Adverse Events and Serious Adverse Events

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Adverse Events and Serious Adverse Events

• Office of Research Education and Regulatory
  Management

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Objectives

• Recognize Adverse Events and serious adverse
  events
• Review FDA inspection findings related to adverse
  events
• Review regulations related to adverse events
• Discuss recording and reporting of adverse events
• Discuss auditing of adverse events
• Demonstrate audit of adverse events

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FDA Inspection

• Failure to prepare and submit complete and
  accurate and timely reports of unanticipated
  adverse device effects

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Recognizing
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Adverse Events

• Any adverse event associated with the use of a
  drug in humans, whether or not considered
  related.
• 21CFR 314.80
• Any untoward medical occurrence in a patient
  administered a pharmaceutical product and which
  does not necessarily have a causal relationship
  with the treatment
• ICH E6

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Adverse Event

• NCI
• An unexpected medical problem that occurs during
  treatment with a drug or other therapy.
• Adverse events do not have to be a caused by the
  drug or therapy

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Serious Adverse Event

• Fred
• Doesnt
• Have
• Any
• Money
• Left

• Fatal
• Disability
• Hospitalization
• Anomaly
• Medically Significant
• Life Threatening

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Expected Vs. Unexpected

• Unexpected
• Not listed in Investigational Brochure, Informed
  Consent, or General Investigational Plan
• Also not listed in a drug package insert

• Expected
• Known to Occur and is Listed in the
  Investigational Brochure, Informed Consent, or
  General Investigational Plan

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Recording
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Recording

• Know which adverse events the protocol requires
  to be captured

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Source Documentation

• Source Documentation of adverse events include
  documentation in the medical records of
• Event
• Date it occurred
• Grade as determined by CTCAE
• Expected or Unexpected
• Attribution as assigned by PI
• Date resolved
• Treatment patient received specifically related
  to event

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Sample Adverse Event Recording Form

• See template behind this presentation

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Attribution (Causality)

• The attribution (relationship or causality or
  drug related assessment) must be determined
• A determination made by a clinical investigator
  that describes the relationship or association
  of the study product with an adverse experience
• This determination must be recorded both in the
  medical record as well as in the case report form.

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Attribution

• What should the investigator consider prior to
  assigning attribution?
• Individual medical history
• Known effects of concomitant medications

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Attribution

• Definite Clearly related to study agent
• Probable Likely related to study agent
• Possible May be related to study agent
• Unlikely Doubtfully related to study agent
• Unrelated Clearly not related to study agent

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How to Capture Adverse Events?

• Split or Lumped
• Fever, Diarrhea, and Vomiting (Viral
  Gastroenteritis)
• Cough, Sniffles, Sore throat (Flu)

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How to Capture Adverse Events?

• Problems with similar terms
• Rash or Dermatitis
• Wheezing, reactive airway disease, congestion,
  cold, , asthma

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Documenting Resolution Dates

• Challenge
• Does the patient remember when their adverse
  event resolved?
• Do you call the patient? Or wait till the next
  visit?

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Patient Toxicity Diary

• Diaries where patients capture toxicities between
  their follow up appointments

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Patient Toxicity Diaries

• Patient writes down constipation because he did
  not have a bowel movement one day
• Research nurse captures constipation without
  assessing further
• Physician copies the research nurses note and
  also dictates constipation
• Did anyone ask about the constipation?
• According to CTC V3, constipation is grade 1 only
  if there is occasional or intermittent symptoms
  occasional use of stool softeners, laxatives,
  dietary modification, or enema

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Patient Adverse Event Diaries

• Advantages

• Disadvantages

• Allows capturing information on a daily basis
  while patient is away from clinic
• A communication tool for patient returns to
  clinic
• Useful in capturing onset and resolution dates of
  adverse events

• Time consuming
• Patient non-compliance
• Patient self diagnosis or interpretation
• Complicated Instructions

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Question to ask

• When should site staff begin collecting adverse
  event information?

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Question to ask

• How long should one collect adverse events after
  the subject completes study treatment?

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Reporting
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Reporting Serious Events

• An investigator must promptly report to the
  sponsor any adverse effect that may reasonably be
  regarded as caused by or probably caused by the
  drug. If the adverse effect is alarming, the
  investigator shall report the adverse effect
  immediately.
• 21CFR312.64

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Reporting Criteria

• Routine Reporting
• Know which events can be reported at interim
  analysis or annual reviews
• Expedited Reporting
• Know which events require immediate reporting

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Reporting Criteria

• Know which type of expedited reports each
  regulatory body requires
• FDA
• Sponsor
• Co-Sponsor
• MD Anderson
• NCI
• Collaborative Groups

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Issues in reporting

• Primary events
• Example
• Patient admitted with Congestive Heart Failure
• Subsequently develops Pulmonary Edema and
  Cardiogenic Shock

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Consequences of Improper Reporting

• Protocol Violations
• IRB will close protocol
• FDA Hold
• Sponsor Hold
• Research Privileges Revoked
• Patient Safety

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Auditing
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Auditing Check Points

• How are AEs being recorded in the medical record?
• Does documentation include grade, onset,
  resolution, and attribution?

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Auditing Check Points

• Were all toxicities included?
• Was the proper CTCAE version used for the
  protocol?
• Were the toxicities graded appropriately?

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Auditing Check Points

• Was the event a dose limiting toxicity?
• Should the dose have been reduced?
• If so, did the research team realize it as such
  and identify it correctly?

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Auditing

• Are adverse events appropriately reported within
  the time periods required by regulations,
  sponsor, and IRB policies?

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We have reviewed.

• Recognizing adverse events and serious adverse
  events
• Inspections and findings related to adverse
  events
• Regulations related to adverse events
• Recording and reporting of adverse events
• Auditing of adverse events