[Federal Register: February 8, 2005 (Volume 70, Number 25)]
[Notices]
[Page 6693-6696]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08fe05-73]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005N-0038]
Reporting of Adverse Events to Institutional Review Boards;
Public Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public hearing; request for comment.
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SUMMARY: The Food and Drug Administration (FDA) is announcing a public
hearing to consider the process by which institutional review boards
(IRBs) obtain and review information on adverse events that occur
during the conduct of clinical investigations. FDA is increasingly
aware of concerns within the IRB community that the process is
burdensome, inefficient, and not as effective as it should be in
providing IRBs the information they need to ensure that the rights and
welfare of human subjects are protected during the course of a clinical
study. The purpose of the hearing is to solicit information and views
from interested persons on issues and concerns regarding the submission
of adverse events to and their review by IRBs. FDA is seeking general
information about the nature of the problem and possible solutions,
responses to specific questions (see section III of this document), and
any other pertinent information stakeholders would like to share.
Date and Time: The public hearing will be held on March 21, 2005,
from 9 a.m. to 5 p.m. Submit written or electronic notices of
participation by 4:30 p.m. on March 4, 2005. Submit written and
electronic comments by April 21, 2005.
Location: The public hearing will be held at the Advisors and
Consultants Staff Conference Room, 5630 Fishers Lane, Rockville, MD
20857.
Addresses: Written or electronic notices of participation should be
submitted to the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852,
e-mail: FDADockets@oc.fda.gov; or on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.accessdata.fda.gov/scripts/oc/dockets/meetings/meetingdocket.cfm.
Written or electronic comments should be submitted to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.accessdata.fda.gov/scripts/oc/dockets/commentdocket.cfm
or to the
Division of Dockets Management (see Addresses above).
Contacts: Nancy L. Stanisic, Center for Drug Evaluation and
Research (HFD-1), Food and Drug Administration, 5600 Fishers Lane, rm.
9-64, Rockville, MD 20857, 301-827-1660, FAX: 301-443-9718, e-mail:
stanisicn@cder.fda.gov.
For Registration and/or to participate in the meeting: Because of
limited seating, we recommend that persons interested in attending the
meeting register at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.accessdata.fda.gov/scripts/oc/dockets/meetings/meetingdocket.cfm.
Registration will be accepted on a first-
come, first-served basis.
The procedures governing the hearing are found in part 15 (21 CFR
part 15). If you wish to make an oral presentation during the open
public comment period of the hearing, you must state your intention on
your registration form (see Addresses). To participate, submit your
name, title, business affiliation, address, telephone, fax number, and
e-mail address. You should also submit a written statement at the time
of registration for each discussion question you wish to address, the
names and addresses of all individuals that plan to participate, and
the approximate time requested to make your presentation. Individuals
who have registered to make an oral presentation will be notified of
the scheduled time for their presentation prior to the hearing.
Depending on the number of presentations, FDA may need to limit the
time allotted for each presentation. Presentations will be limited to
the questions and subject matter identified in section III of this
document. Presenters should submit two copies of each presentation
given. All participants are encouraged to attend the entire day.
If you need special accommodations due to a disability, please
inform the registration contact person when you register.
SUPPLEMENTARY INFORMATION:
I. Background
Clinical investigations regulated by FDA under sections 505(i)
(drugs and biologics) and 520(g) (medical devices) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355(i) and 360j(g)) must be reviewed
and approved by an IRB in a manner consistent with the requirements of
21 CFR part 50 and part 56 (21 CFR part 56). To approve a proposed
clinical investigation, IRBs must determine, among other things, that
the risks to subjects are minimized; the risks are reasonable in
relation to anticipated benefits (if any); the selection of subjects is
equitable; and the informed consent process is adequate for the
anticipated study population and appropriately documented (see Sec.
56.111).
After their initial review and approval of a clinical study, IRBs
are required to conduct continuing review of the study at intervals
appropriate to the degree of risk presented by a study (at least
annually) (Sec. 56.109(f)). IRBs are required to follow written
procedures for continuing review of research and for determining which
studies require review more often than annually (Sec. 56.108(a)), and
must maintain records of continuing review activities (Sec.
56.115(a)(3)).
[[Page 6694]]
Under existing regulations for drugs and biologics, investigators
are required to promptly report to an IRB all unanticipated problems
involving risk to human subjects or others (Sec. 312.66 (21 CFR
312.66)). Under this reporting requirement, IRBs receive many reports
of adverse events from clinical investigators. Under existing
regulations for medical devices, IRBs receive information about
unanticipated adverse device effects from investigators and sponsors.
Investigators are required to submit to the IRB and the sponsor a
report of any unanticipated adverse device effect occurring during an
investigation as soon as possible, and in no event later than 10 days
after the investigator learns of the effect (Sec. 812.150(a)(1) (21
CFR 812.150(a)(1))), and sponsors are required to report the results of
an evaluation of a reported effect to reviewing IRBs and investigators
within 10 working days after the sponsor receives notice of the effect
(Sec. 812.50(b)(1)). In addition, IRBs are required to follow written
procedures to ensure that there is prompt reporting to the IRB,
appropriate institutional officials, and FDA of any unanticipated
problems involving risks to human subjects or others (Sec. 56.108(b)).
The regulations describing IRB responsibilities in part 56 and the
regulations describing sponsor and investigator responsibilities in
parts 312 and 812, were implemented at a time when most clinical
studies were conducted at a single site or a small number of sites. In
the intervening years, the number of multicenter studies has grown
substantially. There are many more studies with very large numbers of
study sites, including trials with both foreign and domestic sites. FDA
is increasingly aware of significant concerns and confusion within the
IRB community about the way IRBs obtain and review adverse event
information during the course of a clinical study, particularly in the
context of a large multicenter study.
A. Volume of Adverse Event Reports
The rapid growth in the number of clinical research programs in
recent years has led to a situation in which many IRBs receive large
volumes of information, including a multitude of individual adverse
event reports. In a recent letter, the Department of Health and Human
Services Secretary's Advisory Committee on Human Research Protections
(SACHRP letter) noted that some institutions are receiving in excess of
12,000 adverse event reports per year.\1\ The clinical significance and
relevance of reported events can vary considerably. FDA is aware that
IRBs receive reports of events that range from serious to relatively
minor, and that in some cases both anticipated and unanticipated events
are reported. FDA is also aware that IRBs receive adverse event reports
from other studies using the same drug, but not necessarily under the
same conditions (e.g., different doses, durations of therapy, diseases,
or subpopulations).
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\1\July 8, 2004, letter from Ernest D. Prentice, Chair of SACHRP
to The Honorable Tommy Thompson, Secretary of Health and Human
Services concerning SACHRP recommendations to improve human research
protections.
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The prevalence of large, multicenter trials further contributes to
the volume of adverse event reports to IRBs. Sponsors of investigations
of drugs and biological products are required to notify all
participating investigators of any adverse experience associated with
the use of a drug that is both serious and unexpected and any finding
from tests in laboratory animals that suggests a significant risk for
human subjects (Sec. 312.32(c)(1)). Investigators typically forward
copies of such reports to their IRBs, and also forward additional
sponsor reports that do not meet these criteria. Thus an IRB for a
single study site commonly receives reports of adverse events and other
information from all study sites.
B. Quality of Adverse Events Information
Another significant concern is that individual adverse event
reports submitted to IRBs are often not sufficiently informative to
permit IRBs to assess the implications of reported events for study
subjects. The SACHRP letter concluded that adverse event reports
``seldom contain adequate information.''
Considerable variation exists among reports in the amount of detail
and quality of information provided. For example, in blinded studies,
reports might not disclose the treatment the subject received (i.e.,
whether the subject received the study drug, an active control, or
placebo). In addition, it may be difficult for IRBs to review and
interpret the significance of large volumes of individual adverse event
reports received in isolation (unaggregated and unanalyzed) at sporadic
intervals over the course of study.
II. Purpose and Scope of the Hearing
This hearing is intended to provide the IRB community, sponsors,
investigators, data monitoring committees, individuals who have
participated in clinical studies, and other interested parties an
opportunity to discuss their experiences and concerns about the process
by which IRBs obtain and review information about adverse events, and
to share their ideas about how the process might be improved to best
meet the purposes of IRB review--to protect human subjects. FDA is not
seeking comment on how to interpret the existing regulations in parts
56, 312, and 812 requiring the reporting of ``unanticipated problems
involving risk to human subjects or others'' at this time. Instead,
given the role of IRB's, FDA is asking what information about adverse
events is necessary or useful for IRBs to consider in how to best
protect human subjects, and is asking what the best process is for
submitting such information. FDA hopes to obtain information that will
help it develop strategies, such as guidance or a change to the
regulations, to address the identified concerns.
III. Issues for Discussion
FDA is interested in hearing about the experiences of IRBs,
investigators, sponsors, data monitoring committee, individuals who
have participated in clinical studies, and other affected parties
concerning the reporting of adverse events to IRBs and how IRBs
evaluate such reports.
In the conduct of a clinical trial, the following parties have
responsibilities related to identifying, evaluating, reporting, and
analyzing adverse events:
Clinical investigators
Clinical investigators have the responsibility of identifying
adverse events associated with a drug, biologic, or device, evaluating
and documenting the occurrence of such events, and making required
safety reports. For drug and biologics trials, the investigator must
report to the sponsor any adverse effect that may reasonably be
regarded as caused by, or probably caused by, a drug (Sec. 312.64(b))
or biologic. The investigator must also report to the IRB all
unanticipated problems involving risk to human subjects (Sec. 312.66).
In a multicenter trial, the investigator at a site may also serve as a
conduit to the site IRB for reports of serious, unexpected adverse
events occurring at other study sites because he or she received
reports of such events from the sponsor (Sec. 312.32(c)). For medical
device trials, the investigator must report to the sponsor and
reviewing IRB any unanticipated adverse device effects occurring during
an investigation Sec. 812.150(b)(1).
Sponsors
[[Page 6695]]
Trial or study sponsors are required to monitor their trials and
provide required safety reports (Sec. 312.32). Sponsors of drug or
biologics trials must report to FDA and clinical investigators any
adverse experience associated with the use of the drug that is both
serious and unexpected or any finding from tests in laboratory animals
that suggests a significant risk for human subjects (Sec. 312.32).
Sponsors are also required to submit to FDA annual reports, a component
of which contains summary information about adverse events (Sec.
312.33). Sponsors of medical device trials are required to report the
results of evaluations unanticipated adverse device effects to FDA and
all reviewing IRBs (Sec. 812.150(b)(1)).
FDA
FDA reviews safety reports, and annual reports of adverse events to
determine whether there is new information that affects its original
evaluation of the reasonableness of the risk to study subjects.
Data Monitoring Committee (DMC)
In large phase 3 trials, there may also be a DMC (sometimes
referred to as a data and safety monitoring board or DSMB) that
conducts periodic review of accumulating data from an ongoing trial to
assess whether the study continues to be safe and scientifically valid.
DMCs report their analyses to the sponsor or an independent steering
committee set up by the sponsor.
IRBs
IRBs are responsible for performing a continuing review of ongoing
research at appropriate intervals (at least annually) (Sec.
56.109(f)). IRBs must have written procedures to ensure prompt
reporting to the IRB, appropriate institutional officials, and FDA of
any unanticipated problems involving risk to human subjects or others
(Sec. 56.108(b)).
FDA would like to understand better how the IRB's responsibility
with respect to adverse events fits with the roles of these other
parties and how the process for reporting adverse events to IRBs can be
improved to better enable IRBs to meet their obligation to protect the
rights and welfare of human subjects. FDA would like interested parties
to address the following issues and questions:
1. The role of IRBs in the review of adverse event information from
ongoing clinical trials.
Given the number of parties with responsibilities related to
adverse events that occur during the course of a clinical trial, what
role should IRBs play in the review of adverse events information from
an ongoing clinical trial? How does that role differ from the current
role of IRBs? Should IRB responsibilities for multi-site trials differ
from those for single-site trials? If so, how should they differ?
2. The types of adverse events about which IRBs should receive
information.
Based on your view of the role of IRBs in the review of adverse
event information from ongoing clinical trials, what types of adverse
events should an IRB receive information about, and what types of
information need not be provided to IRBs? For example, should IRBs
generally receive information only about adverse events that are both
serious and unexpected? Are there circumstances under which IRBs should
receive information about adverse events that are not both serious and
unexpected (e.g., if the information would provide a basis for changing
the protocol, informed consent, or investigator's brochure)? In a
multicenter study, should the criteria for reporting adverse events to
an IRB differ, depending on whether the adverse events occur at the
IRB's site or at another site?
3. Approaches to providing adverse events information to IRBs.
There seems to be a general consensus in the IRB community that
adverse event reports submitted individually and sporadically
throughout the course of a study without any type of interpretation are
ordinarily not informative to permit IRBs to assess the implications of
reported events for study subjects (see, e.g., the SACHRP letter, NIH
Regulatory Burden v. Human Subjects Protection--Workgroups Report,
available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://grants2.nih.gov/grants/policy/regulatoryburden/humansubjectsprotection.htm
, which states that data that are neither
aggregated nor interpreted do ``not provide useful information to allow
the IRB to make an informed judgment on the appropriate action to be
taken, if any.''). What can be done to provide IRBs adverse event
information that will enable them to better assess the implications of
reported events for study subjects? For example, if prior to submission
to an IRB, adverse event reports were consolidated or aggregated and
the information analyzed and/or summarized, would that improve an IRB's
ability to make useful determinations based on the adverse event
information it receives? If so, what kinds of information should be
included in consolidated reports? And when should consolidated reports
be provided to IRBs (e.g., at specified intervals, only when there is a
change to the protocol, informed consent, or investigator's brochure
due to adverse events experience)? Who should provide such reports?
Should the approach to providing IRB's adverse event reports be the
same for drugs and devices?
IV. Notice of Hearing Under Part 15
The Commissioner of FDA is announcing that the public hearing will
be held in accordance with part 15. The hearing will have a presiding
officer, who will be accompanied by senior management from the Center
for Biologics Evaluation and Research, the Center for Drug Evaluation
and Research, the Center for Devices and Radiological Health, and the
agency's Good Clinical Practice Program.
Persons who wish to participate in the part 15 hearing must file a
written or electronic notice of participation with the Division of
Dockets Management (see Addresses). To ensure timely handling, any
outer envelope should be clearly marked with the docket number listed
in brackets in the heading of this document along with the statement
``IRB-Adverse Event Reporting.'' Groups should submit two written
copies. The notice of participation should contain the person's name,
address, telephone number, affiliation, if any; the sponsor of the
presentation (e.g., the organization paying travel expenses or fees),
if any; a brief summary of the presentation (including the specific
discussion questions that will be addressed); and the approximate
amount of time requested for the presentation. The agency requests that
interested persons and groups having similar interests consolidate
their comments and present them through a single representative. After
reviewing the notices of participation and accompanying information,
FDA will schedule each appearance and notify each participant by
telephone of the time allotted to the person and the approximate time
the person's oral presentation is scheduled to begin. If time permits,
FDA may allow interested persons attending the hearing who did not
submit a written or electronic notice of participation in advance to
make an oral presentation at the conclusion of the hearing. The hearing
schedule will be available at the hearing. After the hearing, the
hearing schedule will be placed on file in the Division of Dockets
Management under the docket number listed in brackets in the heading of
this document.
Under Sec. 15.30(f), the hearing is informal, and the rules of
evidence do not apply. No participant may interrupt the presentation of
another participant. Only the presiding officer and panel members may
question any person
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during or at the conclusion of each presentation.
Public hearings under part 15 are subject to FDA's policy and
procedures for electronic media coverage of FDA's public administrative
proceedings (part 10, subpart C (21 CFR part 10, subpart C)). Under
Sec. 10.205, representatives of the electronic media may be permitted,
subject to certain limitations, to videotape, film, or otherwise record
FDA's public administrative proceedings, including presentations by
participants.
Any persons requiring special accommodations to attend the hearing
should contact Nancy L. Stanisic (see Contacts).
To the extent that the conditions for the hearing, as described in
this notice, conflict with any provisions set out in part 15, this
notice acts as a waiver of those provisions as specified in Sec.
15.30(h).
V. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see Addresses) written or electronic notices of participation and
comments for consideration at the hearing. To permit time for all
interested persons to submit data, information, or views on this
subject, the administrative record of the hearing will remain open
following the hearing. Persons who wish to provide additional materials
for consideration should file these materials with the Division of
Dockets Management. You should annotate and organize your comments to
identify the specific questions to which they refer (see section III of
this document). Two copies of any mailed comments are to be submitted,
except that individuals may submit one copy. Comments are to be
identified with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.
Transcripts of the hearing also will be available for review at the
Division of Dockets Management.
VI. Transcripts
The hearing will be transcribed as stipulated in Sec. 15.30(b).
The transcript of the hearing will be available 30 days after the
hearing on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets, and orders
for copies of the transcript can be placed at the meeting or through
the Freedom of Information Staff (HFI-35), Food and Drug
Administration, 5600 Fishers Lane, rm. 12A-16, Rockville, MD 20857, at
a cost of 10 cents per page.
Dated: February 2, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-2300 Filed 2-7-05; 8:45 am]
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