[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 LD50 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 LD50
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 LD50 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 LD50 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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