU, at the first point

 22   in ICU they would get a bunch of labs, and one of

 23   them was the hematocrit.  They found that in those

 24   patients who did receive or did not receive

 25   hetastarch there was a significant difference, a 

                                                               102

  1   crit of almost 34 to 31.  Again, the prothrombin

  2   time was slightly prolonged, not a difference that

  3   would strike you clinically as overwhelming but,

  4   again, something that you would expect from the

  5   laboratory findings about its effect on fibrinogen

  6   and von Willebrand's factor but, again, there is no

  7   way at this point in time clinically to measure or

  8   assess what is happening to platelets in terms of

  9   their function.  We can count platelets, but

 10   platelet counts alone don't do much to help you

 11   unless it is a very low number.

 12             But what is very useful in this paper is

 13   that when they looked at the chest tube drainage,

 14   the rate of chest tube drainage in the first two

 15   and the first eight hours, it was statistically

 16   significantly more in those patients who had

 17   received hetastarch than those who did not receive

 18   hetastarch.  The use of hemostatics refers to just,

 19   you know, when you are at a loss as to what is

 20   going on and because fibrinolytic process can be

 21   part of the bleeding difficulty in the OR, drugs

 22   like Amacar or Aprotinin may be used, some of which

 23   are very expensive.  So, trying to resort to

 24   something to fix the bleeding problem, it was more

 25   frequently used in those patients who received 

                                                               103

  1   hetastarch than those who did not.  Although the

  2   rate of patients who had to go back to the

  3   operating room for reexploration is not significant

  4   in terms of statistics, it is very significant in

  5   terms of the trend for those patients who had to go

  6   back again because of the increase in morbidity,

  7   mortality, expense, length of ICU stay and all

  8   that.

  9             [Slide]

 10             Another study, by Lorraine Herwaldt at the

 11   University of Iowa, again, because of cost issues

 12   they were looking for something cheaper than

 13   albumin at the time.  They had a period of time

 14   where the substituted hetastarch for albumin as

 15   part of the pump prime solution.  They, again,

 16   noticed just subjectively that the bleeding rates

 17   in those patients increased substantially.

 18             So, they did two case-control studies.  In

 19   the first case-control study they looked at the

 20   risk factors associated with more bleeding and

 21   found that it was patient age greater than 60 or

 22   the use of greater than 2 mL/kg of hetastarch that

 23   was associated with bleeding in these patients.

 24   So, they reverted back to albumin; and it was the

 25   risk factor. 

                                                               104

  1             I think one of the values in this paper is

  2   that they carefully defined what bleeding was.

  3   They defined bleeding as any patient who had to go

  4   back for reoperation, with chest tube drainage of

  5   more than 800 cc over four hours, or if the

  6   surgeon, in his judgment, thought that the patient

  7   bled excessively and they wrote it in the chart.

  8             [Slide]

  9             I will switch next to a paper by Jill

 10   Knutson at the Mayo Clinic, who had a surgeon there

 11   who read Cope's paper and, based on that

 12   observation, decided to stop using hetastarch

 13   during surgery, not as part of a pump prime but

 14   just to volume expand or to replace lost blood

 15   during the surgery.           They eventually evaluated

 16   444 cases during this period of time.  So, they had

 17   234 patients that received hetastarch and 210 that

 18   did not receive any hetastarch.

 19             [Slide]

 20             When they looked at these 444 cases in

 21   this period of time when hetastarch was used, one

 22   of the advantages, even though it is retrospective,

 23   is one surgeon for the whole period of time, and

 24   they had this one distinct period of time when no

 25   hetastarch was used so, again, even though it is 

                                                               105

  1   retrospective it is also kind of a crossover.  When

  2   they reviewed, they found that, again, when these

  3   patients left the OR, and this is just

  4   intraoperative use of hetastarch, when they got in

  5   the ICU the mean crit. was 32 in the patients who

  6   did not receive hetastarch but in those who did it

  7   was 27.  I think that is a pretty significant

  8   number, not only because it represents a greater

  9   likelihood for patients to be transfused blood in

 10   the ICU but also that is right at the transfusion

 11   trigger that has been established for when you

 12   would expect this group of patients to be

 13   transfused.  In this group, to keep their

 14   hemoglobin at 10 and hematocrit at 30 is a very

 15   reasonable thing.  As well, the number of platelets

 16   were decreased as well.

 17             [Slide]

 18             Looking at their data in terms of chest

 19   tube drainage, at each interval measured in the

 20   first 24 hours those patients who received

 21   hetastarch had more bleeding from their chest tubes

 22   than those who did not receive it.  Again, part of

 23   the problem here is it is so difficult for the

 24   surgeons sometimes to make a decision as to when

 25   you take that patient back for reoperation because 

                                                               106

  1   of chest tube bleeding.  It is not clear-cut; there

  2   is nothing out there that is a clear-cut trigger

  3   for them.

  4             [Slide]

  5             The same thing you would expect, if you

  6   bleed more, it is more likely that these patients

  7   are going to receive blood and blood products, red

  8   cells, platelets and FFP.  In each instance it was

  9   a very significant difference with those patients

 10   who received hetastarch.

 11             [Slide]

 12             We have three studies, retrospective

 13   studies but that I think are very useful because

 14   they represent kind of a crossover design, where

 15   there is a strong association between the

 16   intraoperative use of hetastarch and more bleeding

 17   or excessive bleeding immediately after surgery.

 18   Although I haven't dwelt on all the details, it

 19   appears that in each of these studies there are no

 20   real differences between these groups.

 21             [Slide]

 22             I think there are some real interesting

 23   points in Dr. Canver's paper, in his review first

 24   of all, because you are looking at patients having

 25   one surgery, bypass surgery, and a very large 

                                                               107

  1   number, 887 patients over this period from 1987 to

  2   the end of 1995.  They classified their patients in

  3   different groups based on the kind of pump prime.

  4             I had the opportunity to speak with

  5   several of the authors and co-authors of these

  6   papers, Greg Nuttle at the Mayo Clinic and Mr.

  7   Nichols, to get a little bit greater background on

  8   how the study was conducted.  One of the problems

  9   with pump bypass priming solutions is that

 10   everybody has their own.  There is no brand out

 11   there; everybody makes their own and it varies from

 12   time to time.  Over a nine-year period, just

 13   knowing from our own experience, the formulations

 14   change.

 15             I wasn't clear from reading the paper

 16   exactly how they formulated their pump prime.  They

 17   used a volume of 20-100 cc and, apparently, what

 18   they did was just, once the patient was hooked up

 19   to the bypass, just added in one of these different

 20   reagents.  They didn't have a constant volume per

 21   pump prime.  I think the best you could say is for

 22   group one that received 500 ml of crystalloid, in

 23   addition to the 2200 for a total of 2700; group

 24   two, 500 of Hespan so a total volume of 2700; for

 25   group three, 25 percent albumin for a total volume 

                                                               108

  1   of 2250, etc., etc., as I understand it in this

  2   pump prime solution.  Maybe we can clarify that in

  3   a minute.

  4             [Slide]

  5             As has already been pointed out, I think

  6   there are significant differences between the group

  7   that received Hespan and the group that received

  8   albumin and a combination of albumin and Hespan,

  9   both in terms of the cross-clamp time which is that

 10   period of time when the heart and lungs are

 11   completely isolated and the bypass which

 12   encompasses the total time before you go on and

 13   completely come off, when you are circulating blood

 14   through that plastic circuit.  To me, clinically as

 15   well as statistically there is a big difference

 16   between a two-hour pump run and a three-hour pump

 17   run.  Even with the other groups too, I think that

 18   there is still some significant difference.

 19             [Slide]

 20             As has already been pointed out, the

 21   groups that received platelets and the ones that

 22   received FFP, it looks like it was really much more

 23   in the Hespan group as opposed to albumin.

 24             [Slide]

 25             In addition, over a nine-year period, even 

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  1   if it is one surgeon, the technique is going to get

  2   better, a little more refined.  Inevitably, in a

  3   teaching hospital you have other people involved

  4   over a nine-year period so there had to be other

  5   surgeons.  I know there were certainly other

  6   anesthesiologists without real distinct transfusion

  7   protocols in mind.  So, it is difficult

  8   retrospectively to standardize the practices.  But

  9   I do think the blood product usage was different in

 10   these groups, and some of the endpoints are not

 11   real useful because the surgeons really didn't have

 12   control over them, like the length of ICU stay.

 13   That was an administrative decision, not based on a

 14   clinical decision.  If there had been data like how

 15   long a patient was on a ventilator, and I assume

 16   they would come off the ventilator based strictly

 17   on a clinical decision, that might have been more

 18   useful.

 19             [Slide]

 20             To wind this up, there are some comments

 21   from the authors, from Greg Nuttle from the Mayo

 22   Clinic.  I should mention that in their study if

 23   they weren't getting a hetastarch solution it was

 24   their practice that almost all of their patients

 25   received albumin as intravascular volume 

                                                               110

  1   replacement.  Although they didn't publish those

  2   numbers, it is behind the actual practice.

  3             [Slide]

  4             I didn't show the data on this, but Cope

  5   also did a correlation in his study on

  6   intraoperative use of hetastarch, and they showed a

  7   positive correlation which I think was something

  8   like 0.4 between hetastarch dose and postop

  9   bleeding.  So, the more you gave, the more you

 10   bled.  So, that led them to think that even at a

 11   low dose, in this group of patients, intraoperative

 12   use of hetastarch may not be safe.

 13             [Slide]

 14             In terms of what I think these are telling

 15   us and what these data are telling and advisory

 16   committee, it is that excessive bleeding and

 17   increased transfusion requirements are associated

 18   with intraoperative use of six percent hetastarch

 19   in these patients undergoing cardiopulmonary

 20   bypass; that there is evidence that there is an

 21   increased risk of reexploration in these patients

 22   following hetastarch use; and that, clearly, three

 23   major centers, Iowa, Mayo Clinic and UVA, are

 24   avoiding the use of hetastarch as pump prime in

 25   their bypass procedures. 

                                                               111

  1             That concludes the comments I want to make

  2   on this.  Any questions?

  3             DR. NELSON:  Thank you.  I have one

  4   question.  The committee was asked, first of all,

  5   whether the evidence or the data would suggest a

  6   warning label and, as an alternative, they were

  7   asked should a prospective, randomized trial be

  8   done to answer the question.  It seems, although it

  9   is not universal, that there are quite a number of

 10   surgical programs that are convinced that

 11   hetastarch does increase the risk of bleeding.

 12   Given that feeling, and I would like your opinion

 13   as to how widespread that feeling is, but given

 14   that feeling, it might be difficult to do a

 15   clinical trial.  I think that surgeons would be

 16   reluctant to randomize patients to an arm when,

 17   even though it might be somewhat cheaper in the

 18   cost of what is being infused, the overall cost

 19   might be more and they might feel it was harming

 20   the patient.  Given your contact with surgeons

 21   throughout the country in review of the literature,

 22   that it would be feasible to do a large clinical

 23   trial?

 24             DR. HAYNES:  There are two or three points

 25   there.  First the clinical trial, it is going to be 

                                                               112

  1   very difficult for a couple of reasons.  One is the

  2   cost, and I don't know who would fund this sort of

  3   thing.  You are speaking not only to surgeons, and

  4   everybody's goal is obviously to minimize the

  5   complications.  You have touched, as a number of

  6   people have touched on the issue of cost.  You

  7   know, the cost of albumin a few years ago was much

  8   higher.  Just general pricing policy for most

  9   academic hospitals is different but it is not that

 10   much different.  In just ball park figures, and I

 11   am just saying this off the top of my head, you are

 12   talking roughly in the $15 to $20 range for 500 ml

 13   of hetastarch solution, at least for Hespan, and

 14   maybe about $30 for five percent albumin so you

 15   double that and you are looking at $60.

 16             The point about drug cost, whether it is

 17   this or any other drug in the perioperative

 18   process, it is a small part of the big picture.

 19   The way we save money is not by using a cheaper

 20   drug; it is avoiding a complication because the

 21   complications are what are devastating and

 22   expensive for the individuals and for the

 23   institutions.

 24             In terms of how you would do this study,

 25   yes, there would be a lot of reluctance on the part 

                                                               113

  1   of surgeons to randomize patients to something that

  2   they now think, based on these studies, might be

  3   dangerous to the patients, and also it would be

  4   very difficult to convince an IRB these days that

  5   the endpoint is going to the OR for an emergency

  6   reoperation.

  7             DR. NELSON:  Particularly if the only

  8   benefit was a small economic benefit.  As you

  9   mentioned, a complication in five percent of the

 10   patients would wipe that out easily.

 11             DR. HAYNES:  Yes.  Well, Herwaldt

 12   mentioned that in her analysis.  They were trying

 13   to save a little bit of money but the cost of

 14   taking patients back to the OR quickly wiped that

 15   out.  The minimum is like a $7,000 bill.

 16             DR. LEW:  In your talk you didn't make

 17   distinction between the two different products, the

 18   Hespan and the Hextend, although in your handout

 19   you started to show some differences and mentioned

 20   another study.  There is, you know, some debate

 21   whether it is the hetastarch itself that is the

 22   problem versus the carrier, the combination of the

 23   hetastarch and a particular carrier.

 24             DR. HAYNES:  Right.

 25             DR. LEWIS:  Can you expand on that? 

                                                               114

  1             DR. HAYNES:  Right.  It is interesting you

  2   bring that up because that was the one thing that

  3   really got my attention initially because the

  4   marketing information associated with the Hextend

  5   product--I want to be careful how I say this, I

  6   mean they just make the statement that it has been

  7   used in very large volumes.  What we have been

  8   talking about and, again, what I think the common

  9   practice is among anesthesiologists and one that I

 10   learned in training is to stick with what Dr.

 11   Landow mentioned at the beginning, a dose of 10-20

 12   cc/kg, which gets you out to about a 1500 cc daily

 13   limit on this.  With Hextend, and that comes out of

 14   a paper where even in the title they suggest very

 15   large use of that product, and in the paper that

 16   refers to the use of up to 5 liters in some

 17   surgical cases, which I think is an enormous amount

 18   of product to use, yes, the difference really is--I

 19   don't know if somebody might be here from Abbott

 20   who markets that--I know in the paper where it was

 21   described, one difference was 550 molecular weight

 22   substance.  I don't know if that was a misprint or

 23   if it really is the same hetastarch that is in the

 24   other product, Hespan.  But the real difference is

 25   that it is just in a different carrier.  I don't 

                                                               115

  1   see that study being based on a real difference in

  2   the solute; it is the solvent that is different in

  3   those solutions.

  4             [Slide]

  5             I thought this issue might come up so I

  6   included a couple of slides at the very end.  I was

  7   going to limit this just to a discussion of the

  8   cardiac surgery patients but this goes outside that

  9   to other general surgical patients.  In the study

 10   that is quoted, they looked at general surgical

 11   patients.  I think it was urologic, gynecologic and

 12   general surgery or orthopedic patients.

 13             In this study they were comparing the two

 14   hetastarch solutions, Hextend which is an

 15   electrolyte solution compared to Hespan.  When they

 16   invented Hespan years ago, I don't know why they

 17   put it in saline.  It makes a certain amount of

 18   sense to put it in an electrolyte solution that is

 19   going to mimic normal plasma.  In their study they

 20   were just infusing some lactated Ringer's

 21   throughout the surgery as a baseline and then they

 22   had certain hemodynamic targets:  if a patient's

 23   blood pressure dropped they infused one of the

 24   study solutions.  If their heart rate went up, they

 25   infused one of the study solutions.  Then, they 

                                                               116

  1   also just estimated what the blood loss was and

  2   replaced it 1 cc for 1 cc of the study solution.

  3             [Slide]

  4             What they were really comparing was an

  5   electrolyte solution with six percent hetastarch to

  6   saline with six percent hetastarch and the

  7   estimated blood loss was about the same.  The total

  8   volumes given to the patients on the average were

  9   the same, although there is considerable variation.

 10   You can see that 35-40 percent of the patients

 11   received in excess of what I think is a safe dose

 12   of this material to use, with some patients

 13   receiving up to 5 L.

 14             So, based on some of the information I

 15   have shown you already, I don't think it should

 16   come as any surprise that, because it is one form

 17   of hetastarch compared to hetastarch in just

 18   another solvent, they are going to have similar

 19   blood losses; similar hematocrits both at the

 20   beginning and end of surgery; and a little change

 21   in the prothrombin time.

 22             I don't think that really tells us that

 23   when you conduct a study looking at one carrier for

 24   hetastarch versus the other, that then it is safe

 25   to give large volumes of a hetastarch solution to a 

                                                               117

  1   surgical patient.  So, that is where that came

  2   from.

  3             DR. LEW:  I think this is going to be for

  4   discussion later, but I have concerns that we were

  5   given confidential information in our packets that

  6   clearly makes a huge distinction, but can we use

  7   that data, since it is marked confidential, in

  8   making our decision?  It sounds like because it is

  9   marked confidential we can't discuss it and I think

 10   it needs to be discussed.

 11             DR. NELSON:  Well, if it was given to us I

 12   think somebody wanted us to look at it.  This is a

 13   public hearing so I don't know.

 14             DR. LEW:  We are scrutinizing what has

 15   been published, but then we have confidential

 16   information which I think we ought to scrutinize

 17   because, certainly, the panel here has a lot of

 18   expertise.

 19             DR. NELSON:  Sometimes we have executive

 20   session, but this is a public hearing that I think

 21   is being recorded.  So, whoever gave it to us, if

 22   they want it to be confidential, then we shouldn't

 23   discuss it.

 24             DR. SMALLWOOD:  The information provided

 25   to the committee that is marked confidential was 

                                                               118

  1   provided by those presenting in the open public

  2   hearing, which are sponsors.  Those sponsors are

  3   here today.  They may address that.

  4             MR. WANGELIN:  Speaking for the sponsors

  5   package, Abbott Laboratories, that Dr. Smallwood is

  6   referring to, the confidential stamp only meant

  7   that we didn't feel, prior to the meeting, the

  8   information should be published on a website, but

  9   it is for open discussion here in this meeting.

 10             DR. NELSON:  Thank you.  Your name?

 11             MR. WANGELIN:  I am sorry, my name is

 12   James Wangelin, and I work in the regulatory

 13   affairs department at Abbott Laboratories.

 14             DR. NELSON:  Toby?

 15             DR. SIMON:  I think this was an excellent

 16   presentation, as were the two previous

 17   presentations.  I think it is worth putting it in

 18   context, and that relates to a couple of the

 19   questions that I asked.  This substance,

 20   hydroxyethyl starch, is, as the speaker pointed

 21   out, known to increase bleeding and the data have

 22   been published over many years.  So, this is old

 23   data.

 24             The question one might ask is if you are

 25   dealing with a surgery where bleeding is a prime 

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  1   consideration, why would you use something that

  2   increases bleeding?  A lot of this use began in the

  3   mid-1990s when, for a while, albumin was hardly

  4   available.  It was in extremely short supply.

  5   Actually, the same thing happened in therapeutic

  6   plasma exchange.  People had to do the procedures.

  7   They didn't have albumin so they began looking for

  8   something, and they also felt in that circumstance

  9   that colloid was superior to crystalloid.  Indeed,

 10   I think that is true with therapeutic plasma

 11   exchange.  So, people developed protocols using

 12   hydroxyethyl starch and seemed to observe that it

 13   worked and that the complications, in some people's

 14   hands, were acceptable.

 15             Then albumin came back into supply.

 16   Originally it was quite expensive.  Even though, as

 17   I think the speaker pointed out, it is a small

 18   percent of the expense in cardiac surgery, the

 19   overall expense to the hospital could be quite

 20   substantial, and in the managed care environment

 21   many hospitals regulate, as was pointed out,

 22   albumin and other such expensive pharmaceuticals to

 23   keep their overall cost down.

 24             Now the albumin price has, I guess, come

 25   down and it is more available so it is an 

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  1   interesting issue in that we wouldn't be discussing

  2   it if it weren't initially for the shortage and

  3   then the difference in cost.  That is why I asked

  4   the prior speaker if albumin were the same cost

  5   would he use albumin.  I believe the answer was

  6   yes.

  7             The other interesting thing I think in the

  8   discussion was the heavy use of this word "may" in

  9   the various inserts and discussions.  I believe it

 10   should be not that hydroxyethyl starch may cause

 11   bleeding but that it sometimes or often does, or

 12   whatever term is most appropriate.  I think that

 13   might get at the issue that we want.  But I think

 14   it is an interesting issue.

 15             There is also the division between the

 16   issue of is there more bleeding with hydroxyethyl

 17   starch, and the answer is probably yes, but then is

 18   it clinically significant enough to require a

 19   warning, and there I think it is much more cloudy,

 20   grey and difficult to determine.  Obviously, with a

 21   strong difference of opinion within the surgical

 22   community, with a lot of retrospective data and

 23   what prospective data we have, not as well

 24   controlled as we would like, I think it makes it

 25   difficult to answer that second question of whether 

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  1   it is clinically significant.

  2             DR. HAYNES:  Do you want me to respond to

  3   that?

  4             DR. NELSON:  Go ahead.

  5             DR. HAYNES:  Again, it is going to be I

  6   think impossible to get a prospective study to get

  7   at that issue.  I can share with you what I do and

  8   what my experiences are.  I am not going to stand

  9   here and speak for the people at the Mayo Clinic,

 10   although I communicate with them most closely and

 11   know them and know what their feelings on the

 12   subject are, and they have clearly discontinued the

 13   use of hetastarch in surgery.  Again, it represents

 14   a unique population because they are already at

 15   risk for several reasons.  So, do you, in that

 16   situation, add some other factor that can make it

 17   worse, knowing that the worst scenario is that you

 18   are going to get your ticket stamped to come right

 19   back to the OR with all the risk and cost

 20   associated with that.

 21             The other driver that you mentioned isn't

 22   only the issue of cost or availability, but we are

 23   looking at studies that span a 20-, 25-year period

 24   and there were many pressures in the 1980s and

 25   early 1990s to reduce any blood product use at all, 

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  1   with it was correctly founded or not, because of

  2   the infectious disease risks associated with

  3   transfusions.

  4             So, there are many variables, but this is

  5   what the experience is.  My guess is that maybe 40

  6   percent or so of medical centers use hetastarch

  7   intraoperatively for cardiac surgeries.  I would

  8   say at least half or the majority are not, are

  9   getting away from it.

 10             DR. SIMON:  Those that use it could do a

 11   prospective study, couldn't they?  They have

 12   already said that it is safe in their view.  Why

 13   couldn't those, like Albany who do use it, do a

 14   prospective study?

 15             DR. HAYNES:  One, you have to have

 16   motivation and time and resources to do it.  You

 17   know what happens in the real world, we are all

 18   busy.  It is no secret that everyone in healthcare,

 19   surgeons and anesthesiologist in particular are

 20   working very hard and, you know, even in academic

 21   centers it is very hard to do this kind of

 22   research.  It is certainly not going to happen in a

 23   community center, and what is out there is just

 24   this sort of gestalt that hetastarch has been safe;

 25   doesn't really cause a problem because most 

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  1   surgeons and anesthesiologists are so busy they are

  2   not even going to have the time to sit down and

  3   read even the retrospective literature, much less

  4   do a prospective study.  So, they are relying on

  5   agencies like yourself as well as academic centers

  6   and others to investigate this problem.  When it

  7   comes to investigating the problem prospectively,

  8   it is going to be very, very tough, if it ever gets

  9   done.  I don't see that happening.

 10             DR. NELSON:  I have one more question.

 11   One of the endpoints that seems to be sort of

 12   consistent in the studies, you said, is the

 13   estimated blood loss volumes.  Those are measured

 14   in the chest tubes; I guess how much is in the

 15   bottle.

 16             DR. HAYNES:  Right.

 17             DR. NELSON:  But is there any variability

 18   related to loculation or poor drainage of fluid

 19   that actually is in the chest but not in the

 20   bottle?  Is that a problem?  Because you can record

 21   exact volumes, but it is not exactly a closed

 22   system, is that pretty reliable, do you think?

 23             DR. HAYNES:  That is a good question to

 24   ask because, first of all, when you talk about

 25   estimated blood loss--let's step out of the cardiac 

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  1   arena for a second, estimated blood loss, like in

  2   this paper, is at best a guess.  You see blood all

  3   over the field.  Some centers will weigh sponges as

  4   an estimate.  It is not very reliable.  It is very

  5   difficult to measure intravascular volume in a

  6   research lab; it is impossible in a clinical

  7   setting.  So, just looking at the surgical field

  8   sponges, drainage or suction intraoperatively, it

  9   is at best an estimate.

 10             In a study like this where you are just

 11   replacing cc for cc, it kind of makes you wonder.

 12   So, you have to look at estimated blood loss with a

 13   very suspicious eye.  In cardiac surgery, as

 14   pointed out, you have two, sometimes four chest

 15   tubes.  Can they get loculated, or some trapped and

 16   not drained?  Sure, it probably does from time to

 17   time.  But these are pretty large drainage tubes;

 18   these aren't small drainage tubes.  They are

 19   probably a half inch in diameter, three-quarters of

 20   an inch.  At the same time, patients in ICUs are

 21   getting chest x-rays and you would see loculations

 22   of fluid, and you are closely studying this over a

 23   24-hour period.

 24             DR. NELSON:  Right.

 25             DR. LEW:  Since you can talk about it, we 

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  1   were provided three articles, some submitted, some

  2   in press, all three articles suggest that Hextend

  3   is quite different from the Hespan, suggesting that

  4   the problems with Hespan do not show up with

  5   Hextend.  That is why I bring that up, because if

  6   we are talking about the package insert, are we

  7   talking about this for hetastarch and anything that

  8   has hetastarch is going to go, or is there really a

  9   difference between Hespan and Hextend?  All the

 10   studies that you have shown, as far as I am aware,

 11   except for this last one, used the Hespan.  Is that

 12   correct?

 13             DR. HAYNES:  Yes, as far as I know.  It is

 14   described as six percent hetastarch in saline, and

 15   the only preparation I know of in the United States

 16   is Hespan.  Now, if there is a difference, you will

 17   have to tell me because I don't know what it is,

 18   other than the solution.

 19             DR. ALLEN:  I have two questions.  I know

 20   that the low molecular weight formulation is not

 21   available in the United States.  If a prospective

 22   study were to be done, would you want to see

 23   mid-weight included as a comparison with the

 24   heavier molecular weight product that currently is

 25   licensed in the United States?  Based on the 

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  1   information from Europe and studies that have been

  2   published?

  3             DR. HAYNES:  Sure, it might be an

  4   interesting observation, but I think what would be

  5   more informative would be to compare any new thing

  6   with what is a common practice.  You know, albumin

  7   has been mentioned; crystalloid has been mentioned;

  8   blood products.  We don't replace intravascular

  9   volume with just any one thing, and when we are

 10   giving blood products, especially in terms of FFP,

 11   I mean you can call it fresh-frozen plasma and you

 12   can also call it a colloidal substance because it

 13   is.  It is a collection of plasma proteins in an

 14   electrolyte solution.

 15             Many anesthesiologists will replace

 16   intravascular volume with a combination.  I know

 17   many who have used Hespan; I have used Hespan.  We

 18   will use it but up to a certain limit.  There

 19   doesn't seem to be any real limit on albumin,

 20   crystalloid.  I mean, it depends on the

 21   circumstances, how much you have to infuse to keep

 22   the patient alive.  But if there is something that

 23   has a limit, I think it might be more instructive,

 24   whether it is Hextend, Hespan or any new one that

 25   comes along, to treat both groups in the same 

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  1   manner and have two arms, one that would continue

  2   with the way we do things normally with blood, FFP

  3   and albumin, and then continue on with the other

  4   arm of an experimental drug.  That would be more

  5   informative to me.

  6             DR. ALLEN:  A second question I had, and

  7   perhaps Dr. Canver could respond also, I was

  8   confused by the volumes in each of the four groups

  9   that you alluded to in Dr. Canver's study, the

 10   priming-plus.  You know, it suggests to me that the

 11   whole issue of the volume received is very highly

 12   variable and wasn't really reflected by the

 13   descriptive four groups.

 14             DR. HAYNES:  Do you want to respond to

 15   that?

 16             DR. CANVER:  The total pump prime was 2200

 17   cc, and then additional substance was given.

 18             DR. ALLEN:  How much did you say?

 19             DR. CANVER:  The total circuitry, 2200

 20   plus whatever each group is given.

 21             DR. ALLEN:  And, was the pump priming

 22   solution the same in all four groups, or did it

 23   vary?

 24             DR. CANVER:  It was 2200 cc, identical in

 25   all four groups. 

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  1             DR. NELSON:  Wait a minute, but the group

  2   with hetastarch was primed with hetastarch; the one

  3   with albumin was primed with albumin?

  4             DR. CANVER:  The way I understand it, the

  5   basic 2200 cc was identical in each of the four

  6   groups.  In addition, they received Hespan, albumin

  7   or Hespan and albumin together.

  8             DR. ALLEN:  What was the 2200 pump prime

  9   solution that you say was the same in all groups?

 10             DR. CANVER:  It was a lactated Ringer's

 11   solution.  I actually wanted to respond, if I am

 12   allowed--

 13             DR. NELSON:  Sure, go ahead.

 14             DR. CANVER:  Dr. Simon raised a very good

 15   issue.  It depends on how you approach the issue.

 16   You may think that this agent has anything to do

 17   with the bleeding after cardiac surgery.  I think

 18   it is so multifactorial because we don't use Hespan

 19   and we still have bleeding.  The bleeding rate

 20   after heart surgery, which includes all types of

 21   procedures, is less than one percent.

 22             I want to clarify, reexploration required

 23   for bleeding is less than one percent.  That is

 24   extremely low.  In fact, it is negligible in our

 25   hands.  But that is only achievable by many 

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  1   strategies, which I skipped in my initial part of

  2   strategies, and I think Gary really elaborated very

  3   nicely.  We don't do only one thing.  I think it

  4   would be very easy if you give Hespan or no Hespan

  5   and you are done with it, but all these patients,

  6   about 80 percent of patients come with aspirin the

  7   day before, emergency operations, have many, many

  8   other anti-platelet agents that they are on.  Every

  9   hospital setup is different.  Surgeons' techniques

 10   and their training is different; what they do is

 11   different.  We also use a lot of hemostatic agents.

 12   We use fibrin glue, a lot of mechanical agents.

 13   Then, also, the amount of transfusions that an

 14   anesthesiologist gives also alone increases

 15   bleeding.  When you look at this drainage from

 16   chest tubes, most of us now like them not to be

 17   visible because the patients like it.  Our

 18   incisions are smaller and the chest tubes are now

 19   softer and sometimes we actually don't even put

 20   them in, in some simple cases.

 21             So, essentially you are dealing with a

 22   very multifactorial issue.  But I still feel,

 23   listening to all the arguments, that low molecular

 24   Hespan versus albumin in some sort of clinical

 25   trial, I think that would be something not done. 

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  1             DR. DIMICHELE:  Dr. Haynes, you really

  2   eloquently reviewed a lot of the literature that we

  3   were also given to review.  I just need to ask your

  4   opinion, because I also had the question that Dr.

  5   Lew asked about what type of starch was actually

  6   used, but the other issues are the other variables

  7   that cause bleeding which you, again, so eloquently

  8   went over.  It is unclear in the retrospective

  9   studies, in fact, in some of them, including pump

 10   time and things like that, you actually criticized

 11   in Dr. Canver's study, but among the other studies,

 12   the other retrospective reviews, can you feel

 13   confident that there were no other variables

 14   accounting for the results in those studies?

 15             DR. HAYNES:  Yes, and it varies among the

 16   studies, but going back to the Mayo Clinic because

 17   some of the things they did, one, it was one

 18   surgeon for all cases requiring coronary-pulmonary

 19   bypass, 565 patients from January of 1995 to

 20   December of 1998.  It was the same group of

 21   anesthesiologists involved.  It was conducted at a

 22   time when we had worked on guidelines for

 23   transfusion for a number of years.  So, the

 24   transfusion triggers are well established.  So,

 25   just because it was all condensed down in a fairly 

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  1   limited period of time, many of these other

  2   confounding variables are not--

  3             DR. DIMICHELE:  But what about things like

  4   pump time?  I mean, there seemed to be some

  5   uniformity in the other study as well.  What about

  6   an issue such as pump time?  You said, for

  7   instance, that pump time of two hours or three

  8   hours, and you do this every day, is quite

  9   significant.

 10             DR. HAYNES:  Right.  Let's see, to answer

 11   your question simply, yes, I do feel confident that

 12   these groups were more comparable in the Virginia

 13   and the Mayo Clinic studies.  I didn't quote all

 14   the details here.  I think you have the papers

 15   there so you might be able to look at some of this

 16   data yourself, but I didn't find any significant

 17   variation between groups, between those who did or

 18   did not receive hetastarch, in terms of

 19   preoperative lab values, or in terms of patient

 20   demographic groups, or any of the other things.  In

 21   terms of bypass duration, for instance, at the Mayo

 22   Clinic study it was a mean of 107 minutes versus

 23   111 minutes.  The time from end of bypass to out of

 24   the OR was 92 versus 99 minutes.  These things were

 25   not significant.  The lowest temperature on bypass, 

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  1   29.9 versus 29.1.  In table 1 of their paper they

  2   showed very nicely that there were very few

  3   differences, if any differences, between the

  4   patients who did and did not receive hetastarch.

  5             DR. DIMICHELE:  Thanks.  My other question

  6   is there is an issue, it seems to me and maybe I am

  7   getting confused, of when exactly this substance is

  8   used in the procedure.  In other words, even in the

  9   studies that you quoted there was less of a

 10   difference when the hetastarch was used actually

 11   postoperatively and not used intraoperatively or as

 12   a priming solution.  Again, I need to ask you

 13   because we are going to be asked to make some

 14   decisions here.  You know, the question is does it

 15   need to be specific to the timing in a certain

 16   preclinical, etc?  These are nuances but they are

 17   very, very important.

 18             DR. HAYNES:  Yes, they are nuances and you

 19   are right.  What I think I am trying to convey here

 20   as a message is that you have a unique surgical

 21   population having a specific kind of surgery where

 22   you are doing an awful lot of stuff to them that

 23   can interfere with coagulation.  Then they survive

 24   the surgery, they go on, they start to recover.

 25   Those perturbations are resolving or diminished or 

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  1   gone, not that the coagulation mechanism suddenly

  2   comes back to normal but do you add one other thing

  3   that can impair coagulation on top of those other

  4   four that could result in patients coming back for

  5   emergency surgery?  Or, do you use it afterwards

  6   when homeostasis is starting to be restored and

  7   then some amount of hetastarch is probably not

  8   deleterious?  I think there is a difference.  Okay?

  9             Also, if you stay within some acceptable,

 10   reasonable guideline because, you know, here we are

 11   dealing with hetastarch that is being given in

 12   reasonable amounts and there is still concern that

 13   it may cause bleeding.  As I said earlier, what

 14   prompted my concern originally was the notion with

 15   some marketed materials that you could give

 16   whopping doses of this stuff whether it is cardiac

 17   or just general surgical patients, which I think

 18   would be very inappropriate today.

 19             So, I think the difference is, yes, once

 20   somebody starts to recover and things come back to

 21   normal, is a little hetastarch going to get you in

 22   trouble?  Probably not.  But do you do it in a

 23   circumstance--and, as I pointed out, we don't use

 24   it in neurosurgical patients, we don't use it in

 25   liver transplant patients, and by analogy you have 

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  1   a somewhat similar circumstance here with

  2   hypothermia, bypass, heparinization, all these

  3   things going on, if you add one more variable that

  4   could have a serious outcome.

  5             DR. NELSON:  Thank you very much, doctor.

  6             DR. HAYNES:  Thank you.

  7             DR. NELSON:  Stay around, we may have more

  8   questions.

  9             DR. LANDOW:  Before the committee

 10   undertakes a discussion of the questions that FDA

 11   has posed to them, I would like to present to you

 12   for your consideration nine reasons to be cautious

 13   about the data that you have seen today from these

 14   non-randomized trials, and not to jump to any

 15   conclusions.

 16             [Slide]

 17             The first reason is that the treatment

 18   arms may not be comparable across these different

 19   trials that we have heard today.  For instance, and

 20   this is not a list that includes everything but

 21   there may be different inclusion and exclusion

 22   criteria, such as related to anti-platelet

 23   medications for a simple example.  Also, there

 24   might be a difference in the severity of illness

 25   scores and how you adjust for those differences 

                                                               135

  1   between studies.

  2             [Slide]

  3             Second, even with sophisticated

  4   statistical techniques, and mainframe computers as

  5   the extreme, one can never be sure that key outcome

  6   predictors have been recognized and adjusted for.

  7   While we all realize that there are different risk

  8   factors in terms of age, gender and severity of

  9   illness, there are many that we are just now

 10   beginning to discover that may also play a role,

 11   and these include genetic predisposition and

 12   socioeconomic status.

 13             [Slide]

 14             Third reasons, standards of medical care

 15   change over time.  We know that Dr. Canver's study

 16   lasted eight years and things do change in that

 17   time period.

 18             [Slide]

 19             Fourth, fluid management, apart from the

 20   hetastarch situation, can vary across particles.

 21   Knutson et al. state specifically in the manuscript

 22   that there were no specific transfusion algorithms

 23   used in the study period.  Second, there were no

 24   rigorous guidelines for infusion of hetastarch,

 25   albumin or crystalloid.  I think that is very 

                                                               136

  1   important.

  2             [Slide]

  3             Patient selection and treatment can be

  4   unintentionally biased.  For instance, in Dr.

  5   Canver's study they stated that the decision to use

  6   a particular type of priming solution for bypass

  7   was arbitrarily made by the clinical perfusionist,

  8   which leaves open the question could hetastarch

  9   have been avoided in certain patient groups, such

 10   as older patients or patients with renal failure?

 11   We don't know that information.

 12             [Slide]

 13             Confounding is very likely.  For instance,

 14   in the study by Knutson et al. the hetastarch

 15   group, as opposed to the non-hetastarch group, had

 16   lower temperatures on bypass, longer time on

 17   bypass, and higher frequency of preoperative

 18   anticoagulant use.

 19             [Slide]

 20             In the study by Cope at al. there were

 21   different volume expanders used at different points

 22   in the operation.  There was a group where

 23   hetastarch was used only after bypass had been

 24   completed and the patient had been reversed; one

 25   where the patient got hetastarch only in the ICU; 

                                                               137

  1   and a third group where there was no hetastarch.

  2   But then you can look at the percent of patients

  3   receiving colloid post-bypass and those receiving

  4   colloid in the ICU and you see that there is a lot

  5   of information that is sort of fuzzy.  We don't

  6   have a good handle on exactly what each of these

  7   patients received.  So, it is hard to draw

  8   conclusions about the effects of hetastarch

  9   compared to the other products.

 10             [Slide]

 11             Confounding is likely also in the

 12   different pump primes that were used.  Cope et al.

 13   used albumin and crystalloid.  Knutson claimed that

 14   they did not use hetastarch at all.  Canver gave

 15   you the four groups.  So, we have different primes

 16   and we are trying to draw conclusions about a

 17   product, and I think it is very difficult to tease

 18   apart the effects of the solutions and the bleeding

 19   problem.

 20             [Slide]

 21             Reason number seven, adequate statistical

 22   power alone does not ensure that there is no bias

 23   or confounding taking place.  You heard a quotation

 24   before that approximately 200 subjects are required

 25   to detect an absolute difference of ten percent 

                                                               138

  1   increase in blood loss.  These studies meet those

  2   criteria, nevertheless, they all are subject to

  3   certain weaknesses that I have listed here.  So,

  4   statistical power, by adequate sample size, does

  5   not solve our problems.

  6             [Slide]

  7             Another reason that is well-known is that

  8   the quality of the data is often uneven in these

  9   retrospective studies.  The endpoints are defined

 10   differently and they are not prespecified.  Many

 11   times the endpoints are chosen after the study is

 12   completed, although the manuscript, obviously, will

 13   not say that.

 14             Also, a big problem with these studies is

 15   that there is missing or inaccurate data, and it is

 16   very hard to pinpoint that in an article published

 17   in a medical journal.         Finally, different

 18   variables are collected.  Some are left out, some

 19   are included.  It depends on which study you are

 20   talking about.

 21             [Slide]

 22             Another reason is reporting bias.  It is

 23   well recognized that positive findings are much

 24   more easily accepted by medical journals than

 25   negative findings.  So, we don't know what those 

                                                               139

  1   negative findings were.

  2             [Slide]

  3             The conclusion that we draw from this is

  4   that non-randomized clinical trials tend to

  5   exaggerate an effect size, in this case the

  6   incidence of bleeding in this population.

  7             Now we come to the questions by the

  8   committee, or do we go to the open session?

  9             DR. NELSON:  There are a number of people

 10   so we will come back to that.  So, stick around.

 11             The other issue, it seems to me, is that

 12   the question that the committee is being asked is a

 13   little more complex in that there already is a

 14   label saying that there is no evidence that

 15   hetastarch causes bleeding.  Are we to deal with

 16   that?  I suspect that there may be some sentiment

 17   that that statement needs to be changed because it

 18   doesn't omit the reference to bleeding; it says

 19   there is no evidence.  This isn't perfect evidence

 20   and I certainly agree with the weaknesses of this

 21   and the necessity to really be sure to do a

 22   randomized, controlled trial, but I am not sure it

 23   is accurate to say that there is no evidence that

 24   there are bleeding problems.

 25             DR. CHAMBERLAND:  I also need some 

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  1   additional clarification, and I apologize if

  2   perhaps you have covered this in your introductory

  3   presentation which, regrettably, I had to miss.  I

  4   think there are a number of issues that are at

  5   least confusing to me that I need some

  6   clarification on.  Some of that will come out in

  7   the public hearing, but initially my approach to

  8   the material for this topic was to read it as it

  9   came, and the issue paper provided by FDA, the

 10   summary issue paper, and the articles that are

 11   referenced in that summary paper kind of initially

 12   led me to believe that these were sort of the

 13   primary papers, the important papers, whatever, but

 14   these were the important papers to consider.

 15             There was also no reference to the fact

 16   that there are apparently a couple of different

 17   versions of this product out on the market, and

 18   these five papers that you just reviewed with

 19   respect to some of the issues that need to be

 20   considered really only addressed one version of

 21   this product.  Then, as Dr. Lew mentioned earlier,

 22   the committee has also been supplied with a lot of

 23   additional materials coming from the sponsors and

 24   manufacturers of these various products.

 25             So, I am a little confused as to what it 

                                                               141

  1   is that we are supposed to use in trying to develop

  2   some recommendations from the FDA and why FDA, in

  3   its own pulling together of the issue, at least to

  4   me, didn't seem to take into consideration

  5   additional literature and information about this

  6   whole other product.  If someone could provide some

  7   clarification--I don't know if that is confusing to

  8   other members of the committee.

  9             DR. NELSON:  Yes, there are two different

 10   products and there could be two different labels I

 11   suppose.  Do you want to comment on that, Dr.

 12   Landow?

 13             DR. LANDOW:  The clinical problem that has

 14   arisen from the medical community is bleeding

 15   associated with hetastarch.  So, that is the reason

 16   this product is under discussion.

 17             DR. NELSON:  So, we are discussing

 18   hetastarch.

 19             DR. CHAMBERLAND:  Generic hetastarch.

 20             DR. LANDOW:  Yes, hetastarch in normal

 21   saline, but not in the lactated Ringer's solution,

 22   not the Hextend.

 23             DR. NELSON:  If that is the case, then it

 24   is not appropriate for any presentations on

 25   Hextend. 

                                                               142

  1             DR. HOLLINGER:  That is very confusing.  I

  2   thought this was just on hetastarch in general and

  3   to determine whether there are any particular

  4   differences that would require different warnings.

  5   I mean, otherwise I am not sure why we got this ton

  6   of information on hetastarch from Abbott.  That is

  7   a lot of information to go over if we are not going

  8   to discuss it, if it is not going to be up for

  9   discussion.

 10             DR. FALLAT:  Isn't Hextend already on the

 11   market as well?

 12             DR. NELSON:  Since '99 I think.

 13             DR. FALLAT:  So, we really have to address

 14   it.

 15             DR. NELSON:  Does FDA want us to discuss

 16   labeling of Hextend as well?

 17             DR. LANDOW:  The reason that you got the

 18   literature about Hextend was because that pertained

 19   to the discussion of the open session, but it does

 20   not pertain to the discussion that we called you

 21   here to agree to.  Now, if you want to discuss it

 22   among yourselves, I suppose that is your

 23   prerogative.  I am just saying that the reason we

 24   are calling this meeting is because of a bleeding

 25   problem that the medical community claims is 

                                                               143

  1   occurring with the Hespan in normal saline.

  2             DR. HOLLINGER:  But that is the problem.

  3   The question talks about six percent hetastarch.

  4   You don't say Hespan in normal saline, and that is

  5   what the question should have said if that is what

  6   we are supposed to discuss.

  7             DR. NELSON:  Yes, I think it does make a

  8   difference.  One of the problems we have is that a

  9   lot of people have airlines leaving at three

 10   o'clock, and what-have-you, and if we are not to

 11   discuss the Hextend at this point, then we probably

 12   shouldn't listen to additional material.

 13             DR. CANVER:  I just wanted to say that the

 14   Hespan is a trade mark given by the company.  So,

 15   you cannot really say Hespan in normal solution;

 16   you can only say in medical scientific form six

 17   percent hetastarch in normal saline.  I mean, that

 18   is the proper way of saying it.

 19             DR. NELSON:  Yes, but what if we were to

 20   talk about hetastarch and Ringer's lactate?

 21             DR. CHAMBERLAND:  FDA really needs to

 22   assist us with their question because the first

 23   question that we have been asked to consider is, is

 24   there evidence for excessive bleeding in cardiac

 25   surgery patients who receive six percent 

                                                               144

  1   hydroxyethyl starch, and there is no additional

  2   qualification of that with respect to the carrier,

  3   which I think you appropriately pointed out.  So,

  4   we need some clarity as to what it is that we are

  5   being asked to consider.

  6             DR. LANDOW:  I will say once again that

  7   the medical community has alerted us to what they

  8   see as a problem with excessive bleeding with six

  9   percent hydroxyethyl starch in normal saline, trade

 10   name Hespan, as correctly pointed out.  We have not

 11   been alerted to a problem with Hextend, which is

 12   hydroxyethyl starch in lactated Ringer's.  The only

 13   reason you got that information is so you could be

 14   aware of what was being discussed in the open

 15   session.

 16             DR. NELSON:  Yes?  Identify yourself, if

 17   you will.

 18             DR. WEINSTEIN:  I think actually we do

 19   need to make a further clarification.  I think Paul

 20   Albersold, in our group here, will make a

 21   clarification of what we intend to do here.  It

 22   turns out that Hextend and Hespan apparently, at

 23   this point in time, both have the same labeled

 24   indication.  In fact, I have to amend the comments

 25   of my colleague, Larry.  We will be talking about 

                                                               145

  1   both of these at this point.

  2             DR. NELSON:  So, you want us to discuss

  3   both?

  4             DR. WEINSTEIN:  Right.

  5             DR. ALBERSOLD:  At the time that the

  6   Hextend product was licensed the labels were

  7   essentially the same for the two products.  There

  8   was no evidence one way or the other--the trial

  9   wasn't designed to test for any differences between

 10   them.  It was designed to show that they could be

 11   used essentially interchangeably.  The labels are

 12   essentially identical and the starch products are

 13   the same in them.  So, FDA has no evidence that

 14   there is any difference between them.  I think that

 15   in the public session Abbott wanted to present some

 16   information.  I think the committee can ask what

 17   the status of those trials is, are they to support

 18   a labeling change?  I can't reveal what is going on

 19   in their INDs.

 20             DR. NELSON:  Dr. Smallwood has a

 21   statement.

 22             DR. SMALLWOOD:  Regarding the open public

 23   hearing, I will try to clear up a little bit of

 24   confusion, that is, when topics come before an

 25   advisory committee for all of the affected products 

                                                               146

  1   or related sponsors, if anything that is being

  2   discussed will have any association with that, they

  3   are notified.  They have the opportunity to present

  4   during the open public hearing.  The FDA will

  5   identify what is the specific issue to be

  6   discussed, but that is the reason why the advisory

  7   committee members did receive information from the

  8   sponsors, and during the open public hearing

  9   individuals are permitted to make such

 10   presentations and we will use the information as we

 11   see fit with respect to the discussion.

 12             I would also like to state before we go

 13   into the open public hearing that the information

 14   that was stamped confidential and was submitted to

 15   the committee cannot be discussed publicly unless

 16   there is a public statement by the sponsor, stating

 17   that the material may be discussed in this public

 18   setting and this material may be publicly posted on

 19   the FDA website.  So, at this time, with the

 20   committee chairman's permission, I would like to

 21   ask those sponsors that submitted information

 22   stamped confidential to please come to the mike and

 23   state publicly that your information may be

 24   discussed at this meeting and that it may be posted

 25   on the FDA website so that we may have a record in 

                                                               147

  1   our transcripts.  Thank you.

  2             DR. NELSON:  Do we have a volunteer?

  3             DR. SCHMIDT:  While somebody is

  4   volunteering, I am sort of irritated to see that

  5   this material was published in 1995, and most of it

  6   is in newsletters dated 2001.  So, somebody puts a

  7   stamp "confidential" on it, which is an old Defense

  8   Department ploy but it shouldn't work in

  9   Gaithersburg.

 10             [Laughter]

 11             DR. FALLAT:  I want a clarification.  Was

 12   Hextend approved on the basis of comparability

 13   studies with Hespan?  Could we have an answer to

 14   that question?

 15             DR. ALBERSOLD:  I believe if you look at

 16   the summary basis of approval you will find that

 17   the primary endpoint was volume comparison to show

 18   that they could be used essentially

 19   interchangeably.  There were no prospective study

 20   endpoints for any differences between them, any

 21   advantage, no clinical benefit to one versus the

 22   other.  It was strictly that they could be used

 23   interchangeably essentially with the same volume.

 24             DR. FALLAT:  So, it was a comparability

 25   study. 

                                                               148

  1             DR. ALBERSOLD:  Essentially, yes, it was.

  2             DR. FALLAT:  Thank you.

  3             DR. WAITZ:  Can I speak?  This is Harold

  4   Waitz, from Biotime, sponsor for Hextend.  About

  5   the confidentiality, we just had a concern that

  6   there are papers that are not printed and approved,

  7   that they appear on the FDA website beforehand.

  8   There are copyright issues with that.  But

  9   certainly a lot of the information in there I

 10   believe can be discussed.  Some of this stuff has

 11   been given in various forums as abstracts and

 12   papers.

 13             DR. NELSON:  So you are saying it can or

 14   cannot be on the FDA website?

 15             DR. WAITZ:  I mean, the papers themselves

 16   shouldn't be posted, but I think we can discuss the

 17   information that we are going to present.

 18             DR. NELSON:  Well, whatever you are going

 19   to present is in a public hearing.

 20             DR. WAITZ:  It is basically the references

 21   to the information that we are going to discuss

 22   that we are concerned with.

 23             DR. NELSON:  I have my lawyer here!

 24             DR. SMALLWOOD:  The procedure is that once

 25   something has been discussed publicly in a public 

                                                               149

  1   setting, it has become public and, therefore, we

  2   can post it on the FDA website because it has been

  3   made public once it has been discussed in this

  4   forum.

  5             DR. WAGELIN:  James Wagelin, Abbott

  6   Laboratories.  Our concern is that any information

  7   that has been published, of course, can be freely

  8   discussed and can be posted on the FDA website.

  9   Those articles which have not yet been published,

 10   those are areas where we have concern because there

 11   could be copyright infringement sort of issues.

 12             DR. HOLLINGER:  I think you will have to

 13   point out, as we often ask in many of these cases,

 14   which is proprietary because there are a lot of

 15   things that are documented as confidential, and

 16   some of them, you are saying, have already

 17   published and some of them were back in 1997 or

 18   1999.  So, which ones are going to remain

 19   confidential?

 20             DR. CHAMBERLAND:  We need clarification, I

 21   guess, from the FDA as to how you want to address

 22   this.  I think all of us would understand that for

 23   pre-publication, things that are in peer review

 24   there are concerns about, having public

 25   dissemination of them on a website.  However, do 

                                                               150

  1   the FDA regulations regarding advisory committees

  2   allow this sort of split, the distinction that we

  3   are being asked here, or does it have to be both?

  4   Do you have the ability to both discuss it in a

  5   meeting and it has to be on the website, or can it

  6   be either/or?  We need to get clarification as to

  7   what we can discuss.

  8             DR. NELSON:  I don't think the publication

  9   is the issue.  I don't think, in most journals,

 10   that would jeopardize publication.

 11             DR. SMALLWOOD:  We have Dr. Bill Freas

 12   here, who is the director of the scientific

 13   advisors and consultants staff, and I would defer

 14   that response to him.

 15             DR. DIMICHELE:  Can also ask another

 16   question that I would like him to address?  That

 17   is, if this information can't be put on the website

 18   but can be used in our discussion, in our free

 19   discussion which will become part of the public

 20   record one way or another.

 21             DR. HOLLINGER:  It may become moot if we

 22   are not going to discuss these issues which are

 23   being talked about in our deliberations.  If we are

 24   only dealing with Hespan basically or hetastarch in

 25   saline, then we can just listen to these issues and 

                                                               151

  1   not discuss anything further, and then just get to

  2   the questions.

  3             DR. WEINSTEIN:  I want to reiterate that

  4   we will be discussing hetastarch in a broad sense,

  5   both Hespan and Hextend.

  6             DR. HOLLINGER:  That will be part of the

  7   question?

  8             DR. WEINSTEIN:  The question has to do

  9   with labeling of these products in general.

 10             DR. HOLLINGER:  So, there could be

 11   different answers for different products, depending

 12   on what information comes out, or they could be the

 13   same.

 14             DR. WEINSTEIN:  You can give us your

 15   advice on either.

 16             DR. FALLAT:  But if Hextend was approved

 17   on the basis of comparability, then it would seem

 18   to me that if we answer the question with regards

 19   to Hespan it should apply to Hextend as well.

 20             DR. WEINSTEIN:  Again, I think we can

 21   listen to the discussion about this.  I don't want

 22   to categorically say that this will necessarily be

 23   the case.  There apparently are perhaps

 24   distinctions between these products that will come

 25   out later on.  There may be further trials that are 

                                                               152

  1   submitted to us and we will have to evaluate the

  2   evidence of those distinctions that are being

  3   perhaps claimed between the two products.

  4             DR. FREAS:  I will try to clarify it.  FDA

  5   is under a law suit, and the law suit states that

  6   what is given to the advisory committee in open

  7   public session is required to be posted on our

  8   website.  Now, FDA is doing its best to be in

  9   compliance with this law suit in order to keep the

 10   public informed.  FDA is always caught between a

 11   rock and a hard place when we come to

 12   pre-publication issues.  In that case, we are

 13   asking the sponsor, and we are putting

 14   responsibility on the people who submit the

 15   material to submit summaries of that material in

 16   advance of the meeting, and not stamp them

 17   confidential.

 18             FDA cannot publish unpublished material.

 19   It can be discussed but, again, we need the

 20   permission of the source person who originated the

 21   material.  If we don't have that permission, then

 22   it puts us in a very bad place because FDA's

 23   obligation is to make material discussed at open

 24   public meetings public.

 25             DR. NELSON:  Thank you.  Dr. Lew? 

                                                               153

  1             DR. LEW:  I just want to clarify what Bob

  2   had mentioned.  A lot of times FDA will do

  3   comparability studies, particularly with

  4   antibiotics because that is what I am most familiar

  5   with, and compare one cephalosporin to another.

  6   But it is clear that some cephalosporins have more

  7   adverse effects and, as that occurs, you do change

  8   the package insert.  So, I don't think they are

  9   obligated to put it in the package insert for both.

 10             DR. BAKER:  Dr. Mary Baker, Abbott

 11   Laboratories, pharmaceutical research and

 12   development.  What we would like to remain

 13   confidential and not be posted on the FDA website

 14   is the resource by Dr. Anthony Roche.  Anything

 15   else will be discussed by the researchers and has

 16   been published in abstract form.

 17             DR. DIMICHELE:  But then my question is

 18   that information cannot be used by us to help make

 19   this decision.

 20             DR. BAKER:  Dr. Roche has also published

 21   that information in abstract form.  That is

 22   available for discussion, but we ask that his

 23   submitted publication not be posted on the website.

 24             DR. DIMICHELE:  But any of the details

 25   from those papers will not be brought up in any 

                                                               154

  1   discussion and cannot be used to help us make the

  2   decision.

  3             DR. BAKER:  I believe you have been

  4   furnished with the abstract as well.

  5             DR. DIMICHELE:  Right, but we can only use

  6   what is in the abstract, is that correct?  I am

  7   asking the committee.

  8             DR. NELSON:  I think that is correct.  Now

  9   we move to the open public hearing.  If you can try

 10   to be concise as possible.

 11                       Open Public Hearing

 12             MR. SPODEN:  Thank you, Mr. Chairman.

 13   Good afternoon.  My name is John Spoden.  I am the

 14   associate director of regulatory affairs for B.

 15   Braun Medical.  It is my privilege to speak before

 16   the committee on behalf of B. Braun today.

 17             [Slide]

 18             I have prepared a brief presentation to

 19   address some of the important issues raised this

 20   morning relative to the use of hetastarch in

 21   cardiac surgery.  Because I am not a clinician, B.

 22   Braun has arranged for Dr. William Shoemaker to

 23   attend this meeting to address any clinical

 24   questions the committee may have.  Dr. Shoemaker is

 25   a professor of surgery, in the Division of Trauma 

                                                               155

  1   and Critical Care at the University of Souther

  2   California, and has studied these colloids and

  3   hemodynamics extensively.  In the interest of full

  4   disclosure, B. Braun has paid for Dr. Shoemaker's

  5   transportation, lodging expenses and will reimburse

  6   him at his normal rate for his time.

  7             [Slide]

  8             B. Braun is the holder of two new drug

  9   applications for Hespan, one in a glass container,

 10   the other in a flexible plastic container.  The

 11   product in glass was originally approved by the FDA

 12   in 1972 for use as a plasma volume expander.  The

 13   original NDA holder of this product was McGow

 14   Laboratories.  Although ownership of Hespan has

 15   changed over the years and was, until recently,

 16   with Dupont, it has been manufactured by McGow

 17   since it was first approved.  When B. Baun

 18   purchased McGow in 1998 and purchased Hespan from

 19   Dupont in 1999, Hespan in a way came home.  I

 20   mention this bit of history because, as discussed

 21   this morning, there is a lot of confusion in the

 22   literature.  Hespan is referred to as a product of

 23   American Critical Care, Dupont Critical Care and

 24   others, but Hespan has always been the same

 25   product, made by the sam manufacturer. 

                                                               156

  1             [Slide]

  2             Hespan is B. Braun's brand of six percent

  3   hetastarch in normal saline.  It is one of several

  4   licensed hetastarches available in the U.S. for

  5   plasma volume expansion.  As discussed earlier this

  6   morning, hetastarches are characterized by their

  7   molecular weight and their degree of hydroxyethyl

  8   substitution.  The hetastarch used in Hespan has an

  9   average molecular weight of 6000 D.  That is how it

 10   is listed in the current package insert.  That

 11   differs from what has been presented earlier today

 12   due to improvements in the way we actually analyze

 13   the hetastarch in the laboratory.  It has a

 14   hydroxyethyl substitution ratio of 0.75.

 15             [Slide]

 16             Differences in molecular weight and degree

 17   of substitution have been shown to affect the

 18   influence of these starches on coagulation and

 19   bleeding.  The association between alteration of

 20   coagulation in the use of hydroxyethyl starches is

 21   well documented, and has been studied for over

 22   three decades.  The effects of Hespan on

 23   coagulation result from hemodilution and a direct

 24   effect on coagulation factors and platelets.  These

 25   effects have been described extensively in the 

                                                               157

  1   medical literature.

  2             Briefly, the hemodilution effect is

  3   largely determined by dose level, single or

  4   multiple infusions, and the frequency of infusion.

  5   Moderate doses may cause dilution of clotting

  6   proteins, but these proteins are usually still

  7   present in amounts adequate to ensure effective

  8   hemostasis.  According to the literature,

  9   significant risk of bleeding is usually associated

 10   with greater than a 25 percent volume replacement.

 11   Above this dose platelets can appear abnormal and

 12   adhesion is decreased.  Some clotting factors

 13   become abnormal.  Fiber and clots are friable and

 14   lack their normal tensile strength.  Factor VIII

 15   also appears to be decreased beyond levels

 16   attributable to hemodilution alone.

 17             [Slide]

 18             Current Hespan labeling includes warning

 19   regarding these and other effects.  If the existing

 20   warnings relative to bleeding beyond normal levels

 21   are heeded, it could be expected that the adverse

 22   events associated with excessive bleeding would be

 23   relatively low.  Indeed, if we graph an annual

 24   number of adverse events related to excessive

 25   bleeding per 100,000 Hespan units, these types of 

                                                               158

  1   adverse events are relatively low.  An absence of

  2   bleeding-related adverse events starting in 1998

  3   may reflect the influence of several published

  4   studies that we have discussed this morning on the

  5   decision whether or not to use Hespan in some

  6   clinical situations.

  7             [Slide]

  8             Two studies already discussed this

  9   morning, specifically papers by Dr. Cope and others

 10   in 1997 and Knutson and others in 2000, raise

 11   questions regarding the use of hetastarch in

 12   cardiac surgery and its possible association with

 13   increased bleeding.  Both studies were

 14   retrospective and both recommended that prospective

 15   studies be conducted in order to fully answer the

 16   questions raised.

 17             It is the opinion of B. Braun that the

 18   retrospective nature and other shortcomings of

 19   these studies, as Dr. Landow summarized in his nine

 20   points, limit their scientific relevance and the

 21   claim of a causal relationship between the use of

 22   hetastarch and excessive bleeding in cardiac

 23   surgery.  However, B. Braun is also of the opinion

 24   that the data presented does show some evidence of

 25   an association between bleeding beyond expected 

                                                               159

  1   levels and the use of hetastarch during certain

  2   periods of cardiac surgery.

  3             [Slide]

  4             Therefore, in order to enhance patient

  5   safety and to provide clinicians with important

  6   information, B. Braun has submitted proposed

  7   changes to Hespan labeling to the FDA.  These

  8   changes are under precautions, contra-indications,

  9   dosage administration and warning section of the

 10   package insert.

 11             In the interest of time, I will only

 12   present some of the more significant changes that

 13   we have made.  B. Braun has proposed that in the

 14   following statement to the warning section:  Hespan

 15   is not recommended for use as a cardiac bypass pump

 16   prime or in the immediate period after the pump has

 17   been discontinued because of the risk of increased

 18   coagulation abnormalities and bleeding in patients

 19   whose coagulation status is already impaired.

 20             [Slide]

 21             Addition to the dosage administration

 22   section has been provided as follows:  Hespan is

 23   reported to be associated with increased bleeding

 24   when used immediately after cardiac bypass pump has

 25   been discontinued.  However, this risk of bleeding 

                                                               160

  1   diminishes rapidly.

  2             [Slide]

  3             This statement has been proposed for

  4   addition to the precautions section:  Increased

  5   risk of coagulation abnormalities and bleeding is

  6   also associated with higher doses.  Patients' vital

  7   signs and hemoglobin, hematocrit, platelet count,

  8   prothrombin time and partial thromboplastin time

  9   should be monitored closely.

 10             [Slide]

 11             In conclusion, while the safety debate

 12   regarding an association between hetastarch and

 13   excessive bleeding during cardia surgery will

 14   continue, B. Braun has acted prudently in taking

 15   definitive steps to enhance Hespan labeling in a

 16   way that we feel will satisfy the needs of the

 17   patients and clinicians using our product.  Because

 18   we are taking these steps, we feel that no further

 19   clinical trials are warranted.

 20             I appreciate the opportunity to articulate

 21   B. Braun's vision this morning and thank you very

 22   much.

 23             DR. NELSON:  Thank you.  Are there

 24   questions?

 25             DR. ALLEN:  Two questions.  First, your 

                                                               161

  1   graph showing the Hespan bleeding adverse events,

  2   do you have an explanation for that drop off?  Is

  3   it with change in usage?

  4             MR. SPODEN:  One thing I didn't include in

  5   there is the sales volume.  We have seen a decrease

  6   in sales volume and, although we cannot pinpoint

  7   it, we are expecting that perhaps the results of

  8   these studies that were published may have

  9   influenced the use of hetastarch in certain

 10   situations.

 11             DR. ALLEN:  Thank you.  The second

 12   question is what is the current status of action on

 13   your proposed labeling and when was that submitted?

 14             MR. SPODEN:  We have been talking with the

 15   reviewers at FDA since October.  We formally

 16   submitted the proposal for the labeling changes in

 17   April of this year and they are still being

 18   reviewed by the agency.

 19             DR. NELSON:  Other questions?

 20             DR. HOLLINGER:  I think you are to be

 21   congratulated for a proactive stand in this.

 22             DR. NELSON:  The next speaker is Harold

 23   Waitz.  No?  Dr. Gan, please.

 24             DR. GAN:  Good afternoon, ladies and

 25   gentlemen.  It gives me great pleasure to be here 

                                                               162

  1   today to share some of the information.

  2             [Slide]

  3             What I am going to present to you today is

  4   to answer the question, Hextend, is it different

  5   from Hespan?  An alternative title would be are all

  6   starches created equal?  I would like to present to

  7   you specifically on one aspect of the difference

  8   between Hextend and Hespan, and that is

  9   coagulation.  Other speakers will present to you

 10   more important differences between Hextend and

 11   Hespan.

 12             [Slide]

 13             What I would like to do this afternoon is

 14   to present data on six specific randomized,

 15   controlled studies and it is important, in contrast

 16   to the unrandomized, retrospective study that you

 17   have heard this morning.  The six studies I am

 18   going to present to you with regards to coagulation

 19   are the following:  The first study is an in vitro

 20   study comparing Hextend versus Hespan and lactated

 21   Ringer's.  In view of time, I would like to call

 22   them Hextend and Hespan as you know what I am

 23   talking about, Hespan being hetastarch in saline

 24   and Hextend being in a balanced electrolyte

 25   carrier. 

                                                               163

  1             The next study I am going to present to

  2   you is the Phase III study comparing Hextend and

  3   Hespan.  That is followed by the next sty where a

  4   lactated Ringer's group was added to that study.

  5   The fourth study is again comparing Hextend and

  6   Hespan in a group of geriatric population

  7   undergoing general surgery.  The next study is an

  8   important one, looking at four different fluids,

  9   Hextend, Hespan, albumin and lactated Ringer's in

 10   200 patients undergoing cardiac surgery.  Lastly, I

 11   am going to present to you a couple of studies that

 12   address comparison of Hextend and albumin, which is

 13   obviously one of the fluids of interest.

 14             [Slide]

 15             I will not go into details of the

 16   composition of hetastarch because that has been

 17   addressed by previous speakers.  But I think it is

 18   important to notice the difference between Hextend

 19   and Hespan, and that is in the electrolyte carrier.

 20   As you can see, hetastarch in saline is formulated

 21   in normal saline.  However, Hextend is formulated,

 22   in addition to sodium and chloride notably in

 23   smaller concentration, 124 versus 154 in Hespan.

 24   In addition to that, it also contains a number of

 25   important electrolytes, notably calcium, potassium 

                                                               164

  1   and magnesium.

  2             [Slide]

  3             Many of the results I am going to present

  4   involve thromboelastograms.  I know that there are

  5   a number or experts in the audience of

  6   thromboelastography but for those who may not be

  7   familiar, I am just going to take a couple of

  8   seconds to explain what a thromboelastogram is.

  9             Thromboelastogram was widely used back in

 10   the 1970s because it was popular, especially in

 11   liver transplantation, to monitor coagulation.  It

 12   is a dynamic coagulation monitor and you can get a

 13   result fairly quickly, much quicker than if you

 14   send it to the lab.

 15             This is a new version of a

 16   thromboelastogram where you introduce a sample of

 17   blood into the cup, here, and there is a pin that

 18   is then lowered, and the pin is under constant

 19   rotation under the influence of the magnet, here.

 20   So, if there is no clot being formed, there is no

 21   resistance between the pin and the site of the cup.

 22   As a clot begins to form there is increasing

 23   resistance, and this increasing resistance and

 24   increase in torque between the pin and the cup is

 25   then translated into a pattern, which is on the 

                                                               165

  1   next slide.

  2             [Slide]

  3             This is a pattern of a thromboelastogram.

  4   It looks a little bit like the end of a party where

  5   you go and smash glasses, sort of an inverted

  6   champaign glass pattern.  There are several

  7   important features that are important here.  The

  8   first is called R time, which is the reaction time.

  9   Reaction time is the time taken from when you

 10   introduce the blood sample into the cup to when

 11   there is the first hint of clot formation.  So,

 12   this is where you introduce the blood into the cup

 13   and as soon as there is a hint of clot formation

 14   this pattern opens up, like this.

 15             K time is a little bit further on.  It is

 16   defined as when there is a significant amount of

 17   clot formation.  So, this is R time and this is K

 18   time, 20 mm apart.  As it opens up, this

 19   coagulation monitor also tells you the speed of

 20   clot formation, how quickly the clot is being

 21   formed.  This is measured by an angle called alpha

 22   angle.  Once a clot is formed, it also measures the

 23   strength of the clot formation, which is donated by

 24   maximum amplitude.  So, this is a dynamic

 25   coagulation monitor which tells us what is 

                                                               166

  1   happening to the patient's coagulation at that

  2   point in time.

  3             [Slide]

  4             First of all, I would like to present to

  5   you the results of a hemodilution study, an in

  6   vitro study that looked at what happens if you take

  7   a sample of blood and hemodilute it all the way up

  8   to 75 percent.

  9             [Slide]

 10             If you hemodilute a sample of blood with

 11   lactated Ringer's which is a common crystalloid we

 12   all use, as you can see, as you hemodilute further

 13   you are going to get hypocoagulation because of

 14   hemodilution.

 15             [Slide]

 16             What happens if you hemodilute the same

 17   sample of blood with Hextend?  Again, you can see

 18   it is very similar to what you would see with

 19   lactated Ringer's, slightly increased with further

 20   hemodilution.

 21             The next one is what happens when you

 22   hemodilute with Hespan.  Clearly, you can see if

 23   you hemodilute this blood sample with Hespan beyond

 24   about 30, 40 percent, which is very close to about

 25   20 cc/kg, it is increased in our time, which is 

                                                               167

  1   measured on the Y axis here, beyond 40, 50 percent

  2   hemodilution with Hespan.

  3             [Slide]

  4             The next data I want to show you is from a

  5   Phase III study.  A Phase III study was actually

  6   conducted to compare the efficacy between Hextend

  7   and Hespan.  We obviously looked at all the other

  8   aspects of fluid management, coagulation being one

  9   of them.

 10             [Slide]

 11             Just to give you a summary of the study,

 12   there were 120 patients, a two-center study,

 13   non-cardiac surgery with an anticipated blood loss

 14   of more than 500 cc.  They were randomized into

 15   either Hextend or Hespan.  The perioperative fluid

 16   management is fairly standard, what we normally do

 17   when we give a patient a bolus of lactated Ringer's

 18   7 cc/kg, followed by a crystalloid infusion.  Based

 19   on the fluid algorithm, based on blood pressure,

 20   heart rate and urine output we administer either

 21   Hextend or Hespan.  The anaesthetic is a balanced

 22   technique to incorporate isolfurane and fentanyl.

 23             [Slide]

 24             This is of particular interest in terms of

 25   coagulation between the two solutions.  Because we 

                                                               168

  1   are concerned about the Hespan causing coagulation

  2   in the higher volume uses, therefore, we divided

  3   our patients into those who received less than 20

  4   cc/kg or those who received more than 22 cc/kg.

  5   When we looked at the R time, which is the length

  6   of time taken fort he clot to form, on the Y axis

  7   the square represents those who received six

  8   percent hetastarch in saline, or Hespan.  The

  9   circle represents those who received Hextend.  The

 10   solid line represents those who received more than

 11   20 cc/kg, and the dotted line represents those who

 12   received less than 20 cc/kg.

 13             Let us look at the result at baseline and

 14   end of surgery.  At baseline there is roughly

 15   similar R time.  For Hextend and Hespan, for those

 16   who were given less than 20 cc/kg, as noted by the

 17   dotted lines here, as you can clearly see, there is

 18   really no significant change at the end of surgery

 19   compared to baseline.  But if you look at the fluid

 20   given at more than 20 cc/kg or a larger volume

 21   used, you can clearly see a difference in that the

 22   Hespan patient had a significant increase in R

 23   time, the time taken for the clot to form, compared

 24   to the Hextend patient who maintained his R time at

 25   the end of surgery compared to baseline. 

                                                               169

  1             [Slide]

  2             This is K time.  As you remember, it is

  3   the time taken for a significant amount of clot

  4   being formed.  Again, you see a very, very similar

  5   picture.  Over 20 cc/kg of Hespan, the K time is

  6   significantly longer compared to an equivalent

  7   volume of Hextend.

  8             [Slide]

  9             Does that translate into a difference in

 10   blood loss?  Well, if we look at the overall blood

 11   loss there is no statistically significant

 12   difference between the Hespan and the Hextend

 13   group.  The Hespan group is in yellow and the

 14   Hextend group is in red.  There may be a slight

 15   trend but there is no significant difference.

 16             But if you look at the subpopulation who

 17   received red blood cells, indicating that these

 18   patients lost more blood and therefore required

 19   transfusion of red blood cells, there was a

 20   significant difference in terms of the red blood

 21   cell transfusion.  That is, blood loss in the

 22   subset or red cell transfused patients, on average

 23   the Hextend patients needed about 1500 cc compared

 24   to the Hespan patients who lost about a liter more

 25   of blood compared to the Hextend patients. 

                                                               170

  1             [Slide]

  2             This is a table that shows you that in the

  3   transfused subset of patients, those patients who

  4   lost more blood, they lost more blood in the Hespan

  5   group.  They also needed on average 500 cc more red

  6   blood cells when they received Hespan compared to

  7   Hextend.  Likewise, the blood product utilization

  8   appeared to be less with Hextend compared to

  9   Hespan.

 10             [Slide]

 11             This study looked at when we added a third

 12   group of patients who received lactated Ringer's, a

 13   commonly used crystalloid in non-cardiac surgery.

 14   So, this is Hextend and Hespan, and this is the

 15   lactated Ringer's group which predominantly had LR

 16   administered during surgery.

 17             [Slide]

 18             Looking again at the thromboelastogram

 19   comparing the three groups, Hespan, Hextend and

 20   Lactated Ringer's, this is the percent change of R

 21   time from baseline and end of surgery.  In this

 22   study we also looked at 24 hours after surgery.

 23             If you look at the Hextend group, which is

 24   a square in yellow, and the lactated Ringer's

 25   group, in the triangle here, you can see very, very 

                                                               171

  1   similar coagulation profiles between Hextend and

  2   lactated Ringer's.  However, if you look at the

  3   patient who received Hespan, there is a significant

  4   increase, about 40 percent increase in R time and

  5   this persisted beyond 24 hours.  So, clearly, there

  6   are differences between Hespan and Hextend in terms

  7   of coagulation.

  8             [Slide]

  9             Next I want to move to the geriatric

 10   study.  This was conducted in the United Kingdom.

 11   It was non-cardiac surgery with an anticipated

 12   blood loss of more than 500 cc.  In this study the

 13   comparison was Hextend and lactated Ringer's being

 14   the colloid and crystalloid groups, compared with

 15   Hespan and normal saline, again colloid and

 16   crystalloid.  The fluid algorithm again is very

 17   similar, with some bolus of fluid up front and then

 18   carried on with crystalloid infusion

 19   intraoperatively.  The fluid administration is very

 20   similar to the previous study where it was based on

 21   an algorithm.

 22             The primary hypothesis of that study was

 23   looking at acid-base changes.  I am not going to

 24   present that aspect of the study; another speaker

 25   will present that.  I am going to concentrate just 

                                                               172

  1   on the coagulation aspect.

  2             [Slide]

  3             In that study they planned to study 60

  4   patients.  However, the study was stopped when 47

  5   patients were enrolled because they were concerned

  6   about severe acidosis in some of the patients in

  7   the study.  When they did the 47th patient, the

  8   patient didn't do very well, developed severe

  9   acidosis.  There was concern among surgeons and

 10   anesthesiologists and, therefore, the study was

 11   stopped.  The blind was broken to say whether they

 12   had reached the primary hypothesis which, indeed,

 13   it had.  There was a difference in acid-base

 14   balance between the two study groups and,

 15   therefore, the study was stopped.  The mean age was

 16   over 70.  The mean volume of study fluid given was

 17   over 4 L.

 18             [Slide]

 19             This is the TEG R-time result I showed you

 20   earlier.  You can see that there was a statistical

 21   difference between the Phase III study.  In the

 22   geriatric study they also did TEG comparing the

 23   Hextend and the Hespan group.

 24             [Slide]

 25             You can see that there was statistical 

                                                               173

  1   significance in the Phase III study.  However, you

  2   also see a trend in the geriatric study but because

  3   the number in the study was smaller, 34 patients,

  4   therefore, that did not achieve statistical

  5   significance.  But clearly you can see similar

  6   trends between the two studies.

  7             [Slide]

  8             This next study was done in cardiac

  9   patients.  It was done in Columbia.  There were 200

 10   patients.  They were randomized into four different

 11   groups, receiving lactated Ringer's, Hextend,

 12   Hespan or albumin.  These were cases of

 13   coronary-artery bypass or valve.  Most of the

 14   patients had been on cardiopulmonary bypass and

 15   there were some off-pump.

 16             [Slide]

 17             Just to give you some detail about the

 18   study.  It is an intraoperative study.  The study

 19   fluid for treatment of hypovolemia.  A liter of the

 20   study fluid was added to the pump prime.  There

 21   were no volume limitations in that study.  They

 22   looked at several outcomes, renal function,

 23   bleeding, coagulation.  Again, I just want to

 24   emphasize or just want to concentrate on the

 25   coagulation aspect of this study. 

                                                               174

  1             [Slide]

  2             The median volume of the study fluid was

  3   about 3.4 L, except LR, obviously being

  4   crystalloid, so a larger volume was given.  The

  5   total volume of fluid is about 5 L.  There was

  6   essentially no difference in hemodynamics, cardiac

  7   output, blood pressure and urine output.

  8             [Slide]

  9             This slide shows you the bleeding outcome

 10   among those four groups.  To recap, hetastarch and

 11   saline or Hespan, Hextend, albumin and lactated

 12   Ringer's.  The first row is the amount of red blood

 13   cells transfused.  In the Hespan group, on average

 14   it was about four units, whereas in the Hextend,

 15   albumin and lactated Ringer's groups it was about

 16   2.0 to 2.5 units.  This was a statistically

 17   significant difference.  The FFP again was

 18   different, 3.8 units in the Hespan group; 2.5 in

 19   the Hextend group; albumin 1.8; lactated Ringer's

 20   0.5  Platelet transfusion, 6.3 in the Hespan group;

 21   4 units, Hextend; 3.7, albumin; and 2.2, lactated

 22   Ringer's.

 23             What is more interesting is if you look at

 24   the percent of patients receiving either

 25   coagulation factors, FFP or platelets, about 70 

                                                               175

  1   percent of the patients who received Hespan had to

  2   have some coagulation product.  However, 47 percent

  3   in Hextend and about 42 in albumin.  If you look at

  4   the number of patients who returned to the

  5   operating room, about 10 percent in the Hespan

  6   group; 2 percent each in the Hextend and albumin

  7   group; and none in the lactated Ringer's group.

  8             [Slide]

  9             The next two studies that I would like to

 10   present to you are comparing Hextend and albumin.

 11   This first study comparing the two procedures is in

 12   radical retropubic prostatectomy and radical

 13   nephrectomy.  These are, again, general urological

 14   procedures.  They were either randomized to Hextend

 15   or albumin according to a fluid algorithm.

 16             Baseline blood samples were collected at

 17   the beginning of surgery, end of surgery and 24

 18   hours following surgery.  Because we are concerned

 19   about platelets and some of the Factor VIII issues,

 20   we measured platelets.  We did PT, PTT as well as

 21   looking at Factor VIII and von Willebrand's

 22   factors.

 23             [Slide]

 24             The following few slides are the results

 25   from this study.  This is comparing Hextend and 

                                                               176

  1   albumin platelets at baseline, in yellow; end of

  2   surgery, in red; and 24 hours following procedures

  3   in the Hextend group and the albumin group.  Again,

  4   there was no statistical significance between

  5   platelet counts between these two groups.

  6             [Slide]

  7             This slide shows the PT and PTT time

  8   between the two groups, PT in the Hextend group,

  9   APTT in the Hextend and PT and PTT in the albumin

 10   group, again, baseline, end of surgery and 24 hours

 11   and again you see no difference between albumin and

 12   Hextend in terms of PT and PTT.

 13             [Slide]

 14             This slide shows you some of the

 15   coagulation factors, for example Factor VIII and

 16   von Willebrand factors antigen, as well as the

 17   collagen ADP, a much more subtle measurement of

 18   what happened to those Factor VIIIs as well as von

 19   Willebrand's Factor.  Again, comparing Hextend and

 20   albumin, this is baseline, end of surgery and 24

 21   hours and you can see, again, there is really no

 22   significant difference between those who were given

 23   Hextend or albumin.  The average volume that was

 24   used in this study is between 2.5-3 L of either

 25   Hextend or albumin. 

                                                               177

  1             [Slide]

  2             A recent study again looking at Hextend

  3   versus albumin in cardiac patients found no

  4   difference in chest tube output, post and

  5   preoperative hematocrits, as well as TEG

  6   differences and blood product usage.

  7             [Slide]

  8             In summary, comparing Hextend and Hespan,

  9   Hextend-treated patients seem to lose less blood.

 10   It seems to have a lower requirement for blood and

 11   blood products; better coagulating factors, as

 12   evidenced by thromboelastogram; better preserved

 13   renal function; less acidosis, which the next

 14   speaker will talk about in greater detail.

 15             [Slide]

 16             When compared to albumin, there appeared

 17   to be a very similar amount of blood loss between

 18   Hextend and albumin; required similar blood and

 19   blood products and an equivalent effect on blood

 20   coagulation, as noted by PT, PTT, von Willebrand's

 21   factor as well as TEG.

 22             [Slide]

 23             In conclusion, I believe that Hextend is

 24   different from Hespan, and I believe that as far as

 25   coagulation it is superior to Hespan bleeding and 

                                                               178

  1   patient outcome.  I also believe that, based on the

  2   data that I presented, that Hextend is very similar

  3   to albumin in terms of coagulation.

  4             The important question is when you look at

  5   data and ask yourself how does it change our

  6   clinical practice, at Duke, about a year and a

  7   half, two years ago, we changed all our Hespan to

  8   Hextend.  I believe that at Mayo Clinic, that Dr.

  9   Haynes talked about, they also stopped using Hespan

 10   and are now using Hextend for their patients.

 11   Thank you very much for your attention.

 12             DR. NELSON:  Thank you, Dr. Gan.

 13   Questions?  Don't go away.

 14             DR. GAN:  We will be happy to answer any

 15   questions.

 16             DR. HOLLINGER:  Just out of interest, if

 17   you look at your cardiac surgery patients, it would

 18   look like Ringer's lactate, which is even cheaper

 19   than anything else, is actually pretty darned good.

 20   I would then say that for this study one should

 21   probably go and use Ringer's lactate instead of

 22   either one of the hetastarches.  That is what that

 23   data shows on that blinded, randomized clinical

 24   trial of 200 patients.

 25             DR. GAN:  I think you are right.  That is 

                                                               179

  1   why we are still using Ringer's lactate.  I think

  2   it is important to notice that that is part of the

  3   coagulation picture.  We know that Ringer's lactate

  4   tends to cause hypercoagulation postoperatively,

  5   and that has been shown for many years.

  6             One aspect which I think was pointed out

  7   earlier is that in that study they also looked at

  8   postoperative outcome in terms of incidence of

  9   edema and how long they stayed in the hospital.

 10   What they found is that patients who received

 11   lactated Ringer's had a significantly high

 12   incidence of edema, nausea and vomiting, probably

 13   because of gut edema.  So, you know, you always

 14   have to trade the pluses and minuses.

 15             DR. DIMICHELE:  Actually, Dr. Hollinger

 16   asked my main question, but in looking at the

 17   data--you went through it very quickly and I was

 18   trying to kind of keep up with you, but what was

 19   very interesting in your Hextend-albumin comparison

 20   studies is that, certainly, there was a trend

 21   toward there being lower values in everything that

 22   you measured in Hextend compared to albumin, and

 23   you said it wasn't statistically significant, but

 24   if you look at, for instance, platelet

 25   counts--again, I don't know exactly what is not 

                                                               180

  1   statistically significant, the level or the

  2   decrease; I am not exactly sure what you were

  3   referring to, but if you actually look at the level

  4   of platelet count at the end of surgery with your

  5   Hextend, it is about 100,000 which is getting very

  6   close to the level for platelet transfusion,

  7   whereas it wasn't for albumin.  Certainly, the

  8   trends are there.

  9             DR. GAN:  I certainly would be happy to

 10   comment on that.  You will also see that the

 11   Hextend patients actually started off with their

 12   platelets lower as well.

 13             DR. DIMICHELE:  Yes, I know.  But you are

 14   saying there are no differences.  That is why I am

 15   saying I don't know what is not statistically

 16   different in terms of the level.  The other thing

 17   about coagulation is that there are no absolutes

 18   here.  It depends on what the level you end up at

 19   is.  In other words, if you start out with a

 20   slightly lower platelet count the question is would

 21   you use Hextend.  That is my question to you.  I

 22   mean, given the drop in platelet count, if a

 23   patient goes into surgery with a slightly lower

 24   platelet count, given that the platelet counts that

 25   we ended up with were lower, would you do that? 

                                                               181

  1             DR. GAN:  Let me give you my perspective.

  2   Just to answer the previous question, the important

  3   point to note also is that the Hextend patients on

  4   average received about 500 cc, 600 cc more Hextend

  5   compared to albumin patients.

  6             DR. DIMICHELE:  Yes, I saw that.

  7             DR. GAN:  So, I think that may also be an

  8   effect, which I think is an important

  9   consideration.

 10             DR. DIMICHELE:  Well, that was one of my

 11   questions as well because if the colloid advantage

 12   is the same for both, why did they?

 13             DR. GAN:  I think because Hextend, we

 14   know, is a larger molecule and I think it stays

 15   within the intravascular space for a longer period

 16   of time compared to albumin.  The average molecular

 17   weight of Hextend is about 450, as we know, whereas

 18   the albumin is only 50,000.  So, I think for those

 19   long procedures that may be the reason why one

 20   received more than the other.

 21             To answer your second question about

 22   whether I would use Hextend in a patient with low

 23   platelets to start off with, I do a lot of liver

 24   transplant and now I use exclusively Hextend for my

 25   liver transplant.  Yes, I do use Hextend and I use 

                                                               182

  1   Hextend exclusively.  I used to use albumin for

  2   liver transplant.

  3             DR. DIMICHELE:  May I ask one more

  4   question?  In the comparison study between Hextend

  5   and the other product, you said that basically the

  6   differences you found in the two products were

  7   mainly in the red blood cell transfusion group.  Is

  8   that correct in terms of bleeding, etc?  Not

  9   bleeding, but the differences that you did mention

 10   were in the packed red cell transfusion group.  The

 11   question is that whole study had 120 patients, how

 12   many of those patients were in the subgroup that

 13   you went on to analyze in which you found the

 14   greatest differences?

 15             DR. GAN:  Yes, there were trend

 16   differences if you look at the overall comparison.

 17   I mentioned that the red cell transfused group,

 18   which formed about 35, 36 percent of the overall

 19   population, did show statistical significance not

 20   only in blood loss but also in the red blood cells

 21   transfused.

 22             DR. DIMICHELE:  Right, that is what I was

 23   trying to get at.  They represented 36 percent of

 24   the total group.

 25             DR. GAN:  Right. 

                                                               183

  1             DR. SCHMIDT:  There was a point that

  2   wasn't answered before Dr. Gan made his thorough

  3   presentation.  That is, if the manufacturer of one

  4   product voluntarily wants to put a warning label on

  5   his product, it seems to me it is sort of an

  6   administrative decision on the part of the FDA as

  7   to whether this other product has to have it also.

  8   They are the people who decided that they both have

  9   to have the same package information.  If that is

 10   the case, it probably doesn't relate to this

 11   committee.  You didn't ask us that question.  But

 12   if one wants to do it voluntarily and the other one

 13   doesn't, why can't they have two separate package

 14   inserts?  I don't know that this committee is the

 15   place to answer that question.  So, does the FDA

 16   have an answer for that?

 17             DR. WEINSTEIN:  I think that depends on

 18   the information that is received by the FDA as to

 19   how we would label the product.  Perhaps the

 20   industry would like to comment on where this

 21   information is with regard to the FDA, the

 22   information that you have presented to us.

 23             DR. GAN:  With regards to--I am sorry, is

 24   that a question directed to me?

 25             DR. WEINSTEIN:  Yes. 

                                                               184

  1             DR. GAN:  Maybe the industry people can

  2   better answer that question.  I am here to present

  3   to you the data that I have.

  4             DR. WEINSTEIN:  Well, we have to evaluate

  5   the information that is presented to the FDA.

  6             DR. GAN:  You mean in terms of the

  7   availability of that information?

  8             DR. WEINSTEIN: No.

  9             DR. NELSON:  I think that the FDA might

 10   still be involved in that because although the

 11   industry would say that they voluntarily put this

 12   or that label on it, I think the FDA would have to

 13   approve--

 14             DR. WEINSTEIN:  Yes, we have to review

 15   data and approve--

 16             DR. NELSON:  --review whatever labeling

 17   was done.  So, you know, we don't take the FDA out

 18   of the loop by voluntary labeling by industry.

 19   Isn't that right?

 20             DR. WEINSTEIN:  Right.  But it is

 21   dependent on data that we receive--

 22             DR. NELSON:  Yes, exactly.  You have to

 23   evaluate the basis for a label or a non-label.

 24   That is why we are here.

 25             DR. WEINSTEIN:  That is right. 

                                                               185

  1             DR. FALLAT:  I take it the FDA has not

  2   received this data formally yet.  Is that right?

  3   Is that what you are saying?

  4             DR. WEINSTEIN:  It is appropriate for the

  5   company to comment on that.

  6             DR. BERMAN:  Keith Berman, Health Research

  7   Associates.  My specialty area is blood products

  8   and biotherapeutics market research and clinical

  9   development.  I have a few points.

 10             DR. NELSON:  You are with Biotime?

 11             DR. BERMAN:  I am here, retained by a

 12   major distributor of plasma products.

 13             DR. NELSON:  We wanted somebody from

 14   Biotime to speak.  They don't have to.

 15             DR. CHAMBERLAND:  While the sponsor is

 16   coming to the mike, I need a point of

 17   clarification.  What is the relationship between

 18   Biotime and Abbott?  We got similar but different

 19   packets of data from Abbott and Biotime and I am

 20   unclear about how the two are related.

 21             DR. WAITZ:  Biotime is the holder of the

 22   NDA and Abbott Laboratories is our manufacturer and

 23   distributer.  So, we work together.  We license

 24   Hextend to Abbott.

 25             DR. CHAMBERLAND:  So, who is the sponsor? 

                                                               186

  1             DR. WAITZ:  Biotime.  Biotime is the NDA

  2   holder.

  3             MR. WANGELIN:  I just wanted to make one

  4   point of clarification for the record.  Abbott is

  5   not at this point seeking any package insert label

  6   revisions for the Hextend product.

  7             DR. WAITZ:  As the NDA holder, Biotime is

  8   not asking for any label change.

  9             DR. NELSON:  I know you are not.

 10             [Laughter]

 11             DR. WAITZ:  I just wanted to make that

 12   clear.

 13             DR. LEW:  I just wanted to get back to the

 14   study.  I didn't get the number of patients that

 15   were enrolled in your prostate/kidney study that

 16   did show kind of a trend with Hextend having more

 17   increased PTT and lower von Willebrand Factor.

 18             DR. GAN:  It was a 30-patient study.  So,

 19   it was a relatively small study.

 20             DR. LEW:  that may be why you don't have

 21   the N.

 22             DR. GAN:  Right, correct.

 23             DR. LEW:  With a small study like that,

 24   the trend looks kind of interesting--

 25             DR. NELSON:  Even in the larger one where 

                                                               187

  1   there were 120, that would be 30 in each arm.

  2   Right?

  3             DR. GAN:  No, 60 in each arm.

  4             DR. HOLLINGER:  I think, Ken, all this is

  5   important information because it gives us a broader

  6   view of the two, but I think the committee has been

  7   asked a very focused question with regard to

  8   cardiac bypass surgery with these two agents and

  9   the information does give us a global view of the

 10   things.

 11             DR. CHAMBERLAND:  That is a nice segue.  I

 12   was actually focusing on your two cardiac surgery

 13   studies that you presented, and I had a couple of

 14   questions.  The first cardiac surgery patient study

 15   with 200, and a lot of this went by very quickly so

 16   I am trying to catch up here, there were four arms.

 17   How many patients were in each arm?

 18             DR. GAN:  Sixty patients in each arm.

 19             DR. CHAMBERLAND:  Did you assess

 20   comparability in each of the arms in terms of

 21   preop. characteristics and what differences were

 22   found, and also intraoperative characteristics like

 23   cross-clamp, time on pump, etc.?  I am assuming

 24   that is going to be very difficult in the kind of

 25   format that we have, but these are the kinds of 

                                                               188

  1   details that I think need to be made available to

  2   make a truly informed decision.

  3             DR. GAN:  Absolutely.  I think that is a

  4   very important question.  But in view of the time,

  5   I wasn't able to present all the data.  Suffice it

  6   to say that there was no difference in the

  7   intraoperative as well as preoperative on

  8   hemodynamics.  There was no difference in renal

  9   function.  There was no difference in coagulation,

 10   to start off with.

 11             DR. NELSON:  To follow-up on that, I think

 12   the question I think Mary asked, which was a good

 13   one, is the pump time and the cross-clamp time.

 14   Those are two questions that I think you didn't

 15   answer.

 16             DR. GAN:  Again, I believe they were

 17   similar.  There was no difference.

 18             DR. CHAMBERLAND:  So, we have to be

 19   provided data in detail for each factor or

 20   characteristic that was examined.

 21             DR. NELSON:  Yes, because I think even in

 22   the earlier published study, even though the

 23   conclusion was that they were the same, they

 24   weren't the same.

 25             DR. STUVER:  Can I follow-up on that?  I 

                                                               189

  1   think we do need to look at the data because if you

  2   only have 50 in each group, even if they are

  3   different they are probably not going to be

  4   statistically significant because the sample size

  5   is so small.  So, it is nice to see the data so you

  6   can get a feel for it.  I mean, you can't just say

  7   they are not different because they are

  8   statistically significantly not different; you need

  9   to look at the data.

 10             DR. GAN:  I would agree wholeheartedly.  I

 11   believe the information is available.  I believe

 12   this article has been accepting; I think it is

 13   pending publication.  So, this information should

 14   be available.

 15             DR. NELSON:  Also some details about the

 16   randomization are important.

 17             DR. CHAMBERLAND:  It would be helpful.

 18             DR. GAN:  I think you bring up a very good

 19   question.  I think this study, which I consider is

 20   truly randomized because to each of the fluids a

 21   dye was added, which makes it look tinged yellow,

 22   very similar to albumin.  So, from the point of

 23   view of looking at color, obviously, the

 24   differences in viscosity as well as the color, it

 25   was as truly randomized as it could possibly be. 

                                                               190

  1             DR. CHAMBERLAND:  One other question, the

  2   outcome measurements that you provided for this

  3   randomized, four-arm trial of 200 did not include

  4   postoperative blood loss in terms of rate, cc per

  5   hour or volume measured in chest tubes at certain

  6   intervals, and in the literature that was discussed

  7   in great detail by the FDA that was an important

  8   factor that emerged in some of these retrospective

  9   case-control studies.  Can you tell us any

 10   information about not estimated blood loss but

 11   actual measured postoperative loss in each of the

 12   arms?

 13             DR. GAN:  I haven't looked at this study

 14   for a little while.  I know there was information

 15   on chest tube drainage postoperatively.  I just

 16   cannot quote you the number, but I believe that it

 17   was measured.  But I think I did present to you the

 18   intraoperative blood loss.

 19             DR. CHAMBERLAND:  It was mentioned

 20   descriptively in the second study as no difference

 21   in chest tube output, but obviously the big issue

 22   with that second study is that it is 28 patients.

 23   So, it is clear that we need more detailed

 24   information.  Certainly, FDA will need that as

 25   well. 

                                                               191

  1             DR. GAM:  Sure.

  2             DR. NELSON:  Question?

  3             DR. PIERCE:  Yes, Ross Pierce, FDA.  I am

  4   a little bit confused because we have been talking

  5   about details of these studies and I thought the

  6   question asked earlier was if the details of these

  7   studies had been submitted to FDA; essentially, has

  8   a final study report for any of these studies been

  9   submitted to FDA, and I heard Dr. Weinstein say

 10   that it would be appropriate for the sponsor to

 11   comment on that, and there was some confusion among

 12   the committee members as to who the sponsor was.

 13   It was clarified that that was Biotime.  We heard

 14   Biotime speak but I just want to make sure I didn't

 15   have an absence moment because I didn't hear the

 16   question answered that the committee seemed to be

 17   interested in as to whether the details of these

 18   studies, including the raw data, in a final study

 19   report had been submitted to FDA.  So, I just

 20   wanted that clarified for the record.

 21             DR. BAKER:  May Baker, Abbott

 22   Laboratories.  The study by Dr. Bennett-Guerrero

 23   was an investigator-initiated study.  We do not

 24   have the raw data.  That paper has been submitted

 25   for publication.  We don't have the manuscript and 

                                                               192

  1   the committee does not have the manuscript either,

  2   but that is an investigator-initiated study.  The

  3   abstract of that study is available on the ASA

  4   website.

  5             DR. SIMON:  So, the answer is no.  Is that

  6   right?

  7             DR. HARVATH:  The data has not been

  8   submitted to FDA?  Is that your answer?

  9             DR. BAKER:  The data has not been

 10   submitted to FDA.  Dr. Bennett-Guerrero is in

 11   possession of the data.

 12             DR. HARVATH:  Thank you.

 13             DR. NELSON:  If there is nothing else

 14   pressing, I would like to move on.  Dr. Shaugnessy?

 15             DR. SHAUGNESSY:  For what it is worth, I

 16   may be going into a lot of the questions that you

 17   just asked concerning that second study.

 18             Good afternoon.  My name is Dr. Thomas

 19   Shaugnessy, and I am an associate clinical

 20   professor of anesthesia and perioperative care at

 21   UCSF Medical Center in San Francisco.

 22             [Slide]

 23             I would like to discuss two topics with

 24   you today that I feel would be of interest,

 25   definitely of interest to the committee.  The first 

                                                               193

  1   that I would like to discuss deals with a recently

  2   published clinical study that deals with the exact

  3   issues that you are having in question today.

  4   Second, I am going to review some of our clinical

  5   experience at UCSF in reference to the use of

  6   Hextend as a substitute for albumin.

  7             [Slide.]

  8             The first study that I would like to

  9   present, that I would like to refer to was recently

 10   published in Anesthesiology in 2001.  It is an

 11   unsponsored, randomized, prospective clinical trial

 12   that addresses the use of albumin compared with the

 13   use of Hextend as a plasma-volume expander in the

 14   perioperative period after cardiac surgery.

 15             In an effort to limit the potential bias

 16   that can be introduced by the patient population,

 17   it was decided to eliminate from study those

 18   patients who had re-do procedures, those patients

 19   who were on anticoagulant therapy at the time as

 20   well as those patients who had any renal or hepatic

 21   dysfunction.  I think we have gone through exactly

 22   why some of those issues, in terms of patient

 23   population characteristics, can impact on

 24   retrospective studies.

 25             In any case, the major outcome 

                                                               194

  1   measurements for this study were thromboelastogram

  2   data which has been considered an excellent in vivo

  3   method of monitoring the coagulation cascade and

  4   the integrity of that cascade as well as monitoring

  5   more clinical parameters such as perioperative

  6   hemorrhage as monitored by chest-tube output for

  7   this specific patient population.  In addition,

  8   blood-product utilization was also monitored.

  9             [Slide.]

 10             Twenty-eight patients were taken into

 11   consideration for this study.  They were randomized

 12   into groups of fourteen.  One group received

 13   exclusively 5 percent albumin as the sole colloid

 14   plasma-volume expander in the perioperative period.

 15   The other group received Hextend for the same

 16   purposes and it was done according to a certain

 17   protocol with parameters for central-venous

 18   pressure and blood pressure.

 19             [Slide.]

 20             These patients, as you can see in some of

 21   these results, are relatively well-matched in terms

 22   of age, sex, the amount of time spent on

 23   cross-clamp as well as cardiac-bypass time and the

 24   amount of colloids given, colloids transfused.

 25             It should also be mentioned that they were 

                                                               195

  1   also the same in terms of preoperative hematocrit

  2   as well as thromboelastogram characteristics.

  3             [Slide.]

  4             To make a long story short, essentially

  5   this study showed no significant differences in

  6   terms of intraoperatively or on postoperative Day 1

  7   in terms of the pre- and postoperative hematocrits,

  8   the thromboelastogram data, or the blood-product

  9   utilization.

 10             [Slide.]

 11             I am going to go into a little bit of

 12   detail in terms of what some of these graphics look

 13   like for these various, albeit negative, studies.

 14   As you can see, the preoperative hematocrits were

 15   about the same in both study groups.  The

 16   preoperative hematocrit was about the same in both

 17   study groups and the postoperative hematocrits were

 18   slightly lower but comparable in both study arms.

 19             [Slide.]

 20             I think probably one of the most

 21   compelling aspects of this negative study is in the

 22   thromboelastogram data because the study was

 23   sufficiently powered to detect relatively small

 24   differences in thromboelastogram resolution.  In

 25   this particular example, the R times, which 

                                                               196

  1   represent the initial clot formation show that,

  2   from the pre-bypass period to the post-bypass

  3   period and all the way into the first postoperative

  4   day, there is no real difference between the 5

  5   percent albumin-treated and the Hextend-treated

  6   patients in both study arms.  Once again, there are

  7   no significant differences.

  8             Also, in terms of the K time which is the

  9   monitor of the rate of clot formation; once again,

 10   no significant differences in the post-bypass

 11   period or the first postoperative day.  However,

 12   you can see a particular trend, in terms of an

 13   upward trend, at the post-bypass period but it

 14   tends to be the same in both the albumin group as

 15   well as in the Hextend-treated patients.

 16             This was felt to be partially due to the

 17   fact of hemodilution which is probably an

 18   under-accounted-for aspect in terms of

 19   perioperative hemorrhage in a lot of patients but

 20   hemodilution may account for the fact that the K

 21   times have increased here.  But they certainly do

 22   return to normal by the first postoperative day.

 23             Finally, the maximum amplitude, on the

 24   next slide, which is a marker of the overall clot

 25   strength as well as platelet function, that tends 

                                                               197

  1   to show that, once again, there are no significant

  2   differences in the post-bypass period or the first

  3   postoperative day for either study arm.

  4             [Slide.]

  5             In terms of a little more clinical marker

  6   such as perioperative hemorrhage, that is monitored

  7   by the chest-tube output for this particular

  8   patient population.  We are actually able to get

  9   quantitative numbers in this particular patient

 10   population about their perioperative hemorrhage.

 11             For this group, what you can see is that,

 12   for every stage of their recovery period, there are

 13   no real differences in perioperative hemorrhage

 14   between the 5 percent albumin patients as well as

 15   the Hextend-treated patients.

 16             [Slide.]

 17             In terms of blood-product utilization,

 18   this study was slightly underpowered to detect any

 19   meaningful differences in blood-product

 20   utilization.  However, it should be noted that,

 21   while 20 patients in the albumin-treated group

 22   required red-cell transfusions, only eight units

 23   were required in the Hextend-treated patients.

 24             Also, it should be noted that, in this

 25   study, there was no significant morbidity or 

                                                               198

  1   mortality associated with the use of either of

  2   these agents in either study arm.

  3             [Slide.]

  4             In my role, and this is more an anecdotal

  5   topic, this is the second point I would like to

  6   make--in my roll as the Vice-Chairman of our

  7   Pharmacy and Therapeutics Committee at UC, we

  8   undertook the approval of Hextend in our formulary

  9   for the use of supplementing our use of albumin

 10   which, back in 1999, had reached the level of about

 11   9,000 units a year.

 12             We are an academic tertiary-care center so

 13   we do a heck of a lot of liver work as well as

 14   transplants.  As you can see from the demographics

 15   that we have, we spent most of our albumin on the

 16   transplant population but we also have a relatively

 17   significant portion being used in our cardiac

 18   population as well as in our major spine surgery,

 19   in our Orthopedics Department.

 20             [Slide.]

 21             We actually undertook a major initiative.

 22   What we did is we place Hextend in our operating

 23   room right next to the albumin and actually

 24   promoted its use, through an educational effort,

 25   basically bringing clinicians' awareness of the UHC 

                                                               199

  1   guidelines, University Hospital Consortium

  2   guidelines, which state that hetastarch should be a

  3   preferred plasma-volume expander in the

  4   perioperative period--in most cases, that is a

  5   first-line or second-line agent--as opposed to

  6   albumin which tends to be reserved as a second-line

  7   or third-line agent.

  8             So, with that educational effort underway,

  9   the Hextend being placed in the hospital formulary

 10   and in the operating rooms, we actually then

 11   ubiquitously placed a requisition form throughout

 12   the operating rooms to just track our albumin use

 13   over time.

 14             What we found, at the end of a year of

 15   doing this, is that, before our intervention, where

 16   we were using 9,000 units a year, we actually

 17   decreased our albumin use to the point of about

 18   2,600 units of albumin a year.  The difference

 19   between those two, in terms of

 20   plasma-volume-expander usage, was made up, for the

 21   most part, with Hextend.

 22             [Slide.]

 23             This was a global, institutional change

 24   for us.  So it affected many different clinical

 25   service lines all at the same time.  When we looked 

                                                               200

  1   back at things, we looked at global clinical

  2   markers to assess the impact of this change on our

  3   clinical practice.

  4             One example of this is the use of our

  5   blood-product transfusions during those two years.

  6   As you can see, in our operating rooms, we actually

  7   noticed an increase in our case volume from 1999 to

  8   2000, just a modest increase.  But, actually, what

  9   we found out was--when we looked at the amount of

 10   the total blood products used in our OR, we

 11   actually saw a slight decrease in the total amount

 12   of blood products used.

 13             Actually, when we teased out the amount of

 14   packed red blood cells that were being used, we

 15   found also a slight decrease in their red-cell

 16   transfusions.  Now, I am not going to hold this up

 17   to scientific rigors or anything, but our

 18   impression of it was that there was no real change

 19   in our transfusion requirements because of this

 20   change we made in terms of our colloid practices.

 21             [Slide.]

 22             In addition, when we looked at

 23   perioperative morbidity and mortality types of

 24   issues, we also found some surprising findings from

 25   one year pre-intervention to post-intervention.  In 

                                                               201

  1   one situation, we found that our CT surgery

  2   fast-track protocols were able to be employed a

  3   little more frequently, from about 10 percent

  4   before institution of this to about 30 percent

  5   afterwards.

  6             [Slide.]

  7             In addition, our admissions in our ICU for

  8   spine surgery tended to decrease from about 9

  9   percent to about 3 percent.  And, in addition, our

 10   average length of stay in our ICU actually

 11   decreased from about seven days down to five.  Once

 12   again, in essence, we found no real change in terms

 13   of our perioperative outcomes for any clinical

 14   marker that we could look at.

 15             [Slide.]

 16             So I think, in summary, it is becoming

 17   increasingly apparent that Hextend is at least

 18   probably clinically equivalent to albumin, at least

 19   in terms of in vivo coagulation studies,

 20   transfusion requirements as well as in

 21   cardiac-surgery clinical outcomes.

 22             I would like to thank the committee for

 23   its time and answer any questions.

 24             DR. NELSON:  Thank you very much, Dr.

 25   Shaughnessy. 

                                                               202

  1             We have a number of people that wanted to

  2   present for Abbott Labs.  One of the concerns I

  3   have is that, if we have four more presentations,

  4   we won't be able to get to a discussion.  I wonder

  5   if there are data that are different than what has

  6   already been presented that is relevant to the

  7   committee's charge.

  8             How many people have to leave at 1:30?  I

  9   don't want to cut your--this is a public forum.

 10   You are certainly welcome to testify.  But if it is

 11   too long, we may preclude looking at the issue.

 12             DR. WANGLIN:  Mr. Chairman, we have two

 13   remaining presentations.  I believe we can hit the

 14   high points, and they do present additional data.

 15             DR. NELSON:  Okay.  The first one is James

 16   Wanglin.

 17             DR. WANGLIN:  I am James Wanglin.

 18   Actually, Abbott Laboratories is being represented

 19   by Dr. Lew Kaplan and by Dr. Moskowitz.

 20             DR. KAPLAN:  Thank you for the opportunity

 21   to present.  I am a trauma surgeon.  I am an

 22   intensivist.  I am different from the

 23   anesthesiologists that you have heard present

 24   already and I am going to talk to you about trauma

 25   surgery but I am going to give you a different 

                                                               203

  1   background.

  2             This is about cardiac surgery.  I actually

  3   had cardiac last July.  The only fluid that I got

  4   for my bypass surgery was Hextend.  My blood loss

  5   was about 600 out of my chest tubes and I did just

  6   fine.  There is anecdote for you.

  7             DR. NELSON:  Obviously.

  8             DR. KAPLAN:  But I only had a 2 kilo

  9   weight gain.  They are terribly uncomfortable when

 10   they come out, let me tell you.

 11             Part of what you are going to hear today

 12   is the physiologic background for identifying that

 13   Hespan and Hextend are very different fluids.  They

 14   are markedly different in their characteristics and

 15   that is part of what I want you to embrace.  If I

 16   can actually get the slides to come up.  We are

 17   threatening to have them come up.

 18             I am at MCP Hahnemann University in

 19   Philadelphia but if you need me later, you will

 20   have to track me down at Yale because I am changing

 21   my job.

 22             How are we doing with the slides?  Let me

 23   start and we can go through a couple of these

 24   things quickly.  One of the things that is missing

 25   from a lot of these studies is acid-base balance 

                                                               204

  1   and how you control acid-base balance has got to be

  2   one of the most dry and boring topics, but it is

  3   absolutely essential to evaluating the differences

  4   between these two products.

  5             When you look at what controls the pH of

  6   pure water, you find that that pH is markedly

  7   different depending on the temperature at which you

  8   measure it.  That process is essential to acid-base

  9   balance, the process of water dissociation.  That

 10   is where all of your protons come from.  That is

 11   what controls the ultimate pH of your body.

 12             All of your enzyme systems, including your

 13   coagulation system which is a series of serine

 14   proteases have a maximum rate at which they work

 15   and they are pH-dependent.  So how we control pH

 16   and how we perturb it is just as important as which

 17   fluid we use because it is related to the fluid.

 18             You should remember that CO2 combines with

 19   water and makes carbonic acid.  Carbonic acid

 20   dissociates into a proton and bicarbonate.  The

 21   bicarb is handled by your kidney and your liver.

 22   You also have a set of buffers in your blood stream

 23   that are related to the proteins which are weak

 24   acids.  They exist either with or without a proton

 25   attached to them. 

                                                               205

  1             They are principally negatively charged

  2   most of which comes from albumin.  The histidine

  3   residues on albumin are what contributes this

  4   negative charge.  Lesser amounts come from

  5   phosphate and a smaller amount from sulfate.  This

  6   negative charge is balanced by a positive charge

  7   from things called strong ions.  Strong ions

  8   dissociate from their partners.

  9             There are strong cations like sodium,

 10   potassium, calcium and magnesium and there are

 11   negative ones like phosphate and lactate and

 12   sulfate.  The net negative on the proteins is

 13   balanced by the net positive from the strong ions.

 14   The relative difference in these two charges

 15   determines whether you dissociate water to generate

 16   a proton or not.

 17             The fluids that we use change the strong

 18   ion difference component of your plasma.

 19             Keep on going with the slides.  We will

 20   get up to where we are.

 21             DR. NELSON:  One of the issues, I think,

 22   is that what the committee is asked to look at is

 23   the label change with regard with to the

 24   coagulation and bleeding issue.  I realize--

 25             DR. KAPLAN:  This will be essential 

                                                               206

  1   understanding that because there is data--

  2             DR. NELSON:  If you could do it as quickly

  3   as possible and particularly focus on what the

  4   committee is--

  5             DR. KAPLAN:  It's coming.  Keep on going.

  6   One more.

  7             [Slide.]

  8             What we do with fluids is we frequently

  9   give fluids that are rich in chloride.  The body

 10   does have a compensatory mechanism which reduces

 11   phosphate and albumin and raises protons in order

 12   to restore balance.

 13             [Slide.]

 14             Hyperchloremia is bad for you and there

 15   are a lot of studies that show it.  If you use

 16   chloride-rich fluids in surgery, you can

 17   predictably increase your chloride and induce an

 18   acidosis.  So what?  Big deal.

 19             [Slide.]

 20             There has to be clinical relevance to it.

 21   Here it is.  I am going to take your blood and put

 22   it in a test tube and I am going to deliberately

 23   change the chloride concentration, raise it by 4

 24   all the way up to 20 milliequivalants per liter.  I

 25   am going to do it with 3 percent saline so I don't 

                                                               207

  1   use a lot and dilute the clotting factors or normal

  2   saline.

  3             Because the 3 percent saline functions

  4   like a colloid, I am going to give starch and

  5   saline, starch in a  balanced salt solution.  Watch

  6   what happens to pH.  Predictably, decreases in the

  7   3 percent group.  Same thing for the normal saline

  8   group.  Plateaus in these two groups.  It is not a

  9   starch effect.  It is a chloride effect.

 10             [Slide.]

 11             If we look at the strong ions, the

 12   arbiters of change in pH, we can see that the

 13   strong-ion difference decreases predictably in the

 14   high-chloride groups, is relatively flat in the two

 15   starch groups but something else unanticipated

 16   happens here.  You got unmeasured ions.  These are

 17   part of what is called the strong-ion gap which is

 18   well beyond this talk, but the induction of a

 19   strong-ion gap has been associated with increased

 20   mortality in liver patients and in trauma patients.

 21             [Slide.]

 22             That is bizarre.  All the fonts got

 23   changed.  This is looking at PT and PTT, gross

 24   arbiters, because I don't have a TEG.  In the 3

 25   percent group and the normal saline group, when I 

                                                               208

  1   raised the chloride up to 20 milliequivalents above

  2   where it started, predictable increases in

  3   prothrombin time and partial thromboplastin time.

  4   No change in the starches because they are given in

  5   small quantities.

  6             [Slide.]

  7             This allowed me to ask some easy

  8   questions.  Can I use starch in a balanced salt

  9   solution and have a clinical benefit, not a

 10   theoretical one?  The study that Dr. Haynes  said

 11   couldn't be ethically done is the one where you use

 12   Hespan because we agree that there are bleeding

 13   problems.

 14             I am going to focus on the patients who

 15   received starch in balanced salt solution well

 16   above what everyone  thinks will be a safe range.

 17   More than 25 cc's per kilo body weight per hour.

 18   Both of these studies are investigator-driven.

 19   This was part of our QA process.  They were not

 20   funded.

 21             Next slide.  Keep on going.  Keep on

 22   going.  I am going to tell you what this showed.

 23             [Slide.]

 24             Most of our patients were trauma patients,

 25   lesser amounts with sepsis and a small amount, the 

                                                               209

  1   lowest monitored patients were just there for

  2   postop fluid management.  In this group, they

  3   started off with a low pH with only Hextend

  4   resuscitation.  They cleared about 80 percent of

  5   their lactate.  They received almost 40 cc's per

  6   kilo bodyweight over the first twenty-four hours,

  7   well above what you would expect.  Improvements in

  8   pH.

  9             For this group, sepsis patients, about

 10   two-thirds of the lacate cleared consistent with

 11   hyperlactatemia.  Not much of a change in pH.  Same

 12   thing for the postop patients because they were

 13   pretty normal.

 14             [Slide.]

 15             What you are missing here are the two

 16   other groups of patients, but these are the trauma

 17   patients.  What you see here in pink is no change

 18   in coagulation profile and increase in coags more

 19   than 0.2 seconds in PT or PTT or a decrease.  The

 20   very patient population with hemorrhage, with holes

 21   in tissues, with inflammatory activation, we would

 22   expect a huge bolus of starch.  If it was the

 23   starch to have a problem, the coags got better.

 24             Only in 25 percent of these patients were

 25   on a massive transfusion protocol.  The rest were 

                                                               210

  1   not.  These patients that had an increase also had

  2   their chloride concentrations go up.  They had

  3   brain injury and we could not get the neurosurgeons

  4   to let go of the chloride.

  5             You will see that, in these other two

  6   groups, the major portions are no change in

  7   coagulation, no change at all.

  8             [Slide.]

  9             This was that same study that Dr. Gan had

 10   shown you.

 11             [Slide.]

 12             What you would have seen here is a giant

 13   bar that says this group that had the high chloride

 14   groups, the Hespan and normal saline, had a

 15   hyperchloremic metabolic acidosis.  This will be

 16   flat where they received Hextend and LR.  So there

 17   is an important profile difference between these

 18   two.

 19             [Slide.]

 20             There is a program called STORMACT,

 21   Strategies to Reduce Military and Civilian

 22   Transfusion.  This was driven by the Military, by

 23   Joint Special Operations Command that had a whole

 24   host of other people that contributed.  This came

 25   out of the Resuscitation Research Conference in 

                                                               211

  1   Bethesda.

  2             [Slide.]

  3             The Military is limited to FDA-approved

  4   plasma-volume expanders.  You see the list here.

  5   You have approved them.

  6             [Slide.]

  7             When we decided which fluid to use,

  8   because the soldiers currently carry saline or LR,

  9   they wanted less space, less weight, a repeatable

 10   dosing for fluids.  What we arrived at, in terms of

 11   safety, was starch.

 12             [Slide.]

 13             We created this fluid algorithm that you

 14   can't see terribly well but the central feature of

 15   it is hydroxyethyl starch in a balanced salt

 16   solution because of the trauma data that has been

 17   shown here and the difference in coagulation times

 18   that you get with hydroxyethyl starch in saline.

 19   They would not agree to use that.

 20             This fluid algorithm, those fluids, are

 21   currently in use by our Special Forces people so

 22   this has already been embraced.

 23             [Slide.]

 24             What this allowed us to do was to create

 25   an algorithm for fluid resuscitation, transfusion 

                                                               212

  1   using things like hemoglobin-based oxygen carriers.

  2             Factor VII, VIII for clotting.

  3             Cytokine manipulation for antioxidants and

  4   cell repair.

  5             [Slide.]

  6             But the central core is the fluid

  7   resuscitation.  The safety of this kind of a fluid,

  8   in terms of coagulation, resuscitation and absence

  9   of coagulopathy sets this apart from everything

 10   else that you have heard and, thankfully, everyone

 11   else presented that data that said starch and

 12   saline is bad.

 13             I would encourage you to think about this

 14   as you review your warning indication, that the

 15   warning is not molecule-specific but carrier

 16   specific because there are valid clinical

 17   difference between the two.

 18             So thank you for bearing with the very

 19   abnormal slides.   I will be happy to take

 20   questions.

 21             DR. NELSON:  Dr. Moskowitz is next.  Would

 22   it be possible for you to do it in five minutes?

 23             DR. MOSKOWITZ:  My name is David

 24   Moskowitz.  I am over at Englewood Hospital and

 25   Medical Center over in New Jersey. 

                                                               213

  1             [Slide.]

  2             What I wanted to start with, essentially

  3   the first slide shows that, in 1994, the New Jersey

  4   Institute for the Advancement of Bloodless Medicine

  5   and Surgery was formed at Englewood Hospital.  We

  6   have become a very worldwide referral center for

  7   blood-management cases.  We perform about 225

  8   noncardiac cases per year that require our services

  9   and that are associated with major blood loss.

 10             These cases, on average, have a

 11   transfusion rate at our hospital of about 10

 12   percent.  These include prostates, hips, knees.  It

 13   is much higher in the general population.

 14             [Slide.]

 15             Just to show how effective it is, the

 16   arrow is 1994.  As you can see, there is a steady

 17   decrease.

 18             [Slide.]

 19             We have had a 50 percent drop since the

 20   Year 2000 in packed red-blood-cell units in the

 21   total hospital based on our program.  As a matter

 22   of fact, the operating room uses less than 5

 23   percent of the total hospital blood supply per year

 24   in blood products.  Most hospitals use somewhere

 25   around 70 to 90 percent.  Barring we don't do liver 

                                                               214

  1   surgery, it is still a significant number.

  2             [Slide.]

  3             In the Year 2000, this is where I came in,

  4   we were granted the certificate of need to perform

  5   cardiac surgery.  It was based on that we can

  6   create a model center for the research regarding

  7   blood conservation and cardiac surgery.  To date,

  8   we have done 452 cardiac cases.  That is not just

  9   CABG or bypass and valve and a combined.  It has to

 10   do with aortic procedures, ascending, descending,

 11   which are very high-risk cases.

 12             [Slide.]

 13             As you know, blood conservation requires a

 14   bunch of techniques, not just one or two techniques

 15   and not just one person involved.  It is

 16   multimodality and multidisciplinary.  In addition

 17   to the standard, what most places don't do is what

 18   we do.  We use on-site, lab-guided transfusion

 19   therapy.  That is the thromboelastogram we have

 20   alluded to in addition to heparin concentration on

 21   bypass.  So we can rule out other causes of

 22   bleeding that are often missed in these other

 23   studies in addition to the standard lab tests.  We

 24   combine them altogether to come up with a plan.

 25             We also perform acute normovolemic 

                                                               215

  1   hemodilution.  I will show you in a second.  And we

  2   tolerate anemia.

  3             [Slide.]

  4             This is acute normovolemic hemodilution.

  5   The patient comes to the operating room.  We remove

  6   a significant amount of blood.  We store it next to

  7   the patient.  The patient tolerates the procedure

  8   anemic but normovolemic.  At the end of bypass, we

  9   give them the blood back.  Removing the blood

 10   allows you to lose dilute blood and, in addition,

 11   you also prevent that blood from being exposed to

 12   the negative effects of bypass.

 13             [Slide.]

 14             Here is a case, a patient who underwent

 15   spine surgery.  Two-and-a-half liters of blood were

 16   removed.  The fluid of choice was hydroxyethyl

 17   starch in a balanced salt solution or Hextend.  The

 18   patient did not bleed afterwards.  This is a very

 19   high-risk scoliotic surgery where just scraping the

 20   spine can cause release of factors that can cause

 21   bleeding.  The patient didn't bleed, didn't require

 22   transfusion of any blood product.

 23             [Slide.]

 24             So, in order to tolerate our maneuvers

 25   during our cardiac surgery, you must be euvolemic 

                                                               216

  1   or normovolemic.

  2             [Slide.]

  3             That means you must have a normal

  4   circulating blood volume in order for this to be

  5   effective.

  6             [Slide.]

  7             What we use is we use colloids greater

  8   than crystalloids.  We use it for specific reasons.

  9   I know this topic has come up today, why don't we

 10   use more crystalloids.  I think it is a very simple

 11   answer.  There is data out there that there is

 12   probably better rheology with the colloids than the

 13   crystalloids in the microcirculatory level and

 14   delivering oxygen to the tissue, to the cellular

 15   level.

 16             In addition, there is less third-space

 17   loss which is a common problem and that can

 18   increase the distance oxygen must travel to the

 19   tissue.  Also, there may be some evidence that

 20   increase in plasma viscosity may improve tissue

 21   oxygenation.  Therefore, by keeping the arterioles

 22   more open, you can deliver oxygen better.

 23             You also want to avoid crystalloid because

 24   you need more to attain more normovolemia.  You

 25   create an iatrogenic-induced anemia which can also 

                                                               217

  1   lead to a  coagulopathy which I think is a major

  2   problem in cardiac surgery.  This leads to

  3   inappropriate use of blood products.

  4             For all our cardiac cases, we use

  5   synthetic hydroxyethyl starch in a balanced salt

  6   solution.  We feel it is safe.  We don't feel there

  7   is any increased risk of bleeding and we also think

  8   it is lower cost than other colloids out there.

  9             [Slide.]

 10             Here is a paper that we presented in the

 11   Canadian Journal of Anesthesia.  This is cardiac

 12   surgery.  This is a gentleman, a Jehovah's Witness

 13   patient who underwent removal of renal-cell

 14   carcinoma that extended into his right atrium.  The

 15   incision goes from his sternum down to his pubis

 16   bone.  It is associated with a significant amount

 17   of blood loss, up to at least 5 to 9 units per case

 18   reported in the literature.

 19             This patient, we used hydroxyethyl starch

 20   in a balanced salt solution, 2 liters.  We didn't

 21   need any more because we also do acute normovolemic

 22   hemodilution.  The patient received no blood, no

 23   blood products and left ten days after the

 24   hospitalization.

 25             [Slide.] 

                                                               218

  1             We have alluded to this study by Dr.

  2   Bennett-Guerrero.  It is an abstract.  What we find

  3   is that it corroborates with our clinical beliefs

  4   that the hydroxyethyl starch in a balanced salt

  5   solution is equivalent to albumin with respect to

  6   blood products, percentage of patients being

  7   transfused these blood products, and the

  8   reexploration for bleeding while the hydroxyethyl

  9   starch in normal saline has a higher incidence of

 10   transfusion and the lactated Ringer's has a lower

 11   incidence.  We don't use solely lactated Ringer's

 12   for the reasons I mentioned before.

 13             [Slide.]

 14             Let me just give you our data.  I looked

 15   at only CABG--valves and CABG valves.  These are

 16   the heart cases that have been reported in the

 17   literature.  We have done a total of 359 cases.

 18   There is how they are split.  Most of them are

 19   bypass that require just grafting.  Others are

 20   valves and CABG valves.

 21             The age is a very respectable 70 years of

 22   age.  They are elderly patients.  The reoperation

 23   rate; these people present for their second and

 24   third heart operations or even one person who had

 25   their fourth heart operation is 10 percent. 

                                                               219

  1             The Parsonnett score--that is a risk

  2   score--it is an overall general score--is 17 which

  3   is a moderate risk to this patient population.  In

  4   addition, the bypass time is two hours which is

  5   very respectable.

  6             [Slide.]

  7             We use the hydroxyethyl starch in a

  8   balanced salt solution for all the cases requiring

  9   colloid.  We use anywhere from 500 to 2 mls

 10   intraoperatively and we keep using it

 11   postoperatively.  Coagulopathies; we rarely see

 12   coagulopathies.  This is because we have on-site

 13   coagulation monitoring that includes not only the

 14   thromboelastogram but also the heparin

 15   concentration.

 16             So if the surgeon sees that there is

 17   bleeding, what we do is we go back, make sure there

 18   is no residual heparin and we make sure that there

 19   is no abnormality on the thromboelastogram.  Most

 20   of the time, these tests show us that it is

 21   surgical or mechanical bleeding.

 22             Our average test-tube drainage is only 429

 23   mls in 24 hours.  That is lower than most reported

 24   studies.  Only two patients have come back for

 25   reexploration.  One of them had a surgical cause, 

                                                               220

  1   so we have only seen one out of 359.  There is a

  2   very low transfusion rate.  10 percent have

  3   received packed red-blood cells.

  4             DR. NELSON:  Could you summarize.  Your

  5   data are interesting, but we have seen it.

  6   Otherwise, we are not going to be able to discuss

  7   the question.

  8             DR. MOSKOWITZ:  Okay.  The summary is

  9   basically we are a blood-conservation institution

 10   and we use hydroxyethyl starch in a balanced salt

 11   solution without reservation.

 12             We might as well go to the last slide.

 13             [Slide.]

 14             There is no significant relationship

 15   between the amount of Hextend and chest-tube

 16   drainage.  The r-squared  value is 0.02.

 17             [Slide.]

 18             Just to show the nation average versus

 19   ours.  We are much lower.

 20             [Slide.]

 21             So we use it, hydroxyethyl starch in a

 22   balanced salt solution.  It is our only colloid

 23   that we use.  No increased risk of bleeding.  I

 24   feel that you have to use transfusion-guided

 25   therapy on site, meaning all the tests that I have 

                                                               221

  1   mentioned.  We use in all cardiac and noncardiac

  2   cases including patients who are Jehovah's

  3   Witnesses where there is no blood bank and that

  4   they are high risk.  We use it without reservation

  5   and we recently added it as our prime in our bypass

  6   circuit.

  7             DR. NELSON:  Thank you.  It is very

  8   impressive.  My secretary is a Jehovah's Witness

  9   so, if she needs surgery, I will send her to you.

 10             The last person, Keith Berman.  Is he

 11   here?  If he is here, I wonder if you can limit

 12   your remarks to under five minutes.

 13             DR. BERMAN:  Thank you very much for

 14   inviting me.  I wanted to speak about one subject,

 15   but while he is preparing the slides, I think that

 16   the comments I make reflect the comments of a

 17   number of anesthesiologists that I have spoken to,

 18   and surgeons.  I think that one thing with regard

 19   to these Hextend data--and, by the way, the one set

 20   I don't know anything about is the UCSF series by

 21   Dr. Shaughnessy.  I have never seen that before.

 22             In all the other studies I want to submit

 23   that, as opposed to issues concerning patient

 24   comparability and whether something is

 25   statistically significant, in the other studies 

                                                               222

  1   presented by Dr. Gan, I want to suggest that the

  2   study design, itself, is very seriously flawed in

  3   several of those studies and raises some serious

  4   questions.

  5             These are the views of a number of

  6   anesthesiologists that I have spoken with beginning

  7   with the Phase III trial in which conventional

  8   hydroxyethyl starch and saline were administered to

  9   patients in volumes of up to 5 liters.  In the

 10   literature, you will find a rare reference to

 11   anyone using more than 1,000 to 1,500 liters.

 12             In the second study, I just want to

 13   mention, involving the 47 patients randomized,

 14   these were elderly, geriatric patients who are

 15   already at risk for hyperkalemic acidosis.  The

 16   study design, I think it is worth noting, that

 17   Hextend is essentially, in essence, very, very

 18   similar to hetastarch--it is hetastarch in a base

 19   of lactated Ringer's.

 20             So, in clinical practice, it is very

 21   common, if not standard practice for many surgeons

 22   and anesthesiologists to take lactated Ringer's and

 23   hang it with hetastarch for some of the very

 24   reasons we have seen.  It is a source of calcium.

 25   It is lactated.  It buffers.  That is why the 

                                                               223

  1   lactated Ringer's was developed in the first place.

  2             What Dr. Gan and others did in that

  3   47-patient study was to take conventional

  4   hetastarch, which is 0.9 percent saline, and

  5   combine it with 0.9 percent saline and then they

  6   compared it against Hextend and lactated Ringer's.

  7             If you think for just a moment whether

  8   that makes sense, I think the study design, itself,

  9   essentially produces an answer that might be

 10   desired.  There is no calcium.  There are no

 11   electrolytes.  There is no buffering in hetastarch

 12   to begin with, so I am wondering if the study

 13   should not have been 6 percent hetastarch with

 14   lactated Ringer's versus Hextend and lactated

 15   Ringer's.

 16             DR. NELSON:  Actually, I am not sure that

 17   this was submitted officially to the FDA.

 18             DR. BERMAN:  No; this was just a--

 19             DR. NELSON:  So if you could proceed with

 20   your--

 21             DR. BERMAN:  Okay.

 22             [Slide.]

 23             I think, with respect to the studies on

 24   hetastarch, the retrospective studies, we looked at

 25   just the economics of what might happen just in 

                                                               224

  1   terms of red-cell transfusions.  As we know, there

  2   are a number of agents, the so-called oxygen

  3   therapeutics blood substitutes, whose primary

  4   endpoint is surgical blood avoidance.

  5             So avoiding red cells and other blood

  6   components is a worthwhile part.  What we did was

  7   we just looked at the number of U.S. cardiac

  8   surgery cases in 1999 from CDC sources.

  9   Altogether, there are just a little over 500,000

 10   adult cardiac surgeries in the U.S. between CABGs,

 11   valves and other procedures.

 12             It turns out that there are about 12

 13   million allogeneic red cells in the U.S. and about

 14   10 percent of them are devoted to cardiac surgery.

 15   Although there have been estimates that are much

 16   higher, we believe it is really closer to 10

 17   percent, not 15 to 20 anymore, for a bunch of

 18   reasons that we could talk about outside the

 19   meeting.

 20             [Slide.]

 21             There is a company called the Marketing

 22   Research Bureau which specializes in blood products

 23   and plasma-volume expanders and coagulation factors

 24   some of you may have heard of.  In late August,

 25   1998, a survey was conducted of 44 cardiac 

                                                               225

  1   anesthesiologists across the country.  It was

  2   determined that about half, taking these overall

  3   results, used hetastarch intraoperatively and/or in

  4   the cardiopulmonary bypass priming solution.

  5             It became more popular through the '90's

  6   for the reasons that some of the speakers talked

  7   about.  It was cheaper and particularly there were

  8   problems with albumin shortages in the early '90s

  9   that really drove a lot of hospitals in this

 10   direction.

 11             [Slide.]

 12             Looking at the Mayo Clinic findings which

 13   we feel very compelling because of some of the

 14   points that Dr. Haynes made earlier, it was simply

 15   a crossover trial, essentially, single surgeon,

 16   about 200-plus patients before, 200-plus patients

 17   after.  They were well-matched.

 18             I want to suggest that there was a small

 19   difference in degree of hypothermia of about 3

 20   degrees, but the literature has several references

 21   that suggest small hypothermic differences make no

 22   real difference in transfusions.  Otherwise, it is

 23   really hard to see any difference between these

 24   patients, single surgeon.  It is as pretty as they

 25   come. 

                                                               226

  1             Dr. Greg Nuttall, who is I think one of

  2   the most highly regarded people in this field,

  3   would defend that paper very vigorously in this

  4   meeting.  The findings from Mayo Clinic were that,

  5   on average, there was about half a unit of mean

  6   red-cell avoidance per case on the cases where they

  7   stopped using hetastarch and reverted to albumin

  8   for volume replacement.

  9             Using the assumption from the '88 report

 10   that about half of the cases are currently infused

 11   intraoperatively with hetastarch and the 500,000

 12   adult surgeries, it suggests that there are well

 13   over 100,000 units of blood that are transfused

 14   today that might not be transfused if this labeling

 15   were changed to reflect these findings.

 16             [Slide.]

 17             They also looked at platelet avoidance.  I

 18   guess now this committee is not charged with

 19   looking at economics but, just in terms of

 20   avoidance of donor blood and blood components, that

 21   is a worthwhile thing.  That works out to a little

 22   over 300,000 platelet concentrate units when you

 23   use the Mayo clinic data.

 24             DR. NELSON:  The committee actually has

 25   your handout so I wonder if you could summarize, 

                                                               227

  1   because I do want to get to the questions.

  2   Otherwise, the meeting will not be productive.

  3             DR. BERMAN:  Okay.  I tell you what.  That

  4   is essentially the same kind presentation that was

  5   done with that data.  The only last thing I need to

  6   do is to present the very last slide

  7             [Slide.]

  8             This is a statement that Dr. Curtis

  9   Tribble, who could not be here today--

 10             DR. NELSON:  The committee also has that.

 11   I think everybody has read it.

 12             DR. BERMAN:  Okay.  That's fine.

 13             DR. NELSON:  Thank you.

 14             DR. BERMAN:  Thank you.

 15             Questions, Discussion and Recommendation

 16             DR. NELSON:  Could we have the questions

 17   for the committee again?  Does everybody have the

 18   questions?  Toby?

 19             DR. SIMON:  It would appear that, with the

 20   hydroxyethyl-starch issue, or the

 21   hydroxyethyl-ethyl-starch-in-saline issue, that we

 22   have already had these--I don't know if it is a

 23   sole manufacturer but the manufacturer present a

 24   warning that has been submitted to FDA.  So I guess

 25   the answer to No. 1 would be yes and, hopefully, 

                                                               228

  1   taken care of with regard to that product.

  2             I guess there is going to be quite a bit

  3   of confusion in the committee in terms of how this

  4   relates to the other product which is in lactated

  5   Ringer's which wasn't analyzed for the committee in

  6   the same way, but it would appear that there is not

  7   the data there to support the bleeding risk.  It is

  8   the same molecule, but I guess we are being told

  9   that the chloride makes a difference.

 10             I think it is difficult to answer that

 11   question the way it has been presented here.

 12             DR. NELSON:  Jim?

 13             DR. ALLEN:  I concur.  I guess my

 14   suggestion would be to split the question with my

 15   answer being urge the FDA to follow Braun's

 16   suggested wording change which I, just on quick

 17   review, find to be quite acceptable given the data

 18   we have heard and I would, at this point, recommend

 19   no change in labeling for the other product.

 20             DR. NELSON:  Mary?

 21             DR. CHAMBERLAND:  My assessment of the

 22   morning and afternoon is that, instead of really

 23   being asked to vote on Question 1, my

 24   recommendation would be to ask FDA to consider the

 25   labeling change that had been presented to it by 

                                                               229

  1   Braun and to consider and review it.

  2             I feel that there were insufficient data

  3   provided to the committee and, by extension, I

  4   would assume, to FDA, for me to adequate evaluate

  5   the need for a warning statement labeling on the

  6   other version of this product.

  7             Also, the information that I have heard

  8   today makes me wonder if there are other issues

  9   besides excessive bleeding that need to be

 10   considered in the FDA evaluation of the need for

 11   warning labels.  We have heard some data about

 12   electrolyte issues and renal issues, et cetera, so

 13   I would put that forward as also something that

 14   needs to be considered.

 15             In regard to Question 2 and the need for

 16   additional trials to extend; I think we have heard

 17   testimony that it would probably be very difficult

 18   from a human-subjects point of view and the current

 19   sentiment among practicing physicians to conduct a

 20   clinical trial for hetastarch--for Hespan, whatever

 21   it is--but for Hextend, I think, before making a

 22   decision about the need for randomized trials, et

 23   cetera, again, I would go back and ask the FDA to

 24   review the data available or that can be presented

 25   to them by the sponsor because, clearly, some of 

                                                               230

  1   the data is not preliminary.  It hasn't been

  2   published.  It couldn't be shared in this public

  3   session.

  4             So I find myself actually really at a loss

  5   to be able to address these questions, at least the

  6   way they have been presented and, instead, am

  7   falling onto some other recommendations.

  8             DR. NELSON:  I have the same thing.  The

  9   numbers, if you look at the error bars, they are

 10   rather wide and whether or not the data are

 11   adequate at this point--I think they would need

 12   careful review, statistical analysis and

 13   comparability data which we didn't have, although

 14   it does look like the two products are different.

 15   But that is not what we were asked.

 16             So I guess we need some advice from the

 17   FDA.  One thing is we could modify the first

 18   question to say hetastarch, is the evidence for

 19   excessive bleeding in cardiac surgery patients who

 20   receive 6 percent hetastarch in saline, or

 21   Hexa--whatever it is--strong enough to warrant a

 22   warning label.

 23             Mark?

 24             DR. WEINSTEIN:  We would appreciate advice

 25   on that. 

                                                               231

  1             DR. NELSON:  So why don't we change that

  2   first--I think it is fairly clear from a number of

  3   studies, even though they are not randomized

  4   prospective trials, in the one trial that was a

  5   retrospective study that didn't seem to show a

  6   difference, there were enough differences in the

  7   patients that it looked like that group was exposed

  8   less to the pump and other things.

  9             DR. HOLLINGER:  And the company has

 10   agreed.

 11             DR. NELSON:  And the company has agreed,

 12   so I think we should support this.  So can we make

 13   that change, then?  Where is Dr. Landow?

 14             DR. LEW:  I just wanted to give more

 15   opportunity or expand FDA's opportunity to decide

 16   on the exact wording of the labeling because, even

 17   though the company nicely proactively suggesting

 18   some changes, they did mention in their proposal to

 19   add on, "However, the risk of bleeding diminishes

 20   rapidly."  I didn't see a whole lot of data that

 21   addressed that, so let's leave it open for FDA to

 22   decide what the wording should be but definitely

 23   the warning should be there.

 24             DR. NELSON:  I think that the FDA will

 25   decide on the wording in conjunction, perhaps, with 

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  1   advice from the company.  But, in fact, it is hard

  2   for a committee to do a warning label.  But I think

  3   what we are supposed to vote on is the principle,

  4   should there be one.

  5             So I would like to vote on this while we

  6   still have enough people here.  We will change

  7   the--

  8             DR. DiMICHELE:  Can I just make one

  9   comment?  I'm sorry.  Could we go over the wording

 10   for this because I think we are being asked two

 11   things; do we agree that the Hespan people should

 12   submit with their own concerns--with their own data

 13   and their own concerns, submit this labeling change

 14   to the FDA.

 15             But then, the way the question stands is

 16   do we think that there is enough evidence.  I think

 17   that I might not be able to vote in that regard if

 18   the question remains the way it is stated because I

 19   think, in both circumstances, I am not sure we have

 20   enough data to comment on that particular

 21   statement, at least I don't.

 22             So, if the question remains the same, then

 23   I may have to vote differently.  That's all.

 24             DR. NELSON:  You mean is there enough

 25   evidence. 

                                                               233

  1             DR. DiMICHELE:  Is there enough evidence

  2   is, I think, a very important--the question says,

  3   is there enough evidence.

  4             DR. HOLLINGER:  Can you rephrase, then,

  5   Question 1 for the vote?

  6             DR. NELSON:  My take on it is is the

  7   evidence for excessive bleeding in cardiac-surgery

  8   patients who receive 6 percent hetastarch in normal

  9   saline strong enough to warrant a warning statement

 10   in the hetastarch labeling.  If the committee

 11   agrees.  Do you want to vote on that change?  Does

 12   everybody agree with that?  How many agree?

 13             [Show of hands.]

 14             DR. NELSON:  How many disagree?  You may

 15   vote no, but--okay; so we have changed the question

 16   slightly.  Let's vote on the question, unless there

 17   are other comments.  We voted first on the change

 18   in the wording.  Now we are voting on the change in

 19   the question.

 20             Linda, do you want a hand vote or do you

 21   want to call people or what?

 22             DR. SMALLWOOD:  I wanted to read into the

 23   record the change in the question; is the evidence

 24   for excessive bleeding in cardiac-surgery patients

 25   who receive 6 percent hetastarch in normal saline 

                                                               234

  1   strong enough to warrant a warning statement in the

  2   hetastarch labeling?

  3             DR. ALLEN:  That would be hetastarch in

  4   saline labeling.

  5             DR. NELSON:  Yes.

  6             DR. SMALLWOOD:  I want to be clear.  The

  7   statement that Dr. Allen made--were you asking a

  8   question, or were you changing what I read.

  9             DR. NELSON:  No, no.  He was just

 10   clarifying.

 11             DR. SMALLWOOD:  Are you ready?

 12             DR. HOLLINGER:  But he did make that

 13   change from what you read, though.  He made sure

 14   that it said 6 percent hetastarch in normal saline

 15   and then, at the bottom part, in the hetastarch in

 16   normal saline labeling.

 17             DR. NELSON:  Or we could just say in the

 18   product labeling.

 19             DR. HOLLINGER:  In that product's

 20   labeling.

 21             DR. NELSON:  Right.

 22             DR. SMALLWOOD:  I am going to try again;

 23   is the evidence for excessive bleeding in

 24   cardiac-surgery patients who receive 6 percent

 25   hetastarch in normal saline strong enough to 

                                                               235

  1   warrant a warning statement in that product's

  2   labeling?

  3             DR. NELSON:  Yes.

  4             DR. SMALLWOOD:  I am going to have to do

  5   this by roll call, quickly.  Dr. Allen.

  6             DR. ALLEN:  Yes.

  7             DR. SMALLWOOD:  Dr. Chamberland.

  8             DR. CHAMBERLAND:  Abstain.

  9             DR. SMALLWOOD:  Dr. DiMichele.

 10             DR. DiMICHELE:  Abstain.

 11             DR. SMALLWOOD:  Dr. Lew.

 12             DR. LEW:  Yes.

 13             DR. SMALLWOOD:  Dr. McGee.

 14             DR. McGEE:  Yes.

 15             DR. SMALLWOOD:  Mr. Rice.

 16             MR. RICE:  Yes.

 17             DR. SMALLWOOD:  Dr. Fallat.

 18             DR. FALLAT:  Yes.

 19             DR. SMALLWOOD:  Dr. Harvath.

 20             DR. HARVATH:  Yes.

 21             DR. SMALLWOOD:  Dr. Hollinger?

 22             DR. HOLLINGER:  Yes.

 23             DR. SMALLWOOD:  Dr. Nelson?

 24             DR. NELSON:  Yes.

 25             DR. SMALLWOOD:  Dr. Simon, do you agree? 

                                                               236

  1             DR. SIMON:  Agree with the yes votes.

  2             DR. SMALLWOOD:  There were eight yes votes

  3   and two abstentions.

  4             DR. NELSON:  So that makes the second

  5   question moot in the sense that, if we are talking

  6   about this product.  The other issue is does the

  7   FDA want us to vote on anything or say anything

  8   about the other product, the Hextend, because,

  9   first of all, we weren't given--I mean, we were

 10   given data but it was sort of incomplete and not

 11   formally reviewed.

 12             DR. WEINSTEIN:  I think, actually, it

 13   would be valuable if we could have some comments on

 14   what we heard today regarding the Hextend if you

 15   would like to.

 16             DR. NELSON:  Blaine?

 17             DR. HOLLINGER:  I think, for the record,

 18   at least as I view it, there are definite

 19   differences between these two products as we see it

 20   with coagulation and, perhaps, even effects on

 21   changes in electrolytes and pH which may be related

 22   to the carrier rather than to the hetastarch.

 23             I think that there probably is less

 24   bleeding.  But I think that there does need to be

 25   additional information that has been brought up 

                                                               237

  1   here in regards to at least one of the larger

  2   trials as regards to pump time and cross-clamp time

  3   and things like this which need to be looked at.

  4   But I do not think it warrants any changing in the

  5   labeling of that product at the present time.

  6             We may come to a different conclusion

  7   later, but I did not see any data that seemed to

  8   suggest to me that there was an issue regarding

  9   bleeding or coagulation problems with this product.

 10             DR. NELSON:  I think so.  There were some

 11   trends in people perhaps that received larger

 12   amounts so that it would be good if the data from

 13   these trials were submitted to the FDA for review.

 14   I think the FDA might consider that given the fact

 15   that in one related product we are recommending the

 16   label change.

 17             DR. WEINSTEIN:  Do you think the FDA

 18   should require that this information be submitted

 19   for the labeling change?

 20             DR. NELSON:  Possibly.  We have heard one

 21   opinion at least that it was the hetastarch

 22   molecule-coating  platelets that was the problem.

 23   But we have also seen some comparative trials that

 24   suggest that there were real differences.

 25             DR. HARVATH:  I believe that if any 

                                                               238

  1   statements are made in terms of superiority claims

  2   of a product or added benefits of a product that

  3   any such data must be submitted to the FDA before

  4   being allowed to make such claims.  I would trust

  5   the FDA's critical review of that data to determine

  6   whether any such statements could be used in any

  7   labeling.

  8             DR. NELSON:  I would agree.

  9             DR. HARVATH:  Or marketing.

 10             DR. CHAMBERLAND:  I think part of this has

 11   to fall back to the FDA because, as I understood it

 12   from FDA's previous comments, these were licensed

 13   as "comparable products."  If a labeling change is

 14   made in one, then it seems like they are not

 15   comparable products.  So I think the FDA needs to

 16   sort of consider the implications of that because I

 17   agree with Dr. Harvath that, de facto, one sort of

 18   has a superiority claim associated with it, or

 19   inferred, if you will.

 20             So I agree.  I think that FDA should

 21   require the sponsor to bring forth additional data

 22   to evaluate the Hextend product.

 23             DR. FALLAT:  I would take Question No. 2

 24   as being applicable to Hextend and, therefore, vote

 25   that we vote yes on Question No. 2 that there be 

                                                               239

  1   additional studies with regards to that product.

  2             DR. LEW:  I don't know about that only

  3   because I don't know what excellent studies may

  4   have already been done or are in press or about to

  5   be written up.  So I think we should allow the

  6   company the opportunity to bring forward all the

  7   studies that have been done and, if that suffices

  8   to FDA, fine.  But, if not, then we could revisit

  9   this.

 10             DR. FALLAT:  That's what I meant.  I

 11   wasn't saying, necessarily, to exclude the studies

 12   that have already been presented.

 13             DR. NELSON:  The FDA would--we are

 14   advisory.  We are not writing labels.  Thank god.

 15   But the FDA would have the option in both products,

 16   if they wanted to, to say a product containing

 17   hetastarch has been shown, in some studies, to be

 18   associated in some patients with excess bleeding,

 19   without--there are ways to nuance and wordsmith

 20   this, I think.

 21             But I agree.  I don't think, by

 22   implication of putting in the saline, that we are

 23   saying that we agree based on the data presented

 24   that the hetastarch in lactate is significantly

 25   different or safe or free of--it is just that the 

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  1   data we were submitted is somewhat convincing that

  2   there is some problem with the saline solution.

  3             DR. ALLEN:  I think where we are now, we

  4   are in the middle, really, of procedural questions

  5   and issues.  It is my understanding that the FDA

  6   can negotiate with Braun and come up with revised

  7   labeling but that any other already licensed

  8   product is off the table for consideration unless

  9   the FDA has evidence sufficient to go back to a

 10   company with a licensed product and require them to

 11   produce additional information.

 12             This committee has not indicated to the

 13   FDA in any way that there is sufficient evidence

 14   that the committee thinks that the FDA should do

 15   that.  So, unless the licenses chooses to bring

 16   forth additional information and submit it and

 17   request consideration of a labeling change, my

 18   guess is that there will not be further action on

 19   this unless the company--

 20             DR. NELSON:  The one way that they might

 21   is if they said, "Our product is superior to the

 22   other."

 23             DR. ALLEN:  Yes; and that is the company

 24   initiating it.  The FDA, similarly, could initiate

 25   if they think that there is a problem the other 

                                                               241

  1   way, but the committee hasn't supported them in

  2   that.

  3             DR. NELSON:  Exactly.  I agree.

  4             DR. ALLEN:  I guess I would like to hear

  5   if the FDA feels that they would like some

  6   direction on that to please give us guidance now.

  7             DR. HOLLINGER:  I don't think I heard

  8   anything by either of the sponsors here today that

  9   said one product was superior to the other in

 10   regards to its oncotic properties.  We heard a lot

 11   of things in regards to its effect maybe on

 12   bleeding or other things, but I don't think I saw

 13   any data or remember reading much data that

 14   suggested that one was any better than the other in

 15   terms of what it is really intended to be used for.

 16             I may be wrong.  Does anybody else

 17   remember anything about that?

 18             DR. NELSON:  I think we are still

 19   discussing warning labels which has to do with

 20   bleeding, not with oncotic problems.

 21             DR. HOLLINGER:  Yes; but someone

 22   mentioned, as a superior product.  I think it is

 23   important to say that--

 24             DR. SIMON:  The claim for superiority was

 25   based on lower side effects. 

                                                               242

  1             DR. NELSON:  It was based on less side

  2   effects.

  3             DR. HOLLINGER:  Okay.  But I think it is

  4   important to point out that they, at least for what

  5   they do, they seem to be--

  6             DR. NELSON:  Exactly; for the indication,

  7   there is no evidence that they are--

  8             MR. RICE:  I think there was clear

  9   implication, even though they didn't necessarily

 10   say it outright.  I think because we have already

 11   made a decision on one hetastarch product that I

 12   think that now they either have to--the Hextend has

 13   to prove their position or not at this point if

 14   they are going to consider these two products

 15   comparable.

 16             Making a new statement on a warning label

 17   for the hetastarch in saline, while the other

 18   product is a comparably approved product, kind of a

 19   Pandora's box has been opened to suggest that it is

 20   better, it is different, and that there is a

 21   question that I would think the FDA would want to

 22   have answered and then, at that point, decide

 23   whether they are going to recommend a change in

 24   their labeling.

 25             DR. CHAMBERLAND:  I guess part of it goes 

                                                               243

  1   back to comments that Dr. Lew made earlier on.  I

  2   guess it is just a point of information for the

  3   committee that we don't know.  I think you have

  4   alluded to the fact that, at least for antibiotics,

  5   you can have "comparable antibiotics," although you

  6   can have subsequently additional information

  7   provided about adverse events about an antibiotic

  8   that is considered comparable.

  9             So I don't know whether there is a direct

 10   applicability to this particular situation or not

 11   that you can have comparable product but one having

 12   a warning label about the potential for adverse

 13   events.  So I think that is what we are struggling

 14   with.  We don't really know under what sort of

 15   regulatory constraints you are under.

 16             DR. LEW:  If I can respond to that,

 17   although I agree that that is one issue, I do feel

 18   that we should make a motion to support FDA to ask

 19   the other company to submit some supporting data

 20   only because--I think Donna brought out some good

 21   points.  There was a trend, even with the Hextend,

 22   that there might be some platelet problems and

 23   there was the von Willebrand's factor that was much

 24   lower and just other little subtle things.

 25             So there may be data out there that the 

                                                               244

  1   company can just get and bring forward and that is

  2   good enough.  But I would like to know, myself, and

  3   I think it would be worthwhile to give FDA the

  4   opportunity to go get that data.

  5             DR. NELSON:  I think the FDA would look at

  6   the data that is submitted to them and if the

  7   company decides not to submit the data, then the

  8   hetastarch--our recommendation is with regard to

  9   hetastarch in saline because that is the main part

 10   of the detailed data that we were originally

 11   presented with.

 12             DR. LEW:  I thought I heard FDA say they

 13   were asking us saying we can ask the FDA, we can

 14   recommend, that Abbott or Biotime submit data and

 15   that, if we recommend that, they can ask.

 16             DR. NELSON:  Do you want us to vote on

 17   that, or just the discussion is good enough?

 18             DR. WEINSTEIN:  I think the discussion is

 19   probably good enough here.  You have, obviously,

 20   raised the issues here that we are going to have to

 21   wrestle with, the idea that these products were

 22   originally approved as being comparable both as far

 23   as safety and efficacy goes and now we are saying

 24   that the 6 percent hetastarch saline will have this

 25   warning statement on it that will differentiate it, 

                                                               245

  1   but we have heard today that there are potentially

  2   differences in efficacy, as I understand it.

  3             Are those legitimate labeling claims?

  4   That kind of information has to be submitted to the

  5   FDA for application to the label.

  6             DR. HOLLINGER:  But, Mark, if you would,

  7   please.  This all came about because there were

  8   several reports in the literature that suggested

  9   that Hespan had some bleeding problems.  And then

 10   you send a letter off to the company I think

 11   regarding something about that.  I think it came

 12   through you back in July or something like that.

 13             I guess the real question is have there

 14   been similar kind of reports regarding Hextend.

 15             DR. WEINSTEIN:  To the best of my

 16   knowledge, no.

 17             DR. HOLLINGER:  I think that is important

 18   because that is what usually generates these

 19   warning labels.  The warning label usually comes

 20   because of adverse events that are reported, either

 21   to the FDA or through some other--either to the

 22   sponsor or to the FDA.

 23             DR. WEINSTEIN:  Right.

 24             DR. HOLLINGER:  So without any

 25   adverse-event reports, and so on, then it makes it 

                                                               246

  1   difficult, I think, to demand that some warnings be

  2   applied to this.  I think when they come, then that

  3   is another issue.

  4             DR. WEINSTEIN:  We will have to examine

  5   the MedWatch database.

  6             DR. KOCHMAN:  These were papers published

  7   over a prolonged period of time for a product that

  8   has been approved for a long time.  These did not

  9   come in as MedWatch reports.

 10             DR. NELSON:  Hopefully, everybody can

 11   catch their plane or train or automobile or

 12   whatever.  So thanks.  Thanks, again.  We will see

 13   you in September.

 14             [Whereupon, at 1:55 p.m., the meeting was

 15   adjourned.]

 16                              - - -