[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