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9/20/2011

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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.

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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

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• 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)


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)


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


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Timing of PIP/Waiver submissions and outcomes


Timing for submission of Art.7 PIP/waiver to EMA(information received on N=146 out of 168 submitted PIPs)


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


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

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• 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


Withdrawals and Modification to agreed PIPs


Outcomes and withdrawal of PIP/waiver applications

47

90

10

200

250

300

350

= 28% of submitted PIPs

n=316


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

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Timing for withdrawals of PIP/waiver applications (n=90)

33%

39%

25%

30%

35%

40%

45%


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


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

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Content and Scope of PIPs


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

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””

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

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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%


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• 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


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


Interaction with EMA and FDAInteraction with EMA and FDAGlobal paediatric development program


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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


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


I t f di t i l ti d d l t d MAImpact of paediatric regulation on drug development and MAs


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Impact of paediatric regulation on drug development (n=34)

24%

44%

65%

59%

21%30%

40%

50%

60%

70%


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

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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

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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


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

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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)

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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


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

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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

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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%


Conclusions and Recommendations


• 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 .


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• 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


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


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


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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


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)

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