[Federal Register Volume 59, Number 29 (Friday, February 11, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-3180]
[[Page Unknown]]
[Federal Register: February 11, 1994]
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Recombinant DNA Research: Proposed Actions Under the Guidelines
AGENCY: National Institutes of Health, PHS, DHHS.
ACTION: Notice of Proposed Actions Under the NIH Guidelines for
Research Involving Recombinant DNA Molecules (51 FR 16958).
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SUMMARY: This notice sets forth proposed actions to be taken under the
National Institutes of Health (NIH) Guidelines for Research Involving
Recombinant DNA Molecules (51 FR 16958). 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 March 3-4, 1994. After consideration of these proposals and
comments by the RAC, the Director of the National Institutes of Health
will issue decisions in accordance with the NIH Guidelines.
DATES: Comments received by February 24, 1994, will be reproduced and
distributed to the RAC for consideration at its March 3-4, 1994,
meeting.
ADDRESSES: Written comments and recommendations should be submitted to
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities
(ORDA), Building 31, room 4B11, National Institutes of Health,
Bethesda, Maryland 20892, or sent by FAX to 301-496-9839.
All comments received in timely 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 p.m.
FOR FURTHER INFORMATION CONTACT:
Background documentation and additional information can be obtained
from the Office of Recombinant DNA Activities, Building 31, room 4B11,
National Institutes of Health, Bethesda, Maryland 20892, (301) 496-
9838.
SUPPLEMENTARY INFORMATION: The NIH will consider the following actions
under the NIH Guidelines for Research Involving Recombinant DNA
Molecules:
I. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Drs. Hersh, Akporiaye, Harris, Stopeck, Unger, and
Warneke
On December 23, 1993, Dr. Evan Hersh of the Arizona Cancer Center
and Drs. Akporiaye, Harris, Stopeck, Unger, and Warneke of the
University of Arizona, Tucson, Arizona (co-sponsored by Vical, San
Diego, California), submitted a human gene transfer protocol to the
Recombinant DNA Advisory Committee for formal review and approval. The
title of this protocol is: Phase I Study of Immunotherapy of Malignant
Melanoma by Direct Gene Transfer.
II. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Walker
On January 4, 1994, Dr. Robert Walker of the National Institutes of
Health, Bethesda, Maryland (co-sponsored by Cell Genesys, Foster City,
California), submitted a human gene transfer protocol to the
Recombinant DNA Advisory Committee for formal review and approval. The
title of this protocol is: A Phase I/II Pilot Study of the Safety of
the Adoptive Transfer of Syngeneic Gene-Modified Cytotoxic T-
Lymphocytes in HIV-Infected Identical Twins.
III. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Drs. Rosenblatt and Seeger
On January 5, 1994, Drs. Joseph Rosenblatt of the University of
California, Los Angeles, California, and Robert Seeger of the Childrens
Hospital, Los Angeles, California, submitted a human gene transfer
protocol to the Recombinant DNA Advisory Committee for formal review
and approval. The title of this protocol is: A Phase I Study of
Immunization with Gamma Interferon Transduced Neuroblastoma Cells.
IV. Addition to Appendix D of the NIH Guideline Regarding a Human Gene
Transfer Protocol/Dr. Brigham
On January 6, 1994, Dr. Kenneth Brigham of Vanderbilt University,
Nashville, Tennessee, submitted a human gene transfer protocol to the
Recombinant DNA Advisory Committee for formal review and approval. The
title of this protocol is: Expression of an Exogenously Administered
Human Alpah-1 Antitrypsin Gene in the Respiratory Tract of Humans.
V. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Freedman
On January 5, 1994, Dr. Ralph Freedman of the MD Anderson Cancer
Center, Houston, Texas, resubmitted a human gene transfer protocol to
the Recombinant DNA Advisory Committee for formal review and approval.
The title of this protocol is: Use of a Retroviral Vector to Study the
Trafficking Patterns of Purified Ovarian Tumor Infiltrating Lymphocytes
(TIL) Used in Intraperitoneal Adoptive Immunotherapy of Ovarina Cancer
Patients--A Pilot Study.
Dr. Freedman first submitted this protocol on March 22, 1993.
During the June 7-8, 1993, RAC meeting, this protocol was deferred
until the investigators could return to the full RAC with the following
information: (1) Data demonstrating efficient transduction of TIL, (2)
sufficient information regarding demonstration of selectivity, i.e.,
specific trafficking of TIL to tumor, (3) complete statistical
analysis, (4) revised Informed Consent document in simplified language,
and (5) address concerns about patient responsibility for research-
related costs. The motion to defer the protocol pending full RAC review
of additional information passed by a vote of 18 favor, 0 opposed, and
no abstentions.
VI. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene
Transfer Protocol/Dr. Vogelzang
On January 6, 1994, Dr. Nicholas Vogelzang, University of Chicago,
Chicago, Illinois, submitted a human gene transfer protocol to the
Recombinant DNA Advisory Committee for formal review and approval. The
title of this protocol is: Phase I Study of Immunotherapy for
Metastatic Renal Cell Carcinoma by Direct Gene Transfer into Metastatic
Lesions.
VII. Addition to Appendix D of the NIH Guidelines Regarding a Human
Gene Transfer Protocol/Dr. Roth
On January 4, 1994, Dr. Jack A. Roth of the MD Anderson Cancer
Center, University of Texas, Houston, Texas, resubmitted a human gene
transfer protocol to the Recombinant DNA Advisory Committee for formal
review and approval. The title of this protocol is: Clinical Protocol
of Modification of Oncogene and Tumor Suppressor Gene Expression in
Non-Small Cell Lung Cancer (NSCLC).
Dr. Roth first submitted this protocol on March 19, 1992. During
the September 14-15, 1992, RAC meeting, approval of this protocol was
recommended contingent on the review and approval of the following
information by RAC primary reviewers (Drs. Miller, Hirano, and
Geiduschek): (1) Data demonstrating the transforming potential of 100
milliliters of retroviral supernatant analogous to the preparation that
will be used for the clinical protocol, (2) data obtained from in vitro
mixing experiments, (3) in vitro data demonstrating that the new vector
preparations have activity, and (4) incorporation of minor changes in
the Informed Consent document as noted by Drs. Carmen and Hirano. The
motion passed by a vote of 18 in favor, 0 opposed, and no abstentions.
On May 11, 1993, Dr. Roth submitted material in response to the RAC's
stipulations for approval and a request for the following
modifications: (1) The producer cell line will be amended to include
GP+envAM12, and (2) the clinical protocol grade supernatant will be
produced by Microbiological Associates. On June 15, 1993, the primary
reviewers agreed to the modification of stipulation, #1, as requested
by Dr. Roth. The revised stipulation is: (1) submit data demonstrating
the transforming potential of a single patient dose, i.e., 10ml of
retrovirus supernatant at 1 x 106 CFU/ml. The primary reviewers
did not accept subsequent data submitted by Dr. Roth as adequately
fulfilling the stipulations for approval of the protocol. For this
reason, the primary reviewers requested that the materials submitted by
Dr. Roth should be reviewed by the full RAC at its December 2-3, 1993,
meeting. During the December 1993 meeting, the consensus of the RAC was
that the protocol was considered administratively inactivated;
therefore, RAC approval of the protocol was withdrawn. The RAC
recommended that Dr. Roth submit a revised protocol including all
additional data for review by the full RAC, based on the following: (1)
Failure of the primary reviewers to recommend approval of the protocol,
(2) lengthy delays in the presentation of data, (3) the fact that there
are several new members who were not on the RAC at the time the
original protocol was reviewed, and (4) the proposed use of a new
vector. The RAC noted that if Dr. Roth submits a revised protocol for
full RAC review, new primary reviewers will be assigned. The RAC
recommended that the Office of Recombinant DNA Activities forward a
letter to Dr. Roth with recommendations for resubmission of his
protocol for full RAC review. The Office of Recombinant DNA Activities
forwarded a letter to Dr. Roth on December 21, 1993, requesting
submission of a revised protocol by February 4, 1994.
VII. Addition to Appendix D of the NIH Guidelines Regarding Deliberate
Transfer of a Chloramphenicol Resistance Gene to an Avirulent Strain of
Rickettsia prowzaeki/Dr. Policastro
On January 4, 1994, Dr. Paul Policastro of the National Institutes
of Health, Rocky Mountain Laboratories, Hamilton, Montana, resubmitted
a request regarding the deliberate transfer of a gene coding for
chloramphenicol resistance to an avirulent strain of Rickettsia
prowzaeki.
Dr. Policastro first submitted this request on March 23, 1993.
During its June 7-8, 1993, meeting, the RAC deferred approval of this
request by a vote of 20 in favor, 0 opposed, and no abstentions. The
RAC deferred approval until the investigator submits the following data
for full RAC review: (1) Data demonstrating that the construct is safe
and useful, and (2) in vitro data demonstrating the selective advantage
of chloramphenicol resistance over other selectable markers.
IX. Report on Minor Modifications to NIH-Approved Human Gene Transfer
Protocols
Dr. LeRoy Walters, RAC Chair, will present an update on minor
modifications to NIH-approved human gene transfer protocols.
X. Amendments to Footnotes 21 and 22 and Section III-A-3 of the NIH
Guidelines Regarding Recombinant DNA Vaccines
Dr. Leonard Post, Chair of the Working Group on Vaccines, will
present an overview of the proposed amendments to Footnotes 21 and 22.
The proposed amendments will define those categories of experiments
involving the administration of recombinant DNA vaccines that are
exempt from RAC review and National Institutes of Health and
Institutional Biosafety Committee approval.
XI. Amendments to Sections I, III, IV, and V of the NIH Guidelines and
the Points to Consider in the Design and Submission of Protocols for
the Transfer of Recombinant DNA into the Genome of Human Subjects
(Points to Consider) Regarding NIH (ORDA) Review and Approval of
Certain Categories of Human Gene Transfer Experiments That Qualify for
the Accelerated Review Process
Dr. Robertson Parkman, Chair of the Working Group on Accelerated
Review Protocols, will present an overview of the proposed amendments
to the NIH Guidelines and the Points to Consider. The proposed
amendments will: (1) Establish an accelerated review process for
certain categories of human gene transfer experiments (i.e.,
``umbrella'' multiple site protocols in which the Principal
Investigator is responsible for the quality control and data reporting
for research conducted at all sites, and duplicate protocols conducted
at sites other than those originally approved by the RAC and in which
there is a new Principal Investigator), (2) allow the National
Institutes of Health (Office of Recombinant DNA Activities) to assign
the appropriate review category to all human gene transfer proposals
that are submitted in compliance with the NIH Guidelines, (3) allow the
National Institutes of Health (Office of Recombinant DNA Activities) to
approve those categories of human gene transfer experiments that
qualify for the accelerated review process in consultation with the
Chair and one or more RAC members, as necessary, and (4) exempt certain
experiments involving the transfer of recombinant DNA or DNA or RNA
derived from recombinant DNA into one or more human subjects which are
not covered by Footnote 21. All human gene transfer experiments
approved by the National Institutes of Health (Office of Recombinant
DNA Activities) through the accelerated review process will be provided
in a report by the RAC Chair at the next regularly RAC meeting and will
be included in the list of approved experiments which is available from
the Office of Recombinant DNA Activities, Building 31, room 4B11,
Bethesda, Maryland 20892. The RAC recommends that these amendments be
published in the Federal Register for public comment and review by the
full RAC during its March 2-3, 1994, meeting. The proposed amendments
to the NIH Guidelines are as follows:
``Section I. Scope of the NIH Guidelines''
``Section I-A. Purpose''
[No Changes] ``The purpose of the NIH Guidelines is to specify
practices for constructing and handling: (i) recombinant DNA
molecules, and (ii) organisms and viruses containing recombinant DNA
molecules.''
[No Changes] ``Any recombinant DNA experiment, which according
to the NIH Guidelines requires approval by the NIH, must be
submitted to the NIH or to another Federal agency that has
jurisdiction for review and approval. Once approval, or other
applicable clearances, are obtained from a Federal agency other than
the NIH (whether the experiment is referred to that agency by the
NIH, or sent directly there by the submitter), the experiment may
proceed without the necessity for NIH review or approval.''
[Amended] ``Certain experiments that involve the deliberate
transfer of recombinant DNA or DNA or RNA derived from recombinant
DNA into one or more human subjects (see Footnote 21) shall be
considered Major Actions to the NIH Guidelines (see Section IV-C-1-
b-(1)-(d)), and shall require RAC review and NIH Director approval,
if determined by NIH (ORDA) in consultation with the RAC Chair and/
or one or more RAC members, as necessary, to: (i) Represent novel
characteristics (e.g., target disease or vector), (ii) represent an
uncertain degree of risk to human health or the environment, or
(iii) contain information determined to require further public
review (see Section III-A-3).''
[Addition] ``Experiments involving the transfer of recombinant
DNA to one or more human subjects that are not considered under
Section III-A-3 may qualify for Accelerated Review (see Section III-
B-2 of the NIH Guidelines and Part V of the Points to Consider) and
will be considered as Minor Actions to the NIH Guidelines (see
Section IV-C-1-b-(2)-(a)). Actions that qualify for Accelerated
Review (see Section III-B-2) will be reviewed and approved by NIH
(ORDA) in consultation with the RAC Chair and/or one or more RAC
members, as necessary.''
[Addition] ``Certain experiments involving the transfer of
recombinant DNA into one or more human subjects (see Footnote 21)
may be considered exempt from RAC and/or NIH (ORDA) review and/or
NIH Director approval and only require registration with NIH (ORDA)
(see Section III-C-6).''
[No Changes--Section 1-B through II.]
``Section III. Experiments Covered by the NIH Guidelines''
[Amended] ``* * * Any change in containment level, which is
different from those specified in the NIH Guidelines may not be
initiated without the express approval of NIH (ORDA) (see Minor
Actions, Section IV-C-1-b-(2) and its subsections.)''
``Section III-A. Experiments that Require RAC Review and NIH and
IBC Approval Before Initiation''
[Amended] ``Experiments in this category are considered Major
Actions to the NIH Guidelines (see Section IV-C-1-b-(1)) and cannot
be initiated without submission of relevant information on the
proposed experiment to NIH, the publication of the proposal in the
Federal Register for 15 days of comment, review by the RAC, and
specific approval by NIH (not applicable for Expedited Review single
patient human gene transfer experiments considered under Part VI of
the Points to Consider). The containment conditions for such
experiments will be recommended by the RAC and set by NIH at the
time of approval. Such experiments also require IBC approval before
initiation. Specific experiments already approved in this section
may be obtained from ORDA, NIH, Building 31, room 4B11, Bethesda,
Maryland 20892.''
[No Changes--Section III-A-1 through III-A-2].
[Amended] ``Section III-A-3. Certain experiments involving the
deliberate transfer of recombinant DNA or DNA or RNA derived from
recombinant DNA into one or more human subjects (see Footnote 21)
shall be considered Major Actions (see Section IV-C-1-b-(1)-(d)),
and shall require RAC review and NIH Director approval, if
determined by NIH (ORDA), in consultation with the RAC Chair and one
or more RAC members, as necessary, to: (i) Represent novel
characteristics (e.g., target disease or vector), (ii) represent an
uncertain degree to risk to human health or the environment, or
(iii) contain information determined to require further public
review. The requirement for RAC review should not be considered to
preempt any other required review of experiments with one or more
human subjects. Relevant IBC and Institutional Review Board (IRB)
reviews of the proposal should be completed before submission to
NIH. See Part III-A of the Points to Consider for guidelines for
submission of human gene transfer protocols. Certain experiments
involving the deliberate transfer of recombinant DNA or DNA or RNA
derived from recombinant DNA into one or more human subjects may
qualify for the Accelerated Review process (see Section III-B-2).
Certain categories of experiments involving the deliberate transfer
of recombinant DNA or DNA or RNA derived from recombinant DNA into
one or more human subjects and that are not covered by Footnote 21,
may be considered exempt from RAC and/or NIH (ORDA) review and/or
NIH Director approval and only require registration with NIH (ORDA)
(see Section III-C-6).''
[No Changes--Section III-B through III-B-1(1).]
[Addition] ``Section III-B-2. Human Gene Transfer Experiments
that Quality for Accelerated Review and Approval by NIH (ORDA)''
[Addition] ``As determined by the NIH (ORDA), in consultation
with the RAC Chair and one or more RAC members, as necessary,
certain categories of human gene transfer experiments may be
considered as Minor Actions to the NIH Guidelines and qualify for
accelerated review and approval (see Section IV-C-1-b-(2)(a)). The
RAC Chair will present a report of all NIH (ORDA)-approved human
gene transfer protocols at the next regularly scheduled RAC meeting.
If NIH (ORDA) determines that an experiment does not qualify for the
accelerated review process, the PI must submit the proposal for full
RAC review at least 8 weeks prior to the next scheduled RAC meeting
(see Section III-A-3). See Part III-A of the Points to Consider for
guidelines for submission of human gene transfer protocols.''
[Addition] ``Section III-B-3. Minor Modifications to Human Gene
Transfer Experiments.''
[Addition] ``A minor change in a human gene transfer protocol is
a change that does not significantly alter the basic design of the
protocol and that does not increase risk to human subjects or the
environment. NIH (ORDA) will consider the change, in consultation
with the RAC Chair and one or more RAC members, as necessary, after
approval has been obtained by the relevant IRB and IBC. The RAC
Chair will provide a report on any such approvals at the next
regularly scheduled RAC meeting.''
[No Changes--Section III-C through III-C-6.]
[Addition] ``Section III-C-6. Human Gene Transfer Experiments
not Covered by Footnote 21.''
[Addition] ``Experiments involving the transfer of recombinant
DNA or DNA or RNA derived from recombinant DNA into one or more
human subjects, and that are not covered by Footnote 21, must be
registered with NIH (ORDA). The relevant IBC and IRB must review all
experiments in this category prior to their initiation. For
experiments in this category, the registration document must
include:''
[Note: The RAC will discuss the information that should be filed
with ORDA for experiments in this category.]
[No Changes--Section III-D through IV-C-1B.]
``Section IV-C-1-b-(1), Major Actions''
[Amended] ``To execute major actions, the NIH Director must seek
the advice of the RAC and provide an opportunity for pubic and
Federal agency comment. Specifically, the agenda of the RAC meeting
citing the major actions shall be published in the Federal Register
at least 15 days before the meeting, and the NIH Director shall also
publish the proposed actions in the Federal Register for comment at
least 15 days before the meeting (not applicable for Expedited
Review human gene transfer experiments considered under Part VI of
the Points to Consider. In addition, the NIH Director's proposed
decision, at his/her discretion, may be published in the Federal
Register for 15 days of comment before final action is taken. The
RAC and IBC Chairs shall be notified of the following decisions:''
[No changes--Section IV-C-1-b-(1)-(a) through IV-C-1-b-(1)-(f).]
[Amended] ``Section IV-C-1-b-(2). Minor Actions''
[Amended] ``NIH (ORDA) shall carry out certain functions as
delegated to it by the NIH Director (see Section IV-C-3). Minor
actions, as determined by NIH (ORDA) in consultation with the RAC
Chair and one or more RAC members, as necessary, will be transmitted
to the RAC and IBC Chairs:''
[Delete the current Section IV-C-1-b-(2)-(a). Interpreting and
determining containment levels upon request by ORDA;]
[Addition] ``Section IV-C-1-b-(2)-(a). Reviewing and approving
certain experiments involving the deliberate transfer of recombinant
DNA or DNA or RNA derived from recombinant DNA into one or more
human subjects that qualify for the Accelerated Review process (see
Section III-B-2);''
[Addition] ``Section IV-C-b-(2)-(b). Reviewing and approving
minor changes to human gene transfer protocols approved under
Section III-A-3 and III-B-2;''
[Renumbered] ``Section IV-C-1-b-(2)-(c). Changing containment
levels for experiments that are specified in the NIH Guidelines (see
Section III);''
[Renumbered] ``Section IV-C-1-b-(2)-(d). Assigning containment
levels for experiments not explicitly considered in the NIH
Guidelines;''
[Renumbered] ``Section IV-C-1-b-(2)-(e). Revising the
Classification of Etiologic Agents for the purpose of these NIH
Guidelines (See Footnote 1).''
[Delete Section IV-C-1-b-(3). Other Actions. The NIH Director's
decision will be transmitted to the RAC and IBC Chairs:]
[Renumbered] ``Section IV-C-1-b-(2)-(f). Interpreting the NIH
Guidelines for experiments to which the NIH Guidelines specifically
assign containment levels;''
[Renumbered] ``Section IV-C-1-b-(2)-(g). Setting containment
under Section III-C-1-d and Section III-C-3-d;''
[Renumbered] ``Section IV-C-1-b-(2)-(h). Approving minor
modifications of already certified host-vector systems (the
standards and procedures for such modifications are described in
Appendix I-II);''
[Renumbered] ``Section IV-C-1-b-(2)-(i). Decertifying already
certified host-vector systems;''
[Renumbered] ``Section IV-C-1-b-(2)-(j). Adding new entries to
the list of molecules toxic for vertebrates (see Appendix F);''
[Renumbered/Amended] ``Section IV-C-1-b-(2)-(k). Determining
appropriate containment conditions for experiments according to case
precedents developed under Section IV-C-1-b-(2)-(d).]
[Renumbered] ``Section IV-C-1-b-(4). The Director, NIH, shall
conduct, support, and assist training programs in laboratory safety
for IBC members, BSOs, PIs, and laboratory staff.''
[Amended] ``Section IV-C-2. Recombinant DNA Advisory Committee
(RAC) * * * The RAC shall be responsible for advising the Director,
NIH, on the actions listed in Section IV-C-1-b-(1).''
[Amended] ``Section IV-C-3. The Office of Recombinant DNA
Activities (ORDA). The ORDA shall serve as a focal point for
information on recombinant DNA activities and provide advice to all
within and outside NIH including Institutions, BSOs, PIs, Federal
agencies, state and local governments, and institutions in the
private sector. The ORDA shall carry out such other functions as may
be delegated to it by the Director, NIH including those authorities
described in Section IV-C-1-b-(2). In addition, ORDA shall be
responsible for the following.''
[No Changes--Section IV-C-3-a.]
[Addition] ``Section IV-C-3-b. Reviewing and approving certain
experiments involving the deliberate transfer of recombinant DNA or
DNA or RNA derived from recombinant DNA into one or more human
subjects, in consultation with the RAC Chair and one or more RAC
members, as necessary, that qualify for the Accelerated Review
process (see Section III-B-2);''
[Addition] ``Section IV-C-3-c. Reviewing and approving minor
changes to human gene transfer protocols approved under Sections
III-A-3 and III-B-2, in consultation with the RAC Chair and one or
more RAC members, as necessary;''
[Renumbered] ``Section IV-C-3-d. Reviewing and approving IBC
membership;''
[Renumbered] ``Section IV-C-3-e. Publishing in the Federal
Register:''
[Renumbered] ``Section IV-C-3-e-(1). Announcements of RAC
meetings and agendas at least 15 in advance;''
[No Changes] ``NOTE--If the agenda for a RAC meeting is
modified, ORDA shall make the revised agenda available to anyone
upon request at least seventy-two hours in advance of the meeting.''
[Renumbered] ``Section IV-C-3-e-(2). Proposed major actions of
the type falling under Section IV-C-1-b-(1) at least 15 days prior
to the RAC meeting at which they will be considered; and''
[Delete old Section IV-C-3-c-(3). The NIH Director's final
decision on recommendations made by the RAC.]
[Renumbered/Amended] ``Section IV-C-3-f. Serve as the focal
point for data management of NIH-approved human gene transfer
protocols approved under Section III-A-3 and III-B-2 and registered
with NIH (ORDA) as required under Section III-C-6.''
[Renumbered] ``Section IV-C-3-g. Serve as executive secretary of
the RAC.''
[Addition] ``Section IV-C-3-h. Maintain a list of major and
minor actions to the NIH Guidelines approved under Sections III-A-3
and III-B-2 and a list of experiments registered with NIH (ORDA) as
described in Section III-C-6.''
[No Changes--Section IV-C-4 through V-T].
[The RAC Will Consider Revision of this Footnote.] ``Footnote
21. Sections III-A-3 and III-B-2 cover only those experiments in
which the intent is to modify stably the genome of cells of one or
more human subjects. Other experiments involving the deliberate
transfer of recombinant DNA into one or more human subjects such as
feeding of bacteria containing recombinant DNA or the administration
of vaccines containing recombinant DNA are not covered in Sections
III-A-3 and III-B-2.''
[The RAC may Modify this Footnote According to Footnote 21
Revision] ``Footnote 22. For recombinant DNA experiments in which
the intent is to modify stably the genome of cells of one or more
human subjects (see Sections III-A-3 and III-B-2).''
[No Changes--Section VI.]
The proposed amendments to the Points to Consider are as
follows:
[Amended] ``These Points to Consider apply 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 the Points to Consider.
Experiments in which recombinant DNA is introduced into one or more
human subjects with the intent of stably modifying the subject's
genome are covered by Sections III-A-3 and III-B-2 of the NIH
Guidelines (see Footnote 21 of the NIH Guidelines). Experiments in
which recombinant DNA is introduced into one or more human subjects
with no risk of stably modifying the subject's genome are covered
under Section III-C-6 of the NIH Guidelines (see Footnote 21 of the
NIH Guidelines). Sections III-A-3, III-B-2, and III-C-6 of the NIH
Guidelines apply both to recombinant DNA and to DNA or RNA derived
from recombinant DNA.''
[Amended] ``This document is intended to provide guidance in
preparing proposals for NIH consideration under Sections III-A-3 and
III-B-2 of the NIH Guidelines. Section III-A-3 addresses Major
Actions to the NIH Guidelines involving the transfer of recombinant
DNA into one or more human subjects that have been determined by NIH
(ORDA), in consultation with the RAC Chair and one or more RAC
members, as necessary, to: (i) represent novel characteristics
(e.g., target disease or vector), (ii) represent an uncertain degree
of risk to human health or the environment, or (iii) contain
information determined to require further public review. Proposals
considered under Section III-A-3 of the NIH Guidelines will be
reviewed by the RAC and approved by the NIH Director. RAC review of
experiments considered under Section III-A-3 of the NIH Guidelines
will follow publication of a precis of the proposal in the Federal
Register and an opportunity for public comment. Section III-B-2
addresses Minor Actions to the NIH Guidelines involving the transfer
of recombinant DNA into one more human subjects that have been
determined by NIH (ORDA), in consultation with the RAC Chair and one
or more RAC members, as necessary, to qualify for the accelerated
review process. Proposals considered under Sections III-A-3 and III-
B-2 will be on a case-by-case basis. A list of actions to the NIH
Guidelines approved under Sections III-A-3 and III-B-2 involving the
transfer of recombinant DNA into one or more human subjects is
available from the Office of Recombinant DNA Activities, Building
31, Room 4B11, National Institutes of Health, Bethesda, Maryland,
20892. The list of actions to the NIH Guidelines involving the
transfer of recombinant DNA into one or more human subjects does not
include experiments considered to be exempt from RAC and NIH (ORDA)
review under Section III-C-6 of the NIH Guidelines.''
[No changes] ``In general, it is expected that the transfer of
recombinant DNA into one or more human subjects will not present a
risk to public health or to the environment as the recombinant DNA
is expected to be confined to human subjects. Nevertheless, Part I-
B-4-b specifically asks the researchers to address this point.''
[No changes] ``This document will be considered for revision as
experience in evaluating proposals accumulates and as new scientific
developments occur. This review will be carried out periodically as
needed.''
[Amended] ``A proposal involving the transfer of recombinant DNA
into one or more human subjects will be considered by the RAC and/or
NIH (ORDA) only after the protocol has been approved by the local
Institutional Biosafety Committee (IBC) and the local Institutional
Review Board (IRB) in accordance with DHHS Federal Regulations for
the Protection of Human Subjects (45 Code of Federal Regulations,
part 46). (If a proposal involves children, special attention should
be paid to subpart D of these DHHS regulations.) The IRB and IBC
may, at their discretion, condition their approval on further
specific deliberation by the RAC and/or NIH (ORDA). Consideration of
human gene transfer proposals by the RAC and/or NIH (ORDA) may
proceed simultaneously with review by other involved federal
agencies (See Part VI-A) provided that NIH (ORDA) is notified of the
simultaneous review. Meetings of the full RAC will be open to the
public except where trade secrets or proprietary information would
be disclosed. The committee prefers that proposals submitted for RAC
review contain no proprietary information or trade secrets, enabling
all aspects of the review to be open to the public. The public
review of these protocols will serve to inform the public not only
on the technical aspects of the proposals but also on the meaning
and significance of the research.''
[No changes] ``The clinical application of recombinant DNA
techniques raises two general kinds of questions: (i) The questions
usually discussed by IRBs in their review of any proposed research
involving one or more human subjects; and (ii) broader issues. The
first type of question is addressed principally in Part III of this
document. Several broader issues are discussed later in this
Introduction and in part II below.''
[Amended] ``Following this Introduction, this document is
divided into four parts. Part I requests a description of the
protocol with special attention to the short-term risks and benefits
of the proposed research to the patient and to other people, the
selection of patients, informed consent, and privacy and
confidentiality. In part II, investigators are requested to address
special issues pertaining to the free flow of information about the
clinical trials. These issues lie outside the usual purview of IRBs
and reflect general public concerns about biomedical research. Part
III summarizes other requested documentation that will assist the
RAC and/or NIH (ORDA) in its review of the proposals. Part IV
specifies reporting requirements.''
[Amended] ``The RAC will not at present entertain proposals for
germ-line alterations but will consider for approval protocols
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 a patient's somatic cells. In germ
line alterations, a specific attempt is made 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.''
[No changes] ``The acceptability of human somatic cell gene
therapy has been addressed in several public documents as well as in
numerous academic studies. The 1982 report of the President's
Commission for the Study of Ethical Problems in Medicine and
Biomedical and Behavioral Research, Splicing Life, resulted from a
two-year process of public deliberations 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 RAC is prepared to consider proposals for
somatic cell gene therapy.''
[Amended] ``In its evaluation of proposals involving the
transfer of recombinant DNA into one or more human subjects, the RAC
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
investigations, namely, to protect the health and well-being of the
individual subject(s) 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 of her
offspring, or (ii) horizontal transmission of viral infection to
other persons with whom the individual comes in contact.
Accordingly, this document requests information that will enable the
RAC and/or NIH (ORDA) to assess the possibility that the proposed
experiments will inadvertently affect reproductive cells or lead to
infection of other people (e.g., personnel or relatives).
[Amended] ``In recognition of the social concern that surrounds
the subject of gene transfer, the RAC and NIH (ORDA) will cooperate
with other groups in assessing the possible long-term consequences
of the transfer of recombinant DNA into one or more human subjects
and related laboratory and animal experiments in order to define
appropriate human applications of this emerging technology.''
[No changes] ``Responses to the questions raised in these Points
to Consider should be provided in the form of either written answers
or references to specific sections of the protocol or its
appendices.''
[No changes] ``Investigators should indicate points which are
not applicable with a brief explanation. Investigators submitting
proposals that employ essentially the same vector systems (or with
minor variations), and/or that are based on the same preclinical
testing as proposals previously reviewed by the RAC, may refer to
preceding documents without having to rewrite such material.''
[No Changes--Part I-A through I-C.]
[Proposed Changes--Parts I-D and I-E. See agenda item XII
proposed amendments.]
[No Changes--Parts II through II-B.]
[Delete--Part III. Requested Documentation. In addition to
responses to the questions raised in these Points to Consider,
please submit the following materials:]
[Delete--Part III-A. Your protocol as approved by your local IRB
and IBC.]
[Delete--Part III-B. Results of local IRB and IBC deliberations
and recommendations that pertain to your protocol.]
[Delete--Part III-C. A one-page scientific abstract of the
protocol.]
[Delete--Part III-D. A one-page description of the proposed
experiment in nontechnical language.]
[Delete--Part III-E. Curricula vitae for key professional
personnel.]
[Delete--Part III-F. An indication of other federal agencies to
which the protocol is being submitted for review.]
[Delete--Part III-G. Any other material which you believe will
aid in the review.]
[Renumbered/Amended] ``Part III. Guidelines for the Submission
of Human Gene Transfer Protocols''
[Addition] ``For consideration of human gene transfer protocols
under Section III-A-3 and III-B-2 of the NIH Guidelines the
following criteria will apply:''
[Renumbered] ``Part III-A. Investigator-Submitted Material''
[Renumbered/Amended] ``Part III-A-1. Written proposals must be
submitted in the following order: (1) Scientific abstract--1 page;
(2) non-technical abstract--1 page; (3) Institutional Biosafety
Committee (IBC) and Institutional Review Board (IRB) approvals and
their deliberations pertaining to your protocol; (4) Points to
Consider (Parts I and II)--5 pages; (6) protocol (as approved by the
local IRB and IBC)--20 pages excluding appendices; (7) Informed
Consent Document--approved by the IRB; (8) appendices including
tables, figures, and manuscripts; (9) Curricula vitae--2 pages in
Biographical sketch format; and (10) an indication of other Federal
agencies to which the protocol is being submitted for review.''
[Renumbered] ``Part III-A-2. When a proposal has been submitted
previously, there should be a short section ( 200 words)
immediately following the abstracts that summarizes the major
revisions since the last review.''
[Renumbered] ``Part III-A-3. Data provided must include: (i) A
description of the elements in the vector, (ii) the source of that
information, (iii) the method by which sequence data were compiled,
and (iv) three 3\1/2\ inch diskettes with the vector sequence in
ASCII format.''
[Renumbered] ``Part III-A-4. Time Frame for Submissions.''
[Added] ``Note: Time frames are applicable only to protocols
that are determined by NIH (ORDA) to require full RAC review and NIH
Director approval. Times frames do not apply to Accelerated Review
human gene transfer experiments (see Section III-B-2 of the NIH
Guidelines) or those that only require registration with NIH (ORDA)
(see Section III-C-6 of the NIH Guidelines).''
[Renumbered] ``Part III-A-4-a. Written material from PI must be
submitted at least 8 weeks before the RAC meeting at which it will
be reviewed.''
[Renumbered] ``Part III-A-4-b. Written comments from the primary
reviewers to the PI must be submitted at least 4 weeks before the
RAC meeting at which it will be reviewed.''
[Renumbered] ``Part III-A-4-c. Written responses (including
critical data in response to the primary reviewers' comments) must
be submitted by the Principal Investigators to ORDA at least 2 weeks
before the RAC meeting.''
[Renumbered] ``Part III-A-5. Oral Responses to the RAC.''
[No changes] ``Principal Investigators must limit their oral
responses to the RAC only to those questions that are raised during
the meeting. Oral presentations of previously submitted material
and/or critical data that was not submitted at least 2 weeks prior
to the RAC meeting is prohibited.''
[Renumbered] ``Part III-B. Primary Reviewers' Responses.''
[Renumbered] ``Part III-B-1. Primary Reviewers' Written
Comments.''
[No changes] ``The primary reviewers' written comments on a
proposal should include the following:''
[Renumbered] ``Part III-B-1-a. Emphasize the issues related to
gene marking, gene transfer, or gene therapy.''
[Renumbered] ``Part III-B-1-b. State explicitly whether the
Points to Consider have been addressed satisfactorily.''
[Renumbered] ``Part III-B-1-c. Examine the scientific rationale,
scientific context (relative to other proposals reviewed by the
RAC), whether the preliminary in vitro and in vivo data were
obtained in appropriate models and are sufficient, and whether
questions related to safety, efficacy, and social and ethical
context have been resolved.''
[Renumbered] ``Part III-B-1-d. Whenever possible, criticisms of
Informed Consent documents should include suggested revisions for
the RAC to consider, provided as written alternatives.''
[Renumbered] ``Part III-B-1-e. Primary reviews should also state
whether the proposal is: (i) Acceptable as written, (ii) expected to
be acceptable with specific revisions or after satisfactory
responses to specific questions raised on review, or (iii)
unacceptable in its present form.''
[Renumbered] ``Part III-B-2. Oral Discussions by Primary
Reviewers at the RAC Meeting.''
[Renumbered] ``Part III-B-2-a. It should be possible for most
primary reviewers to present their oral reviews in 5 minutes or
less.''
[No changes--Part VI through VI-B.]
[Delete--Part V. Minor Modifications to Human Gene Transfer
Experiments Approved by the RAC and NIH Director Under Section III-
A-3 of the NIH Guidelines. A minor modification in a protocol
approved by the RAC and NIH Director under Section III-A-3 (see
Section IV-C-1-b-1--Major Actions) is a change that does not
significantly alter the basic design of a protocol and that does not
increase risk to the subject(s). If the change has been approved by
the relevant IRB and IBC, then the Chair of the RAC may give
approval. It is expected that the Chair will consult with one or
more members of the committees, as necessary. The RAC Chair will
report on any such approvals at the next regularly scheduled RAC
meeting.]
[Addition] ``Part V. Procedures to be Followed for Accelerated
Review of Human Gene Transfer Experiments by NIH (ORDA) Under
Section III-B-2 of the NIH Guidelines.''
[Addition] ``Part V-A. Human gene transfer experiments in this
category must be in accordance with the provisions of Section III-B-
2 of the NIH Guidelines. If the human gene transfer protocol does
not qualify for Accelerated Review (see Section III-B-2 of the NIH
Guidelines) as determined by NIH (ORDA), then the PI must submit the
experiment for full RAC review and NIH approval in accordance with
Section III-A-3 of the NIH Guidelines.''
[Addition] ``Part V-B. No protocol shall be considered without
IBC and IRB approval.''
[Addition] ``Part V-C. At this time, all gene transfer protocols
must be considered experimental.''
[Addition] ``Part V-D-1. PIs requesting Accelerated Review (see
Section III-B-2 of the NIH Guidelines), must submit the relevant
documentation in accordance with Part III of the Points to Consider.
NIH (ORDA) will notify the investigator whether the proposed study
qualifies for the Accelerated Review process. If NIH (ORDA)
determines that an experiment does not qualify for the Accelerated
Review process the PI must submit the proposal for full RAC review
at least 8 weeks prior to the next scheduled RAC meeting.''
[Addition] ``Part V-E. It is expected that NIH (ORDA) will
consult with the RAC Chair and one or more RAC members, as
necessary, when considered Accelerated Review human gene transfer
protocols (see Section III-B-2 of the NIH Guidelines--.''
[Addition] ``Part V-F. The Chair of the RAC will provide a
report on all human gene transfer protocols that have been approved
by NIH (ORDA) at the next regularly scheduled RAC meeting.''
[Addition] ``Part V-F-1. In accordance with Part VI, Reporting
Requirements, of the Points to Consider, any adverse effects of the
treatments should be reported in writing immediately to both the
local IRB and the NIH Office for Protection from Research Risks, and
the report should also be forwarded to NIH (ORDA).''
[Addition] ``Part V-F-2. In accordance with Part IV, Reporting
Requirements, of the Points to Consider, reports regarding the
general progress of patients should be filed with both the local IRB
and ORDA within six months of the commencement of the experiments
and at six-month intervals. In the event of a patient's death, a
summary of the special post-mortem studies and statement of the
cause of death should be submitted to the IRB and ORDA, if
available.''
[Amended] ``Part VI. Procedures to be Followed for Expedited RAC
Review and NIH Approval of Single-Patient Human Gene Transfer
Protocols Considered Under Section III-A-3 (see Section IV-C-1-b-
(1)-(d) of the NIH Guidelines).''
[Amended] ``Part VI-A. An investigator submitting a request to
NIH (ORDA) for expedited review of a single patient gene transfer
protocol must provide detailed information regarding the necessity
of expedited review.''
[No changes--Part VI-B through VI-F.]
[Amend] ``Part VI-G. The NIH (ORDA) will report to the RAC
following expedited review and will include all of the materials on
which the decision was based. The RAC will formally review the
protocol at its next scheduled meeting. Patient privacy will be
maintained.''
[No changes--Part VI-H through VI-J.]
[Renumber ``Part VII. Footnotes.''
[No changes] ``The Food and Drug Administration (FDA) has
jurisdiction over drug products intended for use in clinical trials
of human gene transfer. For general Information on FDA's policies
and regulatory requirements, (see the Federal Register, Volume 51,
pages 23309-23313, 1986).''
[No changes] ``The term ``patient'' and its variants are used in
the text as a shorthand designation for ``patient-subject.''
XII. Amendments to Part I-D of the Points To Consider, NIH Guidelines,
Regarding Informed Consent
During the December 2-3, 1993, meeting, Dr. Gary Ellis, Director of
the Office for Protection from Research Risks (OPRR), NIH, Bethesda,
Maryland, responded to the written comments submitted by Dr. Zallen,
Chair of the Working Group on Informed Consent Issues. Dr. Ellis noted
the RAC's concern regarding specific issues that should be addressed in
human gene transfer protocol Informed Consent documents, i.e., request
for autopsy, recommendations for male, female contraception, separate
Informed Consent documents when gene therapy is separate from a
clinical protocol, commitment to long-term patient follow-up, and
financial responsibility of the institution for all research-related
costs. During his presentation, Dr. Ellis provided the RAC with
background information regarding the roles of both OPRR and local
Institutional Review Boards (IRB) in the review of research proposals
involving human subjects. Dr. Ellis recommended that the RAC draft a
letter outlining their specific recommendations to OPRR for
distribution and consideration by the local IRBs.
In a memorandum dated December 23, 1993, Dr. Ellis further
clarified the avenues that should be pursued by the RAC with regard to
the ``quality and content of informed consent documents into
constructive changes in the informed consent process,'' specifically in
relation to human gene transfer. Dr. Ellis recommended that the Points
to Consider should be amended to introduce consistency in the Informed
Consent document language; therefore, Part I-D of the Points to
Consider has been expanded. Proposed Part I-D-1 addresses the informed
consent process. Proposed Part I-D-2 addresses the informed consent
document. Part I-E has been incorporated into I-D-1. The proposed
amendments read:
``Part I-D-1. Informed Consent Process
``In accordance with the requirements of DHHS regulations for
the protection of human subjects (45 CFR, part 46), investigators
shall indicate how patients will be informed about the proposed
study and how their consent will be solicited. If the study involves
pediatric or mentally handicapped patients, describe the procedures
for seeking the permission of parents or guardians and, where
applicable, the assent of each patient.
``Part I-D-1-a. Communication of the Study to Potential Participants
``Part 1-D-1-a-(1). What processes or procedures will be used to
identify individuals who might be candidates for the proposed study?
``Part 1-D-1-a-(2). Which members of the research group and/or
the institution will be involved in contacting potential
participants and in describing the study to them? Where will
discussions or other means of informing such individuals about the
proposed study take place? What is the length of time that potential
participants will have to make a decision about their participation
in the proposed study?
``Part 1-D-1-a-(3). How will the following items be dealt with
during the informed consent process:
``Part I-D-1-a-(3)-(a). How will the major points covered in
Parts I-A through I-C of the Points to Consider be disclosed to
potential participants in the proposed study and/or their parents or
guardians in language that is understandable to them?
``Part I-D-1-a-(3)-(b). How will the innovative character and
the theoretically possible adverse effects of the experiment be
discussed with the subjects and/or their parents or guardians? How
will the potential adverse effects of the experiment be compared
with the consequences of the disease?
``Part I-D-1-a-(3)-(c). How will participants and/or their
parents or guardians be informed about the innovative character of
the experiment and that their participation in the proposed study
may lead to interest by the media?
``Part I-D-1-1-(3)-(d). How will the participants and/or their
parents or guardians be informed about the possible irreversible
consequences of procedures performed?
``Part I-D-1-a-(3)-(e). How will the participants and/or their
guardians be informed about any expectation that they will cooperate
in long-term follow-up?
``Part I-D-1-a-(3)-(f). How will the participants and/or their
guardians be informed about the adverse medical consequences that
may occur if the subjects withdraw from the study once the
experiment has started?
``Part I-D-1-a-(3)-(g). How will the participants and/or their
parents or guardians be informed that permission to perform an
autopsy will be requested in the event of a subject's death? (An
autopsy shall be requested due to the need for an accurate
determination of the precise cause of the subject's death and the
potential knowledge that may be gained from such information.)
``Part I-D-1-a-(3)-(h). How will estimates of any financial
costs associated with participation in the experiment and in the
long-term follow-up to the experiment that are not covered by the
investigators or the institutions involved be provided to potential
participants and/or their parents or guardians? How will comparable
financial information for other available alternatives, including
other investigational therapies, be provided?
``Part I-D-1-1-(1)-(4). If there are more potential candidates
than the study can accommodate, how will the decision be made about
which to include? How will those who are excluded be informed?
``Part I-D-1-b. Privacy and Confidentiality
``Part I-D-1-b-(1). Provide a description of the measures that
will be taken to protect the privacy of patients and their families
as well as to maintain the confidentiality of the research date.
``Part I-D-1-b-(2). Provide a description of the provisions that
will be made to maintain the confidentiality of research data,
especially in cases where data could be lined to individual
patients.
``Part I-D-1-b-(3). Provide a description of the provision that
will be made to honor the wishes of individual subjects and/or the
parents or guardians of pediatric or mentally handicapped patients,
as to whether, when, or how the identity of patients may be publicly
disclosed.
``Part I-D-1-c. Special Issues
``Although the following issues are beyond the normal purview of
the local IRBs, the RAC requests that investigators respond to the
following questions:
``Part I-D-1-c-(1). Do you or your funding sources intend to
protect under patent or trade secret laws either the products or the
procedures developed in the proposed study? If so, what steps will
be taken to permit as full communication as possible among
investigators and clinicians concerning research methods and
results?
``Part I-D-1-c-(2). What steps will be taken to ensure that
accurate and appropriate information is made available to the public
with respect to such public concerns as may arise from the proposed
study?
``Part I-D-2. Informed Consent Document
``Part I-D-2-a. When gene transfer is a procedure separate from
an IRB-approved clinical protocol, separate informed Consent
documents shall be submitted for both the gene transfer and clinical
protocols.
``Part I-D-2-b. Investigators submitting human gene transfer
proposals for RAC review must include the Informed Consent document
as approved by the local IRB. This document shall include the
following specific information in addition to any requirements of
the DHHS regulations for the protection of human subjects (45 CFR,
part 46):
``Part I-D-1-b-(1). Purpose of the Study
``For experiments in which there is no therapeutic intent, an
explanation shall be provided that no direct clinical benefit is
expected as a result of the subject's participation in the study;
however, knowledge may be gained that could benefit others.
``Part I-D-2-b-(2). Description of the Procedures
``The subject will be provided a detailed description of the
procedures associated with the proposed study, including a
description of the gene transfer procedures in non-technical
language.
``Part I-D-2-b-(3). Possible Risks, Discomforts, and Side Effects
``The subject will be provided with a detailed description of
the risks, discomforts, and side effects, including a warning about
possible unforeseen risks, that may result from their participation
in the proposed study.
``Part I-D-2-b-(4). Benefits
``The subject will be provided with a detailed description of
the possible benefits of the proposed study.
``Part I-D-2-b-(5). Contact Persons
``The subject will be provided with a list of persons who are
available to answer any questions relating to their participation in
the proposed study and to contact in the event that questions arise
during the course of the study, including the follow-up period.
``Part I-D-2-b-(6). Alternatives
``The subject shall be informed about the availability of other
therapies, including the possibility of other investigational
therapies.
``Part I-D-2-b-(7). Voluntary Participation
``The subject shall be informed that their participation in the
study is voluntary and that failure to participate in the study, or
withdrawal of consent, will not incur any penalty or loss of
benefits to which the subject is otherwise entitled.
``Part I-D-2-b-(8). Confidentiality
``The subject shall be informed that the institution and
investigators will make every effort to provide protection from the
media in an effort to protect the participant's privacy.
``Part I-D-2-b-(9). Explanation to Participants of the Specific
Requirements of Gene Transfer Research
``Part I-D-2-b-(9)-(a). Female subjects shall be informed that
they should not be pregnant nor planning to become pregnant during
the course of their participation in the study. Male and female
subjects shall be informed that barrier contraception is required
during the active phase of their participation in the study.
``Part I-D-2-b-(9)-(b). The subject shall be informed about the
extent to which he/she will be responsible for any costs associated
with medical treatment required as a direct result of research-
related injury.
``Part I-D-2-b-(9)-(c). The PI shall request that the subject
keep the laboratory informed of a current address and telephone
number.
``Part I-D-2-b-(9)-(d). The subject shall be informed that in
the event of death, as a result of accident or illness, an autopsy
shall be requested because of the importance of the knowledge that
may be gained from such studies.
``Part I-D-2-b-(9)-(e). The subject shall be informed that any
significant findings resulting from the proposed study will be made
known to them and/or their parent or guardian. This would include
new information about the nature of the experimental procedure or
the physical reactions experienced by other individuals involved in
the study.
``Part I-D-2-b-(9)-(f). The subject shall be informed that
representatives of applicable Federal agencies (e.g., the NIH and
FDA) and representatives of collaborating institutions will have
access to the participant's medical records.''
OMB's ``Mandatory Information Requirements for Federal
Assistance Program Announcements'' (45 FR 39592, June 11, 1980)
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 not to be 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: February 7, 1994.
Daryl A. Chamblee, J.D.,
Acting Deputy Director for Science Policy and Technology Transfer.
[FR Doc. 94-3180 Filed 2-10-94; 8:45 am]
BILLING CODE 4140-01-M
