[Federal Register Volume 62, Number 161 (Wednesday, August 20, 1997)]
[Notices]
[Pages 44387-44390]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22030]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Recombinant DNA Research: Proposed Actions Under the Guidelines

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

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

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SUMMARY: This notice sets forth proposed actions to be taken under the 
NIH Guidelines for Research Involving Recombinant DNA Molecules (59 FR 
34496, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR 
4782). Interested parties are invited to submit comments concerning 
these proposals. These proposals will be considered by the Recombinant 
DNA Advisory Committee (RAC) at its meeting on September 12, 1997. 
After consideration of these proposals and comments by the RAC, the NIH 
Director will issue decisions in accordance with the NIH Guidelines.

DATES: Interested parties are invited to submit comments concerning 
this proposal. Comments received by September 5, 1997, will be 
reproduced and distributed to the RAC for consideration at its 
September 12, 1997, meeting. After consideration of this proposal and 
comments by the RAC, the NIH Director will issue decisions in 
accordance with the NIH Guidelines.

ADDRESSES: Written comments and recommendations should be submitted to 
Debra Knorr, Office of Recombinant DNA Activities, National Institutes 
of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland 20892-7010, Phone 301-496-9838, FAX 301-496-9839.
    All comments received in response to this notice will be considered 
and will be available for public inspection in the above office on 
weekdays between the hours of 8:30 a.m. and 5:00 p.m.

FOR FURTHER INFORMATION CONTACT: Background documentation and 
additional information can be obtained from the Office of Recombinant 
DNA 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 Office of Recombinant DNA Activities web 
site is located at Http://www.nih.gov/od/orda for further information 
about the office.

SUPPLEMENTARY INFORMATION: The NIH will consider the following actions 
under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules (NIH Guidelines):

A. Amendment to the Submission Requirements--Human Gene Transfer 
Experiments Under Appendix M of the NIH Guidelines

    During the June 12-13, 1997, RAC meeting, the following motions 
were approved by the Committee:
    (1) A motion was made to eliminate the point-by-point responses to 
Appendix M-II, Description of the Proposal; however, the questions 
raised in Appendix M-II must be addressed in the clinical protocol. The 
motion passed by a vote of 8 in favor, 0 opposed, and 1 abstention.
    (2) A motion was made that the RAC should not review any gene 
transfer protocol until the investigator has provided ORDA with 
evidence of protocol submission to the Institutional Biosafety 
Committee (IBC). IBC notification is needed in order to avoid the 
circumstances in which the RAC might review a protocol that has not 
been submitted to the IBC. The motion passed by a vote of 8 in favor, 1 
opposed, and no abstentions.
    (3) A motion was made to delete prior IBC and Institutional Review 
Board (IRB) approvals, responses to Appendix M-II through M-V, and 
vector sequence diskettes from Appendix M-I, Submission Requirements--
Human Gene Transfer Experiments. The RAC accepted the submission 
requirements as follows:

``Appendix M-I, Submission Requirements--Human Gene Transfer 
Experiments''

    ``Investigators must submit the following material to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
301-496-9838 (see exemption in Appendix M-IX-A, Footnotes of Appendix 
M). Proposals will be submitted in the following order: (1) Scientific 
abstract; (2) non-technical abstract; (3) protocol (including 
discussion of issues in Appendix M-II through M-V); (4) Informed 
Consent document prepared for IRB submission (see Appendix M-III, 
Informed Consent); (5) letter stating that submission has been made to 
the IBC; (6) appendices (including tables, figures, and manuscripts); 
and (7) curricula vitae for each key professional person in 
biographical sketch format.''
    The motion passed by a vote of 7 in favor, 0 opposed, and 1 
abstention.

B. Amendment to Institutional Biosafety Committee (IBC) Approvals of 
Experiments Involving Transgenic Rodents Under Section III of the NIH 
Guidelines

    Section III-C-4, Experiments Involving Whole Animals, of the NIH 
Guidelines stipulates that all transgenic animal experiments are 
subject to IBC approval before initiation. In correspondence dated 
April 22, 1997, Dr. George Gutman, an IBC representative of the 
University of California, Irvine, California, inquired whether 
experiments involving the production or use of transgenic mice under 
Biosafety Level 1 containment could be initiated simultaneously with 
IBC notification. Current requirements under the NIH Guidelines require 
that IBC approval be obtained prior to initiation of such experiments. 
The RAC discussed this issue during its June 1997 meeting, recommending 
that this requirement be changed to initiation simultaneous with IBC 
notification. The RAC agreed that the requirement of IBC approval prior 
to initiation is unnecessary and recommended that the NIH Guidelines 
should be amended such that: (1) The generation of transgenic rodents 
at the Biosafety Level 1 containment (not all animals) can be initiated 
simultaneous with IBC notification, and (2) the purchase and use of 
transgenic rodents should be exempt from the NIH Guidelines.
    A motion was made that these proposed changes to the NIH Guidelines 
should be published in the Federal Register for consideration at the 
September 12, 1997, RAC meeting. The proposed action would allow: (1) 
The generation of transgenic rodents that require Biosafety Level 1 
containment to be included under Section III-D, Experiments that 
Require IBC Notice Simultaneous with Initiation; and (2) the purchase 
and use of transgenic rodents should be exempt from the NIH Guidelines. 
The motion passed by a vote of 9 in favor, 0 opposed, and no 
abstentions.

C. The Dissociation of Simultaneous Submission of Responses to Appendix 
M of the NIH Guidelines to NIH/ORDA and the Food and Drug 
Administration (FDA)

    In a letter dated November 20, 1996, Dr. Andra Miller, Food and 
Drug Administration, requested that the NIH Guidelines should be 
amended

[[Page 44388]]

regarding procedures for simultaneous submission of Appendix M material 
to the RAC and FDA. In her November 20, 1996, letter, Dr. Miller 
states:
    ``* * * To remove the requirement for submission of Appendix M to 
the FDA. The FDA does not accept Appendix M in place of an IND 
submission. The FDA is not proposed to be and need not be included in 
the decision making process to identify protocols to undergo full RAC 
review. Therefore, there is no reason for sponsors to submit Appendix M 
materials to the FDA.''
    During its December 9, 1996, and March 6-7, 1997, meetings, the RAC 
discussed this issue. The consensus of the RAC was that the requirement 
for submission of responses of Appendix M to the FDA should be removed, 
since FDA does not accept responses to Appendix M in place of an 
Investigational New Drug (IND) application. However, the RAC stated 
that all human gene transfer protocols should include discussion of 
issues raised in Appendix M-II through M-V of the NIH Guidelines in the 
clinical protocols.
    The NIH will consider the following proposed actions under the NIH 
Guidelines:

A. Proposed Amendments to Section I-A. Purpose

    Section I-A-1-a is proposed to be amended to read:

``Section I-A-1-a''

    ``Section I-A-1-a. Experiments involving the deliberate transfer of 
recombinant DNA or DNA or RNA derived from recombinant DNA into human 
subjects (human gene transfer) cannot be initiated without submission 
to NIH/ORDA of such information on the proposed experiment as is 
prescribed by this agency. Submission of human gene transfer protocols 
to the NIH will be in the format described in Appendix M-I, Submission 
Requirements--Human Gene Transfer Experiments, of the NIH Guidelines. 
Submission to NIH shall be for registration purposes, a determination 
regarding the necessity for full RAC discussion, and to ensure 
continued public access to relevant human gene transfer information 
conducted in compliance with the NIH Guidelines.''

B. Proposed Amendments to Section III-A. Experiments That Require 
Institutional Biosafety Committee Approval, RAC Review, and NIH 
Director Approval Before Initiation (See Section IV-C-1-b-(1), Major 
Actions)

    Section III-A-2 is proposed to be amended to read:

``Section III-A-2. Human Gene Transfer Experiments''

    ``Investigators must submit their human gene transfer proposal to 
the NIH in a single submission format. This format includes (but is not 
limited to) the documentation described in Appendix M-I, Submission 
Requirements--Human Gene Transfer Experiments. The NIH/ORDA in 
consultation with the RAC, will evaluate the proposal regarding the 
necessity for RAC review.
    ``Factors that may contribute to the necessity for RAC review 
include: (i) New vectors/new gene delivery systems, (ii) new diseases, 
(iii) unique applications of gene transfer, and (iv) other issues 
considered to require further public discussion. Among the experiments 
that may be considered exempt from RAC review are those determined by 
the RAC and the NIH/ORDA not to represent possible risk to human health 
or the environment (see Appendix M-VII, Categories of Human Gene 
Transfer Experiments that May Be Exempt from RAC Review). Whenever 
possible, investigators will be notified within 15 working days 
following receipt of the submission whether RAC review will be 
required. In the event that the RAC requires review of the submitted 
proposal, all documentation described in Appendix M-I, Submission 
Requirements--Human Gene Transfer Experiments, will be forwarded to the 
RAC primary reviewers for evaluation. RAC meetings will be open to the 
public except where trade secrets and proprietary information are 
reviewed. The RAC prefers that information provided in the submission 
documentation contain no proprietary data or trade secrets, enabling 
all aspects of the review to be open to the public. The RAC will 
recommend approval or disapproval of the reviewed proposal to the NIH 
Director. In the event that a proposal is contingently approved by the 
RAC, the RAC conditions must be satisfactorily met before the RAC's 
recommendation for approval is submitted to the NIH Director. The NIH 
Director's decision on the submitted proposal will be considered as a 
Major Action by the NIH Director.

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

C. Proposed Amendments to Section III-C-4. Experiments Involving Whole 
Animals

    (Section III-C are experiments that require Institutional Biosafety 
Committee approval before initiation.)
    Section III-C-4-c is proposed to be amended to read:

``Section III-C-4-c. Exceptions under Section III-C-4.

    ``Section III-C-4-c-(1). Experiments involving the generation of 
transgenic rodents that require BL1 containment are described under 
Section III-D-3, Experiments Involving Transgenic Rodents.
    ``Section III-C-4-c-(2). The purchase and use of transgenic rodents 
is exempt from the NIH Guidelines under Section III-E, Exempt 
Experiments (see Appendix C-VI, The Purchase and Use of Transgenic 
Rodents).''

D. Proposed Amendments to Section III-D. Experiments That Require 
Institutional Biosafety Committee Notice Simultaneous With Initiation

    Section III-D-3 is proposed to be amended to read:

``Section III-D-3. Experiments Involving Transgenic Rodent''

    ``This section covers experiments involving the generation of 
rodents in which the animal's genome has been altered by stable 
introduction of recombinant DNA, or DNA derived therefrom, into the 
germ-line (transgenic rodents). Only experiments that require BL1 
containment are covered under this section; experiments that require 
BL2. BL3, or BL4 containment are covered under Section III-C-4, 
Experiments Involving Whole Animals.''

E. Section IV-C-1-b-(1)-(e). Responsibilities of the NIH Director

    Section IV-C-1-b-(1)-(e) is proposed to be deleted.
    ``Section IV-C-1-b-(1)-(e). Recommendations made by the NIH 
Director to the FDA Commissioner regarding RAC reviewed human gene 
transfer experiments (see Appendix M-III-E, RAC Recommendations to the 
NIH Director;''
    (The rest of Section IV-C-b-(1) will be renumbered.)

F. Proposed Amendments to Appendix C, Exemptions Under Section III-
E-6

    A new section, Appendix C-VI, is proposed to read:

[[Page 44389]]

``Appendix C-VI. The Purchase and Use of Transgenic Rodents''

    ``The purchase and use of transgenic rodents for experiments that 
require BL1 containment are exempt from the NIH Guidelines.''
    (The old Appendix C-VI, Footnotes and References of Appendix C, 
will be renumbered to Appendix C-VII through Appendix C-VII-E.)

G. Proposed Amendments to Appendix M, The Points to Consider in the 
Design and Submission of Protocols for the Transfer of Recombinant DNA 
Molecules Into the Genome of One or More Human Subjects (Points to 
Consider)

    The preamble of Appendix M is proposed to be amended to read:
    ``Appendix M applies to research conducted at or sponsored by an 
institution that receives any support for recombinant DNA research from 
the NIH. Researchers not covered by the NIH Guidelines are encouraged 
to use Appendix M.
    ``The acceptability of human somatic cell gene therapy has been 
addressed in several public documents as well as in numerous academic 
studies. In November 1982, the President's Commission for the Study of 
Ethical Problems in Medicine and Biomedical and Behavioral Research 
published a report, Splicing Life, which resulted from a two-year 
process of public deliberation and hearings. Upon release of that 
report, a U.S. House of Representatives subcommittee held three days of 
public hearings with witnesses from a wide range of fields from the 
biomedical and social sciences to theology, philosophy, and law. In 
December 1984, the Office of Technology Assessment released a 
background paper, Human Gene Therapy, which concluded: civic, 
religious, scientific, and medical groups have all accepted, in 
principle, the appropriateness of gene therapy of somatic cells in 
humans for specific genetic diseases. Somatic cell gene therapy is seen 
as an extension of present methods of therapy that might be preferable 
to other technologies. In light of this public support, the Recombinant 
DNA Advisory Committee (RAC) is prepared to consider proposals for 
somatic cell gene transfer.
    ``The RAC will not at present entertain proposals for germ line 
alterations but will consider proposals involving somatic cell gene 
transfer. The purpose of somatic cell gene therapy is to treat an 
individual patient, e.g., by inserting a properly functioning gene into 
the subject's somatic cells. Germ line alteration involves a specific 
attempt to introduce genetic changes into the germ (reproductive) cells 
of an individual, with the aim of changing the set of genes passed on 
to the individual's offspring.
    ``Research proposals involving the deliberate transfer of 
recombinant DNA or DNA or RNA derived from recombinant DNA into human 
subjects (human gene transfer) will be considered through a review 
process involving both the NIH/ORDA and the RAC. Public review of human 
gene transfer protocols will serve to inform the public about the 
technical aspects of the proposals as well as the meaning and 
significance of the research. Investigators must submit human gene 
transfer protocols to the NIH/ORDA in the format described in Appendix 
M-I. Submission Requirements--Human Gene Transfer Experiments. NIH/ORDA 
and the RAC will evaluate the proposal regarding the necessity for RAC 
review.
    ``Factors that may contribute to the necessity for RAC review 
include: (I) New vectors/new gene delivery systems, (ii) new diseases, 
(iii) unique applications of gene transfer, and (iv) other issues 
considered to require further public discussion. Among the experiments 
that may be considered exempt from RAC review are those determined by 
the RAC and the NIH/ORDA not to represent possible risk to human health 
or the environment (see Appendix M-VII, Categories of Human Gene 
Transfer Experiments that May Be Exempt from RAC Review). Whenever 
possible, investigators will be notified within 15 working days 
following receipt of the submission whether RAC review will be 
required. In the event that NIH/ORDA and the RAC require RAC review of 
the submitted proposal, the documentation described in Appendix M-I. 
Submission Requirements--Human Gene Transfer Experiments, will be 
forwarded to the RAC primary reviewers for evaluation. RAC meetings 
will be open to the public except where trade secrets and proprietary 
information are reviewed. The RAC prefers that information provided in 
the submission documentation contains no proprietary data or trade 
secrets, enabling all aspects of the review to be open to the public. 
The RAC will recommend approval or disapproval of the reviewed proposal 
to the NIH Director. In the event that a proposal is contingently 
approved by the RAC, the RAC conditions must be satisfactorily met 
before the RAC's recommendation for approval is submitted to the NIH 
Director. The NIH Director's decision on the submitted proposal will be 
considered as a Major Action by the NIH Director.
    ``Public review of human gene transfer proposals will serve to 
inform the public about the technical aspects of the proposals as well 
as the meaning and significance of the research.
    ``In its evaluation of human gene transfer proposals, the RAC and 
NIH/ORDA will consider whether the design of such experiments offers 
adequate assurance that their consequences will not go beyond their 
purpose, which is the same as the traditional purpose of clinical 
investigation, namely, to protect the health and well being of human 
subjects being treated while at the same time gathering generalizable 
knowledge. Two possible undesirable consequences of the transfer of 
recombinant DNA would be unintentional: (i) Vertical transmission of 
genetic changes from an individual to his/her offspring, or (ii) 
horizontal transmission of viral infection to other persons with whom 
the individual comes in contact. Accordingly, Appendices M-I through M-
V requests information that will enable the RAC and NIH/ORDA to assess 
the possibility that the proposed experiment(s) will inadvertently 
affect reproductive cells or lead to infection of other people (e.g., 
medical personnel or relatives).
    ``In recognition of the social concern that surrounds the subject 
of human gene transfer, the RAC and NIH/ORDA will cooperate with other 
groups in assessing the possible long-term consequences of the proposal 
and related laboratory and animal experiments in order to define 
appropriate human applications of this emerging technology.
    ``Appendix M will be considered for revisions as experience in 
evaluating proposals accumulates and as new scientific developments 
occur. This review will be carried out periodically as needed.''
    Appendix M-I is proposed to be amended to read:

``Appendix M-I. Submission Requirements--Human Gene Transfer 
Proposals''

    ``Investigators must submit the following material to the Office of 
Recombinant DNA Activities, National Institutes of Health/MSC 7010, 
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010, 
301-496-9838 (see exemption in Appendix M-IX-A, Footnotes of Appendix 
M). Proposals will be submitted in the following order: (1) Scientific 
abstract; (2) non-technical abstract; (3) clinical protocol (including 
discussion of all issues raised in Appendix M-II through

[[Page 44390]]

M-V); (4) Informed Consent document prepared for IRB submission (see 
Appendix M-III, Informed Consent); (5) letter stating that submission 
has been made to the IBC; (6) appendices (including tables, figures, 
and manuscripts); and (7) curricula vitae for each key professional 
person in biographical sketch format.

    ``Note: Final IBC and IRB approvals should be submitted to NIH/
ORDA upon receipt of the following: (1) NIH notification of 
exemption from full RAC discussion, or (2) subsequent to full RAC 
discussion (if applicable). Human gene transfer protocols shall not 
be initiated prior to submission of final IBC and IRB approvals to 
the NIH/ORDA.''

    Appendix M-VI-A is proposed to be amended to read:

``Appendix M-VI-A. Categories of Human Gene Transfer Experiments That 
Require RAC Review''

    ``Factors that may contribute to the necessity for RAC review 
include, but are not limited to: (i) New vectors/new gene delivery 
systems, (ii) new diseases, (iii) unique applications of gene transfer, 
and (iv) other issues considered to require further public discussion. 
Whenever possible, investigators will be notified within 15 working 
days following receipt of the submission whether RAC review will be 
required. In the event that RAC review is deemed necessary by the NIH 
and the RAC, the proposal will be forwarded to the RAC primary 
reviewers for evaluation. In order to maintain public access to 
information regarding human gene transfer protocols, NIH/ORDA will 
maintain the documentation described in Appendix M-I (including 
protocols that are not reviewed by the RAC).''
    Appendix M-VI-B is proposed to be amended to read:

``Appendix M-VI-B. RAC Primary Reviewers' Written Comments''

    ``In the event that NIH/ORDA or the RAC recommends RAC review of 
the submitted proposal, the documentation described in Appendix M-I 
will be forwarded to the RAC primary reviewers for evaluation.''
    Appendix M-VI-E is proposed to be amended to read:

``Appendix M-VI-E. RAC Recommendations to the NIH Director''

    ``The RAC will recommend approval or disapproval of the reviewed 
proposal to the NIH Director. In the event that a proposal is 
contingently approved by the RAC, the RAC prefers that the conditions 
be satisfactorily met before the RAC's recommendation for approval is 
submitted to the NIH Director. The NIH Director's decision on the 
submitted proposal will be considered as a Major Action by the NIH 
Director.''
    Appendix M-VII is proposed to be amended to read:

``Appendix M-VII. Categories of Human Gene Transfer Experiments That 
May Be Exempt from RAC Review''

    ``A proposal submitted under one of the following categories may be 
considered exempt from RAC review unless otherwise determined by NIH/
ORDA and the RAC on a case-by-case basis (see Appendix M-VI-A, 
Categories of Human Gene Transfer Experiments that Require RAC Review).

    Note: For proposals that are exempt from RAC review, the 
documentation described in Appendix M-I will be maintained by NIH/
ORDA for compliance with annual data reporting and adverse event 
reporting requirements (see Appendix M-VIII, Reporting 
Requirements--Human Gene Transfer Protocols). Any subsequent 
modifications to proposals that were not reviewed by the RAC must be 
submitted to NIH/ORDA in order to facilitate data reporting 
requirements.''

    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 not only virtually 
every NIH program but also essentially every Federal research program 
in which DNA recombinant molecule techniques could be used, it has been 
determined to be not cost effective or in the public interest to 
attempt to list these programs. Such a list would likely require 
several additional pages. 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: August 4, 1997.
Lana R. Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 97-22030 Filed 8-19-97; 8:45 am]
BILLING CODE 4140-01-P