Study Design Issues and Considerations in HUS Trials

1. Study Design Issues and Considerations in HUS Trials Yan Wang, Ph.D. Statistical ReviewerDivision of Biometrics IV OB/OTS/CDER/FDA April 12, 2007

2. Outline • Adequate and well-controlled studies • Study design issues and considerations in HUS trials • Choice of primary efficacy endpoint • Efficacy evaluation and sample size • Safety evaluation and sample size • Conclusion

3. Adequate and Well Controlled Studies 21 CFR 314.126 (b) • Clear statement of objectives • Study design permits valid comparison with appropriate control to provide quantitative assessment of drug effect • Select patients with disease (treatment) or at risk of disease (prevention) • Baseline comparability (randomization) • Minimize bias (blinding, randomization, etc.) • Appropriate methods of assessment of outcome • Appropriate methods of analysis

4. Ideal/Preferred Study Design in HUS Prevention Trials • Randomized, double blind, placebo-controlled • Target population may include • Patients with STEC infection and at risk of developing HUS • Primary efficacy endpoint • Incidence of HUS • Adequate power to detect treatment effect • Adequate data to demonstrate safety

5. Challenges for Designing HUS Prevention Trials • Rare and sporadic nature of STEC infection • Unpredictable nature of HUS development from STEC infection • Therapeutic window may be narrow (possibly within 48 hours after infection) • Low incidence rate of HUS in patients with STEC infection (5%-15%)

6. Sample Sizes Required for Efficacy in HUS Prevention Trials Under Various Scenarios Placebo Incidence Rate of HUS (STEC Infection)

7. Use of a composite endpoint can reduce sample size because the number of events increases Can we use a composite endpoint in a HUS trial (e.g. “HUS + other clinically relevant events) ? Placebo Incidence Rate

8. Difficulty in interpretation when treatment effects on components are not homogenous Hypothetical example of a HUS trial using a composite endpoint Composite Endpoint Component #1: HUS Component #2 Component #3 Treatment Effect

9. Considerations for Using a Composite Endpoint • Are the individual components clinically relevant and of similar importance to patients? • Do the more and less important endpoints occur with similar frequency? • Is the underlying pathophysiology of the components similar? • Are the components likely to have similar relative risk reductions?

10. Issues/considerations for efficacy evaluation in HUS trials • Sample size can be prohibitive if “prevention of HUS” is used for efficacy measurement • Use of a composite endpoint (if possible) can reduce sample size for testing treatment effect • Potential difficulty in interpreting results of the composite endpoint when the treatment effect on composite endpoint cannot be translated to an effect on HUS prevention • Safety evaluation • Need to have an adequate number of treated patients for safety evaluation

11. Chance of Observing No Serious Adverse Events • What does it mean when no serious event (SAE) was observed or no safety issues were identified in a clinical trial of a new product? • It doesn’t necessarily mean that the new product is safe because the chance of observing no events can be high when trial size is small.  

12. Rule of Three (3/N) If no events occur in N treated patients, the upper bound of the 95% confidence interval for the risk (p) can be estimated as 3/N. Provide an answer to “What is the worst possible scenario for the risk of a serious adverse event when no events occur in a trial?”

13. Majority of Patients With STEC Infection May Not Benefit From Prophylactic Therapy for HUS • 85% to 95% of patients with STEC infection will not develop HUS • Number of patients needed to be treated to prevent one HUS case could be large  98%  95%  89%

14. Conclusion • Need to have adequate and well controlled clinical trials to evaluate efficacy and safety of new products for HUS prevention • Challenges for designing HUS prevention trials with • Adequate statistical power to evaluate a clinically meaningful efficacy endpoint • Sufficient data to demonstrate safety Return to Main Menu.