[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