Policies and Procedures for the Use of Human Fetal Tissue (HFT) for Non-Transplantation Research Purposes in the Intramural Research Program

The purpose of this policy is to ensure that HFT is utilized for IRP non-transplantation research only when scientifically justifiable, and in the least amount possible to achieve the scientific outcomes; and to ensure that the acquisition and use of HFT by the IRP complies with all applicable laws and HHS/NIH policies. Intramural researchers must provide detailed information proposing the use of HFT and receive approval, prior to commencing work.

Research on transplantation of HFT for therapeutic purposes requires additional intramural oversight because of additional statutory provisions addressing such research. Please contact the Office of Intramural Research if you are considering research in which HFT would be transplanted as part of clinical research.

Definition

For the purpose of this policy, human fetal tissue (HFT) is defined as tissue or cells obtained from a dead human embryo or fetus after a spontaneous or induced abortion, or after a stillbirth, but does not include established human fetal cell lines. RNA, DNA, protein, or subcellular derivatives of HFT, and data derived by others from HFT, are not covered in this definition.

Procedures

Prior to any NIH intramural investigator obtaining HFT or performing any non-transplantation research utilizing HFT, a proposed protocol to use HFT in research must undergo a review process consisting of two components, an HFT review and a human subjects review; approvals from both review groups are required before HFT is acquired and research begins [see Appendix 1]. This process is required of all HFT research conducted by NIH intramural researchers, including, for example, multisite research in which the NIH is a participating site or research using de-identified HFT that might otherwise be considered by the Institutional Review Board (IRB) to not meet the regulatory definition of human subjects research.

To initiate the human subjects review process of the proposed protocol, the NIH intramural PI must submit the protocol to the IRB using the electronic IRB system (PROTECT). The submission may be either a new human subjects research protocol, a modification to an existing protocol, or a request for a determination that the activity is not human subjects research. Regardless of the request type, the NIH PI must indicate on the IRB application that the research involves HFT.

In addition, within PROTECT, the NIH PI must complete and upload a separate HFT Ancillary Review Form (this form is located in the PROTECT IRB library) that has been signed by the NIH PI and the Scientific Director or delegate/designee¹. This will trigger an ancillary HFT review of the proposed research by the HFT Review Committee (see below). The Office of IRB Operations (IRBO) will not act upon the submitted IRB protocol until the ancillary HFT review has concluded (see Appendix 1).

HFT Review

The HFT Review Committee² will review the HFT Ancillary Review Form to ensure it meets all of the elements outlined below. The HFT Review Committee will also review the HFT review form to ensure that HFT is utilized for IRP research only when scientifically justifiable, and in the least amount possible to achieve the scientific outcomes; and to ensure that the acquisition and use of HFT by the IRP complies with all applicable laws and HHS/NIH policies. It is the responsibility of the NIH PI to submit a complete and accurate HFT proposal to the committee. Elements to be addressed and reviewed are:

1. The research goals of the project and the anticipated benefits of the research.
2. Why the research goals cannot be accomplished using an alternative to HFT (including, but not limited to, induced pluripotent cells not developed from HFT, organoids not developed from HFT, neonatal human tissue, human tissue obtained from adults, animal models, in vitro models that are not developed from HFT, and computational models).
3. The methods used to determine that no alternatives to HFT can be used to accomplish the stated research goals (including, but not limited to, literature review and/or preliminary experiments with non-HFT).
4. The source of the HFT (such as by a Material Transfer Agreement or some other type of agreement, usually with an academic institution, clinic, or hospital; or, from a commercial vendor through a purchase order).
5. How the HFT will be treated and/or used in specific experiments (including, but not limited to, culturing, imaging, differentiating, cell-sorting, DNA/RNA extractions, infecting or transfecting, etc.).
6. Detailed budget information including the quantity and type (catalog number, age of fetus, tissue type, or other biologic feature) of the HFT to be acquired, and the actual cost of the acquisition.
7. How HFT samples will be depleted or disposed of after use.
8. Affirmation that HFT was not acquired for “valuable consideration” per 42 USC 289g. (Valuable consideration does not include reasonable payments associated with the transportation, processing, preservation, quality control, or storage of HFT.)
   1. If the tissue will be obtained directly from a donor, the investigator must affirm that the HFT was not obtained or acquired for valuable consideration. There must be written agreement for the transfer of tissue and informed consent from the donor. Please consult with the IRBO in advance of this process. (Note: NIH researchers are not permitted to perform or otherwise be involved in any procedures to terminate a pregnancy)
   2. If tissue will be purchased from a commercial vendor, the investigator must provide the name, address, and contact phone number or email address for the vendor.
   3. If the tissue will be obtained from any other entity, including a clinic, hospital, or external collaborator, there must be an agreement such as an MTA documenting the transfer to and use of materials by NIH. The provider must affirm in the agreement that the HFT was not obtained or provided for valuable consideration.
   4. The reviewers will confirm that the required affirmations are in place; and assess whether the charges for HFT represent reasonable payments associated with the transportation, processing, preservation, quality control, or storage of HFT.

NIH Principal Investigator Responsibilities and Human Subjects Review

The NIH PI must use PROTECT to submit to the IRBO the following:

1. A protocol describing the proposed use of the HFT. This may be a new human subjects research protocol, an amendment to an existing protocol or a request for a determination that the activity is not human subjects research.
   1. The protocol must describe whether the NIH research team will receive identifying information about the donor of the HFT.
   2. The protocol also must describe whether any research activities will be conducted involving the donor. This includes research obtaining the donor’s data and/or donor derived biospecimens other than the HFT.
   3. If research will be conducted with data or biospecimens from the donor, that individual may be considered a participant in the research and the protocol subject to all applicable human subject policy and regulation.
2. A blank consent form for HFT donation obtained from the source of the tissue to be donated and a summary of the consent process. The consent form used for the donation of the HFT must include statements that provide the following assurances, as applicable:
   1. That the donation of the HFT is voluntary;
   2. There were no enticements, benefits or financial incentives of any kind provided at any point in the process to incentive the abortion (if from an elective termination of pregnancy), or the donation of the HFT.
   3. When the HFT is from an elective abortion: the consent for the donation was obtained by someone other than the person who obtained the consent for the abortion;
   4. When the HFT is from an elective abortion: the consent for the donation of the HFT occurred after the consent for the abortion and that the donation will not alter the method, timing or procedures used for the abortion;
   5. If the HFT is to be obtained directly from a donor, then the consent for donation must include a statement that the HFT was not obtained or acquired for valuable consideration;
   6. That the consent form is or will be signed by both the donor and the person who obtains the consent for the donation.
3. The NIH PI seeking to obtain the HFT for research use must provide written assurance of the following:
   1. That individuals engaged in the research will have or had no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy.
   2. That individuals engaged in the research will have or had no part in determining the viability of a neonate.
4. Any proposal to collect tissue or cells from a viable fetus will be submitted to the IRB for review under all applicable regulations and policies. Please contact OHSRP for guidance.

The Office of IRB Operations (IRBO), OHSRP, will conduct the human subjects review of the IRB protocol to determine whether the proposed research constitutes human subjects research and, if so, determine if the informed consent that was or will be used to acquire the HFT meets applicable regulatory and policy requirements.

Intramural Oversight of Approved HFT Research

All intramural scientists must be knowledgeable of the policies and legal requirements applying to HFT research. Intramural Investigators are required to maintain a copy of all documentation mentioned above in their research records, and are required to indicate on the annual Biospecimen Report whether HFT related to a specific Annual Report project was acquired, used, or stored in the current fiscal year. The Principal Investigator’s Scientific Director is required to review the proposed use of HFT, and only proposals that are approved by the Scientific Director may be submitted for review to OHSRP. The Scientific Director is further required to provide oversight of the HFT use and report on this as required by the annual Management Control Survey.

IRP oversight of HFT research conducted by intramural investigators is summarized below.

• NIH Office of Human Subjects Research Protections (OHSRP). The Office of Human Subjects Research Protections (OHSRP) provides guidance to NIH intramural investigators who are using or contemplate using HFT. All research using HFT must be reviewed and approved either by the NIH Office of IRBO or the NIH IRP IRB.
• Biospecimen Report. Intramural investigators with NIH supported projects that entail the acquisition, use or storage of HFT must submit an annual biospecimen report that tracks this tissue. The Office of Intramural Research and the Scientific Directors of each Institute/Center direct investigators to specifically identify when HFT is used during the reporting period. Please review the NIH Human Biospecimen Program Sourcebook page for additional information.
• Clinical and Scientific Director Review. The Clinical and Scientific Directors, who provide immediate oversight of intramural research in each institute, must be aware of the policies and legal requirements governing acquisition and use of HFT. They are directed to ensure that all scientists who use HFT in their research assure HFT is used and acquired in accordance with such policies and legal requirements.
• Management Controls. In the annual Management Controls review, each Scientific Director must be asked to verify that he or she has reviewed the policies and legal requirements regarding HFT acquisition and use for research in their intramural program, and to identify and correct any potential problem areas. Please review the NIH Management Controls Survey for additional information.

Relevant Policies and Legal Requirements

1. 42 U.S.C. 289g-2 provides that:
   • "It shall be unlawful for any person to knowingly acquire, receive, or otherwise transfer any human fetal tissue for valuable consideration if the transfer affects interstate commerce."
   • The term "valuable consideration" does not include reasonable payments associated with the transportation, implantation, processing, preservation, quality control, or storage of human fetal tissue.
   • The full text of 42 U.S.C. 289g-2 is available at: https://www.gpo.gov/fdsys/pkg/USCODE-2010-title42/html/USCODE-2010-title42-chap6A-subchapIII-partH-sec289g-2.htm.
2. 42 U.S.C. 289g-1 sets forth specific requirements for research involving transplantation of HFT for therapeutic purposes.
   • The full text of 42 U.S.C. 289g-1 is available at: https://www.gpo.gov/fdsys/pkg/USCODE-2010-title42/html/USCODE-2010-title42-chap6A-subchapIII-partH-sec289g-1.htm.
3. NIH Intramural Research involving HFT is also subject to the HHS Regulations for the Protection of Human Subjects (45 CFR 46).
   • §46.206 Research involving, after delivery, the placenta, the dead fetus or fetal material.
     1. Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accord with any applicable federal, state, or local laws and regulations regarding such activities.
     2. If information associated with material described in paragraph (a) of this section is recorded for research purposes in a manner that living individuals can be identified, directly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent subparts of this part are applicable.
   • The full text of the HHS Regulations for the Protection of Human Subjects is available at: https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html.
4. NIH Intramural Research is also subject to NIH policy specified in NOT-OD-16-033, "NIH Policy on Informed Consent for Human Fetal Tissue Research".

Appendices

Appendix 1: Review Workflow

[1] The HFT Ancillary Review form replaces the previous “HFT Investigator Attestation” forms.
[2] The HFT Review Committee will include representatives of the OIR AIRIO, OHSRP, the Board of SD/CD, and HFT researchers. Additional technical subject matter experts may serve as ad hoc members. All members shall be federal employees.