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Unanticipated Problems Involving Risks to Subjects or Others


that wasn t supposed to happen unanticipated problems involving risks to subjects or others & incidents of non-compliance (aka protocol deviations) – PowerPoint PPT presentation

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Title: Unanticipated Problems Involving Risks to Subjects or Others

That Wasnt 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

Todays 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 youre 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
  • the incident may expose subjects to increased
    risk OR
  • fewer benefits OR
  • the incident compromises the integrity of the

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
  • Shortening the duration between planned study
  • Implementing minor wording changes in study
    questionnaires without first obtaining IRB
  • Routine lab missed at scheduled visit and

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
  • 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

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 protocol-related documents,
    such as the IRB-approved research protocol and
    informed consent document and (b) the
    characteristics of the subject population being
  • 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
  • A stolen laptop containing subject data and
    identifiers (investigators must also file the
    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
  • Subjects receiving an investigational product
    which was obtained from donors who were not
    appropriately screened and tested for viral
  • Subjects receiving the wrong medication, whether
    or not they experience adverse events (AEs) that
    are not reportable under the AE reporting policy
  • 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
    participants 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
  • 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 non-compliance that occur only at
    Yales research site(s) to the IRB within 5
    working days of their occurrence or within 5 days
    of the investigator becoming aware of their
  • 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.htmlPost

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,
  • Report incidents of non-compliance and UPIRSOs
    from other areas of the University to the Human
    Subjects Committee (203-436-3650,
  • When in doubtcall your IRB!

(No Transcript)
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

(No Transcript)
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

  • Study participant cancels a study visit and
    reschedules for 3 days 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 doesnt 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
  • Study PHI is accidentally emailed to the wrong
  • Flashdrive with PHI on it is lost.
  • PI enrolls/conducts research during study lapse.

Other Examples?
  • Questions?
  • Call 785-6471
  • tracy.rightmer_at_yale.edu

  • http//www.yale.edu/hrpp/
  • http//www.yale.edu/hrpp/policies/index.html
  • http//www.yale.edu/hrpp/responsibility/compliance
  • http//www.hhs.gov/ohrp/policy/AdvEvntGuid.htm
  • http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  • http//www.fda.gov/AboutFDA/CentersOffices/ORA/def
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