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Adverse event and safety monitoring in clinical trials
Robert Silbergleit, MDUniversity of Michigan
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Objectives
• Purpose• Identifying• Reviewing• Coding• Reporting
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Purpose• To identify safety concerns• To exclude safety concerns• To contextualize risk• To comply with regulations
OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
FDA Guidance: Adverse Event Reporting to IRBs – Improving Human Subject Protection 2009
Safety Reporting Requirements for INDs and BA/BE Studies 2012
Safety Assessment for IND Safety Reporting, DRAFT 2015
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Purpose
To separate the wheat from the chaff… or… to see the dog and the soldier
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Ways of Measuring Safety
• On the primary outcome measure…– i.e. “Negative efficacy”
• On other pre-defined safety outcomes…
• Through monitoring of adverse events…
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Ways of Measuring Safety
• Pre-defined safety outcomes…– AE’s of special interest– Practical– Objective– Using available information– Communicable
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AE Regulations and Guidelines
• Similar (but not identical) terms are defined similarly (but not identically) in multiple places:– 21 CFR 312 (IND) and 314 (NDA)– 21 CFR 812 (IDE) and 814 (Premarket approval)– FDA guidance(s)– ICH GCP E6 and E2A and E9– ISO 14155 GCP for devices– NIH/NCI
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AE Regulations and Guidelines
• Adverse event terms are not defined or described in…– 45 CFR 46 The Common Rule– 21 CFR 50 FDA HSP Regulations– 21 CFR 56 IRB Regulations– ICH E2B Clinical Safety Data Management
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AE Regulations and Guidelines
• Synonyms of adverse “event” include:
Effect
Reaction (to a drug)
OutcomeOccurrence
Health Consequence
Experience
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Quiz
Select the most accurate statement
A. FDA guidance suggests that all AE be reported expeditiously to the IRB
B. The Common Rule distinguishes between Adverse Events and Adverse Occurrences
C. Safety outcomes should be predefined.
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What is an adverse event?
“any UNTOWARD medical occurrence in a subject”
• Syndromes/diagnoses preferably• Symptoms if necessary
• Report separate events individually
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What are not adverse events?
• Outcomes (death, surgery, intubation, etc.)• Pre-existing conditions (unless worsening)• Abnormal results of tests if not considered by
the investigator to be clinically significant• Other people’s problems and near misses
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Unanticipated Problems
Do not report A, Do report B and C
A = Adverse Events that are
not Unanticipated Problems
C = Unanticipated problems that are not AE
B = AE that are
unantici-pated
problems
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Properties of an AE
• Seriousness• Expectedness• Relatedness• Severity• Treatment, Resolution, Outcome
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Seriousness
• Fatal• Life-Threatening• Causes or prolongs hospitalization• Result in disability/congenital anomaly, or • Require intervention to prevent permanent
impairment or damage
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Expectedness
• Expected– adverse reactions anticipated with the study intervention
and pre-defined in the investigator brochure or protocol – (controversial?) adverse events commonly seen in
subject’s clinical scenario
• Unexpected– events not anticipated from the intervention or the
subject’s clinical scenario– aggregate imbalance of anticipated or common event at
interval analysis
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Relatedness
Not Related• The timing is wrong and there
was clearly another cause
Unlikely (one or both)• Another cause is possible• Not something the
intervention is known to cause
Possibly (2 of 3)Probably (must have all 3) • Timing is suggestive. • No other likely causes. • This is something the
intervention is known to cause.
Definitely (must have all 3)• Timing is suggestive. • No other possible cause. • This is something the
intervention is known to cause.
Sample Algorithm
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Severity
• Unrelated to Seriousness (sort of)
NCI Common Terminology Criteria for Adverse Events (CTCAE)
0 No AE (or within normal limits).
1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
2 Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) indicated; limiting age-appropriate instrumental activities of daily living (ADL).
3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
4 Life-threatening consequences; urgent intervention indicated.
5 Death related to AE.
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Treatment, Resolution, Outcome
• Date of onset, date resolved• Action (none, discontinued, other…)• Outcome
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Quiz
Which of these cannot be an adverse event?
A. Vomiting
B. Motor vehicle crash
C. Death
D. Pneumonia
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Identifying AE
• Over what period will events be collected?• When will you look?• Where will you look?
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Identifying AE
• Naming of events– Disambiguate
• Narrative description– Enough but not too much– Templates?
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“I just have to create a few loose ends for other peopleto clear up, and then I can out of here.”
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Reviewing AE
• Internal review– Administrative errors– Completeness– Consistency
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Reviewing AE
• Independent review/adjudication– Source material provided– Determinations to be made– Workloads and timelines
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Coding AE
• Lumping versus splitting
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Coding AE
• Available systems– MedDRA– WHO-ART– COSTART– ICD-10– SNOMED CT
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Coding AE
• Hierarchy imposed
• Multiaxiality
Lowest Level TermFeeling queasy
Preferred TermNausea
Reported TermSick to stomach
High Level TermNausea and vomiting
symptoms
High Level Group TermGastrointestinal signs
and symptoms
System Organ ClassGastrointestinal
disorders
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Coding AE• Completeness: AE “GOLD” requires clarification
• Accuracy: AE “COLD” might mean … Clarification or study specific plan required
• Verbatim: Coder cannot interpret 3 events (polydipsia, high blood sugar, polyuria = diabetes)
• Judgment: “Convulsions on drug withdrawal” codes to… “convulsions” or “drug withdrawal”?
Qureshi S, J Clin Res Best Pract 2012;8(3)
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Coding AE
• Consistency (in systematic review)– Coding agreement 88%– Accuracy 92%
Schroll JB et al. Challenges in Coding Adverse Events in Clinical Trials: A Systematic Review. PLoS ONE 2012;7(7):e41174
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Reporting AE
• To whom– IRB– FDA– DSMB
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Reporting AE
• When– Reporting schedules– MedWatch– Individual reports– Aggregate reports
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Reporting AE
• Future directions– Harmonization: the Safety Reporting Portal,
MedWatchPlus, FAERS or BAER format.(Initiated 2004, implemented in 2010 for NIH gene transfer trials, and non-investigational purposes)
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Other elements of a safety plan
• Emergency unblinding
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Thank you
Questions?