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The EU Paediatric Regulation in 5 minutes EMA workshop on the development of new medicinal products for the treatment of ulcerative colitis and Crohn’s disease

EMA London

Presented on 29 June 2015 by Paolo Tomasi MD PhD Head of Pediatric Medicines, EMA

Paediatric development is mandatory in the EU for new medicines: • Unless a product-specific waiver or

a class waiver (for a class of medicinal products) is granted by EMA (waivers apply only for specific medical conditions)

• Deferrals can also be granted (studies in children can be initiated and/or completed after applying for marketing authorization in other populations or conditions)

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What does the paediatric regulation say?

Regulatory aspects of treatments for T1DM

Off-label use of medicinal products in children

• Use in children despite a relative lack of information on how to prescribe safely.

• The (EU) Paediatric Regulation aims to improve the information available to prescribers and families and therefore to reduce off-label use.

• Studies have shown that off-label use is associated with more adverse reactions to drugs for children; adverse reactions in children may be more severe or different from what is known in adults.

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Why did we need a paediatric regulation?

http://www.ema.europa.eu/ pdfs/human/paediatrics/ 12632704en.pdf

Why did we need a paediatric regulation?

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= for

Why did we need a paediatric regulation?

A word of caution: different response to treatments in adults and children

(GLP1 agonist treatment for T2DM)

Adults (N=12) Adolescents (N=9)

placebo

Lower dose

Higher dose

placebo Higher dose

Lower dose

Postprandial plasma glucose

5 Regulatory aspects of treatments for T1DM

Isn’t it sufficient to study medicines in adults?

Objectives of the EU Paediatric Regulation

• Improve the health of children: – Increase high quality, ethical research into medicines for

children – Increase availability of authorised medicines for children – Increase information on medicines

• Achieve the above: – Without unnecessary studies in children – Without delaying authorization for adults

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So, what are the objectives of the paediatric regulation?

EU Paediatric Regulation: obligations versus incentives Type of MP Obligation Incentive Comments

New# medicinal product

Paediatric Investigation Plan or Waiver

6 months extension of SPC (patent) *

Necessary for validation of application

On-patent and authorized medicine

Paediatric Investigation Plan or Waiver

6 months extension of SPC (patent)*

When new indication or new route or new pharmaceutical form: necessary for validation

Orphan-designated medicine

Paediatric Investigation Plan or Waiver

2 additional years of market exclusivity*

In addition to 10 years

Off-patent medicine

None (voluntary PIP possible for PUMA)

10 years of data protection

Research funds Paed. Use MA (PUMA)

*if compliance with PIP, information, approval EU-wide #according to GMA concept, and not necessarily a new active substance

Are there also incentives, or just obligations?

EU (Paed. Regulation) / USA (BPCA-PREA-FDASIA) US BPCA US PREA EU

Development Optional

Mandatory Mandatory (optional for off-patent)

Instrument Written Request Paediatric Study Plan Paediatric Investigation Plan

Waiver N/A 3 grounds 3 grounds Timing End of phase 2 End of phase 2 > End of phase 1 Reward 6-month exclusivity - Main: 6-month SPC extension

(patent) New drugs Yes, with exclusivity Yes Yes

Biologicals (most) Yes All All

Orphan products Included Excluded Included

Decision FDA FDA EMA (not EC) Opinion: Paed. Committee

Scope of paed. development

not limited to adult indication

= adult indication Derived from adult indication

Scientific advice Normally in global fee Normally in global fee Free for paediatrics

What happens in the USA?

• The Paediatric Investigation Plan must be discussed and agreed early, long before Marketing Authorization is requested

• and before trials are started in children!

• Agreeing a PIP takes on average 8-12 months from start to finish

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Scientific Advice

PDCO

PDCO Scientific Advice

Applicant

Optimal outcome

early!

Come to EMA early, come often!

free

Regulatory aspects of treatments for T1DM

What should a company do to agree a PIP?

Thank you for your attention

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000023.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cd European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

Further information

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Presentation title (to edit, click Insert > Header & Footer) 11

Backup slides

Paediatric Investigation Plan • Basis for development and authorisation of a

medicinal product for all paediatric population subsets

• Includes details of the timing and the measures proposed, to demonstrate: – Quality – Safety – Efficacy

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

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

Marketing Authorisation Criteria

Paediatric Investigation Plan

Formulation (quality)

Non-clinical studies Toxicology

Carcinogenicity Genotox

Juvenile animal studies

Paed clinical trials PK

PK/PD Tolerability, safety

Efficacy and safety…

Extrapolation studies

Including modelling and

simulation

• Contained in a PDCO Opinion with key elements

• Timelines for start and completion of each study

• Opinions cover a condition (relevant for both adult and paed development), within which one paediatric indication is selected for development.

Other measures Registries

When is a PIP necessary?

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• Pharmaceutical companies need to produce data from paediatric studies, done in accordance with an agreed PIP:

– When applying for a new marketing authorisation; – in case of an already authorised and “patented” product, when

applying for a new indication / route / dosage form (but not for new strengths, presentations, etc.)

• Alternatively, they need a “total” waiver (for applicable condition[s], in all paediatric subsets), or a deferral.

– If “total” waiver: no PIP – If deferral[s]: deferral implies a PIP; a deferral is

for initiating or completing a study / measure, NOT for agreeing the PIP!

When is a PIP not required?

• “Off-patent” products already authorised in the EU (authorised products that do not have a valid Supplementary Protection Certificate (SPC) or a valid patent that qualifies for it.)

• New medicinal products that belong to some specific groups: Traditional herbal medicinal products Homeopathic products Generic products Hybrid products Biosimilar products When there is a class-waiver:

− For a class of products in a condition − For all products in a condition

In practice, the “abridged dossier” products, with the exception of fixed-dose combinations (not exempted)

Waivers Three types: • “total” (product-specific) waiver for all paediatric subsets (in

one or more specific condition[s]) • partial waiver: one and more subset(s), indication(s), but there is

a PIP! • Class waiver: for a class of medicinal products in a condition Legal grounds: •Lack of efficacy and safety •Disease or condition occurring only in adults population •Lack of significant therapeutic benefit

Deferral Instrument to avoid delaying marketing authorisation in adults. “Deferred” means: Marketing Authorisation Application for adults is possible before initiation/completion of one or more studies/measures in the PIP • Given by study/measure (cfr US PREA: “total” deferral) • For initiation and/or completion of study/measure: completion

of a clinical trial may be deferred, but initiation may not be! • Completion dates established in any case of deferral

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