Challenges in classifying adverse events in cancer clinical trials
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Challenges in Classifying Adverse Events in Cancer Clinical Trials. Steven Joffe, MD, MPH Dave Harrington, PhD David Studdert, JD, PhD Saul Weingart, MD, PhD Damiana Maloof, RN . Disclosure. Member of clinical trial adverse event review board for Genzyme Corp (not oncology-related).

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Challenges in Classifying Adverse Events in Cancer Clinical Trials

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Challenges in Classifying Adverse Events in Cancer Clinical Trials

Steven Joffe, MD, MPH

Dave Harrington, PhD

David Studdert, JD, PhD

Saul Weingart, MD, PhD

Damiana Maloof, RN


Disclosure

  • Member of clinical trial adverse event review board for Genzyme Corp (not oncology-related)


Adverse Events in Clinical Trials

  • Adverse events (AEs) are critically important outcomes of clinical trials

    • Human subjects protection

    • Endpoints for judgments about benefits & risks of study interventions

  • Captured on Case Report Forms

  • Reported to oversight agencies


Components of AE Assessment

  • Type

  • Severity

  • Relatedness to study agent(s)

  • Expectedness


Global judgment about reportability to IRB

Components of AE Assessment

  • Type

  • Severity

  • Relatedness to study agent(s)

  • Expectedness


Reporting Criteria(to Dana-Farber IRB)

  • Grade 5 (fatal)

  • Grade 4, unless specifically exempted

  • Grade 2/3, if unexpected AND possibly, probably or definitely related

  • Virtually identical to NCI’s Adverse Event Expedited Reporting System (AdEERS) criteria


AE Grading in Oncology

  • NCI’s Common Terminology Criteria for Adverse Events (CTCAE) typically used

    • Effort to standardize nomenclature

    • developed by consensus methods; no formal process to establish reliability of grading

http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_v30


Aims

  • To assess the validity of physician reviewers’ determinations about whether AEs in cancer trials meet IRB reporting criteria

  • To assess the interrater reliability of reviewers’ determinations about whether AEs that occur in cancer trials meet IRB reporting criteria

  • To assess the validity and reliability of revie-wers’ judgments about the components of AEs


Study Methods


Panelists’ Roles

  • Review primary data from criterion sets of AEs

  • Rate each AE:

    • Classification

    • Grade

    • Relatedness

    • Expectedness

    • Reportable to IRB

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from CTCAE


Panelist Demographics


Panelists’ Experience


Panelists’ Experience


Statistical Analysis

  • Validity of judgments regarding reportability to IRB

    • % agreement with gold standard

  • Interrater reliability of raters’ judgments

    • Kappa coefficients


Results


Criterion Set of AEs


Validity of Judgments Regarding Reportability to IRB


Interrater Reliability of Panelists’ Judgments


Role of Experience: Rank

Kappa


Role of Experience: Service as PI

Kappa


Role of Experience: Number of AE Reports Filed

Kappa


Conclusions

  • Oncologists’ judgments about whether or not AEs require reporting to the IRB show high agreement with gold standard

  • Interrater reliability of oncologists’ judgments about components of AEs varies

    • High: expectedness of AE; need for reporting

    • Moderate: grade of AE

    • Low: relationship of AE to study agents


Limitations

  • Small sample sizes

    • Criterion set of AEs

    • Panel of physician reviewers

  • Generalizability of set of AEs

  • Reviewers may not reflect population of investigators who file AE reports

  • Judgments based on document review rather than on firsthand knowledge


Thoughts About Direction of Bias in Agreement Statistics

  • Factors biasing towards less agreement

    • Reviewer experience

  • Factors biasing towards greater agreement

    • Standardized set of documents for review

    • Criterion set selected based on maximum agreement among expert panel reviewers


Implications

  • Judgments about AEs are complex

    • Human subjects: efforts to enhance reliability, or to minimize reliance on judgments about causation, are needed

    • Science: toxicity data from uncontrolled trials may be misleading

    • RCR: education about need for reporting is important but insufficient


Debra Morley

Anna Mattson-DiCecca

Physician panelists

ORI

NCI

Milton Fund

Acknowledgments


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