This presentation will address issues surrounding the development of a pediatric plan for PREA/PMDSIA compliance including: when to develop a pediatric plan, what age groups should be included, is a pediatric formulation necessary, timing of the pediatric studies, what information should be submitted to FDA, and when a waiver or deferral is appropriate.

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
Developing a Feasible Pediatric Plan
for PREA/PMDSIA Compliance
Presented by Charlene Sanders, M.D.,
Feb. 16, 2011
F.A.A.P.

2. Charlene Sanders, M.D.
 Vice President, Global Regulatory Affairs and Pediatric
Strategic Consulting
 15+ years of regulatory and medical affairs experience
– Regulatory portfolio includes NDA approvals for 15
programs which incorporated pediatric protocol design,
pediatric clinical study development, PREA discussions
and/or pediatric related safety issues
 25+ years of clinical patient care management
experience
 Trained in pediatrics and completed post-doctoral
2011 PEDIATRICspecialty fellowship training in critical care pediatrics
CLINICAL RESEARCH WEBINAR SERIES

3. The Challenge:
Pediatric Written Requests (WR)
“Divide each difficulty into as many
parts as is feasible and necessary to
resolve it.”
- Rene Descartes
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

4. The Idea of Reward: Exclusivity
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

5. Pediatric Exclusivity - 6 months
5
Section 505A Modernization FDA can request
Act allows the FDA to make 1) A new formulation for
1) Written request prior to target population
approval or post- approval 2) FDA can ask for
2) FDA must update The List anything
The Rule FDA Authority
Pediatric assessments for: Approved drugs
Indication Dosage 1) that have substantial use in
form kids or 2) meaningful
Route Dosage regimen therapeutic benefit that if use
Safety Effectiveness in children without adequate
Subpopulations Pharma or labeling could pose a risk
biologics
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

6. Pediatric Research Equity Act
(PREA) Renewed 2007
6
 Authorizes FDA to require pediatric studies or
clinical trials of marketed drugs that are not
adequately labeled for children after other
opportunities to obtain such studies or clinical
trials on a voluntary basis have been
exhausted
 Where exclusivity is not an option, PREA
opens the door for Written Requests in post-
marketing phases of drugs, biologics, and
devices where applicable
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

7. FDA Authority – Now
Expansive
7
FDA has the authority to require pediatric studies
on a product for the approved indications:
 IF SUBSTANTIAL USE in the pediatric
population
OR
 MEANINGFUL THERAPEUTIC BENEFIT -
AND the absence of adequate labeling could
pose significant risk (see 21 CFR 201.23(a))
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

8. PREA Realities:
How To Handle A Written Request
8
A PREA generated requirement for pediatric
studies or clinical trials may be waived if:
 Necessary studies or clinical trials in children are
impossible
 Strong evidence suggesting it will not be effective or safe
in children
 Does not represent a meaningful therapeutic benefit over
existing therapies for children
 Not likely to be used in a substantial number of children
Some studies or clinical trials may also be
deferred
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

9. PREA Realities: Applicability &
Feasibility
9
Written Requests and the MESSSI Test
M eaningful therapy for kids
E ffective
S mall numbers, subpopulation, substantial
use
S afety
S cientific sense
I mpossible
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

10. PREA and FDA Authority:
Time and Response
10
FDA has authority to:
 Set a clock for needed studies to be submitted
 Mandate a response from sponsors and set the
timing of that response
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

11. Time and Terms
11
 Deferral: the Pediatric Rule states that FDA may
approve an application for use in adults
SUBJECT TO THE REQUIREMENT that the
applicant submits the required assessments
WITHIN A SPECIFIED TIME
 Waiver and Exemption: removes the
requirement to conduct pediatric studies (and the
"clock") with respect to the particular supplement
or application
 Partial Waiver: a waiver granted only for studies
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

12. Time and Time Bending
12
 Deferrals have clocks
 Waivers and Exemptions
are not bound to clocks
Each Division makes its own decision as to what products,
etc. will be granted waivers/deferrals/exemptions
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

13. A MESSSI Example:
Applicability and Feasibility
13
 FDA requires a sponsor to conduct pediatric studies even
if the disease only occurs in certain pediatric
subpopulations
 FDA requires a sponsor to conduct pediatric studies even
if only a small number of children are affected if the
information would provide a meaningful therapeutic
benefit in pediatric patients
 FDA should issue a partial waiver for the age groups in
which the disease does not occur
 The sponsor tries to conduct a study in the affected
population but cannot complete the study, perhaps due
to a very small number of patients in which the disease
occurs, FDA may issue a waiver
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

14. Carrot on a Stick Reminder
14
An inadequate study that meets the
terms
of a Written Request (FDAMA) may
still
earn pediatric exclusivity
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

15. Formulations
15
Can FDA ask for a new formulation under the
pediatric rule and/or in a Written Request that is tied
to exclusivity?
YES!
Under the rule, FDA not only can ask but can
require a new formulation if it is needed in a
pediatric age group that will use the drug
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

16. Rationale for Pediatric
Formulation
16
 FDA can request a sponsor to conduct studies
in all relevant pediatric populations
 As such, a sponsor will not be able to satisfy
such a Written Request unless it completes
studies in all relevant populations
 To complete such studies, a sponsor may need
to develop a new formulation
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

17. Case Study: ABC Pharma
Applying the MESSSI Rule
Written Request includes the following:
 Pharmacokinetic Studies
 Safety and Efficacy (Clinical) Studies
 Drug Information
 Statistical Information
 Labeling
 Format
 Timeframe for Submission
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

18. Sample Letter
18
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

19. Do the Math
19
#Amendments to a Written Request =
#Negotiations
…You do not usually get what you deserve
(or expect), you get what you negotiate…
“In the spirit of PREA”
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

20. Pediatric Studies
Apply the MESSSI Rule
20
Pharmacokinetics Studies Efficacy and Safety Studies
 Open label, dose escalation  Objective of studies
 PK profile for different ages  Numbers of patients and age
 Appropriate dosages for groups
different age groups
 Powered to 80% to detect
 Numbers of patients (evenly statistically significant
distributed sex/age) difference in primary endpoints
 Inclusion/exclusion criteria
 Inclusion/exclusion criteria
 Study endpoints
 Patient study discontinuation  Study endpoints
criteria
 Data Safety Monitoring Board
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

21. Age Categories
21
 ≥ 28 weeks to ≤ 1 month
 1 month to < 6 months
 6 months to < 12 months
 12 months to < 24 months
 2 years to < 6 years
 6 years to ≤ 16 years
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

22. Pediatric Studies
Apply the MESSSI Rule
22
Drug Information
Statistical Information
Requirements
 Dosage forms  Non-powered trials -
 Route(s) of administration descriptive statistics
 Regimen  SAP for efficacy trials
 Drug-safety concerns  Demographic data
 Descriptive analysis of safety
data
Format Labeling
 Full study reports  Draft labeling
 Ethnic and racial
representation analysis
 Study Data Tabulation (SDTM)
 Clinical Data Interchange
Standards Consortium
(CDISC)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

23. Timeframe
23
Reports of the above studies must be submitted to the Agency on or before
XXX, in order to possibly qualify for pediatric exclusivity extension under
Section 505A of the Act. Please keep in mind that Pediatric Exclusivity attaches
only to existing patent protection of exclusivity that has not expired at the time
you submit your reports of the studies in response to this Written Request.
 Response to Written Request within 180
days!!
 Don’t agree, then, in the spirit of PREA –
Amend!!
 Agree – must sign WR and give a start date
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

24. Housekeeping
24
Pediatric Protocol
submitted for Pediatric to the IND
Exclusivity Study
Proposed Written
Agreement for to the NDA/PMA
Pediatric Studies
to the approved NDA
labeled “Pediatric
Completed Pediatric
Exclusivity
Study Reports
Determination
Requested”
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

25. Proposed Changes =
Negotiations
25
If you wish to discuss ANY amendments to this Written Request, submit
proposed changes and the reasons for the proposed changes to your NDA XX-
XXX. Clearly mark submissions of proposed changes to this request
“PROPOSED CHANGES IN WRITTEN REQUEST FOR PEDIATRIC
STUDIES” in large font, bolded type at the beginning of the cover letter of the
submission. We will notify you in writing if we agree to any changes to this
Written Request.
Carpe Diem!
Or in this case,
seize the opportunity!!
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

26. Advice on Device
Pediatric Medical Device Safety &
Improvement Act 2007 (PMDSIA)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

27. Advice on Device
27
Increased Tracking of Pediatric Device
Approvals
 # and types, approval times PMAs/HDEs
Pediatric Device Contact Point
 NIH designates an office to help innovators
access existing funding for pediatric device
development
Pediatric Advisory Committee Review
 FDA’s Pediatric Advisory Committee to monitor
pediatric devices and make recommendations
for improving their availability and safety
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

28. Advice on Device
28
Authority to Require Post-market Surveillance
 For devices that are expected to have significant
use in pediatric populations, allows FDA to
require a manufacturer to conduct post-market
surveillance for any class II or class III device
Post-market Studies as Condition of Approval
 For a devices that are expected to have
significant use in pediatric populations, allows
FDA to require post-market studies as a
condition of approval
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

29. Summary: Take Home Message
WR has been issued  use the MESSSI
test:
 Break down components of WR
 Submit proposal to amend WR
 “In the spirit of PREA”- Negotiate feasibility/applicability
 Don’t finalize/sign WR until all points
addressed/amended
Have a pediatric plan early in development
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

30. References:
FDA Amendments Act of 2007
30
(FDAAA)
 FDAAA - Title IV: Pediatric Research Equity Act of 2007 (PREA) and
Title V: Best (PDF)
 PREA Retrospective Review (PDF)
 Internal Review Committee - Memorandum Establishing Pediatric
Review Committee (PDF)
 Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric
Studies Conducted under Section 505A and 505B of the Federal
Food, Drug, and Cosmetic Act (the Act), as amended by the FDA
Amendments Act of 2007 (FDAAA)
 New Pediatric Information in Labeling - Searchable (PDF)
 Breakdown of FDAAA Completed Pediatric Studies
 Pediatric Study Characteristics - Searchable (PDF)
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

31. Upcoming Webinars
31
Register at www.premier-research.com/webinars
▪ Planning your Paediatric Investigation Plan (PIP) Submission in
Europe
16 March at 10:00 am ET
Speaker: Susan Bhatti, Ph.D.
▪ Guidelines for Effective and Appropriate Pediatric Assent and
Parental Permission
13 April at 11:00 am ET
Speakers: Angi Robinson and Elizabeth Jay, RN, MA
▪ Pediatric Considerations beyond Assent
11 May at11:00 am ET
Speakers: Krista Armstrong, Ph.D. and Patricia Molloy, M.D.
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

32. Questions?
Charlene Sanders, M.D.
Vice President,
Global Regulatory Affairs and Pediatric Strategic Consulting
Centre Square West
1500 Market Street, Suite 3500
Philadelphia, PA 19102
Telephone: 215.282.5476
charlene.sanders@premier-research.com
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES