Optimising the design of preliminary toxicity studies for pharmaceutical safety testing in the dog.

A working party, comprising two animal welfare organisations and some 12 pharmaceutical companies in Europe, was established to minimise the use of the dog in safety testing. As first step, the participants defined the major objectives of preliminary dose-range finding/MTD toxicity studies in non-rodents, defined the principles and requirements for this study type and agreed on a proposal for an optimised study design, based on collective experience of conducting such studies in industry, involving an evaluation of 100 individual study data sets. The suggested study design is explained and described, and reflects current best practice in the pharmaceutical industry in Europe. The implementation of such an optimised design is believed to result in a reduction in the overall numbers of animals used for this purpose, without jeopardising the scientific rationale and usefulness of the studies for informing the conduct of later regulatory studies.

An approach to minimise dog use in regulatory toxicology: production of a best practice guide to study design.

The primary non-rodent species used in toxicology is the dog. It is generally agreed that, for ethical reasons, dog use should be reduced to the minimum consistent with maintaining the scientific quality of toxicology studies and ensuring human safety. Dog use in toxicology has been discussed widely, both from a scientific and ethical viewpoint, and there appears to be real potential for achieving significant reductions in the number of dogs used in pharmaceutical safety testing. An industry animal welfare initiative commenced in 2000, with the aim of evaluating and, where possible, putting into practice, scientifically valid approaches to minimise dog use in regulatory toxicology without increasing the use of other non-rodent species, such as non-human primates or minipigs. The study's Steering Group categorised potential reduction approaches into three distinct areas, one of which is the production of a best practice guide on aspects of study design, including: group sizes, use of control animals, single sex studies and design of maximum tolerated dose (MTD) studies. Information on current practice and experience within the pharmaceutical industry is now being analysed, and additional input is invited.

Preclinical safety evaluation using nonrodent species: an industry/welfare project to minimize dog use.

This review of the dog, the primary nonrodent species used in toxicology, and its use in the safety evaluation of pharmaceuticals, provides data on the number used in particular projects in an effort to establish a baseline from which some minimization can be measured. Opportunities for reduction and replacement, as identified by a European Industry/Welfare Steering Group, are discussed. The three distinct areas of potential approaches to minimize dog use are categorized as industrial cooperation/data sharing, achieving best practice in study design, and assessing the need for a particular study. The Steering Group prioritized the approaches based on the impact on the number of animals used, the impact on the welfare of the remaining animals, the potential for industry's acceptance of the scientific approach, the potential for regulators' acceptance of the validated approach, and the time/cost of evaluation or implementation. Examples of each category are presented, and the work needed to facilitate industry/regulatory change is discussed.