1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

 

 

            BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

 

                              MEETING #37

 

 

 

 

 

                        Thursday, March 18, 2004

 

                               8:30 a.m.

 

 

                              Hilton Hotel

                        Silver Spring, Maryland

 

                                                                 2

 

                              PARTICIPANTS

 

      Mahendra S. Rao, M.D., Ph.D., Chair

      Gail Dapolito, Executive Secretary

 

      MEMBERS

      Jonathan S. Allan, D.V.M.

      Bruce R. Blazar, M.D.

      David M. Harlan, M.D.

      Katherine A. High, M.D.

      Joanne Kurtzberg, M.D.

      Alison F. Lawton

      James J. Mul, Ph.D.

      Thomas H. Murray, Ph.D.

      Anastasios A. Tsiatis, Ph.D

 

      CONSULTANTS

 

      Jeffrey S. Borer, M.D.

      Susanna Cunningham, Ph.D.

      Jeremy N. Ruskin, M.D.

      Michael E. Schneider, M.D.

      Michael Simons, M.D.

 

      INDUSTRY REPRESENTATIVE

 

      John F. Neylan, M.D.

 

      GUEST HEALTH CANADA REPRESENTATIVE

 

      Norman Viner, M.D.

 

      GUEST SPEAKERS

 

      Stephen Epstein, M.D.

      Silviu Itescu, M.D.

      Robert J. Lederman, M.D.

      Philippe Menasch, M.D.

      Emerson C. Perin, M.D., F.A.C.C.

      Doris A. Taylor, Ph.D.

 

      NIH PARTICIPANTS

 

      Richard O. Cannon, M.D.

      Stephen M. Rose, Ph.D.

 

      FDA PARTICIPANTS

 

      Jesse L. Goodman, M.D., M.P.H.

      Philip Noguchi, M.D.

      Dwaine Rieves, M.D

      Stephen Grant, M.D.

      Richard McFarland, Ph.D., M.D.

      Donald Nick Jensen, D.V.M., M.S.E.E.

 

                                                                 3

 

                            C O N T E N T S

                                                              PAGE

 

      Call to Order

        Mahendra Rao, M.D., Ph.D., Chair                         5

 

      Conflict of Interest Statement

        Gail Dapolito, Executive Secretary                       5

 

      Introduction of Committee                                  9

 

      FDA Opening Remarks

         Presentation of Certificate of Appreciation

         to Retiring Member

         Jesse Goodman, M.D., M.P.H.                            14

         Philip Noguchi, M.D.                                   16

 

                        Open Committee Discussion

                 Cellular Therapies for Cardiac Disease

 

      FDA Introduction and Perspectives

        Dwaine Rieves, M.D.                                     18

 

      Guest Presentations

 

        Overview Cardiomyopathy and Ischemic Heart

           Disease

        Emerson Perin, M.D., Ph.D.                              35

        Q&A                                                     65

 

        Clinical Experience of Autologous Myoblast

        Transplantation

        Philippe Menasch, M.D.                                 85

        Q&A                                                    115

 

        Bone Marrow Cell Therapy for Angiogenesis:

        Present and Future

        Steven Epstein, M.D.                                   128

        Q&A                                                    148

 

      Cellular Therapies for Cardiac Disease

      Richard McFarland, Ph.D., M.D.                           159

 

      Guest Presentations

 

        Myoblasts:  The First Generation Cells for

        Cardiac Repair: What Have We Learned?

        Doris Taylor, Ph.D.                                    169

        Q&A                                                    202

 

        Preclinical Models  - Hematopoietic and

        Mesenchymal Cell Therapies for Cardiac Diseases

        Silviu Itescu, M.D.                                    219

        Q&A                                                    245

 

                                                                 4

 

                      C O N T E N T S (Continued)

 

        From Mouse to Man:  Is it a Logical Step for

        Cardiac Repair?

        Doris Taylor, Ph.D.                                    257

        Q&A                                                    275

 

        Cardiac Catheters for Delivery of Cell Suspension

        Donald Nick Jensen, D.V.M., M.S.E.E.                   292

 

        Transcatheter Myocardial Cell Delivery: Questions

        and Considerations from the Trenches

        Robert Lederman, M.D.                                  307

        Q&A                                                    333

 

      Open Public Hearing                                      343

 

                                                                 5

 

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

 

  2                          Call to Order

 

  3             DR. RAO:  Good morning.  Welcome to the

 

  4   37th meeting of the Biological Response Modifiers

 

  5   Advisory Committee.

 

  6             Today's topic, as you all know, is related

 

  7   to use of cells in cardiovascular disorders, and we

 

  8   have a pretty full schedule for the next couple of

 

  9   days, but before we can start the meeting, we have

 

 10   to have a few sort of committee stuff that needs to

 

 11   be gotten through, so I will turn the mike over to

 

 12   Gail, so that she can make the mandatory

 

 13   announcements.

 

 14                  Conflict of Interest Statement

 

 15             MS. DAPOLITO:  Good morning.

 

 16             The following announcement addresses

 

 17   conflict of interest issues associated with this

 

 18   meeting of the Biological Response Modifiers

 

 19   Advisory Committee on March 18 and 19, 2004.

 

 20             Pursuant to the authority granted under

 

 21   the Committee Charter, the Associate Commissioner

 

 22   for External Relations, FDA, appointed Drs. Jeffrey

 

 23   Borer and Susanna Cunningham as temporary voting

 

 24   members.

 

 25             In addition, the Director of FDA's Center

 

                                                                 6

 

  1   for Biologics Evaluation and Research, appointed

 

  2   Drs. Jeremy Ruskin, Michael Schneider, and Michael

 

  3   Simons as temporary voting members.

 

  4             Based on the agenda, it was determined

 

  5   that there are no specific products considered for

 

  6   approval at this meeting.  The committee

 

  7   participants were screened for their financial

 

  8   interests.  To determine if any conflicts of

 

  9   interest existed, the agency reviewed the agenda

 

 10   and all relevant financial interests reported by

 

 11   the meeting participants.

 

 12             The Food and Drug Administration prepared

 

 13   general matters waivers for participants who

 

 14   required a waiver under 18 U.S.C. 208.  Because

 

 15   general topics impact on many entities, it is not

 

 16   prudent to recite all potential conflicts of

 

 17   interest as they apply to each member.

 

 18             FDA acknowledges that there may be

 

 19   potential conflicts of interest, but because of the

 

 20   general nature of the discussions before the

 

 21   committee, these potential conflicts are mitigated.

 

 22             We note for the record that Dr. John

 

 23   Neylan is participating in this meeting as a

 

 24   non-voting industry representative acting on behalf

 

 25   of regulated industry.  Dr. Neylan's appointment is

 

                                                                 7

 

  1   not subject to 18 U.S.C. 208.  He is employed by

 

  2   Wyeth Research and thus has a financial interest in

 

  3   his employer.

 

  4             With regards to FDA's invited guest

 

  5   speakers and guests, the agency determined that

 

  6   their services are essential.  The following

 

  7   disclosures will assist the public in objectively

 

  8   evaluating presentations and/or comments made by

 

  9   the participants.

 

 10             Dr. Stephen Epstein is the Executive

 

 11   Director, Cardiovascular Research Institute,

 

 12   Washington Hospital Center.  He receives research

 

 13   support, is a consultant to and has financial

 

 14   interests with, firms that could be affected by the

 

 15   committee discussions.

 

 16             Dr. Philippe Menasch is employed at the

 

 17   George Pompidou Hospital in Paris, France.  He has

 

 18   an association with a firm that could be affected

 

 19   by the committee discussions.

 

 20             Dr. Emerson Perin is employed by the Texas

 

 21   Heart Institute.  He receives consultant fees from,

 

 22   and is a scientific advisor to, firms that could be

 

 23   affected by the committee discussions.

 

 24             Dr. Doris Taylor is employed by the

 

 25   University of Minnesota, Center for Cardiovascular

 

                                                                 8

 

  1   Repair.  She receives consultant fees from a firm

 

  2   that could be affected by the committee

 

  3   discussions.

 

  4             Dr. Norman Viner is employed by the

 

  5   Biologics and Radiopharmaceuticals Evaluation

 

  6   Centre, Biologics and Genetic Therapies

 

  7   Directorate, Health Canada, in Ottawa, Canada.

 

  8             FDA participants are aware of the need to

 

  9   exclude themselves from the discussions involving

 

 10   specific products or firms for which they have not

 

 11   been screened for conflicts of interest.  Their

 

 12   exclusion will be noted for the public record.

 

 13             With respect to all other meeting

 

 14   participants, we ask in the interest of fairness

 

 15   that you state your name, affiliation, and address

 

 16   any current or financial involvement with any firm

 

 17   whose product you wish to comment upon.

 

 18             Waivers are available by written request

 

 19   under the Freedom of Information Act.

 

 20             Thank you, Dr. Rao.

 

 21             DR. RAO:  Now you know why I always have

 

 22   Gail read that statement.

 

 23             Before we start any committee work, I

 

 24   would like to welcome two new members to the

 

 25   committee, Dr. Murray and Dr. James Mul.  We

 

                                                                 9

 

  1   generally introduce everyone on the committee

 

  2   first, and we generally go in alphabetical order,

 

  3   but this time I will try and start with the new

 

  4   members, so that they can tell us a little bit

 

  5   about themselves before we have the others

 

  6   introduce themselves.

 

  7                    Introduction of Committee

 

  8             DR. MULE:  I am Dr. Jim Mul.  I am

 

  9   currently the Associate Center Director for the H.

 

 10   Lee Moffitt Cancer Center in Tampa.  I oversee all

 

 11   translational research at the Center including all

 

 12   cell-based therapies for the treatment of cancer as

 

 13   it applies to the clinical treatment of patients

 

 14   with advance tumors.

 

 15             Prior to being in Tampa since September of

 

 16   last year, I was at the University of Michigan

 

 17   Cancer Center for 10 years, and prior to that, the

 

 18   NCI for another 10 years, and I am delighted to be

 

 19   here.

 

 20             DR. MURRAY:  Good morning.  I am Tom

 

 21   Murray.  I am President of the Hastings Center,

 

 22   which is celebrating its 35th years as the world's

 

 23   first research institute devoted to ethics in

 

 24   medicine and the life sciences.

 

 25             I spent 15 years as professor at medical

 

                                                                10

 

  1   schools including 12 at Case Western Reserve

 

  2   University School of Medicine.  My interests are

 

  3   fairly broad.  I write a lot about ethics and

 

  4   ethics in the life science and science policy.

 

  5             Thank you.  I am delighted also to be

 

  6   here.

 

  7             DR. RAO:  If we can go down the table, Dr.

 

  8   Tsiatis.

 

  9             DR. TSIATIS:  Hi.  I am Butch Tsiatis.  I

 

 10   am from the Department of Statistics at North

 

 11   Carolina State University.

 

 12             DR. BORER:  My name is Jeff Borer.  I am a

 

 13   cardiologist.  I work at Weill Medical College of

 

 14   Cornell University in New York City.  I run a

 

 15   division and an institute at Cornell and, relevant

 

 16   to this meeting, I am the Chairman of the

 

 17   Cardiorenal Drugs Advisory Committee of the FDA.

 

 18             DR. CUNNINGHAM:  Good morning.  My name is

 

 19   Susanna Cunningham.  I am a professor in the School

 

 20   of Nursing at the University of Washington in

 

 21   Seattle, and I am the consumer representative for

 

 22   the Cardiovascular Renal Advisory Committee.

 

 23             DR. SCHNEIDER:  I am Michael Schneider.  I

 

 24   co-direct the Center for Cardiovascular Development

 

 25   at Baylor College of Medicine, and our interests

 

                                                                11

 

  1   are in the molecular genetics of cardiac muscle

 

  2   formation, cardiac growth, cardiac cell apoptosis

 

  3   and its relation to heart failure, and, relevant to

 

  4   this meeting, cardiac progenitor cells of different

 

  5   kinds.

 

  6             DR. SIMONS:  Hi.  I am Michael Simons.  I

 

  7   am Chief of Cardiology at Dartmouth Medical School.

 

  8   I work in the area of vascular biology, gene and

 

  9   cell therapy.

 

 10             DR. RUSKIN:  Good morning.  I am Jeremy

 

 11   Ruskin.  I am a cardiologist and

 

 12   electrophysiologist, and I direct the  Cardiac

 

 13   Arrhythmia Service at Massachusetts General

 

 14   Hospital.

 

 15             DR. NEYLAN:  Good morning.  I am John

 

 16   Neylan.  I am a nephrologist and an organ

 

 17   transplanter by training. Currently, I am Vice

 

 18   President of Clinical Research and Development at

 

 19   Wyeth, and I serve as a industry representative to

 

 20   the committee.

 

 21             DR. KURTZBERG:  Hi.  I am Joanne

 

 22   Kurtzberg.  I am a pediatric oncologist.  I direct

 

 23   the Pediatric Bone Marrow and Stem Cell Transplant

 

 24   Program at Duke University and the Carolinas Cord

 

 25   Blood Bank at Duke.

 

                                                                12

 

  1             DR. ALLAN:  Hi.  I am Jon Allan.  I am a

 

  2   virologist at the Southwest Foundation for

 

  3   Biomedical Research.  My area is nonhuman primate

 

  4   models for AIDS pathogenesis.

 

  5             DR. CANNON:  Good morning.  I am Richard

 

  6   Cannon.  I am at the National Heart, Lung, and

 

  7   Blood Institute.  I am Clinical Director of NHLBI,

 

  8   and I am representing NHLBI at this meeting.

 

  9             DR. ROSE:  Good morning.  I am Stephen

 

 10   Rose.  I am Deputy Director for the Recombinant DNA

 

 11   Program in the Office of Biotechnology Activities

 

 12   in the NIH.

 

 13             DR. JENSEN:  Good morning.  My name is

 

 14   Nick Jensen.  I am a reviewer in the Center for

 

 15   Devices and Radiological Health.  I am a

 

 16   veterinarian and an engineer.

 

 17             DR. McFARLAND:  Good morning.  I am

 

 18   Richard McFarland.  I am a reviewer in the

 

 19   Pharm/Tox Branch in the Center for Biologics in the

 

 20   Office of Cellular, Tissue and Gene Therapies.

 

 21             DR. RIEVES:  Good morning.  My name is

 

 22   Dwaine Rieves.  I am a medical officer in FDA's

 

 23   Center for Biologics Evaluation and Research.

 

 24             DR. GOODMAN:  Good morning.  I am Jesse

 

 25   Goodman.  I am the Center Director of the Center

 

                                                                13

 

  1   for Biologics.  I would just like to join in

 

  2   welcoming especially the new members.  My

 

  3   background is as an infectious disease physician in

 

  4   academic medicine for many years.

 

  5             DR. NOGUCHI:  I am Phil Noguchi, Acting

 

  6   Director of the Office of Cellular, Tissue and Gene

 

  7   Therapies in CBER.

 

  8             DR. RAO:  Thank you, everyone.

 

  9             We are very fortunate in having some