Identifying and Reporting Adverse Events and Unanticipated Problems

1
Identifying and Reporting Adverse Events and
Unanticipated Problems

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

2
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

3
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)

4
Regulatory Guidance

• VHA ORD Handbook 1200.5 Requirements for the
  Protection of Human Subjects in Research
• VHA Handbook 1058.1 Reporting AEs in Research to
  the Office of Research Oversight
• VA Memorandum (9/8/05) What to Report to ORO
• OHRP Guidance (1/15/07) Guidance on Reviewing
  and Reporting UPRs and AEs
• Local IRB SOP Manual

5
(Some of) What We Need To Know To Understand The
Issue

• What are Adverse Events (AEs) and Unanticipated
  Problems involving Risk to subjects or others
  (UPRs)?
• What should be reported?
• Who should report?
• To whom should they report?
• When should they report?

6
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.

7
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.

8
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
9
Reportable Adverse Events (AEs)

• Unanticipated Problems involving Risk to subjects
  or others must be reported
• AEs must be reported when they are also UPRs,
  which means when they are
• Unanticipated, and
• Study-Related, and
• Involving (or indicative of) risk to study
  subjects or others

10
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)
11
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
12
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
13
Serious Adverse Event (SAE)

• Death
• Life threatening experience
• Hospitalization or prolongation of
  hospitalization
• Persistent or significant disability or incapacity

• Congenital anomaly and/or birth defects
• An event that may require medical or surgical
  treatment to prevent one of the preceding outcomes

VHA 1200.53(a)(1)
14
Is an Adverse Event a UPR?
OHRP Algorithm
OHRP Guidance Topic III
15
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)

16
PIs Reporting UPRs to IRBs

• Any research-related problems involving
  risks that are not anticipated in terms of
  nature, severity, or frequency of occurrence
  must be reported promptly to the IRB. 5(a)
• Reporting Unanticipated Problems and Adverse
  Events to the IRB
• VA ORO Memorandum December 6, 2006

17
Research-related Events Which Could Be (Or Could
Reveal) UPRs

• Adverse Events (local or global)
• 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.)

18
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

19
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.

20
Information Management Inadequate Reporting To
The IRB

• The IRB Is Uninformed

Poor local management of adverse events and UPRs
?
21
Information ManagementExcessive Reporting To
The IRB

• Too Much
• Information
• ?
• Can hamper the IRBs ability to recognize a
  UPR

22
ORO Guidance

• A popular strategy employed by many
  facilities involves requiring a certain degree of
  over-reporting by investigators and the use of
  triage mechanisms to determine which of the items
  reported by the investigator must actually be
  reviewed by the convened IRB. 7(a)

ORO 12-6-06 Memo
23
AE Assessment By The IRBThe Data Monitoring Plan

• The Data Monitoring Plan needs to include
  procedures for reporting AEs
• Spectrum of events that might occur
• Time frame for reporting
• Stopping rules when action is needed
• The Data Monitoring Plan should be included in
  the protocol and must be reviewed and approved by
  the IRB

VHA 1200.57(a)(6) OHRP Guidance Topic VI
24
AE Assessment By The IRBContinuing Review

• The investigator must submit to the IRB a written
  progress report that includes
• Information that may impact on risk benefit
  ratio summary of AEs and UPRs
• An assurance that all AEs and UPRs have been
  reported as required
• DSMB/DMC reports if applicable

VHA 1200.57(g)
25
AE Management The Adverse Event Report

• IRB establishes policies (requirements) for
  investigator reporting that
• provide adequate protection,
• minimize the volume, and
• are easy to follow.
• The policies may distinguish local (internal)
  from global (external) AEs

26
AE ManagementWhat To Include In An AE Report

• Appropriate identifying information
• Complete, detailed description of event
• Analysis of the event with respect to criteria
  for reportable events
• Nature, severity, frequency
• Relationship to participation
• Expected risk profile
• Actions taken, if any

27
External (Global) Adverse Events

• Individual adverse events occurring at other
  centers should only be reported to investigators
  and IRBs at all institutions if they meet the
  criteria for a reportable unanticipated problem
• Unanticipated
• Study-related and
• Indicative of risk for subjects or others

OHRP Guidance Topic IV B
28
AE Management Guidelines for Reporting External
AEs

• The Investigators report of an external (global)
  AE to the local IRB should include
• the reason the event was determined to be an
  unanticipated problem, and
• a description of changes or actions (recommended
  or required by the sponsor) to be taken in
  response to the problem

Modified from OHRP Guidance Topic IV B
29
IRB Assessment of Reported UPRs A Procedural
Example

• A PI reports a potential UPR to the IRB
• The report is reviewed by a member of the IRB
  (e.g., Chair or designee)
• The reviewer screens the report to determine if
  it warrants IRB attention (i.e., as a potential
  UPR)
• The IRB reviews the event, determines if it is a
  UPR and responds accordingly

30
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
• Reporting to Principal Investigator,
  Institutional Official, ORO, OHRP, FDA

31
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)

32
Reporting To Institutional Officials

• Institutions must have written procedures for
  reporting problems to appropriate institutional
  officials.

45 CFR 46.103(a)
33
Reporting UPRs to Federal Agencies
Office of Human Research Protection
34

• IRBs are also responsible for ensuring that
  reports of unanticipated problems involving risks
  to human subjects or others are reported to the
  FDA. Usually, this reporting is accomplished
  through the normal reporting channel, i.e., the
  investigator to the sponsor to FDA.

FDA Information Sheets Continuing Review after
Study Approval 3(b)
35

• Investigational New Drug Safety Reports
• The sponsor shall notify FDA and all
  participating investigators in a written IND
  safety report of any adverse experience
  associated with the drug that is both serious and
  unexpected
• Report due within 15 calendar days

21 CFR 312.32(c)
36

• An investigator shall submit to the sponsor
  and to the reviewing IRB a report of any
  unanticipated adverse device effect occurring
  during an investigation as soon as possible, but
  in no event later than 10 working days after the
  investigator first learns of the effect.
  - 21 CFR 812.150(a)(1)
• Sponsors must also report adverse device
  effects to PIs and reviewing IRBs, within 10
  working days 21 CFR 812.150(b)(1)

37
Office of Human Research Protection

• Report any unanticipated problems involving risks
  to subjects or others.
• Report should include
• Project identification
• Description of problem
• Action plan
• Report promptly

45 CFR 46.103(b)(5)
38

• Institutional Officials should also report
• any UPR (including events which are not AEs) that
  results in a substantive action by the IRB
• any for-cause suspension or termination of
  VA-approved human subject research
• any serious or continuing noncompliance (with
  Federal regulations, VHA policies, or IRB
  determinations or requirements) and
• any change in the facilitys accreditation, FWA,
  or MOU with an affiliate

Adapted from VHA Handbook 1058.16(a)
39
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)

40
QUESTIONS