U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products Tammy Massie, PhD Mathematical Statistician Team Leader Bacterial, Parasitic and Allergenic Product Team

3. Outline • Goal • Present and Discuss Select Relevant Statistical Concepts • Statistical Concepts Applied to Allergenic Products • Consideration of Standards • Conclusion Note: All graphics presented are simulated for illustrative purposes only

4. Goal Introduce statistical concepts including types of data collected and associated analyses relevant in clinical studies designed to examine the safety and efficacy of allergenic products.

5. Outline • Goal • Select Relevant Statistical Concepts • Statistical Concepts Applied to Allergenic Products • Consideration of Standards • Conclusion

6. Select Relevant Statistical Concepts • Types of Data • Continuous • Longitudinal • Survival • Important Measures • Central Tendency • Spread • Bias • Covariates • Missing Values • Hypothesis Testing/Confidence Intervals

7. Normal Distribution Curves-Continuous Response Data Smaller variance (σ=0.5) Same mean Different variance Observed Response Medium variance (σ=1) Larger variance (σ=2) Observed Data

8. Comparison of Groups Different Mean, Similar Variance Ideal Situation- Clear separation of groups • Inadequate sample size/lack power • Improper subject selection • Inappropriate time frame Different Mean, Similar Variance Limited separation of groups REALITY Different Mean, Different Variance Limited separation of groups

9. Types of Data-Multivariate Continuous Response Data Response Variable Explanatory Variable

10. Types of Data-Continuous Response Data Response Variable Explanatory Variable

11. Types of Data-Longitudinal Response over Time Response Time

12. Types of Data- “Survival”(time until event occurs) Proportion Time in Days

13. Important Issues to Consider • Impediments • Bias • Confounding • Covariates • Missing Values • Some Solutions • Well Designed (pre-specified) Study • Randomization: promotes balance regarding covariates • Stratification • Adequate sample size/Well powered • Appropriate • Endpoints: clinically meaningful, practical, validated, etc. • Timeframe: consider allergy season, frequency of data collection, etc.

14. Outline • Goal • Select Relevant Statistical Concepts • Statistical Concepts Applied to Allergenic Products • Consideration of Standards • Conclusion

15. Allergenic Products Data Collected: Natural Exposure or Chamber Study • Safety Endpoints • Adverse Events • Local Reactions • Systemic Reactions • Pre-Specified Efficacy Endpoints • Symptoms (*) • Use of Rescue Medication (*) • Quality of Life *can be combined

16. Initiation of Allergy Season Illustration of Potential Data-Separated into Two Groups Combined Medication and Symptom Score Time (in weeks) Key

17. Presence of Allergen and Symptom Scores Pollen Count (grains/m3) Combined Medication & Symptom Score Time (in weeks)

18. Illustration of Potential DataIndividual Responses Combined Medication and Symptom Score Time (in weeks)

19. Illustration of Potential Data-Mean and 95% Confidence Interval of Two Groups Combined Medication and Symptom Score Time (in weeks)

20. Illustration of Potential Data-Mean and 95% Confidence Interval of Two Groups Difference between the mean of two groups Combined Medication and Symptom Score Time (in weeks)

21. WHERE THE ACTUAL MEANS OF EACH GROUP COULD BE…. Illustration of Potential Data-Mean and 95% Confidence Interval of Two Groups Combined Medication and Symptom Score Time (in weeks)

22. The 95% confidence interval of the differences between two groups Illustration of Potential Data-95% Confidence Interval of the Two Groups Combined Medication and Symptom Score Time (in weeks)

23. Comparing Groups • Examples have illustrated • How data can scatter • There can be different degrees of separation between groups • Ideally provides reasonable replication of real and meaningful differences • Why examining means (& standard deviations) alone may not sufficient • Differences between groups include variability that must be accounted for

24. Key 95% CI Difference Mean Difference - Δ 0 δ Differences between Groupswith 95% Confidence Intervals (CI)

25. Note:Δ or δ must be pre-specified and depends on • Type of Study • Comparator • Anticipated Safety • Efficacy/Effectiveness • Benefit/Risk Profile -Δ 0 δ+ Non-inferiority Margin Clinically Meaningful Margin Examination of 95% CI of Differences between Treatment Groups

26. -Δ 0 δ Difference between Groups with 95% Confidence Intervals

27. Summary of Allergenic Example • A lowerbound of the 95% CI greater than a pre-specified threshold (δ) ensures reproducible statistical significance that translates into clinically meaningful difference • Example for illustrative purposes examined only single time point; however, this should be extended to an agreeable timeframe using appropriate longitudinal analysis methodologies • Selection of timeframe should consider the potential for missing values

28. Outline • Goal • Present and Discuss Select Relevant Statistical Concepts • Discuss Statistical Concepts Applied to Allergenic Products • Provide Consideration of Standards • Conclusion

29. Standards for Consideration • Measuring Differences • Lower (or Upper) Bound of a Confidence Interval • Pre-defined Difference between Groups based on a specific • Value • % Change

30. Standards for Consideration (cont) • P-value • Probability of observing a result as extreme or more extreme than the one observed, given that the null hypothesis is true • May not be adequate alone • Confidence Interval • Gives an estimated range of values which is likely to include the unknown population parameter, the estimated range being calculated from a given set of sample data. • Provides a range of the magnitude of effect and an estimate of its reliability

31. Outline • Goal • Present and Discuss Select Relevant Statistical Concepts • Statistical Concepts Applied to Allergenic Products • Consideration of Standards • Conclusion

32. Conclusion • Establishment of a meaningful difference as a target in the protocol is critical and should be agreed upon before the study is implemented.

33. Acknowledgement and Thanks • A. Dale Horne, Dr.P.H. • Estelle Russek-Cohen, Ph.D. • Henry Hsu, Ph.D. • Ronald L. Rabin, MD • Jay E. Slater, MD • Drusilla Burns, Ph.D. • Paul Richman, Ph.D. • Colleen Sweeney, CDR, USPHS • Elizabeth Valenti, LCDR, USPHS

34. Questions?