[Federal Register Volume 65, Number 196 (Tuesday, October 10, 2000)]
[Notices]
[Pages 60328-60332]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-25891]



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Part VI





Department of Health and Human Services





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National Institutes of Health



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Office of Biotechnology Activities; Recombinant DNA Research: Action 
Under the Guidelines; Notice

Federal Register / Vol. 65 , No. 196 / Tuesday, October 10, 2000 / 
Notices

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Biotechnology Activities; Recombinant DNA Research: 
Action Under the Guidelines

AGENCY: National Institutes of Health (NIH), PHS, DHHS.

ACTION: Notice of Actions Under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules (NIH Guidelines).

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SUMMARY: This notice describes amendments to the NIH Guidelines 
regarding research participant enrollment in human gene transfer 
studies and the submission of study protocols for NIH Recombinant DNA 
Advisory Committee (RAC) review. NIH's goal in making these 
modifications to the NIH Guidelines is to ensure that no research 
participant is enrolled in a human gene transfer study until the RAC 
review process has been completed, IBC and IRB approvals have been 
obtained, and applicable regulatory authorization(s) have been 
obtained.
    The NIH is modifying the requirements for protocol submission to 
the NIH Office of Biotechnology Activities (OBA) for RAC review so that 
clinical trial proposals: 1) may be submitted for RAC review prior to 
local Institutional Review Board (IRB) approval; and 2) must be 
submitted to the NIH OBA for RAC review and the RAC review process 
completed prior to local Institutional Biosafety Committee (IBC) 
approval.
    In the case of clinical trial proposals that are reviewed publicly 
and lead to specific recommendations from the RAC with regard to the 
protocol, the NIH will send written RAC recommendations to the 
Principal Investigator and the IBC and the IRB within 10 working days 
of public RAC review and discussion. Once the local IBC is in receipt 
of the RAC recommendations, the IBC may proceed with its protocol 
approval process. Investigators may initiate research participant 
enrollment when they have obtained final IBC and IRB approvals and all 
applicable regulatory authorization(s).
    No later than 20 working days after enrollment of the first 
research participant, the investigator must have provided to NIH OBA: 
(1) the final protocol, as approved by the local IRB and IBC and as 
authorized by the FDA along with the IND number; (2) the NIH grant 
number(s), if applicable; (3) a copy of the IRB and IBC approvals; (4) 
as applicable, a written response addressing each of the RAC 
recommendations resulting from public review and discussion of the 
protocol; and (5) the date of the initiation of the trial.

FOR FURTHER INFORMATION CONTACT: Background documentation and 
additional information can be obtained from the Office of Biotechnology 
Activities, National Institutes of Health, MSC 7010, 6000 Executive 
Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-
9838, FAX 301-496-9839. The OBA web site is located at http://www.nih.gov/od/oba/.

Background Information

    Since the inception of both basic and clinical recombinant DNA 
research, the NIH RAC has publicly reviewed and discussed the full 
range of scientific, medical, ethical, legal, and social issues 
attendant to this field of research. Prior to the action described in 
this notice, local IBC and IRB approval of human gene transfer 
protocols were prerequisites for submission of the protocol to the NIH 
OBA for RAC review.
    The actions set forth here: (1) allow all gene transfer protocols 
that meet the requirements set forth in Appendix M of the NIH 
Guidelines (Points to Consider in the Design and Submission of 
Protocols for the Transfer of Recombinant DNA Molecules into One or 
More Human Research Participants) to be submitted for RAC review prior 
to local IRB review and approval; (2) require all gene transfer 
protocols that meet the requirements set forth in Appendix M of the NIH 
Guidelines to be submitted for RAC review prior to local IBC approval; 
(3) require, for protocols selected for public discussion by the RAC, 
that the discussion occur prior to final IBC approval of those 
protocols; and (4) ensure that no research participant is enrolled on a 
clinical study until the RAC review process is completed, and IBC and 
IRB approvals and applicable regulatory authorizations are obtained. 
For the purposes of this action, research participant enrollment is 
defined as the process of obtaining consent from a potential research 
participant, or a designated legal guardian of the participant, to 
undergo any test or procedure associated with the gene transfer 
experiment.
    With this change, research participants can be assured that, prior 
to their participation in a gene transfer clinical trial that is either 
novel and/or raises significant ethical or safety concerns, their local 
IRB and IBC, as well as the principal investigator will be apprised of 
the results of public RAC review and discussion.
    Public RAC discussion of selected gene transfer protocols and 
issues of general relevance to the field enhances human subjects 
protection by informing research participants, investigators, and local 
and Federal oversight bodies about the current state of knowledge of 
risks and benefits, potential safety and ethical concerns, and clinical 
trial design issues associated with gene transfer research. Local 
institutional review bodies, which generally see only that subset of 
gene transfer trials conducted at their institution, benefit from the 
expertise, broad perspective, and the experience of the RAC.
    In developing the actions set forth here, the NIH consulted 
extensively with the public, the RAC, and the Advisory Committee to the 
Director, NIH (ACD). A version of this proposed action was initially 
published in the Federal Register for public notice and comment on 
August 11, 1999 (64 FR 43884). The draft proposal and public comments 
were discussed by the RAC at the September 2-3, 1999, meeting. During 
this discussion, some RAC members noted that optimizing the 
effectiveness of the RAC review process was a high priority, but 
expressed concern that elimination of the requirement for approval of 
gene transfer protocols by IRBs and IBCs before submission of protocols 
to NIH might result in the submission of incomplete or inadequately 
developed clinical protocols. To address these concerns, the NIH 
proposed that protocols submitted to NIH OBA for RAC review must 
address all the elements set forth in Appendix M of the NIH Guidelines. 
Other RAC members expressed concern that RAC review prior to local 
institutional review might be perceived as diminishing the critical 
role of IRBs and IBCs in protecting human research participants and the 
community. To address this concern, NIH proposed that in evaluating 
gene transfer protocols, the IBC should take into consideration the 
issues raised and recommendations made during public RAC review and 
discussion, as well as the Principal Investigator's response to those 
recommendations. The RAC voted on September 3, 1999, to recommend 
implementation of this revised proposal.
    This proposal was not implemented immediately due to events that 
occurred shortly thereafter. For the first time in the history of gene 
transfer research, a research participant's death was attributed 
directly to participation in a gene transfer study. This event raised 
concerns about the safety of gene transfer research. In response, the 
NIH

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Director established in December, 1999, the ACD Working Group on NIH 
Oversight of Clinical Gene Transfer Research (the ACD Working Group) to 
review the role of NIH and the RAC in oversight of clinical gene 
transfer research. The ACD Working Group included scientists, 
clinicians, bioethicists, and representatives of the general public. 
The ACD Working Group was asked to develop recommendations on whether 
the current NIH framework for oversight and public discussion of 
clinical gene transfer research is appropriate, especially with regard 
to the role of the RAC and the NIH Guidelines; whether current NIH 
mechanisms are adequate for coordination of the oversight of clinical 
gene transfer research with the FDA, the Office for Human Research 
Protections, IRBs, and IBCs; whether additional NIH measures are needed 
to minimize risk associated with clinical gene transfer research; and 
the appropriate role of the NIH with regard to reporting, analysis, and 
public discussion of serious adverse events.
    The ACD Working Group concurred that participants must not be 
enrolled in a gene transfer protocol until NIH OBA and the RAC have 
determined whether the protocol requires public RAC review and, in the 
case of a protocol selected for public review and discussion, until 
that review has occurred. If the RAC expresses concerns about the 
safety or design of a protocol, there must be a systematic and 
established mechanism that allows RAC to communicate those concerns to 
the investigators prior to enrollment of participants.
    The ACD Working Group specifically recommended the following:
    <bullet> Research participant safety would be optimally enhanced if 
participants are not enrolled in gene transfer protocols selected for 
public RAC review and discussion until that public review has occurred 
and the investigator has responded to the RAC recommendations.
    <bullet> The timing of review of gene transfer protocols by RAC, 
the IRB, the IBC, and the FDA should be altered to ensure that RAC 
functions as an effective advisory committee to investigators, local 
IRBs and IBCs, NIH, and FDA.
    <bullet> The requirement that the investigator obtain IBC and IRB 
approval prior to submission of a protocol to OBA/RAC should be 
eliminated. This change would allow investigators to receive RAC input 
at an earlier stage of protocol development.
    <bullet> Final IBC approval should be withheld until RAC review is 
complete. In the case of protocols not selected for public RAC review 
and discussion, IBC approval can be granted as soon as the IBC is 
notified that the protocol has not been selected for further review. In 
the case of protocols selected for public RAC review and discussion, 
IBC approval must be withheld until after RAC discussion and the 
investigator has responded to the review, thereby preventing the 
initiation of a trial prior to public RAC review.
    The RAC unanimously endorsed the ACD Working Group recommendations 
on June 29, 2000. On July 15, 2000, the ACD unanimously voted to accept 
the ACD Working Group recommendations regarding review of human gene 
transfer protocols by the NIH RAC. Through this notice of action, the 
NIH is amending the NIH Guidelines in light of the recommendations of 
the RAC and the ACD.
    The actions described in this notice implement fundamental changes 
in the NIH process for protocol submission and review of gene transfer 
clinical research protocols. These changes affect multiple sections of 
the NIH Guidelines, as set forth below. In addition, Appendix M of the 
NIH Guidelines is significantly modified. Specifically, the text has 
been substantially changed and reorganized in order to convey the 
revised protocol review process in a clear and logical manner. For the 
convenience of the reader, those portions of Appendix M that contain 
amended language, as well as those containing reorganized text, are 
reprinted below. The revised NIH Guidelines, in their entirety, can be 
accessed at http://www4.od.nih.gov/oba/guidelines.html. (Note: In the 
text below, adverse event reporting requirements remain unchanged; 
however, a subsequent notice will describe proposed changes for 
reporting to NIH on serious adverse events that occur during clinical 
gene transfer research.)

Actions Amending the NIH Guidelines

Section I. Scope of the NIH Guidelines

    Section I-A-1-a under Purpose is amended to read:

    ``Section I-A-1-a. For experiments involving the deliberate 
transfer of recombinant DNA, or DNA or RNA derived from recombinant 
DNA, into human research participants (human gene transfer), no 
research participant shall be enrolled (see definition of enrollment 
in Section I-E-7) until the RAC review process has been completed 
(see Appendix M-I-B, RAC Review Requirements); Institutional 
Biosafety Committee (IBC) approval (from the clinical trial site) 
has been obtained; Institutional Review Board approval has been 
obtained; and all applicable regulatory authorization(s) have been 
obtained.
    ``For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) IBC 
approval (from the clinical trial site); (2) Institutional Review 
Board approval; (3) Institutional Review Board-approved informed 
consent document; and (4) curriculum vitae of the principal 
investigator(s) (no more than two pages in biographical sketch 
format); and (5) NIH grant number(s) if applicable.''

    A new Section I-E-7 is added to read:

    ``Section I-E-7. ``Enrollment'' is the process of obtaining 
informed consent from a potential research participant, or a 
designated legal guardian of the participant, to undergo a test or 
procedure associated with the gene transfer experiment.''

Section III. Experiments Covered by the NIH Guidelines

    Section III-C is amended to read:

    ``Section III-C. Experiments that Require Institutional 
Biosafety Committee and Institutional Review Board Approvals and RAC 
Review Before Research Participant Enrollment
    ``Section III-C-1. Experiments Involving the Deliberate Transfer 
of Recombinant DNA, or DNA or RNA Derived from Recombinant DNA, into 
One or More Human Research Participants
    ``For an experiment involving the deliberate transfer of 
recombinant DNA, or DNA or RNA derived from recombinant DNA, into 
human research participants (human gene transfer), no research 
participant shall be enrolled (see definition of enrollment in 
Section I-E-7) until the RAC review process has been completed (see 
Appendix M-I-B, RAC Review Requirements).
    ``In its evaluation of human gene transfer proposals, the RAC 
will consider whether a proposed human gene transfer experiment 
presents characteristics that warrant public RAC review and 
discussion (See Appendix M-I-B-2). The process of public RAC review 
and discussion is intended to foster the safe and ethical conduct of 
human gene transfer experiments. Public review and discussion of a 
human gene transfer experiment (and access to relevant information) 
also serves to inform the public about the technical aspects of the 
proposal, meaning and significance of the research, and any 
significant safety, social, and ethical implications of the 
research.''
    ``Public RAC review and discussion of a human gene transfer 
experiment may be: (1) initiated by the NIH Director; or (2) 
initiated by the NIH OBA Director following a recommendation to NIH 
OBA by: (a) three or more RAC members; or (b) a Federal agency other 
than NIH. After a human gene transfer experiment is reviewed by the 
RAC at a regularly scheduled meeting, NIH OBA will send a letter 
within 10 working days to the NIH Director, the Principal 
Investigator, the

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sponsoring institution, and other DHHS components, as appropriate, 
summarizing the RAC recommendations.
    ``For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site); (2) Institutional Review Board approval; (3) Institutional 
Review Board-approved informed consent document; and (4) curriculum 
vitae of the principal investigator(s) (no more than two pages in 
biographical sketch format).
    ``In order to maintain public access to information regarding 
human gene transfer protocols (including protocols that are not 
publicly reviewed by the RAC), NIH OBA will maintain the 
documentation described in Appendices M-I through M-V. The 
information provided in response to Appendix M should not contain 
any confidential commercial information or trade secrets, enabling 
all aspects of RAC review to be open to the public.

    ``Note: For specific directives concerning the use of retroviral 
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral 
Vectors.''

Section IV. Roles and Responsibilities

    Section IV is amended to read in part:

    Section IV-B. Responsibilities of the Institution
    Section IV-B-1. General Information. . .
    Section IV-B-1-f. Ensure that . . . (ii) all aspects of Appendix 
M have been appropriately addressed by the Principal Investigator; 
and (iii) no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) in a human gene transfer experiment 
until the RAC review process has been completed (see Appendix M-I-B, 
RAC Review Requirements). . . .''
    ``Section IV-B-2. Institutional Biosafety Committee (IBC). . .
    ``Section IV-B-2-a. Membership and Procedures
    Section IV-B-2-a-(1). . . . When the institution participates in 
or sponsors recombinant DNA research involving human research 
participants, the institution must ensure that: . . . (ii) all 
aspects of Appendix M have been appropriately addressed by the 
Principal Investigator; (iii) no research participant shall be 
enrolled (see definition of enrollment in Section I-E-7) in a human 
gene transfer experiment until the RAC review process has been 
completed (see Appendix M-I-B, RAC Review Requirements); and (iv) 
final IBC approval is granted only after the RAC review process has 
been completed (see Appendix M-I-B, RAC Review Requirements). 
Institutional Biosafety Committee approval must be obtained from the 
institution at which recombinant DNA material will be administered 
to human research participants (rather than the site involved in 
manufacturing gene transfer products).''
    Section IV-B-2-b. Functions. . .
    On behalf of the Institution, the Institutional Biosafety 
Committee is responsible for:
    ``Section IV-B-2-b-(1). Reviewing recombinant DNA research 
conducted at or sponsored by the institution for compliance with the 
NIH Guidelines as specified in Section III, Experiments Covered by 
the NIH Guidelines, and approving those research projects that are 
found to conform with the NIH Guidelines. This review shall include: 
. . . (iii) ensuring that all aspects of Appendix M have been 
appropriately addressed by the Principal Investigator; (iv) ensuring 
that no research participant is enrolled (see definition of 
enrollment in Section I-E-7) in a human gene transfer experiment 
until the RAC review process has been completed (see Appendix M-I-B, 
RAC Review Requirements); (v) for human gene transfer protocols 
selected for public RAC review and discussion, consideration of the 
issues raised and recommendations made as a result of this review 
and consideration of the Principal Investigator's response to the 
RAC recommendations; (vi) ensuring that final IBC approval is 
granted only after the RAC review process has been completed (see 
Appendix M-I-B, RAC Review Requirements); and (vii) ensuring 
compliance with all surveillance, data reporting, and adverse 
reporting requirements set forth in the NIH Guidelines.''
    ``Section IV-B-7. Principal Investigator (PI). . .
    ``Section IV-B-7-b. Information to Be Submitted by the Principal 
Investigator to NIH OBA
    ``The Principal Investigator shall: . . . .
    ``Section IV-B-7-b-(6). Ensure that all aspects of Appendix M 
have been appropriately addressed prior to the submission of a human 
gene transfer experiment to NIH OBA, and provide a letter signed by 
the Principal Investigator(s) on institutional letterhead 
acknowledging that the documentation being submitted to NIH OBA 
complies with the requirements set forth in Appendix M. No research 
participant shall be enrolled (see definition of enrollment in 
Section I-E-7) in a human gene transfer experiment until the RAC 
review process has been completed (see Appendix M-I-B, RAC Review 
Requirements); IBC approval (from the clinical trial site) has been 
obtained; Institutional Review Board (IRB) approval has been 
obtained; and all applicable regulatory authorization(s) have been 
obtained.
    ``For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) IBC 
approval (from the clinical trial site); (2) IRB approval; (3) IRB-
approved informed consent document; and (4) curriculum vitae of the 
principal investigator(s) (no more than two pages in biographical 
sketch format). . . .''

Appendix M. Points To Consider in the Design and Submission of 
Protocols for the Transfer of Recombinant DNA Molecules Into One or 
More Human Research Participants (Points To Consider)

    Note: For the convenience of the reader, those portions of 
Appendix M that contain amended language, as well as those 
containing reorganized text, are reprinted below.

    Appendix M is amended to read in part:
    ``Appendix M-I. Requirements for Protocol Submission, Review, and 
Reporting--Human Gene Transfer Experiments
    ``Appendix M-I-A. Requirements for Protocol Submission
    ``The following documentation must be submitted (see exemption in 
Appendix M-VII-A, Footnotes of Appendix M) in printed or electronic 
form to the: NIH Office of Biotechnology Activities, National 
Institutes of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, 
Bethesda, Maryland 20892-7010, Telephone: 301-496-9838, Facsimile: 301-
496-9839, E-mail: <a href="/cdn-cgi/l/email-protection#b4c6dbc7d1dac0dcd3f4dbd09adadddc9ad3dbc2"><span class="__cf_email__" data-cfemail="70021f03151e041817301f145e1e19185e171f06">[email protected]</span></a>. NIH OBA will confirm receipt 
within three working days after receiving the submission.
    ``1. A cover letter on institutional letterhead, signed by the 
Principal Investigator(s), that: (1) acknowledges that the 
documentation submitted to NIH OBA complies with the requirements set 
forth in Appendix M-I-A, Requirements for Protocol Submission; (2) 
identifies the Institutional Biosafety Committee (IBC) and 
Institutional Review Board (IRB) at the proposed clinical trial site(s) 
responsible for local review and approval of the protocol; and (3) 
acknowledges that no research participant will be enrolled (see 
definition of enrollment in Section I-E-7) until the RAC review process 
has been completed (see Appendix M-I-B, RAC Review Requirements); IBC 
approval (from the clinical trial site) has been obtained; IRB approval 
has been obtained; and all applicable regulatory authorizations have 
been obtained.
    ``2. The scientific abstract.
    ``3. The non-technical abstract.
    ``4. The proposed clinical protocol, including tables, figures, and 
relevant manuscripts.
    ``5. Responses to Appendices M-II through M-V, Description of the 
Proposal, Informed Consent, Privacy and Confidentiality, and Special 
Issues. Responses to Appendices M-II through M-V may be provided either 
as an appendix to the clinical protocol or incorporated in the clinical 
protocol. If responses to Appendices M-II through M-V are incorporated 
in the clinical protocol, each response must refer to the appropriate 
Appendix M-II through M-V.
    ``6. The proposed informed consent document (see Appendix M-III, 
Informed Consent).
    ``7. Curricula vitae of the principal investigator(s) (no more than 
two pages in biographical sketch format).

    Note: A human gene transfer experiment submitted to NIH OBA 
should not contain

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confidential commercial information or trade secrets, enabling all 
aspects of the review to be open to the public.

``Appendix M-I-B. RAC Review Requirements

``Appendix M-I-B-1. Initial RAC Review

    ``The initial RAC review process shall include a determination as 
to whether the human gene transfer experiment presents characteristics 
that warrant public RAC review and discussion. During the RAC's initial 
review, individual committee members may request additional information 
relevant to the protocol. NIH OBA will immediately notify the Principal 
Investigator(s) of RAC requests for additional information. In making a 
determination whether an experiment presents characteristics warranting 
public RAC review and discussion, reviewers will examine the scientific 
rationale, scientific content, whether the preliminary in vitro and in 
vivo safety data were obtained in appropriate models and are 
sufficient, and whether questions related to relevant social and 
ethical issues have been resolved. Other factors that may warrant 
public review and discussion of a human gene transfer experiment by the 
RAC include: (1) a new vector/new gene delivery system; (2) a new 
clinical application; (3) a unique application of gene transfer; and/or 
(4) other issues considered to require further public discussion.
    ``Initial RAC review shall be completed within 15 working days of 
receipt of a complete submission (see Appendix M-I-A, Requirements for 
Protocol Submission). At the end of the15-day review period, NIH OBA 
will notify the Principal Investigator(s) in writing about the results 
of the RAC's initial review. Two outcomes are possible: (1) the 
experiment does not present characteristics that warrant further review 
and discussion and is therefore exempt from public RAC review and 
discussion; or (2) the experiment presents characteristics that warrant 
public RAC review and discussion. Completion of the RAC review process 
is defined as: (1) receipt by the Principal Investigator(s) of a letter 
from NIH OBA indicating that the submission does not present 
characteristics that warrant public RAC review and discussion; or (2) 
receipt by the Principal Investigator(s) of a letter from NIH OBA after 
public RAC review that summarizes the committee's key comments and 
recommendations (if any).
    ``If a human gene transfer protocol is submitted less than eight 
weeks before a scheduled RAC meeting and is subsequently recommended 
for public RAC review and discussion, the review of the protocol by the 
RAC will be deferred until the next scheduled RAC meeting. This eight-
week period is needed to ensure adequate time for public notice and 
comment and thorough review by the committee members.
    ``No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) in the human gene transfer experiment 
until: (1) the RAC review process has been completed; (2) Institutional 
Biosafety Committee (IBC) approval (from the clinical trial site) has 
been obtained; (3) Institutional Review Board (IRB) approval has been 
obtained; and (4) all applicable regulatory authorization(s) have been 
obtained.
    ``For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) IBC approval 
(from the clinical trial site); (2) IRB approval; (3) IRB-approved 
informed consent document; and (4) curriculum vitae of the principal 
investigator(s) (no more than two pages in biographical sketch 
format).''

``Appendix M-I-B-2. Public RAC Review and Discussion

    ``Public RAC review and discussion of a human gene transfer 
experiment may be: (1) initiated by the NIH Director; or (2) initiated 
by the NIH OBA Director following a recommendation to NIH OBA by: (a) 
three or more RAC members; or (b) a Federal agency other than NIH. In 
making a determination whether an experiment presents characteristics 
warranting public RAC review and discussion, reviewers will examine the 
scientific rationale, scientific content, whether the preliminary in 
vitro and in vivo safety data were obtained in appropriate models and 
are sufficient, and whether questions related to relevant social and 
ethical issues have been resolved. Other factors that may warrant 
public review and discussion of a human gene transfer experiment by the 
RAC include: (1) a new vector/new gene delivery system; (2) a new 
clinical application; (3) a unique application of gene transfer; and/or 
(4) other issues considered to require further public discussion.
    ``After a human gene transfer experiment is reviewed by the full 
RAC at a regularly scheduled meeting, NIH OBA will send a letter 
summarizing the RAC key comments and recommendations (if any) regarding 
the protocol to the NIH Director, the Principal Investigator, the 
sponsoring institution, and other DHHS components, as appropriate. 
Completion of RAC review is defined as receipt by the Principal 
Investigator(s) of a letter from NIH OBA that summarizes the 
committee's findings. Unless NIH OBA determines that there are 
exceptional circumstances, the RAC summary letter will be sent to the 
Principal Investigator(s) within 10 working days after the completion 
of the RAC meeting at which the experiment was reviewed.
    ``RAC meetings will be open to the public except where trade 
secrets or confidential commercial information are reviewed. To enable 
all aspects of the protocol review process to be open to the public, 
information provided in response to Appendix M should not contain trade 
secrets or confidential commercial information. No application 
submitted to NIH OBA shall be designated as `confidential' in its 
entirety. In the event that an investigator determines that specific 
responses to one or more of the items described in Appendix M should be 
considered as confidential commercial information or a trade secret, 
each item must be clearly identified as such. The cover letter 
(attached to the submitted material) shall: (1) clearly designate the 
information that is considered as confidential commercial information 
or a trade secret; and (2) explain and justify each designation.''

``Appendix M-I-C. Reporting Requirements

``Appendix M-I-C-1. Initiation of the Clinical Investigation

    ``No later than 20 working days after enrollment (see definition of 
enrollment in Section I-E-7) of the first research participant on a 
human gene transfer experiment, the Principal Investigator(s) shall 
submit the following documentation to NIH OBA: (1) a copy of the 
informed consent document approved by the Institutional Review Board 
(IRB); (2) a copy of the protocol approved by the Institutional 
Biosafety Committee (IBC) and IRB; (3) a copy of the final IBC approval 
from the clinical trial site; (4) a copy of the final IRB approval; (5) 
a brief written report that includes the following information: (a) how 
the investigator(s) responded to each of the RAC's recommendations on 
the protocol (if applicable); and (b) any modifications to the protocol 
as required by FDA; (6) applicable NIH grant number(s); (7) the FDA 
Investigational New Drug Application (IND) number; and (8) the date of 
the initiation of the trial. The purpose of requesting the FDA IND 
number is for facilitating interagency collaboration in the Federal 
oversight of human gene transfer research.''

``Appendix M-I-C-2. Additional Clinical Trial Sites

    ``No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) at a clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site); (2) Institutional Review Board approval; (3) Institutional 
Review Board-approved informed consent document; (4) curriculum vitae 
of the principal investigator(s) (no more than two pages in 
biographical sketch format); and (5) NIH grant number(s) if 
applicable.''

``Appendix M-I-C-3. Annual Reporting

    ``Investigators shall comply with annual data reporting 
requirements. Annual data report forms will be forwarded by NIH OBA to 
investigators. Information submitted in these annual reports will be 
evaluated by NIH OBA and the RAC, and possibly considered at a future 
RAC meeting. Information obtained through the annual data reporting 
process will be included in the NIH Human Gene Transfer Information 
System to: (1) provide clinical trial information; (2) provide 
administrative details of protocol registration; (3) provide annual 
status reports of protocols; (4) facilitate risk assessment of 
individual applications of human gene transfer; and (5) enhance public 
awareness of relevant scientific, safety, social, and ethical issues.''

``Appendix M-I-C-4. Serious Adverse Event Reporting

    ``Investigators who have received authorization from FDA to 
initiate a human gene transfer protocol must report any

[[Page 60332]]

serious adverse event immediately to the local Institutional Review 
Board, Institutional Biosafety Committee, Office for Human Research 
Protections (if applicable), and NIH OBA, followed by the submission of 
a written report filed with each group. Reports submitted to NIH OBA 
shall be sent to the Office of Biotechnology Activities, National 
Institutes of Health/MSC 7010, 6000 Executive Boulevard, Suite 302, 
Bethesda, Maryland 20892-7010, (301) 496-9838.''
    ``Appendix M-II. Description of Proposal . . .''
    ``Appendix M-III. Informed Consent . . .

``M-III-B. Informed Consent Document

    ``Submission of a human gene transfer experiment to NIH OBA must 
include a copy of the proposed informed consent document. A separate 
informed consent document should be used for the gene transfer portion 
of a research project when gene transfer is used as an adjunct in the 
study of another technique, e.g., when a gene is used as a ``marker'' 
or to enhance the power of immunotherapy for cancer. . . .''
    ``Appendix M-IV. Privacy and Confidentiality . . .''
    ``Appendix M-V. Special Issues . . .''
    Appendix M-VI, RAC Review--Human Gene Transfer Experiments has been 
incorporated into new Appendix M-I-B, RAC Review Requirements.
    Appendix M-VII, Reporting Requirements, has been incorporated into 
new Appendix M-I-C, Reporting Requirements.
    Appendix VIII, Footnotes of Appendix M, will be renumbered to 
Appendix VI.
* * * * *
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592) requires a statement concerning 
the official government programs contained in the Catalog of Federal 
Domestic Assistance. Normally, NIH lists in its announcements the 
number and title of affected individual programs for the guidance of 
the public. Because the guidance in this notice covers virtually every 
NIH and Federal research program in which recombinant DNA techniques 
could be used, it has been determined not to be cost effective or in 
the public interest to attempt to list these programs. In addition, NIH 
could not be certain that every Federal program would be included as 
many Federal agencies, as well as private organizations, both national 
and international, have elected to follow the NIH Guidelines. In lieu 
of the individual program listing, NIH invites readers to direct 
questions to the information address above about whether individual 
programs listed in the Catalog of Federal Domestic Assistance are 
affected.

    Dated: September 30, 2000.
Ruth L. Kirschstein,
Principal Deputy Director, National Institutes of Health.
[FR Doc. 00-25891 Filed 10-6-00; 8:45 am]
BILLING CODE 4140-01-P


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