An agency of the European Union

Introducing EMA to the RSV

research community

Eric Pelfrene

European Medicines Agency

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In this talk…

• Key principles

• General considerations in relation to medicinal development

– RSV treatment

– RSV vaccine

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Key Principles

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• The EU is a Single Market for pharmaceuticals ~ 0.5 billion people.

• In order to market a medicinal product in the EU, a company needs a Marketing Authorisation.

• There are different ways (‘Procedures’) for a company to obtain a Marketing Authorisation.

• The main scientific principle used in the evaluation of medicines is the benefit/risk balance, based on quality, efficacy and safety aspects.

• Economic considerations are excluded from the assessment.

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European Marketing Authorisation

Procedures

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European MA Procedures prior to 1995

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12 National Competent Authorities 12 Parallel National Reviews 12 Independent Marketing Authorisations

Poor resource utilisation Divergent scientific opinions Divergent patient / doctor information

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Centralised Procedure

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Centralised Procedure

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Mutual Recognition/Decentralised Procedure

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Access to the Centralised Procedure

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It is not open to all products:

It is not for ‘old’ or established products in established indications,

e.g. aspirin for headache

it may be open to old products with innovation: new indications, or an

old drug in a new delivery system, etc.

“Products eligible are defined in the legislation”

– Art 3(1) & 3(2) & Annex to Regulation (EC) 726/2004

(into force since 20 November 2005)

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Elegibility: “Mandatory Scope”

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Assessment Procedure

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Working Parties and other Groups

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Development of Medicines

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Drug Development Overview

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What is a P.I.P.?

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• Basis for development and authorisation of a medicinal product for all paediatric population subsets.

• Includes details of the measures and the timing proposed,

to demonstrate:

• Quality

• Safety

• Efficacy

• To be agreed upon and/or amended by the PDCO.

• Binding on company compliance check (but modifications are possible, at the company’s request)

Marketing

Authorisation

Criteria

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What is a P.I.P.?

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• Data on efficacy, safety and age-appropriate formulation are needed.

• Timelines for start and completion of each study. • In practice: discussion on each condition/indication and

formulation, for each paediatric subset (not only age-groups).

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Why is a P.I.P. necessary?

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• Pharmaceutical companies need to produce data from paediatric

studies, done in accordance with an agreed PIP, at the time of:

– applying for a new marketing authorisation.

– in case of an already authorised product, for new indications / routes / formulations (but not for new

strengths).

• Alternatively, they need a total waiver (for all indications/conditions,

in all paediatric subsets), or a deferral.

– If total waiver: no PIP

– If deferral: deferral implies a PIP; deferral is for completing the studies / measures, NOT for

describing the PIP!

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Integration into Development Plan

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Scientific Advice

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Scientific Advice Working Party (SAWP)

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• EU legislation

• Expertise based appointees

• Multidisciplinary Expert Group

• Chairperson and 30 Members,

• who are experts from National Authorities / University

• 11 meetings a year

– 3-4 day meeting

• Members

– Committee for Advanced Therapies (CAT) and

– Committee for Orphan Medicinal Products (COMP).

– The paediatric committee

– CHMP

• Supported by the Scientific Advice (SA) Office of the EMA secretariat

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Re Paediatric scientific advice

Scientific advice can be sought at any time except during the marketing

application process.

As such scientific advice can be sought before , during or after the Paediatric

Investigation plan (PIP)

A wide range of questions on the paediatric development plan can be

sought, however decisions on waivers, and deferrals are the exclusive remit

of the Paediatric Committee PDCO and the PIP procedure.

SAWP/CHMP will consult with the Paediatric Committee during the procedure

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Additional types of procedures

• Joint EMA/FDA advice

– Request advice on the same issues at the same time

– Does not guarantee a single opinion BUT increases the chances of a

harmonized opinion

– Clusters: Oncology, Vaccines, Orphan Drugs, drugs in the Paediatric

Population, Nanotechnologies, Advanced Therapies, Pharmacogenomics

and Blood products

• Joint EMA/HTA advice

• Qualification of novel technologies

– Qualification advice

(adequacy of the proposed qualification exercise)

– Qualification opinion to qualify the use of the biomarker

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General considerations in relation to

medicinal development (RSV treatment)

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• Non-clinical

– Mechanism of action / PD.

– PK

– Toxicology juvenile animals

• No carcinogenicity

• No reproductive toxicology (but: pre-post natal studies)

• Clinical

– Healthy adults

• PK / Safety (Ia)

• RSV challenge study (IIa)

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General considerations in relation to

medicinal development (RSV treatment)

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• Clinical

– Study population

• Hospitalised RSV: safety/tolerability, PK, PD (Ib)

• Dose finding (II)

• Pivotal trials (III): staggered approach?

• Infant +/- co-morbidities

• Immunocompromised

• Newborn

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General considerations in relation to

medicinal development (RSV treatment)

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• Phase III

– 2 studies unless compelling evidence

– Placebo controlled + standard of care (allowed/disallowed)

– Enrolment: RTD confirmed via centralised lab

– Hospitalised

– Endpoints:

– Primary: duration of oxygen supplementation

+ length of hospitalisation (comparable criteria)

Or: Time between hospital admission for RSV LRTI, and achieving "Clinical Response“ (oxygen /feeding)

– Secondary: Viral RNA titers AUC

ICU length of stay

Rate of secondary bacterial infection

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General considerations in relation to

medicinal development (RSV treatment)

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• Post-Authorisation

– Observational: Long-term safety follow-up

*incidence of wheezing

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General considerations in relation to

medicinal development (RSV vaccines)

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• Obstacles

– Peak incidence very early on (3-4 months of age)

– Previous failures

– Vaccine- mediated disease enhancement

– RSV naïve infants

– NOT if: previously infected

maternally acquired Abs after immunisation in pregnancy

Dual immunisation approach?

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General considerations in relation to

medicinal development (RSV vaccines)

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Primary endpoint in vaccine pivotal trial

– Reduction of severity of RSV disease ?????

– Reduction in age-specific hospitalization and ED visit due to RSV

Cave: “variability across centres”:

Disease features leading to referral

Cultural difference in “self-referral” threshold

Accessibility to healthcare system

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General considerations in relation to

medicinal development (RSV vaccines)

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Case definition

– Clinical: wheeze, rhinorrhea, hypoxia, tachypnea,….(one or more)

plus

– Lab: RT-PCR nasal swab / naso-pharyngeal aspirate

– Case ascertainment important !

– Protective immunity to be shown: subgroup A and B?

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Thank you