As part of its campaign to facilitate research on drugs and medical products, the US Food and Drug Administration recently
issued new policies that encourage sponsors to conduct more informative and less costly early clinical trials. A new guidance
on exploratory investigational new drug applications (INDs) explains how scientists in industry and academia may test small
doses of a candidate compound to see if a pharmacologic effect exists before investing in the more extensive in vitro and animal tests required for conventional Phase I trials. The aim is to quickly identify those 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 make it easier for study sponsors to produce the
small quantities of test compounds needed for early clinical trials. To this end, FDA is exempting manufacturers and research
organizations from compliance with good manufacturing practices (GMPs) when producing drugs for all Phase I studies. A 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
laboratory to the clinic, pointed out FDA Deputy Commissioner for Operations Janet Woodcock in announcing the new policy at
the beginning of the year. These innovations aim to spur faster clinical development.
FDA also issued its long-awaited final drug labeling regulation in January after years of debate and delay (see sidebar "New
labels challenge manufacturers)." Although the basic framework of the new labeling requirement is no surprise, compliance
will require significant investment by manufacturers to redesign the format of professional labeling, which will significantly
extend the length of most package inserts and require an overhaul of packaging lines.
New labels challenge manufacturers
When FDA officials wrapped up the first two years of its effort to modernize "GMPs for the 21st Century" in September 2004,
one of the items on the list of unfinished business was the need to streamline GMPs for clinical supplies. The original 1978
GMP regulations specified that the rules applied to investigational drug products, but the regulators left the door open to
future modifications. They recognized that a prime objective of setting manufacturing standards for clinical supply production
is to establish a framework for the manufacturer to operate a well-documented and controlled process for reproducing a product
for further testing and ultimate commercial production. The new policy reflects FDA's current belief that manufacturers can
meet these objectives without fully complying with GMP requirements; this approach, according to Woodcock, fits FDA's initiative
to end a "one-size-fits-all approach to manufacturing."
The new rule explains that researchers and manufacturers may adopt modified approaches for producing small quantities of test
products for use in Phase I studies, which usually involve less than 80 participants (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, FDA explains, because investigational production does not raise many of the issues related
to manufacturing products for later clinical studies or for commercial marketing. Limited production operations have no need
for rules about rotating stock for drug product containers, for example, or repackaging and relabeling drug products or maintaining
separate packaging and production areas. Small-scale production may involve just a few steps within a single facility, and
operations may use disposable equipment and prepackaged water.
FDA specifies that the Phase I exemption policy also applies to investigational biological products subject to GMPs. Such
products include recombinant therapeutics, vaccines, allergenic products, in vivo diagnostics, plasma derivative products, blood and blood products, gene therapies, and somatic cellular therapies.