The new exploratory approach permits researchers to administer low doses to very few individuals (less than 20) for a short period of time (as much as 7 days). These trials may involve very low microdoses (less than 1/100 of the dose calculated to yield a pharmacologic effect) or slightly higher doses that still have no toxic effect on the participant. Single-dose studies may collect pharmacokinetic information or data from imaging studies, although repeat dose studies may examine pharmacologic or pharmacodynamic endpoints. Even though research participants may not feel any effect from the test compound or show any obvious response, modern imaging technology and test methods will permit the researcher to detect whether a test substance hits a target organ or metabolizes in a certain way.

The IND application filed with FDA to launch an exploratory study may contain less information than for the usual application. It would briefly describe the research program and anticipated outcomes, including a rationale for selecting a test compound and for adopting a certain study plan. The guidance also notes that CMC information can be presented as a summary report that describes 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 needed 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 will need data on fewer animals and at lower doses, reducing the number of animals involved in preclinical testing overall.

Although some skeptics regard the exploratory IND as merely a way for drug companies to cut costs while creating additional risks for patients, Woodcock maintained that this approach will save people and animals from being exposed unnecessarily to higher and more toxic doses of untested compounds. Acting commissioner Andrew Von Eschenbach added that the new policy does not allow any compromise in standards for clinical trials or laboratory testing, but offers a way to use modern diagnostic tools to gain more insight.

If an exploratory microdose study shows promising results, the manufacturer must start over. Before launching conventional Phase I 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 involve those compounds that appear most likely to have a positive effect on human health.

Exploratory "phase zero" studies offer a way to gain much more valuable information about whether a mechanism of action seen in preclinical studies also occur in humans and whether a compound binds to certain molecular receptors, affects a target body organ, has a desired effect on enzyme activity or has anticipated pharmacokinetic effects—all possible signs of potential therapeutic value. Such information may lead to more efficient clinical study plans and improve the success rates of the current drug development process, one of the prime goals of FDA's Critical Path initiative. Nine out of ten compounds developed in the laboratory fail in human studies, explained von Eschenbach, because test therapies often behave differently in people than in animals and test tubes. 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 regulation."

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com