Adverse Events in Clinical Research Studies What we are suppose to do. What we do. What we intend to

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Adverse Events in Clinical Research StudiesWhat
we are suppose to do.What we do.What we intend
to do.

• Henry Parkman, MD

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Regulatory Requirements of Reporting Adverse
Events

• Code of Federal Regulations (Common Rule)
• 45 CFR 46.103 Prompt reporting of any
  unanticipated problems involving the risks to
  subjects and others. Reporting is to the IRB,
  appropriate institutional officials and the
  Department or Agency head. If federally funded
  research, report to Department or Agency. If
  pharmaceutically funded, report to sponsor.
• 21 CRF 312.32 The sponsor must notify the FDA
  and participating investigators of any adverse
  event associates with the use of a test article
  that is both serious and unexpected.
• 21 CFR 312.52 An investigator shall promptly
  report to the sponsor any adverse effect hat may
  reasonably be regarded as caused by, or probably
  caused by, the drug. If the adverse event is
  alarming, the investigator shall report the
  adverse effect immediately.

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Interpretation of Regulations in View of
Increasing Demand of IRBs time

• IRBs are required to review only events that are
  both serious and unexpected (serious adverse
  events).
• Serious Death, Life threatening experience,
  inpatient hospitalization, prolongation of
  hospitalization, persistent or significant
  disability/incapacity, a congenital anomaly/birth
  defect.
• Unexpected Any adverse experience the
  specificity or severity of which is not
  consistent with the current protocol description
  that was approved by the IRB or the currently
  approved informed consent form.
• Amdur R. IRB Member Handbook. 2003.

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The Adverse Events Subcommittee ofTemple
University Health Sciences Center

• Meets monthly 3rd Thursday of each month
• Members
• Henry Parkman, MD (Chair, IRB AE Subcommittee)
• Michael Jacobs, PharmD (Chair, IRB Committees A1
  A2)
• John Travaline, MD
• Jesse Goldman, MD
• Bill Hirschhorn, MS
• Richard Throm, BA (IRB Coordinator)
• Ken Geller, PhD (ex-officio Assistant Vice
  President for Research/HSC

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Duties of Temples AE Subcommittee

• Committee meets at least monthly
• Review all serious adverse events reported to the
  IRB for studies followed by the A1 and A2 IRB
  committees
• Discuss what action to take, if any, in response
  to the reported A/Es
• Summary report presented at the next IRB meeting
• Help ensure that regulations are followed.
• Prompt reporting of SAEs to the IRB
• Investigator reporting of SAEs to sponsor

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• In whom did the adverse event occur?
• Temple patient
• Non-Temple patient multicenter study
• same agent but different study
• What is the status of research protocol at
  Temple?
• Ongoing, closed to enrollment, closed.
• Was the adverse event related to participation in
  the research study? Was it serious?
• Often involves comparison of observed vs
  expected occurrences.
• Incidence of AE requires total number and number
  of people exposed, not just the isolated event
  reported to the IRB. The IRB often does not have
  this information in multicenter study to make an
  informed decision.

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• Is the adverse event currently mentioned in the
  consent form and/or protocol summary?
• Depending on the study, is it listed in the
  package insert or investigator's drug brochure?
• Is there is change in the risk / benefit profile?
• Who is supplying information on AE and making
  this decision?
• PI, Pharmaceutical sponsor, Data monitoring
  committee,
• Independent Data and Safety Monitoring Board.
• Should the consent form/protocol be changed?
• Addition to the consent form?
• If so, should currently enrolled subjects be
  reconsented?
• Should the study be monitored more closely?
• Should the study protocol be revised?
• Should the study be stopped?

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General Outcomes of AE Subcommittees Review of
Adverse Events

• The investigator is sent written documentation of
  review Acknowledge submission and review
• Addition/change to consent form
• Need for more information
• Case narrative of AE, DSMB results
• Investigator to sign forms
• Information as to sponsor notification
• Suspend study
• Review of protocol steps pharmacy not
• Summary report presented at the next IRB meeting

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Some Problems

• Adverse events in clinical research trials is of
  great concern to everyone. Investigators,
  sponsors, and IRBS all bear responsibility for
  addressing AEs in clinical trials.
• Recent public SAEs have felt to erode public and
  government confidence of clinical research and
  drug development.
• Growing number of AE submission to IRBs for
  review. IRBs find themselves at the center of
  the debate on how to handle the growing problem
  of AEs even though they do not have primary
  reporting responsibility.
• Pharmaceutical companies referring most AEs to
  IRB to be reviewed (CYA), not just serious not
  unexpected.
• AEs are reported, but how frequent are they?
  Need the number of patients exposed to a drug to
  find out the incidence of the AE. Is the
  observed incidence above the expected incidence
  (outside of the study)?

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Hammerschmidts Eight Steps to Help IRBs Manage
Adverse Events

• 1. Keep subject safety at the top of the
  priority.
• 2. Insist on timely, complete, and accurate
  information
• 3. Recognize the limits of what the local IRB
  can do.
• Give precedence to the following types of AEs.
• 4. Intramural events over extramural events.
• 5. Events rated by on-site investigators as
  likely study-related.
• 6. Events in the same study or similar studies
  that the IRB is watching.
• 7. Life-threatening events
• 8. Studies without formal safety monitoring
  (investigator-initiated.
• Hammerschmidt. Clinical Trials Advisor
  200493-4.

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Some New Events

• Data and Safety Monitoring Boards for Multicenter
  Studies. These are helpful to take the burden
  off local IRBs.
• Electronic reporting of AEs at Temple.
• Software on line. Pilot testing by several
  coordinators.
• Attempting to harmonize the policies of OHRP,
  NIH, FDA for defining AEs that should be reported
  to whom and when.