Therapeutic Human Fetal Tissue Transplantation Research Activities Funded by the National Institutes of Health in FY 1998

Report to Congress
July 1999

I. Introduction

In compliance with Section 498A of the Public Health Service Act [42 USC 289g-1], this report describes research conducted during FY 1998 involving therapeutic transplantation of human fetal tissue supported or conducted by the National Institutes of Health (NIH). The report describes specific projects and the extent to which they were conducted in accordance with statutory provisions regarding the separation of transplantation research activities from abortion. It also indicates the level of funding for the projects, which totaled $2,126,3331 in FY 1998.

1This funding level reflects a broad definition of fetal tissue transplantation research. That is, it encompasses research that is directly related to fetal tissue transplantation, such as follow-up studies, even if the transplantation procedure itself was not part of the funded project.


II. Scope of Report

Research involving human fetal tissue is classified into three categories—basic, pre-clinical, and therapeutic (or clinical). Basic research involving human fetal tissue is focused on the advancement of knowledge of basic biological processes, knowledge that may ultimately lead to applications with a wide-ranging impact on human health. Pre-clinical investigations aim to further therapeutic research through transplantation studies in animals or the development of improved methodologies for processing and preserving tissue. Projects involving the transplantation of human fetal tissue into humans are classified as therapeutic or clinical research if they are conducted on human subjects and are aimed at the development of therapeutic approaches for the cure or amelioration of diseases and disorders. The scope of this report is limited to this last category of activity-clinical or therapeutic research studies involving the transplantation of human fetal tissue into humans-but also encompasses the related category of follow-up studies of therapeutic fetal tissue transplantation.


III. Policy Background

In the Fall of 1987, the NIH requested approval of the Assistant Secretary for Health (ASH) to conduct a clinical study assessing the efficacy of implanting human fetal tissue into the brain of a patient with Parkinson's disease. In March 1988, the ASH advised the NIH that it was withholding approval of the project and imposing a temporary moratorium on Federal support of therapeutic transplantation research using human fetal tissue from induced abortions pending consideration of the relevant ethical, legal, and scientific issues by an outside group of experts. In December 1988, that group—known as the Human Fetal Tissue Transplantation Research Panel—concluded in a report that the use of tissue from induced abortions in therapeutic transplantation research was acceptable public policy provided certain safeguards existed to separate research activities from abortion. The Panel presented its report and recommendations to the Advisory Committee to the Director, NIH. The Advisory Committee approved the Panel report and recommended that the moratorium be lifted. In January 1989, the Panel report, the Advisory Committee's recommendations, and NIH concurring opinion in the matter were forwarded to the ASH. In November 1989, after careful consideration of these recommendations and opinions, the Secretary of Health and Human Services extended the temporary moratorium for an indefinite period.

In subsequent years, legislative proposals to overturn the moratorium were introduced and considered by the United States Congress. One such measure, for example, was approved by the House of Representatives in July 1991 and by the Senate in April 1992, but was vetoed by President Bush in June 1992.

On January 22, 1993, the moratorium on Federal funding of human fetal tissue transplantation research was reversed by President Clinton. In his directive to the Secretary of Health and Human Services, the President noted that the moratorium "has significantly hampered the development of possible treatments for individuals afflicted with serious diseases and disorders, such as Parkinson's disease, Alzheimer's disease, diabetes, and leukemia." The Secretary implemented the President's instructions to end the moratorium and further directed the NIH to develop interim policy guidelines based on the recommendations of the 1988 Human Fetal Tissue Transplantation Research Panel and the Advisory Committee to the Director to assure that Federal support of such research does not encourage abortion. These interim policy guidelines were issued March 19, 1993, in the NIH Guide for Grants and Contracts.

In Congress, efforts to nullify the moratorium legislatively and to provide statutory authority for Federal support of such research continued, culminating with the enactment, on June 10, 1993, of the NIH Revitalization Act (P.L. 103-43). Title I, Subtitle A, Part II, Section 111 of this law added Section 498A of the Public Health Service Act, authorizing the Secretary to conduct or support research on the transplantation of human fetal tissue for therapeutic purposes "regardless of whether the tissue is obtained pursuant to a spontaneous or induced abortion or pursuant to a stillbirth." Section 111 defined human fetal tissue as "tissue or cells obtained from a dead human embryo or fetus after a spontaneous or induced abortion, or after a stillbirth."

To ensure that the research does not encourage abortion, P.L. 103-43 set forth requirements governing the conduct of research and directed the Secretary to confirm that such research activities are being conducted in compliance with those safeguards. Section 111 established a detailed informed consent procedure for the research and requires that the research be conducted in accordance with State and local laws. Section 112 of the law added Section 498B of the Public Health Service Act, prohibiting the transfer of human fetal tissue for "valuable consideration" and imposing criminal penalties for violations of this prohibition. The law defines "valuable consideration" as excluding reasonable payments associated with the transportation, implantation, processing, preservation, quality control, or storage of human fetal tissue. On August 30, 1993, the NIH published a notice in the Federal Register withdrawing the interim policy guidelines and outlining superseding provisions of P.L. 103-43. These are discussed again in Section V.


IV. Research Activities

Human fetal tissue is important in medical research because it has certain biological properties that are not present in adult tissue. For example, human fetal cells divide frequently and can readily adapt to a new environment. They can change shape, induce blood vessel formation that enhances their own survival and growth, and they can become functionally integrated into new surroundings. Fetal tissue is also less likely than adult tissue to trigger an immune response, a process that can lead to tissue rejection. All of these biological properties make human fetal tissue especially important for clinical transplantation studies.

In the late 1980s, following successful preliminary work in animals, clinical investigators began to study the efficacy of transplanting human fetal tissue into patients with diseases, such as Parkinson's disease, that are caused by the absence, deficiency, or degradation of tissues and cells essential to the functioning of the body. In Parkinson's disease, neurons in the brain that produce dopamine, a chemical that regulates motor control, are destroyed. These patients consequently suffer from severe motor problems ranging from rigidity to uncontrollable, abnormal movements. Over time, patients become less responsive to the standard drug therapy, levodopa, used in the treatment of Parkinson's disease.

After the moratorium was lifted, a number of NIH Institutes and Centers identified a range of potential applications for human fetal tissue transplantation research. Rather than initiating research studies in this area, however, the Institutes and Centers decided that the traditional investigator-initiated research mechanisms would be used to determine which, if any, studies in this area would be supported. Decisions regarding the funding of this research are based on the customary criteria of scientific merit, programmatic relevance, and availability of funds.

Since FY 1993, the NIH has funded several extramural studies involving therapeutic uses of human fetal tissue. Descriptions of the studies conducted during the period FY 1993–FY 1995, and FY 1996–97 are described in previous reports.

In FY 1998, the National Institute of Neurological Disorders and Stroke (NINDS) supported two clinical research projects at the University of Colorado ($1,276,284) and Mount Sinai Medical Center in New York ($504,108). The Mount Sinai Study also involves the participation of Rush Presbyterian Medical Center in Chicago and the University of South Florida in Tampa. Both of these studies are randomized, double-blind, controlled trials to assess the safety and efficacy of fetal tissue transplantation for the treatment of Parkinson's disease. This trial design allows researchers to determine whether observed effects are due to the therapy or to psychological factors.

Initial results from the University of Colorado study (which was the first Federally funded fetal tissue transplant trial) indicate that the surgery provided some improvement in control of movement in a subset of Parkinson's patients who underwent the experimental therapy. The treatment did not appear to benefit patients over the age of 60. More analysis and patient follow-up are necessary to determine whether the benefits will last over time and why the treatment did not appear to benefit older patients. Results from the Mount Sinai study are not expected until 2001.

The NINDS also funded a follow-up study at the University of Denver on the quality of life of patients with neural implants. This study measures mostly psychosocial outcomes for the patients participating in the University of Colorado study. Funding for this follow-up study was $97,618 in FY1998. This study does not involve the actual transplantation of human fetal tissue. Funding for these three NINDS-supported studies totaled $1,878,010 in FY 1998.

In FY 1998, the National Center for Research Resources (NCRR) provided support for two follow-up studies on neurological function in patients with Parkinson's disease who had previously received human fetal tissue implants. The studies were carried out at General Clinical Research Centers (GCRCs) at Mount Sinai School of Medicine of City University of New York ($61,134) and Columbia University in New York ($187,189). No actual fetal tissue transplantations have been performed at GCRC sites with Federal funds. Support for these NCRR-funded studies totaled $248,323 in FY1998.

Results from the Mount Sinai follow-up study indicate that fetal tissue can be transplanted into the brains of patients with advanced Parkinson's disease safely and with little morbidity, and that the implanted cells make normal connections with host nerve cells and appear to have normal metabolic function. In addition, follow-up of an open-label pilot study of six patients who had undergone fetal cell transplantation for advanced Parkinson's disease indicates that significant improvement in disease symptoms has persisted through a mean follow-up time of more than 30 months.


V. Compliance with Legal and Ethical Requirements

The requirements set forth in Section 498A of the Public Health Service Act are intended to ensure that the decision to undergo an abortion and the decision to donate fetal tissue for research are made independently. In addition to prohibiting directed donations and the commercialization of human fetal tissue, Section 498A requires Federally funded studies to adhere to a detailed informed consent process. The procedures require written statements—from the tissue donor, the donor's attending physician, the principal investigator, and the tissue transplant recipient—before any research protocol involving fetal tissue transplantation can be conducted. Section 498A applies to both intramural research (carried out on the NIH campus) and extramural studies (funded by the NIH and conducted at academic institutions). The law also requires NIH research projects to be conducted in accordance with applicable State law. The specific informed consent provisions of the law are outlined below.

  1. The woman donating the human fetal tissue must sign a statement declaring that: the tissue is being donated for therapeutic transplantation research; the donation is being made without any restriction regarding the identity of individuals who may be the transplant recipients of the tissue; and the donation is being made without informing the donor of the identity of those individuals who may become the recipients.
  2. The donor's attending physician must sign a statement declaring that the tissue has been obtained in accordance with the donor's signed statement and that full disclosure has been made to the donor of: (1) the attending physician's interest, if any, in the research to be conducted with the tissue, and (2) any known medical risks to the donor or risks to her privacy that might be associated with the donation of the tissue and that are in addition to the risks associated with the woman's medical care. In the case of tissue obtained pursuant to an induced abortion, the attending physicians's statement must also declare that the consent of the woman for the abortion was obtained prior to requesting or obtaining consent for donation, the abortion was conducted in accordance with applicable State law, and no alteration of the timing, method, or procedures used to terminate the pregnancy was made solely for the purposes of obtaining the tissue.
  3. The individual with the principal responsibility for conducting the research must sign a statement declaring that the individual is aware that the tissue is human fetal tissue donated for research purposes and may have been obtained pursuant to a spontaneous or induced abortion or pursuant to a stillbirth; that the principally responsible researcher has provided such information to other individuals with responsibilities regarding the research; that the principally responsible researcher will require, prior to obtaining the consent of a person to be a transplant recipient of the tissue, written acknowledgment of receipt of the foregoing information by such recipient; and that the principally responsible researcher has had no part in any decisions as to the timing, method, or procedures used to terminate the pregnancy made solely for the purposes of the research.
  4. Human fetal tissue may be used only if the head of the agency or other entity conducting the research involved certifies to the Secretary of Health and Human Services that the required informed consent statements will be available for audit by the Secretary.

The Office for Protection from Research Risks (OPRR) is responsible for assuring that all research supported by the Department of Health and Human Services (HHS) is in compliance with the HHS Regulations for the Protection of Human Research Subjects (45 CFR Part 46). As a condition of receipt of HHS support for research involving human subjects, awardee institutions must provide written Assurances of Compliance to OPRR describing the means they will employ to comply with the HHS Regulations. A Multiple Project Assurance is an agreement negotiated with an institution in which the institution pledges that all HHS funded research will comply with applicable Federal, State, and local laws. The OPRR has a current Multiple Project Assurance in place with each institution that receives HHS funds supporting fetal tissue research. Since 1995, OPRR has taken the additional measure of annually requesting, from each institution which has been awarded HHS funds for fetal tissue research, a letter verifying that in fact these projects are being conducted in full accord with applicable Federal, State, and local laws. OPRR has received such verification letters from all six institutions that are currently engaged in research supported by the NIH involving fetal tissue.

Finally, another oversight mechanism has involved scrutiny from the General Accounting Office (GAO), which in 1996 conducted a study of whether researchers were indeed complying with the requirements set forth in P.L. 103-43. In addition to reviewing Federal records, GAO staff visited project personnel at the academic medical centers where this type of work was taking place. This study confirmed that researchers were obtaining informed consent in the appropriate manner and that there were no reported violations of requirements concerning the acquisition of human fetal tissue for use in transplantation.


VI. Conclusion

Most earlier non-NIH studies of therapeutic human fetal tissue transplantation for Parkinson's disease have not been controlled studies and their results have been inconsistent. Previous studies have also had a number of variations in patient selection, transplant variables, rating systems, functional assessments, and clinical expertise of the investigator. Consequently, the outcomes from different studies cannot be compared or combined in order to draw conclusions about efficacy. The studies being supported by the NIH, in contrast, are rigorously controlled. By supporting double-blind, controlled clinical trials, the NIH expects to facilitate the production of more definitive information concerning the efficacy of human fetal tissue transplantation in Parkinson's disease.

While studies involving therapeutic human fetal tissue transplantation research are carried out, the NIH will also continue to support clinical investigation of alternative lines of research. In the area of Parkinson's disease, for example, many other promising approaches are being explored, including the implantation of cells engineered to produce dopamine, surgery to lessen damage to brain areas that direct movement, and the use of specific growth factors to protect dopamine-producing cells and to help them recover.