1. www.diahome.org Adverse Event Reporting: A Patient or a Clinician Report? Ethan Basch, M.D., M.Sc. Memorial Sloan-Kettering Cancer Center October 26, 2009

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3. www.diahome.org Overview 1.Background on adverse event data collection –Current approaches –Focus on adverse symptom reporting, preapproval setting 2.Limitations of current adverse symptom reporting model, opportunities for improvement –Who reports –What is reported –How is reported

4. www.diahome.org Safety Data Collection Pre-INDPreapprovalPostapproval IND Lifecycle of a Drug/Biologic in the United States: Preclinical studies Non-US trials NDA/BLA Clinical trials (Phase 1,2,3)Spontaneous reporting systems Active surveillance programs Retrospective database mining Prospective studies - Postmarket commitment - Non-industry

5. www.diahome.org Institute of Medicine Report (2007) Cited a crisis in drug safety evaluation Rising importance of understanding safety of drugs throughout their lifecycle Recommendations focus on AE monitoring in the postapproval setting, and on FDA internal processes Multiple resulting postmarket-oriented initiatives Less attention on methods in the preapproval setting when prospectively collecting data in trials

6. www.diahome.org Uses of Preapproval AE Data –Regulatory review: Assess risk Provide safety data to balance with efficacy Provide safety signals to prompt requests for postmarketing further study –Labeling: Populate Adverse Reactions section Can be the basis of a claim

7. www.diahome.org Data Sources Differ By Type of AE (1) CATEGORYEXAMPLE DOMAINDATA SOURCE Laboratory valuesHemoglobinLab report EventsHospitalizationAdministrative data Clinical measurementsBlood PressureClinical staff (ClinRO) SymptomsNauseaClinical staff (ClinRO)

8. www.diahome.org Data Sources Differ By Type of AE (2) Adverse symptoms differ from other categories in terms of their data source, process of data collection, and documentation procedures Evaluation of these processes can aid in improving the efficiency and quality of adverse symptom data in clinical trials CATEGORYEXAMPLE DOMAINDATA SOURCE Laboratory valuesHemoglobinLab report EventsHospitalizationAdministrative data Clinical measurementsBlood PressureClinical staff (ClinRO) Adverse symptomsNauseaClinical staff (ClinRO)

9. www.diahome.org Adverse Events in Current Labels Basch: Ann Oncol, 2009 Almost half are symptoms Indication # of U.S. Approved Drug Labels Average # of AEs per Label Total # of Unique AEs across Labels Proportion of AEs which Are Symptoms Asthma 3554368 49% (180/368) Breast Cancer 3278616 36% (223/616) GERD 18115472 45% (213/472) Hyperlipidemia 2882365 43% (158/365) Osteoarthritis 3994684 41% (278/684)

10. www.diahome.org Process Questions 1.Who is in the best position to report adverse symptoms in clinical trials? 2.How should these data be elicited? 3.What information about symptoms should be collected? 4.When/Where should this information be collected during trials?

11. www.diahome.org Process Questions (1) 1.Who is in the best position to report adverse symptoms in clinical trials? 2.How should these data be elicited? 3.What information about symptoms should be collected? 4.When/Where should this information be collected during trials?

12. Patient Experiences Symptom Clinician Interprets Symptom Clinician interviews patient at visit Chart Representation of Symptom Clinician writes in chart Data Manager Interpretation of Symptom Data manager abstracts chart, converts findings to standardized terminology Research Database Manual data entry Basch: JCO, 2005 Common Approach to Adverse Symptom Reporting in Trials

13. Patient Experiences Symptom Research Database Basch: JCO, 2005 Alternative Approach: PROs (Not Standard)

14. Patient Experiences Symptom Research Database Clinical Research Personnel Basch: JCO, 2005 Approach

15. www.diahome.org FDA Draft Guidance Patient is in the best position to report on his or her symptoms, in the setting of making efficacy claims

16. www.diahome.org PROs for Adverse Symptoms? Should we expand this approach to encompass safety reporting? –i.e., Should patient-reported outcomes (PROs) become a standard approach to adverse symptom evaluation in clinical trials? What is the scientific evidence?

17. www.diahome.org Patient vs. Clinician Reports At any given visit: –Clinicians report fewer symptoms than patients –Clinicians report lower severity of symptoms than patients Across disease types Clinical trial and routine care settings Basch: Lancet Oncol, 2007 Stromgren: Acta Anesth, 2001 Weingart: Arch Intern Med, 2005 Basch: J Nat Cancer Inst, 2009 Pakhomov: Am J Manag Care, 2008 Sprangers, Acta Oncologica, 2000

18. www.diahome.org Cumulative Incidence of Fatigue Patient-reporting Clinician-reporting Moderate Severe Patient reporting Clinician reporting Basch: J Nat Cancer Inst, 2009

19. www.diahome.org Why Might They Differ? Limited time during visits Patients may downplay concerns Clinicians may downgrade Patients and clinicians have different clinical orientations when they report

20. www.diahome.org Different Orientations Clinician adverse symptom reports are more highly associated with clinical endpoints (such as death or hospitalization) while: Patient adverse symptom reports are more highly correlated with measures of day-to-day health status (such as HRQL or global health measures) Basch: ISOQOL, 2009

21. www.diahome.org Complementary Perspectives Clinician-reporting better reflects trajectory towards major clinical benchmarks –Clinicians are oriented towards these events Patient-reporting better reflects suffering from day-to-day –This represents additional information which is not currently collected in trials Basch: ISOQOL, 2009

22. www.diahome.org Is Patient AE Reporting Feasible? Patients willing and able to self-report their own adverse symptoms Over long periods of time Even end-stage with high symptom burdens Via wide variety of approaches (paper, computer, IVR/automated telephone systems) From clinic and from home Similar methods can be used as for efficacy-related PRO collection Basch: JAMIA, 2007

23. www.diahome.org Regulatory No specific requirement regarding the source of safety information (i.e., clinicians or patients) 21 CFR 314.50

24. www.diahome.org Advantages and Disadvantages Patient Reporting Eliminates data transcription errors More direct account of experience Patients can take time to report Enables between-visit reporting Capitalize on existing PRO methods Informs future patients about their peers May become unable to report (too ill) May neglect to report (too busy, etc.) Would require new infrastructure Clinician Reporting Professional training and experience Understand medical concepts and terms Can contextualize within/across patients Can appreciate seriousness of AEs Able to report if patient unable (SAEs) Already standard, established approach Often have limited time Can only document what they elicited Cannot report between visits Basch: JAMIA, 2007

25. www.diahome.org Process Questions (2) 1.Who is in the best position to report adverse symptoms in clinical trials? 2.How should these data be elicited? 3.What information about symptoms should be collected? 4.When/Where should this information be collected during trials?

26. www.diahome.org Current Approach in Trials Ad hoc elicitation/documentation by clinicians Checklists or CRFs which include specific symptoms are more sensitive –But, they rely on a priori lists which may not include all possible adverse symptoms Optimal approach therefore includes a checklist of selected symptoms, as well as a mechanism for ad hoc reporting Bent: Ann Intern Med, 2009

27. www.diahome.org Process Questions (3) 1.Who is in the best position to report adverse symptoms in clinical trials? 2.How should these data be elicited? 3.What information about symptoms should be collected? 4.When/Where should this information be collected during trials?

28. www.diahome.org Current Approach In most clinical trials, abstracted chart information is mapped to preferred terms from the MedDRA item bank for reporting MedDRA items are not graded for their magnitude (severity), they only demarcate the presence/absence of that issue MedDRA: Medical Dictionary for Regulatory Activities

29. Search for MedDRA Term

30. www.diahome.org Current Approach In oncology, AEs are reported as CTCAE items, which are each graded for magnitude –Provides more granular information –May include severity, frequency, interference –Information is published in trial results and labels CTCAE: NCI’s Common Terminology Criteria for Adverse Events

31. Docetaxel Drug Label Data from “Tax 327” pivotal trial

32. www.diahome.org Process Questions (4) 1.Who is in the best position to report adverse symptoms in clinical trials? 2.How should these data be elicited? 3.What information about symptoms should be collected? 4.When/Where should this information be collected during trials?

33. www.diahome.org How Often Should AEs be Reported? Currently, documentation of adverse symptoms in trials is done at clinic visits, which may be spread far apart, requiring recall of remote events May be reasonable for between-visit laboratory tests which are captured in real-time Not for symptoms: memory substantially degrades after several days Between-visit reporting improves detection of intervening symptoms which would otherwise be missed Broderick: Pain, 2008

34. www.diahome.org Summary Comprehensiveness of safety data in clinical trials may be enhanced by: 1.Collecting data from patients and clinicians 2.Including study-specific symptom checklists as well as ad hoc symptom reporting 3.Capturing information about magnitude 4.Considering between-visit assessments

35. www.diahome.org Current NCI Initiative Development of PRO-CTCAE –Item bank of adverse symptoms for patient self-reporting in oncology trials –Software system for prospective, scheduled data collection –Includes checklists and ad-hoc reporting –Collects incidence and magnitude data –Conveys data to clinicians to aid their reports Currently in beta testing http://outcomes.cancer.gov/tools/pro-ctcae.html