Statistical methodologies for absolute and relative efficacy assessment based on single-arm trials: a scoping review

Area of Science:

• Biostatistics
• Regulatory Science
• Pharmacoeconomics

Background:

• Marketing authorization for Advanced Therapy Medicinal Products (ATMPs) faces challenges due to reliance on non-randomized evidence, such as single-arm trials (SATs).
• Conditional marketing authorizations may necessitate cross-trial comparisons with existing treatments.
• A comprehensive overview of statistical methodologies for evaluating non-randomized evidence in ATMP applications is lacking.

Purpose of the Study:

• To provide a general overview of statistical methods supporting efficacy claims in marketing authorization applications for ATMPs, primarily using non-randomized evidence.
• To identify and summarize methodologies from relevant scientific literature.
• To discuss the relevance of these methods for regulatory decision-making and suggest future research directions.

Main Methods:

• A systematic literature search was conducted, yielding 63,671 initial results.
• Inclusion and exclusion criteria were applied to select relevant papers.
• Methodologies from 120 selected papers were summarized and reviewed.

Main Results:

• A broad range of statistical methodologies exists to support efficacy claims based on non-randomized evidence.
• There is a lack of systematic empirical comparisons between these available methods.
• The review discusses the potential relevance of these methods for regulatory decision-making.

Conclusions:

• Biostatisticians should conduct systematic empirical comparisons of existing methods.
• Generating comparative evidence is crucial for developing recommendations on appropriate statistical approaches for ATMP approval.
• Further research is needed to guide regulatory decision-making for ATMPs relying on non-randomized data.