Drug Development Philosophy and Procedures

I. Background

The mission of the Developmental Therapeutics Program (DTP) of the Division of Cancer Treatment and Diagnosis (DCTD) of the National Cancer Institute (NCI) centers on the discovery and preclinical development of agents with clinical anti-cancer potential. Investigations focusing on the hazards of these compounds to healthy organs in intact experimental animals or in vitro systems are the final steps in the preclinical stages of new drug development. Data generated from these studies on lead compounds and potential drug candidates are evaluated in light of potential human toxicity and form a major portion of the information required by the Food and Drug Administration (FDA) for an Investigational New Drug Application (IND). Such laboratory investigations comprise the primary responsibility of the Toxicology & Pharmacology Branch (TPB) within the DTP.

Toxicology studies that are conducted by TPB are designed to meet this responsibility and include the following major objectives:

• Determination of a maximum tolerated dose (MTD).
• Determination of dose limiting toxicities (DLT).
• Determination of schedule-dependent toxicity.
• Determination of the reversibility of adverse effects.
• Determination of a safe clinical starting dose.

In addition to these objectives, these studies are also designed to make the following determinations:

• Whether the efficacious drug levels can be attained in plasma in vivo.
• Whether the drug crosses the blood-brain barrier (if required).
• Whether the drug is orally bioavailable (if required).

II. Drug Evaluation Philosophy

Over the past ten years, the emphasis of preclinical toxicology studies has continued to shift away from the use of standardized protocols to evaluate the potential adverse effects of new anti-cancer agents. Current practice involves designing and performing more tailored agent-directed studies within a pharmacologically-guided framework. This is accomplished through the acquisition and use of pharmacokinetics information to reliably extrapolate toxic effects across species by relating plasma drug levels [peak and steady state and/or area-under-the-curve (AUC)] to safety and the occurrence and severity of toxicity. Integration of these studies with efficacy data and the proposed clinical protocol permits a more rational evaluation of the role of schedule dependence and pharmacokinetics in the development of toxicity.

In addition to this philosophical change in the approach to the development of toxicity information, the development of drugs within the DTP has evolved into two stages that require a toxicological evaluation at each stage. The first involves a preliminary assessment of toxicity in two preclinical animal models with the determination of maximum tolerated doses (MTD) in both species and pharmacokinetics in at least one of the preclinical animal models. If the drug meets the program criteria for full-scale development, a more complete toxicity evaluation is performed that will lead to the filing of an IND. This two-step approach allows the program to determine if full development is reasonable with a limited expenditure of resources (drug, animals and funds).

Note: A listing of relevant publications that document the changes in cancer drug development over the last 30+ years is available.

III. Drug Evaluation Procedures

Preclinical toxicology and pharmacology studies are conducted at the various DTP toxicology and pharmacology contractors in accordance with the protocol developed for each agent by the toxicologist or pharmacologist in the TPB. It is inappropriate to set guidelines that would be encompass all drugs, therefore, the general procedures below will be tailored to account for data on each agent’s in vitro cytotoxicity, biochemistry, pharmacology and schedule dependence as well as in vivo activity in tumored animal models.