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

Allergenic Products Advisory Committee May 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

Allergenic Products Advisory Committee May 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.

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

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

Allergenic Products Advisory Committee May 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

Allergenic Products Advisory Committee May 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

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

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

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

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

Allergenic Products Advisory Committee May 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.

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

Allergenic Products Advisory Committee May 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

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

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

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

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

Allergenic Products Advisory Committee May 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)

Allergenic Products Advisory Committee May 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….

Allergenic Products Advisory Committee May 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

Allergenic Products Advisory Committee May 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

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

Allergenic Products Advisory Committee May 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

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

Allergenic Products Advisory Committee May 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

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

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

Allergenic Products Advisory Committee May 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

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

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

Allergenic Products Advisory Committee May 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

Allergenic Products Advisory Committee May Questions?