National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells

(Effective August 25, 2000, 65 FR 51976)
(Corrected November 21, 2000, 65 FR 69951)

This Federal Register Announcement has been superceded as it pertains to human embryonic stem cell research. Please refer to the Federal Register Announcement.

SUMMARY: The National Institutes of Health (NIH) is hereby publishing final "National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells." The Guidelines establish procedures to help ensure that NIH-funded research in this area is conducted in an ethical and legal manner.

EFFECTIVE DATE: These Guidelines are effective on August 25, 2000. The moratorium on research using human pluripotent stem cells derived from human embryos and fetal tissue put in place by the Director, NIH, in January 1999, was lifted on August 25, 2000.

SUMMARY OF PUBLIC COMMENTS ON DRAFT GUIDELINES: On December 2, 1999, the NIH published Draft Guidelines for research involving human pluripotent stem cells (hPSCs) in the Federal Register for public comment. The comment period ended on February 22, 2000.

The NIH received approximately 50,000 comments from members of Congress, patient advocacy groups, scientific societies, religious organizations, and private citizens. This Notice presents the final Guidelines together with NIH's response to the substantive public comments that addressed provisions of the Guidelines.

Scope of Guidelines and General Issues

Respondents asked for clarification of terminology used in the Guidelines and some commented that the language was not appropriate or was too technical, particularly the informed consent sections. The NIH agrees that these Guidelines should be clear and understandable. Changes, including some reorganization of the sections, were made to this end. The Guidelines are written primarily for the purpose of informing investigators of the conditions that must be met in order to receive NIH funding for research using hPSCs and, therefore, some technical language is required. The Guidelines do not define the precise language that should appear in informed consent documents because these should be developed by the investigator/clinician specifically for a particular study protocol or procedure for which the consent is being sought. Existing regulatory provisions require (45 CFR 46.116) that the language in informed consent documents be understandable to prospective participants in the study.

Respondents suggested that NIH funding for research using hPSCs would be in violation of the DHHS appropriations law and that derivation of hPSCs cannot be distinguished from their use. For this reason, a number of respondents asked that the NIH withdraw the draft Guidelines. The NIH sought the opinion of the DHHS General Counsel, who determined that "federally funded research that utilizes hPSCs would not be prohibited by the HHS appropriations law prohibiting human embryo research, because such cells are not human embryos." Comments questioning this conclusion did not present information or arguments that justify reconsideration of the conclusion.

Respondents commented that the Guidelines are too restrictive or that there is no need for Federal Guidelines for this arena of research. Comments asserted that federally funded research using hPSCs should go forward without formal requirements, in the same manner as in the private sector. In order to help ensure that the NIH-funded research using hPSCs is conducted in an ethical and legal manner, the NIH felt it was advisable to develop and implement guidelines. To this end, the NIH Director convened a Working Group of the Advisory Committee to the Director, NIH (ACD), to advise the ACD on the development of guidelines and an oversight process for research involving hPSCs. The NIH Director charged the Working Group with developing appropriate guidelines to govern research involving the derivation and use of hPSCs from fetal tissue and research involving the use of hPSCs derived from human embryos that are in excess of clinical need.

Respondents commented regarding the sources of stem cells. Some respondents stated that research on hPSCs was unnecessary because stem cells from adults, umbilical cords, and placentas could be used instead. Other respondents asked the NIH to restrict Federal funding for hPSC research to those cells derived from fetal and adult tissue but not embryos. Other respondents asked that the Guidelines encompass research using stem cells from adult tissues. As stated under Section I. Scope of Guidelines, the Guidelines apply to the use of NIH funds for research using hPSCs derived from human embryos or human fetal tissue. The Guidelines do not impose requirements on Federal funding of research involving stem cells from human adults, umbilical cords, or placentas.

Given the enormous potential of stem cells to the development of new therapies for the most devastating diseases, it is important to simultaneously pursue all lines of promising research. It is possible that no single source of stem cells is best or even suitable/usable for all therapies. Different types or sources of stem cells may be optimal for treatment of specific conditions. In order to determine the very best source of many of the specialized cells and tissues of the body for new treatments and even cures, it is vitally important to study the potential of adult stem cells for comparison to that of hPSCs derived from embryos and fetuses. Unless all stem cell types are studied, the differences between adult stem cells and embryo and fetal-derived hPSCs will not be known.

Moreover, there is evidence that adult stem cells may have more limited potential than hPSCs. First, stem cells for all cell and tissue types have not yet been found in the adult human. Significantly, cardiac stem cells or pancreatic islet stem cells have not been identified in adult humans. Second, stem cells in adults are often present in only minute quantities, are difficult to isolate and purify, and their numbers may decrease with age. For example, brain cells from adults that may be neural stem cells have been obtained only by removing a portion of the brain of an adult with epilepsy, a complex and invasive procedure that carries the added risk of further neurological damage. Any attempt to use stem cells from a patient's own body for treatment would require that stem cells would first have to be isolated from the patient and then grown in culture in sufficient numbers to obtain adequate quantities for treatment. This would mean that for some rapidly progressing disorders, there may not be sufficient time to grow enough cells to use for treatment. Third, in disorders that are caused by a genetic defect, the genetic error likely would be present in the patient's stem cells, making cells from such a patient inappropriate for transplantation. In addition, adult stem cells may contain more DNA abnormalities caused by exposure to daily living, including sunlight, toxins, and errors made during DNA replication than will be found in fetal or embryonic hPSCs. Fourth, there is evidence that stem cells from adults may not have the same capacity to multiply as do younger cells. These potential weaknesses may limit the usefulness of adult stem cells.

Respondents were concerned that these are guidelines and not requirements or regulations. Although these are guidelines and not regulations, they prescribe the documentation and assurances that must accompany requests for NIH funding for research utilizing hPSCs. If the funding requests do not contain the prescribed information, funding for hPSC research will not be provided. Compliance with the Guidelines will be imposed as a condition of grant award.

Respondents commented that there had not been enough widespread public disclosure/discussion of this research or the Guidelines. Prior to the development of draft Guidelines, there were two Congressional hearings on hPSCs. In a further effort to ensure substantial discussion and comment, the NIH convened a Working Group of the Advisory Committee to the Director, NIH (ACD), to advise the ACD on the development of these Guidelines. The Working Group was composed of scientists, patients and patient advocates, ethicists, clinicians, and lawyers. The Working Group met in public session on April 8, 1999, and heard from members of the public, as well as professional associations and Congress. In developing the draft Guidelines, the NIH also considered advice from the National Bioethics Advisory Commission (NBAC). Draft Guidelines were published for public comment in the Federal Register on December 2, 1999, for 60 days, and, in response to public interest, the comment period was extended an additional 28 days. Approximately 50,000 comments were received. NIH issued a national press release announcing the Federal Register notice and many of the Nation's newspapers carried articles on this area of research and on the Guidelines. Patient groups, scientific societies, and religious organizations convened meetings and discussion groups and disseminated materials about this area of research and about the Guidelines.

Comment was received about whether the Guidelines apply to hPSC lines developed outside of the United States. The Guidelines make no distinction based upon the country in which an hPSC line is developed. All lines to be used in hPSC cell research funded by NIH must meet the same requirements.

Derivation and Use of hPSCs From Fetal Tissue

Respondents made the point that the NIH has specified certain requirements for the use of human fetal tissue to derive hPSCs in addition to those imposed on other areas of human fetal tissue research. These respondents suggested that the section of the Guidelines pertaining to fetal tissue sources be omitted. In order to ensure uniformity in NIH's oversight of research using hPSCs, the Guidelines were extended to govern hPSCs derived from both human embryos and fetal tissue.

Use of hPSCs Derived From Human Embryos

Respondents suggested that the Guidelines refer to "fertility treatment" rather than to "infertility treatment" in order to clarify that they allow the use of human embryos from treatments that employ assisted reproductive technologies to facilitate reproduction in fertile, as well as in infertile, individuals. The Guidelines have been changed accordingly.

Respondents suggested dropping the word "early" throughout the document or more clearly defining "early." The word "early" in reference to human embryos has been deleted; the Guidelines make it clear that NIH funding of research using hPSCs derived in the private sector from human embryos can involve only embryos that have not reached the stage at which the mesoderm is formed.

Some respondents were concerned that embryos might be created for research purposes. Other respondents stated there should be no distinction between embryos created for research purposes and those created for fertility treatment. Investigators seeking NIH funds for research using hPSCs are required to provide documentation, prior to the award of any NIH funds, that embryos were created for the purposes of fertility treatment. President Clinton, many members of Congress, the NIH Human Embryo Research Panel, and the NBAC have all embraced the distinction between embryos created for research purposes and those created for reproductive purposes.

Respondents were concerned about the creation of a "black market" for human embryos, and expressed concerns that individuals will be coerced into donating embryos. The Guidelines state that there can be no incentives for donation and that a decision to donate must be made free of coercion. In addition, the Guidelines set forth conditions that will help ensure all donations are voluntary. For example, with regard to hPSCs derived from embryos, research using Federal funds may only be conducted if the cells were derived from frozen embryos that were created for the purpose of fertility treatment and that were in excess of clinical need.

Respondents commented on the requirement that human embryos be frozen in order to qualify for derivation of hPSCs to be used in NIH-funded research. Respondents suggested that the freezing requirement would preclude the use of hPSCs derived from embryos that are genetically and chromosomally abnormal, since such embryos are usually not frozen for reproductive purposes. While the NIH acknowledges that research on hPSCs derived from such embryos could yield important scientific information, limiting research to hPSCs derived from frozen human embryos will help ensure that the decision to donate the embryo for hPSC research is distinct and separate from the fertility treatment.

Financial Issues

Respondents expressed concern regarding the sale of fetal tissue for profit and whether hPSC research would encourage such activity. Respondents also were concerned about whether clinics or doctors would profit from the derivation of hPSCs and/or their sale. Section 498B of the Public Health Service Act prohibits any individual from knowingly acquiring or selling human fetal tissue for "valuable consideration." In addition, the Guidelines prohibit any inducement for the donation of human embryos for research purposes. The Guidelines also call for an assurance that the hPSCs to be used in NIH-funded research were obtained through a donation or through a payment that does not exceed the reasonable costs associated with the transportation, processing, preservation, quality control and storage of the hPSCs. All grantees must sign an assurance that they are in compliance with all applicable Federal, State, and local laws. Each funded research institution is responsible for monitoring compliance by individual investigators with any such applicable laws.

Respondents questioned the prohibition against embryo donors benefitting financially from their donation. This clause was retained in the final Guidelines to help ensure that the donating individuals are offered no inducements to donate and that all donations are voluntary.

Respondents suggested that the Guidelines be strengthened to include a waiver of intellectual property rights. This proposed change would be inconsistent with 45 CFR 46.116 of the regulation for the protection of human subjects of research, which provides that no informed consent may include language through which the subject waives or appears to waive any of the subject's legal rights.

Respondents questioned the reference in the requirements for informed consent related to the commercial potential of donated material. The paragraphs providing for disclosure in the informed consent of the possibility that the donated material could have commercial potential were modified. The reference in these paragraphs to "donated material" did not accurately reflect the intent of the provision. The Guidelines now make clear that the "results of research on the human pluripotent stem cells may have commercial potential."

Ineligible Research

Respondents objected to the areas of research that the NIH has deemed ineligible, particularly research that is not restricted by statute or regulation, such as research utilizing hPSCs that were derived using somatic cell nuclear transfer, i.e., the transfer of a human somatic cell nucleus into a human egg. The NIH determined that, at this time, research using hPSCs derived from such sources has not received adequate discussion and consideration by the public and is, therefore, ineligible for NIH funding.

Separation of Fertility Treatment and Abortion From Research

Respondents were concerned that hPSC research would encourage abortion. The law and the Guidelines guard against encouraging abortion by requiring that the decision to have an abortion be made apart from and prior to the decision to donate tissue.

Respondents objected to the condition in the Guidelines that the fertility physician could not be the same person as the researcher deriving stem cells. Some respondents stated that the Institutional Review Board (IRB) or an independent physician would be able to guard against this conflict of interest. The restriction was designed so that the person treating the individuals seeking fertility treatment, who is involved in decisions such as how many embryos to produce, is not the person seeking to derive hPSCs. This separation will help ensure that embryos will not be created in numbers greater than necessary for fertility treatment.

Respondents suggested that the clauses regarding donation of fetal tissue or human embryos for derivation of stem cells for eventual use in transplantation be changed explicitly to prevent directed donation. This change has been made.

Identifiers

Respondents were concerned about removing identifiers. There was concern that the investigator would not be able to document compliance with the Guidelines requirements without identifiers, or that the removal of identifiers would make it impossible to conduct certain genetic studies or develop therapeutic materials. The Guidelines have been modified to clarify that the term "identifier" refers to any information from which the donor(s) can be identified, directly or through identifiers linked to the donors. However, since information identifying the donor(s) may be necessary if the tissue or cells are to be used in transplantation, the Guidelines have also been modified to state that the informed consent should notify donor(s) whether or not identifiers will be retained.

Respondents commented that DNA is an identifier and that all donors of human embryos or fetal tissue should be told that identifiers such as DNA will be retained with the samples. Although DNA can be used to determine the individual from whom a tissue sample was taken, this can be done only when one has a sample from both the tissue in question and the putative donor; it cannot be used to identify an individual out of a population. Moreover, it is difficult to identify a donor using tissue derived from a fetus or embryo, since the tissue is not genetically identical to the donor.

Informed Consent and IRB Review

Respondents asked why investigators were expected to provide documentation of IRB review of derivation from human embryos, but not for derivation from fetal tissue. Respondents suggested that the requirements be changed so that protocols for both sources of hPSCs must be approved by an IRB. The Guidelines have been changed to make clear that the IRB review requirements regarding the derivation of cells from fetal tissue and human embryos are the same.

Comment was received expressing concern that the informed consent explicitly state that the donor will have no dispositional authority over derived pluripotent stem cells. The Guidelines state that donation of human embryos should have been made without any restriction regarding the individual(s) who may be the recipient of the cells derived from the hPSCs for transplantation. Such a statement is consistent with the statutory provision applicable to the donor informed consent for the use of fetal tissue for transplantation. The Guidelines now provide for the inclusion of a statement to this effect in the informed consent.

Respondents urged that the Guidelines be revised to remove the prohibition on potential donors receiving information regarding subsequent testing of donated tissue in the situation when physicians deem disclosure to be in the donors' best interest. This change has been made.

Respondents requested clarification regarding the persons from whom consent for donation of embryos for research must be obtained. The Guidelines call for informed consent from individual(s) who have sought fertility treatment. Only the individual(s) who were part of the decision to create the embryo for reproductive purposes should have been part of the decision to donate for the derivation of hPSCs.

Respondents urged that fertility clinics should be able to discuss with patients the option of donating embryos for research at the beginning of the IVF process. The Guidelines do not delineate the timeframe during which the general option of donating embryos for research can be discussed. However, according to the Guidelines, obtaining consent for donation of embryos for the purpose of deriving hPSCs should not occur until after the embryos are determined to be in "excess of clinical need."

Oversight

Respondents stated that the NIH's oversight in this area of research was very important to the legal and ethical conduct of this research, and asked for more information regarding the oversight process. Information about the operations of the Human Pluripotent Stem Cell Review Group (HPSCRG) can be found in the final Guidelines and on the NIH Web page.

Respondents were concerned about whether and how NIH would monitor research after a researcher receives NIH funds. Compliance with the Guidelines will be largely determined prior to the award of funds. Follow-up to ensure continued compliance with the Guidelines will be conducted in the same manner as for all other conditions of all other NIH grant awards. It is the responsibility of the investigator to file progress reports, and it is the responsibility of the funded institution to ensure compliance with the NIH Guidelines. NIH staff will also monitor the progress of these investigators as part of their regular duties.

Respondents asked about penalties for not following the Guidelines. The following actions may be taken by the NIH when there is a failure to comply with the terms and conditions of any award: 1) Under 45 CFR 74.14, the NIH can impose special conditions on an award, including increased oversight/monitoring/reporting requirements for an institution, project or investigator; 2) Under 45 CFR 74.62, if a grantee materially fails to comply with the terms and conditions of the award, the NIH may withhold funds pending correction of the problem or, pending more severe enforcement action, disallow all or part of the costs of the activity that was not in compliance, withhold further awards for the project, or suspend or terminate all or part of the funding for the project. Individuals and institutions may be debarred from eligibility for all Federal financial assistance and contracts under 45 CFR Part 76 and 48 CFR Subpart 9.4, respectively. Because these sanctions pertain to all conditions of grant award, the NIH did not reiterate them in the Guidelines.

Respondents suggested that the HPSCRG hold periodic Stem Cell Policy Conferences (similar to the Gene Therapy Policy Conferences conducted by the Recombinant DNA Advisory Committee (RAC)) in order to solicit and consider public comment from interested parties on the scientific, medical, legal, and ethical issues arising from stem cell research. Members of the HPSCRG will serve as a resource for recommending to the NIH any need for Human Pluripotent Stem Cell Policy Conferences.

Other Changes

Because compliance materials may be made public prior to funding decisions, we have added a sentence requiring the principal investigator's written consent to the disclosure of such material necessary to carry out public review and other oversight procedures.

The draft Guidelines required HPSCRG review of proposals from investigators planning to derive hPSCs from fetal tissue. Because the Guidelines address proposals for NIH funding for the use of hPSCs, this requirement has been removed from the Guidelines.

The text of the Guidelines follows.