[Federal Register: February 8, 2005 (Volume 70, Number 25)]
[Page 6693-6696]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



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.


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 
    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: 
    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.


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.  
    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.  

[[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).

    \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 

    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).

[[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 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 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 
    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

[[Page 6696]]

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 
    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.  

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]