[Federal Register Volume 66, Number 223 (Monday, November 19, 2001)]
[Notices]
[Pages 57970-57977]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-28774]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Office of Biotechnology Activities; Recombinant DNA Research: 
Actions Under the NIH Guidelines

AGENCY: National Institutes of Health (NIH), PHS, DHHS.

ACTION: Notice of actions under the NIH Guidelines for research 
involving recombinant DNA molecules (NIH Guidelines) and request for 
comment on the information collection provisions under the Paperwork 
Reduction Act of 1995.

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SUMMARY: The actions described in this Notice amend the NIH Guidelines 
to enhance oversight of human gene transfer research by modifying the 
requirements for the reporting and analysis of serious adverse events 
in human gene transfer research studies governed by the NIH Guidelines.
    The first action modifies the scope of serious adverse events that 
are reportable on an expedited basis. Expedited reporting will now be 
required for those serious adverse events that are unexpected and 
associated with the use of the gene transfer product (i.e., there is a 
reasonable possibility that the experience may have been caused by the 
gene transfer product). The change also provides timeframes for 
expedited reporting and definitions of serious, associated, and 
unexpected adverse events. Under the amendments, summary information 
about other adverse events would be included in annual reports. 
Principal Investigators with multiple studies may submit a single 
annual report, provided that data are attributed to discrete sites. The 
annual reporting requirements are set forth in Appendix M-I-C-3 and the 
safety reporting requirements are in Appendix M-I-C-4. Those two 
sections have been submitted for OMB approval under the Paperwork 
Reduction Act of 1995 and this notice provides 30 days for public 
comment on those information collection requirements. Following this 
comment period, OMB analysis of the comments, and approval of the 
requirements, NIH OBA will publish a notice setting forth the effective 
date of Appendices M-I-C-3 and M-I-C-4.
    The second action clarifies that, in accordance with applicable law 
and longstanding policy of the NIH Office of Biotechnology Activities 
(OBA), when information submitted in serious adverse event reports and 
annual reports is labeled trade secret or confidential commercial 
information, the NIH OBA will assess this claim and make a 
determination. If NIH OBA determines that the data so labeled are 
confidential commercial or trade secret and that their public 
disclosure would promote an understanding of key scientific or safety 
issues, the NIH OBA will seek agreement from the appropriate party to 
release such data.
    The third action adds specific language to the NIH Guidelines to 
prohibit the submission of individually-identifiable patient 
information in serious adverse event and annual reports.
    The fourth action 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 (GTSAB), that will play a role in 
the analysis of safety information in gene transfer research studies. 
The working group will report safety information to the RAC and, 
thereby, disseminate it to the scientific and patient communities, as 
well as the general public.
    In toto, these four changes will enhance the identification of 
significant safety issues across human gene transfer trials, increase 
public knowledge, and strengthen the protection of research 
participants in human gene transfer research studies. These changes are 
an important step toward harmonization of Federal safety reporting 
requirements. Additional efforts are underway within the Department of 
Health and Human Services to further enhance consistency in the 
collection of safety information and submission of safety reports, 
increase the quality of safety reports, and expedite review of critical 
safety information. NIH will continue to monitor and participate in 
these efforts, reevaluating and, as appropriate, changing the NIH 
Guidelines.

DATES: Comments on the information collection requirements in Appendix 
M-I-C-3 and Appendix M-I-C-4 must be submitted to the OMB at the 
address shown below by December 19, 2001. As information collection 
requirements, Appendix M-I-C-3 and Appendix M-I-C-4 will take effect 
upon OMB approval. All other provisions will take effect 30 days after 
November 19, 2001.

ADDRESSES: Comments should be sent to: Office of Information and 
Regulatory Affairs, Office of Management and Budget, New Executive 
Office Bldg., 725 17th Street, NW., Room 10235, Washington, DC 20503, 
Attn: Desk Officer for NIH.

FOR FURTHER INFORMATION: Background documentation and additional 
information can be obtained from the Office of Biotechnology 
Activities, National Institutes of Health, MSC 7985, 6705 Rockledge 
Drive, Suite 750, Bethesda, Maryland 20892, Phone 301-496-9838, FAX 
301-496-9839. The NIH OBA Web site is located at http://
www4.od.nih.gov/oba/

SUPPLEMENTARY INFORMATION:

I. Background

    This Action follows from a Proposed Action published in the 
December 12, 2000 Federal Register (65 FR 77655) and derives from an 
extensive process of deliberation and public consultation. It takes 
into account the reports of two specially convened NIH working groups 
as well as numerous written comments from the public on two separate 
proposals. The preponderant view emerging from this process supports 
the four main objectives of this Action, which are to: (1) Harmonize 
NIH requirements for expedited reporting of serious adverse events in 
gene transfer trials with those of FDA; (2) clarify how claims that 
annual and safety reports contain confidential commercial or trade 
secret information will be resolved, given the need for disclosure of 
information to ensure broad public knowledge of issues raised by gene 
transfer research; (3) maintain the privacy of individuals 
participating in gene transfer research; and (4) develop a new 
mechanism for the analysis and dissemination of adverse event 
information with the goal of enhancing knowledge about scientific and 
safety trends. The history leading up to each element of this Action is 
discussed below.

A. Scope and Timing of Serious Adverse Event Reports

    A major purpose of this Action is to harmonize NIH requirements for 
the reporting of serious adverse events with those of the FDA. This 
harmonization is expected to enhance compliance with the NIH 
Guidelines. Significant non-compliance with the NIH Guidelines became 
evident in 1999 following the death of a participant in a human gene 
transfer research study. Subsequent to this event, the NIH OBA called 
on investigators conducting these studies to submit to the Office 
comprehensive pre-

[[Page 57971]]

clinical and clinical data. In the course of gathering and assessing 
this data, the NIH OBA discovered that serious adverse events were not 
being reported as required by the NIH Guidelines. Concerted efforts 
were immediately initiated to enhance awareness of, and compliance 
with, the reporting requirements. To that end, NIH proposed that the 
NIH Guidelines be amended to make the requirements for reporting 
serious adverse events more explicit.
    The proposed amendments, adding specific definitions and timeframes 
for the expedited reporting of serious adverse events, were first 
published for public comment in the November 22, 1999, Federal Register 
(64 FR 63827). The proposal clarified existing NIH policy, which 
required that all serious adverse events occurring in conjunction with 
human gene transfer trials be reported immediately to the NIH OBA, the 
IBC, the IRB, and, if applicable, the Office for Human Research 
Protections. This requirement applied whether or not the event was 
expected or deemed to be associated with the gene transfer product. 
FDA, on the other hand, requires expedited reporting of only those 
serious adverse events that are unexpected and associated with the gene 
transfer product (i.e., there is a reasonable possibility that the 
experience may have been caused by the gene transfer product). Unlike 
the NIH requirement, the FDA rules (21 CFR 312.32) provide specific 
timeframes for reporting these events. Since most investigators are 
subject to both the NIH Guidelines and FDA regulations, and full 
compliance is essential to federal oversight of gene transfer research, 
greater uniformity is an important objective.
    The Advisory Committee to the Director, NIH (ACD) formed a working 
group in early December 1999 to review NIH's role in the oversight of 
human gene transfer studies, including serious adverse event reporting. 
The ACD working group recommended that the NIH and FDA work together to 
simplify, streamline, and harmonize reporting of serious adverse 
events. 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 adopted 
the recommendations of the working group at a publicly accessible 
teleconference.
    These ACD recommendations, RAC endorsement of the recommendations, 
and public commentary all culminated in the Proposed Action of December 
12, 2000. The proposal called for reporting unexpected serious adverse 
events possibly associated with the gene transfer product to the NIH 
OBA within 15 days after sponsor notification, or within 7 days if such 
an event were also fatal or life-threatening.

B. Analysis of Serious Adverse Events

    The ACD Working Group also re-affirmed the need for the NIH OBA to 
gather cumulative safety data on gene transfer trials. They noted that 
systematic analyses of adverse event data would improve the conduct and 
safety of such research by revealing trends related to, for example, 
specific diseases, routes of administration, or vectors.
    Public deliberations of the ACD and the RAC emphasized the 
importance of NIH's role in ensuring the safety of human gene transfer 
research studies. The NIH studies scientific and safety trends in gene 
transfer research and disseminates that information to investigators. 
This role in important ways complements the regulatory responsibility 
of the FDA, which includes assessing the overall safety of individual 
gene transfer products used in multiple trials and assessing the safety 
of broader classes of gene transfer products sharing related vectors. 
The NIH and FDA share the goal of developing a body of knowledge about 
the science and outcomes of this form of clinical investigation.
    In this regard, the ACD recommended creation of a standing expert 
body that would review all reports of adverse events, analyze the data 
for trends, develop a cumulative report that would 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. They suggested that this standing body 
should include basic scientists, clinicians, patient advocates, and 
ethicists, and that ad hoc members should be appointed to provide 
additional expertise on an as-needed basis.
    Thus, as part of the December 12, 2000 Federal Register notice, the 
NIH proposed the establishment of a new working group of the RAC, 
called the NIH Gene Transfer Safety Assessment Board (GTSAB). The 
GTSAB's specific functions were proposed to involve: (1) Reviewing in 
closed session serious adverse event reports, annual reports, and other 
relevant safety information and assessing toxicity and safety data 
across gene transfer trials and analyzing the data for trends; (2) 
identifying significant trends or single events; and (3) reporting 
aggregated data to the RAC. This Board is expected to enhance review of 
new protocols and public understanding and awareness of the safety of 
human gene transfer research studies as well as inform the decision-
making of potential trial participants.

C. Confidentiality of Adverse Event and Annual Reports and Patient 
Privacy

    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 the NIH 
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. 
This principle is accommodated in the NIH Guidelines. The concept that 
serious adverse events per se should be considered from a commercial 
standpoint as confidential, however, is contrary to NIH's longstanding 
commitment to public access to information about the safety of human 
gene transfer research. NIH has always sought to ensure public access 
to safety information and, in Appendix M-I-B-2, actively discourages 
the labeling of information submitted in accordance with Appendix M as 
confidential. In instances where data have been properly labeled as 
confidential commercial or trade secret, NIH has acknowledged that 
claim, in accordance with applicable law, and sought agreement for any 
proposed public disclosure of that data. Nonetheless, the NIH 
Guidelines were not explicit about the confidentiality of serious 
adverse event reports, and thus the 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 
concurred that adverse event data are essential to decision-making by 
IBCs, IRBs, and potential subjects of gene transfer research in humans. 
The RAC added that the public disclosure of adverse events is essential 
to public understanding and evaluation of gene transfer in humans.
    The December 12, 2000 proposal elaborated on existing language on 
this topic by stating that adverse event and annual reports would not 
be considered confidential commercial information. In this Action, this 
statement has been revised in accordance with existing law to provide 
for case-by-case resolution of claims that adverse event or annual 
reports contain confidential commercial

[[Page 57972]]

information. This statement has also been repositioned within Appendix 
M of the NIH Guidelines to enhance its salience and clarity.
    Finally, the proposal reinforced a longstanding tenet that in 
submitting adverse event reports, investigators should take measures to 
protect the privacy of patients and their families.

II. Summary

    The amendments that emerged from this extensive process of public 
deliberation were published for public comment in the December 12, 2000 
Federal Register. The specific changes proposed to the NIH Guidelines 
were 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 and annual reports and that those reports would not be 
classified by the NIH OBA 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. The deadline for public comment was February 10, 2001.

III. Public Comments

    A total of 28 comments were received on the proposal by the 
deadline, and another ten were received subsequently, for a total of 
38. These comments, in the form of letters and e-mails, reflected the 
views of patients, industry, academic officials, an ethicist, 
scientists, a law firm, and the public at large. All comments have been 
reviewed by NIH staff, as well as members of the RAC, who considered 
the substance and scope of public comments in open session on March 8, 
2001.

A. Overview of Comments

    All commenters supported the principle of harmonizing requirements 
with FDA. The majority of comments were supportive of the proposal as 
written and urged its adoption. These came from associations 
representing patients, an ethicist, academic officials responsible for 
biosafety and human subjects oversight, a law firm, and a number of 
individuals expressing no particular affiliation. A scientific society 
representing researchers working on gene transfer techniques also 
expressed support for the proposal, though it made a number of 
suggestions for modifying specific components.
    Opposition to the proposal was expressed by two industry trade 
associations, four companies, and two patient groups. These letters 
expressed a view that the NIH OBA and the RAC should not receive raw 
data on serious adverse events under any circumstances.
    Taken together, objections can be categorized under four thematic 
headings: (1) Concern about public dissemination of confidential 
commercial and trade secret information; (2) assertions that such 
reporting was a duplication of effort, given existing FDA reporting 
requirements; (3) objections to the perceived regulatory stance on the 
part of NIH; and (4) challenges to the scope of adverse events 
reportable in an expedited manner. These are discussed below.

B. Responses to Specific Comments

    Comment: The Proposed Action will cause inappropriate release to 
the public of confidential commercial and trade secret information. 
These comments suggested that many of the data items specified for 
inclusion in annual and serious adverse event reports had inherent 
commercial value, because they could conceivably allow others to infer 
information about the staging of the clinical trial, the 
bioavailability of the product, the dose response profile of the 
intervention, and other matters that would allow competitors to gain 
advantage in the design of their own trials.
    Response: It has been a longstanding and widely accepted tenet of 
the NIH's 25-year-old system of oversight of recombinant DNA research 
conducted at NIH-funded institutions that the public dissemination of 
safety data is key to protecting public health and assuring the public 
that problems are being identified and addressed in a timely way. The 
RAC has been receiving and publicly reviewing safety data in gene 
transfer studies for over a decade. The NIH OBA, in fact, has provided 
a suggested reporting format that industry has used for a number of 
years (which can be viewed at http://www4.od.nih.gov/oba/rac/SAEForm.rtf). 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.
    Since the current version of the NIH Guidelines is not explicit 
about the specific content of serious adverse event reports, the Action 
lists specific data elements that should be reported to the NIH OBA 
(found in proposed M-I-C-4-a). Before developing this list, NIH OBA 
staff asked the RAC to consider whether the NIH Guidelines should 
include such clarifications and be modified to make clear that these 
data would be publicly accessible. In response, the RAC issued in 
September 1999 the aforementioned consensus statement that expressed 
unambiguously that adverse event reports must not be designated as 
confidential, either in whole or in part, given their importance to 
decision-making by IBCs, IRBs, and potential research subjects. The 
Proposed Action elaborated on the RAC recommendation by providing that 
the NIH OBA would not consider adverse event and annual reports to be 
confidential commercial information.
    The NIH OBA uses this information to issue periodic scientific 
reports as well as analyses of safety data. When such information is 
labeled as confidential, the Action clarifies the NIH OBA policy for 
assessing, in accordance with applicable laws, whether the data are 
indeed confidential commercial information. In making this assessment, 
the NIH must carefully consider the views of the owner of the 
information on the competitive harm that could be caused by disclosure 
of the labeled information. As necessary, the NIH OBA will seek 
agreement from the appropriate party to release that information for 
the purposes of ensuring broad public knowledge of issues raised by 
gene transfer research. NIH will not publicly disclose information that 
it determines, under applicable law, to be confidential commercial 
without the agreement of the owner of that information. This policy is 
reflected in a new Appendix M-I-C-5 to clarify that it applies to any 
information submitted under Appendix M-I-C.
    Comment: It should suffice to send raw adverse event information to 
the FDA only under its investigational new drug (IND) application 
process; submission to the NIH OBA for analysis by the Gene Transfer 
Safety Assessment Board (GTSAB) represents an unnecessary burden and 
duplication of effort. These commenters expressed the view that FDA has 
the scientific expertise, experience, and mechanisms in place to 
monitor adverse events effectively and in real-time, and has the 
authority to take action as appropriate to protect research 
participants. They also valued the broad confidentiality protections 
that the FDA process offers,

[[Page 57973]]

which are not consistent with NIH OBA's mission of disseminating 
information to patients, scientists, and other members of the public. 
Some companies suggested that a system might be set up to allow FDA to 
aggregate, synthesize, and analyze the data before delivering a report 
to the RAC, which would then look at the gross-level safety trends. 
Several letters pointed to a concurrent proposal by the FDA (January 
18, 2001; 66 Federal Register 4688) to amend the biologics regulations 
to make available for public disclosure certain data and information 
related to human gene therapy and xenotransplantation. Given that FDA 
would be making similar kinds of information routinely available, these 
commenters questioned why the NIH should duplicate this role.
    Response: The GTSAB will have a purpose that is different, though 
complementary to that of the FDA and other review groups, such as data 
safety and monitoring boards (DSMBs). The FDA provides immediate 
responses to reports of safety problems in the context of specific 
trials. The FDA has the authority to put those trials on hold to allow 
a full assessment of risks, shield research participants from any 
potential harm, and preclude the exposure of potential participants to 
the risks of the trials. In addition, the FDA assesses the overall 
safety of individual gene transfer products used in multiple trials and 
assesses the safety of classes of gene transfer products such as 
products using similar vectors. DSMBs are usually used to review data 
from a single trial at regular intervals; trials using DSMBs are 
usually in Phase III. The GTSAB would meet quarterly and conduct macro 
and longitudinal analyses of data accumulated across gene transfer 
trials to address questions that will allow the field of gene transfer 
research to advance safely.
    The comprehensive public review of aggregated serious adverse event 
data by the RAC (through the GTSAB) has been endorsed by the ACD, the 
RAC, and members of the public as a critical component of the system of 
federal oversight of human gene transfer research. NIH and FDA will 
have a broad view of scientific and safety trends in gene transfer 
research and have the goal of advancement of knowledge in this area. 
The GTSAB will enhance the public dissemination of information about 
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. The GTSAB will augment the NIH's ability to perform 
this critical function, in accordance with the recommendations of the 
ACD and in keeping with the agency's responsibility to enhance the 
science, safety, and ethics of research conducted under the auspices of 
the NIH Guidelines. NIH and FDA will continue to work closely together 
in analyzing gene transfer adverse events and will involve the GTSAB as 
appropriate.
    FDA's information disclosure regulations limit that agency's 
ability to share confidential information regarding gene transfer 
research with the NIH for the purpose of public disclosure, just as 
they limit FDA's ability to make such information available directly to 
the public. Thus, under current FDA regulations, NIH OBA cannot rely on 
disclosures from the FDA to achieve the objective of public disclosure 
of the scientific and safety issues. As observed by some commenters, 
the FDA has a proposal pending to disclose publicly specific categories 
of data from human gene therapy and xenotransplantation trials. At such 
time as this proposal is implemented, NIH will reassess and may, as 
appropriate, change the processes and mechanisms for gathering safety 
information as outlined in this action. If any future changes in FDA 
regulations alter reporting requirements so that they are no longer 
harmonized with the NIH Guidelines, the NIH will modify the NIH 
Guidelines as appropriate.
    The RAC and a majority of public commenters favored the GTSAB, 
citing the unique role and purpose it will serve. For all of the above 
reasons, and because of the majority view expressed in public 
commentary, the GTSAB will be retained.
    Comment: In requiring annual reporting and collecting severe 
adverse event data, the NIH is acting in an inappropriately regulatory 
manner. This comment suggested that the NIH Guidelines have 
``mushroomed'' into an elaborate, burdensome set of rules, departing 
from their intended role as ``guidance.''
    Response: The applicability of the NIH Guidelines has remained 
relatively constant since their inception in 1976, and there has been 
little change in safety reporting requirements since the 1985 version, 
which first described reporting policies for human gene transfer 
activities. Thus, the notion that the NIH Guidelines have expanded into 
an elaborate set of regulations is unfounded. To the contrary, this 
Action harmonizes the NIH safety reporting requirements with those of 
the FDA and entails an approximately 90 percent reduction in events 
that investigators will have to report to the NIH OBA on an expedited 
basis. NIH is offering flexibility in how this requirement is met. The 
NIH OBA has historically accepted adverse event reports on the FDA 
MedWatch form to minimize the burden on investigators. Investigators 
may also choose to use the NIH reporting format, which is based on the 
MedWatch form with certain reporting items tailored to the context of 
gene transfer research. Under these amendments to the NIH Guidelines, 
both formats will continue to be acceptable reporting mechanisms, 
provided reports are complete with regard to the information specified 
under new M-I-C-4-a.
    In further harmonization with FDA, the NIH has modified the annual 
reporting requirement to allow investigators with multiple studies to 
submit a single annual report, provided that data are attributed to 
discrete sites. To facilitate compliance further, language has been 
added to explicitly allow the investigator to delegate the reporting 
task to the sponsor. The ultimate accountability for whether reporting 
occurs, however, rests with the investigator. Both changes reflect the 
fact that the NIH's oversight relationship is with institutions and 
investigators, as reflected historically in NIH Guidelines.
    While NIH is not a regulatory agency, it does place conditions upon 
the funds that it awards to institutions. One of those conditions is 
compliance with the NIH Guidelines (see 42 CFR 52.8). Thus, the NIH 
Guidelines apply directly to biotechnology companies only if they 
receive funding from the NIH for recombinant DNA research. Most 
biotechnology companies do not receive such funding. Biotechnology 
companies that are not direct recipients of NIH funding for recombinant 
DNA research may be affected by the NIH Guidelines, nonetheless. When a 
company conducts recombinant DNA research in collaboration with an 
institution that receives any NIH funding for recombinant DNA research, 
all recombinant DNA research conducted at or sponsored by that 
institution is subject to the NIH Guidelines. Thus, the industry-
sponsored recombinant DNA research conducted at that institution is 
subject to the reporting requirements addressed in this notice. In 
addition, a company may voluntarily choose to comply with the NIH 
Guidelines in accordance with Section IV-D, Voluntary Compliance. Many 
companies have chosen such voluntary compliance, including compliance 
with the safety reporting requirements.

[[Page 57974]]

    Comment: The scope of serious adverse events (related and 
unexpected) that would have to be reported on an expedited basis is too 
narrow. In support of this view, commenters expressed concern that the 
significance of serious adverse events might not be readily 
discernable, and thus all such events should be reportable on an 
expedited basis. Comments also expressed the viewpoint that sponsors 
and scientists may not be objective in making determinations of 
``relatedness'' or ``expectedness.''
    Response: The NIH OBA agrees that complete reporting of adverse 
event data is important. Events that may not seem to be of 
generalizable concern may have implications for the field that are not 
fully appreciated until they are aggregated and analyzed. Therefore, 
the NIH OBA will continue to collect summary information about other 
adverse events in annual reports to this office.
    It is important to note that the criteria of ``relatedness'' and 
``expectedness'' are harmonized with the reporting requirements of the 
FDA to enhance compliance with expedited reporting of serious adverse 
events. The goal of harmonization has been considered and supported 
vigorously by the RAC, the ACD, and a diverse and broad-based public 
constituency. To employ the broad scope of promptly reportable events 
that was suggested in some comments would be equivalent to retaining 
the current requirements and would run counter to the harmonization 
objective.
    Although this change will depend on investigators to make 
determinations of ``relatedness'' and ``expectedness,'' secondary 
oversight will occur through clinical monitoring plans that NIH and FDA 
require for clinical trials. Furthermore, it is anticipated that 
harmonization will enhance compliance with the expedited reporting of 
those events for which expedited reporting is likely to be of value 
and, overall, will improve the availability of safety and scientific 
information for analysis. Consequently, this Action retains the 
proposed scope of serious adverse events that are reportable on an 
expedited basis.

IV. RAC Discussion

    The Recombinant DNA Advisory Committee (RAC) received copies of all 
comment letters, as well as synopses of each letter, and an analysis of 
the commentary in the aggregate. At its March 8, 2001 meeting the RAC 
reviewed these materials and heard oral commentary by members of the 
public. The RAC deliberated extensively on the merits of these various 
arguments and perspectives, and each member individually summarized his 
or her stance on the proposal. RAC perspectives were overwhelmingly in 
favor of adopting the Proposed Action, as reflected by a vote of 12 in 
favor, none opposed, and one abstention.

V. Paperwork Reduction Act of 1995

    This Action contains information collections that are subject to 
review by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act (PRA) of 1995 (44 U.S.C. 3507(d)), and have been 
submitted for OMB approval as a modification of OMB Control No. 0925-
0001. A description of the information collection provisions and an 
estimate of the annual reporting burden are provided below.
    Title: Annual reporting.
    Description: The annual reporting provisions in Appendix M-I-C-3 
would clarify the specific information items that investigators would 
have to report to NIH OBA within 60 days after the one-year anniversary 
of the date on which the investigational new drug (IND) application was 
filed with the FDA, and after each subsequent anniversary until the 
trial is completed. Appendix M-I-C-3 reduces the reporting burden by 
providing that, when multiple studies are conducted under the single 
IND, the Principal Investigator (or delegate) may choose to submit a 
single annual report covering all studies, provided that each study is 
identified by its OBA protocol number. Table 1 depicts the estimated 
reporting burden of complying with this aspect of the proposal. The 
estimated burden has been calculated by multiplying the approximate 
number of open protocols presently (since there is one report per 
protocol) by the number of hours typically required to prepare each 
report.
    Description of Respondents: Investigators conducting human gene 
transfer research.

                                                     Table 1
----------------------------------------------------------------------------------------------------------------
                                     Total number of reports
    NIH guidelines for research      annually (based on one     Hours to prepare each
     involving recombinant DNA           report per open               report                  Total hours
             molecules                      protocol)
----------------------------------------------------------------------------------------------------------------
Appendix M-I-C-3..................                      200                         4                       800
----------------------------------------------------------------------------------------------------------------

    Title: Serious adverse event reporting.
    Description: Under Appendix M-I-C-4, expedited reporting will be 
required for those serious adverse events that are unexpected and 
associated with the use of the gene transfer product (i.e., there is a 
reasonable possibility that the experience may have been caused by the 
gene transfer product). Appendix M-I-C-4 provides that these reports 
must be made as soon as possible, but not later than 15 calendar days 
after the sponsor's initial receipt of the information, or 7 days if 
the event is fatal or life-threatening. Table 2 provides an estimate of 
the total reporting burden based on the number of reports NIH expects 
to receive (per past experience). The burden is calculated by 
estimating the number of event that will be reportable on an expedited 
basis (by culling events that fit this classification out of the total 
reports received by OBA) and multiplying them by the time it takes to 
fill out an FDA MedWatch form or the NIH OBA reporting format.
    Description of Respondents: Investigators conducting human gene 
transfer research.

                                                     Table 2
----------------------------------------------------------------------------------------------------------------
                                        Number of serious
    NIH guidelines for research      adverse events reported    Hours to prepare each
     involving recombinant DNA          annually that are             response                 Total hours
             molecules               unexpected and related
----------------------------------------------------------------------------------------------------------------
Appendix M-I-C-4..................                      120                         1                       120
----------------------------------------------------------------------------------------------------------------


[[Page 57975]]

    These information collection requirements are intended to reduce 
the burden of reporting important safety data to the NIH by harmonizing 
the reporting requirements with those of FDA, limiting data elements to 
those necessary for NIH to identify significant safety issues in human 
gene transfer trials, and providing a reasonable timeframe for 
submission of the reports.
    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995, the agency has submitted the information collection provisions 
of this Action to OMB for review. Interested persons are requested to 
send comments regarding information by December 19, 2001 to Office of 
Information and Regulatory Affairs, Office of Management and Budget, 
New Executive Office Bldg., 725 17th Street, NW., Room 10235, 
Washington, DC 20503, Attn: Desk Officer for NIH. Upon OMB approval, 
NIH OBA will publish a notice setting forth the effective date of these 
requirements.

Amendments to the NIH Guidelines

    Pursuant to the rationale expressed above and the recommendations 
of the NIH RAC, the ACD, and the majority of public commentary, the NIH 
Guidelines are amended as follows:

A New Section I-E-8 Is 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 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 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 available in the current 
investigator's brochure.''

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 the NIH OBA of the delegation and of the 
name(s), address, telephone, and fax numbers of the contact. 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 Modified in Its Entirety To Read

``Appendix M-I-C-3. Annual Reports
    Within 60 days after the one-year anniversary of the date on which 
the investigational new drug (IND) application was filed with the FDA, 
and after each subsequent anniversary until the trial is completed, the 
Principal Investigator (or delegate) shall submit the information set 
forth in (a), (b), and (c). When multiple studies are conducted under 
the single IND, the Principal Investigator (or delegate) may choose to 
submit a single annual report covering all studies, provided that each 
study is identified by its OBA protocol number.
    (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 site; 
(3) the Principal Investigator; (4) clinical protocol identifiers, 
including the NIH OBA protocol number, NIH grant number(s) (if 
applicable), and the FDA IND application number; (5) participant 
population (such as disease indication and general age group, e.g., 
adult or pediatric); (6) 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 with a brief description of the reasons; 
(7) the status of the trial, e.g., open to patient accrual, closed but 
data collection ongoing, or fully completed, and (8) 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 were expected or considered to 
have causes not associated with the use of the gene transfer product 
such as disease progression or concurrent medications; (4) if any 
deaths have occurred, the number of participants who died during 
participation in the investigation and causes of death; and (5) a brief 
description of any information obtained that is 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 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 
associated with the use of the gene transfer product (i.e., there is 
reasonable possibility that the event may have been caused by the use 
of the product; investigators should not await definitive proof of 
association before reporting such events); 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 NIH Office of 
Biotechnology Activities (NIH 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.
    Principal Investigators may delegate to another party, such as a 
corporate sponsor, the reporting functions set forth in Appendix M, 
with written

[[Page 57976]]

notification to the NIH OBA of the delegation and of the name(s), 
address, telephone and fax numbers of the contact(s). 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 the NIH 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 7985, 6705 Rockledge Drive, Suite 
750, Bethesda, Maryland 20892.
Appendix M-I-C-4-a. Safety Reporting: Content and Format
    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, identification of all safety 
reports previously filed for the clinical protocol concerning a similar 
adverse event, and an analysis of the significance of the adverse event 
in light of previous similar reports; (3) clinical site; (4) the 
Principal Investigator; (5) NIH Protocol number; (6) FDA's 
Investigational New Drug (IND) Application number; (7) vector type , 
e.g., adenovirus; (8) vector subtype, e.g., type 5, relevant deletions; 
(9) gene delivery method, e.g., in vivo, ex vivo transduction; (10) 
route of administration, e.g., intratumoral, intravenous; (11) dosing 
schedule; (12) a complete description of the event; (13) relevant 
clinical observations; (14) relevant clinical history; (15) relevant 
tests that were or are planned to be conducted; (16) date of any 
treatment of the event; and (17) the suspected cause of the event. 
These items may be reported by using the recommended Adverse Event 
Reporting Format available on NIH OBA's web site at: http://www4.od.nih.gov/oba/, the FDA MedWatch forms, or other means provided 
that all of the above elements are specifically included.
    Reports from laboratory animal studies as delineated in Appendix M-
I-C-4 must be submitted in a narrative format.
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 associated with the use of the gene transfer product 
must be reported to the 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 associated with the 
use of the gene transfer product, but are not fatal or life-
threatening, must be reported to the 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).
    Changes in this schedule are permitted only where, under the FDA 
IND regulations [21 CFR 312(c)(3)], changes in this reporting schedule 
have been approved by the FDA and are reflected in the protocol.
    If, after further evaluation, an adverse event initially considered 
not to be associated with the use of the gene transfer product is 
subsequently determined to be associated, then the event must be 
reported to the 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 associated with the use of the 
gene transfer product, that event shall be reported to the 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-C-5 Is Added To Read

``Appendix M-I-C-5. Confidentiality
    Data submitted in accordance with Appendix M-I-C that are claimed 
to be confidential commercial or trade secret information must be 
clearly labeled as such. Prior to making its determination about the 
confidentiality of data labeled confidential commercial or trade 
secret, the NIH will contact the Principal Investigator or delegate to 
ascertain the basis for the claim and subsequently will notify the 
Principal Investigator or delegate of its final determination regarding 
the claim.
    If NIH determines that the data so labeled are confidential 
commercial or trade secret and that their public disclosure would 
promote an understanding of key scientific or safety issues, the NIH 
will seek agreement from the appropriate party to release such data. 
Public discussion of scientific and safety issues raised by data 
submitted in accordance with Appendix M-I-C is vital to informing both 
investigators and patients about the safety of gene transfer research.
    To protect the privacy of participants in gene transfer research, 
any serious adverse event or annual reports submitted to NIH OBA must 
not contain individually identifiable patient information.''

A New Appendix M-I-D Is Added To Read

    Appendix M-I-D. Safety Assessment in Human Gene Transfer Research
    A working group of the RAC, the NIH Gene Transfer Safety Assessment 
Board, with staff support from the NIH OBA, will: (1) Review in closed 
session as appropriate safety information from gene transfer trials for 
the purpose of assessing toxicity and safety data across gene transfer 
trials; (2) identify significant trends or significant single events; 
and (3) report significant findings and aggregated trend data to the 
RAC. It is expected that this process will enhance review of new 
protocols, improve the development, design, and conduct of human gene 
transfer trials, promote public understanding and awareness of the 
safety of human gene transfer research studies, and inform the 
decision-making of potential trial participants.''

Current Appendix M-IV. Privacy and Confidentiality Is Modified To Read

``Appendix M-IV. Privacy
    Indicate what measures will be taken to protect the privacy of 
patients and their families as well as maintain the confidentiality of 
research data. These measures should help protect the confidentiality 
of information that could directly or indirectly 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

[[Page 57977]]

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: October 19, 2001.
Ruth L. Kirschstein,
Acting Director, National Institutes of Health.
[FR Doc. 01-28774 Filed 11-16-01; 8:45 am]
BILLING CODE 4140-01-P