Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products

1 / 33

# Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products - PowerPoint PPT Presentation

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.

## PowerPoint Slideshow about 'Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products' - wayne

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

### Statistical Criteria for Establishing Safety and Efficacy of Allergenic Products

Tammy Massie, PhD

Mathematical Statistician

Bacterial, Parasitic and Allergenic Product Team

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

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.

Outline
• Goal
• Select Relevant Statistical Concepts
• Statistical Concepts Applied to Allergenic Products
• Consideration of Standards
• Conclusion
Select Relevant Statistical Concepts
• Types of Data
• Continuous
• Longitudinal
• Survival
• Important Measures
• Central Tendency
• Bias
• Covariates
• Missing Values
• Hypothesis Testing/Confidence Intervals
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

Different Mean, Similar Variance

Ideal Situation-

Clear separation of groups

• 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

Response Variable

Explanatory Variable

Types of Data-Continuous Response Data

Response Variable

Explanatory Variable

Types of Data-Longitudinal

Response over Time

Response

Time

Important Issues to Consider
• Impediments
• Bias
• Confounding
• Covariates
• Missing Values
• Some Solutions
• Well Designed (pre-specified) Study
• Randomization: promotes balance regarding covariates
• Stratification
• Appropriate
• Endpoints: clinically meaningful, practical, validated, etc.
• Timeframe: consider allergy season, frequency of data collection, etc.
Outline
• Goal
• Select Relevant Statistical Concepts
• Statistical Concepts Applied to Allergenic Products
• Consideration of Standards
• Conclusion
Allergenic Products

Data Collected: Natural Exposure or Chamber Study

• Safety Endpoints
• 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

Combined Medication and Symptom Score

Time (in weeks)

Key

Initiation of Allergy Season

Presence of Allergen and Symptom Scores

Pollen Count (grains/m3)

Combined Medication & Symptom Score

Time (in weeks)

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

Combined Medication and Symptom Score

Time (in weeks)

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 Groups

WHERE THE ACTUAL MEANS OF EACH GROUP COULD BE….

Combined Medication and Symptom Score

Time (in weeks)

The 95% confidence interval of the differences between two groups

Combined Medication and Symptom Score

Time (in weeks)

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 Groupswith 95% Confidence Intervals (CI)

Key

95% CI Difference

Mean Difference

- Δ 0 δ

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