As part of its campaign to facilitate research on drugs and medical products, the Food and Drug Administration (FDA) recently
issued new policies to encourage sponsors to conduct more informative and less costly early clinical trials. A new guidance
on exploratory investigational drug applications (INDs) explains how scientists in industry and academia may test very small
doses of a candidate compound to detect any pharmacologic effect before investing in more extensive in vitro and animal studies required for conventional phase 1 trials. The goal is to quickly identify products that show some promise
of efficacy, and to halt research on those that fail to hit preliminary targets.
A key element in this streamlined approach to early clinical testing is to facilitate production of small quantities of test
compounds needed for early clinical trials. To this end, FDA issued a new rule exempting manufacturers and research organizations
from compliance with Good Manufacturing Practices (GMPs) when producing drugs for all phase 1 studies. A companion guidance
offers advice for ensuring that test products meet quality standards and that study sponsors document production processes
and procedures, particularly for sterile products and biologics. A major bottleneck in drug development is moving from the
lab to the clinic, said Janet Woodcock, FDA deputy commissioner for operations when she announced the new policy in January
of this year. These innovations aim to establish more efficient clinical study plans and improve the success rates of the
current drug development process, a primary goal of FDA's Critical Path Initiative.
The new rule reflects FDA's belief that manufacturers can establish a controlled process for reproducing a test product, even
if they don't fully comply with GMP requirements. The regulation explains how researchers and manufacturers can adopt modified
approaches for producing small quantities of test materials for phase 1 studies [see "Current Good Manufacturing Practice Regulation and Investigational New Drugs," Federal Register, Dec. 17, 2006, found at
http://www.fda.gov/OHRMS/DOCKETS/98/fr/06.353.pdf.] This approach is appropriate, according to FDA, because limited production operations have no need for rules regarding
stock rotation for drug product containers or for repackaging and relabeling drug products. Small-scale production may involve
just a few steps within a single facility, and operations may use disposable equipment and prepackaged water to accomplish
FDA specifies that the phase 1 exemption applies to investigational biological products normally subject to GMPs. These include
recombinant therapeutics, vaccines, allergenic products, in vivo diagnostics, plasma derivative products, blood and blood products, gene therapies and somatic cellular therapies. The rule
modification does not pertain to previously approved products now in phase 1 studies, or to phase 2 and 3 trials.
Consequently, pharma and biotech companies are likely to continue manufacturing clinical supplies in GMP-compliant facilities
to avoid complications with later scale-up activities. At the same time, the new policy provides an option for biotech manufacturers
to modify their operating procedures and validation requirements for producing early test products. The rule may also enable
some companies to produce investigational agents in-house instead of contracting them out.
Even without full GMP compliance, FDA expects manufacturers to document processes for ensuring the safety and quality of an
investigational drug as part of an IND filing. This involves providing sufficient chemistry, manufacturing, and control (CMC)
information to describe the composition, manufacture, and control of the investigational drug product. FDA emphasizes that
it still retains the authority to terminate a study, seize an investigational drug, or halt production if the manufacturer
does not provide sufficient risk information in the IND, or fails to "establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety."