Clinical/Regulatory CTD Submission - Integrated Pooling of Phase 1 Safety Data

In order to identify all potential safety signals in your Phase 1 clinical trial program for clinical/regulatory submission, an integrated analysis of the safety data from all studies is recommended. The FDA most definitely recommends "some pooling across all Phase 1 Clinical Studies". There are several approaches. The most common approach is a pooling of single dose exposure trials and a second pooling for multiple dose exposure trials. Due to the heterogeneity of Phase 1 studies often pharma will choose to only pool "like" clinical studies and present fixed dose, parallel group, dose escalation, crossover design, drug-drug and special populations separately, by individual study.

For example, safety data is available at the time of clinical/regulatory submission for 22 completed Phase 1 trials -

• 7 studies were single dose studies - integrated Pool 1
• 8 studies were multiple dose studies - integrated Pool 2
• 5 studies were drug-drug - presented individually
• 2 studies were special populations - presented individually
• 15 studies would then be integrated
• 7 studies presented individually.

Not advised and definitely not advised without FDA communication and consensus. If the Phase 1 clinical program consists of 22 clinical trials, FDA will want all studies pooled. Why? To ensure that all AEs are captured and reported. To ensure patient safety. To ensure a benign safety profile, especially if the drug is a new chemical entity. Early communication and consensus with FDA is a must pertaining to the integration of your Phase 1 data. A RTF - refusal to file will be issued by FDA, without question, if the pooling strategy is not agreed to prior to filing. Always communicate with FDA early on when determining the presentation of your Phase 1 integrated safety data and statistical pooling strategy for clinical/regulatory CTD submission.