medicines for children: strategic considerations

An agency of the European Union

Medicines for Children: Strategic Considerations

Module 1 – Strategic Planning in Regulatory AffairsTOPRA MSc in Regulatory Affairs

Presented by Paolo Tomasi MD PhD, on 12 December 2014

Head of Paediatric Medicines – European Medicines Agency – London E14 5EU

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 EMAby 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 authorisation in other populations or conditions)

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The EU Paediatric Regulation

Regulation:

• Most “powerful” type of EU law

• Immediately applicable in all EU Member States

2

Why was there a need for a

EU Paediatric Regulation?

3

=for

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 Paediatric Investigation 6 months extension When new indication or new On-patent and authorized medicine


6 months extension of SPC (patent)*

When new indication or new route or new pharmaceutical form:

necessary for validation

Orphan-designated medicine


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

Rewards

-> if development is compliant with agreed PIP (compliance statement in MA);

-> if results of studies included in Summary of PC + patient’s leaflet;

-> if product is authorised in all MSs (except for PUMA):

Reward is given for all PIPs correctly completed, but PIPs are “always” required (cfr. US PREA, where: obligation but no reward)

• Non-orphan products: 6-month extension of SPC (patent protection) [not when MAH applied for +1 market protection]

• Orphan medicinal products: + 2 additional years of market exclusivity

• PUMA: 8+2 years of data+market protection

- Product-specific or class waiver does NOT trigger the reward- « negative » PIP results allow reward- Inconclusive studies in PIP do NOT trigger the reward

Differences EU (Paediatric 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 groundsWaiver 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

6

A7 taking the paediatric need into accountAuthor, 06/09/2013

New Drug Development Process: US vs EU

Pre

clin

ica

l P

ha

se

Phase One Phase Three

ND

A S

ub

mis

sio

n

Ma

rke

tin

g A

pp

rova

l

EC/EMA

PIP (all inclusive) Required for Filing

Pre

clin

ica

l P

ha

se

Phase One

Phase Two

Phase Three

ND

A S

ub

mis

sio

n

Ma

rke

tin

g A

pp

rova

l

Postmarketing

FDA

Written RequestPREA*/WR

From Dianne Murphy, FDA

The role of EMA in paediatric medicines developmentdevelopment

Medicines for children - strategic aspects8

EMA works with own staff (scientific/administrative) +

Scientific Committees (nominated by Member States/EC)All EMA Scientific Committees are involved with paediatric medicines:

CHMP: authorises medicines for paediatric (and adult) use

PRAC: monitors safety of paediatric (and adult) authorised medicines

CHMP

SAWP

PRAC

HMPC EMA Scientific and

Administrative

Secretariat

CAT: assesses advanced therapies for children(and adults)

COMP: designates medicinal products as orphan drugs, for paediatric (and adult) use

HMPC: discusses herbal medicinal products for paediatric (and adult) use

SAWP: provides scientific advice on medicines being developed for paediatric (and adult) use

PDCO: agrees Paediatric Investigation Plans, Waivers, modifications of plans, checks compliance with plans, advises other Committees / EC on paediatric uses…9

COMP

PDCOCAT

Secretariat

The EMA and its Paediatric Committee (PDCO)

• EMA: European Medicines Agency

� Staff: 25-26 (Scientific Administrators and Assistants).

� Work and (usually) live in London, UK

• PDCO: Paediatric Committee

� External experts from all EU

� 1 expert + 1 alternate from each EU member state

� 3 representatives (+ alt.) for healthcare professions

� 3 patient representatives (+ alt.) (parents)

� Meetings in London every month for 2.5 days

• Procedures at PDCO:

� Evaluation team

(1 staff, 1 PDCO Rapporteur, 1 PDCO peer-reviewer)10

Small increase in total PIP + waiver + modification procedures in the last years

The EMA's role in paediatric medicines11

These are procedures, not products

PIPs, waivers and deferralsPIPs, waivers and deferrals


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:

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measures proposed, to demonstrate:

– Quality

– Safety

– Efficacy

• To be agreed upon and/or amendedby the PDCO

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

Marketing

Authorisation

Criteria

Paediatric Investigation Plan

• 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

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Formulation

(quality)

Non-clinical studiesToxicology

Carcinogenicity

Genotox

Juvenile animal studies

Paed clinical trialsPK

PK/PD

Tolerability, safety

Efficacy and safety…

Extrapolation

studiesIncluding

modelling and

simulation

• Opinions cover a condition (relevant for both adult and paed

development), within which one paediatric indication is

selected for development.

Other

measuresRegistries

When is a PIP necessary?

• 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

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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 or waiver

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 (legal basis):to some specific groups (legal basis):

� 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

*a PIP can optionally be agreed for future PUMA application

Waivers:

Three types:Three types:

•• ““totaltotal”” (product(product--specific) waiver specific) waiver �� for all paediatric subsets (in

one or more specific condition[s])

•• partial waiver: partial waiver: one and more subset(s), indication(s), but there is a PIP!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(s):

Instrument to avoid delaying marketing authorisationInstrument to avoid delaying marketing authorisationin adults.in adults.

““DeferredDeferred”” means: Marketing Authorisation Application for means: Marketing Authorisation Application for adults is possible before completion of one or more adults is possible before completion of one or more adults is possible before completion of one or more adults is possible before completion of one or more studies/measures in the PIP studies/measures in the PIP

•• Given by study/measure Given by study/measure ((cfrcfr. US PREA: . US PREA: ““totaltotal”” deferral)deferral)

•• For initiation and/or completion of study/measure: 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

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Application Number Substance(s) PIP completion date

Lag (years)

EMEA-000145-PIP01-07

denosumab Juvenile idiopathic arthritis 31/12/2034 26

EMEA-001098-PIP01-10

Lorcaserin Obesity 31/12/2026 15

Lag time between planned MAA date and agreed PIP completion date examples of long deferrals

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10EMEA-000157-PIP01-07

belatacept Renal transplantation 31/12/2021 13

EMEA-000063-PIP01-07

Laropiprant / Nicotinic Acid

Familial hypercholesterolemia 31/03/2019 12

EMEA-001100-PIP01-10

Anacetrapib Hypercholesterolemia 31/12/2028 12

EMEA-000927-PIP01-10 Linaclotide Functional constipation 31/03/2023 12

EMEA-000737-PIP02-11 Afamelanotide Erythropoietic protoporphyria 30/06/2022 11

EMEA-001123-PIP01-11 Odanacatib Osteoporosis 30/09/2023 11

EMEA-000237-PIP01-08 Azilsartan medoxomil Hypertension 31/12/2020 11

EMEA-000601-PIP01-09 Pazopanib Rhabodomyosarcoma, Ewing, soft tissue sarcomas

30/09/2021 11

PIP/waiver agreement procedurePIP/waiver agreement procedure


Application(pharma

company)

Validation(EMA staff)

Simplified workflow of the PIP/waiver application

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(EMA staff)

Assessment(EMA staff +

PDCO members)

Opinion(PDCO)

Decision(EMA)

When should the PIP be requested?

Non-clin Phase 1 Phase 2 Phase 3 Post approval

MA

Non-clin Phase 1 Phase 2 Phase 3 Post approval

Paediatric Investigation Plan Compliance

check

(PIP Amendments)

Paediatric Committee(PDCO)

1st discussion

PDCO

Day 30

Overview PIP procedure

~ 3

Day 61

Update Sum

Report

StartStop60 days 60 days

2nd discussion

PDCO + OE

Day 60Adoption of

Opinion

© EMA

Adoption of

Opinion,

OR

List of Issues

Day 1

After

Validation,

Sum Report

~ 3

months

Start

Clock

Stop

Clock60 days 60 days

3rd discussion

PDCO

Day 90

OE

OE= oral explanation

How to prepare the perfect applicationHow to prepare the perfect application

For a PIP or a waiver


How to use existing resources efficiently…

Scientific Scientific Advice

PDCO

PDCOScientific Scientific

Applicant

early!

free

to ensure a successful PIP/waiver procedure and paediatric development

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PDCOScientific Scientific Advice

Optimal outcome

Come early, come often!

1 - What to do first

Read the basics – do the homework!

• Paediatric Regulation

• Revised EC Guideline on Format and Content of PIP applications (September 2014)applications (September 2014)

• EMA Procedural Advice (Q&A format): revised version December 2014

• Other documents/guidelines:

� standard PIPs

� scientific guidelines,

� policy on the scope of the condition, other Q&As…)

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EMA decisions on Paediatric Investigation Plans

• Contains information on paediatric trials agreed between EMA and company (+dosage form company (+dosage form and non-clinical studies)

• From 2014: Summary of PDCO evaluation of the PIP/ waiver application

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Paediatric clinical trials in EU-CTR

All clinical trials and of other trials submitted to National Authorities (protocol-related information)information)

• Third countries trials linked to a PIP

• Results from2014

• Global search inWHO-ICTRP

28

Presentations and conclusions from Expert Meetings / Workshops at EMA

Repeat interaction with interaction with experts to design better Paediatric Investigation Plans

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Don’t forget that the PIP application needs to be:

1. a stand-alone document. Don´t put essential

2 - Have clear in mind where you want to go

information into appendices!

2. well written, self-explanatory and with a good

storyline.

Count on spending at least 3 months on the PIP

drafting process. 30

3 – Decide on the role / amount of extrapolation: “complete” vs. “partial” extrapolation

– anything less than 2 fully powered confirmatory trials is extrapolation?

– “partial” extrapolation is highly prevalent, but often unacknowledged. Examples:

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unacknowledged. Examples:

– One-sided vs. two-sided significance tests and/or higher p values allowed in specific situations

– Bayesian methods

– One confirmatory study only

– No confirmatory study (orphan conditions)

– Registration after failed superiority vs placebo (but superiority vs active comparator demonstrated!)

A9

A9 will this be understood by your audience (regulatory folks)?Author, 06/09/2013

European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)

• Network of research networks

• EU and extra-EU

• EMA implementing strategy of the • EMA implementing strategy of the European network

• Stimulation of quality research in EU

• Annual workshop, meeting with industry

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Global developmentGlobal development

FDA-EMA interactions

(and HC, PMDA, TGA…)


Paediatric Type 2 Diabetes

• Areas of agreement

– Age group for study• 10 to less than 18 years• 10 to less than 18 years

– Study population• Treatment naïve and non-naïve and stratify by background therapy

– Primary endpoint• HbA1c

– Total study duration• 1 year

– Timing• During or after adult Phase 3

Paediatric Type 2 Diabetespartially unresolved: duration of studies

Duration of placebo-controlled period and timing for measurement of primary EP

• EMA guideline• EMA guideline– 12 weeks if HbA1c >8.5% (but exceptions possible, e.g. for long half-life

products)

– 24 weeks if HbA1c <8.5%

• FDA– 24 weeks provided baseline HbA1c not dangerously high, glycemic monitoring

is adequate and strict glycemic rescue criteria are implemented

Conclusion: Different time point for primary efficacy assessment and different approaches in modulating hyperglycemic risk

Hypertension: Age Resolution

• Indication: Essential and secondary HTN

PIP already agreed from 6 months

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PIP already agreed from 6 months

-FDA only asked for 1year and above because additional

interim data had been received from animal studies

which supported conservative approach

- No need to ask for changes: just include patients from

1 year of age!

Conclusions

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• Coordination of various EMA activities / Scientific Committees has been key to achieve better paediatric plans:

� Paediatric Committee (PDCO)� Scientific Advice Working Party (SAWP)Authorising Committee (CHMP)� Authorising Committee (CHMP)

� Pharmacovigilance Committee (PRAC)� Committee for Advanced Therapies (CAT)...

• More good quality research, leading to more information on medicines for children, and more (good) medicines authorised for children

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Thank you for your attention

Further information

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/gene

ral_content_000023.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

Follow us on @EMA_News

Backup slides


Backup slides

Weblinks

• Annual EMA Report to the European Commission, May 2013: http://ec.europa.eu/health/files/paediatrics/2012_report_paed_regulation.pdf

• Proceedings from Expert groups at EMA:http://tinyurl.com/PaedExpGroups

• EMA decisions on PIPs and waivers:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&mid=WC0b01ac058001d129rch.jsp&mid=WC0b01ac058001d129

• EU Clinical Trials Register:https://www.clinicaltrialsregister.eu/

• EnprEMA:http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/general/general_content_000303.jsp&mid=WC0b01ac05801df74a

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Paediatric clinical trials are increasing!


% of CTs including children(of all studies in EudraCT)

Number of children to be included in CT is increasing

Data from:

Vaccine studies excluded

A significant number of PIPs are not completed in time (or at all)

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Data from EMA annual

reports to the EC

Will all Paediatric Investigation PlansWill all Paediatric Investigation Plans

be completed?

Completion of studies under PREA obligations

(USA / FDA)

chemicals biologicals

completed

22%

not completed

/ delayed

78%

completed

46%not completed

/ delayed

54%

Source: AAP as cited in Nature (doi:10.1038/nature.2012.10132)45

Completion of studies under BPCA written request

(optional, but 80% suggested by applicant)

Will all Paediatric Investigation PlansWill all Paediatric Investigation Plansbe completed?

Source: IOM report on “Safe and Effective Medicines for Children: Pediatric Studies Conducted Under BPCA and PREA”46

Annual Reports on deferred measures

Only applies to

authorised

products

(not before MA)

47 The EMA's role in paediatric medicines

Problems reported in Annual Reports


Attrition rate (new medicinal products)

J Arrowsmith, Nature Drug Dev, 11:17, 201249

And all negative compliance check became positive (after modification of the agreed PIP – no major violations)

Data at 25/09/14

Compliance is confirmed at the first attempt in > 96% of cases

50 The EMA's role in paediatric medicines

Data at 25/09/14

Applicants are compliant, EMA is flexible

EMA – FDA concordance for waiver requests

(products evaluated by both Agencies)


FDA asks for more PIPs for FDCFDA asked for a few more PIPs for single AS products

Egger G and Tomasi P, 2014, unpublished data

Market exclusivity: - vs. generic- vs. similar

0 10 11 12 years8orphans

all products

2 years ““““market protection””””:- Data available- MAA for generic receivable- MA for generic cannot be granted

Possible 2 year extension of

ME for ““““off-patent”””” orphan drugs which complete a PIP

0 10 11 years8

Data protection vs. reward

Data protection: - vs. generic only

all products

Qualifying patent (20 years)SPC(variable)

Reward

(6 m.)

Paediatric reward:

There has to be a SPC (SPC is prolonged, not patent)

0 10 20 years

1 year possible extension of market

protection:

- new indication in first 8 years + s.b.

- OTC switch

- WEU: complicated!

- MA for generic cannot be granteduntil expiration of the total 10 years

Incompatible with extension of ME or MP

0 10 11 years8

medicines for children: strategic considerations

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