Transcript Gifts to Referral Sources: Guidelines for MLH Employees

Main Line Hospitals Institutional Review Board
Unanticipated Problems
Anne Marie Hobson, BSN, JD, ORA Director
Theresa Greaves, ORA Manager
Overview
• Review new Policy and Procedures
• Identify what events and problems are
reportable to the IRB
• Review some brief case studies
Definitions
Unanticipated Problems:
• Unanticipated problems involving risks to subjects or
others are defined as any incident, experience or
outcome that meets all of the following criteria:
• Unexpected (in terms of nature, severity, or frequency)
given the research procedures and the subject
population being studied; and
• Related or possibly related to a subject’s participation in
the research; and
• Suggests that the research places subjects or others at a
greater risk of harm (including physical, psychological,
economic, or social harm) than was previously known or
recognized.
Definitions
Adverse Event:
Any untoward or unfavorable medical
occurrence in a human subject, including any
abnormal sign (for example, abnormal physical
exam or laboratory finding), symptom, or
disease, temporally associated with the
subject’s participation in the research whether
or not considered related to the subject’s
participation in the research
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Definitions
Serious Adverse Event:
Any adverse event temporally associated with the subject’s
participation in research that meets any of the following criteria:
• results in death;
• A life-threatening event (places the subject at immediate risk of
death from the event as it occurred);
• requires inpatient hospitalization or prolongation of an existing
hospitalization;
• results in a persistent or significant disability/incapacity;
• results in a congenital anomaly or birth defect; or
• any other adverse event that based upon appropriate medical
judgment, may jeopardize the subject’s health and may require
medical or surgical intervention to prevent one of the outcomes in
this definition
Definitions
Unanticipated Adverse Device Effect (UADE):
• Any serious adverse effect on health or safety,
or any life-threatening problem or death, caused
by or associated with a device, if that effect,
problem, or death was not previously identified
in nature, severity, or degree of incidence in the
investigational plan or application, or any other
unanticipated serious problem associated with a
device that relates to the rights, safety, or
welfare of subjects.
Reportable Problems/Events
• An adverse event (or serious adverse
event) may be expected, based on the
known risks of the study and information in
the informed consent and other study
related documents. An adverse event is
reportable only if it is also an unanticipated
problem. In addition, unanticipated
problems, even if not involving physical
risks, need to be reported.
Adverse Events
• Adverse events may be the result of:
– the interventions and interactions used 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
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Adverse Events
• Most adverse events are not reportable to the
IRB
• The majority of adverse events that occur in the
context of research are expected:
– the known toxicities and side effects of the research
procedures
– the expected natural progression of the subjects’
underlying diseases, disorders, and conditions, and
– subjects’ predisposing risk factor profiles for adverse
events
Why the Policy Change…
• OHRP Guidance (January, 2007)
• FDA Guidance (January 2009)
• Association for the Accreditation of
Human Research Protections Programs
(AAHRPP)
IRB Process
Unanticipated Problem Involving Risk
To Participants Or Others
•
Unexpected (in terms of nature, severity, or frequency) given (a) the
research procedures that are described in the IRB-approved documents,
such as the protocol and informed consent document, and (b) the
characteristics of the subject population being studied; AND
•
Related or possibly related to participation in the research (possibly
related means there is a reasonable possibility that the event or problem
may have been caused by the procedures/drugs or devices involved in the
research); AND
•
Suggests that the research places subjects or others at a greater risk of
harm (including physical, psychological, economic, or social harm) than
was previously known or recognized
Ask Three questions…
• Is the adverse event unexpected? AND
• Is the adverse event related or possibly related to
participation in the research? AND
• Does the adverse event suggest that the research
places subjects or others at a greater risk of harm than
was previously known or recognized?
• When the answer to all three questions is YES, the
adverse event is an unanticipated problem and must be
reported to the MLH IRB.
Unanticipated Problems…
• Under 45 CFR Part 46 and 21 CFR Part 56 the IRB is required to
have written procedures for ensuring prompt reporting to the IRB,
appropriate institutional officials, and the department or agency head
of any unanticipated problems involving risks to subjects or others
• MLH IRB is trying to capture events and problems in B and C but not
in A
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Case Study #1
•
A subject enrolled in a Phase 3, randomized, doubleblind, placebo-controlled clinical trial evaluating the
safety and efficacy of a investigational antiinflammatory agent for management of osteoarthritis.
•
The subject develops severe abdominal pain and
nausea one month after randomization.
•
Subsequent medical evaluation reveals gastric ulcers.
The IRB-approved protocol and informed consent
document indicated that the there was a 10% chance
of developing mild to moderate gastritis and a 2%
chance of developing gastric ulcers for subjects
assigned to the active investigational agent.
Case Study #1
• Should this event/problem be reported to
the IRB?
• NO, although the event is related to the research
intervention, the risk was foreseeable (described
in the IRB-approved documents) and the subject
was not placed at greater risk of harm than was
previously recognized.
Case Study #2
• As a result of a processing error by a pharmacy
technician, a subject enrolled in a multicenter
clinical trial receives a dose of an experimental
agent that is 10-times higher than the dose
dictated by the IRB-approved protocol. While the
dosing error increased the risk of toxic
manifestations of the experimental agent, the
subject experienced no detectable harm or
adverse effect after an appropriate period of
careful observation.
Case Study #2
• Should this event/problem be reported
to the IRB?
• Yes, the dosing error constitutes a
protocol violation - accidental or unintentional
changes to, or non-compliance with the IRB
approved protocol without prior sponsor and
IRB approval. Violations generally increase risk
or decrease benefit, affects the subject's rights,
safety, or welfare, and/or the integrity of the
data
Case Study #3
• A subject with seizures enrolls in a randomized, Phase 3 clinical trial
comparing a new investigational anti-seizure agent to a standard,
FDA-approved anti-seizure medication. The subject is randomized
to the group receiving the investigational agent.
• One month after enrollment, the subject is hospitalized with severe
fatigue and on further evaluation is noted to have severe anemia.
• The known risk profile of the investigational drug does not include
anemia, and the IRB-approved protocol and informed consent
document for the study do not identify anemia as a risk of the
research.
Case Study #3
• Should this event/problem be reported to
the IRB?
• Yes, anemia is (a) unexpected in nature; (b)
possibly related to participation in the
research; and (c) places subjects at greater
risk of harm.
Case Study #4
• Subjects with coronary artery disease presenting with unstable
angina are enrolled in a multicenter clinical trial evaluating the safety
and efficacy of an investigational vascular stent
• Based on prior studies, the investigators anticipate up to 5% of
subjects receiving the stent will require emergency CABG surgery
• Emergency CABG risk is described in the protocol and informed
consent document
• After the first 20 subjects enrolled in the study a DSMB interim
analysis reports10 subjects have undergone emergency CABG
surgery soon after placement of the investigational stent.
Case Study #4
• Should this event/problem be reported
to the IRB?
Yes, (a) the frequency subjects needed to
undergo emergency CABG was
significantly higher than the expected
frequency (b) these events were related to
participation in the research; and (c) these
events were serious
Points to Consider…
• There is not an “easy answer” to determine if an
adverse event is reportable to the MLH IRB.
• Researchers must look beyond the categories of
“related” or “possibly related” and “unexpected”
when determining whether to report an event or
series of events.
• Many reports labeled “unexpected” will not meet
the definition of an unanticipated problem.
• MLH investigators participating in multicenter
studies receive a large volume of reports of
external adverse events and each report must be
considered individually.
Points to Consider Continued…
External Adverse Events
• Both FDA and the HHS Office of Human Research Protections have
stated their expectation that an individual external adverse event
will rarely meet the criteria for an unanticipated problem.
• OHRP has provided guidance urging sponsors that individual
adverse events should only be reported to investigators at all
institutions when a determination has been made by the sponsor
that the events meet the criteria for an unanticipated problem.
– OHRP recommends that any distributed reports include: (1) a
clear explanation of why the adverse event or series of adverse
events has been determined to be an unanticipated problem;
and (2) a description of any proposed protocol changes or other
corrective actions to be taken by the investigators in response to
the unanticipated problem.
Points to Consider Continued…
External Adverse Events
– External adverse event reports from a different study, or
use of the agent or procedure in a different population or
route of administration may constitute an unanticipated
problem for an MLH study. The MLH Investigator should
assess whether or not the information in the report
indicates a problem that affects the rights and welfare of
MLH subjects. If in the judgment of the MLH investigator it
does, the report should be submitted.
– If the external report does not contain sufficient information
for the MLH investigator to make the needed assessment
AND the source of the report (e.g. the sponsor) did not
state the event is an “unanticipated problem” or an
“unanticipated adverse device effect”, then submission to
the IRB is not required.
Please contact us…
Lankenau Institute for Medical Research
Suite G-44, NEB
Alia Dudley
Theresa Greaves
Anne Marie Hobson, JD
Albert A. Keshgegian, MD, Ph.D.
610-645-2678
610-645-3414
610-645-2692
610-645-3552