The infectious disease risks inherent in all forms of xenotransplantation warrant a consistent regulatory framework. FDA soon will publish a draft guidance document to provide further practical information to the transplant community.
FDA regulates numerous products intended to prevent, treat or diagnose diseases or injuries under the authority of the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act. Clinical studies of new experimental biologics, such as xenogeneic cells, tissues and organs, should be performed under an Investigational New Drug (IND) application that is filed with FDA. IND applications should contain information on product manufacturing and testing to ensure that trial subjects will not be exposed to unreasonable risks, taking into account the potential for benefit.
Critical Events Leading to the Guideline
Nov. 17, 1994: Philip R. Lee, M.D., the assistant secretary for health, requested that FDA, NIH and CDC hold a consensus conference on infectious disease risks associated with xenotransplantation. At about the same time, several institutional review boards contacted FDA regarding proposed xenotransplant studies at their institutions, expressing concern about the safety of donor animal tissues. A meeting was planned for early 1995 to discuss the need for specific guidelines.
January 1995: CDC, FDA, NIH, HRSA, the Department of Defense, academic institutional review boards, animal-care committees, transplant surgeons, the National Organization of Rare Diseases, and the National Academy of Sciences Institute of Medicine met to discuss public health concerns regarding xenotransplantation. It was decided that a comprehensive guideline was needed. Several working groups were formed to discuss what key elements needed to be included in the guideline.
April 1995: At FDA's Biological Response Modifiers Advisory Committee, infectious disease issues were discussed. Here also, a sponsor of a xenotransplant experiment described one approach to controlling infectious disease risks. The committee outlined preliminary public health safety concerns that should be included in any guideline for xenotransplantation.
June 25-27, 1995: The Institute of Medicine (IOM) held a public workshop on scientific, medical, public health, socioeconomic, legal, and ethical issues. The Public Health Service agencies brought the issue of infectious disease risks to the workshop for further public discussion and comment.
June 28, 1995: A day later, PHS held a "Federal Day" workshop to bring the PHS working groups together to discuss their progress on the guidelines and to create a guideline that would address the issues presented at the IOM meeting. The goal set was to create a draft guideline for discussion by July 1995.
July 13-14, 1995: FDA's Biological Response Modifiers Advisory Committee met on July 13 to discuss xenotransplantation issues. Issues discussed included animal source qualification and exclusion criteria, location and review of experiments, a national patient data base, surveillance and specimen archiving, screening and post-transplant patient surveillance, and informed consent.
On July 14, the committee discussed a highly publicized experimental protocol that had been submitted to the agency for review--a baboon bone marrow transplant to treat a patient with AIDS. The committee recognized the need for well-designed protocols to control infectious disease risks. Although questions were asked about the outcome of the experiment, from the perspective of both the patient and the public health, the committee recommended that this protocol be approved for one patient. The committee also discussed extracorporeal liver-assist devices, which may contain live animal cells such as pig liver cells.
Nov. 30, 1995 New England Journal of Medicine: Sounding Board article "Xenotransplantation and Xenogeneic Infections" discussed the potential risks for transplant recipients and to the public health. Written by Drs. Chapman and Folks (CDC), Dr. Salomon (Scripps Research Institute), and Drs. Patterson, Eggerman and Noguchi (FDA), the article clarifies the reasons why guidance is needed in the field of xenotransplantation.
March 1996: PHS met with representatives of the American Society of Transplant Surgeons and the American Society of Transplant Physicians to discuss principles of the draft guideline and the perspectives of the transplant community. The transplant surgeons recommended that FDA, CDC and NIH collaborate with HRSA in establishing a national registry, since that agency currently oversees the Scientific Registry of Transplant Recipients.
April 1996: The British Nuffield Council on Bioethics published a study calling for national regulation of xenotransplantation to be in place before any clinical trials could proceed.
July 1996: A request for proposals was published for a pilot study of the National Xenotransplantation Registry operated under contract by HRSA.
July 1996: The Institute of Medicine issued a report on xenotrans plantation calling for national guidelines. Both the IOM and Nuffield reports supported the concept of a national registry as proposed by PHS.
September 1996: The draft PHS guideline for xenotransplantation is published.