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Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products

Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products. Tammy Massie, PhD Mathematical Statistician Team Leader Bacterial, Parasitic and Allergenic Product Team. Outline. Goal Present and Discuss Select Relevant Statistical Concepts

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Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products

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

  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. 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

  7. 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

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

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

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

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

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

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

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

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

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

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

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

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

  24. Examination of 95% CI of Differences between Treatment Groups • 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

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

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

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

  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. 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. Questions?

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