Post on 19-Apr-2020
9/20/2011
1
Impact of EU Paediatric Regulation on drug development and Marketing authorisations – Industry experience
Judith CrebaHead EU Liaison and Policy, DRA Novartis Pharma AG, Switzerland
The views and opinions expressed in the following PowerPoint slidesare those of the individual presenter and should not be attributed toDrug Information Association, Inc. (“DIA”), its directors, officers,employees, volunteers, members, chapters, councils, Special InterestArea Communities or affiliates, or any organization with which thepresenter is employed or affiliated.
Disclaimer
p p y
These PowerPoint slides are the intellectual property of the individualpresenter and are protected under the copyright laws of the UnitedStates of America and other countries. Used by permission. All rightsreserved. Drug Information Association, DIA and DIA logo areregistered trademarks or trademarks of Drug Information AssociationInc. All other trademarks are the property of their respective owners.
2www.diahome.orgDrug Information Association
Introduction
Industry experiences with Paediatric Legislation:
EFPIA survey on the the impact of the paediatric regulation on
Marketing Authorisation Holders (Jan 2007- June 2010)
Agenda
Marketing Authorisation Holders (Jan 2007- June 2010)
Conclusion/ recommendations
Acknowledgements
EFPIA for permission to use the data from the survey
EFPIA Paediatric Working Group
Drug Information Association www.diahome.org 3
9/20/2011
2
• Continuous effort for paediatric drug development– PIP and waivers situation (PDCO report August 2011)
Implementation of the EU Paediatric RegulationProgress
Total PIP/waiver applications 1087
Total of agreed PIP/waiver 683
Indications covered by PIP/waiver applications
1516
Positive opinion on PIPs 475
Positive opinion on Full waiver 208
Negative opinion on PIP/waiver 27
Positive opinion on compliance check 25
Positive opinion on modification PIPs 259
• Increased paediatric information– Article 45 and Article 46 assessments (2009 – 2010)
Drug Information Association www.diahome.org 4
EMA CMD(h)
Art.45 Number of products submitted 60 1000
Outcome Update of the SmPC for 6 products
44 products completed the assessment
Art.46 Number of studies submitted 60 N/A
Outcome Update of SmPC for 19 cases
Industry ExperienceEFPIA survey on the the impact of theEFPIA survey on the the impact of the paediatric regulation on Marketing Authorisation Holders (Jan 2007- June 2010)
Drug Information Association www.diahome.org 5
Objective - to assess the impact of the first 3.5 years of implementation of
the paediatric regulation on marketing authorization holders (Jan 2007 –
June 2010)
Extensive survey of 61 questions covering all aspects relating to PIP
application/outcomes and the impact on company drug development and
EFPIA survey on impact of Paediatric regulation (Jan 2007 – Jun 2010)
pp p p y g p
resources.
Very good response rate - 34 companies including large and small firms
Data from 316 PIPs/partial waivers analysed Legal basis - 53% Art 7, 46% Art 8, 1% Art 30
12% Orphan products
4% paediatric indications only, 96% paedaitric development as part of ongoing
adult programme
Drug Information Association www.diahome.org 6
9/20/2011
3
Timing of PIP/Waiver submissions and outcomes
Drug Information Association www.diahome.org 7
Timing for submission of Art.7 PIP/waiver to EMA(information received on N=146 out of 168 submitted PIPs)
Drug Information Association www.diahome.org 8
majority of PIP/waiver applications were submitted to EMA following the proof of concept (PoC) or confirmation of the adult dose
Timing and outcomes of Art.7 PIP/waiver applications(information received on N=146 out of 168 submitted PIPs)
20%12% 4%4%
2% 4%50% 47%
18% 15% 15%
PIP agreed unchanged or with minor modificationsPIP agreed with major modificationsPIP agreed with suggestion to come back for later discussion in a "Modification of agreed PIP" procedurePIP refused (negative PDCO opinion)PIP withdrawn
Drug Information Association www.diahome.org 9
18% 18%31%
19%
50%24%
39%
40% 58%12%
20%
Before first human dose in adults
End of Phase 1 in adults
Following confirmation of adult dose or proof of concept, but before the start of paediatric trials
Following completion of confirmatory clinical trials in adults, but before the start of
paediatric trials
After starting paediatric trials
n=2 n=17 n=49 n=52 n=26
9/20/2011
4
• Submission timings for Paediatric Investigation Plans vary
Majority of PIPS were submitted following proof of concept or
confirmation of adult dose
• Submission of PIP before PoC resulted in high rate of withdrawal
Key findings on the timing and outcome of PIP submissions
• Companies obtaining agreement on PIP submitted after PoC, are
still requested to come back for later discussion in a modification
process
• A high proportion of PIPs agreed with major modifications
regardless of the submission timing
Drug Information Association www.diahome.org 10
Withdrawals and Modification to agreed PIPs
Drug Information Association www.diahome.org 11
Outcomes and withdrawal of PIP/waiver applications
47
90
10
200
250
300
350
= 28% of submitted PIPs
n=316
Drug Information Association www.diahome.org 12
169
70 81
6217
54
0
50
100
150
PIPs Full waiver requests Confirmations of class waivers
Agreed Ongoing Withdrawn Negative EMA decision
n=98 n=87
9/20/2011
5
Timing for withdrawals of PIP/waiver applications (n=90)
33%
39%
25%
30%
35%
40%
45%
Drug Information Association www.diahome.org 13
11%
17%
0%
5%
10%
15%
20%
Day 1‐60 During clock stop Day 61‐120 Day 120 – EMA Decision
Key findings for withdrawals
• High percentage of withdrawals is of concern• Majority of the withdrawals occurred after Day 60 PDCO review (during clock-stop or
between D61-120)
• Main reasons for PIP withdrawals (n=90):– termination or reconsideration of the development that was unrelated to the PIP (33%)
– divergent positions between the applicant and the PDCO (21%)
– need for additional time for applicants to consider requests by PDCO (11%)
– studies or key binding elements requested by the PDCO being considered unfeasible (7%)
– cost of the pediatric programme (6%) or the inability to achieve the reward in the remaining time
(13%)
• Main reasons for withdrawals of Full waiver request (n=17):– PDCO identified a medical need for a pediatric population in the development programme (41%)
– Reasons unrelated tp paediatric development (e.g adult development stopped (29%)
www.diahome.org 14Drug Information Association
Almost half of agreed PIPs in survey have been modified
One fifth of agreed PIPs in survey have been modified at least twice (n=33)
High proportion of requested changes are fully accepted by PDCO
Modification to agreed PIPs(N=82 out of 169 agreed PIPs)
Although companies are
Drug Information Association www.diahome.org 15
0% 10% 20% 30% 40% 50%
% of agreed PIPs (n=169)that have been modified
29% 20%
Only 1 modification/PIP At least 2 modifications/PIP
submitting PIP
applications after Proof of
Concept, over half of the
agreed PIPs in survey have
been modified
Maintenance of agreed
PIPs is resource‐intensive
9/20/2011
6
Content and Scope of PIPs
Drug Information Association www.diahome.org 16
Consistency between adult and paediatric indications in submitted PIPs/waiver (n=414)
246
200
250
300
PIP/waiver applications Companies usually align the PIP/waiver indications with the
targeted adult indications
“Detailed target indication language difficult at a point when this is not clear in the development path.”
41 32
0
50
100
150
indications consistent with the intended adultindication(s)
indications not consistent with the intended adultindications, but were covered by the intended adult
condition(s)
indications not covered by the intended adultconditions
www.diahome.org17
””
Drug Information Association
PDCO requests for different development program than initially proposed by companies (n=316 PIPs submitted)
Additional Non‐clinical studies
Additional formulations
Additional efficacy studies (including efficacy studies with…
Additional paediatric subsets
14%
18%
21%
27%
Additional program/studies requested by PDCO
www.diahome.org18
Additional "dose finding" studies
Additional paediatric indications outside the intended adult…
Others (e.g. juvenile tox studies, longterm maintenace…
Additional dosage forms
Additional Safety studies
Additional paediatric indications within the intended adult…
Additional PK/PD studies
8%
9%
10%
12%
12%
13%
14%
Drug Information Association
9/20/2011
7
• Additional PDCO requests are routinely received on
company PIP proposals
– Requests include additional programmes and studies
Key findings on content and scope of PIPs
q p g
• High proportion of PDCO requests impact on
– study feasibility and
– incur unplanned costs in development
Drug Information Association www.diahome.org 19
Interaction with EMA and PDCO
Interactions with EMA usually work well. Clarification TC following receipt of
request for modification is particularly valued
However, the interactions with PDCO during the procedures could improve
Compliance check
Some other findings
Companies reported 100% of positive opinion on partial check (n = 34)
However, 2 negative opinions on full compliance check were reported
(2/20), although EMA reported one case. This may indicate that 1 company
was able to remedy the issues and reach positive compliance
Survey did not reveal any specific issues to date
Drug Information Association www.diahome.org 20
Interaction with EMA and FDAInteraction with EMA and FDAGlobal paediatric development program
Drug Information Association www.diahome.org 21
9/20/2011
8
FDA/EMA requests for changes to identical paediatric development program proposals (N=27 from EMA, N=18 from FDA)
20
Yes Not yet known No Not reported
Drug Information Association www.diahome.org 22
9
41
421
4
FDA requested additional/different development than agreed with
PDCO/EMA
PDCO requested additional/different development than agreed with FDA
• Companies carry-out global development and strive for alignment of
paediatric development programmes between US and EU
• Companies may opt to submit Paediatric plans in parallel to EMA
Key findings on interaction with EMA and FDA
and FDA to facilitate Inter-Agency discussion
• Higher rate of requests from PDCO for changes to FDA-agreed
paediatric plans
– Possible reflects early experiences with the EU Regulation, but need
for continued monitoring
Drug Information Association www.diahome.org 23
I t f di t i l ti d d l t d MAImpact of paediatric regulation on drug development and MAs
Drug Information Association www.diahome.org 24
9/20/2011
9
Impact of paediatric regulation on drug development (n=34)
24%
44%
65%
59%
21%30%
40%
50%
60%
70%
Drug Information Association www.diahome.org 25
15%
9%9%
15%
6%
0%
6%3% 3%
0%0%
10%
20%
My company considers pediatric development an integral part of the overall development of a product
The introduction of the EU pediatric Regulation has led to an earlier
discussion of pediatric development within my company for new
products
The introduction of the requirement for submission of a PIP
has led to earlier discussion of pediatric development with regulators for new products
Strongly agree Agree Neither agree nor disagree Disagree Strongly disagree
7
Impact on development in adults
Has the development in adults of any of your company's products been delayed or abandoned in expectation of or as a consequence of additional costs and requirements associated with paediatric development?
The objectives of the paediatric regulation should be achieved “without ... delaying the authorisation of medicinal products for other age
157
7
0 20 40 60 80 100 120 140 160 180
Yes, for new indications/extensions to existing products Yes, for NCEs/NBEs No
26
medicinal products for other age populations.”
Drug Information Association www.diahome.org
• 139 (=87%) of 159 MAAs or variations for a new adult indication were not postponed due to requirements of the paediatric regulation.
• However, 19 MAAs or variations were postponed
Postponement of submission of a Marketing Authorization application, or a variation, for a new adult indication due to requirements of the paediatric Regulation (N=159)
Due to divergence between EMA/PDCO and company
Due to intrinsic length of the PIP/waiver procedure
Drug Information Association www.diahome.org 27
0 1 2 3 4 5 6 7
Due to non‐validation of MAA/Type II variation due to formalistic interpretation of PIP scope by EMA
Due to too late submission of PIP/waiver application by applicant
Due to intrinsic length of the Compliance Check procedure
Other reasons
9/20/2011
10
Key findings on the impact on drug development and Marketing Authorisations
• Companies have integrated paediatric development into the overall
development of a product
Early discussion within company and with regulators
• However
In 14 cases the development in adults had been delayed or abandoned inIn 14 cases, the development in adults had been delayed or abandoned in
expectation, or as a consequence, of additional cost and requirements
associated with the paediatric regulation (7 cases for NCEs/NMEs and 7
cases for new indications)
19 marketing authorisation applications or variations experienced a delay
due to requirements of the EU Paediatric Regulation (out of 159 regulatory
applications)
www.diahome.org28
Drug Information Association
Key findings on the impact on drug development and company resources
• Impact on company resources:
Paediatric Regulation has had a significant impact on R&D and regulatory
resources
- Actual management of regulatory procedure is resource intensive
- Additional PDCO requests routinely received on company PIP
proposals
- Withdrawal of PIPs/abandoned development programmes results in
wasted resource
www.diahome.org29Drug Information Association
Overall impact of the Paediatric Regulation to June 2010
316
169
Drug Information Association www.diahome.org 30
169
98
22 18 10 7
Applications for PIPs/partial
waiver submitted
PIPs/partial waiver requests
agreed
Applications for modification to an agreed PIP submitted
Any paediatric information
added to SmPCs based on agreed
PIP
Positive Full compliance
check
Pediatric indications
approved based on studies in agreed PIPs
SPC extensions requested
9/20/2011
11
Overall impact of the Paediatric Regulation to June 2010
• 111 Art.45 procedures initiated – 54 finalised
• Of finalised procedures, 25 (46%) have resulted in revised product
information
Impact of finalised Art.45 procedures
www.diahome.org 31
0% 10% 20% 30% 40% 50% 60%
No impact on PI?
deletion of a paediatric indication from PI
new paediatric use (indication and/or dosing) …
safety updates in PI
54%
0%
13%
33%
Drug Information Association
Conclusions and Recommendations
Drug Information Association www.diahome.org 32
• First survey of industry experience with Paediatric Regulation
gathering extensive information from 34 companies on 316 PIPs
Some beneficial results realised for paediatric patients:
22 SmPCs with updated paediatric information based on agreed PIPs,
including 10 paediatric indications
Conclusions
Article 45: 25 procedures resulted in revised SmPCs
• Industry has embedded paediatric development in its development
process .
Drug Information Association www.diahome.org 33
9/20/2011
12
• Paediatric Regulation has impacted R&D productivity
– significant impact on R&D resources
– some development programmes (including adult programmes) have
been negatively impacted
Some companies are beginning to realise the incentives
Conclusions
Signals in survey highlight some areas for future work
Drug Information Association www.diahome.org 34
PIP process
Day 90 of procedure- Allow clock-stop, allow optional interactive discussion with
PDCO
Allow clock-stop during the PIP modification procedure
Facilitate more direct discussions between PDCO Rapporteur(s) and sponsors
where required
Proposals for improvement
Guidance
Definition of condition vs indication for the scope of the PIP
Publish available data and regulatory guidance related to epidemiology for known
disease areas in order to avoid duplication
Facilitation of discussions between regulatory experts, academia, learned
society and the pharmaceutical industry - building consensus on most
appropriate paediatric plan in disease areas, balancing unmet or critical
paediatric needs and current practical/feasibility limitations
Drug Information Association www.diahome.org 35
Medium-long term measures
An initial PIP should generally be submitted and discussed with regulators once
Proof of Concept in adults is established/reached
Limit the initial PIP to "high-level" information and agree paediatric needs, target
Proposals for improvement
indication, target population
Include commitment to return to the PDCO with detailed study design proposals
before pediatric studies are started
Limit the scope of mandatory paediatric development to the corresponding adult
indication and defined critical unmet medical needs
Drug Information Association www.diahome.org 36
9/20/2011
13
Thank You !
Basel, Switzerland
37www.diahome.orgDrug Information Association
PDCO request for changes to clinical study design that impacted feasibility to conduct studies (n=316 PIPs submitted)
24%
Request to include specific procedures inthe protocol that presented practical or
logistical challenges (e.g. specificmonitoring or sample collection
procedures)
PDCO request for changes to the study design impacting on feasibility
Drug Information Association www.diahome.org 38
11%
24%
Others (e.g. request for DSMB or requestrelated to ethical aspects...)
Additional patients (leading to enrolmentrates that would not allow meeting theagreed completion date or that would
make the conduct of the study unfeasible)