药物毒性试验的设计

Optimising the design of preliminary toxicity studies

for pharmaceutical safety testing in the dog David Smith a, , , Robert Combes b, Olympe Depelchin c, Soren Dyring Jacobsen d, Ruediger Hack e, Joerg Luft f, Lieve Lammens g, Friedrich von Landenberg h, Barry Phillips i, Rudolf Pfister j, Yvon Rabemampianina k, Susan Sparrow l, Claudia Stark m and Markus Stephan-Gueldner n

a AstraZeneca, Alderley Park, UK

b FRAME, Nottingham, UK

c Lilly, Mont-Saint Guibert, Belguim

d NovoNordisk, Maaloev, Denmark

e Aventis, Frankfurt, Germany

f AltanaPharma, Hamburg, Germany

g Janssen, Beerse, Belgium

h Merck KGaA, Darmstadt, Germany

i RSPCA, Horsham, UK

j Novartis Pharma, Basel, Switzerland

k Pfizer, Amboise, France

l GlaxoSmithKline, Ware, UK

m Schering AG, Berlin, Germany

n Hoffmann-La Roche AG, Basel, Switzerland

Abstract

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.

Keywords: Reduction; Refinement; Alternatives; Animal use; Dogs; Laboratory animal science; Toxicity tests; Regulatory toxicology 1. Introduction

1.1. Background

The pharmaceutical industry recognises the need to implement strategies for reducing, refining, and replacing the use of animals in toxicity studies (The Three Rs) (Tweats, 2000), particularly regarding the use of companion species in safety testing (Baker and Broadhead, 2000). To this end, several pharmaceutical companies based in Europe have formed a working party with two scientific and animal welfare charities in the UK, the Royal Society for the Prevention of Cruelty to Animals (RSPCA) and the Fund for the Replacement of Animals in Medical Experiments (FRAME). The formation of this collaborative group in 2000 was prompted by a recommendation made at a workshop held to discuss the use of the dog as a second species in regulatory toxicity testing, which in turn was organised as a result of some preliminary research conducted by FRAME and the RSPCA (Broadhead et al., 1998, Broadhead et al., 1999 and Broadhead et al., 2000).

The principal remit of the working party is to propose and, where possible, put into practice scientifically valid and feasible approaches to optimise dog use in the safety evaluation of pharmaceuticals, without compromising human safety or increasing the use of other non-rodent species.

1.2. Initial approach—analysis of the design of preliminary repeat dose toxicity studies

As one of its first tasks, the working party identified many potential approaches for optimising dog use, and these have been prioritised for further consideration (Smith et al., 2002). One promising approach related to the design of repeat dose toxicity studies, and included a comprehensive analysis of the different designs currently