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.

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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.

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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

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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

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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

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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.

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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

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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

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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;

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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;

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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

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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

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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

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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

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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

109

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

119

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

120

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

121

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,

122

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

123

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

124

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

125

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

126

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

127

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.

128

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

129

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.

130

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

131

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,

132

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

133

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

134

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

140

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

232

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

240

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

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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

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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

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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.\]

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