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.
In the European Union (EU), the May 2004 implementation of the Clinical Trial Directive (CTD),1 involved Good Clinical Practices (GCPs), as outlined in ICH E6,2 Good Manufacturing Practices (GMPs),3 and Annex 13 to GMPs, Manufacture of Investigational Medicinal Products (IMPs).
4 Most notably, for the past two years, the CTA process has been in force in the EU. The CTD and CTA were intended to harmonize
early drug development in the 25 member states in the EU. For the most part, these new procedures have been viewed as increased
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
These guidances and initiatives were intended to address the challenges and difficulties facing the newly reorganized FDA
Office of New Drug Quality Assessment (ONDQA), concurrent with establishing and nurturing a framework of improvement and innovation
in chemistry, manufacturing, and controls (CMC) development. These challenges included the FDA resources needed for generating
comprehensive CMC summaries from the raw data in NDAs, multiple CMC review cycles for NDAs, and numerous postapproval manufacturing
supplements. These new initiatives focus on critical quality attributes (chemistry, pharmaceutical processes, and product
performance) and their relationship to safety and efficacy.
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.