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2 Animal Reduction Opportunities in Genotoxicity In Vivo Testing: Integration in Standard Toxicity Studies and Combination of Endpoints

2 Animal Reduction Opportunities in Genotoxicity In Vivo Testing: Integration in Standard Toxicity Studies and Combination of Endpoints

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Regulatory Acceptance of Alternative Methods in the Development…



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investigated the sensitivity and practicality of integrating the liver Comet assay into

acute and 2- or 4-week repeat-dose rat toxicity studies (Rothfuss et al. 2010). These

and other data were considered by the Basle 2009 IGWT working groups as part of

their recommendations on in vivo genotoxicity testing, in particular the suitability

of tests with multiple genotoxicity endpoints integrated into acute or RDT studies.

The combination of the acute in vivo MN and Comet assays was considered by the

working group to represent a technically feasible and scientifically acceptable alternative to conducting independent assays. For the integration of Comet assays into

RDT studies, the working group reached the consensus that, based upon the limited

amount of data available, integration is scientifically acceptable and that the liver

Comet assay can complement the MN assay in blood or bone marrow in detecting

in vivo genotoxins. Practical issues need to be considered when conducting an integrated Comet assay study (Rothfuss et al. 2010).

The ICH EWG has adopted these advices for combining different endpoints into

one study in the revised ICH S2 guideline. When in vivo assessment of genotoxicity

with two tissues is required the guideline encourages the incorporation of two genotoxicity assays in one study using the same animals, e.g. bone marrow micronucleus

test and liver DNA strand breakage assay.

Recent study report submissions to regulatory health authorities clearly indicate

that the new options offered by the ICH S2R1 are increasingly utilized by pharmaceutical industry. In particular, integration of MN analysis in RDT studies in cases

where in vitro testing is negative and acute combined in vivo MN/comet assay to

follow-up positive findings in in vitro mammalian cell tests are the preferred options

in recently performed genotoxicity testing programs. It can thus be roughly estimated that the number of animals used for in vivo genotoxicity assessment in new

drug development may be decreased by nearly 50 % as a result of the revisions of

the ICH S2 guideline.

In summary, the experiences with the process leading to revision of the ICH S2

guideline clearly show that formal validation is not a necessary prerequisite for

regulatory acceptance of new 3R testing approaches. Instead, the scientific credibility of new methodologies and its use for regulatory purposes is pragmatically

assessed in a formalized ICH procedure by a working group of recognized industry

and regulatory experts in the field based on high quality data from different sources.



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4.1



The EMA Approach to Regulatory Acceptance

of 3R Test Methods

The JEG 3Rs



To demonstrate its commitment to the application of replacement, reduction and

refinement (the 3Rs) of animal testing as detailed in Directive 2010/63/EU (Directive

2010), in October 2010, the EMA endorsed the establishment of a Joint ad hoc

Expert Group on the application of 3Rs in the development of medicinal products



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(JEG 3Rs). The JEG 3Rs has as a mandate to improve and foster the application of

3Rs in the regulatory testing of medicinal products throughout their lifecycle.

Moreover, this group provides advice and recommendations to the Committees (i.e.

CHMP and CVMP) on all matters related to the use of animals in regulatory testing

of medicinal products.

The core of the JEG 3Rs consists of experts from CVMP and CHMP and their

working parties for which animal testing is relevant, and can be complemented, as

necessary, by specific experts. As such, all relevant disciplines (i.e. quality, safety

and, in the case of veterinary medicinal products, efficacy) are represented, for both

pharmaceutical and biological/immunological products.

As it is recognised that much work is already being done in the 3Rs area by other

European Commission bodies and consequently it is considered that duplication of

efforts should be avoided, the JEG 3Rs works in close cooperation with EURL

ECVAM (European Union Reference Laboratory for Alternatives to Animal

Testing) and EDQM (European Directorate for the Quality of Medicines and

Healthcare).

Amongst the achievements of the JEG 3Rs so far are the efforts to ensure compliance of existing regulatory guidance with the 3Rs. As such, a concept paper

announcing a review of existing EMA guidance to ensure compliance with best 3Rs

practice was published in February 2014 (Concept paper on review and update of

European Medicines Agency Guidelines 2014) and publication of the first amended

guidelines will ensue. Eight guidelines have so far been identified for revision but

the review is not yet complete. In addition, a draft guideline on regulatory acceptance of 3Rs testing approaches has been published for a 3-month period of consultation (Draft Guideline on regulatory acceptance of 3R 2014). This guideline

describes the process for submission and evaluation of a proposal for regulatory

acceptance of 3R (Replacement, Reduction and Refinement) testing approaches for

use in the development and quality control during production of human and veterinary medicinal products. Furthermore, scientific and technical criteria for validation

of 3R testing approaches are presented and pathways for regulatory acceptance of

3R testing approaches are described.

Another work stream of the JEG 3Rs is related to the implementation of the 3Rs

in batch release testing of human and veterinary medicinal products. To this end, a

statement was published highlighting the need for marketing authorization holders

(MAHs) to ensure that batch safety and potency tests comply with 3Rs options

available in the Ph Eur (Recommendation to marketing authorisation holders 2012).

A statement was published highlighting the need for MAHs for veterinary vaccines

to update MAs to remove the target animal batch safety test following removal of

the requirement from the Ph Eur (“Recommendation to marketing authorisation

holders” 2013). At their July 2014 meetings CXMP adopted a concept paper for

publication for consultation, announcing the development of guidance on transferring validated quality control methods to a product/laboratory specific context

(Concept paper on tranferring quality control methods 2014). Work on developing

the guideline is now underway. In addition, review of batch release testing for

human and veterinary vaccines is conducted and follow-up communications to

MAHs ensured.



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Regulatory Acceptance of Alternative Methods in the Development…



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JEG 3Rs coordinates responses to requests from the European Union Reference

Laboratory for Alternatives to Animal Testing (EURL ECVAM) for preliminary

analysis of regulatory relevance of new alternative methods (PARERE).

The existence of the JEG 3Rs provides a strong signal indicating that EMA takes

3Rs issues seriously. A clear statement of the EMA on the application of the 3Rs in

regulatory testing of human and veterinary medicinal products was published in the

EMA website at the very beginning of the JEG 3Rs’ first mandate (Statement of the

EMA position on the application of the 3Rs 2011). This reads as follows:

The European Medicines Agency (EMA) commits to the application of replacement, reduction and refinement (the 3Rs) of animal testing as detailed in Directive

2010/63/EU1. To this end, a Joint ad hoc Expert Group (the JEG 3Rs) has been

created in order to promote best practice in the implementation of the 3Rs in regulatory testing of medicinal products and to facilitate full and active cooperation with

other European groups working in the 3Rs area.

While significant progress has been made in relation to regulatory testing involving animals it remains the case that certain types of data can only be generated by

means of animal studies. Where such studies are needed they should be selected and

conducted in strict adherence to the 3Rs principles.

As a European body with responsibility for developing harmonised European

regulatory requirements for human and veterinary medicinal products the EMA has

and will continue to play a key role in eliminating repetitious and unnecessary animal testing in the European Economic Area (EEA), in collaboration with other

European organisations such as EDQM. Through its active participation and collaboration in the work of other multinational organisations such as the ICH and the

VICH, the EMA contributes to the application of the 3Rs in the development of

globally harmonised requirements, the implementation of which contributes to the

elimination of unnecessary animal testing.

The JEG 3Rs is now recognised at international level and is often cited as an

example of how regulatory agencies should tackle 3Rs issues whilst providing a

clear entry point for questions or comments in this area. The JEG 3Rs mandate was

renewed in October 2014 for the second time, thus allowing this group to continue

its work in order to achieve progress in the field of 3Rs, an area for which Europe is

clearly a global frontrunner.



4.2



Draft Guideline on Regulatory Acceptance of 3R

Testing Approaches



4.2.1



Ontogeny



The application of the 3Rs were already highlighted in the Position on the

Replacement of Animal studies by in vitro models (Replacment of animal studies

by in vitro models 1997), adopted by the then called EMA Committee on Proprietary

Medicinal Products (CPMP) at its meeting in February 1997. This Position Paper



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addressed the feasibility of replacing in vivo animal studies by in vitro investigations in the preclinical development of medicinal products. In addition, considerations regarding validation procedures for in vitro methods and their incorporation

into CPMP Notes for Guidance were presented.

Whilst replacement of animal studies remains the ultimate goal, the application

of all 3Rs needs to be the focus. As exemplified by the ICH regulatory safety guidelines described earlier, approaches aiming at reducing or refining animal studies are

being routinely implemented in regulatory guidelines, where applicable. At the

same time, over the past years, new in vitro methods have been accepted for regulatory use via multiple and flexible approaches, either as pivotal, supportive or as

exploratory mechanistic studies, wherever applicable. As such, although regulatory

acceptance of 3Rs testing approaches is currently possible, a formal regulatory

acceptance process has been lacking and implementation of new test methods in

routine regulatory testing has sometimes proven problematic.

Consequently, a review of the position paper focusing primarily on Replacement

was needed. As such, on March 11th 2011 a Concept Paper on the Need for Revision

of the Position on the Replacement of Animal studies by in vitro models (Concept

paper on the Need for Revision of the Position on the Replacement of Animal

Studies 2011) was drafted by the CHMP Safety Working Party and published on the

EMA website. Herein, aside from the extended focus to all 3Rs principles, the revision intended to describe a clear process for regulatory acceptance of 3Rs testing

approaches, to discuss qualification criteria and bring the requirements in line with

Directive 2010/63/EC.

As 3Rs principles apply to all regulatory testing requirements involving animal

use for both human and veterinary medicinal products, a multidisciplinary drafting

group was set up under the JEG 3Rs to develop the draft Guideline for Regulatory

acceptance of 3Rs testing approaches (Draft Guideline on regulatory acceptance of

3R testing approaches 2014). Concomitantly the JEG 3Rs started a thorough review

of the current regulatory testing requirements for human and veterinary medicinal

products and identification of opportunities for implementation of the 3Rs.

The Draft guideline was forwarded to the relevant EMA Working Parties and

Committees for comments on the 17th of March 2014 and the final draft was

launched for public consultation on the 3rd of October 2014. Comments received

are being considered and an update of the guideline is currently under way.



4.2.2



Draft Guideline for Regulatory Acceptance of 3Rs Testing

Approaches



This guideline only applies to testing approaches that are subject to regulatory guidance for human and veterinary medicinal products. More specifically, those that are

used to support regulatory applications, such as clinical trial and marketing authorisation applications. The process of uptake of 3Rs testing methods in the Ph. Eur.

Monographs is excluded.



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