[Federal Register Volume 65, Number 239 (Tuesday, December 12, 2000)]
[Notices]
[Pages 77655-77659]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-31524]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Biotechnology 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 NIH is proposing changes to the NIH Guidelines to enhance 
its oversight of human gene transfer research by making modifications 
to the reporting and analysis of serious adverse events in human gene 
transfer research studies. The purpose of this Notice is to inform the 
public about the proposed changes and to seek public comment on them. 
The proposed changes involve four main issues: (1) The scope and timing 
of serious adverse event reporting; (2) public access to information 
about serious adverse events; (3) protection of individually 
identifiable patient information as it relates to serious adverse event 
reporting; and (4) a new mechanism for the review and assessment of 
data on serious adverse events and other relevant safety information.
    The NIH currently requires all serious adverse events to be 
reported immediately whether or not they are expected or considered to 
be associated with the gene transfer product. The first proposed change 
would require expedited reporting for those serious adverse events that 
are unexpected and considered possibly associated with the use of the 
gene transfer product. The proposed change also provides timeframes for 
expedited reporting and definitions of serious, associated, and 
unexpected adverse events. Under this proposal, other reportable 
serious adverse events would be included in annual reports.
    The second proposed change would clarify that serious adverse event 
reports submitted to the NIH may not be classified as confidential 
information and that trade secret or other commercial confidential 
information should not be included in serious adverse event reports.
    The third proposed change adds specific language to the NIH 
Guidelines to prohibit the submission of individually-identifiable 
patient information in serious adverse event reports.
    The fourth and final change is the establishment of a working group 
of the NIH Recombinant DNA Advisory Committee (RAC), to be known as the 
NIH Gene Transfer Safety Assessment Board, that will be responsible for 
the review and analysis of serious adverse event reports and other 
relevant safety information in gene transfer research studies. The 
working group will report safety information to the RAC and information 
will, thereby, be disseminated to the scientific and patient 
communities and the public.

DATES: The public is encouraged to submit written comments on these 
proposed changes. Comments may be submitted to NIH Office of 
Biotechnology Activities (OBA) in paper or electronic form. Comments 
received on or before February 10, 2002 will be reproduced and 
distributed to the RAC for consideration at a future meeting to be 
announced.
    All comments received in response to this notice will be considered 
by the NIH and will be available for public inspection in the NIH OBA 
office weekdays between the hours of 8:30 a.m. and 5 p.m.

FOR FURTHER INFORMATION: If you have questions, or require additional 
information about these proposed changes, please contact OBA by e-mail 
at [email protected], or telephone at 301-496-9838. Comments can be 
submitted to the same email address or by fax to 301-496-9839 or mail 
to the Office of Biotechnology Activities, National Institutes of 
Health, Building 1, Room 103, Bethesda, Maryland 20892.
    For additional information about the RAC meeting at which these 
proposed changes will be deliberated, please visit the NIH/OBA Web site 
at: http://www.nih.gov/od/oba/.

[[Page 77656]]


SUPPLEMENTARY INFORMATION:

Introduction

    NIH's oversight of human gene transfer research, especially its 
requirements for serious adverse event reporting in human gene transfer 
research, has been the subject of an in-depth, year-long, public debate 
and discussion. In September 1999, the RAC initiated a discussion 
relating to public access to serious adverse event reports. The RAC's 
interest in this issue was prompted by claims from several human gene 
transfer investigators and sponsors that serious adverse event reports 
were confidential, commercial information and, therefore, should not be 
made publicly available. In November, following the death of a 
participant in a human gene transfer research protocol--a death 
directly attributable to the study--a number of new concerns arose 
about the collection, analysis, and dissemination of gene transfer 
safety information. The RAC subsequently expanded its discussions to 
include the scope and timing of NIH reporting requirements for serious 
adverse events and investigator compliance with those requirements.
    In December 1999, the NIH Director established the Advisory 
Committee to the Director (ACD) Working Group on NIH Oversight of 
Clinical Gene Transfer Research. The charge to this Working Group was 
to review the role of NIH in oversight of this area of research, 
including an assessment of protocol review, analysis of serious adverse 
event reports, and the interaction between the various Federal agencies 
and local oversight bodies involved in regulation and oversight of this 
research. The ACD Working Group met four times and issued a final 
report to the ACD, which concurred with the Working Group's 
recommendations. The ACD Working Group report is posted at the 
following URL:
    The changes proposed in this Notice respond to recommendations made 
by the ACD and by the RAC. They also reflect the views expressed by 
patients, patient advocates, investigators, industry representatives, 
and professional associations regarding the purpose, public good, and 
appropriate scope of toxicity and safety data collection and 
dissemination in human gene transfer research subject to the NIH 
Guidelines.

Background

    The NIH Guidelines (Appendix M-I-C-4) currently require immediate 
reporting of all serious adverse events to NIH OBA, the IBC, the IRB, 
and, if applicable, the Office for Human Research Protections. This NIH 
requirement for immediate reporting of all serious adverse events, 
whether or not they are associated with the gene transfer product, was 
added to the NIH Guidelines in 1990, shortly after human gene transfer 
studies began. Because gene transfer was a novel and untested area of 
clinical investigation and because of the potential risks, NIH 
determined, with advice from the RAC, that it would be prudent to 
collect information on all serious adverse events in these studies.
    These and other provisions of the NIH Guidelines apply to NIH-
funded as well as non-NIH-funded gene transfer projects that are 
conducted at or sponsored by an institution that receives NIH support 
for recombinant DNA research. All human gene transfer research studies 
are also 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.
    Roles and Responsibilities of NIH and FDA. The scope and timeframe 
of the serious adverse event reporting to the NIH and the FDA currently 
differ. As noted above, NIH requires immediate reporting of all serious 
adverse events. FDA requires expedited reporting of only those serious 
adverse events that are unexpected and considered possibly associated 
with the gene transfer product.
    The two agencies also have different roles and responsibilities 
with respect to adverse event reports and initiate different, but 
complementary, processes in response to these reports. The FDA conducts 
an analysis of an adverse event(s) and related data and, if necessary, 
places the study, and others like it, on clinical hold until the safety 
issues have been adequately addressed. The FDA is required by law to 
maintain the confidentiality of all information connected with an 
investigational new drug (IND). In contrast, the reporting of serious 
adverse events to NIH enables the identification of trends in serious 
adverse events, the assessment of their significance for the safety of 
patients enrolled in similar human gene transfer studies, and public 
discussion by the RAC of important developments in the safety of human 
gene transfer research.
    Confidentiality of Adverse Event Reports. In September 1999, the 
RAC initiated discussions regarding public access to serious adverse 
event information. This discussion was in response to several serious 
adverse event reports submitted to OBA which were labeled as 
confidential. The NIH has always acknowledged and affirmed the need to 
protect trade secret and other proprietary information, such as the 
details of a sponsor's manufacturing process, and this principle is 
accommodated in the NIH Guidelines. The concept that reports of serious 
adverse events should be considered from a commercial standpoint as 
confidential, however, is contrary to NIH's commitment to public access 
to information about the safety of human gene transfer research. Since 
the NIH Guidelines were not explicit about the confidentiality of 
serious adverse event reports, NIH OBA asked the RAC to consider 
whether the NIH Guidelines should be modified to clarify the 
requirement for public access to these reports. In response, the RAC 
issued the following consensus statement:

    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 
is also essential to public understanding and evaluation of gene 
transfer in humans. Adverse event reports must be made available for 
public discussion without the inclusion of proprietary or trade 
secret information.

    Compliance with NIH Adverse Event Reporting Requirements. 
Subsequent to the death of a participant in a human gene transfer 
research protocol, which was directly attributable to the study, NIH 
OBA called on investigators conducting related studies to submit 
comprehensive pre-clinical and clinical data from their trials. In the 
course of gathering and assessing this data, it became evident that 
serious adverse events were not being reported to OBA, as required by 
the NIH Guidelines. Concerted efforts were immediately initiated to 
ensure enhanced awareness of, and compliance with, the reporting 
requirements. NIH also proposed that the NIH Guidelines be amended to 
make the requirements for reporting serious adverse events more 
explicit. The proposed amendments were published for public comment in 
the November 22, 1999, Federal Register (64 FR 63827). The proposed 
amendments added explicit definitions and spelled out timeframes for 
immediate reporting of serious adverse events.
    In response to the notice, NIH OBA received a wide range of public 
comments from investigators, sponsors, industry, and patient advocacy 
organizations. Some commenters expressed vigorous support for the 
requirement that all serious adverse events be reported to OBA 
immediately, arguing that the requirement was warranted for the same 
reasons it was established in the first place'the field

[[Page 77657]]

was still young and the manipulation of genetic material posed risks 
that were still not fully known or understood. Other commenters 
suggested that NIH harmonize its requirements with those of the FDA so 
that it would receive, on an expedited basis, only those serious 
adverse events that are unexpected and considered to be possibly 
associated with the gene transfer product, and, on an annual basis, a 
summary of adverse events that are expected or considered to have other 
causes such as disease progression or concurrent medications. According 
to these commenters, requiring the immediate submission of all serious 
adverse events was counter-productive given the priority that should be 
placed on events that are unexpected and considered to be possibly 
associated with the gene transfer product. Other commenters stated that 
reporting any serious adverse event to OBA was unnecessary because FDA 
receives such reports by law and has authority to stop trials when 
necessary for safety concerns. Given that most serious adverse events 
are associated with disease progression, not the experimental gene 
transfer product, some commenters expressed concern that reporting of 
all serious adverse events had the potential to mislead or confuse the 
public about the cause of adverse events. They argued that the 
reporting of all such events would give the public the wrong impression 
about the risks involved in human gene transfer research.
    Members of the RAC also expressed differing views about the 
appropriate scope of reporting. At its December 10, 1999, meeting, the 
Committee did not reach a consensus on whether the proposed amendments 
making more explicit the requirement for immediate reporting of all 
serious adverse events should be adopted. Consideration of the proposed 
amendments was deferred pending further RAC deliberations. Moreover, as 
noted previously, the ACD Working Group, formed in early December 1999, 
was also charged with considering the issue of serious adverse event 
reporting in the context of its broader review of NIH's role in the 
oversight of human gene transfer studies.
    After extensive deliberations, the ACD Working Group submitted a 
report to the NIH ACD which concluded that: (1) public discussion of 
serious adverse events is an important component of the NIH oversight 
process; (2) serious adverse events should not be considered trade 
secrets or proprietary; (3) serious adverse event data should be 
disseminated to the public in an analyzed and interpreted form; and (4) 
because FDA is unable to disclose information, NIH OBA should continue 
to receive reports of serious adverse events directly from 
investigators or sponsors. With regard to the scope of what should be 
reported, the ACD Working Group recommended that NIH and FDA work 
together to simplify, streamline, and harmonize reporting of serious 
adverse events. The ACD Working Group also agreed that all reasonable 
measures be taken to protect the privacy of the individual who 
experienced the adverse event, without compromising the health of 
others in similar trials.
    In addition, the ACD Working Group affirmed the need to gather 
cumulative data on gene transfer trials to improve the conduct and 
overall safety of such research, noting that systematic analyses of 
adverse event data could reveal trends related to, for example, 
specific diseases, routes of administration, or vectors. In this 
regard, the ACD Working Group recommended that a new mechanism was 
needed for ongoing analyses of the nature and frequency of adverse 
events reported over time, analyses that would be made available to the 
RAC, FDA, scientific community, and public. They recommended that a 
standing expert body be established to conduct ongoing analyses of 
adverse event data. The standing expert body should include basic 
scientists, clinicians, patient advocates, and ethicists. Ad hoc 
members could be appointed to provide additional expertise on an as-
needed basis. The standing body should review all reports of adverse 
events, analyze the data for trends, develop a cumulative report that 
should be presented annually at a public RAC meeting and made available 
to the public, and identify trends or even single events that may 
warrant further public discussion or Federal action.
    In June 2000, the RAC reviewed the conclusions and recommendations 
of the ACD Working Group and, after engaging in further discussion 
about the appropriate timing and scope of serious adverse event 
reporting, endorsed the ACD Working Group recommendations by a 
unanimous vote. In September 2000, the full ACD reviewed and endorsed 
the recommendations of the Working Group at a publicly accessible 
teleconference.
    The public deliberations of the ACD and the RAC affirmed the 
importance of NIH's role in ensuring the safety of human gene transfer 
research studies. This role differs from, and in important ways 
complements, the role of the FDA, which is to respond on a timely basis 
to serious, life-threatening, unexpected events that are associated 
with the investigational product. NIH's role is to gather information 
about the safety of the field in general and to disseminate that 
information to investigators and the public with the purpose and goal 
of developing a body of knowledge about the risks and benefits of this 
form of clinical investigation.
    The NIH concurs with the need to harmonize Federal requirements for 
reporting serious adverse events and other safety information. With 
this action, NIH is proposing to amend the NIH Guidelines to require 
expedited reporting of serious adverse events that are unexpected and 
considered to be possibly associated with the use of the gene transfer 
product. The scope and timeframe for reporting these events and other 
safety information, as well as definitions used, would parallel those 
of the FDA as set forth in volume 21 of the CFR. Submission of a 
comprehensive summary of serious adverse event data will be required on 
an annual basis, again in harmony with the FDA requirements.
    The comprehensive public review of serious adverse event data by 
the RAC is a critical component of Federal oversight of human gene 
transfer research. A systematic and publicly accountable review and 
assessment of toxicity and safety data from these trials over time is 
essential for identifying trends and recognizing patterns that may have 
important implications for the future development of human gene 
transfer research. In order to enhance NIH's ability to perform this 
critical function, and in accordance with the recommendations of the 
ACD, the NIH is proposing to establish a new mechanism for the review 
and assessment of serious adverse events. The specific proposed 
mechanism is a working group of the RAC, to be known as the NIH Gene 
Transfer Safety Assessment Board. The working group's specific 
functions would involve: (1) Reviewing serious adverse event reports, 
annual reports, and other relevant safety information and assessing 
toxicity and safety data across all gene transfer trials and analyzing 
the data for trends; (2) identifying significant trends or single 
events; (3) developing information that will enhance the development, 
design, and conduct of human gene transfer clinical trials; and (4) 
reporting aggregated data to the RAC to enhance review of new protocols 
and to enhance public understanding and awareness of the safety of 
human gene transfer research studies as well as the informed decision-
making of potential trial participants. The working group would

[[Page 77658]]

be composed of government and non-governmental experts in relevant 
clinical specialties; pediatric, adult, and geriatric medicine; 
relevant basic science disciplines such as genetics, virology, and 
immunology; biostatistics; bioethics; and patient advocacy. The working 
group would include liaison representation from the FDA. The working 
group would consist of approximately 15 members, at least two of whom 
would be RAC members, appointed by the NIH Director. The working group 
would meet quarterly or more frequently if needed.
    Patient safety is the utmost concern. NIH believes that the 
proposed changes will expand knowledge, advance the science and ethics 
of the field of human gene transfer research, and optimize NIH 
oversight of the field.

Proposed Amendments to the NIH Guidelines

    Although the NIH has received a considerable amount of valuable 
advice and a range of perspectives from the public and advisory groups, 
NIH wishes to provide another opportunity for public comment before 
finalizing these proposed amendments regarding serious adverse event 
reporting. The specific proposed amendments to the NIH Guidelines are 
as follows: (1) Change the requirements for expedited reporting of 
serious adverse events; (2) clarify that trade secret or other 
commercial confidential information should not be included in serious 
adverse event reports and that serious adverse event reports may not be 
classified as confidential information; (3) add a new section 
prohibiting individually identifiable patient information from being 
included in serious adverse event reports; and (4) establish a working 
group of the RAC, to be known as the NIH Gene Transfer Safety 
Assessment Board, to be responsible for the review and analysis of 
serious adverse events and other relevant safety information in gene 
transfer research studies and dissemination of safety information to 
the RAC, and, thereby, to the scientific and patient communities, and 
the public.
    A new Section I-E-8 is proposed to be added to read:
    ``Section I-E-8. A `serious adverse event' is any event 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, 
upon the basis of appropriate medical judgment, 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.''
    A new Section I-E-9 is proposed to be added to read:
    ``Section I-E-9. An adverse event is `associated with the use of a 
gene transfer product,' when there is a reasonable possibility that the 
event may have been caused by the use of that product.''
    A new Section I-E-10 is proposed to be added to read:
    ``Section I-E-10. An unexpected serious adverse event is any 
serious adverse event for which the specificity or severity is not 
consistent with the risk information currently available in the 
protocol.''
Section IV-B-7. Principal Investigator (PI) is modified to read:
Section IV-B-7. Principal Investigator (PI)
    On behalf of the institution, the Principal Investigator is 
responsible for full compliance with the NIH Guidelines in the conduct 
of recombinant DNA research. A Principal Investigator engaged in human 
gene transfer research may delegate to another party, such as a 
corporate sponsor, the reporting functions set forth in Appendix M, 
with written notification to NIH OBA of the delegation and of how the 
delegate may be contacted. The Principal Investigator is responsible 
for ensuring that the reporting requirements are fulfilled and will be 
held accountable for any reporting lapses.''
Current M-I-C-3, Annual Reporting, is proposed to be modified proposed 
to read in its entirety:
Appendix M-I-C-3, Annual Reports
    Within 60 days of the one-year anniversary of the date on which the 
clinical trial was initiated and of each subsequent anniversary until 
the trial is completed, the Principal Investigator (or delegate) shall 
submit a summary report of the progress of the investigation that 
includes:
    (a) Clinical Trial Information. A brief summary of the status of 
each trial in progress and each trial completed during the previous 
year. The summary is required to include the following information for 
each trial: (1) The title and purpose of the trial; (2) clinical 
protocol identifiers, including the NIH OBA protocol number, NIH grant 
number(s) (if applicable), and the FDA IND application number; (3) 
participant population; (4) the status of the trial; (5) the total 
number of participants planned for inclusion in the trial; the number 
entered into the trial to date; the number whose participation in the 
trial was completed; and the number who dropped out of the trial for 
any reason; and (6) if the trial has been completed, a brief 
description of any study results.
    (b) Progress Report and Data Analysis. Information obtained during 
the previous year's clinical and non-clinical investigations, 
including: (1) A narrative or tabular summary showing the most frequent 
and most serious adverse experiences by body system; (2) a summary of 
all serious adverse events submitted during the past year; (3) a 
summary of serious adverse events that are expected or considered to 
have causes not associated with the use of the gene transfer product 
such as disease progression or concurrent medications; (4) the number 
of participants who died during participation in the investigation and 
causes of death; (5) a brief description of any information obtained 
pertinent to an understanding of the gene transfer product's actions, 
including, for example, information about dose-response, information 
from controlled trials, and information about bioavailability.
    (c) A copy of the updated clinical protocol including a technical 
and non-technical abstract.
Current Appendix M-I-C-4, Serious Adverse Event Reporting is proposed 
to be modified in its entirety to read:
Appendix M-I-C-4, Safety Reporting
    Principal Investigators must submit, in accordance with this 
section, Appendix M-I-C-4-a and Appendix M-I-C-4-b, a written report 
on: (1) Any serious adverse event that is both unexpected and possibly 
associated with the use of the gene transfer product; and (2) any 
finding from tests in laboratory animals that suggests a significant 
risk for human research participants including reports of mutagenicity, 
teratogenicity, or carcinogenicity. The report must be clearly labeled 
as a ``Safety Report'' and must be submitted to the Office of 
Biotechnology Activities (OBA) and to the local Institutional Biosafety 
Committee within the timeframes set forth in Appendix M-I-C-4-b.
    Principal Investigators should adhere to any other serious adverse 
event reporting requirements in accordance with Federal regulations, 
state laws, and local institutional policies and procedures, as 
applicable.

[[Page 77659]]

    Principal Investigators may delegate to another party, such as a 
corporate sponsor, the reporting functions set forth in Appendix M, 
with written notification to NIH OBA of the delegation and of how the 
delegate may be contacted. The Principal Investigator is responsible 
for ensuring that the reporting requirements are fulfilled and will be 
held accountable for any reporting lapses.
    The three alternative mechanisms for reporting serious adverse 
events to OBA are: by e-mail to [email protected]; by fax to 301-496-9839; 
or by mail to the Office of Biotechnology Activities, National 
Institutes of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, 
Bethesda, Maryland 20892-7010.

Appendix M-I-C-4-a, Safety Reporting: Content and Format

    Reports of serious adverse events should follow the format provided 
in the Adverse Event Reporting Format available on NIH OBA's web site 
at: http://www.nih.gov/od/oba/. The serious adverse event report must 
include, but need not be limited to: (1) The date of the event; (2) 
designation of the report as an initial report or a follow-up report; 
(3) a complete description of the event; (4) relevant clinical 
observations; (5) relevant clinical history; (6) relevant tests that 
were or are planned to be conducted; (7) the suspected cause of the 
event; (8) gene delivery method; (9) vector type, e.g., adenovirus; 
(10) vector subtype, e.g., type 5, relevant deletions; (11) dosing 
schedule; (12) route of administration; (13) identification of all 
safety reports previously filed with the clinical protocol concerning a 
similar adverse event and an analysis of the significance of the 
adverse event in light of previous similar reports; (14) clinical site; 
(15) the principal investigator; (16) NIH Protocol number; and (17) 
FDA's Investigational New Drug (IND) Application number.
    Serious adverse event reports must not contain individually 
identifiable patient information.
    Reports from laboratory animal studies must be submitted in a 
narrative format.
    Unless NIH OBA determines that there are exceptional circumstances, 
all information submitted in accordance with Appendix M-I-C will be 
considered public. Safety reports submitted in accordance with Appendix 
M-I-C will not be considered to 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.

Appendix M-I-C-4-b, Safety Reporting: Time-Frames for Expedited 
Reports

    Any serious adverse event that is fatal or life-threatening, that 
is unexpected, and possibly associated with the use of the gene 
transfer product must be reported to NIH OBA as soon as possible, but 
not later than 7 calendar days after the sponsor's initial receipt of 
the information (i.e., at the same time the event must be reported to 
the FDA).
    Serious adverse events that are unexpected and possibly associated 
with the use of the gene transfer product, but are not fatal or life-
threatening, must be reported to NIH OBA as soon as possible, but not 
later than 15 calendar days after the sponsor's initial receipt of the 
information (i.e., at the same time the event must be reported to the 
FDA).
    If, after further evaluation, an adverse event initially considered 
not to be possibly associated with the use of the gene transfer product 
is subsequently determined to be possibly associated, then the event 
must be reported to NIH OBA within 15 days of the determination.
    Relevant additional clinical and laboratory data may become 
available following the initial serious adverse event report. Any 
follow-up information relevant to a serious adverse event must be 
reported within 15 calendar days of the sponsor's receipt of the 
information. If a serious adverse event occurs after the end of a 
clinical trial and is determined to be possibly associated with the use 
of the gene transfer product, that event shall be reported to NIH OBA 
within 15 calendar days of the determination.
    Any finding from tests in laboratory animals that suggests a 
significant risk for human research participants including reports of 
mutagenicity, teratogenicity, or carcinogenicity must be reported as 
soon as possible, but not later than 15 calendar days after the 
sponsor's initial receipt of the information (i.e., at the same time 
the event must be reported to the FDA).''
    A new Appendix M-I-D is proposed to be added:
Appendix M-I-D, Safety Assessment in Human Gene Transfer Research
    A standing working group of the RAC, the NIH Gene Transfer Safety 
Assessment Board, will: (1) Review serious adverse event reports, 
annual reports, and other relevant safety information made to OBA for 
the purpose of assessing toxicity and safety data across all gene 
transfer trials and analyzing the data for trends; (2) identify 
significant trends or single events; (3) develop information that will 
enhance the development, design, and conduct of human gene transfer 
clinical trials; and (4) report aggregated trend data to the RAC to 
enhance review of new protocols and to enhance public understanding and 
awareness of the safety of human gene transfer research studies as well 
as the informed decision-making of potential trial participants. The 
working group members are appointed by the NIH Director.''
    Current Appendix M-IV. Privacy and Confidentiality is proposed to 
be amended by the addition of the following sentence at the end of the 
section:
Current Appendix M-IV. Privacy and Confidentiality
    ``* * * These measures should protect the confidentiality of 
information that could indirectly enable identification of study 
participants, as well as information that would directly identify study 
participants.''
    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. 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: December 4, 2000.
Ruth L. Kirschstein,
Principal Deputy Director, National Institutes of Health.
[FR Doc. 00-31524 Filed 12-11-00; 8:45 am]
BILLING CODE 4140-01-P