Expertly navigating the most complex development programs

The foundation of any integrated marketing application is the integrated clinical data that supports the overall risk-benefit analysis of the product. It’s imperative that the FDA reviewers are confident that the submitted, integrated databases are accurate, complete, and allow for a full assessment of the risk-benefit profile. Our integrated team of statisticians, scientists, regulatory experts, and medical writers work together to navigate the most complex marketing applications and data analysis issues.

Our statisticians have designed and delivered integrated clinical databases and analyses for more than 50 marketing applications (NDAs, BLAs, MAAs, JNDAs, etc.). They have also:

• Designed and delivered databases and analyses to support integrated summaries of safety (ISS), integrated summaries of efficacy (ISE), and integrated summaries of microbiology (ISM).
• Successfully distilled and analyzed the most complex development programs (> 50 studies) to the smallest/most targeted (3 studies).

Through the entire process, our statisticians provide robust strategic consulting support, including regulatory interaction support.

Integrated Summary of Safety

Developing an ISS analytical strategy generally starts with answering, and likely revisiting, three key questions:

• • • • What are the safety parameters of interest?
      • How do we present the key safety messages and the overall safety profile?
      • How do we best characterize (i.e., ‘pool’) safety information from the clinical studies in the development program?

Most time is spent on question 3: How should data be pooled in the safety parameters of interest to allow a reviewer to get to the true value of those parameters (e.g., an event in the target population)?

Three topics/questions to consider when making data pooling decisions include:

• • Do safety data need to be pooled? In general, there is a regulatory obligation to present all safety data from a clinical development program. However, there is no regulatory obligation to pool all studies for analysis. The pooling strategy may include all studies from a program in the safety database, but there is no regulatory requirement to do so. Pooling is ultimately the sponsor’s decision; however, the Division/Agency (and/or an Advisory Committee) must be convinced of the validity of the strategy.
  • Why pool safety data? In general, two reasons: 1) we are trying to produce precise and reliable estimates (i.e., narrow confidence intervals) of safety parameters used to describe the overall safety profile (e.g., rare but serious/fatal events); and 2) we can perform interaction explorations (where it would otherwise not be possible) due to increased sample size.
  • What should drive the pooling strategy? The safety message(s) should drive the pooling strategy. Frequently this comes down to judgment, and there can be more than one ‘right way’. Summaries produced from pooled data should yield transparent results. Specifically, pooling should not mask safety signals and should be unbiased (if at all possible) estimates of the safety experience(s) in the target population. Differences in the following introduce variation in the parameters of interest and are considered by reviewers when assessing the utility of a pooled analysis and/or the meaningfulness of parameter estimates:
    • Study design similarity
    • Doses studies
    • Duration
    • Controlled/uncontrolled studies
    • Region in which study was conducted
    • Population studied

Integrated Summary of Efficacy

• Unlike the ISS, the ISE should focus on the pivotal efficacy studies of the development program.
• Data analysis should be limited to the well-controlled phase 3 trials at the anticipated labeling dosages(s).