[Federal Register Volume 64, Number 224 (Monday, November 22, 1999)]
[Notices]
[Pages 63827-63828]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-30342]
[[Page 63827]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Office of Recombinant DNA Activities; Recombinant DNA Research:
Proposed Actions Under the NIH Guidelines
AGENCY: National Institutes of Health (NIH), PHS, DHHS.
ACTION: Notice of proposed actions under the NIH Guidelines for
Research Involving Recombinant DNA Molecules (NIH Guidelines).
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SUMMARY: The purpose of this document is to inform the public of
proposed changes to the NIH Guidelines related to the reporting of
serious adverse events involving human gene transfer research. This
notice describes a proposed action to amend the NIH Guidelines
regarding the reporting and public disclosure of serious adverse
events.
DATES: The public is encouraged to submit written comments on these
proposed changes to the NIH Office of Recombinant DNA Activities
(ORDA). Written comments may be submitted to NIH/ORDA in paper or
electronic form. Written comments received by December 3, 1999, will be
reproduced and distributed to the RAC for consideration at its December
8-10, 1999, meeting.
All comments received in response to this notice will be considered
by the NIH and will be available for public inspection in the NIH/ORDA
office weekdays between the hours of 8:30 a.m. and 5 p.m.
FOR FURTHER INFORMATION CONTACT: If you have questions, or require
additional information about these proposed changes to the NIH
Guidelines, please contact the Office of Recombinant DNA Activities
(ORDA) by e-mail at: ci4e@nih.gov, or telephone at: 301-496-9838.
Written comments on these proposed changes to the NIH Guidelines can be
submitted by e-mail to: ci4e@nih.gov, fax to: 301-496-9839, or mail to:
the Office of Recombinant DNA Activities, National Institutes of
Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,
Maryland 20892-7010.
For additional information about the December 8-10, 1999, RAC
meeting at which these proposed changes will be deliberated, please
visit the NIH/ORDA web site at: http://www.nih.gov/od/orda/.
SUPPLEMENTARY INFORMATION: Appendix M-VII-C of the NIH Guidelines
requires Principal Investigators (or their designated sponsors) to
report serious adverse events immediately to the local Institutional
Review Board (IRB), Institutional Biosafety Committee (IBC), Office for
Protection from Research Risks (OPRR) (if applicable), NIH/ORDA, and
Food and Drug Administration (FDA).
All non-NIH funded projects involving recombinant DNA techniques
conducted at or sponsored by an institution that receives NIH support
for projects involving such techniques must comply with the NIH
Guidelines. Noncompliance may result in: (i) Suspension, limitation, or
termination of NIH funds for recombinant DNA research at the
institution, or (ii) a requirement for prior NIH approval of any or all
recombinant DNA projects at the institution.
All gene transfer clinical studies are subject to FDA regulations
found in volume 21 of the Code of Federal Regulations (CFR), including
specific requirements at 21 CFR 312.32 related to adverse events.
The immediate reporting of serious adverse events to NIH/ORDA by
investigators allows rapid notification of the RAC. This, in turn,
allows notification, as appropriate, of other IBCs, IRBs, and Principal
Investigators in the field. Immediate reporting also provides a unique
mechanism for early recognition of trends in the occurrence of serious
adverse events that may raise significant implications for the safety
of patients enrolled in similar human gene transfer studies. For
example, there have been several instances in which public RAC
discussion of serious adverse events has resulted in important changes
in the design of vectors for gene delivery. When deemed appropriate,
NIH/ORDA will initiate additional data collection for a comprehensive
and public review by the RAC and ad hoc experts. This process fosters
broad public awareness of issues and developments in human gene
transfer research. The comprehensive public review of data by the RAC
is a critical component of Federal oversight of gene transfer research.
Recently some investigators and sponsors have begun to designate
human gene transfer protocols or serious adverse event reports
confidential, thereby precluding public RAC review. Out of concern
about this development, the NIH requested that the RAC consider whether
the requirement for serious adverse event reporting as set forth in the
NIH Guidelines needed to be clarified.
During the September 2-3, 1999, meeting, the RAC developed the
following consensus statement with regard to serious adverse event
reporting to NIH/ORDA and the RAC: ``Adverse event reports shall not be
designated as confidential, either in whole or in part. Adverse event
reports are essential to decision-making by IBCs, IRBs, and potential
subjects of gene transfer research in humans. The public disclosure of
adverse events [in human gene transfer research] is also essential to
public understanding and evaluation of gene transfer in humans. Adverse
event reports must be made available for public discussion [by the RAC]
without the inclusion of proprietary or trade secret information.''
Some investigators have not complied with the NIH Guidelines
requirement to report serious adverse events immediately to the NIH/
ORDA. While the NIH Guidelines are clear on this matter, the NIH is
proposing to amend the NIH Guidelines to restate the requirements for
serious adverse event reporting and to include: (1) A definition of
serious adverse events and a stipulation of the time-frame in which
they are to be reported in writing (adapted from 21 CFR 312.32 IND
Safety Reports); (2) a mandate that serious adverse event reports must
not contain any trade secret or commercial or financial information
that is privileged or confidential and that all information submitted
in accordance with Appendix M-VII-C will be considered public unless
NIH ORDA determines that there are exceptional circumstances; and (3) a
directive that serious adverse event reports submitted to ORDA be
stripped of individually-identifiable patient information.
Proposed Amendments to the NIH Guidelines
A new Section I-E-7 is added to read:
``Section I-E-7. A ``serious adverse event'' is defined as any
expected or unexpected adverse event, related or unrelated to the
intervention, occurring at any dose that results in any of the
following outcomes; death, a life-threatening event, in-patient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization also may be
considered a serious adverse event when, based upon appropriate medical
judgement, they may jeopardize the human gene transfer research subject
and may require medical or surgical intervention to prevent one of the
outcomes listed in this definition.''
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Appendix M, Points To Consider in the Design and Submission of
Protocols for the Transfer of Recombinant DNA Molecules Into One or
More Human Subjects (Points To Consider)
Appendix M-VII-C, Serious Adverse Events, is proposed to read:
``Appendix M-VII-C-1, Serious Adverse Event Reporting
``Principal Investigators who have received authorization from
FDA to initiate a human gene transfer protocol must report
immediately in writing any serious adverse event (as defined in
Section I-E-7) to the local Institutional Review Board,
Institutional Biosafety Committee, Office for Protection from
Research Risks (if applicable), NIH/ORDA, and FDA.
``Serious adverse event reports must not contain any trade
secret or commercial or financial information that is privileged or
confidential as defined under the Freedom of Information Act, 5
U.S.C. 552; therefore, unless NIH/ORDA determines that there are
exceptional circumstances, all information submitted in accordance
with Appendix M-VII-C will be considered public.
``Reports of serious adverse events may be submitted by e-mail
to: ci4e@nih.gov, fax to: 301-496-9839, or by mail to: the Office of
Recombinant DNA Activities, National Institutes of Health, MSC 7010,
6000 Executive Boulevard, Suite 302, Bethesda, Maryland 20892-7010.
Appendix M-VII-C-2, Serious Adverse Event Reporting: Content and Format
``Reports of serious adverse events must follow the format
provided in the Adverse Event Reporting Form available on NIH/ORDA's
web site at: http://www.nih.gov/od/orda/. The serious adverse event
report must include, but need not be limited to: (1) The date of the
event; (2) a complete description of the event; (3) relevant
clinical observations; (4) relevant clinical history; (5) relevant
tests that were or are planned to be conducted; (6) the suspected
cause of the event; (7) gene delivery method; (8) vector type, e.g.,
adenovirus; (9) vector subtype, e.g., type 5, relevant deletions;
(10) dosing schedule; (11) route of administration; (12) clinical
site; (13) principal investigator(s); (14) NIH Protocol number; and
(15) Investigational New Drug (IND) number.
``Serious adverse event reports should be stripped of
individually-identifiable patient information. Examples of such
information include, but are not limited to, the patient's name,
address, contact information, social security number, date of birth.
``Appendix M-VII-C-3, Time-Frames for Serious Adverse Event Reporting:
Initial and Follow-Up Reports
``Immediate reporting of serious adverse events is essential for
the early identification of acute events related to a gene transfer
procedure, as well as the identification of patterns that may signal
potential safety concerns. For the purposes of the NIH Guidelines,
`immediate' written reporting of all serious adverse events is to
occur as soon as possible but no later than 15 calendar days after
such an event has occurred. This applies to all serious adverse
events, related or unrelated to gene transfer, which occur during
the course of the clinical trial.
``Relevant additional clinical and laboratory data may become
available following the initial serious adverse event report. The
Principal Investigator(s) must provide any relevant follow-up
information to a serious adverse event report within 15 calendar
days of receipt of the relevant information. In addition, if a
serious adverse event occurs after the end of a clinical trial, and
is determined to be related to gene transfer, that event shall be
reported by the Principal Investigator within 15 calendar days of
the determination.''
OMB's ``Mandatory Information Requirements for Federal
Assistance Program Announcements'' (45 FR 39592) 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 virtually every NIH and Federal research program
in which recombinant DNA 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.
Dated: November 16, 1999.
Lana Skirboll,
Associate Director for Science Policy, National Institutes of Health.
[FR Doc. 99-30342 Filed 11-19-99; 8:45 am]
BILLING CODE 4140-01-P
