New Product Development. A pharmaceutical company has been given the opportunity to license a new product from a developer. The product is targeted for use by men and women of reproductive age. The developer has performed several of the preclinical, Phase I, and Phase II studies that are required by the Food and Drug Administration, and has written protocols for Phase III trials. The pharmaceutical company needs to make a decision on whether the product is worth licensing.

There are two issues in the licensing decision: how likely is the product to be effective, and what safety concerns are likely to arise? Product effectiveness will be evaluated in Phase III trials in humans; these trials will be costly. The preclinical studies suggest that the product will be effective, but Phase II trials suggest that the dose necessary to achieve effectiveness will be approximately 25 mg/day. This dose produces plasma concentrations of the product that are substantially greater than those achieved in the experimental animal pharmacokinetic studies. In addition, reproductive testing shows full litter loss in rats at oral dose levels of 200 mg/kg/day. Plasma concentrations of the product in pregnant animals are not available.

The pharmaceutical company has made a decision that it does not want to market this product if the label contains a strong warning against becoming pregnant while using it. Pharmaceutical pregnancy warnings are developed based on anticipated risks and benefits of the product. Sciences International, Inc. personnel are asked to review the data and to advice the pharmaceutical company on the likelihood of such a warning. Based on an examination of the pharmacokinetic data in nonpregnant animals, the anticipated effective therapeutic concentrations of the drug in women, the preclinical reproductive studies, and the nature of the disorder for which the drug will be marketed, Sciences personnel are able to predict that the Food and Drug Administration will require a strong pregnancy warning. The pharmaceutical company makes a decision not to license the product.

The Use of Experimental Animal Data in Assessing a Developmental Hazard. A manufacturer with plants in North and South America and in Europe consulted Sciences about a chemical that had demonstrated developmental toxicity in experimental animals. The chemical was a contaminant of a raw material and was eliminated from the final product during the manufacturing process. The manufacturer was concerned about exposure of workers as the chemical was off-gassed. Questions raised in the consultation included the use and applicability of exposure information for different species, methods to assess employee exposure, and possible biomarkers of toxicity. This case was made more complex by the discordant responses of experimental species and the need to determine which species would be most appropriate for human risk assessment. The determination was made that the anticipated risk to nonpregnant workers was negligible and that inadvertent exposure of pregnant workers would be unlikely to result in a significant risk of adverse outcome. In spite of this determination, the consultation also included options for the education of employees who might be concerned about the presence of this chemical in their workplace.