piani di indagine pediatrica (pip) il punto di vista istituzionale

1
PIANI DI INDAGINE PEDIATRICA (PIP)
IL PUNTO DI VISTA ISTITUZIONALE
29
A. Jenkner, Clinical Trial Center, Dipartimento Pediatrico Universitario Ospedaliero
Ospedale Pediatrico Bambino Gesù IRCCS
Seminario SSFA,
Dipartimento
di: Auditorium Servier Italia, Roma, 12 giugno 2014
2
1
3
4
Human Medicines Development and Evaluation
Human Medicines
Development and
Evaluation
Human Medicines Special
Areas
Safety and Efficacy of
Medicines
Quality of Medicines
Research Activities
Orphan Medicines
Anti-Infectives and
Vaccines
Biologicals
Paediatric Medicines
Central Nervous
System and
Ophthalmology
Chemicals
Scientific Advice
Endocrinology,
Metabolism and
Cardiovascular
Scientific Support
and Projects
Oncology,
Haematology and
Diagnostics
SME Office
Rheumatology,
Respiratory,
Gastroenterology
and Immunology
2
5
Registration Procedures in the EU
PRE 1995
15 National Regulatory Authorities
15 Separate National Assessments
15 Independent Marketing
Authorisations:
•
poor resource utilisation
•
divergent scientific opinions/patient
and doctor information
6
New legislation in 1995 and in 2004
Approval in 1 MS => National Authorisation System
Approval in n or all MSs => EU Authorisation System
3 EU procedures:
• Centralised Procedure (CP)
• Mutual Recognition Procedure (MRP)
• Decentralised Procedure (DCP)
Route? Choice?
•
•
Depending on type of product and authorisation history in EU
Regulatory & marketing strategy, company preferences, …
3
7
National Procedure (NP)
Application in:
• 1 Member State only, e.g. Spain
National marketing authorisation in:
• 1 Member State
8
Mutual Recognition Procedure (MRP)
1 assessment of Member State (e.g.
Spain) performs application:
• 1 National MA
Subsequent application to n MSs
Other Member States to
“mutually recognise”
the Spanish assessment:
• n National MAs
4
9
Decentralised Procedure (DCP)
No MA yet for the product in EU:
•
•
Parallel submissions in n MSs
‘Reference’ MS performs
assessment
Peer review by other MSs
(concerned MSs)
n MSs grant national MA after
agreement (in 30 days)
•
•
10
Centralised Procedure (CP)
EU Agency in London:
•
•
•
•
1 Application to Agency
1 scientific evaluation (CHMP)
1 EU scientific opinion
1 Assessment à 1 Opinion
EU Commission issues:
• 1 EU marketing authorisation
applicable in all Member States
5
11
12
Off-label use of medicinal products in children
Widespread 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
6
13
Off-label use of medicinal products in children/2
Initial answers to off-label use were:
• List of Paediatric Needs by EMA’s Paediatric Expert Group (2006) with
the aim of identifying the needs in the different therapeutic areas where
there should be research and development of medicinal products,
either old (i.e. off patent) or new ones (revised annually)
• Consultation of EU member states, learned societies
• Funding of studies for off-patent medicinal products provided by
Paediatric Regulation through the EU Framework Program 7 (FP7)
• The list is adopted after public consultation and is not ranked
• Shared with FDA/NIH to avoid overlap or duplication of efforts, and
facilitate multinational trials where necessary
• Used by EU Commission to assign FP7 funds to projects
14
7
15
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
16
Pillars of the Paediatric Regulation
•
•
•
•
•
Paediatric Committee (PDCO)
Paediatric Investigation Plan (PIP)
A system of OBLIGATIONS and REWARDS
TRANSPARENCY MEASURES
OTHER MEASURES
8
17
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 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)
18
EMA Staff vs. PDCO
EMA Staff: Section Paediatric Medicines
• Currently 30 staff: 20 Scientific Administrators (physicians,
pharmacists, biologists…) + 10 Assistants (secretaries, database
administrator…)
• Scientific and Secretariat (legal, regulatory) support to PDCO
• Based in London, at EMA
PDCO: >60 members/alternates
• Not EMA staff! (hospitals, academia, national agencies…)
• Scientific discussions and opinions
• Based in EU member states
9
19
Paediatric Committe (PDCO)
20
Composition of PDCO
•
•
•
27 members, 1 from each EU member state and 5 nominated by the
CHMP (members of both committees)
The remaining 22 are nominated by the remaining 22 member states
•
6 representatives nominated by EU Commission: 3 representatives of
Healthcare professionals
3 representatives of Patients’ and Parents’ organizations
•
•
2 representatives of EEA MS (Norway, Iceland): no right to vote
Each member has an alternate
10
21
Functioning of PDCO
Chair and vice-chair nominated among its members (not alternates). Can
be renewed once. Members, chair and vice-chair have 3-year terms:
•
•
Meets 12 times a year, for 2.5-3 days, in London at EMA
1-2 informal meetings per year (1.5 days) in rotating EU countries
22
“Main” roles of PDCO
•
•
•
To adopt opinions on PIP/waivers (decision signed by EMA Executive
Director, not by EU Commission)
To provide advice on any question relating to paediatric medicines (at
the request of the Agency's Executive Director or the European
Commission)
To assess data generated in accordance with agreed PIP, to adopt
opinions on the quality, safety or efficacy of any medicine for use in the
paediatric population (at the request of the CHMP or a national
competent authority)
11
23
“Other” roles of PDCO
•
•
•
•
To advise Member States on the content and format of data to be
collected for a survey on all existing uses of medicinal products in the
paediatric population
To establish and regularly update an inventory of paediatric medicinal
product needs
To advise and support the EMA on the creation of a European network
of persons and bodies with specific expertise in the performance of
studies in the paediatric population
To advise the EMA and the EU Commission on the communication of
arrangements available for conducting research into paediatric
medicines.
24
Waivers and Deferral(s)
Three types of waivers:
1. Total (product -specific) waiver: for all conditions/indications being
applied for a product
2. Partial waiver: for one and more subset(s), indication(s), but there is a
PIP
3. Class waiver: for a class of products in a condition, or for all products
aimed at a condition
Legal grounds: Lack of efficacy/safety, lack of significant therapeutic benefit , disease not occurring
Deferral(s):
• Instrument to avoid delaying MA in adults
• “Deferred” means MAA for adults is possible before initiation and/or
completion of one or more measures in the PIP
12
25
Paediatric Investigation Plans (PIPs)/1
A development plan (binding for the pharmaceutical company) aimed at
ensuring that the necessary data are obtained through studies in
children, when it is safe to do so, to support the authorisation of a
medicine for children
Pharmaceutical companies submit proposals for PIPs to the European
Medicines Agency's Paediatric Committee (PDCO) which is
responsible for agreeing or refusing the plan
A system of obligations, rewards and incentives for new drugs and
those covered by patent (6 months of extension) but also for generic
drugs
26
Paediatric Investigation Plans (PIPs)/2
Details of timing and measures proposed (i.e studies, trials and
pharmaceutical development) necessary to obtain a paediatric
indication with an age appropriate formulation in all paediatric subsets
affected by the condition
•
•
•
Quality
Safety
Efficacy
}
Marketing Authorisation criteria
13
27
28
Involvement in the centralised procedure
Start D.1
Pre-submission
D.120
Primary
Evaluation
Clock
Stop
Questions
Scientific
Advice
Paediatrics
(PIP)
Rap/Co-Rap
Assessment
Reports
(Day 80)
Opinion D.210
D.121
Secondary
Evaluation
EU MA D.277
Post
Authorisation
Answers
Joint
Assessment
Report
(Day 150)
PhVig
Variations
Extensions
Renewal
Hearing
(Day 180)
14
29
30
PDCO opinions on procedures are increasing
Deferral: 82% of trials (until after
adult development)
Legal timelines always respected
15
31
New PIP+ waiver applications are stable, modifications are increasing
Trends for PIP/waiver and modification applications
(data EXCLUDING IMMUNOTHERAPY PIPs in 2010)
- 2007 data: last 6 months, extrapolated to 12
- 2012 and 2013 data: linear interpolation
600
N. of applications
500
Modifications
400
PIPs
300
225
8
51
103
280
177
200
0
271
100
273
170
226
187
222
221
2012
2013
0
2007
2008
2009
2010
2011
Years
32
The number of paediatric trials is increasing
1200
1000
800
600
400
200
0
2006 2007 2008 2009 2010 2011
(EudraCT data)
16
33
Increase in the % of paediatric trials over years
% paed CTs over total CTs
16
14
12
10
8
6
4
2
0
2005
2006
2007
2008
2009
2010
2011
(EudraCT data)
34
Il Clinical Trial Center (CTC) all’OPBG/1
Alla luce delle stime ufficiali del Comitato Pediatrico (PDCO) presso
l’Agenzia Europea del Farmaco (EMA), si assisterà ad un
significativo aumento degli studi farmacologici in età pediatrica in
ottemperanza al nuovo Regolamento Pediatrico
Ciò permetterà di valutare con sempre maggiore precisione dose,
formulazione, sicurezza ed efficacia delle terapie in età evolutiva
17
35
Il Clinical Trial Center (CTC) all’OPBG/2
Come si è organizzato un’ospedale come il Bambino Gesù, uno dei tre
IRCCS pediatrici in Italia e sede di un Dipartimento Pediatrico
Universitario Ospedaliero (DPUO), Cattedra e Scuola di
Specializzazione in Pediatria dell’Università di Tor Vergata?
• Istituendo un Comitato Etico (CE) indipendente
• Creando una Clinical Research Organization (CRO) indipendente
• Inaugurando un Clinical Trial Center (CTC) in seno al DPUO
36
Il Clinical Trial Center (CTC) all’OPBG/3
Il Clinical Trial Center è nato nel 2010 al fine di rispondere a questa
esigenza, organizzando ed eseguendo a livello locale e coordinando a
livello nazionale e internazionale studi clinici promossi da industrie,
società scientifiche, enti di ricerca e singoli ricercatori allo lo scopo di:
• fornire una leadership clinica e scientifica nonché tutte le
infrastrutture a sostegno dello sperimentatore e dei pazienti
• disseminare la cultura della sperimentazione clinica e della ricerca
traslazionale in pediatria.
18
37
Il Clinical Trial Center (CTC) all’OPBG/4
Si avvale di: medici, farmacologi, metodologi, infermieri di ricerca,
personale amministrativo e data entry, dedicati e con esperienza di trial
clinici pediatrici
Opera secondo le direttive delle Good Clinical Practice (GCP)
Assicura allo sperimentatore (PI) supporto organizzativo e documentale
utile a garantire l’efficace conduzione della sperimentazione sotto
l’aspetto etico, clinico, economico e regolatorio
38
Il Clinical Trial Center (CTC) all’OPBG/5
Le attività del CTC si svolgono in un’area dedicata dotata di:
• stanze di degenza per il ricovero ordinario, Day Hospital e Ambulatorio
• sala visita e medicheria
• farmacia centralizzata
• locali climatizzati per stoccaggio temporaneo di farmaci
• laboratorio con cappa, frigoriferi, congelatori a -80°C e -20°C e
armadi ignifughi
• archiviazione dei file degli studi
• server centralizzato dell’ospedale per la gestione dei dati sensibili
19
39
Il Clinical Trial Center (CTC) all’OPBG/6
Lo sperimentatore che collabora con il CTC può avvalersi di:
• supervisione per la progettazione degli studi clinici
• preparazione dei protocolli di ricerca
• preparazione dei Case Report Form (CRF)
• gestione delle procedure di registrazione e randomizzazione
• ricezione e archiviazione delle CRF
• controllo della qualità dei dati, dell’emissione e f/u del piano di analisi
• controlli periodici sulla qualità dei dati
• analisi statistiche intermedie e finali
• accesso alle facilities dell’ospedale necessarie alla conduzione dello
studio
40
Andamento sperimentazioni cliniche 2010 vs primo
semestre 2013
20
41
Attivazione nuovi studi anno 2012 e proiezione 2013
42
European Network of Paediatric Research (Enpr-EMA)
Enpr-EMA's main objective is to facilitate studies to
increase availability of medicinal products
authorised for use in children, by:
•
•
•
•
•
•
fostering high-quality, ethical research on the
quality, safety and efficacy of medicines for
use in children
helping with the recruitment of patients for
clinical trials
enabling collaboration between networks and
stakeholders
avoiding unnecessary studies
building up scientific and administrative
competence at a European level
promoting European Commission framework
programme applications
21
43
18 networks are members of Enpr-EMA
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
European Cystic Fibrosis Society - Clinical Trials Network (ECFS-CTN)
EUNETHYDIS (the European Network for Hyperkinetic Disorders)
European paediatric oncology off-patent medicines consortium (EPOC)
FINPEDMED- Finnish Investigators Network for Pediatric Medicines
German Neonatal Network (GNN)
Innovative Therapies for Children with Cancer (ITCC)
International BFM Study Group (I-BFM-SG)
FIMP - MCRN (Italian Paediatric Federation- Medicines for Children Research Network)
Medicines for Children Research Network (MCRN)
Mother Infant Child Youth Research Network "MICYRN“
National Institute for Health Research (NIHR) Medicines for Children Research Network (MCRN)
Newcastle CCLG Pharmacology Studies Group
PENTA: Paediatric European Network for the Treatment of AIDS
Pediatric Rheumatology International Trials Organisation (PRINTO)
Scottish Medicines for Children Network
UKPVG - United Kingdom Paediatric Vaccines Group
EBMT PD WP – European Group for Blood and Marrow Transplantation
Paediatric Network of Clinical Investigation Centers - CICPed
44
Global Research in Paediatrics (GRIP)
GRIP is a FP7 EU-funded project running from
01 January 2011 to 31 December 2015,
aimed at improving the health of children
globally, by :
•
•
•
stimulating and facilitating the development
and safe use of paediatric medicines
implementing a comprehensive
educational programme in paediatric
pharmacology (WP1)
Integrating the use of existing research
capacities to reduce the fragmentation and
duplication of activities (WP2-WP6)
22
45
46
Disclaimer
The views expressed in this presentation are the personal views of the
author(s) and may not be understood or quoted as being made on
behalf of or reflecting the position of the European Medicines Agency or
one of its committees or working parties.
23
47
Copyright (slides 2-11, 14, 19 and 27-33)
© EMEA 2011-2013. Reproduction and/or distribution of this document is
possible for non-commercial purposes provided that the Agency is
always acknowledged as the source in each copy. Citations may be
made without prior permission, provided the source is always
acknowledged.
See: http://www.ema.europa.eu/htms/technical/dmp/copyritel.htm
24