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extent and type of use, concentration of use, subchronic or chronic toxicity, skin penetration, skin irritation, and skin sensitization.

In each final report, the CIR Expert Panel reaches one of four conclusions on the safety of a cosmetic ingredient: (1) safe as currently used, (2) safe with qualifications, (3) unsafe, or (4) insufficient data. If data are considered insufficient, the panel notes what data are lacking. In practice, this conclusion of insufficient data encourages manufacturers to undertake additional studies.

NEW DRUGS

Unlike dietary supplements, premarket approval of new drugs places the burden of proof regarding safety on the manufacturer rather than on FDA. The evaluation of new drugs, new uses for approved drugs, and classification of OTC drugs is an intensive interactive process that evaluates both safety and efficacy. Manufacturers that want to develop and market a new drug must follow the FDA approval process that is modeled on a risk-benefit approach. Approval of a new drug requires extensive studies of the chemistry, manufacturing, and controls of the drug, toxicology and pharmacology of the compound in animals, and clinical trials of effectiveness and safety in humans. The timeframe and resources for this process are extensive (21 C.F.R. § 300 [2001]).

A key initial step in the drug approval process is submission by the manufacturer of an Investigational New Drug (IND) application to FDA. The IND is a large collection of information that enables FDA to review the safety of the substance before clinical testing in humans is allowed to begin. The IND describes the ingredients, synthesis, manufacturing, purity, and microbiology of the drug product, as well as the stability, packaging, and labeling. Also included in the IND are data from rodent and nonrodent animal studies, such as pharmacokinetic and pharmacodynamic data from animal studies, genotoxicity studies, carcinogenicity studies, reproductive and teratogenic studies, and other toxicological data. When available, the application also includes published or unpublished human data. Because these data help FDA determine whether the human testing process will be allowed to proceed, the manufacturer also provides protocols outlining the Phase I, II, and III clinical studies it plans to conduct. After the IND is submitted, FDA has 30 days to review its content. If FDA does not contact the sponsor within that time, the proposed Phase I study may begin (21 C.F.R. § 312 [2001]).

During Phase I studies, which focus on safety but not efficacy, human volunteers (who are usually healthy) are carefully monitored for tolerability, and pharmacokinetic data are often collected. The aim of Phase II is to evaluate the dose-response relationship and effectiveness of the drug in a



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