Over the last few years, the European and US regulatory authorities have undertaken substantial new regulatory initiatives regarding the conduct of drug development activities and the regulatory approval of Investigational New Drug (IND), Clinical Trial Application (CTA), and New Drug Application (NDA) submissions.
On the US side, consistent with the "Pharmaceutical cGMPs for the 21st Century," initiative,5 FDA has issued numerous guidelines, including those related to pharmaceutical development (ICH Q8),6 Process Analytical Technology (PAT),7 and GMPs for early development (INDs—Approaches for Complying with cGMP for Phase 1).8 The agency also began a significant new initiative, the "Risk-Based Pharmaceutical Quality Assessment System."9
The new system also relies more on the applicant to provide easily reviewable data in the form of the Pharmaceutical Development and Quality Overall Summary (QOS) section of NDAs. ICH Q8 is intended to provide the regulators with a historical synopsis of the development of a drug product so that the agency may better understand the evolution of the drug and dosage form. Generating more information during development will allow a larger "design space" that is intended to provide additional regulatory flexibility post approval. The new system emphasizes the utilization of the principles embodied in Quality by Design concepts to determine the critical aspects of pharmaceutical manufacturing quality. Although the original intent of these initiatives was to ultimately provide increased regulatory flexibility to implement future (i.e., post approval) changes, they also have clear advantages to streamlining and expediting early CMC drug development programs.
In addition, in January 2006 the FDA issued both a draft Guideline and a final rule related to the cGMP requirements for Phase 1 clinical trials. This guidance said that "...particular requirements in 21 CFR 211 need not be met for most investigational use manufactured for use during Phase 1 development."8 The intent of the draft guidance was to codify the principle of a sliding scale of expected compliance during early CMC development and to facilitate the manufacture of investigational drug products for Phase 1 clinical trials. Due to substantial negative comments on the risks to subject safety, however, the final rule was withdrawn in May 2006, but the draft Guidance remains, presumably to be revised based on public comments.