CTD Clinical Submission of Phase 2-3 Trial Data

Phase 2 - 3 clinical safety data presentation, pooling and integration strategies are developed by the clinical submission team and illustrated in your SAP, statistical analysis plan, for all therapeutic indications to be filed in your clinical submission. On an average, a Phase 2 - 3 clinical program consists of 10-15 studies, conducted simultaneously in the US, Europe, rest of world and are designed to "flush" out AEs, SAEs, dosing regimen, safety and efficacy. The Phase 2 - 3 clinical program reflects the "final marketing image" of the drug to be filed. Phase 2 - 3 integrated safety data, is the clinically meaningful information used to develop the "prescribing" label, package insert, information for the PDR (Physician's Desk Reference) for the drug under investigation. The process of integration, pooling strategy and presentation methodologies for Phase 2 - 3 safety data is analogous and linked to your Phase 1 SAP.

For example, a Phase 2 - 3 clinical program consists of 13 clinical trials - a common pooling strategy for safety data would be as follows -

• Pool 1 - 5 clinical studies, double-blind, placebo-controlled, fixed-dose (primary therapeutic indication)
• Pool 2 - 3 open-label, long-term exposure studies - (primary therapeutic indication)
• Pool 3 - 3 double-blind, placebo-controlled, forced-dose titration studies (primary therapeutic indication)
• Pool 4 - 2 special studies, in a different, but related therapeutic indication
• Pool 5 - 10 double-blind, placebo-controlled studies, regardless of indication, pooling of Pools 1, 3 and 4.
• 5 Pools - 13 Phase 2 - 3 clinical studies.

The integrated analyses of clinical safety data includes Adverse Events, clinical laboratory evaluations, vitals signs, physical findings and other observations related to safety and safety in special groups and situations. In the integrated analysis, the Medical Dictionary for Regulatory Activities (MedDRA), is used to classify all Treatment Emergent Serious Events (TEAEs), reported by System Organ Class (SOC) and Preferred Term (PT) as per FDA regulations and data compliance guidelines.

A separate safety integrated and pooled database for Phase 1, 2, 3 Clinical Pharmacology data is submitted to FDA as well at the time of filing. Likewise, statistical analyses, integration and pooling rigor and strategies are developed for the best presentation and evaluation of pharmacology safety data for clinical submission and FDA review.