During this presentation, Dr. Susan Bhatti, an experienced regulatory affairs professional, shared best practices and experiences learned from submitting PIPs. This included a brief review of the pediatric regulation requirements, insight for interacting with PDCO, and an overview of the PIP submission including procedures, timelines, structure and compliance.

1. 2 0 11 P E D I AT R I C C L I N I C A L R E S E A R C H W E B I N A R
SERIES
Planning your
Paediatric Investigation Plan (PIP)
Submission in Europe
March 16, 2011 Presented by Susan Bhatti, Ph.D.

2. Susan Bhatti, Ph.D.
 Director International Regulatory
Affairs
 Based in Germany
 15+ years of regulatory experience
 Expertise includes Paediatric
Investigation Plans (PIPs) and
pediatric strategies for product
development
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

3. Paediatric Regulation
Requirements
3
 Submission of an approved PIP is mandatory for:
– Marketing authorisation applications for new substances
– New indications for patent protected authorised products
 Without a PIP, the application for marketing
authorisation
will not be validated in EU
 PIP has to be approved by the EMA Paediatric
Committee (PDCO) or a waiver or deferral has to be
granted
 PIP defines the clinical studies to be conducted in
2011 children
PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

4. Paediatric Regulation
Requirements
4
 The PIP is the document upon which the development
of a medicinal product for the treatment of a defined
condition in the various paediatric age groups is based
 Should include details of timing of studies and the
measures proposed to show quality, safety and efficacy
of the product in children
 PIP should cover all subsets of the paediatric
population, existing and new indications, different
pharmaceutical forms and routes of administration
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

5. Paediatric Committee (PDCO)
5
 Established in July 2007
 Members are appointed for 3 years (renewable)
 33 members
– 5 CHMP members
– One expert from each of the 22 Member States
not already represented by a CHMP member
– 3 representatives of patients’ associations
– 3 health care professional representatives
 Nearly all of the current PDCO members are
paediatricians
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

6. Timing of PDCO Consultation
6
CTA
according Paediatric
CTA CT to PIP MAA studies defined in
A deferral
Marketing
Phase
Preclinical Phase 2 Phase 3 Authorisati Post Approval
1
on
1
PIP Compliance
PIP Ammendments
or Deferral
or Waiver
5 CHMP members
Opinio 22 member states
Pediatric Committee n 3 patient organisation professionals
3 healthcare professionals
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

7. PIP Structure
7
Part A: Administrative and product information ← intelligent pdf
file
Part B: Overall development of the product
 Information on the target disease/condition
 information on the product/mode of action
 Significant therapeutic benefit/therapeutic needs
Scientific
Part C: Applications for product specific waivers document
(Word + pdf)
Part D: Overall strategy for development in children 50 pages
<
if possible
 Existing data in adults and children
 Details of proposed studies (ongoing or future)
 Proposed timelines
Part E: Applications for deferrals
Part F: Annexes (References)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

8. Part A
Administrative and Product
Information
8
Electronic Application
 Choice of Article 7, 8 or 30
 General information
 Information about
completed, ongoing and
proposed studies
 Intelligent pdf file containing
all data (reusable)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

9. Part B
Overall Development
9
B.1 Similarities and differences:
 Similarities and differences of the condition between populations (to
include info on prevalence/incidence in children)
 Summary of pharmacology (to include structure, absorption,
metabolism, PK, PD, elimination)
B.2 Current methods of diagnosis, prevention or
treatment in paediatric populations
 How does your product differ from existing options available to treat
the indication in children?
B.3 Significant therapeutic benefit/fulfilment of
therapeutic needs
 Is there a need for a new product to treat this condition and is your
product likely to satisfy this need?
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

10. Part C
Product Specific Waivers
10
 Possible lack of efficacy or lack of safety in children “Likely
to be ineffective or unsafe” (NOT lack of data)
 Disease or condition does not occur in some or all
paediatric age groups
 Lack of significant therapeutic benefit
Over existing treatments
As clinical studies are not feasible (e.g. extreme rarity)
Paediatric needs already covered
 Proposed clinical studies cannot be expected to be of
significant therapeutic benefit to or fulfil a therapeutic need
of the paediatric population (for example, because sufficient
data are already available as studies have been conducted)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

11. Part D
Paediatric Investigation Plan
11
D.1 Existing Data/Overall Strategy Proposed for the Paediatric
Development
 D.1.a: Paediatric Investigation Plan indication
 D.1.b: Selected paediatric subset(s)
 D.1.c: Information on the existing quality, non-clinical and
clinical data, including existing data in adults and completed
studies in children
D.2 Quality Aspects
 D.2.a: Strategy in relation to quality aspects
 D.2.b: Outline of each of the planned and/or ongoing
studies and steps in the pharmaceutical development
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

12. Part D
Paediatric Investigation Plan
12
D.3 Non-clinical Aspects
 D.3.a: Strategy in relation to non-clinical aspects
 D.3.b: Overall Summary Table of non-clinical studies
 D.3.c: Synopsis/outline of protocol of each of the planned
and/or ongoing non-clinical studies
D.4 Clinical Aspects
 D.4.a: Strategy in relation to clinical aspects
 D.4.b: Overall Summary Table of clinical studies
 D.4.c: Synopsis/outline of protocol of each of the planned
and/or ongoing clinical studies
D.5 Timeline of Measures in the Paediatric Development Plan
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

13. Part E
Deferrals
13
 Article 7 (and 8) requires submission of “the results of all
studies performed and details of all information collected in
compliance with an agreed paediatric investigation plan”
 A deferral only means that the MAA is validated prior to
completion of the studies listed in the PIP and so there is no
need to submit the results yet
 Deferrals can be requested for all paediatric studies or for
certain subsets of the paediatric population and always have to
be JUSTIFIED
 NOTE: There MUST be an agreed PIP; only the agreed
measures can be deferred
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

14. Part E
Grounds for Deferrals
14
PIP Guideline:
 Conduct studies in adults prior to initiating studies in the
paediatric population
 Studies in the paediatric population will take longer to conduct
than studies in adults
 Additional nonclinical data are considered necessary
 Major quality problems prevent development of the relevant
formulation(s)
If an unmet medical need is identified then PDCO can request
shortening of the deferral timeline or deny deferral due to the need
for availability of the product in children
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

15. Part F
Annexes
15
 References (published literature)
 Investigator’s brochure, protocol synopsis (if available)
 Previous opinions and decisions from other authorities (EU
Member States, FDA…)
 Scientific advice
 Product information (for an authorised product)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

16. PIP Submission
Timelines for validation
16
Day -60 Day -30
Day -90 Rapp/ PR PIP
Letter of Day 0
designati Applicatio
Intent on n
Preparation Validation Start
Preparation of EMA
Summary Report
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17. Overview of PIP Procedure
17
APPLICATION
max 30 days
VALIDATION &
Summary Report
Day 1
Day 30 1st Discussion PDCO
Possible teleconference
↓
Day 60 2nd Discussion PDCO List of Issues
Update
No issues d Clock stop
PIP 3 months
PDCO Opinion 3rd Discussion PDCO Updated Summary
Day 120 Day 90 Report
Possible oral Day 61
Explanation
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

18. How is a PIP Assessed?
18
EMA staff (Scientific Administrators)
 The Paediatric Coordinator of the procedure acts as the
interface between companies and PDCO
 Perform regulatory checks (validation)
 Writes and comments on the draft version of the Summary
Report
 Participates in the PDCO meeting
 Writes PDCO documents (i.e. requests for modification,
opinions)
 Assists and initiate the preparation of scientific and
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
regulatory procedural advice

19. How is a PIP Assessed?
19
PDCO members
 Members and Alternates share the work
 Designated Rapporteur and Peer Reviewer both review
and comment on the Summary Report, (Day 30) then
present to PDCO (Day 60)
 Other Members comment on it during and after discussion
(verbally or in writing)
 Achieve consensus or vote if necessary
 Experts invited if necessary
 Teleconference with applicant may be requested
 Oral Explanation meetings possible
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

20. PIP Procedure
Key to Success
20
Establish a close cooperation with EMA coordinator
 Consider that major changes can occur between Day 30
and Day 60 Summary Report
 Major issues are difficult to clarify during the procedure
– New indications/age groups etc. are required
– Requested switch from full waiver to PIP (if a waiver is
refused, the PIP procedure has to be started again
from the beginning)
 Important issues should be clarified prior to Day
61(difficult to solve major issues between Day 61 and
120, even with a face to face meeting)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

21. PIP Procedure
Key to Success
21
Before Day 61
Teleconference with EMA coordinator, Rapporteur, Peer
Reviewer and external experts
 Discuss draft response (submitted previously together with
questions)
 If high risk exists for PIP/Waiver refusal: exclude “critical”
conditions (re-submit separately)
Day 90 - 120: Meeting/Teleconference
Final PDCO position and issues communicated to the
applicant
 Last chance for clarification in oral explanation
 No submission of additional or modified documents possible
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

22. Outcome
The PDCO Opinion
22
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23. Compliance Check
23
A compliance check is performed to verify that all
the measures agreed in a PIP and reflected in the
EMA decision have been conducted in
accordance with the decision, including the
agreed timelines
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

24. PIP Compliance Check
Key Points
24
Comparison of the key binding elements in the Opinion
with:
 The full clinical study report(s)
 All measures are checked
 Can be partial (i.e. in case of a deferral only those
measures are checked that should have already been
completed before the MAA submission)
If non-compliance is found then the MAA will not be
validated!
Solution: Request a PIP modification in a timely manner
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

25. PIP Compliance Check
Key Points
25
To avoid delays: compliance check should be initiated by
applicant prior to submission (30 or 60 day procedure)
once final clinical trial report is available
NOTE: Request to modify agreed PIP may be needed
prior to compliance check (60 days + 2 months to
notify intent)
 Keep paediatric trials off the critical path (timely PIP,
deferral)
 Regular monitoring of compliance to avoid surprises
 Detailed advance planning of submission - identify
potential delays to allow anticipatory actions
 Discuss time-critical steps (and solutions) during pre-
submission meeting
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

26. Compliance Check!
26
Every word matters!
✓ Definition of condition
✓ Details of waivers
✓ PIP indication
✓ Lists applicable age
subsets
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

27. Compliance Check!
27
✓ Specifies formulation
✓ Table of all
studies/measures
✓ Overall timelines
✘Not published: Details of
individual
studies/measures
(however, most will be
available on EudraCT)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

28. PIP Modifications
28
Modifications are always possible if there are difficulties with
the PIP implementation i.e. the original plan is either
unworkable or is no longer appropriate
 Preferably prospective
 Multiple modifications possible
 60-day procedure - same EMA coordinator/Rapporteur/Peer
Reviewer
 New waivers/deferrals can also be requested
 New opinion/decision supersedes original
Changes have to be justified and should not be perceived to
gradually erode the original PIP requirements
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

29. PIP Modifications
29
 Application has similar
structure to the original PIP
application but it is a Word
document
 PIP modifications required
during product development
should be submitted in a
TIMELY manner!
 Remember – the majority of
PIPs will have to be
modified at least once!
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

30. Take Home Messages
 Paediatric Investigation Plan is a requirement for all
new medicinal products (new substances and
indications)
 It needs careful preparation and it takes nearly a year
to obtain a PDCO opinion, which is then binding
 A PIP will probably have to be modified at least once
prior to the marketing authorisation submission
 Keep your paediatric trials off the critical submission
path
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

31. Information on PIP
Requirements
31
 EMA Paediatrics website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/ge
neral/general_content_000023.jsp&murl=menus/regulations/regulat
ions.jsp&mid=WC0b01ac05800240cd&jsenabled=true
 EU Commission Guideline on Format and Content of
applications for PIPs/waivers/deferrals:
http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2008:2
43:0001:0012:EN:PDF
 Scientific guidelines and procedural advice on the EMA
website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/do
cument_listing/document_listing_000293.jsp&murl=menus/regulatio
ns/regulations.jsp&mid=WC0b01ac0580025b91#section1
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

32. Upcoming Webinars
32
Register at www.premier-research.com/webinars
▪ Guidelines for Effective and Appropriate Pediatric
Assent and Parental Permission
13 April at 11:00 am EDT
Speakers: Angi Robinson and Elizabeth Jay, RN, MA
▪ Pediatric Considerations beyond Assent
11 May at11:00 am EDT
Speakers: Krista Armstrong, Ph.D. and Patricia Molloy,
M.D.
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

33. Questions?
Dr. Susan Bhatti
Director International Regulatory Affairs
Birkenweg 14
D-64295 Darmstadt
Germany
Telephone: +49 (6151) 8280-310
susan.bhatti@premier-research.com
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES