Non-anim al approaches in support of m edicinal product developm - - PowerPoint PPT Presentation

Safety Working Party, EMA London, UK 05.10.2017

Non-anim al approaches in support of m edicinal product developm ent: Setting the scene

Sonja BEKEN

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Current preclinical testing paradigm w as established 3 0 years ago 7 0 % of hum an toxicity in clinical trials is predicted by preclinical studies ( Olson et al 2 0 0 0 , Regul. Toxicol. Pharm acol 3 2 ; 5 6 -6 7 ) . More recent review by Tam aki et al 2 0 1 3 ( J. Toxicol. Sci. 3 8 ; 5 8 1 - 5 9 8 ) dem onstrates that 4 8 % of hum an ADRs are predicted in non- clinical testing Classical paradigm based largely on descriptive toxicology, not MOA-based

I ntroduction

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• Better prediction of hum an relevant effect – efficacy and

safety

• Anim al w elfare considerations -3 Rs

Main drivers for change

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Anim al experim entation in Europe

2 0 1 1 : ~ 1 1 .5 m illion of anim als used in 2 7 Mem ber States

Anim als used in toxicological

• r other safety experim ents

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• f 2 2 Septem ber 2 0 1 0 on the protection of anim als

used for scientific purposes

Article 4 clearly states that: Member States shall ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure . Member States shall ensure that the number of animals used in projects is reduced to a minimum without compromising the objectives of the project. Member States shall ensure refinement of breeding, accommodation and care, and

• f methods used in procedures, eliminating or reducing to the minimum any possible

pain, suffering, distress or lasting harm to the animals. Article 13 states that:

• 1. Without prejudice to national legislation prohibiting certain types of methods,

Member States shall ensure that a procedure is not carried out if another method

• r testing strategy for obtaining the result sought, not entailing the use of a live

animal, is recognised under the legislation of the Union.

• 2. In choosing between procedures, those which to the greatest extent meet the

following requirements shall be selected: (a) use the minimum number of animals; (b) involve animals with the lowest capacity to experience pain, suffering, distress or lasting harm; (c) cause the least pain, suffering, distress or lasting harm; and are most likely to provide satisfactory results.

Directive 2 0 1 0 / 6 3 / EU of the European Parliam ent and of the Council

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Kola and Landis 2 0 0 4

Nature Review drug Discovery 3 , 7 1 1 -7 1 5

Hornberg et al 2 0 1 4

Drug Discovery Today 1 9 ; 1 1 3 1 -1 1 3 6

Most noted safety reasons for w ithdraw al of m arketed drugs:

• Liver toxicity
• Cardiovascular toxicity
• CNS effects

Main reasons for drug attrition

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Hay et al, 2 0 1 4 ,

Nature Biotechnology 2 1 ; 4 0 -5 4 1

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I n vitro m ethods in drug developm ent

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Butler et al, 2 0 1 7

Regulatory Toxicology and Pharm acology 8 7 ; S1 -S1 5

Confidence in assay specificity and sensitivity:

DILI, Cardiovascular toxicity >>> CNS, lung, adapative immune system

Confidence in prediction of human clinical adverse effects based upon in vitro alone decreases with:

• highly complex organisation of organs
• significant genetic variation
• large variation in toxicological phenotypes
• lack of well annotated organ-specific toxicants

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Early tox / com pound screening:

in-house validation by companies, NO regulatory

involvement Exploratory/ m echanistic studies for regulatory decision-m aking: regulatory acceptance based upon demonstrated scientific validity Pivotal ( guideline-driven) studies: formal regulatory acceptance, different modalities:

• historically introduced in vitro models
• transition from exploratory/ mechanistic screening models

to pivotal studies based on accumulating experiences (review of databases)

• targeted replacement of established animal study by in

silico or in vitro model(s) requires “formal” validation

Moving beyond discovery tow ards regulatory acceptance of novel m ethods

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Guideline describes:

• regulatory acceptance
• a

new procedure for submission and evaluation

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a proposal for regulatory acceptance of 3R testing approaches

• scientific

and technical criteria for regulatory acceptance of 3R testing approaches (incl. Safe Harbour)

• pathways

for regulatory acceptance of 3R testing approaches

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Regulatory acceptance

• the incorporation of a new 3R testing approach into a regulatory

testing guideline

• on a case-by-case basis: the acceptance by regulatory authorities of

new approaches not (yet) incorporated in testing guidelines but used for regulatory decision making

Guideline on the principles of regulatory acceptance of 3 Rs testing approaches

• Defined test methodology (protocol, endpoints)
• Relevance within a particular context of use (including accuracy)
• Context of use (including limitations). For example, demonstration that the

new or substitute method or testing strategy provides either new data that fill a recognised gap or data that are at least as useful as, and preferably better than those obtained using existing methods.

• Reliability/ robustness
• Voluntary submission of data obtained by using a new 3Rs testing approach

can be made in parallel with data generated using existing methods (safe harbour)

Criteria for regulatory acceptance

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Technological progress – organ-on-chip

EUROTOX – 1 3 / 0 9 / 2 0 15 fam hp/ DG PRE/ Non-clinical Evaluators

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Regulatory science to be kept in pace w ith technological developm ents. Past and current regulatory revisions, w hilst being m ostly reform atting of the existing requirem ents ( excl. biosim ilars) has led to im proved predictive pow er and higher im plem entation of the 3 Rs. BUT there is room for im provem ent! Regulatory non-clinical testing should evolve to m echanistic based safety and efficacy testing – quid upgrading exploratory safety testing For this close interaction betw een m ultiple stakeholders is needed to ensure qualification of fit- for-purpose m ethods and science- driven, m echanism - based testing strategies

W hat is needed?

EUROTOX – 1 3 / 0 9 / 2 0 15 fam hp/ DG PRE/ Non-clinical Evaluators

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2 4 -2 8 / 8 / 2 0 1 4 ,

Prague, Czech Republic

Scientific Session I -3 b Hum an-on-a-chip – advancing regulatory science through innovation and w orldw ide netw orking for alternative testing

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Objectives for today’s w orkshop

• Mapping of state of the art for organs-on chips
• Com m on understanding of benefits and lim its of organs-
• n-chips
• I dentification of gaps in non-clinical safety testing and

how organs-on chips could address these

• Exchange of inform ation betw een developers, users and

regulators

• Facilitate regulatory acceptance of innovative 3 R

m ethods for a defined context of use for the approval of safe and effective m edicines.

So here w e are ….

EUROTOX – 1 3 / 0 9 / 2 0 15 fam hp/ DG PRE/ Non-clinical Evaluators

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Contact

Federal Agency for Medicines and Health Products – FAMHP Place Victor Horta 40/ 40 1060 BRUXELLES tel. + 32 2 528 40 00 fax + 32 2 528 40 01 e-mail welcome@fagg-afmps.be www.afmps.be

Your m edicines and health products,

• ur concern