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United States
Food and Drug Administration
Center for Biologics Evaluation and Research

XENOTRANSPLANTATION SUBCOMMITTEE

Holiday Inn, Bethesda, MD
June 3-4, 1999


Overview...

The United States Food and Drug Administration (FDA) held a meeting of the Xenotransplantation Subcommittee on June 3-4, 1999 in order to seek expert and public input into the creation of a final regulatory framework for xenotransplantation. As well as members of the FDA, many of the top experts in related fields were present, representing disciplines such as:
 

Xenotransplantation Virology and Retrovirology
Allotransplantation Veterinary Science
Pediatrics Surgery
Immunology Bioethics
Microbiology Epidemiology
Recombinant DNA Clinical Trials
Immunobarrier Technology Regulatory Issues

The FDA did an excellent job of convening a panel of experts whose input will shape xenotransplantation regulations in the United States. My impression was that FDA was genuinely seeking guidance, and was not pushing its own agenda. Unlike many European governments who quietly wrote their own regulations with minimal input from outsiders, the FDA encouraged a democratic and science-based process.

The Bottom Line...

In this report, I would like to start at the end. For those of us whose health and even survival may depend on a reasonable regulatory framework for xenotransplantation, the outcome could not have been better! On the second day of the conference, Dr. Hugh Auchincloss - Chair of the FDA Xenotransplantation Subcommittee - told me in clear and definite terms that:

  • the FDA will allow clinical trials of cellular xenotransplantation to proceed; and
  • the discussion is now focussed on whole organ xenotransplantation, and whether it offers sufficient benefit today to approve clinical trials. 
This commitment was made in the presence of the FDA xenotransplantation management team, as well as all participants at the conference. Later, Dr. Auchincloss again reassured me that cell-level xenografts had a green light from the FDA, and that only whole organ xenografts were under discussion. Of course, applications for islet or other cell xenografts must meet FDA standards of safety, archiving and record-keeping.  In effect, I believe Dr. Auchincloss was telling me to "Shut up and quit selling. The sale's been made!"  I cannot remember when I have ever been so happily silenced.

The Hard Facts...

Speaker after speaker presented hard facts supporting the position that the much-feared Pig Endogenous Retrovirus (PERV) was not capable of infecting humans. Some of the highlights:

  • Dr Carolyn Wilson of the FDA presented the FDA perspective. She described how the FDA placed a hold on the 10 xenotransplantation clinical trials then approved in October 1997 until each researcher could demonstrate that he or she had sufficiently sensitive assays to detect low levels of PERV infection. Of the 10 trials, 6 were restarted when the FDA was satisfied with the assays being used.  In these trials, of 29 recipients who received pig cells, 0/29 tested positive for PERV infection.

  •  
  • Dr. Walid Heneine of the Centers for Disease Control (CDC) presented data on Porcine Factor 8 (PF8) sold under the trade name of Hyate C. PF8 is an agent derived from pigs and used by hemophiliacs who are unable to tolerate human clotting factor. A large number of batches of PF8 were tested for PERV, and 100% were found to be PERV-positive (as PERV is part of a pig's DNA, it is present from birth even without infectious exposure). However, of 88 recipients who received transfusions of  PF8, 0/88 were found to be PERV-positive. These transfusions present an ideal opportunity for PERV infection, and yet the retrovirus once again proved incapable of infecting human cells. The tragic irony here is that many of the hemophiliacs who received human clotting factor contracted AIDS and hepatitis, demonstrating once again that material derived from sterile, purpose-bred pigs is safer than material from humans.

  •  
  • Dr Walid Heneine of CDC also presented data on people receiving pig islet cells. Each received 200,000 to 2,000,000 islets, and all had levels of porcine C-peptide, indicating that the islets were surviving and secreting pig insulin. Of the 10 recipients tested, 0/10 were PERV-positive (both PCR and serological antibody assays). In one recipient, there was a weak positive for PERV infection, but when tested 7 days later, the results were PERV-negative. PCR is very susceptible to false positives as a result of contamination or microchimerism, and so it is sometimes necessary to test more than once.

  •  
  • Dr Gillian Langford of Imutran Limited presented the results of pig organs transplanted into non-human primates (monkeys and baboons). All these animals were heavily immunosuppressed, and so were relatively incapable of fighting any infection. Of 100 monkeys and baboons that received pig organs, 0/100 showed PERV infection in multiple tissues tested. The tests looked for PERV viral fragments amplified through Polymerase Chain Reaction (PCR) as well PERV antibodies. Pig cells were detected in all tissue tested, indicating either microchimerism or the release of cells during rejection. Once again, the conditions for infection were ideal, and none occurred.

  •  
  • Dr. Zorina Pitkin of Circe Biomedical presented the results of assays on people whose blood was circulated through pig liver cells in Circe's HepatAssist liver support system. Again, all recipients tested negative for PERV infection.

  •  
  • Dr. Jonathan Dinsmore of Diacrin, Inc. presented data from patients who received pig neural cells as a treatment for Parkinson's disease, Huntington's disease, and focal epilepsy. Of the 33 patients tested, 0/33 were PERV-positive. These patients received approximately 12,000,000 cells each.  Half were immunosuppressed, and half underwent antibody depletion prior to transplant.

  •  
  • Dr. John Logan of Nextran, Inc. presented results from humans and baboons who received cell xenografts from transgenic pigs. All recipients showed a powerful alpha-Gal response, indicating the presence of pig cells, but no PERV infection.

  •  
  • Dr. Khazil Paradis of Imutran Limited described the extensive testing of humans who have received various pig cells over the past decade. This testing was undertaken collaboratively by Imutran and the CDC. Dr. Paradis was only able to describe the methodology of this investigation, and not its results as publication is planned for later this summer. However, if I were a betting man, I would place a huge bet on a PERV-negative outcome.
To summarize from this growing body of evidence:
  • All pigs are positive for PERV
  • All humans who have received pig tissue are negative for PERV
  • All non human primates who have received pig tissue are negative for PERV
  • All humans who received Pig Factor 8 as a clotting agent are negative for PERV
  • Many recipients were heavily immunosuppressed, presenting very little defense against any infection
The Ethics Perspective...

Dr. Harold Vanderpool of the University of Texas Institute for Medical Humanities presented a perspective on the ethic of xenotransplantation that was refreshingly different from what I have heard here in Canada. Dr. Vanderpool described the ethical considerations as having three equal parts:

  • Benefit - Is it reasonable to expect that xenotransplantation will potentially relieve human suffering and prolong life?
  • Risk - Is is reasonable to expect that xenotransplantation is safe for the patient, and more importantly, for society at large?
  • Justice - Do other groups enjoy access to medical procedures that are of similar or greater cost and risk ?
In my bioethics discussions so far, risk was the only area of interest to the ethicist, and one that had no scientific backing. Dr. Vanderpool's perspective was refreshing and reassuring.

Anti-CD40-Ligand a.k.a. Anti-CD154...

Dr. David K. C. Cooper of the Transplantation Biology Research Center at Harvard Medical School presented some fascinating data on xenografts of pig whole organs into primates. Dr. Cooper pointed out that in 1991 there were 4 reports on pig-to-primate transplants. In 1999, there have been 150 reports in the first six months. Many researchers are seeing enough promise in this field to focus their careers on it. 

Dr. Cooper described the stages of rejection that must be overcome before a whole xeno-organ will be accepted by its host. The rejection process seems to follow 4 stages: hyperacute rejection (HAR), acute vascular rejection (AVR), cell-mediated rejection, and chronic rejection. In the case of islets, HAR does not seem to happen, likely because alpha-Gal is not present on islet cells. AVR likewise does not happen to islets, as they are not vascularized (grafted to blood vessels). Without immune protection, the remaining two stages of rejection will destroy islets just like any other transplanted tissue. 

Dr Cooper discussed the work of Drs. David Harlan and Allan Kirk of the U.S. Naval Medical Research Institute in which monkeys have accepted a mismatched kidney allograft for up to 1.5 years without ongoing immunosuppression. During the first month, these monkeys received a course of Anti-CD40-Ligand (now known as Anti-CD154) and no immunosuppression thereafter. Not only have the kidneys worked well, but the monkeys have avoided the adverse effects normally associated with immunosuppression.

The next challenge is to use Anti-CD154 to prevent rejection of pig organs in primates, especially humans. Although some increase in the acceptance period was observed, Dr. Cooper speculated that Anti-CD154 may have to be combined with transgenic donors and bone marrow transplantation before it can induce xenotolerance.

Other Items...

This summary is a quick overview of the FDA Xenotransplantation Subcommittee meeting, with the items of interest to islet xenotransplantation being emphasized. There were many interesting presenters, and dozens of excellent questions and discussions. 

All in all it was a watershed event!
 

Participants at the Meeting...
 

Executive Secretary:
Gail Dapolito
Scientific Advisors and Consultants Staff
Center for Biologics Evaluation and Research
Food and Drug Administration (HFM 71 )
1401 Rockville Pike
Rockville, MD 20852-1448
Committee Management Specialist:
Rosanna L. Harvey
Scientific Advisors and Consultants Staff
Center for Biologics Evaluation and Research
Food and Drug Administration (HFM 71)
1401 Rockville Pike
Rockville, MD 20852-1448

Subcommittee Participants


Chair:
Hugh Auchincloss, Jr., M.D:
Associate Professor of Surgery
Harvard Medical School
Transplantation Unit, Department of Surgery
Massachusetts General Hospital
55 Fruit Street, GRBSO4
Boston, MA 02144-2696
Jonathan S. Allan, D.V.M.
Adjunct Associate Professor
Department of Microbiology
University of Texas Health Science Center
Scientist, Department of Virology and lmmunology
Southwest Foundation for Biomedical Research
San Antonio, TX 78228
John M. Coffin, Ph.D.
Professor of Molecular Biology
Tufts University School of Medicine
Department of Molecular Biology
136 Harrison Avenue
Boston, MA 02111
Ronald C. Desrosier, Ph.D. (Not attending)
Professor of Microbiology and Molecular Genetics
Harvard Medical School
Chairman, Microbiology Division
New England Regional Primate Research Center
One Pine Hill Drive, Box 9102
Southborough, MA 01772
Martin S. Hirsch, M.D.
Professor of Medicine
Harvard Medical School
Director of Virology
Infectious Disease Division
Massachusetts General Hospital
55 Fruit Street
Boston, MA 02114
Richard Kaslow, M.D., M.P.H.
Professor of Epidemiology, Medicine
 and Microbiology
University of Alabama at Birmingham
212C Tidwell Hall
720 South 20th Street
Birmingham, AL 35294-0008
Nicholas W. Lerche, D.V.M.
Associate Adjunct Professor
Applied Virology and Special Pathogens Section
Virology and Immunology Unit
California Regional Primate Research Center
University of California, Davis
Davis, CA 95616-8542
Ms. Abbey S. Meyers
President and Executive Director
National Organization for Rare Disorders
Fairwood Professional Building
P.O. Box 8923
New Fairfield, CT 06812-8923
Claudia A. Mickelson, Ph.D.
Director, Biosafety Office, 56-255
Environmental Medical Service
Massachusetts Institute of Technology
77 Massachusetts Avenue
Cambridge, MA 02139-4307
David Onions, BVSC, Ph.D., MRCVS, FRSE
Professor of Veterinary Pathology
Honorary Director LRF Human Virus Centre
University of Glasgow
Bearsden, Glasgow G61 1 QH
Scotland, United Kingdom
Prem S. Paul, D.V.M., Ph.D.
Associate Dean for Research and
 Graduate Studies
Assistant Director, Agricultural and
 Home Economics Experiment Station
2522 Veterinary Medicine Administration
Iowa State University
Ames, IA 50011
Daniel R. Salomon, M.D.
Director, Transplantation Research and
 Graduate Studies
Division of Organ Transplantation
Scripps Clinic and Research Foundation
Assistant Member, Department of Molecular
  and Experimental Medicine
The Scripps Research Institute
10550 North Torrey Pines Road, 858
La Jolla, CA 92037
David Sachs, M.D.
Paul S. Russell/Warner Lambert Professor
 of Surgery and Immunology
Harvard Medical School
Director, Transplantation Biology Research
 Center
Massachusetts General Hospital
MGH East, Building 1499010
l3th Street
Boston, MA 02129
Harold Y. Vanderpool, Ph.D., Th.M.
Professor of Preventive Medicine and
  Comznunity Health
University of Texas Medical Branch
Institute for the Medical Humanities
2.208 Ashbel Smith Building
301 University
Galveston, TX 77555-1311
Leroy Walters, Ph.D.
Director
Kennedy Institute of Ethics
Georgetown University
Washington, D.C. 20057

Consultants

Mr. Antonio Benedi
Vice President
Transplant Recipient International Organization
7772 Turlock Road
Springfield, VA 22153
William G. Lawrence, J.D.
Director of Patient Affairs
United Network for Organ Sharing
9506 Sylvan Dell
Columbia, MD 21045
E. Steve Woodle, M.D.
Director, Renal Transplantation
Section of Transplantation
Department of Surgery
University of Chicago
5841 South Maryland Avenue, RM J517 MC5027
Chicago, IL 60637
Manikkam Suthanthiran, M.D.
Chief, Department of Transplantation
 and Extracorporeal Therapy
The New York Hospital - Cornell Medical Center
525 East 68th Street, Box 3
New York, NY 10021

Guests

Marian Michaels, M.D., M.P.H.
Assistant Professor of Pediatrics and Surgery
University of Pittsburgh School of Medicine
Division of Pediatric Infectious Diseases
Children's Hospital of Pittsburgh
3705 Fifth Avenue
Pittsburgh, PA 15213
Robert E. Michler, M.D.
Karl P. Klassen Professor of Surgery
Chief, Division of Cardiothoracic Surgery
Ohio State University Medical Center
North 847 Doan Hall
410 West lOth Avenue
Columbus, OH 43210
John Conte, M.D.
Director
Johns Hopkins Heart and Heart-Lung
 Transplant Programs
Johns Hopkins Hospital
Blalock 618
600 N. Wolfe Street
Baltimore,1V 21287
Ralf R. Toenjes, Ph.D.
Paul Erlich Institut
Paul Erlich-Strasse 51-59
D-63225 Langen
Germany

Guest Speakers

Gillian Langford, Ph.D.
Head, Retrovirus Research
Imutran Limited
P.O. Box 399
Cambridge, CB2 2YP
United Kingdom
Khazal Paradis, MDCM FRCP(C)
Director of Clinical Research
Imutran Limited
P.O. Box 399
Cambridge, CB2 2YP
United Kingdom
Zorina Pitkin, M.D.
Vice President
QA/QC and Regulatory Affairs
Circe Biomedical
99 Hayden Avenue
Lexington, MA 02421-7995
Taylor Wang, Ph.D.
Centennial Professor and Director, MI Center
Vanderbilt University
Box B 1743, Station B
Nashville, TN 37235
Claudy Mullon, Ph.D.
Circe Biomedical
99 Hayden Avenue
Lexington, MA 02421-7995
Christopher G.A. McGregor, M.B., FRCS
Director of Cardiothoracic Transplantation
Mayo Clinic
Rochester, MN 55905
Jonathan Dinsmore, Ph.D.
Senior Director
Cell Transplantation Research
Diacrin, Inc.
96 l3th Street
Charlestown Navy Yard
Charlestown, MA 02129
Marlin Levy, M.D., FACS
Assistant Director
Transplantation Services
Baylor University Medical Center
3500 Gaston Avenue
Dallas, TX 75246
John S. Logan, Ph.D.
Vice President, Research and Development
Nextran, Inc.
303B College Road East
Princeton, NJ 08540
Emanuele Cozzi, M.D.
Head of Transplantation
Imutran Limited
P.O. Box 399
Cambridge CB2 2YP
United Kingdom
David K. C. Cooper, M.D., Ph.D., FRCS
Associate Professor of Surgery
Harvard Medical School
Transplantation Biology Research Center
Massachusetts General Hospital
MGH-East, Building 149-9019
l3th. Street
Boston, MA 02129

CDC Participants

Louisa E. Chapman, M.D.
HIV and Retrovirology Branch
National Center for Infectious Diseases
Center for Disease Control and Prevention
1600 Clifton Rd., NE (MS-G19)
Atlanta, GA 30333
Walid M. Heneine, Ph.D.
HIV and Retrovirology Branch
National Center for Infectious Diseases
Center for Disease Control and Prevention
1600 Clifton Rd., NE (MS-G19)
Atlanta, GA 30333
Rima F. Khabbaz, M.D.
Associate Director for Medical Science
Division of Viral and Rickettsial Diseases
National Center for Infectious Diseases
Center for Disease Control and Prevention
1600 Clifton Rd., Mailstop A-30
Atlanta, GA 30333

NIH Participants


Mary Groesch, Ph.D.
Senior Science Policy Analyst
Office of Science Policy
Office of the Director
National Institutes of Health
Building 1, Room 218
Bethesda, MD 20892-0166

FDA Participants

Jay P. Siegel, M.D.
Director
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-500
1401 Rockville Pike
Rockville, MD 20852-1448
Philip D. Noguchi, M.D.
Director
Division of Cellular and Gene Therapies
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-515
1401 Rockville Pike
Rockville, MD 20852-1448
Eda Bloom, Ph.D.
Chief
Division of Cellular and Gene Therapies
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-518
1401 Rockville Pike
Rockville, MD 20852-1448
Carolyn Wilson, Ph.D.
Senior Investigator
Division of Cellular and Gene Therapies
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-518
1401 Rockville Pike
Rockville, MD 20852-1448
Karen D. Weiss, M.D.
Director
Division of Clinical Trial Design
 and Analysis
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-570
1401 Rockville Pike
Rockville, MD 20852-1448
Louis Marzella, M.D., Ph.D.
Medical Reviewer
Division of Clinical Trial Design
 and Analysis
Office of Therapeutics Research
 and Review
Center for Biologics Evaluation
 and Research
Food and Drug Administration, HFM-582
1401 Rockville Pike
Rockville, MD 20852-1448


Other Xenotransplantation Links
The Xenotransplantation Debate - Science or Superstition?
National Forum on Xenotransplantation - Ottawa
The Xenotransplantation Debate Continues
Testimony to Committee on Health of the Canadian House of Commons on Xenotransplantation - February 4, 1999
OECD/NYAS International Xenotransplantation Workshop
Xenotransplantation is safe! CDC Report and Latest Xeno Events
Televised Debate on Xenotransplantation - Margaret Somerville and Alastair Gordon - March 5, 1999

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