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

Release Date:  November 21, 2000

NOTICE:  OD-01-003 (amended) (See Notice OD-02-007 dated November 7, 2001)

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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html).  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 (http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp),
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:  

NIH Office of Science Policy
Attention:  HPSCRG
Building 1, Room 218
MSC 0166
9000 Rockville Pike
Bethesda, MD  20892
(301) 594-7741

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

!-------------------------------------------------------!
!Submission Window !Materials   !Review  !Consideration !
!of Competing      !received by !by      !on by CSRAC   !
!Applications(new, !Office of   !HPSCRG  !              !
!continuation,     !Science     !        !              !
!revised,          !Policy      !        !              !
!supplements)      !            !        !              !
!------------------+------------+--------+--------------!
!January 10 to     !March 15    !April   !May           !
!May 1             !            !        !              !
!------------------+------------+--------+--------------!
!May 10 to         !July 15     !August  !September     !
!September 1       !            !        !              !
!------------------+------------+-----------------------!
!September 10 to   !November 15 !December!January       !
!January 2         !            !        !              !
!-------------------------------------------------------!

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, 
(http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#chgproj) 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 are set forth below at parts I and II, 
respectively.

I.  HUMAN PLURIPOTENT STEM CELLS DERIVED FROM EMBRYOS

   A.  MATERIALS TO BE SUBMITTED TO THE OFFICE OF SCIENCE POLICY
   
      1.  Cover Page with the following information (See sample below)

         a.  Name of the Principal Investigator (PI).

         b.  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).

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

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

         e.  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.

         a.  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.

         b.  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.

         c.  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

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

         b.  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).

         c.  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).

         d.  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).

   B.  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.

   C.  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.


   D.  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.

II.  HUMAN PLURIPOTENT STEM CELLS DERIVED FROM FETAL TISSUE

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

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

         a.  Name of the Principal Investigator (PI).

         b.  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).

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

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

         e.  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 FETAL 
          TISSUE.

         a.  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.  

         b.  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.

         c.  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

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

         b.  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).

         c.  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).

         d.  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).

   B.  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.

   C.  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.

   D.  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.


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