New IRB Policies
Reporting Unanticipated
Problems & Adverse Events
Data & Safety Monitoring
Susan Burner Bankowski, M.S., J.D.
Chair, OHSU IRB
Old Policy
Everything and the Kitchen Sink.
Lacks Context and Meaning
Results in waste of resources &
arbitrary revisions to consent form
PI Reporting Requirements
To the IRB
•
All Unanticipated Problems involving risks to
human subjects or others. 45 CFR
46.103(b)(5).
To the Sponsor
•
Any adverse effect that may reasonably be
regarded as caused by, or probably caused by,
the drug. If the adverse effect is "alarming," the
investigator must report the adverse effect
immediately (§ 312.64(b))
IRB Reporting Requirements
•
An assured institution must have Written procedures for ensuring prompt
reporting to the IRB, appropriate
institutional officials, and the department
or agency head of (i) any unanticipated
problems involving risks to subjects or
others…..
45 CFR 46.103(b)(5).
•
OHSU IRB Reports to IO and OHRP.
Sponsor’s Reporting Requirements
To the PI
• “Keep each participating investigator informed of new observations
discovered by or reported to the sponsor on the drug, particularly
with respect to adverse effects and safe use” (§ 312.55(b))
• Notify investigators of any adverse experience “associated with the
drug that is both serious and unexpected” and “any finding from
tests in laboratory animals that suggest a significant risk for human
subjects,”
21 C.F.R. § 312.32(c)(1)(i)(A), (B);
To the FDA
• For devices - any “unanticipated adverse device effect” 21 C.F.R. §
812.46(b), 21 C.F.R. § 812.50(b)(1).
• Safety and effectiveness data (annual reports & IND safety reports)
What is an Adverse Event?
•
Any untoward or undesirable, although not
necessarily unexpected, event experienced by
a human subject that may be a result of:
–
–
–
–
The interventions and interactions use in the
research
The collection of identifiable private information in
the research
An underlying disease, disorder, or condition of the
subject ; and/or
Other circumstances unrelated to the research or
any underlying disease, disorder, or condition of the
subject.
What is a Serious
Adverse Event?
Any AE that is:
• Is fatal
• Is life-threatening
• Is persistent or significantly disabling or incapacitating
• Results in inpatient hospitalization or prolongation of
hospitalization
• Results in psychological or emotional harm requiring
treatment
• Creates a persistent or significant disability
• Causes a congenital anomaly or birth defect and/or
• Results in a significant medical incident
What is an
Unanticipated Problem?
•
Events that are not expected given the
nature of the research procedures and
the subject population being studied and
suggest that the research places
subjects or others at a greater risk of
harm or discomfort related to the
research than was previously known or
recognized. Harm to a subject need not
occur for an event to be an unanticipated
problem.
All AEs are not UPs!
What to Report?
Do not Report A to IRB – only B &C
Unanticipated Problems
A = AEs that
are not UPs
B = AEs
that are
UPs
C = UPs
that are not
AEs
When is an AE an UP?
•
In order for the PI (or the Monitor) to determine
whether a particular AE is also considered a
UP, the following should be taken into account:
–
–
–
The description of known or foreseeable adverse
events and risks in the IRB-approved research
protocol, any applicable investigator brochure, the
current IRB-approved consent form, and other
relevant sources of information.
Any underlying disease or conditions of the subject
experiencing the adverse event.
A careful assessment of whether the adverse event
is related or possibly related to the subject’s
participation in the study.
Unanticipated Problem Analysis Chart
Categories of Reportable AEs
1.
On Protocol SAEs that are unanticipated and related or possibly related
to the research participation.
2.
On Protocol SAEs or AEs that are anticipated and related or possibly
related, but are occurring at a significantly higher frequency or severity
than expected.
3.
On or Off Protocol Unanticipated SAEs or AEs that are related or possibly
related, regardless of severity, that may alter the risks for subjects and,
as a result, warrant changes to the protocol and/or consent process
4.
On or Off Protocol other events that are unanticipated that may place
subjects or others at a greater risk of harm or discomfort than was
previously known or recognized. Harm to a subject need not have
occurred.
What’s Meant by Unexpected?
Any AE may be considered unexpected if it occurs in one or
more subjects, the nature, severity, or frequency of which is not
consistent with either:
•
the known or foreseeable risk of AEs associated with the
procedures involved in the research that are described in
– the protocol-related documents, such as the IRBapproved research protocol, any applicable investigator
brochure, and the current IRB-approved informed
consent document, and
– other relevant sources of information, such as product
labeling and package inserts; or
•
the expected natural progression of any underlying disease,
disorder, or condition of the subject(s) experiencing the
adverse event and the subject’s predisposing risk factor
profile for the adverse event.
What’s Meant by Possibly Related?
Adverse events may be caused by one or more of the
following:
1. the procedures involved in the research;
2. an underlying disease, disorder, or condition of the
subject; or
3. other circumstances unrelated to either the research
or any underlying disease, disorder, or condition of
the subject.
However, AEs that are determined to be at least partially
caused by (1) would be considered related to participation
in the research, whereas adverse events determined to be
solely caused by (2) or (3) would be considered unrelated
to participation in the research.
Who is doing the Monitoring?
•
•
Not the IRB!
A Monitoring Entity
•
•
•
•
Investigator Monitor
Independent Monitor
Data Safety Monitoring Board (DSMB)/Data
Monitoring Committee (DMC)
In a multi-site study, there must be a
monitoring entity that is central to all
sites.
All should have a Centralized
Monitor.
• It is the monitor’s responsibility to analyze and
review applicable Non-OHSU AEs and Different
Protocol Events, determine if the AEs are UPs,
and report the UPs to the PI for subsequent
reporting to the PIs IRB.
• If OHSU is serving as a coordinating center, then
the PI of the coordinating center is responsible
for this determination via an approved
monitoring plan.
Monitoring Provisions
All research requires some level of monitoring and principal
investigators are responsible for monitoring their studies.
However, the IRB must approve the plan for monitoring
data and safety for all research except minimal risk
research where OHSU is the only site
•
The monitoring provisions should be tailored to the
expected risks of the research, the type of subject
population being studied and the nature, size and
complexity of the research protocol.
•
The monitoring provisions must be described in
sufficient detail, including the type of monitoring entity,
for the IRB to determine whether they are appropriate
for the research.
Monitoring Entities
• Investigator Monitor – The Principal Investigator or a Coinvestigator who is responsible for data and safety
monitoring.
• Independent Monitor - A qualified and objective individual
or group not directly involved with the design and
conduct of the study (e.g., safety officer, designated
Medical Monitor or Monitoring Group). These individuals
may or may not be employees of OHSU or the study
sponsor. However, conflict of interest is an important
consideration when employees of the study sponsor
have the primary responsibility for monitoring data from
the standpoint of scientific integrity and participant
safety.
Monitoring Entities Continued
• Data Safety Monitoring Board (DSMB)/Data Monitoring
Committee (DMC) – an independent formal committee
that is established specifically to monitor data throughout
the life of a study to determine if it is appropriate, from
both the scientific and ethical standpoint, to continue the
study as planned.
• DSMBs/DMCs are typically made up of individuals who
have expertise in the field, experience in the conduct of
clinical trials, and/or statistical knowledge, and who do
not have any serious conflicts of interest, such as
financial interests that could be substantially affected by
the outcome of the trial, strong views on the relative
merits of the interventions under study, or relationship
with the sponsor or those in trial leadership positions that
could be considered reasonably likely to affect their
objectivity.