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 Jacobn 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
节能降耗方案f AltanaPharma, Hamburg, Germany
g Jansn, Beer, Belgium
h Merck KGaA, Darmstadt, Germany
i RSPCA, Horsham, UK
j Novartis Pharma, Bal, Switzerland
k Pfizer, Amboi, France
l GlaxoSmithKline, Ware, UK
酒店营销方案
m Schering AG, Berlin, Germany
n Hoffmann-La Roche AG, Bal, Switzerland
Abstract
A working party, comprising two animal welfare organisations and
some 12 pharmaceutical companies in Europe, was established to minimi the u of the dog in safety testing. As first step, the
participants defined the major objectives of preliminary do-range finding/MTD toxicity studies in non-rodents, defined the principles and requirements for this study type and agreed on a proposal for an optimid study design, bad on collective experience of conducting such studies in industry, involving an evaluation of 100 individual study data ts. The suggested study design is explained and
described, and reflects current best practice in the pharmaceutical industry in Europe. The implementation of such an optimid design is believed to result in a reduction in the overall numbers of animals ud for this purpo, without jeopardising the scientific rationale and b b s .y a o z h .c o m
ufulness of the studies for informing the conduct of later regulatory studies.
Keywords: Reduction; Refinement; Alternatives; Animal u; Dogs; Laboratory animal science; Toxicity tests; Regulatory toxicology
1. Introduction
1.1. Background
The pharmaceutical industry recognis the need to implement
strategies for reducing, refining, and replacing the u of animals in toxicity studies (The Three Rs) (Tweats, 2000), particularly regarding the u of companion species in safety testing (Baker and Broadhead, 2000). To this end, veral pharmaceutical companies bad 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 u of the dog as a cond species in regulatory toxicity testing, which in turn was organid as a result of some preliminary rearch conducted by FRAME and the RSPCA (Broadhead et al., 1998, Broadhead et al., 1999 and Broadhead et al., 2000).
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网络稳定测试The principal remit of the working party is to propo and, where possible, put into practice scientifically valid and feasible approaches to optimi dog u in the safety evaluation of pharmaceuticals, without compromising human safety or increasing the u of other non-rodent species. 1.2. Initial approach—analysis of the design of
preliminary repeat do toxicity studies
As one of its first tasks, the working party identified many potential approaches for optimising dog u, and the have been prioritid for further consideration (Smith et al., 2002). One promising
approach related to the design of repeat do toxicity studies, and included a comprehensive analysis of the different designs currently b b
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being ud by the member companies of the working party for preliminary escalating do/maximum tolerated do (MTD) and do range finding (DRF) studies, which precede pivotal repeat do toxicity testing. The objective of this investigation was to define the principles and requirements of MTD and DRF studies so that an optimid study design could be identified. Such a design should deliver appropriate early information on the characteristics of the test compound in non-rodents and allow a reliable prediction of appropriate do levels for the 14 day/1 month regulatory toxicity study, thus achieving the most effective u of the animals. The information from this optimid study design should also meet single do (acute) toxicity study requirements.
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1.3. Objective of the paper
We intend to share the results of our co-operation and propo an optimid study design, which was formulated as a result of the sharing of data, current working practices, and experiences among members of the working party. Publication of this paper is also intended to promote dialogue with other toxicologists in the industry, and with regulators, who are involved with generating data bad on the tests, or who have to asss such information. The work described in this manuscript is part of a wider effort by the working party to optimi and minimi the u of the dog as a cond species in the regulatory safety asssment of new pharmaceuticals. Preliminary findings have been published elwhere (Phillips et al., 2004; Smith et al., 2003). 2. Results of discussions 2.1. The purpo of preliminary studies
The sharing of information between members of the collaborative group soon revealed that, although each organisation ud the MTD/DRF study to lect do levels for the repeat do, regulatory study, the additional us to which this study were put varied greatly between companies. As a conquence of this difference in custom and practice between each company, different study designs were in u in nearly all cas. b b s .y a o z h .c o m
In conquence, agreement was sought on the primary and condary purpos of such studies, together with reaching
connsus on the nature of any optional data ts that could also be generated, before an optimid protocol could be developed. The results of this discussion exerci are summarid in Table 1 and Table 2.
Table 1. Primary and condary purpos of preliminary DRF/MTD study in the dog Purpo Description
Primary Do lection (highest do) for the pivotal repeat do studies conducted prior to first do to man
Secondar
y Detection of rious toxicity (often referred to as target organ toxicity) to confirm the lection of candidate drugs
Obtaining toxicokinetic data at a range of dos to allow optimal do lection for subquent repeat do studies in relation to estimated clinical dos
Asssment of suitability of the dog as the cond species
Also ud for estimating compound requirements for the subquent repeat do studies able 2.
论语英文
Further information obtainable from preliminary MTD/DRF studies in the dog Parameter
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Comments No obrved effect level (NOEL)
After single or multiple dos
No obrved adver effect level (NOAEL)After single or multiple dos
Systemic exposure
Measured at each do level in plasma
Overt clinical signs Characterisation of overt toxicity after single or multiple dos b b s .y a o z h .c o m
基金知识Parameter Comments
Do proportionality Saturation of absorption/elimination
Tachyphylaxis Induction after multiple dos
Tolerability/responsiveness To confirm species lection
Delayed ont of toxicity During the repeat do pha
Recovery from toxic insult After single or multiple dos, e.g., clinical signs
Clinical pathology Within the constraints of the design After considerable discussion concerning the intended us of maximum tolerated do (MTD) and do range finding (DRF) studies, it was agreed that an MTD study should be designed to detect a tolerance limit bad on the results of an in vivo test, following the administration of single, escalating dos of test chemical. It was also agreed that DRF studies should be designed to identify a tolerance limit following the repeated administration of the highest feasible do, bad on the outcome of an MTD study. The working party paid particular attention to make suggestions for improving the design of the MTF/DRF preliminary studies that would allow the collection of data compatible with further regulatory requirements for non-rodent safety testing, so as to avoid
compromising its overall objective of minimising dog usage. To this end, proposals for a new study design were made so that data generated by the new protocol would meet the requirements to
replace the single do (acute) toxicity study in non-rodents, since according to the experience of some members of the working party, the strategy of using MTF/DRF data instead of especially gener
ated single do toxicity data in non-rodents is well accepted by some regulators (namely tho in Japan), which still request this type of information collected in non-rodents. Moreover, some regulatory guidelines provide sufficient flexibility to cater for the submission of b b s .y a o z h .c o m
data obtained in this manner (FDA Guidance for Industry, 1996:
Single Do Acute Toxicity Testing for Pharmaceuticals; Yakuji Nippo, Japan’s and ICH guidelines for new drug registration, 1999). In addition to the primary and condary purpos of MTD/DRF studies, the working group identified further information that could also be obtained or derived from such studies (Table 2).
The ufulness of including each of the above requirements in any study design is discusd later. It is most important to balance the welfare implications of intensive animal handling, treatment
procedures and sampling methods with the overall number of dogs ud when designing studies.
2.2. Factors affecting design The following factors were considered by the working party to influence the design of any MTD/DRF study. It should, however, be noted that the following list is unlikely to be exhaustive, but reflects the current approach to drug development. 2.2.1. The overall number of ani
mals required The total number of animals per study depends on the number of do groups and the group size. Thus, any approach to minimi the total number of animals ud has to target on limiting the number of parate do groups and on minimising the group size needed to achieve a sufficient and relevant data t. If it is accepted that such studies are only designed to detect
significant levels of toxicity, then it is possible to u small group sizes, without control animal groups. Data prented later show that the relevance and predictability of such studies do not correlate to the group sizes ud, although the fact that there are limits to reducing group sizes should be recognid. 2.2.2. The amount of compound available for
testing It is, of cour, mandatory for such studies to have sufficient chemical, or drug supply to allow inclusion of do levels high enough to b b
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