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

2. Allergenic Products Advisory Committee May 2011 2 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

3. Allergenic Products Advisory Committee May 2011 3 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.

4. Allergenic Products Advisory Committee May 2011 4 Outline Goal Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

5. Allergenic Products Advisory Committee May 2011 5 Select Relevant Statistical Concepts Types of Data –Continuous –Longitudinal –Survival Important Measures –Central Tendency –Spread Bias Covariates Missing Values Hypothesis Testing/Confidence Intervals

6. Allergenic Products Advisory Committee May 2011 6 Normal Distribution Curves- Continuous Response Data Same mean Different variance Smaller variance (σ=0.5) Larger variance (σ=2) Medium variance (σ=1) Observed Data Observed Response

7. Allergenic Products Advisory Committee May 2011 7 Comparison of Groups Different Mean, Similar Variance Ideal Situation- Clear separation of groups Different Mean, Similar Variance Limited separation of groups Different Mean, Different Variance Limited separation of groups Inadequate sample size/lack power Improper subject selection Inappropriate time frame

8. Allergenic Products Advisory Committee May 2011 8 Types of Data- Multivariate Continuous Response Data Explanatory Variable Response Variable

9. Allergenic Products Advisory Committee May 2011 9 Types of Data- Continuous Response Data Explanatory Variable Response Variable

10. Allergenic Products Advisory Committee May 2011 10 Types of Data- Longitudinal Time Response over Time Response

11. Allergenic Products Advisory Committee May 2011 11 Types of Data- “Survival” (time until event occurs) Proportion Time in Days

12. Allergenic Products Advisory Committee May 2011 12 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.

13. Allergenic Products Advisory Committee May 2011 13 Outline Goal Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

14. Allergenic Products Advisory Committee May 2011 14 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

15. Allergenic Products Advisory Committee May 2011 15 Illustration of Potential Data- Separated into Two Groups Combined Medication and Symptom Score Time (in weeks) Initiation of Allergy Season Key

16. Allergenic Products Advisory Committee May 2011 16 Presence of Allergen and Symptom Scores Combined Medication & Symptom Score Time (in weeks) Pollen Count (grains/m 3 )

17. Allergenic Products Advisory Committee May 2011 17 Illustration of Potential Data Individual Responses Combined Medication and Symptom Score Time (in weeks)

18. Allergenic Products Advisory Committee May 2011 18 Illustration of Potential Data- Mean and 95% Confidence Interval of Two Groups Time (in weeks) Combined Medication and Symptom Score

19. Allergenic Products Advisory Committee May 2011 19 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)

20. Allergenic Products Advisory Committee May 2011 20 Illustration of Potential Data- Mean and 95% Confidence Interval of Two Groups Combined Medication and Symptom Score Time (in weeks) WHERE THE ACTUAL MEANS OF EACH GROUP COULD BE….

21. Allergenic Products Advisory Committee May 2011 21 Illustration of Potential Data- 95% Confidence Interval of the Two Groups The 95% confidence interval of the differences between two groups Time (in weeks) Combined Medication and Symptom Score

22. Allergenic Products Advisory Committee May 2011 22 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

23. Allergenic Products Advisory Committee May 2011 23 Differences between Groups with 95% Confidence Intervals (CI) - Δ 0 δ Key 95% CI Difference Mean Difference

24. Allergenic Products Advisory Committee May 2011 24 Examination of 95% CI of Differences between Treatment Groups Non-inferiority Margin Note: Δ or δ must be pre- specified and depends on 1)Type of Study 2)Comparator 3)Anticipated Safety 4)Efficacy/Effectiveness 5)Benefit/Risk Profile - Δ 0 δ + Clinically Meaningful Margin

25. Allergenic Products Advisory Committee May 2011 25 -Δ 0 δ Difference between Groups with 95% Confidence Intervals

26. Allergenic Products Advisory Committee May 2011 26 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

27. Allergenic Products Advisory Committee May 2011 27 Outline Goal Present and Discuss Select Relevant Statistical Concepts Discuss Statistical Concepts Applied to Allergenic Products Provide Consideration of Standards Conclusion

28. Allergenic Products Advisory Committee May 2011 28 Standards for Consideration Measuring Differences –Lower (or Upper) Bound of a Confidence Interval –Pre-defined Difference between Groups based on a specific Value % Change

29. Allergenic Products Advisory Committee May 2011 29 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

30. Allergenic Products Advisory Committee May 2011 30 Outline Goal Present and Discuss Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

31. Allergenic Products Advisory Committee May 2011 31 Conclusion Establishment of a meaningful difference as a target in the protocol is critical and should be agreed upon before the study is implemented.

32. Allergenic Products Advisory Committee May 2011 32 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

33. Allergenic Products Advisory Committee May 2011 33 Questions?