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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. Outline. Goal Present and Discuss Select Relevant Statistical Concepts

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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
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

slide3
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.

outline1
Outline
  • Goal
  • Select Relevant Statistical Concepts
  • Statistical Concepts Applied to Allergenic Products
  • Consideration of Standards
  • Conclusion
select relevant statistical concepts
Select Relevant Statistical Concepts
  • Types of Data
    • Continuous
    • Longitudinal
    • Survival
  • Important Measures
    • Central Tendency
    • Spread
  • Bias
  • Covariates
  • Missing Values
  • Hypothesis Testing/Confidence Intervals
normal distribution curves continuous response data
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

comparison of groups
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

types of data multivariate continuous response data
Types of Data-Multivariate Continuous Response Data

Response Variable

Explanatory Variable

types of data continuous response data
Types of Data-Continuous Response Data

Response Variable

Explanatory Variable

types of data longitudinal
Types of Data-Longitudinal

Response over Time

Response

Time

important issues to consider
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.
outline2
Outline
  • Goal
  • Select Relevant Statistical Concepts
  • Statistical Concepts Applied to Allergenic Products
  • Consideration of Standards
  • Conclusion
allergenic products
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

illustration of potential data separated into two groups
Illustration of Potential Data-Separated into Two Groups

Combined Medication and Symptom Score

Time (in weeks)

Key

Initiation of Allergy Season

presence of allergen and symptom scores
Presence of Allergen and Symptom Scores

Pollen Count (grains/m3)

Combined Medication & Symptom Score

Time (in weeks)

illustration of potential data individual responses
Illustration of Potential DataIndividual Responses

Combined Medication and Symptom Score

Time (in weeks)

illustration of potential data mean and 95 confidence interval of two groups
Illustration of Potential Data-Mean and 95% Confidence Interval of Two Groups

Combined Medication and Symptom Score

Time (in weeks)

illustration of potential data mean and 95 confidence interval of two groups1
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)

illustration of potential data mean and 95 confidence interval of two groups2
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)

illustration of potential data 95 confidence interval of the two groups
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)

comparing groups
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
differences between groups with 95 confidence intervals ci
Differences between Groupswith 95% Confidence Intervals (CI)

Key

95% CI Difference

Mean Difference

- Δ 0 δ

examination of 95 ci of differences between treatment groups
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

summary of allergenic example
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
outline3
Outline
  • Goal
  • Present and Discuss Select Relevant Statistical Concepts
  • Discuss Statistical Concepts Applied to Allergenic Products
  • Provide Consideration of Standards
  • Conclusion
standards for consideration
Standards for Consideration
  • Measuring Differences
    • Lower (or Upper) Bound of a Confidence Interval
    • Pre-defined Difference between Groups based on a specific
      • Value
      • % Change
standards for consideration cont
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
outline4
Outline
  • Goal
  • Present and Discuss Select Relevant Statistical Concepts
  • Statistical Concepts Applied to Allergenic Products
  • Consideration of Standards
  • Conclusion
conclusion
Conclusion
  • Establishment of a meaningful difference as a target in the protocol is critical and should be agreed upon before the study is implemented.
acknowledgement and thanks
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