[Federal Register Volume 60, Number 81 (Thursday, April 27, 1995)]
[Notices]
[Pages 20726-20737]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-10381]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Recombinant DNA Research: Actions Under the Guidelines

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice of Actions under the NIH Guidelines for Research 
Involving [[Page 20727]] Recombinant DNA Molecules (59 FR 34496 and 59 
FR 40170).

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SUMMARY: This notice sets forth an action to be taken by the Director, 
National Institutes of Health (NIH), under the NIH Guidelines for 
Research Involving Recombinant DNA Molecules (59 FR 34496 and 59 FR 
40170).

FOR FURTHER INFORMATION CONTACT: Additional information can be obtained 
from Dr. Nelson A. Wivel, Director, Office of Recombinant DNA 
Activities (ORDA), Office of Science Policy and Technology Transfer, 
National Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 
7052, Bethesda, Maryland 20892-7052, (301) 496-9838.

SUPPLEMENTARY INFORMATION: Today's action is being promulgated under 
the NIH Guidelines for Research Involving Recombinant DNA Molecules. 
This proposed action was published for comment in the Federal Register 
of February 8, 1995 (60 FR 7630), and reviewed and recommended for 
approval by the NIH Recombinant DNA Advisory Committee (RAC) at its 
meeting on March 6-7, 1995.

I. Background Information and Decisions on Actions Under the NIH 
Guidelines

A. Amendments to Sections I, III, IV, V, and Appendices C, F, G, I, and 
M of the NIH Guidelines Regarding Consolidated Review of Human Gene 
Transfer Protocols

    On July 18-19, 1994, the National Task Force on AIDS Drug 
Development held an open meeting for the purpose of identifying 
barriers to AIDS Drug Discovery that included a proposal to streamline 
the dual review process for human gene transfer experiments. Members of 
the Task Force recommended a consolidated review process to enhance 
interactions between the NIH and the Food and Drug Administration 
(FDA). As a result of the Task Force's deliberations, recommendations 
were adopted in order to eliminate any unnecessary overlap between the 
NIH and FDA review of human gene transfer proposals. Both Drs. Varmus 
and Kessler noted that their respective agencies would cooperate fully 
to effect the changes necessary to implement these recommendations.
    The NIH and FDA proposed that the RAC become advisory to both the 
NIH Director and the FDA Commissioner with regard to the review of 
human gene transfer protocols. In the interest of maximizing the 
resources of both agencies and simplifying the method and period of 
review for research protocols involving human gene transfer, the NIH 
and FDA should institute an interagency consolidated review process 
that incorporates the following principal elements:
    (1) All human gene transfer protocols shall be submitted directly 
to the FDA. Submission will be in the format required by the FDA and 
the same format will be used by the RAC when public review is deemed 
necessary.
    (2) Upon receipt, FDA review will proceed. The NIH/ORDA staff will 
simultaneously evaluate the protocol for possible RAC review.
    (3) Factors which may contribute to the need for RAC review 
include: (a) New vectors/new gene delivery systems, (b) new diseases, 
(c) unique applications of gene transfer, and (d) other issues that 
require further public review.
    (4) If either the NIH/ORDA or FDA decides that a proposal should be 
reviewed by the RAC, the proposal will be forwarded to the RAC primary 
reviewers immediately. Whenever possible, Principal Investigators will 
be notified within 15 working days following receipt of the submission 
whether RAC review will be required. (RAC reviewed applications will be 
distributed to RAC members approximately four weeks prior to the next 
quarterly RAC meeting.)
    (5) Semiannual data reporting procedures will remain the 
responsibility of NIH (ORDA). Semiannual data reports will be reviewed 
by the RAC in a public forum.
    In a letter dated August 2, 1994, Dr. Nelson A. Wivel, Director, 
ORDA, NIH, provided the RAC with background information regarding the 
National Task Force on AIDS Drug Development meeting, and proposed 
amendments to Sections I, III, IV, V, and Appendices C, F, G, I, and M 
of the NIH Guidelines, to reflect the proposed consolidated review 
process. The revised review process was proposed as follows:
    (1) Investigators will be required to submit all human gene 
transfer proposals directly to the FDA in the format required by the 
FDA; therefore, investigators will no longer be required to provide a 
separate submission to NIH/ORDA for RAC review. The FDA Division of 
Cellular and Gene Therapies will forward a copy of each submission to 
NIH/ORDA. Both the FDA Division of Cellular and Gene Therapies and NIH/
ORDA will simultaneously evaluate each proposal for the necessity for 
RAC review. Whenever possible, the investigators will be notified 
within 15 working days following receipt of the submission regarding 
the necessity for RAC review.
    (2) If either the NIH/ORDA or FDA decides that a proposal should 
undergo RAC review, the proposal will be forwarded to the RAC primary 
reviewers immediately. Any protocol submitted less than 8 weeks before 
a RAC meeting will be reviewed at the following quarterly RAC meeting.
    (3) The RAC will make recommendations regarding approval/
disapproval of protocols, including any relevant stipulations, to the 
NIH Director. The NIH Director will review, approve, and transmit the 
RAC's recommendations/stipulations to the FDA Commissioner.
    (4) The FDA will consider such recommendations/stipulations and 
will be responsible for completion of review. The RAC and NIH/ORDA will 
no longer have the responsibility for reviewing material submitted for 
Accelerated Review or for the review of minor modifications to human 
gene transfer protocols.
    These proposed actions were discussed during the September 12-13, 
1994, RAC meeting (published for public comments in the Federal 
Register, August 23, 1994 (59 FR 43426)). Dr. Philip Noguchi, Director, 
Division of Cellular and Gene Therapies, Center for Biologics 
Evaluation and Research, FDA, provided additional suggestions regarding 
the proposed review process including FDA adoption of the Appendix M, 
Points to Consider in the Design and Submission of Protocols for the 
Transfer of Recombinant DNA Molecules into the Genome of One or More 
Human Subjects (Points to Consider), of the NIH Guidelines. The FDA 
will require investigators to submit the Points to Consider with their 
proposed experiments. A lengthy discussion ensued involving RAC 
members' concerns and suggestions regarding the consolidated review 
process.
    Dr. Noguchi submitted the following compromise proposal regarding 
the NIH/FDA consolidated review of human gene transfer experiments:
    (1) Appendix M, Points to Consider, will not be deleted from the 
NIH Guidelines. The NIH Guidelines will be modified to provide for 
submission of Appendix M, Points to Consider, directly to the FDA prior 
to IND submission. The FDA will update their guidance documents in a 
similar manner. When necessary, the RAC will continue to be responsible 
for modifying Appendix M, Points to Consider.
    (2) The RAC, NIH/ORDA, and FDA will decide on the necessity for 
full RAC review. The submitted Appendix M, Points to Consider, will be 
publicly available for all human gene transfer 
[[Page 20728]] submissions even if RAC review is not required.
    (3) The RAC and FDA will broaden their scope of review for human 
gene transfer proposals to jointly and prospectively address global 
issues on a regular basis, e.g., ethical consideration in the 
implementation of gene therapy patient registry, access for ``orphan'' 
genetic disease patients to therapies, criteria for prenatal gene 
therapy, and transgenic technology for xenotransplantation.
    (4) The RAC, NIH/ORDA, and FDA will establish a working group to 
enhance data monitoring efforts.
    (5) A RAC, NIH/ORDA, and FDA working group will be established to 
propose long-term consolidation. The working group will have input from 
public, academic, and corporate sources.
    The RAC approved a motion to (1) accept the FDA proposal submitted 
by Dr. Noguchi; (2) adopt the Categories for Accelerated Review that 
were approved by the RAC at its March 3-4, 1994, meeting as guidelines 
for proposals that will not require RAC review; (3) establish a working 
group to examine the review process for human gene transfer protocols 
(in response to Dr. Varmus' request to establish such a group); (4) the 
RAC prefers that any stipulation requirements should be satisfactorily 
met prior to forwarding its recommendation for approval to the NIH 
Director; and (5) accept the proposed amendments to the NIH Guidelines 
to reflect this revised consolidated review process (including 
acceptance of a revised Appendix M and incorporation of minor editorial 
changes). The motion was approved by a vote of 15 in favor, 0 opposed, 
and 1 abstention.
    On October 26, 1994, NIH/ORDA forwarded the revised actions to the 
NIH Director for approval and the FDA Commissioner for concurrence. FDA 
legal counsel expressed concern that implementation of these actions 
would require amendment to the FDA Investigational New Drug Application 
Regulations (21 CFR Part 312) to accommodate the release of proprietary 
information. To resolve this concern, a waiver for release of 
information from the FDA to the NIH was proposed. While the NIH 
Guidelines could require such a waiver for NIH-funded investigators, it 
would be voluntary for others submitting proposed human gene transfer 
experiments to the FDA. The NIH expressed concern that failure to 
comply with voluntary waiver procedures may result in the loss of 
critical information necessary to maintain: (1) The human gene therapy 
database, (2) ``real-time'' reporting of serious adverse events, and 
(3) comprehensive overview (by category) by the RAC in a public forum. 
Public review and access to submission, review, and follow-up 
information is critical to the safe and focused advancement of human 
gene therapy research. As a result of these concerns, the NIH and FDA 
agreed on a compromise proposal that would accommodate the single 
submission format proposed at the July 18-19, 1994, meeting of the 
National Task Force on AIDS Drug Development, yet maintain public 
access to critical information and ``real-time'' reporting of adverse 
events. The compromise proposal involves simultaneous submission of 
human gene transfer protocols to both NIH and the FDA in a single 
submission format. This format includes (but is not limited to) the 
documentation described in Appendices M-I through M-V, of the NIH 
Guidelines. NIH/ORDA and the FDA will simultaneously evaluate the 
proposal regarding the necessity for RAC review.
    These revisions to the consolidated review process were discussed 
during the March 6-7, 1995, RAC meeting (published for public comments 
in the Federal Register, February 8, 1995 (60 FR 7630)). The following 
motions were made in response to the February 24, 1995, comments 
submitted by Ms. Sheryl Osborne of Viagene, Inc., San Diego, 
California: (1) A motion to retain the current requirement for 
obtaining Institutional Review Board (IRB) approval prior to RAC 
submission. A friendly amendment was made and accepted that ORDA should 
notify the Director of the Office for Protection from Research Risks 
regarding the necessity for IRB adherence to the detailed questions 
contained in Appendices M-II through M-V of the NIH Guidelines 
(Informed Consent issues). The amended motion was approved by a vote of 
17 in favor, 0 opposed, and 1 abstention. (2) A motion was made that 
the RAC should continue to review and approve Phase I follow-up 
studies, i.e., Phase II and Phase III trials. Such studies may be 
submitted through the Accelerated Review process; however, the RAC 
retains the option to require full RAC review. The motion passed by a 
vote of 18 in favor, 0 opposed, and no abstentions.
    The RAC approved a motion to approve the proposed amendments to 
Sections I, III, IV, V, and Appendices C, F, G, I, and M of the NIH 
Guidelines regarding NIH and FDA consolidated review of human gene 
transfer protocols, by a vote of 18 in favor, 0 opposed, and no 
abstentions.
    The actions are detailed in Section II--Summary of Actions. I 
accept these recommendations, and the NIH Guidelines will be amended 
accordingly.

II. Summary of Actions

A. Amendments to Section I, Scope of the NIH Guidelines

    The amended version of Section I-A, Purpose, reads:
Section I-A. Purpose
    The purpose of the NIH Guidelines is to specify practices for 
constructing and handling: (i) Recombinant deoxyribonucleic acid (DNA) 
molecules, and (ii) organisms and viruses containing recombinant DNA 
molecules.
    Section I-A-1. 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 approvals, or other applicable clearances, have been 
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 (see exception in Section I-A-1-a).
    Section I-A-1-a. In the interest of maximizing the resources of 
both the NIH and the Food and Drug Administration (FDA) and simplifying 
the method and period for review, research proposals involving the 
deliberate transfer of recombinant DNA or DNA or RNA derived from 
recombinant DNA into human subjects (human gene transfer) will be 
considered through a consolidated review process involving both the NIH 
and the FDA. Submission of human gene transfer proposals will be in the 
format described in Appendices M-I through M-V of the Points to 
Consider. Investigators must simultaneously submit their human gene 
transfer proposal to both the NIH and the FDA in a single submission 
format. This format includes (but is not limited to) the documentation 
described in Appendices M-I through M-V, of the Points to Consider. 
NIH/ORDA and the FDA will simultaneously evaluate the proposal 
regarding the necessity for RAC review.

B. Amendments to Section III, Experiments Covered by the NIH Guidelines

    The amended version of Section III beginning paragraphs 
reads: [[Page 20729]] 
    This section describes five categories of experiments involving 
recombinant DNA: (i) Those that require Institutional Biosafety 
Committee (IBC) approval, RAC review, and NIH Director approval before 
initiation (see Section III-A), (ii) those that require NIH/ORDA and 
Institutional Biosafety Committee approval before initiation (see 
Section III-B), (iii) those that require Institutional Biosafety 
Committee approval before initiation (see Section III-C), (iv) those 
that require Institutional Biosafety Committee notification 
simultaneous with initiation (see Section III-D), and (v) those that 
are exempt from the NIH Guidelines (see Section III-E).

    Note: If an experiment falls into either Section III-A or 
Section III-B and one of the other categories, the rules pertaining 
to Section III-A or Section III-B shall be followed. If an 
experiment falls into Section III-E and into either Sections III-C 
or III-D categories as well, the experiment is considered exempt 
from the NIH Guidelines.

    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).
    The amended version of Section III-A reads:
    Section III-A. Experiments that Require Institutional Biosafety 
Committee Approval, RAC Review, and NIH Director Approval Before 
Initiation (see Section IV-C-1-b-(1)).
Section III-A-1. Major Actions Under the NIH Guidelines
    Experiments considered as Major Actions under the NIH Guidelines 
cannot be initiated without submission of relevant information on the 
proposed experiment to the Office of Recombinant DNA Activities, 
National Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 
7052, Bethesda, Maryland 20892-7052, (301) 496-9838, the publication of 
the proposal in the Federal Register for 15 days of comment, review by 
the RAC, and specific approval by the NIH (see Appendix M for 
submission requirements on human gene transfer experiments). The 
containment conditions or stipulation requirements for such experiments 
will be recommended by the RAC and set by the NIH at the time of 
approval. Such experiments require Institutional Biosafety Committee 
approval before initiation. Specific experiments already approved are 
included in Appendix D which may be obtained from the Office of 
Recombinant DNA Activities, National Institutes of Health, Suite 323, 
6006 Executive Boulevard, MSC 7052, Bethesda, Maryland 20892-7052, 
(301) 496-9838.
    Section III-A-1-a. The deliberate transfer of a drug resistance 
trait to microorganisms that are not known to acquire the trait 
naturally (see Section V-B), if such acquisition could compromise the 
use of the drug to control disease agents in humans, veterinary 
medicine, or agriculture, will be reviewed by the RAC.
Section III-A-2. Human Gene Transfer Experiments
    Investigators must simultaneously submit their human gene transfer 
proposal to both the NIH and the FDA in a single submission format. 
This format includes (but is not limited to) the documentation 
described in Appendices M-I through M-V, of the Points to Consider. The 
NIH/ORDA and the FDA will simultaneously evaluate the proposal 
regarding the necessity for RAC review.
    Factors that may contribute to the necessity for RAC review 
include: (i) New vectors/new gene delivery systems, (ii) new diseases, 
(iii) unique applications of gene transfer, and (iv) other issues 
considered to require further public discussion. Among the experiments 
that may be considered exempt from RAC review are those determined by 
the NIH/ORDA and FDA not to represent possible risk to human health or 
the environment (see Appendix M-VII, Categories of Human Gene Transfer 
Experiments that May Be Exempt from RAC Review). Whenever possible, 
investigators will be notified within 15 working days following receipt 
of the submission whether RAC review will be required. In the event 
that NIH/ORDA or the FDA require RAC review of the submitted proposal, 
the documentation described in Appendices M-I through M-V of the Points 
to Consider, will be forwarded to the RAC primary reviewers for 
evaluation. RAC meetings will be open to the public except where trade 
secrets and proprietary information are reviewed. The RAC and FDA 
prefer that information provided in response to Appendix M contain no 
proprietary data or trade secrets, enabling all aspects of the review 
to be open to the public. The RAC will recommend approval or 
disapproval of the reviewed proposal to the NIH Director. In the event 
that a proposal is contingently approved by the RAC, the RAC prefers 
that the conditions be satisfactorily met before the RAC's 
recommendation for approval is submitted to the NIH Director. The NIH 
Director's decision on the submitted proposal will be transmitted to 
the FDA Commissioner and considered as a Major Action by the NIH 
Director.
    The amended version of Section III-B reads:
Section III-B. Experiments That Require NIH/ORDA and Institutional 
Biosafety Committee Approval Before Initiation
Section III-B-1. Experiments Involving the Cloning of Toxin Molecules 
with LD<INF>50 of Less than 100 Nanograms per Kilogram Body Weight
    Deliberate formation of recombinant DNA containing genes for the 
biosynthesis of toxin molecules lethal for vertebrates at an LD<INF>50 
of less than 100 nanograms per kilogram body weight (e.g., microbial 
toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin, 
and Shigella dysenteriae neurotoxin). Specific approval has been given 
for the cloning in Escherichia coli K-12 of DNA containing genes coding 
for the biosynthesis of toxic molecules which are lethal to vertebrates 
at 100 nanograms to 100 micrograms per kilogram body weight. Specific 
experiments already approved under this section may be obtained from 
the Office of Recombinant DNA Activities, National Institutes of 
Health, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda, 
Maryland 20892-7052, (301) 496-9838.
    Section III-B-1-(a). Experiments in this category cannot be 
initiated without submission of relevant information on the proposed 
experiment to NIH/ORDA. The containment conditions for such experiments 
will be determined by NIH/ORDA in consultation with ad hoc experts. 
Such experiments require Institutional Biosafety Committee approval 
before initiation (see Section IV-B-2-b-(1)).
    The following section, Section III-C-7, is deleted:
Section III-C-7. Human Gene Transfer Experiments Not Covered by 
Sections III-A-2, III-B-2, III-B-3, and Not Considered Exempt under 
Section V-U
    Certain experiments involving the transfer of recombinant DNA or 
DNA or RNA derived from recombinant DNA into one or more human subjects 
that are not covered by Sections III-A-2, III-B-2, III-B-3, and that 
are not considered exempt under Section V-U must be registered with 
NIH/ORDA. The relevant Institutional Biosafety Committee and 
Institutional Review Board must review and approve all experiments in 
this category prior to their initiation. [[Page 20730]] 

C. Amendments to Section IV, Roles and Responsibilities

    In Section IV-B-4-b, Submissions by the Principal Investigator to 
the NIH/ORDA, the following sections are amended to read:
    Section IV-B-4-b-(3). Petition NIH/ORDA, with concurrence of the 
Institutional Biosafety Committee, for approval to conduct experiments 
specified in Sections III-A-1 and III-B of the NIH Guidelines;
    In Section IV-B-4-e, Responsibilities of the Principal Investigator 
During the Conduct of the Research, the following section is added:
    Section IV-B-4-e-(5). Comply with semiannual data reporting and 
adverse event reporting requirements for NIH and FDA-approved human 
gene transfer experiments (see Appendix M-VIII, Reporting 
Requirements--Human Gene Transfer Protocols).
    In Section IV-C-b-(1), Major Actions, the first paragraph is 
amended to read:
    To execute Major Actions, the NIH Director shall seek the advice of 
the RAC and provide an opportunity for public and Federal agency 
comment. Specifically, the Notice of Meeting and Proposed Actions shall 
be published in the Federal Register at least 15 days before the RAC 
meeting. The NIH Director's decision/recommendation (at his/her 
discretion) may be published in the Federal Register for 15 days of 
comment before final action is taken. The NIH Director's final 
decision/recommendation, along with responses to public comments, shall 
be published in the Federal Register. The RAC and Institutional 
Biosafety Committee Chairs shall be notified of the following 
decisions:
    Section IV-C-1-B-(1)-(e) is amended to read:
    Section IV-C-1-b-(1)-(e). Recommendations made by the NIH Director 
to the FDA Commissioner regarding RAC-reviewed human gene transfer 
experiments (see Appendix M-VI-E, RAC Recommendations to the NIH 
Director);
    Except for renumbering, the rest of the Section IV-C-1-B-(1) 
remains unchanged.
    In Section IV-C-1-b-(2), Minor Actions, the following sections are 
deleted:
    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);
    Section IV-C-1-b-(2)-(b). Reviewing and approving minor changes to 
human gene transfer protocols under Section III-A-2 and III-B-2;
    The rest of the section has been renumbered.
    Section IV-C-3, Office of Recombinant DNA Activities (ORDA), will 
be amended to read:
Section IV-C-3. Office of Recombinant DNA Activities (ORDA)
    ORDA shall serve as a focal point for information on recombinant 
DNA activities and provide advice to all within and outside NIH 
including institutions, Biological Safety Officers, Principal 
Investigators, Federal agencies, state and local governments, and 
institutions in the private sector. ORDA shall carry out such other 
functions as may be delegated to it by the NIH Director. ORDA's 
responsibilities include (but are not limited to) the following:
    Section IV-C-3-a. Evaluating human gene transfer protocols for the 
necessity for RAC review (see Appendix M-VI-A);
    Section IV-C-3-b. Serving as the focal point for data management of 
NIH and FDA approved human gene transfer protocols (see Appendix M-
VIII, Reporting Requirements--Human Gene Transfer Protocols);
    Section IV-C-3-c. Administering the semiannual data reporting 
requirements (and subsequent review) for human gene transfer 
experiments, including experiments that are reviewed solely by the FDA 
(see Appendix M-VI, Categories of Human Gene Transfer Experiments that 
May Be Exempt from RAC Review);
    Section IV-C-3-d. Maintaining an inventory of NIH and FDA-approved 
human gene transfer experiments (including subsequent modifications);
    Section IV-C-3-e. Reviewing and approving experiments in 
conjunction with ad hoc experts involving the cloning of genes encoding 
for toxin molecules that are lethal for vertebrates at an LD<INF>50 of 
less than or equal to 100 nanograms per kilogram body weight in 
organisms other than Escherichia coli K-12 (see Section III-B-1 and 
Appendices F-I and F-II);
    Section IV-C-3-f. Serving as the executive secretary of the RAC;
    Section IV-C-3-g. Publishing in the Federal Register:
    Section IV-C-3-g-(1). Announcements of RAC meetings and agendas at 
least 15 days in advance (NOTE--If the agenda for a RAC meeting is 
modified, ORDA shall make the revised agenda available to anyone upon 
request in advance of the meeting);
    Section IV-C-3-g-(2). Proposed Major Actions (see Section IV-C-1-b-
(1)) at least 15 days prior to the RAC meeting; and
    Section IV-C-3-h. Reviewing and approving the membership of an 
institution's Institutional Biosafety Committee, and where it finds the 
Institutional Biosafety Committee meets the requirements set forth in 
Section IV-B-2 will give its approval to the Institutional Biosafety 
Committee membership;

D. Amendments to Section V, Footnotes and References of Section I 
through IV

    The following sections are deleted:
    Section V-U. Human studies in which the induction or enhancement of 
an immune response to a vector-encoded microbial immunogen is the major 
goal, such an immune response has been demonstrated in model systems, 
and the persistence of the vector-encoded immunogen is not expected, 
are not covered under Sections III-A-2, III-B-2, or III-B-3. Such 
studies may be initiated without RAC review and NIH approval if 
approved by another Federal agency.
    Section V-V. 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-2, III-B-2, and III-B-3).
    Section V-W has been renumbered to Section V-U:
    Section V-U. In accordance with accepted scientific and regulatory 
practices of the discipline of plant pathology, an exotic plant 
pathogen (e.g., virus, bacteria, or fungus) is one that is unknown to 
occur within the U.S. (see Section V-R). Determination of whether a 
pathogen has a potential for serious detrimental impact on managed 
(agricultural, forest, grassland) or natural ecosystems should be made 
by the Principal Investigator and the Institutional Biosafety 
Committee, in consultation with scientists knowledgeable of plant 
diseases, crops, and ecosystems in the geographic area of the research.

E. Amendments to Appendix C, Exemptions under Section III-E-6

    The following sections are amended to read:
Appendix C-I-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation. [[Page 20731]] 
Appendix C-II-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation.
Appendix C-III-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation.
Appendix C-IV-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation.
Appendix C-V-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation.
    Appendix C-VI-A-1. The NIH Director, with advice of the RAC, may 
revise the classification for the purposes of these NIH Guidelines (see 
Section IV-C-1-b-(2)-(b)).

E. Amendments to Appendix F, Containment Conditions for Cloning of 
Genes Coding for the Biosynthesis of Molecules Toxic for Vertebrates

    The following sections are amended, due to reference changes, to 
read:
Appendix F-I. General Information
    . . . The results of such tests shall be forwarded to NIH/ORDA, 
which will consult with ad hoc experts, prior to inclusion of the 
molecules on the list (see Section IV-C-1-b-(2)-(c)).
Appendix F-III. Cloning of Toxic Molecule Genes in Organisms Other Than 
Escherichia coli K-12
    Requests involving the cloning of genes coding for toxin molecules 
for vertebrates at an LD<INF>50 of <100 nanograms per kilogram body 
weight in host-vector systems other than Escherichia coli K-12 will be 
evaluated by NIH/ORDA in consultation with ad hoc toxin experts (see 
Sections III-B-1 and IV-C-1-b-(2)-(c)).

F. Amendments to Appendix G, Physical Containment

    The following sections are amended, due to reference changes, to 
read:
    Appendix G-II. Physical Containment Levels.
    . . . Consideration will be given by the NIH Director, with the 
advice of the RAC, to other combinations which achieve an equivalent 
level of containment (see Section IV-C-1-b-(2)-(a)).

G. Amendments to Appendix I, Biological Containment

    The following sections are amended, due to reference changes, to 
read:
Appendix I-II-A. Responsibility
    . . . Proposed host-vector systems will be reviewed by the RAC (see 
Section IV-C-1-b-(1)-(f)). . . . Minor modifications to existing host-
vector systems (i.e., those that are of minimal or no consequence to 
the properties relevant to containment) may be certified by the NIH 
Director without prior RAC review (see Section IV-C-1-b-(2)-(f)). . . . 
The NIH Director may rescind the certification of a host-vector system 
(see Section IV-C-1-b-(2)-(g)).

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

    Appendix M is amended to read:
    Appendix M. The Points to Consider in the Design and Submission of 
Protocols for the Transfer of Recombinant DNA Molecules into the Genome 
of One or More Human Subjects (Points to Consider)
    Appendix M applies to research conducted at or sponsored by an 
institution that receives any support for recombinant DNA research from 
the NIH. Researchers not covered by the NIH Guidelines are encouraged 
to use Appendix M.
    The acceptability of human somatic cell gene therapy has been 
addressed in several public documents as well as in numerous academic 
studies. In November 1982, the President's Commission for the Study of 
Ethical Problems in Medicine and Biomedical and Behavioral Research 
published a report, Splicing Life, which resulted from a two-year 
process of public deliberation and hearings. Upon release of that 
report, a U.S. House of Representatives subcommittee held three days of 
public hearings with witnesses from a wide range of fields from the 
biomedical and social sciences to theology, philosophy, and law. In 
December 1984, the Office of Technology Assessment released a 
background paper, Human Gene Therapy, which concluded: civic, 
religious, scientific, and medical groups have all accepted, in 
principle, the appropriateness of gene therapy of somatic cells in 
humans for specific genetic diseases. Somatic cell gene therapy is seen 
as an extension of present methods of therapy that might be preferable 
to other technologies. In light of this public support, the Recombinant 
DNA Advisory Committee (RAC) is prepared to consider proposals for 
somatic cell gene transfer.
    The RAC will not at present entertain proposals for germ line 
alterations but will consider proposals involving somatic cell gene 
transfer. The purpose of somatic cell gene therapy is to treat an 
individual patient, e.g., by inserting a properly functioning gene into 
the subject's somatic cells. Germ line alteration involves a specific 
attempt to introduce genetic changes into the germ (reproductive) cells 
of an individual, with the aim of changing the set of genes passed on 
to the individual's offspring.
    In the interest of maximizing the resources of both the NIH and the 
Food and Drug Administration (FDA) and simplifying the method and 
period for review, research proposals involving the deliberate transfer 
of recombinant DNA or DNA or RNA derived from recombinant DNA into 
human subjects (human gene transfer) will be considered through a 
consolidated review process involving both the NIH and the FDA. 
Submission of human gene transfer proposals will be in the format 
described in Appendices M-I through M-V of the Points to Consider. 
Investigators must simultaneously submit their human gene transfer 
proposal to both the NIH and the FDA in a single submission format. 
This format includes (but is not limited to) the documentation 
described in Appendices M-I through M-V of the Points to Consider. NIH/
ORDA and the FDA will simultaneously evaluate the proposal regarding 
the necessity for RAC review.
    Factors that may contribute to the necessity for RAC review 
include: (i) New vectors/new gene delivery systems, (ii) New diseases, 
(iii) unique applications of gene transfer, and (iv) other issues 
considered to require further public discussion. Among the experiments 
that may be considered exempt from RAC review are those determined by 
the NIH/ORDA and FDA not to represent possible risk to human health or 
the environment (see Appendix M-VII, Categories of Human Gene Transfer 
Experiments that May Be Exempt from RAC Review). Whenever possible, 
investigators will be notified within 15 working days following 
[[Page 20732]] receipt of the submission whether RAC review will be 
required. In the event that NIH/ORDA and the FDA require RAC review of 
the submitted proposal, the documentation described in Appendices M-I 
through M-V of the Points to Consider, will be forwarded to the RAC 
primary reviewers for evaluation. RAC meetings will be open to the 
public except where trade secrets and proprietary information are 
reviewed. The RAC and FDA prefer that information provided in response 
to Appendix M contain no proprietary data or trade secrets, enabling 
all aspects of the review to be open to the public. The RAC will 
recommend approval or disapproval of the reviewed proposal to the NIH 
Director. In the event that a proposal is contingently approved by the 
RAC, the RAC prefers that the conditions be satisfactorily met before 
the RAC's recommendation for approval is submitted to the NIH Director. 
The NIH Director's decision on the submitted proposal will be 
transmitted to the FDA Commissioner and considered as a Major Action by 
the NIH Director.
    Public review of human gene transfer proposals will serve to inform 
the public about the technical aspects of the proposals as well as the 
meaning and significance of the research.
    In its evaluation of human gene transfer proposals, the RAC, NIH/
ORDA, and the FDA will consider whether the design of such experiments 
offers adequate assurance that their consequences will not go beyond 
their purpose, which is the same as the traditional purpose of clinical 
investigation, namely, to protect the health and well being of human 
subjects being treated while at the same time gathering generalizable 
knowledge. Two possible undesirable consequences of the transfer of 
recombinant DNA would be unintentional: (i) Vertical transmission of 
genetic changes from an individual to his/her offspring, or (ii) 
horizontal transmission of viral infection to other persons with whom 
the individual comes in contact. Accordingly, Appendices M-I through M-
V requests information that will enable the RAC, NIH/ORDA, and the FDA, 
to assess the possibility that the proposed experiment(s) will 
inadvertently affect reproductive cells or lead to infection of other 
people (e.g., medical personnel or relatives).
    In recognition of the social concern that surrounds the subject of 
human gene transfer, the RAC, NIH/ORDA, and the FDA, will cooperate 
with other groups in assessing the possible long-term consequences of 
the proposal and related laboratory and animal experiments in order to 
define appropriate human applications of this emerging technology.
    Appendix M will be considered for revisions as experience in 
evaluating proposals accumulates and as new scientific developments 
occur. This review will be carried out periodically as needed.
Appendix M-I. Submission Requirements--Human Gene Transfer Proposals
    Investigators must simultaneously submit the following material to 
both: (1) The Office of Recombinant DNA Activities (ORDA), National 
Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 7052, 
Bethesda, Maryland 20892-7052, (301) 496-9838 (see exemption in 
Appendix M-IX-A); and (2) the Division of Congressional and Public 
Affairs, Document Control Center, HFM-99, Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, Rockville, Maryland 
20852-1448. Proposals will be submitted in the following order: (1) 
Scientific abstract--1 page; (2) non-technical abstract--1 page; (3) 
Institutional Biosafety Committee and Institutional Review Board 
approvals and their deliberations pertaining to your protocol (the IBC 
and IRB may, at their discretion, condition their approval on further 
specific deliberation by the RAC); (4) Responses to Appendix M-II, 
Description of the Proposal--5 pages; (5) protocol (as approved by the 
local Institutional Biosafety Committee and Institutional Review 
Board)--20 pages; (6) Informed Consent document--approved by the 
Institutional Review Board (see Appendix M-III); (7) appendices 
(including tables, figures, and manuscripts); (8) curricula vitae--2 
pages for each key professional person in biographical sketch format; 
and (9) three 3\1/2\ inch diskettes with the complete vector nucleotide 
sequence in ASCII format.
Appendix M-II. Description of the Proposal
    Responses to this appendix should be provided in the form of either 
written answers or references to specific sections of the protocol or 
its appendices. Investigators should indicate the points that are not 
applicable with a brief explanation. Investigators submitting proposals 
that employ the same vector systems may refer to preceding documents 
relating to the vector sequence without having to rewrite such 
material.
Appendix M-II-A. Objectives and Rationale of the Proposed Research
    State concisely the overall objectives and rationale of the 
proposed study. Provide information on the specific points that relate 
to whichever type of research is being proposed.
Appendix M-II-A-1. Use of Recombinant DNA for Therapeutic Purposes
    For research in which recombinant DNA is transferred in order to 
treat a disease or disorder (e.g., genetic diseases, cancer, and 
metabolic diseases), the following questions should be addressed:
    Appendix M-II-A-1-a. Why is the disease selected for treatment by 
means of gene therapy a good candidate for such treatment?
    Appendix M-II-A-1-b. Describe the natural history and range of 
expression of the disease selected for treatment. What objective and/or 
quantitative measures of disease activity are available? In your view, 
are the usual effects of the disease predictable enough to allow for 
meaningful assessment of the results of gene therapy?
    Appendix M-II-A-1-c. Is the protocol designed to prevent all 
manifestations of the disease, to halt the progression of the disease 
after symptoms have begun to appear, or to reverse manifestations of 
the disease in seriously ill victims?
    Appendix M-II-A-1-d. What alternative therapies exist? In what 
groups of patients are these therapies effective? What are their 
relative advantages and disadvantages as compared with the proposed 
gene therapy?
Appendix M-II-A-2. Transfer of DNA for Other Purposes
    Appendix M-II-A-2-a. Into what cells will the recombinant DNA be 
transferred? Why is the transfer of recombinant DNA necessary for the 
proposed research? What questions can be answered by using recombinant 
DNA?
    Appendix M-II-A-2-b. What alternative methodologies exist? What are 
their relative advantages and disadvantages as compared to the use of 
recombinant DNA?
Appendix M-II-B. Research Design, Anticipated Risks and Benefits
Appendix M-II-B-1. Structure and Characteristics of the Biological 
System
    Provide a full description of the methods and reagents to be 
employed for gene delivery and the rationale for their use. The 
following are specific points to be addressed: [[Page 20733]] 
    Appendix M-II-B-1-a. What is the structure of the cloned DNA that 
will be used?
    Appendix M-II-B-1-a-(1). Describe the gene (genomic or cDNA), the 
bacterial plasmid or phage vector, and the delivery vector (if any). 
Provide complete nucleotide sequence analysis or a detailed restriction 
enzyme map of the total construct.
    Appendix M-II-B-1-a-(2). What regulatory elements does the 
construct contain (e.g., promoters, enhancers, polyadenylation sites, 
replication origins, etc.)? From what source are these elements 
derived? Summarize what is currently known about the regulatory 
character of each element.
    Appendix M-II-B-1-a-(3). Describe the steps used to derive the DNA 
construct.
    Appendix M-II-B-1-b. What is the structure of the material that 
will be administered to the patient?
    Appendix M-II-B-1-b-(1). Describe the preparation, structure, and 
composition of the materials that will be given to the patient or used 
to treat the patient's cells: (i) If DNA, what is the purity (both in 
terms of being a single DNA species and in terms of other 
contaminants)? What tests have been used and what is the sensitivity of 
the tests? (ii) If a virus, how is it prepared from the DNA construct? 
In what cell is the virus grown (any special features)? What medium and 
serum are used? How is the virus purified? What is its structure and 
purity? What steps are being taken (and assays used with their 
sensitivity) to detect and eliminate any contaminating materials (for 
example, VL30 RNA, other nucleic acids, or proteins) or contaminating 
viruses (both replication-competent or replication-defective) or other 
organisms in the cells or serum used for preparation of the virus stock 
including any contaminants that may have biological effects? (iii) If 
co-cultivation is employed, what kinds of cells are being used for co-
cultivation? What steps are being taken (and assays used with their 
sensitivity) to detect and eliminate any contaminating materials? 
Specifically, what tests are being conducted to assess the material to 
be returned to the patient for the presence of live or killed donor 
cells or other non-vector materials (for example, VL30 sequences) 
originating from those cells? (iv) If methods other than those covered 
by Appendices M-II-B-1 through M-II-B-3 are used to introduce new 
genetic information into target cells, what steps are being taken to 
detect and eliminate any contaminating materials? What are possible 
sources of contamination? What is the sensitivity of tests used to 
monitor contamination?
    Appendix M-II-B-1-b-(2). Describe any other material to be used in 
preparation of the material to be administered to the patient. For 
example, if a viral vector is proposed, what is the nature of the 
helper virus or cell line? If carrier particles are to be used, what is 
the nature of these?
Appendix M-II-B-2. Preclinical Studies, Including Risk-Assessment 
Studies
    Provide results that demonstrate the safety, efficacy, and 
feasibility of the proposed procedures using animal and/or cell culture 
model systems, and explain why the model(s) chosen is/are most 
appropriate.
Appendix M-II-B-2-a. Delivery System
    Appendix M-II-B-2-a-(1). What cells are the intended target cells 
of recombinant DNA? What target cells are to be treated ex vivo and 
returned to the patient, how will the cells be characterized before and 
after treatment? What is the theoretical and practical basis for 
assuming that only the target cells will incorporate the DNA?
    Appendix M-II-B-2-a-(2). Is the delivery system efficient? What 
percentage of the target cells contain the added DNA?
    Appendix M-II-B-2-a-(3). How is the structure of the added DNA 
sequences monitored and what is the sensitivity of the analysis? Is the 
added DNA extrachromosomal or integrated? Is the added DNA 
unrearranged?
    Appendix M-II-B-2-a-(4). How many copies are present per cell? How 
stable is the added DNA both in terms of its continued presence and its 
structural stability?
Appendix M-II-B-2-b. Gene Transfer and Expression
    Appendix M-II-B-2-b-(1). What animal and cultured cell models were 
used in laboratory studies to assess the in vivo and in vitro efficacy 
of the gene transfer system? In what ways are these models similar to 
and different from the proposed human treatment?
    Appendix M-II-B-2-b-(2). What is the minimal level of gene transfer 
and/or expression that is estimated to be necessary for the gene 
transfer protocol to be successful in humans? How was this level 
determined?
    Appendix M-II-B-2-b-(3). Explain in detail all results from animal 
and cultured cell model experiments which assess the effectiveness of 
the delivery system in achieving the minimally required level of gene 
transfer and expression.
    Appendix M-II-B-2-b-(4). To what extent is expression only from the 
desired gene (and not from the surrounding DNA)? To what extent does 
the insertion modify the expression of other genes?
    Appendix M-II-B-2-b-(5). In what percentage of cells does 
expression from the added DNA occur? Is the product biologically 
active? What percentage of normal activity results from the inserted 
gene?
    Appendix M-II-B-2-b-(6). Is the gene expressed in cells other than 
the target cells? If so, to what extent?
Appendix M-II-B-2-c. Retrovirus Delivery Systems
    Appendix M-II-B-2-c-(1). What cell types have been infected with 
the retroviral vector preparation? Which cells, if any, produce 
infectious particles?
    Appendix M-II-B-2-c-(2). How stable are the retroviral vector and 
the resulting provirus against loss, rearrangement, recombination, or 
mutation? What information is available on how much rearrangement or 
recombination with endogenous or other viral sequences is likely to 
occur in the patient's cells? What steps have been taken in designing 
the vector to minimize instability or variation? What laboratory 
studies have been performed to check for stability, and what is the 
sensitivity of the analyses?
    Appendix M-II-B-2-c-(3). What laboratory evidence is available 
concerning potential harmful effects of the transfer (e.g., development 
of neoplasia, harmful mutations, regeneration of infectious particles, 
or immune responses)? What steps will be taken in designing the vector 
to minimize pathogenicity? What laboratory studies have been performed 
to check for pathogenicity, and what is the sensitivity of the 
analyses?
    Appendix M-II-B-2-c-(4). Is there evidence from animal studies that 
vector DNA has entered untreated cells, particularly germ-line cells? 
What is the sensitivity of these analyses?
    Appendix M-II-B-2-c-(5). Has a protocol similar to the one proposed 
for a clinical trial being conducted in non-human primates and/or other 
animals? What were the results? Specifically, is there any evidence 
that the retroviral vector has recombined with any endogenous or other 
viral sequences in the animals? [[Page 20734]] 
Appendix M-II-B-2-d. Non-Retrovirus Delivery/Expression Systems
    If a non-retroviral delivery system is used, what animal studies 
have been conducted to determine if there are pathological or other 
undesirable consequences of the protocol (including insertion of DNA 
into cells other than those treated, particularly germ-line cells)? How 
long have the animals been studied after treatment? What safety studies 
have been conducted? (Include data about the level of sensitivity of 
such assays.)
Appendix M-II-B-3. Clinical Procedures, Including Patient Monitoring
    Describe the treatment that will be administered to patients and 
the diagnostic methods that will be used to monitor the success or 
failure of the treatment. If previous clinical studies using similar 
methods have been performed by yourself or others, indicate their 
relevance to the proposed study. Specifically:
    Appendix M-II-B-3-a. Will cells (e.g., bone marrow cells) be 
removed from patients and treated ex vivo? If so, describe the type, 
number, and intervals at which these cells will be removed.
    Appendix M-II-B-3-b. Will patients be treated to eliminate or 
reduce the number of cells containing malfunctioning genes (e.g., 
through radiation or chemotherapy)?
    Appendix M-II-B-3-c. What treated cells (or vector/DNA combination) 
will be given to patients? How will the treated cells be administered? 
What volume of cells will be used? Will there be single or multiple 
treatments? If so, over what period of time?
    Appendix M-II-B-3-d. How will it be determined that new gene 
sequences have been inserted into the patient's cells and if these 
sequences are being expressed? Are these cells limited to the intended 
target cell populations? How sensitive are these analyses?
    Appendix M-II-B-3-e. What studies will be conducted to assess the 
presence and effects of the contaminants?
    Appendix M-II-B-3-f. What are the clinical endpoints of the study? 
Are there objectives and quantitative measurements to assess the 
natural history of the disease? Will such measurements be used in 
patient follow-up? How will patients be monitored to assess specific 
effects of the treatment on the disease? What is the sensitivity of the 
analyses? How frequently will follow-up studies be conducted? How long 
will patient follow-up continue?
    Appendix M-II-B-3-g. What are the major beneficial and adverse 
effects of treatment that you anticipate? What measures will be taken 
in an attempt to control or reverse these adverse effects if they 
occur? Compare the probability and magnitude of deleterious 
consequences from the disease if recombinant DNA transfer is not used.
    Appendix M-II-B-3-h. If a treated patient dies, what special post-
mortem studies will be performed?
    Appendix M-II-B-4. Public Health Considerations
    Describe any potential benefits and hazards of the proposed therapy 
to persons other than the patients being treated. Specifically:
    Appendix M-II-B-4-a. On what basis are potential public health 
benefits or hazards postulated?
    Appendix M-II-B-4-b. Is there a significant possibility that the 
added DNA will spread from the patient to other persons or to the 
environment?
    Appendix M-II-B-4-c. What precautions will be taken against such 
spread (e.g., patients sharing a room, health-care workers, or family 
members)?
    Appendix M-II-B-4-d. What measures will be undertaken to mitigate 
the risks, if any, to public health?
    Appendix M-II-B-4-e. In light of possible risks to offspring, 
including vertical transmission, will birth control measures be 
recommended to patients? Are such concerns applicable to health care 
personnel?
    Appendix M-II-B-5. Qualifications of Investigators and Adequacy of 
Laboratory and Clinical Facilities
    Indicate the relevant training and experience of the personnel who 
will be involved in the preclinical studies and clinical administration 
of recombinant DNA. Describe the laboratory and clinical facilities 
where the proposed study will be performed. Specifically:
    Appendix M-II-B-5-a. What professional personnel (medical and 
nonmedical) will be involved in the proposed study and what is their 
relevant expertise? Provide a two-page curriculum vitae for each key 
professional person in biographical sketch format (see Appendix M-I, 
Submission Requirements).
    Appendix M-II-B-5-b. At what hospital or clinic will the treatment 
be given? Which facilities of the hospital or clinic will be especially 
important for the proposed study? Will patients occupy regular hospital 
beds or clinical research center beds? Where will patients reside 
during the followup period? What special arrangements will be made for 
the comfort and consideration of the patients. Will the research 
institution designate an ombudsman, patient care representative, or 
other individual to help protect the rights and welfare of the patient?
Appendix M-II-C. Selection of the Patients
    Estimate the number of patients to be involved in the proposed 
study. Describe recruitment procedures and patient eligibility 
requirements, paying particular attention to whether these procedures 
and requirements are fair and equitable. Specifically:
    Appendix M-II-C-1. How many patients do you plan to involve in the 
proposed study?
    Appendix M-II-C-2. How many eligible patients do you anticipate 
being able to identify each year?
    Appendix M-II-C-3. What recruitment procedures do you plan to use?
    Appendix M-II-C-4. What selection criteria do you plan to employ? 
What are the exclusion and inclusion criteria for the study?
    Appendix M-II-C-5. How will patients be selected if it is not 
possible to include all who desire to participate?
Appendix M-III. Informed Consent
    In accordance with the Protection of Human Subjects (45 CFR Part 
46), investigators should indicate how subjects will be informed about 
the proposed study and the manner in which their consent will be 
solicited. They should indicate how the Informed Consent document makes 
clear the special requirements of gene transfer research. If a proposal 
involves children, special attention should be paid to the Protection 
of Human Subjects (45 CFR Part 46), Subpart D, Additional Protections 
for Children Involved as Subjects in Research.
Appendix M-III-A. Communication About the Study to Potential 
Participants
    Appendix M-III-A-1. Which members of the research group and/or 
institution will be responsible for contacting potential participants 
and for describing the study to them? What procedures will be used to 
avoid possible conflicts of interest if the investigator is also 
providing medical care to potential subjects?
    Appendix M-III-A-2. How will the major points covered in Appendix 
M-II, Description of Proposal, be disclosed to potential participants 
and/or their parents or guardians in language that is understandable to 
them?
    Appendix M-III-A-3. What is the length of time that potential 
participants will have to make a decision about their participation in 
the study? [[Page 20735]] 
    Appendix M-III-A-4. If the study involves pediatric or mentally 
handicapped subjects, how will the assent of each person be obtained?
Appendix M-III-B. Informed Consent Document
    Investigators submitting human gene transfer proposals must include 
the Informed Consent document as approved by the local Institutional 
Review Board. A separate Informed Consent document should be used for 
the gene transfer portion of a research project when gene transfer is 
used as an adjunct in the study of another technique, e.g., when a gene 
is used as a ``marker'' or to enhance the power of immunotherapy for 
cancer.
    Because of the relative novelty of the procedures that are used, 
the potentially irreversible consequences of the procedures performed, 
and the fact that many of the potential risks remain undefined, the 
Informed Consent document should include the following specific 
information in addition to any requirements of the DHHS regulations for 
the Protection of Human Subjects (45 CFR 46). Indicate if each of the 
specified items appears in the Informed Consent document or, if not 
included in the Informed Consent document, how those items will be 
presented to potential subjects. Include an explanation if any of the 
following items are omitted from the consent process or the Informed 
Consent document.
Appendix M-III-B-1. General Requirements of Human Subjects Research
Appendix M-III-B-1-a. Description/Purpose of the Study
    The subjects should be provided with a detailed explanation in 
nontechnical language of the purpose of the study and the procedures 
associated with the conduct of the proposed study, including a 
description of the gene transfer component.
Appendix M-IIIB-1-b. Alternatives
    The Informed Consent document should indicate the availability of 
therapies and the possibility of other investigational interventions 
and approaches.
Appendix M-III-B-1-c. Voluntary Participation
    The subjects should be informed that participation in the study is 
voluntary and that failure to participate in the study or withdrawal of 
consent will not result in any penalty or loss of benefits to which the 
subjects are otherwise entitled.
Appendix M-III-B-1-d. Benefits
    The subjects should be provided with an accurate description of the 
possible benefits, if any, of participating in the proposed study. For 
studies that are not reasonably expected to provide a therapeutic 
benefit to subjects, the Informed Consent document should clearly state 
that no direct clinical benefit to subjects is expected to occur as a 
result of participation in the study, although knowledge may be gained 
that may benefit others.
Appendix M-III-B-1-e. Possible Risks, Discomforts, and Side Effects
    There should be clear itemization in the Informed Consent document 
of types of adverse experiences, their relative severity, and their 
expected frequencies. For consistency, the following definitions are 
suggested: side effects that are listed as mild should be ones which do 
not require a therapeutic intervention; moderate side effects require 
an intervention; and severe side effects are potentially fatal or 
lifethreatening, disabling, or require prolonged hospitalization.
    If verbal descriptors (e.g., ``rare,'' ``uncommon,'' or 
``frequent'') are used to express quantitative information regarding 
risk, these terms should be explained.
    The Informed Consent document should provide information regarding 
the approximate number of people who have previously received the 
genetic material under study. It is necessary to warn potential 
subjects that, for genetic materials previously used in relatively few 
or no humans, unforeseen risks are possible, including ones that could 
be severe.
    The Informed Consent document should indicate any possible adverse 
medical consequences that may occur if the subjects withdraw from the 
study once the study has started.
Appendix M-III-B-1-f. Costs
    The subjects should be provided with specific information about any 
financial costs associated with their participation in the protocol and 
in the longterm followup to the protocol that are not covered by the 
investigators or the institution involved.
    Subjects should be provided an explanation about the extent to 
which they will be responsible for any costs for medical treatment 
required as a result of researchrelated injury.
Appendix M-III-B-2. Specific Requirements of Gene Transfer Research
Appendix M-III-B-2-a. Reproductive Considerations
    To avoid the possibility that any of the reagents employed in the 
gene transfer research could cause harm to a fetus/child, subjects 
should be given information concerning possible risks and the need for 
contraception by males and females during the active phase of the 
study. The period of time for the use of contraception should be 
specified.
    The inclusion of pregnant or lactating women should be addressed.
Appendix M-III-B-2-b. Long-Term Follow-Up
    To permit evaluation of long-term safety and efficacy of gene 
transfer, the prospective subjects should be informed that they are 
expected to cooperate in long-term follow-up that extends beyond the 
active phase of the study. The Informed Consent document should include 
a list of persons who can be contacted in the event that questions 
arise during the follow-up period. The investigator should request that 
subjects continue to provide a current address and telephone number.
    The subjects should be informed that any significant findings 
resulting from the study will be made known in a timely manner to them 
and/or their parent or guardian including new information about the 
experimental procedure, the harms and benefits experienced by other 
individuals involved in the study, and any long-term effects that have 
been observed.
Appendix M-III-B-2-c. Request for Autopsy
    To obtain vital information about the safety and efficacy of gene 
transfer, subjects should be informed that at the time of death, no 
matter what the cause, permission for an autopsy will be requested of 
their families. Subjects should be asked to advise their families of 
the request and of its scientific and medical importance.
Appendix M-III-B-2-d. Interest of the Media and Others in the Research
    To alert subjects that others may have an interest in the 
innovative character of the protocol and in the status of the treated 
subjects, the subjects should be informed of the following: (i) That 
the institution and investigators will make efforts to provide 
protection from the media in an effort to protect the participants' 
privacy, and (ii) that representatives of applicable Federal agencies 
(e.g., the National Institutes of Health and the Food and Drug 
[[Page 20736]] Administration), representatives of collaborating 
institutions, vector suppliers, etc., will have access to the subjects' 
medical records.
Appendix M-IV. Privacy and Confidentiality
    Indicate what measures will be taken to protect the privacy of 
patients and their families as well as to maintain the confidentiality 
of research data.
    Appendix M-IV-A. What provisions will be made to honor the wishes 
of individual patients (and the parents or guardians of pediatric or 
mentally handicapped patients) as to whether, when, or how the identity 
of patients is publicly disclosed?
    Appendix M-IV-B. What provisions will be made to maintain the 
confidentiality of research data, at least in cases where data could be 
linked to individual patients?
Appendix M-V. Special Issues
    Although the following issues are beyond the normal purview of 
local Institutional Review Boards, investigators should respond to the 
following questions:
    Appendix M-V-A. What steps will be taken, consistent with Appendix 
M-IV, Privacy and Confidentiality, 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?
    Appendix M-V-B. 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?
Appendix M-VI. RAC Review--Human Gene Transfer Protocols
Appendix M-VI-A. Categories of Human Gene Transfer Experiments That 
Require RAC Review
    Factors that may contribute to the necessity for RAC review 
include, but are not limited to: (i) New vectors/new gene delivery 
systems, (ii) new diseases, (iii) unique applications of gene transfer, 
and (iv) other issues considered to require further public discussion. 
Whenever possible, investigators will be notified within 15 working 
days following receipt of the submission whether RAC review will be 
required. In the event that RAC review is deemed necessary by the NIH 
and FDA, the proposal will be forwarded to the RAC primary reviewers 
for evaluation. In order to maintain public access to information 
regarding human gene transfer protocols, NIH/ORDA will maintain the 
documentation described in Appendices M-I through M-V (including 
protocols that are not reviewed by the RAC).
Appendix M-VI-B. RAC Primary Reviewers' Written Comments
    In the event that NIH/ORDA or the FDA recommend RAC review of the 
submitted proposal, the documentation described in Appendices M-I 
through M-V will be forwarded to the RAC primary reviewers for 
evaluation.
    The RAC primary reviewers shall provide written comments on the 
proposal to NIH/ORDA. The RAC primary reviewers' comments should 
include the following:
    Appendix M-VI-B-1. Emphasize the issues related to gene marking, 
gene transfer, or gene therapy.
    Appendix M-VI-B-2. State explicitly whether Appendices M-I through 
M-V have been addressed satisfactorily.
    Appendix M-VI-B-3. 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/ethical context have been resolved.
    Appendix M-VI-B-4. Whenever possible, criticisms of Informed 
Consent documents should include written alternatives for suggested 
revisions for the RAC to consider.
    Appendix M-VI-B-5. Primary reviews should 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.
Appendix M-VI-C. Investigator's Written Responses to RAC Primary 
Reviewers
    Appendix M-VI-C-1. Written responses (including critical data in 
response to RAC primary reviewers' written comments) shall be submitted 
to NIH/ORDA greater than or equal to 2 weeks following receipt of the 
review.
Appendix M-VI-D. Oral Responses to the RAC
    Investigators shall limit their oral responses to the RAC only to 
those questions that are raised during the meeting. Investigators are 
strongly discouraged from presenting critical data during their oral 
presentations that was not submitted greater than or equal to 2 weeks 
in advance of the RAC meeting at which it is reviewed.
Appendix M-VI-E. RAC Recommendations to the NIH Director
    The RAC will recommend approval or disapproval of the reviewed 
proposal to the NIH Director. In the event that a proposal is 
contingently approved by the RAC, the RAC prefers that the conditions 
be satisfactorily met before the RAC's recommendation for approval is 
submitted to the NIH Director. The NIH Director's decision on the 
submitted proposal will be transmitted to the FDA Commissioner and 
considered as a Major Action by the NIH Director.
Appendix M-VII. Categories of Human Gene Transfer Experiments That May 
Be Exempt From RAC Review
    A proposal submitted under one of the following categories may be 
considered exempt from RAC review unless otherwise determined by NIH/
ORDA and the FDA on a case-by-case basis (see Appendix M-VI-A, 
Categories of Human Gene Transfer Experiments That Require RAC Review).

    Note: In the event that the submitted proposal is determined to 
be exempt from RAC review, the documentation described in Appendices 
M-I through M-V will be maintained by NIH/ORDA for compliance with 
semiannual data reporting and adverse event reporting requirements 
(see Appendix M-VIII, Reporting Requirements--Human Gene Transfer 
Protocols). Any subsequent modifications to proposals that were not 
reviewed by the RAC must be submitted to NIH/ORDA in order to 
facilitate data reporting requirements.
Appendix M-VII-A. Vaccines
    This category includes recombinant DNA vaccines not otherwise 
exempt from RAC review (see Appendix M-IX-A for exempt vaccines).
Appendix M-VII-B. Lethally Irradiated Tumor Cells/No Replication-
Competent Virus
    This category includes experiments involving lethally irradiated 
tumor cells and: (1) vector constructs that have previously been 
approved by the RAC (or with the incorporation of minor modifications), 
or (2) a different tumor cell target.
Appendix M-VII-C. New Site/Original Investigator
    This category includes the following: (1) initiation of a protocol 
at an additional site other than the site that was originally approved 
by the RAC, and (2) the investigator at the new site is the same as the 
investigator approved for the original study. [[Page 20737]] 
Appendix M-VII-D. New Site/New Investigator
    This category includes the following: (1) initiation of a protocol 
at an additional site other than the site that was originally approved 
by the RAC, and (2) the investigator at the new site is different than 
the investigator approved for the original site.
Appendix M-VII-E. ``Umbrella'' Protocols
    This category includes initiation of a RAC-approved protocol at 
more than one additional site (the Principal Investigator may be the 
same or different than the Principal Investigator approved for the 
original site).
Appendix M-VII-F. Modifications Related to Gene Transfer
    This category includes experiments involving a modification to the 
clinical protocol that is not related to the gene transfer portion of 
study.
Appendix M-VII-G. Gene Marking Protocols
    This category includes human gene marking experiments involving 
vector constructs that have previously been approved by the RAC and: 
(1) minor modifications to the vector constructs, or (2) a different 
tumor cell target.
Appendix M-VIII. Reporting Requirements--Human Gene Transfer Protocols
Appendix M-VIII-A. Semiannual Data Reporting
    Investigators who have received approval from the FDA to initiate a 
human gene transfer protocol (whether or not it has been reviewed by 
the RAC) shall be required to comply with the semiannual data reporting 
requirements. Semi-annual Data Report forms will be forwarded by NIH/
ORDA to investigators. Data submitted in these reports will be 
evaluated by the RAC, NIH/ORDA, and the FDA and reviewed by the RAC at 
its next regularly scheduled meeting.
Appendix M-VIII-B. Adverse Event Reporting
    Investigators who have received approval from the FDA to initiate a 
human gene transfer protocol (whether or not it has been reviewed by 
the RAC) must report any serious adverse event immediately to the local 
IRB, IBC, NIH Office for Protection from Research Risks, NIH/ORDA, and 
FDA, followed by the submission of a written report filed with each 
group. Reports submitted to NIH/ORDA shall be sent to the Office of 
Recombinant DNA Activities, National Institutes of Health, 6006 
Executive Boulevard, Suite 323, Bethesda, Maryland 20892-7052, (301) 
496-9838.
Appendix M-IX. Footnotes of Appendix M
    Appendix M-IX-A. Human studies in which the induction or 
enhancement of an immune response to a vector-encoded microbial 
immunogen is the major goal, such an immune response has been 
demonstrated in model systems, and the persistence of the vector-
encoded immunogen is not expected, may be initiated without RAC review 
if approved by another Federal agency.
    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.

    Effective Date: April 17, 1995.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 95-10381 Filed 4-26-95; 8:45 am]
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