Regulatory Testing in Europe
CURRENT 3Rs ISSUES & OPPORTUNITIES
HUMANE SOCEITY INTERNATIONAL
EUROPE
About HSI Europe
• HSI is the international arm of the Humane Society of the United
States, the world’s largest animal protection organisation, with
nearly 11 million supporters worldwide
• HSI has a long history of building lasting partnerships with
members of the regulatory and regulated communities for the
furtherance of common goals
• As do most scientists, HSI wants to see the day when no animal
is used in harmful experiments, and regards the “3Rs”
(replacement, reduction, refinement) as a win/win strategy for
achieving this goal
• HSI-Europe has been engaged in constructive dialogue with EU
institutions, member states and industry since 1991
Committee/Expert Group Involvement
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REACH Competent Authorities Group
ECHA Risk Assessment Committee
USEPA Pesticide Program Dialogue Committee
ILSI-US/Europe Steering Committees on TTC
EPAA Mirror Group and Working Groups
OECD Test Guidelines Programme
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Working Group of National Co-ordinators
New design for reproductive toxicity studies
Revision of chronic toxicity/carcinogenicity TGs
Integrated approaches to testing and assessment
• EPAA Mirror Group, Working Groups & Task Forces
Why Deviate From Status Quo?
• Low throughput and expensive
• Multiplicity of in vivo tests for some toxicity endpoints
• Many in vivo tests are between 50-80 years old and have never
been subject to formal validation by contemporary standards
– Reliable and relevant to humans?
• Uncertainties associated with extrapolation
– Inter- and intra-species, high to low dose, exposure durations, etc.
• Methods have not kept pace with scientific progress
• Animal welfare concerns
– ~80% of the most invasive procedures are performed in the field of
regulatory toxicology (CCAC, 2007)
• Public opinion
Case Study – Carcinogenicity
• 18-24 months of chemical exposure + 2-3 years of data analysis
• Multi-species design, consuming 400 rats + 400 mice at a cost of
up to 3 million  per chemical evaluated
• Dubious reliability and relevance to humans, e.g.:
– Poor (57%) concordance among >120 replicate studies
– Numerous tumour types, organs, and mechanisms of action in
rodents considered irrelevant to humans
– Marked strain differences and high “background” tumour rates
– Maximum tolerated dose (MTD) in rodents can be up to 100-times
the equivalent daily intake for humans
– Implausibly high rate of positive findings (false +ve classifications)
(Gottmann et al., 2001; Cohen, 2004; IARC, 1995; 1999; 2003; Haseman, 2000,
ACSH, 1997; Fung et al., 1995; Gold & Slone, 1993; Ennever et al., 1987)
Case Study – Reproductive Toxicity
• Several overlapping study designs prescribed as separate data
requirements in one or more species:
– 2-generation rat reproduction studies use upwards of 2,600 animals
and cost as much as 300,000 
– Prenatal developmental toxicity studies use 1,300 rats or 660 rabbits
and cost between 34,000-50,000 
– DNT studies use at least 1,300 rats at a cost of more than 300,000 
• Dubious reliability and relevance to humans, e.g.:
– Breeding a second generation adds little/no value to risk assessment
– Poor (<70%) concordance among rats, mice and rabbits in detecting
known teratogens
– Use of a second species increases an already 40% false +ve rate
(Derelanko & Hollinger, 2002; Cooper et al., 2006; Janer et al., 2007;
Hurtt et al., 2003; Bremer et al., 2007; Schardein, 2000)
Case Study – Acute Systemic Toxicity
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WWI-era science; never formally validated
Mortality or moribundity as the endpoint
5-40 animals killed per test, depending on test guideline
Testing may be required by up to 3 routes (oral, inhalation, skin)
Dubious reliability and relevance to humans, e.g.:
– Rodent LD50 prediction of human lethal blood levels (R2 = 0.65)
– “… even if the LD50 could be measured exactly and reproducibly, the
knowledge of its precise numerical value would barely be of practical
importance, because extrapolation from the experimental animals to
man is hardly possible.”
(Trevan, 1927; Ekwall et al., 1999; Lorke, 1983)
Case Study – Agrochemicals Sector
• Current costs of bringing a new pesticide to market can range
from $152 to $184 million, consuming upwards of 12,000 animals
for registration testing battery alone
(ECPA/CLA, 2003; Mattsson et al., 2003)
• As noted by the ILSI-HESI Task Force on Agricultural Chemical
Safety Assessment:
“In most cases, when the database is complete using the large
number of animals mandated by the test guidelines, only one study is
used to set the [reference dose] for each risk assessment. The
question then arises: Would it have been possible to leave out the
studies which were not used and still protect health?”
(Doe et al., 2006)
Case Study – Pharmaceuticals Sector
• Current costs of bringing a new medicine to market can range
from $0.8 to $1.7 billion, consuming upwards of 7,000 animals
– 92% of drugs that pass preclinical testing fail clinical trials
(Tufts Center for the Study of Drug Development, 2001; FDA, 2004)
• As noted in the 2004 FDA Critical Path report:
– “Currently available animal models, used for evaluating potential
therapies prior to human clinical trials, have limited predictive value
in many disease states.”
– Traditional animal toxicology “… is laborious, time-consuming,
requires large quantities of product, and may fail to predict the
specific safety problem that ultimately halts development.”
(FDA, 2004)
Change Is Needed
“It is simply not possible with all the animals in the world to go
through new chemicals in the blind way that we have at the
present time and reach credible conclusions about the hazards
to human health. We are at an impasse. It is one with deep
scientific roots and we had better do something about it.”
–Dr Joshua Lederberg
Nobel Laureate in Medicine
(Chemical Engineering News, 1980)
Short-Term Solution: The “3Rs”
• The principle of reduction, refinement and
replacement of animal use was first
articulated in the 1959 publication, The
Principles of Humane Experimental
Technique, by British scientists William
Russell and Rex Burch
• During the subsequent half-century,
tens of millions have been invested
by corporations, governments and
other stakeholders with the goal
of advancing the 3Rs in research
and testing
The Road to Regulatory Acceptance
Research &
Development
? yrs
Prevalidation
~2 yrs
Regulatory
Valid- Peer
ation review acceptance
(regional)
~1 yr
~1 yr
~2 yrs
Regulatory
acceptance
(international)
3+ yrs
Factors Affecting Progress
• Lack of co-ordinated global strategy for prioritisation and funding
of new test method R&D
• Access to sufficient quantity and quality of (human-relevant)
reference data for validation
– Recent material transfer agreements between pharma companies
and US EPA
• Uneven acceptance of validated 3Rs methods
– International validation criteria now harmonised, yet resistance
continues in some regions
• Trend toward new and complex in vivo data requirements
– Developmental neuro-, immuno-, cardio-toxicity, endocrine, acute
reference dose, etc.
Is replacing animal tests one endpoint at
a time a viable long-term strategy
Long-Term Solution: Paradigm Shift
• US National Academy of Sciences (NAS) Report “Toxicity
Testing in the 21st Century” (2007):
– Recognises that current approaches are not
only cumbersome, but simply not optimal for
toxicity testing in the 21st century
– The NAS envisions “... a not‐so‐distant future
where all routine toxicity testing will be
conducted in human cells or cell lines in vitro
by evaluating perturbations of cellular
responses in a suite of toxicity pathway
assays using rapid robotic‐assisted
methodologies.”
Current High Throughput Capabilities
(US National Institutes of Health Chemical Genomics Center)
# wells per plate, including controls
1,536
# chemicals per plate
1,408
# concentrations per chemical
# assays
Concentrations (including controls)
x Assays x Wells
Current NCGC capabilities
Time needed to run 1,408 chemicals
(~5 million wells)
Cost per dose-response curve
Cost per chemical (200 assays)
Costs per 10,000 chemicals
15
200
~5 million wells
2.5 million wells per week
2 weeks
US$50
US$10,000
US$100 million
Advantages of a High Throughput Paradigm
2-species cancer
bioassay
NCGC HTS
platform
Cost
2.5-3 million €
2.5 million €
# chemicals
1
350
# animals
800+
0
# endpoints
?
~200
Duration
150 weeks
1 week
HSI Perspective on NAS Vision
Implementation
• HSI’s goal is a permanent end to animal testing worldwide
• HSI welcomes ongoing 3Rs initiatives in the EU/US, but
recognises the need for a much larger-scale research effort to
make this vision a reality
Toxicology’s equivalent to the Human Genome Project
(“HUMAN TOXICOLOGY PROJECT”)
• Funding target: 150M € per year over 10 years (total=1.5B €)
– Public-private partnership between G8 countries and corporations
• Goal: a targeted research programme that is:
– Multi-year, multi-discipline and multinational
• Current partners:
– Corporate: Dow, Dupont, Exxon-Mobil, Johnson & Johnson, Procter
& Gamble, Unilever
– NGOs: HSI & its US affiliates
– Research: Hamner Institutes for the Health Sciences
• Aims:
– Facilitate global implementation of the NAS report
– Promote dialogue, information sharing & establishment of an R&D
roadmap
– Lobby for, coordinate & provide resources for transatlantic efforts
– Urgently develop a targeted research program to jumpstart the
transformation
•
The
Project
Accelerating the transition to a toxicity pathway-based
paradigm for chemical safety assessment
through internationally co-ordinated research
and technology development
•EU FP7 Coordination Action developed on the initiative of HSI
• 3.5 year, >550,000 € project designed to fulfill the growing need of a
focal point for co-ordination among 3Rs research projects in Europe
as well as internationally
• Partners
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Free University of Berlin (Horst Spielmann & Monika Schäfer-Korting)
CARDAM-VITO (Greet Schoeters)
The
Project
• AXLR8 will:
– Organise a series of annual workshops to map research progress,
gaps and needs in the FP6/FP7 programme on alternative testing
strategies
– Provide a range of tools and opportunities for enhanced
interdisciplinary and international communication, co-ordination and
collaboration in order to maximise the impact of available resources
– Work to streamline regulatory acceptance procedures to provide for
the uptake of validated 3Rs methods, including a smooth transition
to 21st century systems as they become available
– Produce annual progress reports on the state of the science,
including recommendations on priority research and funding targets,
in order to ensure a prominent role for European science in this
rapidly developing global research area
Thank You!
For further information, contact:
Emily McIvor
Senior EU Policy Adviser
Research & Toxicology Department
+44 (0)7812 354 144 emcivor@hsi.org
HSIEurope.org | AXLR8.eu