1. Risk Assessment Public Meeting - 4/9/03 1 Premarketing Risk Assessment: Considerations for Data Analysis and Data Presentation Ellis F. Unger, M.D. Division of Clinical Trial Design and Analysis Office of Therapeutics Research and Review Center for Biologics Evaluation and Research

2. Risk Assessment Public Meeting - 4/9/03 2 Considerations for Data Analysis and Data Presentation Many aspects of these topics addressed in: “Guideline for the Format and Content of the Clinical and Statistical Sections of an Application” (1988) “Guideline for the Format and Content of the Clinical and Statistical Sections of an Application” (1988) “ICH guideline for industry E3 Structure and Content of Clinical Study Reports” (ICH-E3, 1995) “ICH guideline for industry E3 Structure and Content of Clinical Study Reports” (ICH-E3, 1995)

3. Risk Assessment Public Meeting - 4/9/03 3 Issues for Discussion Grouping of adverse events Grouping of adverse events Temporal relations between adverse events and Temporal relations between adverse events and product exposure product exposure Analyses of dose effects Analyses of dose effects Data pooling Data pooling Missing safety data Missing safety data

4. Risk Assessment Public Meeting - 4/9/03 4 Coding and Grouping of Adverse Events MedDRA or other coding dictionary should be used consistently throughout clinical development program, with adverse events examined as coded MedDRA or other coding dictionary should be used consistently throughout clinical development program, with adverse events examined as coded Specific adverse effects or toxicities (those with constellation of symptoms and signs; those with common pathophysiological bases) may merit analyses of grouped terms Specific adverse effects or toxicities (those with constellation of symptoms and signs; those with common pathophysiological bases) may merit analyses of grouped terms

5. Risk Assessment Public Meeting - 4/9/03 5 Coding of Adverse Events Utility of Combining Related Terms: Amplification of weak safety signals: Linking terms by pathophysiologic mechanism Linking terms by pathophysiologic mechanism Linking symptoms, signs, and lab abnormalities Linking symptoms, signs, and lab abnormalities Example: Ischemic events - arterial thrombosis/occlusion, embolism, claudication, ischemic necrosis, gangrene, intestinal ischemia, pulmonary embolism, acute MI Ischemic events - arterial thrombosis/occlusion, embolism, claudication, ischemic necrosis, gangrene, intestinal ischemia, pulmonary embolism, acute MI

6. Risk Assessment Public Meeting - 4/9/03 6 Coding of Adverse Events Downside of Combining Related Terms: Potential to mask serious, unusual events with less serious, more common events: e.g., toxic megacolon masked by constipation e.g., toxic megacolon masked by constipation

7. Risk Assessment Public Meeting - 4/9/03 7 Coding of Adverse Events Division of One Event into Many Terms: Potential to decrease apparent incidence of an adverse event: e.g., including pedal edema, generalized edema, and peripheral edema as separate terms will decrease the apparent incidence of fluid retention e.g., including pedal edema, generalized edema, and peripheral edema as separate terms will decrease the apparent incidence of fluid retention

8. Risk Assessment Public Meeting - 4/9/03 8 Coding of Adverse Events Whenever possible, we recommend that the sponsor prospectively group adverse event terms and develop case definitions in consultation with FDA. We recognize that some groupings can only be constructed after the safety data are obtained.

9. Risk Assessment Public Meeting - 4/9/03 9 Temporal Associations Between Adverse Events and Product Exposure Time to Event Analyses are Appropriate for: Clinically important events that occur on a delayed basis, e.g., progression of disability, development of cardiac toxicity, need for surgical intervention, malignancy Clinically important events that occur on a delayed basis, e.g., progression of disability, development of cardiac toxicity, need for surgical intervention, malignancy Adverse events that occur at initiation of treatment but diminish in frequency over time Adverse events that occur at initiation of treatment but diminish in frequency over time

10. Risk Assessment Public Meeting - 4/9/03 10 Time-to-Event Analyses of Adverse Events Suggested Methods: Descriptions of risk as a function of duration of exposure or time since initial exposure (i.e., life table analyses for cumulative incidence) Assessment of risk within discrete time intervals over the observation period (i.e., a hazard rate curve) to illustrate the change in risk over time

11. Risk Assessment Public Meeting - 4/9/03 11 Time to First Malignancy: Rheumatoid Arthritis Patients Treated with Adalimumab (Abbott - Arthritis Advisory Committee Meeting; 3/4/03) (n=2468)

12. Risk Assessment Public Meeting - 4/9/03 12 Flu-Like Symptoms vs. Time (Interferon  -1b)

13. Risk Assessment Public Meeting - 4/9/03 13 Analyses of Adverse Events by Dose The relationship between adverse events and exposure may help determine whether an event is actually related to the product and, if so, the magnitude of the risk.

14. Risk Assessment Public Meeting - 4/9/03 14 Adverse Events by Dose: Methods of Analysis Adverse events as a function of administered dose (especially for dose-ranging studies, or development programs that evaluate >1 dose) Adverse events as a function of administered dose (especially for dose-ranging studies, or development programs that evaluate >1 dose) Adverse events as a function of weight- or body surface area-adjusted dose Adverse events as a function of weight- or body surface area-adjusted dose Adverse events as a function of cumulative dose received prior to event Adverse events as a function of cumulative dose received prior to event Adverse events as a function of drug plasma concentration Adverse events as a function of drug plasma concentration

15. Risk Assessment Public Meeting - 4/9/03 15 Tenecteplase in Acute MI: Intracranial Hemorrhage by Weight-Adjusted Dose Absence of dose-response

16. Risk Assessment Public Meeting - 4/9/03 16 Darbepoetin alfa vs. Epoetin alfa for Anemia of Chronic Renal Failure: Dyspnea/Tachypnea by Total Weight- Adjusted Dose Administered in the 4 Weeks Preceding Event Presence of apparent dose-response

17. Risk Assessment Public Meeting - 4/9/03 17 Absence of dose-response Darbepoetin alfa vs. Epoetin alfa for Anemia of Chronic Renal Failure: Back Pain by Total Weight-Adjusted Dose Administered in the 4 Weeks Preceding Event

18. Risk Assessment Public Meeting - 4/9/03 18 Stepped Dosing Algorithm (Incremental dosing Based on Age, Weight, or BSA) Cut points are necessarily arbitrary. Cut points are necessarily arbitrary. Important to make a specific effort to examine safety (and efficacy) at doses just above and below the cut points. Important to make a specific effort to examine safety (and efficacy) at doses just above and below the cut points.

19. Risk Assessment Public Meeting - 4/9/03 19 Stepped Dosing Algorithm: Tenecteplase (Thrombolytic Agent) in Acute MI Tenecteplase dose

20. Risk Assessment Public Meeting - 4/9/03 20 Tenecteplase in Acute MI: Subject Weight Distribution in Phase 3 Study (ASSENT II) = weight ending in “0” n = 9028

21. Risk Assessment Public Meeting - 4/9/03 21 Tenecteplase in Acute MI: Rounding Weight to the Nearest 10 kg Increases Dose Tenecteplase dose

22. Risk Assessment Public Meeting - 4/9/03 22 Tenecteplase in Acute MI: Intracranial Hemorrhage by Last Digit of Estimated Weight (Patients with no recorded weight, n=3861) Similar frequency of intracranial hemorrhage

23. Risk Assessment Public Meeting - 4/9/03 23 Role of Data Pooling in Risk Assessment Pooling is actually a meta-analysis of individual patient data (i.e., retrospectively combining patient-level data from different clinical studies to assess a safety outcome of interest).

24. Risk Assessment Public Meeting - 4/9/03 24 Used Appropriately, Pooled Analyses Can: Facilitate detection of relatively rare events Facilitate detection of relatively rare events Enhance the power to detect a statistical association Enhance the power to detect a statistical association Aid interpretation of chance findings in individual studies Aid interpretation of chance findings in individual studies Provide more reliable estimates of the magnitude and constancy of risk over time Provide more reliable estimates of the magnitude and constancy of risk over time

25. Risk Assessment Public Meeting - 4/9/03 25 Characteristics of Valid Pooled Analyses: Phase 1 pharmacokinetic and pharmacodynamic studies excluded Phase 1 pharmacokinetic and pharmacodynamic studies excluded Risk of safety outcome of interest is expressed in person-years, or a time-to- event analysis is conducted Risk of safety outcome of interest is expressed in person-years, or a time-to- event analysis is conducted Pooled patient population is relatively homogeneous Pooled patient population is relatively homogeneous Studies use similar methods of adverse event ascertainment Studies use similar methods of adverse event ascertainment

26. Risk Assessment Public Meeting - 4/9/03 26 Data Pooling: Interpretation of Negative Results A negative result from a pooled analysis does not prove absence of risk. A negative result from a pooled analysis does not prove absence of risk. Negative results should be interpreted in the context of the potential limitations of the analysis. Negative results should be interpreted in the context of the potential limitations of the analysis. Ensure that the previously mentioned principles have been appropriately considered in the analysis. Ensure that the previously mentioned principles have been appropriately considered in the analysis.

27. Risk Assessment Public Meeting - 4/9/03 27 What is the Role of Subgroup Analysis in the Safety Assessment? Subgroup analyses are critical to the overall risk-benefit assessment, and should be addressed in NDA/BLA submissions in detail: Demographics Demographics Baseline disease status Baseline disease status Concomitant illness Concomitant illness Concomitant therapy Concomitant therapy

28. Risk Assessment Public Meeting - 4/9/03 28 How Can the Analyses of Missing Safety Data be Most Informative? FDA would be interested in public comment on ways this issue affects risk assessment and/or unique methods that could be used to address the challenge that missing data presents.

29. Risk Assessment Public Meeting - 4/9/03 29 Important Aspects of Data Presentation (1) Relationship of exposure time to the development of the adverse event Relationship of exposure time to the development of the adverse event Summary of adverse event rates using a range of more restrictive to less restrictive definitions (e.g., myocardial infarction versus myocardial ischemia) Summary of adverse event rates using a range of more restrictive to less restrictive definitions (e.g., myocardial infarction versus myocardial ischemia) Summary of the distribution of important demographic variables across the pooled data Summary of the distribution of important demographic variables across the pooled data

30. Risk Assessment Public Meeting - 4/9/03 30 Important Aspects of Data Presentation (2) Where complete case report forms are called for [21 CFR 314.50], hospital records, autopsy reports, biopsy reports, and radiological reports should also be included, where applicable Where complete case report forms are called for [21 CFR 314.50], hospital records, autopsy reports, biopsy reports, and radiological reports should also be included, where applicable Assuring that narrative summaries include important supplementary data (e.g., pertinent lab data, ECG data, biopsy data), as previously articulated in guidance