[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]



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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: [email protected], or telephone at: 301-496-9838. 
Written comments on these proposed changes to the NIH Guidelines can be 
submitted by e-mail to: [email protected], 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: [email protected], 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