1 / 16

Issues Regarding Choice of the Margin in Non-Inferiority Trials February 19, 2002

FDA Anti-Infective Drugs Advisory Committee. Issues Regarding Choice of the Margin in Non-Inferiority Trials February 19, 2002 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington. Dual Goal of Non-Inferiority Trials. • To enable a direct evaluation

kelli
Download Presentation

Issues Regarding Choice of the Margin in Non-Inferiority Trials February 19, 2002

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. FDA Anti-Infective Drugs Advisory Committee Issues Regarding Choice of the Margin in Non-Inferiority Trials February 19, 2002 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington

  2. Dual Goal of Non-Inferiority Trials • To enable a direct evaluation of the clinical efficacy of EXP relative to A.C. • To contribute evidence to the evaluation of efficacy of EXP relative to PLA

  3. 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 • Quality of the Design & Conduct of the NI Trial

  4. 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

  5. •Active Control Effect ICH E9: “A suitable active comparator… could be a widely used therapy whose efficacy in the relevant indicator 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.” Factors Influencing Choice of Margin

  6. 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%

  7. Factors Influencing Interpretation of Trial Results • • Quality of the Design & Conduct • of the NI Trial • ICH E9: “Many flaws in the design or conduct • of the trial will tend to bias the results • toward a conclusion of equivalence” • … it is especially important to minimize • incidence of violations in the entry criteria, • non compliance, withdrawals, • losses to follow-up, missing data • and other deviations in the protocol.”

  8. Factors Influencing Interpretation of Trial Results • •ICH E9: … it is especially important to minimize... • losses to follow-up, missing data • “ITT” vs “Evaluable” (  variability &  bias ) • •Absence of targeted microbial at baseline • •Not assessed due to: • ~ termination due to adverse clinical events • ~ termination due to perceived drug ineffectiveness • ~ treatment with prohibited concomitant interventions • ~ “missing” evaluations

  9. Sample Sizes in Non-inferiority trials Non-inferiority trials having scientifically rigorous margins always require very large sample sizes... … fact or myth?

  10. Illustration: AC Antibiotic having 80% Cure Rate Relative  in Non-Cure Rate ( for EXP – AC Cure Rate ) 75% 50% 25% ~ 25% 50%  – 15 – 10– 5 0 5 10

  11. Probability of a Positive Trial as a function of true EXP–ACCure Rate Scenario #1 (Superiority) 2N = 340 Evaluable pts .025 .90 * –15 –10 –5 0 5 7.3 10 12

  12. Probability of a Positive Trial as a function of true EXP–ACCure Rate Scenario #1 (Superiority) 2N = 340 Evaluable pts .025 .90 * –15 –10 –5 0 5 7.3 10 12 Scenario #2 (Non-Inferiority) 2N = 300 Evaluable pts .025 .18 .58 .90 * –15–10 –5.90 5 10

  13. Probability of a Positive Trial as a function of true EXP–ACCure Rate Scenario #1 (Superiority) 2N = 340 Evaluable pts .025 .90 * –15 –10 –5 0 5 7.3 10 12 Scenario #2 (Non-Inferiority) 2N = 300 Evaluable pts .025 .18 .58 .90 * –15–10 –5.90 5 10 Scenario #3 (Non-Inferiority) 2N = 672 Evaluable pts .025 .367 .90 * –10–3.90 5 10

  14. Probability of a Positive Trial as a function of true EXP–ACCure Rate Scenario #1 (Superiority) 2N = 340 Evaluable pts .025 .90 * –15 –10 –5 0 5 7.3 10 12 Scenario #2 (Non-Inferiority) 2N = 300 Evaluable pts .025 .18 .58 .90 * –15–10 –5.90 5 10 Scenario #3 (Non-Inferiority) 2N = 672 Evaluable pts .025 .367 .90 * –10–3.90 5 10 Scenario #4 (Non-Inferiority) 2N = 374 Evaluable pts .025 .238 .703 .90 * –15 –10–5 –2.1 0 3 5 10

  15. “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% Mucosis Study Gp #32 •Voriconazole vs Ambisome 23.7% v 30.1% 95% CI: (– 12, – 0.1)

  16. Conclusions •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.” • Non-inferiority trials having scientifically rigorous margins do not necessarily require very large sample sizes.

More Related