[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]="" billing="" code="" 4140-01-p="">