Approval Process for the Documentation of Compliance With NIH Guidelines on the Use of Human Pluripotent Stem Cells in NIH Research Proposed for Support Under Grants and Cooperative Agreements, November 21, 2000

Release Date: November 21, 2000

NOTICE: OD-01-003 (amended)

This Guideline Notice has been superceded as it pertains to human embryonic stem cell research. Please refer to the Notice of Withdrawal of NIH Guidelines for Research Using Pluripotent Stem Cells.

National Institutes of Health

INTRODUCTION

The only significant difference in this notice and that published on October 16, 2000, is that there are separate descriptions of the materials to be submitted for human pluripotent stem cells derived from embryos or fetal tissue. The documentation to be submitted and the timetable for submission have not changed. However, a separate discussion of the process for embryos or fetal tissue clarifies the compliance approval process.

On August 23, 2000, the National Institutes of Health (NIH) published an outline of procedures for the approval of the use of human pluripotent stem cells in NIH supported intramural and extramural research). This second notice details the specific procedures that must be followed by extramural investigators proposing to use existing or seeking new NIH funds for research using human pluripotent stem cells derived from human embryos and human fetal tissue. These procedures are based on the NATIONAL INSTITUTES OF HEALTH GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS, hereinafter referred to as the NIH GUIDELINES, published in the Federal Register (65 FR 51976) and effective on August 25, 2000. Because the GUIDELINES contain a few incorrect citations and other minor errors, a notice of correction (65 FR 69951) is being published on November 21, 2000. The present notice details required procedures for research using pluripotent stem cells to be supported under grants and cooperative agreements.

All research to be supported under NIH grants and cooperative agreements undergoes regular scientific peer review, including the customary two-stage process involving review by a Scientific Review Group (Study Section) and the Advisory Council of an Institute/Center. In addition, for research that proposes the use of human pluripotent stem cells, there will be a formal review of documentation of compliance with the NIH GUIDELINES. This latter review will be conducted by the Human Pluripotent Stem Cell Review Group (HPSCRG) which is a working group of the Center for Scientific Review Advisory Council (CSRAC). The process for documenting compliance with the NIH GUIDELINES is separate from the grant and cooperative agreement scientific review process. The two processes will take place in parallel in order to ensure that all aspects of scientific review and review of compliance are considered in a timely manner. Institutions and investigators proposing research using human pluripotent stem cells must be mindful of the requirements and deadlines for both processes in order to avoid delays in the potential funding of proposed research. NIH will not provide funds or allow existing funds to be used for research utilizing human pluripotent stem cells derived from human embryos or human fetal tissue until appropriate approvals have been obtained. Evidence of compliance with the NIH GUIDELINES does not affect the scientific merit review of a grant application nor does it ensure a favorable funding decision by the NIH.

Review of compliance with the NIH GUIDELINES is a two-stage process. Any request proposing to use existing or seeking new NIH funds for research utilizing human pluripotent stem cells derived from human embryos or human fetal tissue must include the submission of compliance documentation to the NIH. The HPSCRG members will review the submitted documentation and forward their recommendation(s) to the CSRAC for final consideration. When the HPSCRG receives compliance documentation in support of a request for funds that proposes the use of a line of human pluripotent stem cells that has not been previously reviewed by HPSCRG and recommended to, and approved by, the CSRAC, the HPSCRG review will take place in a public meeting. Thus, although HPSCRG will review all requests for funds, the review of compliance documentation for the use of a cell line previously approved by the NIH will not take place in a public meeting of the HPSCRG. The final approval of documentation of compliance will always take place in a public meeting of the CSRAC.

SUBMISSION OF DOCUMENTATION

Timetable

Documentation is to be submitted to the Office of Science Policy, Office of the Director, NIH, by institutions on behalf of principal investigators. An original and two copies of the documentation are to be submitted to:

The schedule for receipt and review by the HPSCRG and the CSRAC follows:

Packages of documentation received by the Office of Science Policy after the established deadlines will be held for the next cycle of HPSCRG and CSRAC consideration.

To avoid delays, the required documentation of compliance with the NIH GUIDELINES may need to be submitted to the Office of Science Policy in advance of the submission of the actual grant application. Thus, institutions planning on submitting competing grant applications whether for standing receipt dates or special receipt dates (responses to Requests for Applications or special Program Announcements) between January 10 and May 1 will need to submit the required documentation to the Office of Science Policy by March 15 in order to prevent delay in the consideration of the application. Specifically, institutions planning to submit small business applications on April 1, individual fellowship applications on April 5, or AIDS applications on May 1 should plan to submit the documentation to the Office of Science Policy by March 15 in order to avoid delays in the process. Likewise, planned submissions for August 1 (small business), August 5 (fellowships), or September 1 (AIDS) need documentation submitted on July 15 and planned submissions for December 1 (small business), December 5 (fellowships), and January 2 (AIDS) by November 15. When institutions are submitting applications for RFAs and other special receipt dates, they must also consider the HPSCRG schedule and submit documentation accordingly. For administrative supplements to existing grants or proposals to use human pluripotent stem cells in studies funded as part of existing awards without a request for additional funds, institutions must comply with the NIH GUIDELINES and should also submit documentation for HPSCRG review. Investigators and institutions are advised that it may be prudent to first contact the awarding Institute or Center to discuss the proposed administrative supplement. If existing funds are to be used and the proposed research constitutes a change in scope of the funded project, the principal investigator must obtain prior approval for the change in scope from the funding Institute/Center at NIH (see the NIH Grants Policy Statement) prior to the submission of compliance material to HPSCRG. Approval of the documentation of compliance with the NIH GUIDELINES does not ensure the approval of the Institute/Center of an administrative supplement or for a change in scope of the funded project.

Materials to be submitted to NIH for research on human pluripotent stem cells derived from EMBRYOS and FETAL TISSUE

1. HUMAN PLURIPOTENT STEM CELLS DERIVED FROM EMBRYOS

   1. MATERIALS TO BE SUBMITTED TO THE OFFICE OF SCIENCE POLICY

      1. Cover Page with the following information (See sample below)

         1. Name of the Principal Investigator (PI).

         2. Title of the grant or cooperative agreement application (See NIH GUIDELINES, Section II.A.1.f). If part of a multicomponent submission (for example a Program Project), include the name of the PI, the title of the overall application, and the title(s) of the project(s) involving the use of human pluripotent stem cells. If a competing continuation, revised application, administrative supplement, or existing award without a request for additional funds, also include the grant number (for example, R01 CA123456).

         3. Anticipated date of submission of the competing grant/cooperative agreement application.

         4. Name, title, telephone number, fax number, and e-mail address of the institutional official submitting the information.

         5. Signature of the institutional official.

         SAMPLE COVER PAGE

         Principal Investigator:	Roberta Dilan, M.D.
         Title of Project:	"Use of Human Pluripotent Stem Cells to Treat XYZ Disease," Project 4 of Renewal of Program Project, "Diagnosis and Therapy of XYZ Disease," Renewal of P01 ZZ123456 (P01 Principal Investigator: James Blue, M.D., Ph.D.)
         Anticipated Submission Date of Grant Application:	February 1, 2001
         Submitted by:	University of Lakeview
         Institutional Official:	Eileen Smith, Ph.D. Associate Provost for Research University of Lakeview 555-555-1212 (voice) 555-555-2121 (fax) smithe@lakeview.edu

      2. Documentation of compliance with the NIH GUIDELINES specific to research using human pluripotent stem cells derived from HUMAN EMBRYOS.

         1. An assurance signed by the responsible institutional official that the pluripotent stem cells were derived from human embryos in accordance with the conditions set forth in Section II.A.2 of the NIH GUIDELINES and that the institution will maintain documentation in support of this assurance. The official's signature will attest that the institution has documentation (or an assurance) from the person(s) who derived the human pluripotent stem cells stating that the derivation process was conducted in accordance with the NIH GUIDELINES (See NIH GUIDELINES Section II.A.1.a). Specifically, the institutional assurance should include a statement that the embryo(s) used to derive the pluripotent stem cells were created through in vitro fertilization for the purpose of fertility treatment and that the embryos had not reached the stage at which the mesoderm is formed at the time of donation. The assurance should also include statements that the donation of the embryo was voluntary; that the researcher who derived or proposed to derive the cells was a different person than the physician who provided fertility treatment; that the individuals undergoing fertility treatment were approached about consent for the donation of embryos to derive pluripotent stem cells only at the time of deciding the disposition of frozen embryos that were in excess of clinical need; that the donor placed no restrictions regarding the individual(s) who may be the recipients of transplants derived from the human embryo; and that the required informed consents and Institutional Review Board (IRB) approval were obtained.

         2. A sample of the informed consent document for the donation of the embryo(s) for the purpose of deriving the human pluripotent stem cells that was used in this research (with patient identifying information removed) (See NIH GUIDELINES, Section II.A.1.b). A description of the required elements in the informed consent process is set forth in Section II.A.2.e of the NIH GUIDELINES.

         3. An abstract of the scientific protocol that was used to derive the human pluripotent stem cells, obtained from the person(s) who derived the human pluripotent stem cells, describing the methods and materials used (See NIH GUIDELINES Section II.A.1.c). Note: This is not the abstract of the grant application.

      3. Other Documentation

         1. Documentation of the IRB approval of the derivation protocol (See NIH GUIDELINES, Section II.A.1.d).

         2. An assurance signed by the responsible institutional official that the human pluripotent stem cells to be used in the proposed research were, or will be, obtained through donation or through payment that does not exceed the reasonable costs associated with the transportation, processing, preservation, quality control, and storage of the stem cells (See NIH GUIDELINES, Section II.A.1.e).

         3. An assurance signed by the responsible institutional offical that the proposed use of human pluripotent stem cells is not a class of research that is ineligible for NIH funding as set forth in Section III of the NIH GUIDELINES (See NIH GUIDELINES, Section II.A.1.g).

         4. The Principal Investigator's written consent to the disclosure of all material submitted as part of this documentation of compliance, as necessary to carry out the public review and other oversight procedures set forth in the NIH GUIDELINES (See NIH GUIDELINES, Section II.A.1.h).

   2. MATERIALS TO BE SUBMITTED TO THE CENTER FOR SCIENTIFIC REVIEW (CSR)

      A cover letter should accompany the submission of a competing grant application to the Division of Receipt and Referral, CSR (see instructions in the application form for complete address and application information), indicating that the documentation of compliance with the NIH GUIDELINES has been, or will be, provided to the NIH Office of Science Policy.

   3. DECISIONS

      HPSCRG may ask the institution to provide additional materials to clarify the documentation of compliance with the NIH GUIDELINES. This could delay the completion of the HPSCRG review. Following the meeting of the CSRAC, the NIH Office of Science Policy will convey the results of the compliance review to the principal investigator, the institution, and the potential funding Institute or Center within the NIH.

   4. FURTHER INFORMATION

      Questions regarding this process should be directed to stemcell@mail.nih.gov or call the Office of Science Policy at (301) 594-7741.

2. HUMAN PLURIPOTENT STEM CELLS DERIVED FROM FETAL TISSUE

   1. MATERIALS TO BE SUBMITTED TO THE OFFICE OF SCIENCE POLICY

      1. Cover Page with the following information (See sample below)

         1. Name of the Principal Investigator (PI).

         2. Title of the grant or cooperative agreement application (See NIH GUIDELINES, Section II.B.1.f). If part of a multicomponent submission (for example a Program Project), include the name of the PI, the title of the overall application, and the title(s) of the project(s) involving human pluripotent stem cells. If a competing continuation, revised application, administrative supplement, or existing award without a request for additional funds, also include the grant number (for example, R01 CA12345).

         3. Anticipated date of submission of the competing grant/cooperative agreement application.

         4. Name, title, telephone number, fax number, and e-mail address of the institutional official submitting the information.

         5. Signature of the institutional official.

         SAMPLE COVER PAGE

         Principal Investigator:	Roberta Dilan, M.D.
         Title of Project:	"Use of Human Pluripotent Stem Cells to Treat XYZ Disease," Project 4 of Renewal of Program Project, "Diagnosis and Therapy of XYZ Disease," Renewal of P01 ZZ12345 (P01 Principal Investigator: James Blue, M.D., Ph.D.)
         Anticipated Submission Date of Grant Application:	February 1, 2001
         Submitted by:	University of Lakeview
         Institutional Official:	Eileen Smith, Ph.D. Associate Provost for Research University of Lakeview 555-555-1212 (voice) 555-555-2121 (fax) smithe@lakeview.edu

      2. Documentation of compliance with the NIH GUIDELINES specific to research using human pluripotent stem cells derived from FETAL TISSUE.

         1. An assurance signed by the responsible institutional official that the pluripotent stem cells were derived from human fetal tissue in accordance with the conditions set forth in Section II.B.2 of the NIH GUIDELINES and that the institution will maintain documentation in support of this assurance. The official's signature will attest that the institution has documentation (or an assurance) from the person(s) who derived the human pluripotent stem cells stating that the derivation process was conducted in accordance with the NIH GUIDELINES (See NIH GUIDELINES Section II.B.1.a). The assurance should also include statements that the research complies with all of the requirements of 42 U.S.C. 289g-1, 42 U.S.C. 289g-2(a) and (b) and 45 C.F.R. 46.210; that the required informed consents were obtained; and that IRB approval was obtained.

         2. A sample of the informed consent document that was used for the donation of the human fetal tissue for the purpose of deriving the human pluripotent stem cells (with patient identifying information removed) (See NIH GUIDELINES, Section II.B.1.b). A description of the required elements in the informed consent process is given at Section II.B.2.b of the NIH GUIDELINES.

         3. An abstract of the scientific protocol that was used to derive the human pluripotent stem cells obtained from the person(s) who derived the human pluripotent stem cells, describing the methods and materials used (See NIH GUIDELINES Section II.B.1.c). Note: This is not the abstract of the grant application.

      3. Other Documentation

         1. Documentation of IRB approval of the derivation protocol (See NIH GUIDELINES, Section II.B.1.d).

         2. An assurance signed by the responsible institutional official that the human pluripotent stem cells to be used were, or will be, obtained through donation or through payment that does not exceed the reasonable costs associated with the transportation, processing, preservation, quality control, and storage of the stem cells (See NIH GUIDELINES, Section II.B.1.e).

         3. An assurance signed by the responsible institutional official that the proposed use of human pluripotent stem cells is not a class of research that is ineligible for NIH funding, as set forth in Section III of the NIH GUIDELINES (See NIH GUIDELINES, Section II.B.1.g).

         4. The Principal Investigator's written consent to the disclosure of all material submitted as part of this compliance documentation, as necessary to carry out the public review and other oversight procedures set forth in the NIH GUIDELINES (See NIH GUIDELINES, Section II.B.1.h).

   2. MATERIALS TO BE SUBMITTED TO THE CENTER FOR SCIENTIFIC REVIEW (CSR)

      A cover letter should accompany the submission of a competing grant application to the Division of Receipt and Referral, CSR (see instructions in the application form for complete address and application information), indicating that the documentation of compliance with the NIH GUIDELINES has been, or will be, provided to the NIH Office of Science Policy.

   3. DECISIONS

      HPSCRG may ask the institution to provide additional materials to clarify the documentation of compliance with the NIH GUIDELINES. This could delay the completion of the HPSCRG review. Following the meeting of the CSRAC, the NIH Office of Science Policy will convey the results of the compliance review to the principal investigator, the institution, and the potential funding Institute or Center within the NIH.

   4. FURTHER INFORMATION

      Questions regarding this process should be directed to stemcell@mail.nih.gov or call the Office of Science Policy at (301) 594-7741.

TITLE 42--THE PUBLIC HEALTH AND WELFARE, CHAPTER 6A--PUBLIC HEALTH SERVICE, SUBCHAPTER III--NATIONAL RESEARCH INSTITUTES, Part H--General Provisions, Sec. 289g-1. Research on transplantation of fetal tissue

TITLE 42--THE PUBLIC HEALTH AND WELFARE, CHAPTER 6A--PUBLIC HEALTH SERVICE, SUBCHAPTER III--NATIONAL RESEARCH INSTITUTES, Part H--General Provisions, Sec. 289g-2. Prohibitions regarding human fetal tissue

TITLE 45--PUBLIC WELFARE AND HUMAN SERVICES, PART 46--PROTECTION OF HUMAN SUBJECTS--Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization