removing obstacles on the way to implement 3r methods in … · 2018-04-20 · s5, detection of...

Federal agency for medicines and health products

Removing obstacles on the way to implement 3R methods in toxicology:

regulator’s point of view

Sonja BekenJEG 3Rs & SWP

Federal Agency Medicines and Health Products, Belgium

EUROTOX – 13/09/2015famhp/DG PRE/Non-clinical Evaluators 2

The views and opinions expressed in the following presentation are

personal and should not be attributed to the Belgian Federal Agency

for Medicines and Health Products or to the European Medicines

Agency

Disclaimer


Introduction

Current preclinical testing paradigm was established 30 years ago

70% of human toxicity in clinical trials is predicted by preclinical studies (Olson et al 2000, Regul. Toxicol. Pharmacol 32; 56-67).More recent review by Tamaki et al 2013 (J. Toxicol. Sci. 38; 581-598) demonstrates that 48% of human ADRs are predicted in non-clinical testing

Classical paradigm based on descriptive toxicology, not MOA-based


Better prediction of human relevant effects – efficacy and safety

Animal welfare considerations – 3Rs

Main drivers for change


Major reasons for drug attrition

Kola and Landis, 2004Nature Review Drug Discovery 3; 711-715

Hay et al, 2014, Nature Biotechnology 21; 40-541

Hornberg et al 2014Drug Discovery Today 19; 1131-1136

Most noted safety reasons for withdrawal of marketed drugs:•Liver toxicity•Cardiovascular toxicity•CNS effects

Suspended programmes:395 phase 3

95 NDA


of 22 September 2010 on the protection of animals used for scientific purposes

Article 4 clearly states that:Member States shall ensure that, wherever possible, a scientifically satisfactorymethod or testing strategy, not entailing the use of live animals, shall be usedinstead of a procedure .Member States shall ensure that the number of animals used in projects is reducedto a minimum without compromising the objectives of the project.Member States shall ensure refinement of breeding, accommodation and care, andof methods used in procedures, eliminating or reducing to the minimum anypossible 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 methodor testing strategy for obtaining the result sought, not entailing the use of a liveanimal, is recognised under the legislation of the Union.

2. In choosing between procedures, those which to the greatest extent meet thefollowing 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 2010/63/EU of the European Parliament and of the Council


Created in 2010/2011 toprovide advice and recommendations to CVMP and CHMP onall matters relating to the use of animals in the testing ofmedicines for regulatory purposes

Membership:experts from existing committees and WPs for whichanimal testing is relevant and observers from EURL ECVAMand EDQMChair: Dr Sonja BekenVice Chair: Dr Ellen-Margrethe Vestergaard

Two one-day meetings per year

http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CVMP/people_listing_000094.jsp&mid=WC0b01ac05803a9d6d

Joint ad hoc Expert Group on the Application of the 3Rs in Regulatory Testing of Medicinal Products - JEG 3Rs

http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CVMP/people_listing_000094.jsp&mid=WC0b01ac05803a9d6d


o Concept paper on review and update of EMA guidelinesto implement best practice with regard to 3Rs inregulatory testing of medicinal products(EMA/CHMP/CVMP/JEG-3Rs/704685/2012)

o Reviewing existing guidance with recommendations toWPs to consider revisions where appropriate

o Development of guidance relating to gaining acceptancefor 3Rs testing paradigms (EMA/CHMP/CVMP/JEG-3Rs/450091/2012)

o Pilot project to review batch testing requirements forindividual products and highlight possible shortcomingsdirectly to MAHs

o Guidance on transferring quality control methodsvalidated in collaborative trials to a product/lab specificcontext (CHMP/CVMP/JEG-3Rs/94304/2014)

o PARERE – coordination of EMA responses to requestsform EURL ECVAM on potential regulatory relevance oftest approaches

o Assessor’s training on 3Rs

JEG 3Rs – recent/ongoing activities


Enhanced exploratory drug safety testing to reduce attrition(Hornberg et al 2014, Drug Discovery Today 19; 1137-1144)


Technological progress – stem cells

EBiSCEuropean Bank for induced pluripotentStem Cells

EPAA Stem cell project


Technological progress – organ-on-chip


Better prediction – a lot of projects


Better prediction – synergy


Early tox / compound screening: in-house validation by companies, NO regulatory involvement

Exploratory/mechanistic studies for regulatory decision-making: regulatory acceptance based upon demonstratedscientific validity

Pivotal (guideline-driven) studies:formal regulatory acceptance, different modalities:o historically introduced in vitro modelso transition from exploratory/mechanistic screening models

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

o targeted replacement of established animal study by insilico or in vitro model(s) requires “formal” validation

Moving beyond discovery towards regulatory acceptance of novel methods


Guideline describes:o regulatory acceptance

o a new procedure for submission and evaluation of aproposal for regulatory acceptance of 3R testing approachesfor use in the development and quality control duringproduction of human and veterinary medicinal products.

o scientific and technical criteria for regulatory acceptance of3R testing approaches (incl. Safe Harbour)

o pathways for regulatory acceptance of 3R testingapproaches

EMA Draft Guideline on regulatory acceptance of 3R (Replacement, Reduction, Refinement) testing approaches


oRegulatory acceptance the incorporation of a new 3R testing approach into a

regulatory testing guideline

on a case-by-case basis: the acceptance by regulatoryauthorities of new approaches not (yet) incorporated intesting guidelines but used for regulatory decision making

regulatory guidelines concerned: those related to thequality or non-clinical (safety and residues) requirementsfor human or veterinary medicinal products and regulatoryguidelines related to clinical requirements for veterinarymedicinal products



oCriteria for regulatory acceptance1. demonstration of method validation (protocol, reliability,

relevance)

2. demonstration that the new or substitute method or testingstrategy provides either new data that fill a recognised gapor data that are at least as useful as, and preferably betterthan those obtained using existing methods.

3. demonstration of adequate testing of medicinal productsunder real-life conditions (human and veterinary) whichcan be generated through the safe harbour process



oProcedure1. Submission of proposal to the EMA in accordance with the

procedure described in the Guideline on Qualification ofNovel Methodologies for Drug Development(EMA/CHMP/SAWP/72894/2008 Rev. 1).

For veterinary medicinal products only, proposalsubmission is to be in accordance with existing scientificCVMP guidance for companies requesting scientific advice



oProcedure1. Submission of proposal to the EMA in accordance with the procedure

described in the Guideline on Qualification of Novel Methodologies for DrugDevelopment (EMA/CHMP/SAWP/72894/2008 Rev. 1).

For veterinary medicinal products only, proposal submission is to be inaccordance with existing scientific CVMP guidance for companies requestingscientific advice

1. Assessment in accordance with criteria as defined incollaboration with relevant 3R experts from CHMP and/orCVMP working parties

2. Recommendations:• new 3R testing approaches is based on sufficient data and can be

recommended for regulatory acceptance to the relevant working parties

• new 3R testing approaches needs real-life data collection period undersafe harbour provisions

• new 3R testing approaches is rejected because it is immature



Added value of a process for regulatory acceptance at the EU level:

• Regulatory acceptance process at EMA level encompasses more than ICH S-related topics

• Proposals intended to be submitted to the (V)ICH can be thoroughly prepared at the EU level

• EMA regulatory acceptance process needed for topics that are subjected to EMA guidelines



oM3 (R2), Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals

oS1 Regulatory notice on changes to core guideline on rodent carcinogenicity testing of pharmaceuticals

oS2 (R1), Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use

oS3, Toxicokinetics: A guidance for assessing systemic exposure in toxicology studies

oS5, Detection of toxicity to reproduction for medicinal productsand toxicity to male fertility

oS9, Non-clinical Evaluation for Anticancer PharmaceuticalsoS6 (R1), Addendum to ICH S6: Preclinical Safety Evaluation of

Biotechnology-Derived Pharmaceuticals oS10, Photosafety evaluation of pharmaceuticalsoS11, Non-clinical Safety Testing in Support of Development of

Paediatric Medicines

Quick overview of ICH Guidelines either revised or under revision

http://www.ich.org/

http://www.ich.org/


In vitro studies•binding studies (e.g. receptors, antigens, enzymes) • cell-based assays (signal transduction & functional activity)

may be more specific and sensitive than in vivo comparability studies considered fundamentalAppropriate # batches of product representative for clinical use.

In vivo studies• designed to maximise the information obtained (PD/PK/Tox)• relevant species

High species-specificity of some biosimilars triggered discussion onappropriateness of non-clinical in vivo studies

A step-wise approach is proposed

Case study 1:Non-clinical development of biosimilars


Biosimilars entering the clinic without animal studies in the EU

Van

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2014

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5,11

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Case study 2: Novel testing approaches for embryofoetal development testing, the long and winding road of regulatory acceptance…


What precedes regulatory discussions:

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=UCJXsuc3m7d6EM&tbnid=T0M951CC8HPTVM:&ved=0CAUQjRw&url=http://www.nature.com/protocolexchange/protocols/2121&ei=LNMQU9qqKMrVtQbQyYDgCQ&bvm=bv.62286460,d.ZGU&psig=AFQjCNHFaDXkaSXv_tNIWIKa0p3V2Q5vlQ&ust=1393697944144710

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=UCJXsuc3m7d6EM&tbnid=T0M951CC8HPTVM:&ved=0CAUQjRw&url=http://www.nature.com/protocolexchange/protocols/2121&ei=LNMQU9qqKMrVtQbQyYDgCQ&bvm=bv.62286460,d.ZGU&psig=AFQjCNHFaDXkaSXv_tNIWIKa0p3V2Q5vlQ&ust=1393697944144710

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=9vdL1iPCei_lzM&tbnid=Ma02-QjM4TrvoM:&ved=0CAUQjRw&url=http://www.pnas.org/content/102/9/3296.figures-only&ei=H9AUU82fGcqctQa9zIDQBA&bvm=bv.61965928,d.bGE&psig=AFQjCNEXF_9kiGxF65H6_dcP0YwBBIL70A&ust=1393959260324267

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=9vdL1iPCei_lzM&tbnid=Ma02-QjM4TrvoM:&ved=0CAUQjRw&url=http://www.pnas.org/content/102/9/3296.figures-only&ei=H9AUU82fGcqctQa9zIDQBA&bvm=bv.61965928,d.bGE&psig=AFQjCNEXF_9kiGxF65H6_dcP0YwBBIL70A&ust=1393959260324267


In Vitro Models for Reproduction Toxicity Workshop –Use?

Workshop held as part of an assessment of whetherthe S5(R2) Guideline on Detection of Toxicity toReproduction for Medicinal Products and Toxicity toMale Fertility needed to be revised.It was agreed that no further work needed to beundertaken on the topic at the current time at theICH levelMore work needed on: Enhancing applicability of mEST for risk

assessment rat vs rabbit comparison Establish robustness of in vitro approaches with

more pharmaceuticals in different labs

ICH Workshop, Tallinn, June 2010:


Follow-up on reproductive toxicity testing

Public Workshop on Reproductive and Developmental Toxicology: From In Vivo to In Vitro, April 16, 2012, White Oak Campus, Silver Spring US

Objectives:

o to bring scientific information aboutnew in vitro technologies forreproductive and developmentaltoxicology testing to FDA

o to provide a forum for scientists fromFDA, academia, and industry todiscuss how these new technologiescould eventually be integrated intoFDA's regulatory paradigm.

discussion on:

o Value of rodent versus non-rodentspecies (rat or rabbit) in the evaluationhuman pharmaceuticals for their effectson embryo-foetal developmental: whatdata are needed?

o Value of 3R methods to detect crucialdevelopmental effects? What type ofdata is available? Can recommendationsbe given for further evaluation of thesein vitro methods?

o mEST: various endpoints, variousprotocols!

o Other 3R models used: zebrafish, wholerat embryo culture

http://www.fda.gov/default.htm

http://www.fda.gov/default.htm


2011- 2014: HESI Developmental and Reproductive Toxicology (DART) Technical Committee (US) will conduct a cross pharma survey to collect data regarding the relative value of non-rodent vsrodent in signal detection of developmental toxicity and the influence on human risk assessment ILSI HESI DART 2nd species working group: database

compilation and analysis

HESI DART 2nd species Workgroup:


Progress report presented at Safety Brainstorming Meeting, 10-15/11/2012, San Diego, US

Points addressed:• Update on the activities of the HESI DART 2nd Species

Working Group• Applicability of 3R methods: additional data

requirements• A stepwise approach to an integrated testing strategy

for embryofoetal development

Follow up by ICH

http://www.ich.org/

http://www.ich.org/


Proposal at Safety Brainstorming Meeting, 9-17/11/2013, Osaka, Japan

oNeed to develop a new strategy for EFD testingoStepwise approach!

• Data gathering to evaluate 3R methods to replace one species for developmental toxicity testing

• Participation to and follow-up of the outcome of the HESI DART 2nd species working group: recommendations for primary species selection

• Design and real life evaluation of a integrated testing strategy phased approach!

• Generate a reference list of reproductive toxicants that the ITS need to be able to identify

• Provide recommendations on how to revise the ICH S5 guidance

Follow up by ICH

http://www.ich.org/

http://www.ich.org/


After two rounds of discussions during ICH SC Meeting (1-5/6/2014, Minneapolis, US & 10-14:11/2014, Lisbon, Portugal)

ICH SC endorsement of Concept Paper - March 2015


Issues to be resolved

Revision ICH S5(R2)

• Agreement on appropriate multiples above human exposure or other endpoints that could be used for dose selection

• Agreement on criteria for species selection taking into account relevance to humans

• Development of performance criteria for possible regulatory acceptance of in vitro, ex vivo, and non-mammalian in vivo EFD assays

• Design of optional integrated testing strategies involving an in vivo mammalian EFD assessment and in vitro, ex vivo and non-mammalian in vivo EFD assays and the limited circumstances under which such a testing strategy would be considered

First F2F Meeting of the Expert Working Group, June 2015, Fukuoka, Japan

http://www.ich.org/

http://www.ich.org/


Key question addressed by 2 expert panels withmembers from industry, regulatory authorities andacademia: What will drug development look like ifwe stop using animals for safety testing?

Some interesting brainstorming ….


Future Nonclinical Safety Testing – Regulatory &Industry views

EFPIA PDC / EMA Non-clinical Assessors brainstormingworkshopApril 9th 2014, Vienna, Austria

Key Question:The Nonclinical Regulatory Landscape: Can we reducethe number of guidelines? What type of data are reallyneeded?Since the Directive 75/318 is the number of guidelinescontinuously growing. Seldom guidelines are withdrawn(except for acute toxicity). Is it possible to rethink our testingparadigms?

Some interesting brainstorming ….


Regulatory science clearly needs to be kept in pacewith technological developments. Early involvement ofregulators in international initiatives (e.g. EU IMI, EUFPs, etc) is crucial to achieve progress in this rapidlyevolving field

Past and current regulatory revision efforts have beenmostly reformatting of the existing non-clinicalrequirements (excl. biosimilars). Although this hasentailed improvements both with respect to predictivepower as with regards to the 3Rs there is still room forimprovement

Regulatory non-clinical testing should be movedforward to mechanistic based safety and efficacytesting – quid upgrading exploratory safety testingThis will necessitate close interaction by multiplestakeholders to ensure qualification of fit-for-purposemethods and science-driven, mechanism-based testingstrategies

So … is this the future?


Sonja Beken, PhDChair JEG 3Rs (EMA)Vice-Chair SWP (EMA)Coordinator Non-Clinical Assessors (FAMHP)

FAMHPPlace Victor Horta 40/40 1060 Bruxellestel.: +32 2 524 82 04e-mail [email protected]

www.afmps.be

mailto:[email protected]

http://www.afmps.be/

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