Transcript That Wasn’t Supposed to Happen

That Wasn’t Supposed to
Happen
UNANTICIPATED PROBLEMS
INVOLVING RISKS TO SUBJECTS
OR OTHERS & INCIDENTS OF
NON-COMPLIANCE
(AKA
PROTOCOL DEVIATIONS)
TRACY RIGHTMER, JD, CIP
COMPLIANCE MANAGER
YALE UNIVERSITY HUMAN RESEARCH PROTECTION PROGRAM
Today’s Discussion
 Definitions of UPIRSOs, minor non-compliance,
serious non-compliance, continuing non-compliance
and protocol deviations
 How to identify those that need to be reported
 How to report to the IRBs
 What to do if you’re not sure
Non Compliance
The IRB recognizes that non-compliance with
approved protocols may occur. It is the
responsibility of the Principal Investigator to notify
the IRB if:
1) the incident may expose subjects to increased
risk OR
2) fewer benefits OR
3) the incident compromises the integrity of the
study
Definitions: Minor Non-compliance
Minor Noncompliance: Any behavior, action or omission in the conduct
or oversight of research involving human subjects that deviates from the
approved research plan, federal regulations or institutional policies but,
because of its nature, research project or subject population, does not:
 place, or have the potential to place, participants and others at greater risk
than previously anticipated;
 have a substantive effect on the value of the data collected; and
 result from willful or knowing misconduct on the part of the investigator(s)
or study staff.
Examples of minor noncompliance may include, when such noncompliance
does not create additional risks to subjects:
 Changing study personnel without notifying the IRB;
 Shortening the duration between planned study visits;
 Implementing minor wording changes in study questionnaires without first
obtaining IRB approval;
 Routine lab missed at scheduled visit and re-drawn
Definitions: Serious Non-compliance
Serious Noncompliance: Any behavior, action or omission in the conduct or
oversight of human research that has been determined to:
 affect the rights and welfare of participants and others;
 increase risks to participants and others, decreases potential benefits or otherwise
unfavorably alter the risk/benefit ratio;
 compromise the integrity or validity of the research; or
 result from the willful or knowing misconduct on the part of the investigator(s) or
study staff.
Examples include, but are not limited to:
 Conducting non-exempt research that requires direct interaction or interventions
with human subjects without first obtaining IRB approval;
 Enrolling subjects who fail to meet the inclusion or exclusion criteria in a protocol
that involves greater than minimal risk and that places the participant(s) at greater
risk; or
 Failure to report adverse events, unanticipated problems, or substantative changes
to the proposed protocol to the Committee in accordance with IRB Policy 710 and
Form 100 FR.4: Request for Approval of Amendment.
Definitions: Continuing Non-compliance
Continuing Noncompliance: A pattern of
noncompliance that indicates a lack of understanding or
disregard for the regulations or institutional
requirements that protect the rights and welfare of
participants and others, compromises the scientific
integrity of a study such that important conclusions can
no longer be reached, suggests a likelihood that
noncompliance will continue without intervention, or
involves frequent instances of minor noncompliance.
Continuing noncompliance may also include failure to
respond to a request from the IRB to resolve an episode
of noncompliance or a pattern of minor noncompliance.
Definitions: Unanticipated Problems Involving
Risks to Subjects or Others (UPIRSO)
UPIRSO is any incident, experience, or outcome that meets all
of the following criteria:
 unexpected (in terms of nature, severity, or frequency) given
(a) the research procedures that are described in the protocolrelated documents, such as the IRB-approved research
protocol and informed consent document; and (b) the
characteristics of the subject population being studied;
 related or possibly related to participation in the research.
Possibly related means there is a reasonable possibility that
the incident, experience, or outcome may have been caused by
the procedures 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.
UPIRSO Examples
Unanticipated problems can include incidents such as:
 A stolen laptop containing subject data and identifiers (investigators must
also file the http://www.yale.edu/its/forms/LostStolenForm.doc with
Information Security and provide a copy to the IRB.)
 A processing error resulting in a subject receiving a dose of study
medication 10 times higher than the dose dictated by the IRB approved
protocol but that produces no detectable adverse effect
 Subjects receiving an investigational product which was obtained from
donors who were not appropriately screened and tested for viral
contaminants
 Subjects receiving the wrong medication, whether or not they experience
adverse events (AEs) that are not reportable under the AE reporting policy
http:/yale.edu/hrpp/policy/AdverseEventPolicy
 Any publication in the literature, safety monitoring reports, interim results
or other findings that indiciates an unexpected change to the risks or
potential benefits of the research
Definitions: Serious Adverse Events
Serious Adverse Events
Investigators must report to the IRB within 48 hours of discovery any adverse events
that are:
 Serious AND unanticipated AND possibly, probably or definitely related events;
and/or
 Anticipated adverse events occurring with a greater frequency than expected
Serious
Any event that results in any of the following outcomes: death, a life-threatening
experience, inpatient hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital anomaly/birth defect,
or any other adverse event that, based upon appropriate medical judgment, may
jeopardize the participant’s health and may require medical or surgical intervention
to prevent one of the other outcomes listed in this definition.
Other adverse events must be summarized in the re-approval request. The summary
may be a simple brief statement that adverse events have occurred at the expected
frequency and level of severity as previously documented.
Adverse Events vs. Unanticipated Problems
The following Venn diagram summarizes the general
relationship between adverse events and unanticipated
problems:
Federal Regulations
The rationale for reporting non-compliance to the IRB is to enable the
IRB to fulfill its role of oversight for protection of human subjects.
Federal regulations (21 CFR 56.108(b)(1) (FDA) and 45 CFR 46.103.b.5
(HHS)), require the IRB to review reports of non-compliance that may
impact subjects’ welfare. In doing so, the IRB can ask investigators to
think about and implement additional subject protections.
Consideration should involve assessing whether there has been a
change to the risk/benefit ratio and assessing whether changes to the
protocol or procedures are necessary in order to minimize risks.
The regulations also require the IRB to follow written procedures for
reporting certain types of non-compliance to the Institutional Officials
and Federal Authorities (if applicable).
IRB Policy
Investigators are required to report serious or continuing noncompliance that occur only at Yale’s research site(s) to the IRB
within 5 working days of their occurrence or within 5 days of the
investigator becoming aware of their occurrence.
UPIRSOs must be reported within 48 hours.
Investigators are also required to report results of audits or
inspections conducted by sponsors or other external entities such
as the Food and Drug Administration (FDA), which involve any
of the above.
Minor noncompliance should be summarized for the IRB at the
time of continuing review
http://www.yale.edu/hrpp/policies/index.html#PostApproval
What Do I Do?
 Determine if the incident of non-compliance is minor or if it qualifies as
serious or continuing or is an unanticipated problem



Serious non-compliance: does it affect the rights and welfare of subjects, increase risks or decrease
benefits, compromise the integrity or validity of the research, is it knowing or willful? If yes- then report.
Continuing non-compliance: is there a pattern of non-compliance that indicates a lack of understanding or
respect of the regulations, a pattern of non-compliance that compromises the integrity of the research? If
yes- then report.
UPIRSO: is it unexpected, related or possibly related and place the subject at greater risk than previously
known? If yes- then report.
 Report serious or continuing non-compliance to the IRB within 5 days
using the UPIRSO report form on the HRPP website
 Report UPIRSOs to the IRB within 48 hours using the UPIRSO report
form
Report incidents of non-compliance and UPIRSOs from the School of Medicine and
School of Nursing to the Compliance Manager located at the Human Investigation
Committee (203-785-4688, [email protected]).
 Report incidents of non-compliance and UPIRSOs from other areas of the University to
the Human Subjects Committee (203-436-3650, [email protected]).
 When in doubt…call your IRB!

http://www.yale.edu/hrpp/
UPIRSO Report Form
 The form asks for several things:
 Description of the event
 Why the event occurred
 Outcome
 Were subjects adversely affected
 Description of changes to the protocol/consent
 A Corrective Action Plan
Corrective Action Plan
 In crafting an effective plan, the investigator needs to
really think about why the event occurred. Is it a
system problem? Problem with procedure? A
training issue?
 Once the “why” is determined, the plan must address
ways to prevent it from happening again
 Education is almost always appropriate
Examples
 Study participant cancels a study visit and reschedules for 3 days
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outside the visit window.
A research assistant forgets to perform one of the assessments for a
study participant.
Inclusion/exclusion criteria for a study prohibit enrollment of
participants with a cardiac history. A participant with a history of
myocardial infarction is enrolled and begins study medication.
A study participant receives the wrong study medication but
experiences no adverse events.
A research participant doesn’t receive an infusion of study medication
according to the schedule as set out in the protocol.
A participant currently enrolled in a medication study dies from causes
not related to participation.
Study PHI is accidentally emailed to the wrong recipient.
Flashdrive with PHI on it is lost.
PI enrolls/conducts research during study lapse.
Other Examples?
Questions?
Call 785-6471
[email protected]
References
 http://www.yale.edu/hrpp/
 http://www.yale.edu/hrpp/policies/index.html
 http://www.yale.edu/hrpp/responsibility/complianc
e.html
 http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm
 http://www.hhs.gov/ohrp/humansubjects/guidance
/45cfr46.htm
 http://www.fda.gov/AboutFDA/CentersOffices/ORA
/default.htm