Regulatory considerations for preclinical development of anticancer drugs.

The entry of new anticancer treatments into phase I clinical trials is ordinarily based on relatively modest preclinical data. This report defines the battery of preclinical tests important for assessing safety under an Investigational New Drug application (IND) and outlines a basis for extrapolating starting doses of investigational anticancer drugs in phase I clinical trials from animal toxicity studies. Types of preclinical studies for the support of marketing of a new anticancer drug are also discussed. This report addresses differences and similarities in the preclinical development of cytotoxic drugs (including photosensitizers and targeted delivery products), drugs used chronically (chemopreventive drugs, hormonal drugs, immunomodulators), and drugs intended to enhance the efficacy (MDR-reversing agents and radiation/chemotherapy sensitizers) or diminish the toxicity of currently used anticancer therapies. Factors to consider in the design of preclinical studies of combination therapies, alternative therapies, and adjuvant therapies in the treatment of cancer, and to support changes in clinical formulations or route of administration, are also discussed.

Growth-rate periodicity of Streptomyces levoris during space flight.

Streptomyces levoris Kras was used is an experimental test micro-organism during the Apollo Soyuz Test Project to study alternating vegetative mycelial and spore ring periodicity during space flight. Four cultures were launched in each of the spacecrafts (Apollo and Soyuz). During the joint space-flight activities, two cultures from each spacecraft were exchanged. Selected duplicate cultures were maintained as controls in both the USA and the USSR. Spore ring morphology was periodically documented by photographing the specimens at approximately 12-hr intervals during the pre-, in-, and post-flight periods of the experiment. A decreased growth-rate periodicity in all but one of the eight space-flight cultures was in part attributed to the reduced temperature in the spacecraft. One of the eight cultures grew at a faster rate in the reduced temperature environment of Apollo than did the ground controls. Three of the space-flight cultures developed double spore rings during the immediate post-flight period. This anomaly was attributed to re-entry into the earth's gravity. The absence of spores in portions of one ring formed during space flight may have been caused by nutritional defects or media abnormality. Extensive studies will be required to elucidate the cause of this detect with certainty. There was no visible evidence of wedges in the cultures which would suggest naturally occurring or radiation-induced mutagenic alteration during space flight.

Considerations for toxicology studies of respiratory drug products.

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.