medicines for children: strategic considerations
TRANSCRIPT
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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
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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
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Why was there a need for a
EU Paediatric Regulation?
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=for
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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
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
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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
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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
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Slide 7
A7 taking the paediatric need into accountAuthor, 06/09/2013
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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
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The role of EMA in paediatric medicines developmentdevelopment
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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
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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
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Small increase in total PIP + waiver + modification procedures in the last years
The EMA's role in paediatric medicines11
These are procedures, not products
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PIPs, waivers and deferralsPIPs, waivers and deferrals
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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
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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
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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!
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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
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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
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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
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PIP/waiver agreement procedurePIP/waiver agreement procedure
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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)
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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)
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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
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How to prepare the perfect applicationHow to prepare the perfect application
For a PIP or a waiver
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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!
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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
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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
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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
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Slide 32
A9 will this be understood by your audience (regulatory folks)?Author, 06/09/2013
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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…)
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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
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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
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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!
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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
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Backup slides
Medicines for children - strategic aspects41
Backup slides
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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!
The EMA's role in paediatric medicines43
% of CTs including children(of all studies in EudraCT)
Number of children to be included in CT is increasing
Data from:
Vaccine studies excluded
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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
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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
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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
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Annual Reports on deferred measures
Only applies to
authorised
products
(not before MA)
47 The EMA's role in paediatric medicines
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Problems reported in Annual Reports
The EMA's role in paediatric medicines48
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Attrition rate (new medicinal products)
J Arrowsmith, Nature Drug Dev, 11:17, 201249
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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
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EMA – FDA concordance for waiver requests
(products evaluated by both Agencies)
The EMA's role in paediatric medicines51
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
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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