Medicines for Children:
Strategic Considerations
Module 1 – Strategic Planning in Regulatory Affairs
TOPRA MSc in Regulatory Affairs
Presented by Paolo Tomasi MD PhD, on 12 December 2014
Head of Paediatric Medicines – European Medicines Agency – London E14 5EU
An agency of the European Union
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 authorisation in other populations or
conditions)
1
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?
for
3
=
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
Orphandesignated
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
to GMA concept, and not necessarily a new active substance
#according
Rewards
Reward is given for all PIPs correctly completed,
but PIPs are “always” required (cfr. US PREA,
where: obligation but no reward)
-> 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):
•
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 (BPCAPREA-FDASIA)
US BPCA
US PREA
EU
Optional
Mandatory
Mandatory
(optional for off-patent)
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
Yes
All
All
Included
Excluded
Included
FDA
FDA
EMA (not EC)
Opinion: Paed. Committee
Development
Instrument
Biologicals (most)
Orphan products
6
Decision
Slide 7
A7
taking the paediatric need into account
Author, 06/09/2013
New Drug Development Process: US vs EU
EC/EMA
Phase Three
Phase Two
PREA*/WR
Marketing Approval
Phase One
NDA Submission
Preclinical Phase
PIP (all inclusive) Required for Filing
Postmarketing
Written Request
FDA
From Dianne Murphy, FDA
The role of EMA in paediatric medicines
development
8
Medicines for children - strategic aspects
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
CAT:
assesses advanced therapies for children
(and adults)
COMP: designates medicinal products as orphan
drugs, for paediatric (and adult) use
CHMP
PRAC
SAWP
HMPC
CAT
PDCO
EMA Scientific and
Administrative
Secretariat
COMP
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
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:
10
Evaluation team
(1 staff, 1 PDCO Rapporteur, 1 PDCO peer-reviewer)
Small increase in total
PIP + waiver +
modification
procedures in the last
years
These are procedures, not
products
11
The EMA's role in paediatric medicines
PIPs, waivers and deferrals
12
Medicines for children - strategic aspects
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
Marketing
Authorisation
Criteria
• To be agreed upon and/or amended
by the PDCO
• Binding on company compliance check
(but
13
modifications possible, at the company’s request)
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
development), within which one paediatric indication is
selected for development.
Non-clinical studies
Formulation
(quality)
14
Toxicology
Carcinogenicity
Genotox
Juvenile animal studies
Paed clinical trials
PK
PK/PD
Tolerability, safety
Efficacy and safety…
Extrapolation
studies
Including
modelling and
simulation
Other
measures
Registries
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
(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!
15
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):
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:
• “total
total”
” (product(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(s):
Instrument to avoid delaying marketing authorisation
in adults.
“Deferred”
Deferred” means: Marketing Authorisation Application for
adults is possible before completion of one or more
studies/measures in the PIP
• Given by study/measure (cfr
cfr.. US PREA: “total”
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
18
Lag time between planned MAA date and agreed PIP completion date
examples of long deferrals
Application Number
denosumab
Juvenile idiopathic arthritis
PIP
completion
date
31/12/2034
Lorcaserin
Obesity
31/12/2026
15
belatacept
Renal transplantation
31/12/2021
13
Laropiprant / Nicotinic
Acid
Anacetrapib
Familial hypercholesterolemia
31/03/2019
12
Hypercholesterolemia
31/12/2028
12
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
Rhabodomyosarcoma, Ewing,
soft tissue sarcomas
30/09/2021
11
EMEA-000145-PIP0107
EMEA-001098-PIP0110
EMEA-000157-PIP0107
EMEA-000063-PIP0107
EMEA-001100-PIP0110
EMEA-000927-PIP01-10
Substance(s)
19
EMEA-000601-PIP01-09 Pazopanib
Lag
(years)
26
PIP/waiver agreement procedure
20
Medicines for children - strategic aspects
Simplified workflow of the PIP/waiver application
Application
(pharma
company)
Validation
(EMA staff)
Assessment
(EMA staff +
PDCO members)
Opinion
(PDCO)
Decision
21
(EMA)
When should the PIP be requested?
MA
Non-clin
Phase 1
Phase 2
Phase 3
Paediatric Investigation Plan (PIP Amendments)
Paediatric Committee
(PDCO)
Post approval
Compliance
check
Overview PIP procedure
1st discussion
PDCO
Day 30
60 days
Day 1
After
Validation,
Sum Report
© EMA
2nd discussion
PDCO + OE
Day 60
Stop
Clock
Adoption of
Opinion,
OR
List of Issues
Day 61
Update Sum
Report
Start
~3
Clock
months
Adoption of
Opinion
60 days
3rd discussion
PDCO
Day 90
OE
OE= oral explanation
How to prepare the perfect application
For a PIP or a waiver
24
Medicines for children - strategic aspects
How to use existing
resources efficiently…
Applicant
early!
Scientific
Advice
PDCO
free
PDCO
to ensure a successful
PIP/waiver procedure and
paediatric development
Scientific
Advice
Optimal
outcome
Come early, come often!
25
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)
•
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…)
26
EMA decisions on Paediatric Investigation Plans
• Contains information on
paediatric trials agreed
between EMA and
company (+dosage form
and non-clinical studies)
• From 2014: Summary of
PDCO evaluation of the
PIP/ waiver application
27
Paediatric clinical trials in EU-CTR
All clinical trials and of
other trials submitted to
National Authorities
(protocol-related
information)
• Third countries trials
linked to a PIP
• Results from
2014
• Global search in
WHO-ICTRP
28
Presentations and conclusions from Expert Meetings /
Workshops at EMA
Repeat
interaction with
experts to design
better Paediatric
Investigation
Plans
29
2 - Have clear in mind where you
want to go
Don’t forget that the PIP application needs to be:
1. a stand-alone document. Don´t put essential
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:
31
– One-sided vs. two-sided significance tests and/or higher p values
allowed in specific situations
– Bayesian methods
– One confirmatory study only
A9
– No confirmatory study (orphan conditions)
– Registration after failed superiority vs placebo (but superiority vs
active comparator demonstrated!)
Slide 32
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
European network
• Stimulation of quality research in EU
• Annual workshop, meeting with
industry
32
Global development
FDA-EMA interactions
(and HC, PMDA, TGA…)
33
Medicines for children - strategic aspects
Paediatric Type 2 Diabetes
• Areas of agreement
– Age group for study
• 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 Diabetes
partially unresolved: duration of studies
Duration of placebo-controlled period and timing for
measurement of primary EP
•
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
-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!
36
Conclusions
37
• 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)
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
38
39
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
Follow us on
@EMA_News
Backup slides
41
Medicines for children - strategic aspects
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_sea
rch.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/g
eneral/general_content_000303.jsp&mid=WC0b01ac05801df74a
42
Paediatric clinical trials are increasing!
% of CTs including children
(of all studies in EudraCT)
Vaccine studies excluded
Data from:
43
The EMA's role in paediatric medicines
Number of children to be
included in CT is increasing
A significant number of PIPs are not completed in time (or at all)
Data from EMA annual
reports to the EC
44
Will all Paediatric Investigation Plans
be completed?
Completion of studies under PREA obligations
(USA / FDA)
chemicals
biologicals
completed
22%
not completed
/ delayed
54%
not completed
/ delayed
78%
45
Source: AAP as cited in Nature (doi:10.1038/nature.2012.10132)
completed
46%
Will all Paediatric Investigation Plans
be completed?
Completion of studies under BPCA written request
(optional, but 80% suggested by applicant)
46
Source: IOM report on “Safe and Effective Medicines for Children: Pediatric Studies Conducted Under BPCA and PREA”
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
48
The EMA's role in paediatric medicines
Attrition rate (new medicinal products)
49
J Arrowsmith, Nature Drug Dev, 11:17, 2012
Compliance is confirmed at the first attempt in > 96% of cases
And all negative
compliance
check became
positive
(after modification of
the agreed PIP – no
major violations)
Data at 25/09/14
Applicants are
compliant, EMA
is flexible
50
The EMA's role in paediatric medicines
EMA – FDA concordance for waiver requests
(products evaluated by both Agencies)
FDA asked for a few more PIPs for single AS products
51
The EMA's role in paediatric medicines
FDA asks for more PIPs for FDC
Egger G and Tomasi P, 2014, unpublished data
Data protection vs. reward
0
orphans
Market exclusivity:
8
- vs. generic
- vs. similar
all products
0
10 11 12 years
8
10 11 years
Data protection: - vs. generic only
Possible 2 year extension of
ME for “off-patent”
” orphan
drugs which complete a PIP
2 years “market protection”
”:
- Data available
- MAA for generic receivable
- MA for generic cannot be granted
until expiration of the total 10 years
1 year possible extension of market
protection:
- new indication in first 8 years + s.b.
- OTC switch
- WEU: complicated!
0
Paediatric reward:
10
Qualifying patent (20 years)
Incompatible with extension of ME or MP
20 years
SPC
(variable)
There has to be a SPC
(SPC is prolonged, not patent)
Reward
(6 m.)