Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003

1. FDA Anti-Infective Drugs Advisory Committee Design Issues in ABS Trials: Surrogates Endpoints & Non-Inferiority Trials October 29, 2003 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington

2. Design Issues in ABS Trials • Criteria for Study Endpoints • Use of Surrogate Endpoints • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Active vs.Placebo controlled trials • Time to Event Analyses in ABS Trials

3. Design Issues in ABS Trials • Criteria for Study Endpoints • Use of Surrogate Endpoints • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Active vs. Placebo controlled trials • Time to Event Analyses in ABS Trials

4. Criteria for Study Endpointsin ABS Clinical Trials • Measurable/Interpretable • Sensitive • Clinically relevant ~ Resolution/Improvement of ABS Symptoms ~ Reducing the time to Resolution

5. Design Issues in ABS Trials • Criteria for Study Endpoints • Use of Surrogate Endpoints • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Active vs. Placebo controlled trials • Time to Event Analyses in ABS Trials

6. Use of Surrogate Endpoints Treatment Effects on Surrogate Endpoints eg:~Radiological Resolution of Disease ~Microbiological Outcomes • Establishes Biological Activity • But Not Necessarily Clinical Efficacy

7. Time Intervention Surrogate True Clinical Endpoint Outcome Disease

8. Illustration: AIDS Patients with MAI Bacteremia Clarithromycin Dose (mg bid) 500 1000 2000 Bacterial Load 145 34 25 12 wk Mortality 5.7% 25.5% 28.0% Chaisson et al, 1994

9. Time Intervention Bacterial 12 week Load Mortality Disease

10. Validation of Surrogate Endpoints Property of a Valid Surrogate ·Effect of the Intervention on the Clinical Endpoint is reliably predicted by the Effect of the Intervention on the Surrogate Endpoint

11. Prentice’s Sufficient Conditions 1.The surrogate endpoint must be correlated with the clinical outcome 2.The surrogate endpoint must fully capture the net effect of treatment on the clinical outcome

12. Validation of Surrogate Endpoints Statistical ·Meta-analyses of clinical trials data Clinical ·Comprehensive understanding of the ~Causal pathways of the disease process ~Intervention’s intended and unintended mechanisms of action

13. Clinical Endpoints & Surrogates in ABS Clinical Trials •Clinical Endpoints: ~ Resolution/Improvement of ABS Symptoms • Surrogate Endpoints: ~Radiological Resolution of Disease ~Microbiological Outcomes Validation of Surrogate Endpoints requires more than correlation with Clinical Endpoints

14. Design Issues in ABS Trials • Criteria for Study Endpoints • Use of Surrogate Endpoints • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Active vs. Placebo controlled trials • Time to Event Analyses in ABS Trials

15. Dual Goals of Non-Inferiority Trials • To enable a direct evaluation of the clinical efficacy of EXP relative to Active Control • To contribute evidence to the evaluation of efficacy of EXP relative to Placebo

16. •Active Control Effect ICH E9: “A suitable active comparator… could be a widely used therapy whose efficacy in the relevant indication has been clearly established& quantified in well-designed & well documented superiority trials & which can be reliably expected to have similar efficacy in the contemplated AC trial.” Non-Inferiority Trials… Some Requirements

17. Non-Inferiority Trials… Some Requirements STD should have clinical efficacy • that is of substantial magnitude • that is precisely estimated • with estimates that arerelevant to the setting in which the non-inferiority trial is being conducted

18. Factors Influencing Choice of Margin • Active Control Effect ~magnitude of Active Control effect Eg:  = 45% – 80% = –35% ~precision of estimate Eg: 2 s.e. =  10% ( 175/arm ) ~estimates relevant to setting of NI trial •Population •Supportive care •Endpoint assessment PLA – AC Cure Rate * ( ) –45% –35%–25% –12.5% 0%

19. Factors Influencing the Choice of Margin and Interpretation of NI Trial Results • Clinical Relevance of Changes in: Benefits, Risks/Tolerance, Convenience, Resistance, etc. • Active Control Effect

20. Factors Influencing Choice of Margin •Clinical Relevance of Changes in: Benefits, Risks/Tolerance, Convenience, Resistance, etc. Clinical importance of: - reduction in efficacy by  - altered safety/tolerance profile - altered convenience of administration - altered resistance or drug/drug interactions

21. The Choice of the Margin in an NI Trial ICH E10: “The determination of the margin in a non-inferiority trial is based on both statistical reasoning & clinical judgment, and should reflect uncertainties in the evidence on which the choice is based, and should be suitably conservative.”

22. “Bio-creep” with Repeated NI Trials Eg: Anti-viral Drugs Advisory Comm (10/4/01) Empiric Anti-fungal therapy of febrile neutropenic patients •Amphotericin B Deoxycholate •Ambisome vs Amphotericin B 49.9% v 49.1% Mycosis Study Gp #32 •Voriconazole vs Ambisome 23.7% v 30.1% 95% CI: (– 12, – 0.1)

23. Overview of Placebo-controlled ABS Trials • Fourteen Placebo-controlled Trials of Antimicrobials conducted in ’69 –’03 (with nine conducted since ’96) • Outcome: Antimicrobial effect on Resolution or improvement of ABS symptoms, assessed at fixed time between 7-14 days

24. 70 50 30 10 -10 -30 -50 -70 1 14 2 11 3 4 10 7 5 12 6 8 9 16 13 15 Antimicrobial Efficacy ( 95% CI) Study

25. NI Trials vs Placebo Controlled Superiority Trials •ICH E10: “The determination of the margin in a non-inferiority trial is based on both statistical reasoning & clinical judgment, should reflect uncertainties in the evidence on which the choice is based, and should be suitably conservative.” • When one cannot justify a non-trivial margin, placebo controlled trials provide an ethically and scientifically reliable approach to assessing the benefit-to-risk profile

26. Design Issues in ABS Trials • Criteria for Study Endpoints • Use of Surrogate Endpoints • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Active vs Placebo controlled trials • Time to Event Analyses in ABS Trials

27. Time to Event Analyses in ABS Trials • “In self-resolving diseases, it may be • more appropriate to measure time to • resolution or improvement of symptoms” • To have 90% power to detect a reduction • in time to resolution from 7 days to 5 days • (with the standard 2.5% false positive error rate) • one needs approximately 200 pts/arm. • (Stat Significance if one obtains about 1.3 days )

28. Conclusions • Criteria for Study Endpoints • A Correlate does not a Surrogate Make • Non-Inferiority Design Issues • Choice of the NI Margin • Bio-creep with Repeated NI Trials • Placebo controlled trials • Time to Event Analyses in ABS Trials