FDA provides additional instructions for manufacturers on how to ensure the quality and safety of clinical test products in one new guidance (available at http://www.fda.gov/cder/guidance/6164dft.htm) and notes that it may issue additional information to help clarify GMP requirements for producing investigational drugs for later stage clinical trials. The guidance advises researchers to establish quality control procedures that describe how they will control production components and laboratory testing. Sponsors need to keep complete records of production processes, including equipment maintenance, analytical tests, and distribution. Reagents and components should be properly labeled and organized. Additional steps should be taken to prevent contamination of investigational biologics and sterile products.

This modification of GMP requirements is "incredibly important," says Woodcock, because it will allow researchers to produce small quantities of a test product without adhering to policies designed for large-scale production. Laboratories at academic institutions and the National Institutes of Health that don't have ready access to large production facilities stand to benefit immediately. Until now, academic researchers have been "at the mercy of the large pharmaceutical and biotech companies," commented Steven Rosenberg of the National Cancer Institute (NCI). He explained that if NCI researchers want to move a promising compound from the test tube to the clinic, they have had to find a company with GMP-compliant facilities to produce it. Now NIH researchers, who strongly support the new policy, can produce compounds in the labs "much more readily," Rosenberg said.

EARLY EXPLORATION

The aim is to generate information on a candidate drug's mechanism of action or pharmacologic effect before investing in the full battery of preclinical and animal testing required for even a small phase 1 safety study. The policy applies to drugs and to well-characterized therapeutic biological products, but not to human cell or tissue products, blood proteins, vaccines or medical devices.

The IND application filed with FDA to launch an exploratory study may contain less information than normally submitted for routine applications. It would describe the research program and anticipated outcomes, including a rationale for test compound selection and for adopting a particular study plan. The guidance also notes that CMC information can be presented as a summary report, describing the product's characteristics, source, therapeutic class, dosage form, route of administration, formulation, method of preparation, manufacturer, and composition.

A certain amount of analytical testing is necessary to demonstrate the identity, structure, purity, and potency of the candidate product and its physical and microbiological characteristics. FDA always will require some animal testing before launching even a micro-study, Woodcock explained, but exploratory INDs may include data on fewer animals and at lower doses, reducing the number of animals involved in overall preclinical testing.

Although some skeptics regard the exploratory IND as merely a way for drug companies to cut costs while creating additional risks for patients, Woodcock maintains that this approach will save people and animals from unnecessary exposure to higher and more toxic doses of untested compounds.

If an exploratory microdose study indicates promising results, the manufacturer has to start over. Before launching conventional phase 1 studies, the sponsor must conduct additional animal and in vitro testing and file a new IND. The hope is that further testing and development will be targeted to those compounds that appear most likely to have a positive effect on human health. The new policy does not change FDA's rules, Woodcock noted, but advises researchers on "how they can take advantage of the inherent flexibility in the current regulations."

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301 656 4634, jwechsler@advanstar.com