Human Research Protection Program: Policy
Unanticipated Problems
Adopted By: All Campus IRB
Revised: April 10, 2008
Revised: December 4, 2008
Revised: September 10, 2009
Purpose: Under DHHS and FDA regulations,
“unanticipated problems involving risks to subjects or others” must
be promptly reported to the IRB, institutional officials and relevant federal
agencies and departments. This document describes how the UW-Madison complies
with these reporting requirements.
Policy
I. Investigators must notify the
UW-Madison IRBs “promptly,” as defined in Section IV.A of this
Policy, of any unanticipated problems involving risks to participants or others
occurring in their research.
§
In multi-center trials, an unanticipated problem involving risks
to participants or others occurring at a non-UW-Madison research site must be
reported to the UW-Madison IRB only if the unanticipated problem poses risks to
UW-Madison participants.
II. An “unanticipated problem
involving risks to participants or others” is an event that is
unanticipated and reasonably related to the research. Both factors must be
present for an event to be considered an unanticipated problem.
A. An “unanticipated” event is one that was not described in
the protocol, Investigator’s Brochure or informed consent document. An
event is also “unanticipated” if the event exceeds the specificity,
severity, or frequency described in the protocol or the Investigator’s
Brochure.
B. An event is “reasonably related to the research” if it is
more likely than not to be caused by the research procedures.
III. Investigators must
“promptly,” as defined in Section V of this Policy, report the
following events to the IRB if the events occur within 30 days of
participants’ active participation or treatment:
A. An accidental or unintentional change to the IRB approved protocol that
placed one or more participants at increased risk, or has the potential to
occur again.
B. A change to the protocol made without prior IRB review to eliminate an
apparent immediate hazard to a research participant.
C. Data safety monitoring board report or interim findings that alters the
risks, including severity or frequency, to participants.
D. Receipt of new safety information (such as from an Action Letter or
journal article) that alters the risks, including severity or frequency, to
participants.
E. Publication in the literature that indicates an unexpected change to
the risks, including severity or frequency, to participants.
F. A complaint of a participant that indicates unexpected risks or that
cannot be resolved by the research team.
H. Incarceration of a participant in the course of a study.
G. Inadvertent breach of a participant’s confidentiality or privacy
(e.g., theft or loss of identifiable subject data) that involves risk to that
participant or others.
I. Premature completion of a study.
J. Adverse events in FDA-regulated studies that are also unanticipated
problems under the UW-Madison Unanticipated Problem Policy, Section IV.
K. Any other unanticipated event reasonably related to the research that
poses risks to participant or others or alters the risks, including severity or
frequency, to participants (e.g., medication overdose).
IV. Events that are Reportable as Unanticipated Problems in FDA-regulated
studies (in addition to those events listed in Section III, above).
A. In general, an adverse event observed during the conduct of a study
should be considered an unanticipated problem involving risk to human subjects,
and reported to the IRB, only if it were unexpected, serious, and
would have implications for the conduct of the study (e.g., requiring a
significant, and usually safety-related, change in the protocol such as
revising inclusion/exclusion criteria or including a new monitoring requirement,
informed consent, or investigator’s brochure). An individual adverse
event occurrence ordinarily does not meet these criteria because,
as an isolated event, its implications for the study cannot be understood.
B. Many types of adverse events generally require an evaluation of their
relevance and significance to the study, including an aggregate analysis of
other occurrences of the same (or similar) event, before they can be determined
to be an unanticipated problem involving risk to human subjects. For example,
an aggregate analysis of a series of adverse events that are commonly
associated with the underlying disease process that the study intervention is
intended to treat (e.g., deaths in a cancer trial), or that are otherwise
common in the study population independent of drug exposure (e.g.,
cardiovascular events in an elderly population) may reveal that the event rate
is higher in the drug treatment group compared to the control arm. In this
case, the adverse event would be considered an unanticipated problem. In the
absence of such a finding, the event is uninterpretable.
C. In FDA clinical trials, all reports to the IRB of unanticipated
problems should explain clearly why the event described represents a
“problem” for the study and why it is “unanticipated.”
D. The following adverse drug experiences (or events) should be reported
promptly to the IRB as “unanticipated problems”:
1. A single occurrence of a serious, unexpected event that is uncommon
and strongly associated with drug exposure (such as angiodema, agranulocytosis,
hepatic injury, or Stevens-Johnson syndrome).
2. A single occurrence, or more often a small number of occurrences, of
a serious, unexpected event that is not commonly associated with drug exposure,
but uncommon in the study population (e.g., tendon rupture, progressive
multifocal leukoencephalopathy).
3. Multiple occurrences of an adverse event that, based on an aggregate
analysis, is determined to be an unanticipated problem. There should be a
determination that the series of adverse events represents a signal that the adverse
events were not just isolated occurrences and involve risk to human subjects
(e.g., a comparison of rates across treatment groups reveals higher rate in the
drug treatment arm versus a control). We recommend that a summary and analyses
supporting the determination accompany the report.
4. An adverse event that is described or addressed in the
investigator’s brochure, protocol, or informed consent documents, but
occurs at a specificity or severity that is inconsistent with prior
observations. For example, if transaminase elevation is listed in the
investigator’s brochure and hepatic necrosis is observed in study
subjects, hepatic necrosis would be considered an unanticipated problem
involving risk to human subjects. We recommend that a discussion of the
divergence from the expected specificity or severity accompany the report.
5. A serious adverse event that is described or addressed in the
investigator’s brochure, protocol, or informed consent documents, but for
which the rate of occurrence in the study represents a clinically significant
increase in the expected rate of occurrence (ordinarily, reporting would only
be triggered if there were a credible baseline rate for comparison). We
recommend that a discussion of the divergence from the expected rate accompany
the report.
6. Any other adverse event or safety finding (e.g., based on animal or
epidemiologic data) that would cause the sponsor to modify the
investigator’s brochure, study protocol, or informed consent documents,
or would prompt other action by the IRB to ensure the protection of human
subjects. We recommend that an explanation of the conclusion accompany the
report.
E. A change in FDA labeling or withdrawal from marketing of a drug,
device, or biologic used in a research protocol.
F. Any unanticipated adverse device effect occurring during the
investigation. [21 CFR 812.150(a)]
V. Timing of Reporting
A. “Promptly,” for purposes of Sections I, III and IV of this
policy, means:
1. Investigators must report an event listed above (“possible
unanticipated problem”) to the IRB within 48 hours of receiving notice of
the event, if the event requires immediate intervention to prevent serious harm
to participants or others.
2. Investigators must report all other possible unanticipated problems
occurring at UW-Madison research sites and non-UW-Madison research sites to the
IRB as soon as possible but no later than fourteen (14) business days from the
date of the event or from the date the investigator is notified of the event by
using the Unanticipated Problem Report Form.
3. In FDA trials involving an investigational device, any unanticipated
adverse device effect occurring during the investigation must be reported to
the IRB within ten (10) working days after the investigator receives notice of
the event. [21 CFR 812.150(a)(1)]
VI. Submission of Reports
A. Where reports are to be made.
Initial reports of possible
unanticipated problems should be made to the Office of the IRB that has been
involved in reviewing the research protocol or exemption. Unanticipated
Problem Report Form.
B. Reporting obligations of investigators and research study staff.
Investigators or study staff must
report possible unanticipated problems to the IRB Office. The investigator
should contact the IRB Office by phone or email. The IRB Office will instruct
the person making the report to submit the report in writing using the Unanticipated
Problem Report Form. The written report should contain the following:
1. Detailed information about the possible unanticipated problems,
including relevant dates.
2. Any corrective action, planned or already taken, to ensure that the
possible unanticipated problems is corrected and will not occur again.
3. An assessment of whether any subjects or others were placed at risk
as a result of the event or suffered any physical, social, or psychological
harm and any plan to address these consequences.
4. Any other relevant information.
5. Any other information requested by the IRB Office.
C. Others who may identify and report possible unanticipated problems.
Others who may report possible
unanticipated problems include IRB members or staff (such as when discovery is
made during a protocol review); subjects or potential subjects or others, such
as family members; members of staff of another IRB; patient relations offices
at University of Wisconsin Hospital and Clinics, University of Wisconsin
Medical Foundation, or the VA; sponsors and other auditors; and others not
involved with the research project but having information about a possible
unanticipated problem.
The report can be made to the IRB
Office by phone or email. The report may be made anonymously. The IRB Office
will ask the reporter to provide the following information:
1. Detailed information about the possible unanticipated problem,
including relevant dates.
2. How the person reporting obtained the information provided in the
report.
3. Information about any injury, potential harm, or risk to the subject
or others.
4. How the reporter may be contacted for further information, if
needed.
5. Any other relevant information requested by the IRB Office.
D. A report of a possible unanticipated problem involving risks to
participants or others will be immediately forwarded by IRB Office staff to the
IRB director and/or IRB chair if the IRB Office staff believes that immediate
intervention may be required to protect participants or others from serious
harm.
E. Upon receipt of a report of a possible unanticipated problem from someone
other than the investigator or study staff, the IRB director will notify the
principal investigator on the study when appropriate.
VII. IRB Procedures for Handling Reports of
Possible Unanticipated Problems
A. Review by IRB Staff and Chair
1. IRB Staff will refer reports of possible unanticipated problems to
the IRB director. After reviewing the report, the IRB director will determine
whether consultation with the IRB chair is needed.
2. If the IRB director or chair determines that the report (i) does not
constitute an unanticipated problem or (ii) does not require any action and
that the research may continue without change, the IRB director or chair will
promptly notify the investigator in writing when appropriate.
3. If a report suggests that participant safety is at risk, the IRB
chair may immediately suspend the protocol pursuant to the UW-Madison
Suspension and Termination of Research Policy.
a. Any suspension of research by the IRB
chair must be promptly reported to the IRB and the Institutional Official (IO).
See, UW-Madison Suspension and Termination of Research Policy.
b. If the IRB chair immediately suspends
research to protect participant safety, the chair will promptly notify the
investigator of the suspension.
c. If the IRB chair immediately suspends
research to protect participant safety, the IRB chair’s decision and the
reasons for the decision will be scheduled for discussion at the next meeting
of the IRB. The IRB will determine whether to lift or continue the suspension.
The IRB will promptly notify the investigator and the IO of its decision. IRB
discussion and resolution of issues of noncompliance relating to the suspension
may be scheduled for a subsequent IRB meeting.
4. Any report that does not require immediate action by the IRB chair
will be referred to the full IRB for review at its next scheduled meeting. If
a report did not come from the investigator, IRB staff may provide the
investigator with an opportunity to respond to the report before forwarding the
report to the IRB. When appropriate, the IRB director and IRB chair may make
recommendations to the full IRB as to what actions should be taken in response
to the report.
B. Review by IRB
1. The IRB will review reports of possible unanticipated problems
referred to it by the IRB director or chair.
2. Materials reviewed
a. ED IRB and SBS IRB
i. The ED/SBS Office forwards the report of
a possible unanticipated problem and all related materials to all members of
the reviewing IRB, including any alternate substituting for an IRB member,
except for the complete protocol file, which is reviewed by one member of the
reviewing IRB. The complete protocol file is available from the ED/SBS Office
to any IRB member who wishes to review it before or during the convened meeting.
b. HS IRB and MR IRB
i. Reports of a possible unanticipated
problem that need review by the full IRB are first assigned to staff reviewers
by the HS IRB Office Director.
ii. The HS IRB Office forwards to the
assigned staff reviewer the report of a possible unanticipated problem and all
related materials in addition to the complete protocol file.
iii. Staff reviewers prepare a summary and
detailed analysis of each report.
iv. The HS IRB Office Director also assigns
each report to primary reviewers, who are IRB members and who review the report
in a preliminary review session (PRS) held prior to a scheduled meeting of the
full IRB. The assigned primary reviewers are provided the following
information:
§
The complete protocol file
§
Copy of the report of a possible unanticipated problem and any
other relevant supporting materials
§
A staff reviewer report that provides a detailed summary and
expert analysis of the report assigned to the primary reviewers
v. In the preliminary review session (PRS), the
primary reviewers evaluate each staff reviewer report in conjunction with the
report of a possible unanticipated problem. The primary reviewers prepare
written assessments of each possible unanticipated problem report and make
recommendations to the full IRB regarding (a) whether the a incident described
in the report is an unanticipated problem involving risks to participants or
others (b) what action in response to the report is appropriate, (c) whether
suspension or termination of approval is warranted and (d) whether further
reporting to university officials, federal agencies and department heads is
required. As part of their assessment, primary reviewers may request
additional information or review by someone with a specific expertise.
vi. The unanticipated problem report, copies
of all related documents, the staff reviewers’ summary along with written
assessments and recommendations by the PRS are sent to the full IRB, including
any alternate substituting for an IRB member. Copies of protocol files for
those reports scheduled for review by the full IRB are available to all IRB
members, including any alternate substituting for an IRB member, from the HS
IRB Office before or during the convened meeting.
3. If a report suggests that participant safety is at risk, the IRB may
immediately suspend or terminate the research, pursuant to the UW-Madison
Suspension and Termination of Research Policy. Any suspension or termination
of research by the IRB must be promptly reported to the IO. See, UW-Madison
Suspension and Termination of Research Policy.
4. Before making a determination that the event constitutes an
unanticipated problem involving risks to participants or others, the IRB may
invite the investigator to present additional materials and to appear in
person. The IRB members may ask questions of the investigator.
5. After reviewing a report, the full IRB will make determinations on
the following issues:
§
Whether the reported event is an unanticipated problem involving
risks to participants or others according to the definition in this policy
§
What action in response to the report is appropriate
§
Whether suspension or termination of approval is warranted (See, Suspension
or Termination of Research Policy), and
§
Whether further reporting to university officials, federal
agencies and department heads is required pursuant to the UW-Madison Reporting
to Federal Authorities Policy.
a. If the IRB determines that the event is
not an unanticipated problem involving risks to participants or others, according
to the definition in the policy, the IRB may take any of the following actions:
i. No action
ii. Requiring modifications to the protocol
iii. Revising the continuing review timetable
iv. Modifying the consent process
v. Modifying the consent document
vi. Providing additional information to
current participants (e.g. whenever the information may relate to the
participant’s willingness to continue participation)
vii. Providing additional information to past
participants
viii. Requiring additional training of the
investigator and/or study staff
ix. Other actions appropriate for the local
context
b. If the IRB determines that the event is an
unanticipated problem involving risks to participants or others, according to
the definition in the policy, the IRB may take any of the following actions:
i. Requiring modifications to the protocol
ii. Revising the continuing review timetable
iii. Modifying the consent process
iv. Modifying the consent document
v. Providing additional information to
current participants (e.g. whenever the information may relate to the
participant’s willingness to continue participation)
vi. Providing additional information to past
participants
vii. Requiring additional training of the
investigator and/or study staff
viii. Reconsidering approval
ix. Requirement that current participants
re-consent to participation
x. Monitoring of the research
xi. Monitoring of the consent
xii. Referral to other organizational entities
(e.g., legal counsel, risk management, institutional official)
xiii. Suspending the research
xiv. Terminating the research
xv. Other actions appropriate for the local
context
NOTE: Any
suspension or termination of research by the IRB must be promptly reported to
the IO. See, UW-Madison Suspension and Termination of Research Policy.
6. After making its determinations, the IRB will:
a. notify the investigator in writing of the
its determinations, with copies to the chair of the investigator’s
department and/or research unit, and the investigator’s dean or director,
and
b. if further reporting is required, report
its determination to the IO for further reporting pursuant to the UW-Madison
Reporting to Federal Authorities Policy. (See, Section VII, below)
7. Record of determination
a. IRB minutes should reflect discussion and
determination by the IRB on each of the following issues:
i. Whether an unanticipated problem posing
risks to subjects or others occurred, and
ii. If the IRB determines an unanticipated
problem posing risks to subjects or others occurred, whether:
§
Reporting to federal agencies is required
§
Reporting to other campus or affiliate entities (e.g., the VA) is
required
§
Any further action is needed to prevent the problem from
recurring
§
New information has resulted that may affect subjects’
willingness to participate in the study and how this information should be
disseminated to subjects or others
C. Appeal to Human Research Protection Program Advisory Committee
1. A decision of the IRB may be appealed by the investigator to the
Human Research Protection Program Advisory Committee (Advisory Committee).
2. The notice to the investigator of the IRB’s decision will
inform the investigator that he or she has 10 business days from receipt of the
notice to appeal the IRB’s decision to the Advisory Committee. The notice
of the right to appeal should include contact information for the Advisory
Committee Chair. The investigator may appeal the IRB’s decision by
sending the Advisory Committee Chair a written notice of appeal, including the
basis of the investigator’s appeal. The investigator should send a copy
of the notice of appeal to the IRB. The basis for an appeal to the Advisory
Committee is limited to one or more of the following:
a. that the UW-Madison IRB has failed to
follow its own procedures
b. that the UW-Madison IRB has incorrectly
applied federal regulatory criteria or state law, or
c. that the UW-Madison IRB has incorrectly
applied UW-Madison policies.
3. If an investigator appeals the IRB’s decision, the
investigator’s written appeal will be considered at a regularly scheduled
meeting of the Advisory Committee and the Advisory Committee will review the
appeal following the procedures described in the Advisory Committee Charter,
Section A.2. The Advisory Committee will notify the investigator of the
outcome of the appeal.
4. If the Advisory Committee receives a notice of appeal from the
investigator, the Advisory Committee will notify the IRB and the IO of the
request and of the final outcome.
D. Need for Additional Information
If, at any point in the
review process, additional information is necessary to make the required
findings, recommendations, determinations or reports, additional information
may be requested from the investigator or other sources.
VIII. Reporting Unanticipated Problems to
UW-Madison Officials and Federal Departments and Agencies
A. The Institutional Official will report an unanticipated problem
involving risks to participants or others to appropriate UW-Madison officials
and to appropriate federal department or agency heads pursuant to the
UW-Madison’s Reporting to Federal Authorities Policy.
