DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

September 5, 2001

The Honorable Edward M. Kennedy
United States Senate
Washington, D.C. 20515-2101

Dear Senator Kennedy:

During the past few weeks, concerns have been raised about human embryonic pluripotent stem cells (HEPSC) and their eventual use in human clinical trials for a variety of therapies. The Food and Drug Administration would like to take this opportunity to clarify these issues. A similar letter is being sent to Senator Judd A. Gregg.

While many questions are being raised, the science has not advanced far enough to answer them yet. HEPSCs were first isolated in 1998, and the scientific research about them is in its infancy. The FDA stands ready to work with the scientific community as they near the stage of human clinical trials. We encourage investigators to work closely with us to ensure that testing occurs in the most expedient and safest manner.

Most of the concerns raised to date are not unique to human embryonic stem cells. The use of irradiated mouse feeder layers in deriving HEPSC raises concerns that also occur for other xenotransplantation products. FDA regulations do not prohibit using mouse feeder layers to make HEPSC products for human clinical trials. Of course, appropriate testing and precautions are necessary. FDA has a number of active Investigations for New Drugs (INDs) for xenotransplantation products currently in clinical trials.

Xenotransplantation products raise issues that several Public Health Service agencies address, including the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) and Health Resource Services Administration (HRSA). In order to provide guidance to maximize the safe conduct of xenotransplantation trials, these agencies together with staff from the Office of the Assistant Secretary for Planning and Evaluation (OASPE) developed the PHS Guideline on Infectious Disease Issues in Xenotransplantation (1/18/01). The PHS Guideline on Infectious Disease Issues in Xenotransplantation and several FDA Guidance Documents (see below*) have defined xenotransplantation as "any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with nonhuman animal cells, tissues or organs."

FDA regulates xenotransplantation products using the regulatory framework established for other biologics. Xenotransplantation products are, by their nature, also cellular therapies, and some are also gene therapies, and as biologics are subject to the provisions of the Food, Drug and Cosmetics Act and the Public Health Service Act and the appropriate regulations in 21 CFR. A number of clinical trials of FDA-regulated xenotransplantation protocols, including several in which the contact with the animal cells is ex vivo, are currently enrolling patients, after adequately addressing FDA's concerns. Addressing FDA's concerns have included use of precautions such as: (1) testing the xenotransplantation product for infectious agents by appropriate methods including co-culture assays to detect potentially unknown viruses, (2) educating patients regarding the potential infectious disease risks and monitoring and testing them for xenogeneic infections following treatment, (3) educating xenotransplantation product recipients to not donate blood or tissues for use in humans, (4) educating patient contacts, and in some cases monitoring them, (5) maintaining appropriate records of treatment with xenotransplantation products, (6) maintaining archived biologic samples from the patient, animal source, and product in the event that a public health investigation is needed, and (7) maintaining animal sources of xenotransplantation products in a manner appropriate to reducing the infectious disease risks of the product when used in humans. This latter precaution might not be necessary if a long-term established, well-characterized cell line with adequate documentation is used in xenotransplantation.

Thus, as intended and practiced, the FDA regulation of xenotransplantation products, while aimed first and foremost at safeguarding the public health, should not impose a substantial impediment to xenotransplantation product development, including HEPSC that are produced by culture in vitro with mouse cells. HEPSC, as with any other product, will be reviewed on a case-by-case basis to evaluate safety when an application for investigational use is submitted to FDA. In the meantime, sponsors planning the clinical use of HEPSC that have been developed by exposure to animal cells should visit the FDA Xenotransplantation Action Plan website (<http://www.fda.gov/cber/xap/xap.htm>) where links to all the published material and transcripts can be found. They are also encouraged to phone the agency (301 827-2000) with questions and concerns. Potential sponsors of any xenotransplantation products are often counseled directly by FDA personnel on how best to comply with FDA requirements on xenotransplantation.

__________________________________________________

*Guidance documents defining xenotransplantation:

· PHS Guideline on Infectious Disease Issues in Xenotransplantation, January 2001
· Draft Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning Use of Xenotransplantation Products in Humans, February 2001

· Draft Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Xenotransplantation Product Recipients and Their Close Contacts, Through Whole Blood, Blood Components, Source Plasma, and Source Leukocytes, December 1999
· Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans, April 6, 1999 (The actual wording of the definition of xenotransplantation in this document "the use of live cells, tissues, or organs from a nonhuman animal source transplanted or implanted into a human, or used for ex vivo contact with human body fluids, cells, tissues or organs that are subsequently given to a human recipient.")

Sincerely yours,

/s/
Bernard A. Schwetz, D.V.M., Ph.D.
Acting Principal Deputy Commissioner

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