Transcript Adverse Events, Serious Adverse Events and Disease Response

Adverse Events and Serious
Adverse Events
Office of Research Education and
Regulatory Management
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
FDA Inspection
• “Failure to prepare and submit complete and
accurate and timely reports of unanticipated
adverse device effects”
Recognizing
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
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
Serious Adverse Event
Fred
Doesn’t
Have
Any
Money
Left
Fatal
Disability
Hospitalization
Anomaly
Medically Significant
Life Threatening
Expected Vs. Unexpected
• Expected
– Known to Occur and is
Listed in the
Investigational
Brochure, Informed
Consent, or General
Investigational Plan
• Unexpected
– Not listed in
Investigational
Brochure, Informed
Consent, or General
Investigational Plan
– Also not listed in a drug
package insert
Recording
Recording
• Know which adverse events the protocol
requires to be captured
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
Sample Adverse Event Recording Form
• See template behind this presentation
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.
Attribution
• What should the investigator consider prior to
assigning attribution?
– Individual medical history
– Known effects of concomitant medications
Attribution
•
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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
How to Capture Adverse Events?
• Split or Lumped
– Fever, Diarrhea, and Vomiting (Viral
Gastroenteritis)
– Cough, Sniffles, Sore throat (Flu)
How to Capture Adverse Events?
• Problems with similar terms
– Rash or Dermatitis
– Wheezing, reactive airway disease, congestion,
cold, , asthma
Documenting Resolution Dates
• Challenge
– Does the patient remember when their adverse
event resolved?
– Do you call the patient? Or wait till the next visit?
Patient Toxicity Diary
• Diaries where patients capture toxicities
between their follow up appointments
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 nurse’s 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
Patient Adverse Event Diaries
Advantages
• 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
Disadvantages
• Time consuming
• Patient non-compliance
• Patient self diagnosis or
interpretation
• Complicated Instructions
Question to ask
• When should site staff begin collecting
adverse event information?
Question to ask
• How long should one collect adverse events
after the subject completes study treatment?
Reporting
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
Reporting Criteria
• Routine Reporting
– Know which events can be reported at interim
analysis or annual reviews
• Expedited Reporting
– Know which events require immediate reporting
Reporting Criteria
• Know which type of expedited reports each
regulatory body requires
– FDA
– Sponsor
– Co-Sponsor
– MD Anderson
– NCI
– Collaborative Groups
Issues in reporting
• Primary events
– Example
• Patient admitted with Congestive Heart Failure
• Subsequently develops: Pulmonary Edema and
Cardiogenic Shock
Consequences of Improper Reporting
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Protocol Violations
IRB will close protocol
FDA Hold
Sponsor Hold
Research Privileges Revoked
Patient Safety
Auditing
Auditing Check Points
• How are AEs being recorded in the medical
record?
• Does documentation include grade, onset,
resolution, and attribution?
Auditing Check Points
• Were all toxicities included?
• Was the proper CTCAE version used for the
protocol?
• Were the toxicities graded appropriately?
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?
Auditing
• Are adverse events appropriately reported
within the time periods required by
regulations, sponsor, and IRB policies?
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