FDA Presentation and

Discussion

Institute of MedicineFebruary 2, 2011

Topics• Pediatric Labeling

– Lisa Mathis, MD, and Nisha Jain, MD

• Pediatric Review Committee (PeRC)

RecommendationsRecommendations

– Lisa Mathis, MD

• European Union Legislation

– Julia Dunne, MD, and Dianne Murphy, MD

• Concluding Remarks

– Robert “Skip” Nelson, MD PhD

2

Pediatric Labeling

• 1979 – Pediatric Use subsection of labeling introduced

• 1994 – Requested sponsors to submit any • 1994 – Requested sponsors to submit any data and introduced extrapolation

• 2007 Labeling requirement under FDAAA

3

Evolution of Labeling

• Studies performed under PREA/BPCA are usually the only studies done in pediatrics.– Exception: sponsor seeking pediatric indication.

• Important to have information from completed studies in labeling regardless of outcome.studies in labeling regardless of outcome.

• Became policy (but not regulation, rule, or law) after BPCA 2002.

• PREA assessments not consistently incorporated until FDAAA 2007.– Unique labeling requirement for PREA PMRs

– Non-PREA PMRs may be submitted in many ways.4

Example of Pediatric Labeling: 2004

DIFLUCAN (fluconazole) indicated for treatment of:

1. Vaginal candidiasis (vaginal yeast infections due to

Candida).

2. Oropharyngeal and esophageal candidiasis. In open 2. Oropharyngeal and esophageal candidiasis. In open

noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of

Candida urinary tract infections, peritonitis, and systemic

Candida infections including candidemia, disseminated candidiasis, and pneumonia.

3. Cryptococcal meningitis.

5

Fluconazole

• 1/21/04 - Exclusivity granted for studies performed for treatment of tinea capitis.

• No evidence of these studies in labeling.• No evidence of these studies in labeling.

• Rational – primary efficacy endpoints not achieved, no new safety signals, thus no need for new labeling.

6

Imiquimod

• 03/22/2007 - Label approved after submission of

pediatric studies in response to a Written

Request.

• INDICATIONS AND USAGE: Limitations of Use: • INDICATIONS AND USAGE: Limitations of Use:

Efficacy was not demonstrated for molluscum

contagiosum in children aged 2-12.

• All information under section 8.4, Special

populations, pediatrics.

7

Approach to Labeling for Pediatrics• Are the new data sufficient to warrant a pediatric

indication?

• If yes, information incorporated into label in

applicable sections:applicable sections:

– Indications and Usage

– Dosage and Administration

– Adverse Reactions

– Use in Specific Populations – Pediatric Use

– Pharmacokinetics/Pharmacodynamics

– Clinical Studies8

Approach to Labeling for Pediatrics (con’t)

• If no, all information should appear in Use in

Specific Populations – Pediatric Use

– Will avoid implication of “approval”

– Contextual language may be needed to explain this.– Contextual language may be needed to explain this.

• Some older labels don’t have specific ages listed

in the indication.

• Some older labels have been revised several

times and do not follow this format.

9

10

Example: Tamoxifen• Indications: McCune Albright not mentioned (all breast

cancer indications without age)

• Pediatric Use: The safety and efficacy of NOLVADEX

for girls aged two to 10 years with McCune-Albright

Syndrome and precocious puberty have not been Syndrome and precocious puberty have not been

studied beyond one year of treatment. The long-term

effects of NOLVADEX therapy for girls have not been

established. In adults treated with NOLVADEX, an increase in incidence of uterine malignancies, stroke and

pulmonary embolism has been noted

• Adverse event: Information on safety findings from pediatric studies.

11

Tamoxifen in New Format• 8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

McCune-Albright Syndrome Limited data are available on McCune-Albright Syndrome Limited data are available on

the use of tamoxifen in girls with McCune-Albright syndrome and long term effects of tamoxifen use in girls

have not been established. A single, uncontrolled

multicenter trial of tamoxifen 20 mg once a day was

conducted in a heterogenous group of girls with McCune-Albright syndrome…

Safety information from studies included.

12

Pediatric Labeling For Biologics

• Staff trained in pediatrics

– Nisha Jain, M.D.

• Chief, Clinical Review Branch, Division of • Chief, Clinical Review Branch, Division of

Hematology, OBRR/CBER/FDA

– Stephanie Omokaro

13

Example of Change implemented

in CBER Pediatric Labeling• ARTISS (old Label)

– Indication and Usage:

• ARTISS is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations

• New label:

– ARTISS is indicated to adhere autologous skin grafts

to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than

or equal to1 year of age

14

FDA Decision Making:

The Pediatric Review Committee

Recommendations

Lisa Mathis, MD

15

Waivers

• Granted if legal criteria met– Most common reason is that the studies

would be impossible or impracticable because condition does not occur or is rare in children.condition does not occur or is rare in children.

– PeRC relies on data and tries to be reasonable.

– Limited number of patients not always a reason for waiver under this criteria as patients may be available for study.

16

Waivers (con’t)

• For the criteria that product would be unsafe or ineffective, we rely on data from studies (preclinical or clinical).

• For criteria that product would not provide • For criteria that product would not provide meaningful therapeutic benefit and would not be used in an adequate number of patients, we generally use 50,000 as “adequate” number.

17

Example: Waiver not granted

• NDA 22-090 Eovist® (gadoxetate disodium)

Injection for use in magnetic resonance imaging

(MRI) of the liver in adult patients to provide

contrast in the T1 weighted images to aid in the contrast in the T1 weighted images to aid in the

detection and characterization of focal liver

pathologies in pre-surgical evaluation.

• Approved 07/03/2008

– Required studies 2 years – 18 years

– Required studies for patients less than 2 years after

additional safety information collected due to renal elimination. 18

Reasons for Waiver9/27/2007- 9/30/2010

Total waivers requested/granted 324/253

Necessary Studies Impossible or Highly Impracticable 188

Evidence Strongly Suggests Product would be Ineffective and or Unsafe

26

Product Does Not Represent a Meaningful Therapeutic Benefit over Existing Therapies and Is Not Likely to be Used by a Substantial Number of Pediatric Patients

42

Reasonable Attempts to Produce a Pediatric Formulation Necessary Have Failed

0

19

Deferrals

• Granted if criteria are met.

• Must be accompanied by plan

• If additional safety or efficacy information • If additional safety or efficacy information is needed, additional information needed must be a specified with a plan to obtain (for example, it is not enough to say that the product should be out on the market for a couple of years…)

20

Deferrals (con’t)

• Adult studies completed and ready for approval

– Most common reason.– Most common reason.

– All products can qualify for a deferral if

pediatric development is delayed.

21

Reason for Deferral9/27/2007- 9/30/2010

Total deferrals requested/granted 161/112

Ready for approval in adults 106Ready for approval in adults 106

Need additional safety or effectiveness data 12

Other 2

22

Complete Listing:http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm194030.htm

Pediatric Plan

• Data submitted to support dosing, safety, and efficacy of a product in the relevant population.population.

• 1 year ago, only 50% of applications had plans

– Often it is not that PREA is not addressed, but

more frequently that Sponsor seeks waiver

that is not supported.

23

Pediatric Plan (con’t)

• Rational product development requires planning and discussions.

• At time of application submission, law • At time of application submission, law requires “plan” defined in legislation as “a description of the planned or ongoing studies”

– Often very brief information on program.

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Pediatric Plan (con’t)

• If no Pediatric Plan is submitted:

– Communicate with Sponsor to address the deficiency.

– FDA could refuse to file application.

• FDA has not done this to date.

• FDA does not want to delay approval of therapy that would benefit adult patients.

– If deficiency not addressed, could take “complete

response” action rather than approval, requesting that Sponsor address PREA.

• FDA also has not done this to date.

• FDA does not want to delay approval of a therapy that would benefit adult patients

25

Complete Response (CR) Action• Prior to PDUFA IV, CDER took one of three actions in

response to an application

– Approve, Not Approve, Approvable

• CR provides more consistent and neutral mechanism to

convey that initial review of application complete and convey that initial review of application complete and

cannot be approved in its present form.

– Provides information on changes that must be made before an application can be approved.

• Resubmissions have two categories, Class 1 gets a 2

month review clock, Class 2 has a 6 month review clock

– Class 1 includes labels, changes in PMRs, minor chemistry issues, safety updates, minor reanalysis of data.

– Class 2 includes everything else.26

Written Requests (WRs)

• Most often issued in response to a Proposed Pediatric Study Request (PPSR) submitted by industry. submitted by industry.

• FDA must determine that there is a public health benefit to studying the product in the pediatric population.

• FDA will issue WRs without a PPSR.

27

Public Health Benefit

• Adding to a limited armamentarium.

• Improves ease of use.

• Potential safety or efficacy advantage.• Potential safety or efficacy advantage.

28

Written Request Statistics

PPSRs received 662

Written Requests Issued 396

Written Requests with PPSRs 320Written Requests with PPSRs 320

Written Requests without PPSRs 76

Incomplete Responses 302

Written Request Withdrawals 9

Written Request Amendments 467

29

European Union Legislation

Background

Julia Dunne, MD, and Dianne Murphy, MD

Legislative Process

• Co-decision procedure

– Commission, Council and Parliament

• Regulations• Regulations

– Legally binding on all Member States

– Little room for interpretation

• Directives

– Framework for harmonisation

31

Co-Decision Procedure

32

EU marketing authorisation (MA) procedures

• Centralized

– Submit Marketing Authorisation Application (MAA) to EMA

– CHMP appoints rapporteur & corapporteur to assess dossier

– Simultaneous EU MA in all EU Member States– Simultaneous EU MA in all EU Member States

• National

– Submit MAA to one Member State (MS)

– Mutual recognition procedure

• MS(s) recognise MA in a reference member state (RMS)

– Decentralised procedure

• Simultaneous MAA in >2 MSs. RMS-led assessment.

33

EU Paediatric Regulation

• Regulation (EC) No 1901/2006

• Entered into force 26 January 2007• Entered into force 26 January 2007

• Informed by US paediatric legislation

34

Elements of Paediatric Regulation

• Paediatric Committee (PDCO)

– Independent; external experts

• bound by confidentiality agreements

– Opinions are legally binding

• Paediatric investigation plan (PIP)• Paediatric investigation plan (PIP)

• Obligations

– PIP results/waiver/deferrals included for valid new MAA– also changes to existing MAs

– PIP submitted at end phase I in adults

• Incentives

– 6 months Supplementary Protection Certificate extension

35SLIDE 1 of 2

Elements of Paediatric Regulation

• Penalties

• Public paediatric clinical trials database

• New type of MA (PUMA)• New type of MA (PUMA)

• EU clinical trials network

• Paediatric research programme

36SLIDE 2 of 2

Committee interrelationships within EMA

EMA

PDCO CHMPOther committees

eg CAT, COMP

Scientific

advice working

group

Other committees

eg CAT, COMPOther committees

eg CAT, COMP

37

Interrelationship between PDCO and CHMP

Scientific advice MAA

CHMP

38

Non-clin Phase 1 Phase 2 Phase 3 Post approval

PIP

PDCO

Amendments Compliance

Major differences between US and EU paediatric legislation

• Timing of interaction between sponsor and

regulator different for US and EUregulator different for US and EU

• EU: Penalties for lack of a paediatric plan and

other transgressions

• EU: Single comprehensive plan (modifications)

• EU: Support for development of paediatric

networks

39

Timing in Paediatric Legislation

Pre

clin

ica

l P

ha

se

EC/EMA

PIP (all inclusive) Required for Filing

ND

A S

ub

mis

sio

n

Ma

rke

tin

g A

pp

rova

l

FDA

W r i t t e n R e q u e s t

Pre

clin

ica

l P

ha

se

ND

A S

ub

mis

sio

n

Ma

rke

tin

g A

pp

rova

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PostmarketingPhase One Phase Three

Phase Two

Pediatric Rule

PREA

PeRC

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EU Penalties

• Refusal to validate MAA if does not contain results

of PIP/deferral/waiver

– no validation = no review

• Refusal to grant SPC extension if • Refusal to grant SPC extension if

– paediatric submission does not comply with agreed PIP

– product is not authorised in all Member States

– paediatric information (+/-) is not included in the

summary of product characteristics (SmPC) [=US label]

41

Penalties EU

• Financial penalties

• “Naming and shaming”• “Naming and shaming”

• Third party rights

42

Single comprehensive plan

• All paediatric subsets

• All relevant (adult) indications

• Paediatric formulation(s)• Paediatric formulation(s)

But…

• PDCO cannot request modifications

• PDCO cannot require study of indications not studied in adults

43

EU Paediatric Regulation• Mandated Reports (Commission)

• By January 2013

– Experience acquired

– Inventory of medicines authorised for paediatric use– Inventory of medicines authorised for paediatric use

• By January 2017

– Economic impact analysis of rewards and incentives

– Analysis of consequences to public health

– Proposals for amendments

If sufficient data available, requirements for second report can

be fulfilled by 2013.44

FDA reports

• Economic return of clinical trials performed under the pediatric exclusivity program Li at al, JAMA 2007 Li at al, JAMA 2007

• FDA internal economic analysis of cost/benefits of 2 products studied under FDA pediatric exclusivity program

– In progress

45

Concluding Remarks

Robert “Skip” Nelson, MD PhD