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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 It was current when produced, but is no longer maintained and may be outdated.

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

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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.

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13th International Paul-Ehrlich-Seminar, Sept. 15, Outline Goal Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

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13th International Paul-Ehrlich-Seminar, Sept. 15, Select Relevant Statistical Concepts Types of Data –Continuous –Longitudinal –Survival Important Measures –Central Tendency –Spread Bias Covariates Missing Values Hypothesis Testing/Confidence Intervals

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Types of Data- Multivariate Continuous Response Data Explanatory Variable Response Variable

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13th International Paul-Ehrlich-Seminar, Sept. 15, Types of Data- Continuous Response Data Explanatory Variable Response Variable

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13th International Paul-Ehrlich-Seminar, Sept. 15, Types of Data- Longitudinal Time Response over Time Response

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13th International Paul-Ehrlich-Seminar, Sept. 15, Types of Data- “Survival” (time until event occurs) Proportion Time in Days

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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.

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13th International Paul-Ehrlich-Seminar, Sept. 15, Outline Goal Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

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13th International Paul-Ehrlich-Seminar, Sept. 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Illustration of Potential Data- Separated into Two Groups Combined Medication and Symptom Score Time (in weeks) Initiation of Allergy Season Key

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13th International Paul-Ehrlich-Seminar, Sept. 15, Presence of Allergen and Symptom Scores Combined Medication & Symptom Score Time (in weeks) Pollen Count (grains/m 3 )

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13th International Paul-Ehrlich-Seminar, Sept. 15, Illustration of Potential Data Individual Responses Combined Medication and Symptom Score Time (in weeks)

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13th International Paul-Ehrlich-Seminar, Sept. 15, Illustration of Potential Data- Mean and 95% Confidence Interval of Two Groups Time (in weeks) Combined Medication and Symptom Score

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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)

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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….

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Differences between Groups with 95% Confidence Intervals (CI) - Δ 0 δ Key 95% CI Difference Mean Difference

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Δ 0 δ Difference between Groups with 95% Confidence Intervals

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Outline Goal Present and Discuss Select Relevant Statistical Concepts Discuss Statistical Concepts Applied to Allergenic Products Provide Consideration of Standards Conclusion

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13th International Paul-Ehrlich-Seminar, Sept. 15, Standards for Consideration Measuring Differences –Lower (or Upper) Bound of a Confidence Interval –Pre-defined Difference between Groups based on a specific Value % Change

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Outline Goal Present and Discuss Select Relevant Statistical Concepts Statistical Concepts Applied to Allergenic Products Consideration of Standards Conclusion

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13th International Paul-Ehrlich-Seminar, Sept. 15, Conclusion Establishment of a meaningful difference as a target in the protocol is critical and should be agreed upon before the study is implemented.

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13th International Paul-Ehrlich-Seminar, Sept. 15, 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

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13th International Paul-Ehrlich-Seminar, Sept. 15, Questions?

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