[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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,
[[Page 35775]]
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 Presidents 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
[[Page 35776]]
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
[[Page 35777]]
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