Commentary

International Journal of Toxicology

2018, Vol. 37(2) 121-124
Reviewing the Utility of Two Species in ª The Author(s) 2018
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General Toxicology Related to Drug DOI: 10.1177/1091581818760564
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Development

Helen Prior1 , Paul Baldrick2, Lolke de Haan2, Noel Downes2,

Keith Jones2, Elisabeth Mortimer-Cassen2, and Ian Kimber3

Abstract
As part of the safety assessment of new drugs, the use of two species (a rodent and a nonrodent) for regulatory toxicology studies
is the typical approach taken for small molecules. For biologics, species selection is dictated by pharmacological relevance, and
single species toxicology packages (typically using the nonhuman primate) are common. The UK National Centre for the
Replacement, Refinement, and Reduction of Animals in Research and the Association of the British Pharmaceutical Industry are
collaborating on a project to review the utility of two species in regulatory toxicology studies, with the aim to explore whether
there are wider circumstances when data from a single species could be sufficient to enable safe progression in humans. An
international working group consisting of 37 representatives from pharmaceutical and biotechnology companies, contract research
organizations, academia, and regulatory bodies is coordinating a large-scale data sharing exercise to examine the potential for
changes in current practice to reduce the number of species used for nonclinical safety testing at different stages of development.
The challenge will be to determine whether two species toxicology adds significant value or whether in some instances data from a
single species are sufficient (across a broader range of molecules than is currently the case) without compromising human safety.

Keywords
biologics, drug development, first-in-human, nonrodent, rodent, safety assessment, small molecules, toxicology

Why Do We Use Two Species in Regulatory of species used for regulatory general toxicology (this project
Toxicology Studies? does not include reproductive toxicology or carcinogenicity
testing considerations).
It is a global regulatory requirement that potential new For small molecules, the use of two species (a rodent and a
medicines are tested in animals for safety and tolerability prior nonrodent) for toxicological assessment is mandated by regula-
to first-in-human (FIH) trials. This is to support the FIH dose tory guidance (eg, in ICHM3(R2), ICHS9). This strategy has
setting and benefit/risk assessment but additionally to support evolved over many decades from multispecies testing
longer term dosing in humans and to support special popula- concepts4 (summarized by Monticello et al5) and a thorough
tions (eg, women of childbearing potential, children, etc). Reg- approach for safety evaluation has been shown to be
ulatory toxicology studies are conducted to stipulated standards warranted.6 For large molecules, two species toxicology is also
(eg, Good Laboratory Practice compliance) and follow recom- mandated; however, the selection of species may be limited by
mendations within various regulatory guidances1-3 as appropri-
ate to the particular molecule and intended therapeutic
application. Potential new medicines come from a large and 1
National Centre for the Replacement, Refinement and Reduction of Animals
diverse range of molecules, which includes new chemical enti- in Research (NC3Rs), London, United Kingdom
2
ties (“small molecules”), new biological entities (“large Nonclinical and Biological Discovery Expert Network (NaBDEN), The
Association of the British Pharmaceutical Industry (ABPI), London, United
molecules” or biologics), vaccines, and others. Small mole- Kingdom
cules are chemically derived, while large molecules are 3
Faculty of Biology, Medicine and Health, University of Manchester,
typically protein-based and derived from cells, including Manchester, United Kingdom
antibody-based products such as monoclonal antibodies
(mAbs). Similar general concepts apply to any drug in devel- Corresponding Author:
Helen Prior, National Centre for the Replacement, Refinement and Reduction
opment, but due to the nature of differences between investi- of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Rd, London NW1
gative new drugs, there can be diverse approaches in the 2BE, United Kingdom.
nonclinical safety testing strategy, which includes the number Email: [email protected]
122 International Journal of Toxicology 37(2)

pharmacological relevance (eg, the presence of a highly specific  Could single species approaches be used more broadly
epitope). The nonhuman primate (NHP) is often the only species across a wider range of molecules?
relevant for regulatory general toxicology studies, and therefore,  To support the FIH clinical studies?
single species toxicology programs are common.7 Nevertheless,  To support continued clinical development through
if a large molecule does demonstrate cross-reactivity with mul- to marketing application?
tiple species (including rodent), then toxicology testing using
two species is required (examples in the paper by Sewell et al
 Might it be possible to conduct some development pro-
and Blaich et al8,9). Provided the toxicity profile is identical in
grams with two species and move to one or vice-versa?
short-term toxicology studies, it is possible to justify assessment
of chronic toxicity in a single species only (typically rodent),  For example, two species to support the FIH studies
although there seems to be no published evidence to confirm that but 1 species for support of chronic clinical dosing?
this scenario is being adopted. There are also disease-specific
guidance documents for certain drugs, which also have to be
taken into account along with ICHM3 or ICHS6, as applicable.  Are the current guidelines and access/use of scientific
For example, the guideline for development of oncology phar- advice (or equivalent) meetings with regulatory agen-
maceuticals3 provides guidance on a reduced scope for the non- cies appropriate to support flexible strategies and chal-
clinical toxicology program, with a view to accelerate the lenging approaches such as single species use for a
development of new therapies for advanced cancer. Although wider range of molecules?
ICHS9 indicates toxicology testing in two species is still gener-
Our intention is to consider whether different approaches
ally expected, it does contain examples where consideration for
may be applied to the number of species used for nonclinical
development in a single species might be possible for certain
safety testing, for example, within specific classes of com-
molecules.
pounds, therapeutic indications, or phases of development.
The species used for small molecules are generally the rat
Additionally, new opportunities may become apparent by
and dog,6,10,11 although the mouse, minipig,12 NHP, and others
reviewing standard and case-by-case examples and sharing
can be used as alternatives when these are considered to be the
these more widely across the industry.
more relevant species (with regard to pharmacological rele-
vance, pharmacokinetic/metabolic profiles, and/or class-
related tolerability/precedents).6 The use of two phylogeneti-
cally unrelated animal species may increase the likelihood of
Compounds For Review and Process Plans
detection of adverse effects in humans.13 Reviews of nonclini- The pharmaceutical and related industries are proactive in
cal data indicate that nonrodent data identify toxicities addi- reviewing requirements, justifying the relevance of current
tional to those detected in rodents for packages supporting FIH testing strategies, and identifying opportunities for adoption
trials,11,14,15 whereas a specific analysis of 20 anticancer com- of new or different approaches which may provide more pre-
pounds found that the rodent and nonrodent were equally sen- dictive data and of course apply 3Rs principles to the use of
sitive for detection of human adverse events.16 Comparisons of animals. Other consortia have, or are actively considering, spe-
target organ toxicities from short-term (3 months) and long- cific questions which align with and/or complement this proj-
term (3 months) dosing studies also found it equally likely ect, including the predictivity of nonclinical to clinical (FIH)
that the rodent and nonrodent species detected new or increased data,13 predevelopment attrition of pharmaceuticals,19 the
severity toxicities.17,18 appropriate use of animals for mAbs,8,20 and other biothera-
peutics development,9 among others. Within this busy colla-
borative environment, it is realized that any new data analysis
Purpose of the Project should not duplicate or replicate other initiatives but identify a
The UK National Centre for the Replacement, Refinement, and unique topic/question or opportunities to supplement and
Reduction of Animals in Research (NC3Rs) and the Associa- expand the overall picture.
tion of the British Pharmaceutical Industry (ABPI) are colla- A working group has been established, bringing together 37
borating on a project to review the utility of 2 species in representatives from international pharmaceutical and biotech-
regulatory toxicology studies and to explore circumstances nology companies, contract research organizations, academia,
when data from a single species could be sufficient to enable and regulatory agencies (covering Europe and the United
safe progression in humans, at different stages of development. States). The aim of the working group is to undertake a data
The use of two species for regulatory toxicology studies is the sharing exercise and to collect information on the species used
normal approach for small molecules, based on regulatory gui- and types of toxicology studies conducted over the course of
dance. For biologics, species selection is dictated by pharma- (1) late discovery/candidate selection phases (pre-FIH general
cological relevance, and as outlined above, single species toxicology packages), (2) the general toxicology studies to
toxicology programs (typically using the NHP) are common. support Investigational New Drug (IND) phase I trials (FIH
Therefore, it is pertinent to continue to review approaches used package), and (3) the general toxicology studies to support
and challenge thinking, in this case asking questions including: longer term dosing phase II/III trials (post-FIH package). The
Prior et al 123

types of compounds selected include small molecules and bio- Mortimer-Cassen, Drug Safety and Metabolism, Innovative Medi-
logics that are currently in or have recently stopped develop- cines and Early Development, AstraZeneca, Melbourn, United
ment in any of the 3 categories described. Some of the data Kingdom.
collected will be quantitative (eg, target class, therapy area, The NC3Rs is an independent scientific organization. It supports
the UK science base by driving and funding innovation and techno-
numbers and types of studies performed, types of target organ
logical developments that replace or reduce the need for animals in
toxicities observed). Other information will be qualitative (eg,
research and testing and lead to improvements in welfare where ani-
the impact of each study on decisions made, retrospective con- mals continue to be used. The Centre promotes robust and ethical
siderations around whether data from the second species [if scientific practice through collaborating with research funders, acade-
used] added value or if use of a single species would have been mia, industry, regulators, and animal welfare organisations, both in the
justified). In order to reduce inadvertent selection bias within United Kingdom and internationally.
the data set, participating companies were asked to provide data
from the most recent compounds in their portfolios, dating back Author Contributions
no further than 2012. The main data set collection period was All authors made equal contributions to the drafting and reviewing of
May to August 2017, and after collation by the UK NC3Rs, the this publication. H. Prior contributed to conception and design, con-
working group initiated review of all data in late 2017. Further tributed to acquisition, analysis, and interpretation, and drafted the
publications will describe the results of this initiative, provide manuscript. P. Baldrick contributed to conception and design and
recommendations for industry and regulators to consider, and critically revised the manuscript. L. De Haan contributed to design,
discuss the implications for future safety studies for drug contributed to interpretation, and critically revised the manuscript.
N. Downes contributed to design, contributed to interpretation, and
development.
critically revised the manuscript. K. Jones contributed to conception
and design and drafted the manuscript. E. Mortimer-Cassen contrib-
In conclusion uted to design and critically revised the manuscript. I. Kimber con-
tributed to conception and design and drafted the manuscript. All
Flexibility in current drug development practices and regula- authors gave final approval and agree to be accountable for all aspects
tions allows the most appropriate approaches to be taken for of work ensuring integrity and accuracy.
individual drug candidate programs, and following established
routines provides a high level of volunteer and patient safety. Declaration of Conflicting Interests
Reviews of industry data can promote best practice approaches, The author(s) declared no potential conflicts of interest with respect to
identifying new and/or efficient/streamlined ways of working, the research, authorship, and/or publication of this article.
which may also create opportunities for replacement, refine-
ment, or reduction in animal use within the drug development Funding
process. The challenge for this project will be to determine The author(s) received no financial support for the research, author-
whether two species toxicology adds significant value or ship, and/or publication of this article.
whether data from a single species could be justified (across
a broader range of molecules than is currently the case) without ORCID iD
compromising human safety. Considered together with the Helen Prior http://orcid.org/0000-0002-8700-7226
work of other consortia, these projects illustrate the willingness
of the industry and regulators to collaborate toward a more References
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