Identifying and Reporting Adverse Events and Unanticipated Problems

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Identifying and Reporting Adverse Events and
Unanticipated Problems

• Presented by
• Marisue Cody, PhD
• Deputy Director, PRIDE

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Why Report Adverse Events and Unanticipated
Problems?

• Because it helps ensure the safety of
  participants in human subject research, by
  providing information to the IRB and cognizant
  oversight agencies, and
• Because its the law

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The Common Rule Requires

• 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 or any serious or continuing
  noncompliance and (ii) any suspension or
  termination of IRB approval.
• 38 CFR 16.103(b)(5)

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Regulatory Guidance

• VHA ORD Handbook 1200.05 Requirements for the
  Protection of Human Subjects in Research
• VHA Handbook 1058.01 Reporting AEs in Research
  to the Office of Research Oversight
• OHRP Guidance (1/15/07) Guidance on Reviewing
  and Reporting UPRs and AEs
• Local IRB SOP Manual

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VHA Handbook 1058.01 Reporting Research Events

• Replaces All Previous ORO Reporting Requirements
• Includes Reporting
• Within the Facility
• To ORO
• New Definitions and Reporting for Human Research
• Unanticipated Problems / Serious Adverse Events
• Serious or Continuing Noncompliance

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What Is An Adverse Event (AE)?

• An AE is any untoward occurrence (physical,
  psychological, economic, social, or legal) which
  affects a study subject.
• An AE does not require (or imply) a causal
  relationship with the research.
• AEs which are also Unanticipated Problems
  involving Risk to study subjects or others (UPRs)
  must be reported.
• Most AEs are not UPRs.

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VHA Handbook 1058.01 Reporting Research Events

• New Definitions
• Local Adverse Event (AE)
• An AE occurring at a site for which the VA
  investigators VA IRB of Record is responsible

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What Is A UPR?

• A Unanticipated Problem involving Risk to
  subjects or others is a study-related event (or
  item of new information) which is
• unexpected, by frequency, severity, or nature,
  given the research procedures and the subject
  population being studied and
• related to participation in the research and
• indicative of increased risk to study subjects or
  others.

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Unanticipated

• An Adverse Event is unanticipated if the
  frequency, severity, or nature of the event is
  not consistent with the risks identified in the
• Informed consent
• Investigator brochure or product label
• Investigational plan or protocol

OHRP Guidance Topic III A VHA 1200.53(a)(2)
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Study-Related

• An Adverse Event is study-related if it is
  clearly or possibly caused by research procedures
  or participation
• An Adverse Event is not study-related if it is
  solely caused by underlying disease, condition,
  treatment, or if it is solely caused by
  circumstances other than the research or
  underlying disease

OHRP Guidance Topic III B
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Indicative of Increased Risk

• An Adverse Event is indicative of increased risk
  when it suggests that the research places the
  study subjects or others at greater risk of harm
  than was previously known or recognized
• Serious adverse events always pose a greater risk
  of harm, but are not always UPRs (i.e.
  unanticipated and study-related)

OHRP Guidance Topic III C
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VHA Handbook 1058.01 Reporting Research Events

• Unanticipated Problems include
• Interruptions of research due to concerns about
  safety, rights, or welfare of subjects, research
  personnel, or others
• Work-related injuries requiring more than minor
  medical intervention or lead to serious injury or
  death
• Any VA Pharmacy Benefits Management (PBM) Alerts
  related to a facility research project

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VHA Handbook 1058.01 Reporting Research Events

• Unanticipated Problems include
• Any Data Monitoring Committee (DMC) report
  describing a safety problem.
• Any sponsor analysis describing a safety problem.
  NOTE Sponsor "AE Reports" lacking meaningful
  analysis are not considered problems.

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Serious Adverse Event (SAE)

• Any AE or Problem that results in
• Death, a life-threatening experience, inpatient
  hospitalization, prolongation of hospitalization,
  persistent or significant disability or
  incapacity, congenital anomaly, or birth defect
  or
• Substantive harm or damage (or risk of
  substantive harm or damage) to the safety,
  rights, or welfare of research subjects, research
  staff or
• Substantive harm or damage (or risk of
  substantive harm or damage) to the safety or
  welfare of laboratory animals or
• The need for medical, surgical, behavioral,
  social, or other intervention to prevent any of
  the above

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Is an Adverse Event a UPR?
OHRP Algorithm
OHRP Guidance Topic III
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Reportable Adverse Events

AE/UPR
Adverse Events
UPRs

• Some, but not all, Unanticipated problems
  involving
• risk to subjects or others are also AEs
• Most adverse events are not UPRs
• AEs which are UPRs need to be reported

Modified from OHRP Guidance Topic III
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VHA Handbook 1058.01 Reporting Research Events

• General Requirement
• All Members of the Research Community Must Report
  Up the Chain
• Within 5 Business days of Discovering or Learning
  About A Reportable Event

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VHA Handbook 1058.01 Reporting Research Events

• Problems Involving Risks to Subjects or Others
  and
• Local Serious Adverse Events (Local SAEs)
• Must be reported to the IRB and the ACOS/R
• Within 5 business days of discovery

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Who Reports UPRs and to Whom?

• Principal Investigators (PIs) report potential
  UPRs to IRBs, and (when applicable) to study
  sponsors
• Study sponsors report UPRs (and other
  study-related information) to PIs, who, in turn,
  report them to the IRB
• IRBs determine when events are UPRs and report to
  Institutional Officials and oversight agencies
  (FDA, OHRP, ORO)

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What Should PIs Report to the IRB?

• Apparent and potential UPRs, including
• Adverse Events
• Other Study-related Problems/Information
• Serious and/or continuing noncompliance
• Suspension/termination of a study
• Breach of privacy/confidentiality

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Research-related Events Which Could Be (Or Could
Reveal) UPRs

• PI-initiated changes in protocol
• Study amendments, for example
• revision of the Consent Form
• revision of inclusion/exclusion criteria
• addition/deletion of study procedures etc.
• Suspension of enrollment
• New Information (e.g., DSMB reports,
  publications, sponsor alerts, etc.)

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IRB Authority for Managing AEs

• IRBs must have SOPs that provide detailed
  instructions on how to report and manage AEs
• Investigators must comply with the reporting
  requirements of the IRB.
• IRBs have flexibility in establishing local
  adverse event reporting requirements.

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VHA Handbook 1058.01 Reporting Research Events

• IRB Review of Serious Problems and SAEs
• If the AE or problem is serious and unanticipated
  and related or possibly related to the research,
  the IRB Chairperson must report the AE or problem
  to the Facility Director within 5 days of the
  determination
• If an informed consent modification is warranted,
  the convened IRB must determine and document
• Whether or not previously enrolled subjects must
  be notified
• If so, when notification is to occur and how it
  is to be documented

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VHA Handbook 1058.01 Reporting Research Events

• The IRB Member-Reviewer (or the convened IRB)
  must also document whether or not one of the
  following applies
• Immediate Action Is Needed to Prevent Harm, and
  Review by the Convened IRB Is Required
• Immediate Action Not Needed to Prevent Harm, but
  Review by the Convened IRB is Required

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VHA Handbook 1058.01 Reporting Research Events

• Within 5 business days of the report to the IRB,
  a qualified voting IRB Member-Reviewer (or the
  convened IRB) must determine and document whether
  the event is
• Serious or Not Serious
• Anticipated or Unanticipated
• Related, Possibly Related, or Unrelated to the
  Research

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IRB Actions in Response to UPRs

• Require study modification and/or related actions
  (e.g., providing additional information to
  participants, reconsenting subjects, etc.)
• Require additional monitoring
• Suspension or termination

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UPRs Reporting By The IRB And Institutional
Officials

• When the IRB determines that a study-related
  event is an Unanticipated Problem involving Risk
  to subjects or others, the UPR must be reported
  to
• Institutional Officials, and
• cognizant oversight agencies ORO, OHRP, FDA
  (usually, through the Institutional Official)

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VHA Handbook 1058.01 Reporting Research Events

• General Requirement
• Facility Director Must Report to ORO
• Within 5 business days of being informed of a
  reportable event
• Report must be in writing and signed
• Report required whether or not event has been
  resolved
• Followup reports as required by ORO

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Summary Procedures and Policies Should Be In
Place To Ensure That

• PIs report study-related events which could be
  UPRs (including AEs) to the IRB
• the IRB reviews the reported events and
  identifies UPRs (i.e., events which are
  unexpected, study-related, and involve risk to
  study subjects or others) and
• UPRs are addressed (for safety) and reported to
  Institutional Officials and oversight agencies
  (FDA, ORO, OHRP)

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QUESTIONS