[Federal Register Volume 61, Number 131 (Monday, July 8, 1996)]
[Notices]
[Pages 35774-35777]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-17349]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Recombinant DNA Research: Notice of Intent To Propose Amendments 
to the NIH Guidelines for Research Involving Recombinant DNA Molecules 
(NIH Guidelines) Regarding Enhanced Mechanisms for NIH Oversight of 
Recombinant DNA Activities

AGENCY: National Institutes of Health (NIH), HHS.

ACTION: Notice of Intent to Propose Amendments.

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SUMMARY: The NIH Director intends to propose amendments to the NIH 
Guidelines (59 FR 34496, amended 59 FR 40170, amended 60 FR 20726, 
amended 61 FR 1482, amended 61 FR 10004) to enhance NIH mechanisms for 
scientific and ethical oversight of recombinant DNA activities. To 
accomplish this objective, the NIH Recombinant DNA Advisory Committee 
(RAC) will be discontinued and all approval responsibilities for 
recombinant DNA experiments involving human gene transfer will be 
relinquished to the Food and Drug Administration (FDA) which retains 
statutory authority for such approval. Enhancement of NIH oversight of 
human gene therapy will be accomplished through three distinct 
mechanisms: (1) Establishment of the Office of Recombinant DNA 
Activities (ORDA) Advisory Committee (OAC) to ensure public 
accountability for recombinant DNA research and relevant data, (2) 
implementation of Gene Therapy Policy Conferences (GTPC) to augment the 
quality and efficiency of public discussion of the scientific merit and 
the ethical issues relevant to gene therapy clinical trials, and (3) 
continuation of the publicly available, comprehensive NIH database of 
human gene transfer clinical trials, including adverse event reporting.
    Specifically, the NIH Director proposes to realign and extend the 
current roles and responsibilities of NIH oversight of human gene 
transfer by establishing OAC. This chartered committee will be 
comprised of a standing membership of 6 to 10 individuals representing 
the scientific, legal, ethical, and public advocacy communities. The 
OAC will meet regularly to: (1) advise ORDA regarding relevant gene 
therapy issues, (2) identify and prioritize proposed conference topics 
and participants, and (3) periodically review and analyze data 
submitted to the NIH gene therapy database. Through ORDA, the OAC will 
administer, propose modifications, and promulgate amendments to the NIH 
Guidelines. These NIH Guidelines, which set forth accepted principles, 
practices, and procedures under which investigators and institutions 
may safely conduct recombinant DNA research under a variety of 
settings, will continue to be the responsibility of the NIH Director. 
Investigator compliance with the relevant physical and biological 
containment standards in the NIH Guidelines ensures acceptable 
protection for human health and the environment.
    The NIH Director proposes to convene the Gene Therapy Policy 
Conferences at regular intervals (3-4 times per year). These 
conferences will offer the unique advantage of assembling numerous 
participants who possess significant scientific, ethical, and legal 
expertise and/or interest that is directly applicable to a specific 
recombinant DNA research issue. In order to enhance the depth and value 
of scientific and ethical/social discussion, each GTPC will be devoted 
to a single issue relevant to scientific merit and/or safety as it 
relates to human gene therapy clinical trials. These may include topics 
such as basic research on the use of novel gene delivery vehicles and 
applications to human gene therapy, novel applications of gene 
transfer, or relevant ethical/societal implications of a particular 
application of gene transfer technology. Although NIH will no longer be 
responsible for the approval of gene therapy protocols, these 
modifications do not preclude the use of a novel protocol as a focus 
for a conference discussion, i.e., a novel protocol captured by the NIH 
database could be added by OAC, in consultation with ORDA, to a list of 
potential policy conference topics.
    The findings and recommendations of the GTPC will be submitted to 
the NIH Director and will be made available to multiple Department of 
Health and Human Services (DHHS) components, including the FDA and the 
Office for Protection from Research Risks (OPRR). The NIH Director 
anticipates that this expanded public policy forum will serve as a 
model for interagency communication and collaboration, concentrated 
expert discussion of novel scientific issues and their potential 
societal implications, and enhanced opportunity for public discussion 
of specific issues and the potential impact of such applications on 
human health and the environment.
    Finally, the NIH Director proposes to maintain the administration 
of gene therapy clinical trial data management functions through ORDA 
and in consultation with the OAC. Using current definitions, NIH will 
continue to capture incoming protocol information, ongoing data 
(including adverse and significant clinical events), and long-term 
follow-up data. In compliance with the NIH Guidelines, investigators 
will continue to be required to register human gene transfer 
experiments with ORDA to ensure continued public access to the 
comprehensive human gene transfer clinical trial database.

DATES: Written comments must be received by August 7, 1996.

ADDRESSES: Written comments should be submitted to the Office of 
Recombinant DNA Activities, Office of Science Policy, National 
Institutes of Health, 6000 Executive Boulevard, Suite 302, Bethesda, 
Maryland, 20892-7010. Fax transmissions may be sent to (301) 496-9839.

FOR FURTHER INFORMATION CONTACT: Debra Knorr, Office of Recombinant DNA 
Activities, 6000 Executive Boulevard, Suite 302, Bethesda, Maryland, 
20892-7010, (301) 496-9838.

SUPPLEMENTARY INFORMATION:

I. Background

    In 1974, the National Academy of Sciences (NAS) established a 
Committee on Recombinant DNA Molecules which was charged with examining 
the risks associated with recombinant DNA research and recommending 
specific actions or guidelines. The NAS Committee report requested: (1) 
that certain experiments be voluntarily deferred; (2) that plans to 
construct recombinants with animal DNA should be carefully weighed; (3) 
that the NIH Director establish a committee to oversee a program to 
evaluate hypothetical risks, to develop procedures to minimize the 
spread of recombinant DNA molecules, and to recommend guidelines to be 
followed by investigators; and (4) that an international meeting be 
convened to review progress and discuss ways to deal with potential 
hazards.
    In that same year, the Department of Health, Education, and Welfare 
(currently the Department of Health and Human Services (DHHS)) 
chartered a committee (later identified as the RAC) in response to the 
NAS report. In 1975,

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RAC held its first meeting to establish appropriate biological and 
physical containment practices and procedures that were later developed 
into a set of guidelines for the safe conduct of recombinant DNA 
research (the NIH Guidelines). Subsequently, the NIH created ORDA to 
provide administrative support to the RAC.
    In 1982, an in-depth examination of the broad ethical implications 
of human gene therapy research, The Social and Ethical Issues of 
Genetic Engineering with Human Beings (Splicing Life), was published by 
the Presidents Commission for the Study of Ethical Problems in 
Medicine and Biomedical and Behavioral Research. Splicing Life proposed 
that, ``. . . since laboratory biohazards related to recombinant DNA 
research were no longer regarded as urgent matters, the NIH should 
extend its purview over recombinant DNA research beyond environmental 
issues to human gene therapy.''
    They recommended that the membership of the RAC should be broadened 
to include a combination of Federal and non-Federal scientists, lay 
public participants, and ethicists. In response to Splicing Life, the 
NIH established the RAC Human Gene Therapy Subcommittee which was 
subsequently merged with the parent committee to become the current 
RAC.

II. Rationale for Change

    In recognition of the committee's critical role in maintaining 
public accountability for recombinant DNA research, the NIH Director 
weighed a variety of factors prior to announcing NIH's intent to change 
and enhance its current oversight responsibilities for recombinant DNA 
research. In order to clarify the rationale for the proposed changes 
described herein, a series of questions and answers are provided below.

1. On what basis does the NIH conclude that this is the optimal time to 
eliminate the RAC and realign NIH's responsibilities to public 
discussion and data management of human gene therapy clinical trials?

    Since its inception, the NIH has continuously relinquished 
oversight of various elements in the field of recombinant DNA research, 
as such elements reached maturity. From l979-l983, several major 
revisions were made to the NIH Guidelines when putative risks to the 
public did not materialize and the initial restrictions were deemed 
unnecessary. In 1991, the NIH's oversight of environmental release of 
genetically modified organisms was relinquished and these 
responsibilities were ceded to the U.S. Department of Agriculture and 
the Environmental Protection Agency. These changes were, in part, 
motivated by the recognition that NIH did not have the statutory 
authority or the ``tools'' to function as a regulatory agency.
    In 1995, a similar devolution of NIH oversight of human gene 
therapy occurred. By this time, the RAC had reviewed and approved 113 
gene therapy protocols and over 1,000 patients had been enrolled in 
world-wide trials. The RAC, the scientific community, and the public 
had a substantial base of information regarding the use and safety of 
many of the vectors employed in, and target diseases addressed by, 
human gene therapy. Subsequent analyses revealed that the human health 
and environmental safety concerns expressed at the inception of gene 
therapy clinical trials had not materialized. Absent evidence for 
substantial safety concerns for gene therapy protocols which have been 
previously tested, on March 6, 1995, the RAC voted to recommend 
approval of amendments to the NIH Guidelines that would eliminate RAC 
review and approval of human gene therapy experiments not considered to 
be novel. Under this mechanism, all protocols determined not to 
represent a novel gene therapy delivery strategy or target disease that 
could adversely affect human health were considered exempt from RAC 
review and approval and were forwarded directly to the FDA. This 
streamlined process, which became known as the NIH and FDA 
``Consolidated Review,'' eliminated unnecessary and time consuming 
duplication of effort by the NIH and the FDA. On April 17, 1995, the 
NIH Director approved these amendments to the NIH Guidelines. Once 
again, the NIH relinquished a portion of its oversight of recombinant 
DNA research to the agency (FDA) with statutory responsibility to 
approve such protocols.
    Since the implementation of consolidated review in July 1995, only 
six of the 36 protocols submitted to ORDA required RAC review and 
approval; and five of those six protocols were already in the system 
before consolidated review. The consolidated review process proved to 
be so successful in eliminating the need for RAC review and approval, 
that NIH canceled both the March and June 1996 RAC meetings due to the 
lack of novel protocols requiring RAC attention.
    The NIH Director has concluded that the current proposal to enhance 
NIH oversight of recombinant DNA activities is timely and appropriate 
based on the current base of knowledge, the need for substantial 
discussion of gene therapy techniques which are not yet being tested in 
humans, and the duplication of review and approval by the NIH while the 
FDA holds the statutory authority. Thus, the NIH Director proposes the 
termination of the RAC, relinquishing of all protocol approval to the 
FDA and the creation of two new entities to enhance the depth and 
breadth of public discussion of gene therapy issues.

2. Why does the NIH propose to replace the RAC?

    The proposed actions regarding the RAC should not be viewed 
narrowly as ``eliminating'' the RAC. Rather, these actions were 
developed in a timely and appropriate response to a series of publicly 
debated discussions over a period of several years. The NIH Director 
maintains that the establishment of the OAC and the convening of the 
GTPC are effective and innovative responses to this rapidly changing 
area of biomedical research based on the foundation of scientific 
knowledge that has been gained over the last six years and overlapping 
responsibilities of other Federal agencies. This proposal optimizes 
current Federal resources, maintains public access to information, and 
facilitates public discussion of novel issues relevant to human gene 
therapy research. NIH concludes that it is not the RAC per se that is 
critical for public accountability, but the system by which NIH 
continues to provide public discussion of the scientific, safety, and 
ethical/legal issues related to human gene therapy.
    As proposed, the OAC will provide a smaller, but fully 
representational, standing committee with a range of advisory and 
administrative oversight responsibilities similar, but not identical 
to, the RAC. In contrast, participation in the proposed GTPC will be 
subject to recommendations by the OAC and ORDA and, as such, will 
provide the necessary flexibility to engender in-depth, expert 
discussion of scientific issues and societal implications that cannot 
be achieved under current mechanisms. The GTPC will continue to 
maintain favorable RAC attributes such as continued public access to 
conference discussions and recommendations, publication of scheduled 
meeting dates and proposed agendas in the Federal Register, and 
publication of official conference minutes. Eliminating RAC protocol 
approval reduces duplication of effort with the FDA while enhancing the 
time and effort devoted to both ongoing and

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anticipated gene therapy policy issues deserving of substantial public 
discussion.

3. Why not continue RAC review and approval of gene therapy protocols?

    In 1990, when the RAC first turned its attention to human gene 
therapy, the NIH was the sole source of the substantial expertise 
necessary to review the relatively new field of human gene therapy. 
Since that time, the FDA has created a new Division of Cellular and 
Gene Therapies and has committed substantial resources to the 
development of review capabilities in this arena. At its inception, it 
was critical for the RAC to conduct a case-by-case review of human gene 
transfer protocols, since each new protocol invariably set a new 
precedent. Six years later, the RAC has relinquished most of its review 
and approval activities under the ``consolidated'' review plan which 
forwards all but novel protocols directly to the FDA for consideration.
    During the six years of RAC review and approval, there has been 
considerable discussion of the juxtaposition of the NIH mandate to 
oversee the most meritorious medical research and the RAC mission to 
approve or disapprove individual protocols based predominantly on 
issues of safety. By adopting a new model of public discussion that 
does not require approval, the NIH can, through the proposed policy 
conferences, engage in substantive critique of the scientific merit of 
a line of research without having to give an NIH stamp of approval on 
the basis of limited threat to human health or safety.

4. Did NIH accept the recommendations of the RAC Ad Hoc Advisory 
Committee (Verma Committee)?

    The decision to retire the RAC does not foreclose on the 
recommendations of the Verma Committee. The NIH Director accepted most 
of the recommendations of the RAC Ad Hoc Review Committee. However, 
rather than implement the recommendations through the RAC, the Director 
proposes a new structure for NIH oversight of human gene therapy.
    Specifically: (1) The first recommendation calls for continuation 
of consolidated review by the RAC. Under the proposal contained herein, 
the RAC is eliminated and consolidated review will not be maintained. 
(2) A second recommendation calls for an open public forum for 
discussion of protocols which contain a new technology or novel 
departures in human gene transfer research. The proposed Gene Therapy 
Policy Conferences will not only preserve such a forum, but will 
provide for more in-depth discussion of both the science and the 
ethical issues related to a specific gene therapy issue. In this 
manner, it will enhance the type of public access that has been 
characteristic of the RAC. Although this proposal does not provide for 
review and approval of individual protocols, it does not preclude the 
use of a novel protocol as a focus for a conference discussion; a novel 
protocol captured by the NIH database could be raised by the OAC, in 
consultation with ORDA, to the list of policy conference topics. (3) 
The recommendation that RAC should develop criteria for consolidated 
review would not be applicable to the proposed new structure, since 
this proposal cedes review and approval to the FDA. However, as stated 
above, the OAC will have the authority to recommend a novel protocol 
captured by the NIH database for public discussion at a policy 
conference. (4) The fourth recommendation that the RAC should provide 
advice on policy matters revolving around gene therapy and other 
recombinant DNA issues would be fully met by the proposed Gene Therapy 
Policy Conferences. Because each of these conferences will focus on a 
single issue, it is the Director's contention that policy advice will 
be substantially augmented under this new mechanism. The NIH cannot, 
however, give the RAC, or any other NIH standing or ad hoc body, the 
authority to give policy advice or make recommendations to the FDA. The 
NIH has had and will continue to have open and frequent dialogue with 
the FDA about gene therapy policy matters related to safety, scientific 
and ethical issues and fully expects the FDA to recommend policy 
conference topics to OAC and ORDA. (5) The proposed maintenance of the 
NIH gene therapy database fully responds to the recommendation 
regarding the continued need for data monitoring and adverse event 
reporting. The Office of Recombinant DNA Activities (ORDA) has retained 
the services of a contractor to assist in the development of a computer 
software package that will have sufficient capacity to monitor and 
evaluate gene transfer protocols.

5. Will there be a mechanism for continuing to review gene therapy 
informed consent documents?

    As needs dictate, both OAC and the GTPC will provide a forum for 
the oversight of human gene therapy informed consent. It is expected 
that an entire conference may be devoted to such informed consent 
issues in the context of gene therapy. The NIH Director will continue, 
when appropriate, to make amendments to sections of the NIH Guidelines, 
Points to Consider relevant to informed consent procedures during gene 
therapy clinical trials. Investigators and IRBs engaged in, or 
reviewing, human gene therapy trials are expected to employ the NIH 
Guidelines, Points to Consider for this purpose. However, under the 
proposal contained herein, neither the OAC nor the GTPC will engage in 
protocol-by-protocol review of informed consent documents.
    The sixteen Federal agencies that engage in human subjects research 
reference the Common Rule and, thus, abide by the principle of giving 
full authority of individual approval of informed consent documents to 
locally constituted Institutional Review Boards (IRBs). These 
responsibilities remain solely within the regulatory framework of OPRR 
through the local IRBs. OPRR oversees implementation of 45 CFR Part 46 
in all domestic and foreign institutions or sites receiving DHHS funds. 
OPRR requires each institution that conducts or supports research 
involving human subjects to set forth the procedures it will use to 
protect human subjects in a policy statement called an Assurance of 
Compliance.
    Finally, there is no other disease, disability, or methodology 
that, at present, requires a Federal review of individual informed 
consent documents. It is the proposal of the NIH Director that human 
gene therapy informed consent documents be subject to the same 
procedures as all other forms of human subject research.
    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

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NIH Guidelines. In lieu of the individual program listing, NIH invites 
readers to direct questions to the information address above about 
whether individual programs listed in the Catalog of Federal Domestic 
Assistance are affected.

    Dated: June 28, 1996.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 96-17349 Filed 7-5-96; 8:45 am]
BILLING CODE 4140-01-P