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Update: USA Pediatric Drug Development

Dr. Dianne Murphy, Director
Office of Pediatric Therapeutics
March 28, 2007

OVERVIEW OF PRESENTATION

• Brief Historical Overview
• Brief Process Overview
• Ethical considerations
• BPCA Summary
• PREA Update
• Important Components

History of Pediatric Regulations/Legislation

• FDAMA Pediatric Exclusivity 1997
• Pediatric Rule Regulation 1998 (enjoined 2002)
• January 2002
  • January 2002
  • Best Pharmaceuticals for Children Act (BPCA)
• December 2003
  • Pediatric Research Equity Act (PREA)
• October 2007: Sunset for BPCA & PREA

BPCA vs. PREA

PREA

• Studies are required
• Orphan drugs designated exempt
• Biologics and Drugs
• Studies limited to drug/indication under development
• No focused post-marketing safety review
• No central review
• 10-1-07 Sunset 

BPCA

• Studies are voluntary
• Includes orphan drugs and orphan drug indications
• Drugs only
• Studies on whole moiety
• 1 year safety reviews
• Summary posted on Web
• Central review=PDIT
• 10-1-07 Sunset

BPCA: Before a Written Request (WR) is issued, we answer these questions.

• Public Health Benefit – yes
• Risk/Benefit appropriate – yes

Then we ask …

• What information do we need?
• In what age groups do we need the information?
• What studies are needed to obtain this information?

Process: BPCA

1. Sponsor makes proposal for WR. Division rejects, accepts, or modifies.     OR
2. Division develops WR independent of sponsor
3. Division presents WR to PDIT(Pediatric Team)
4. Office Director signs off on WR to sponsor
5. Sponsor accepts or declines.
6. If sponsor declines, may be sent to FNIH
7. There is tracking of applications submitted for an exclusivity determination
8. A summary of the studies is posted for all studies
9. There is a 1 year post exclusivity safety review

Process: PREA

1. Sponsor submits an IND for an adult indication
2. Division must decide if pediatric studies are needed and if they can be deferred or if pediatric studies can be waived.
3. If studies are required the time table and general outline are decided before an action is taken on the application.
4. There may or may not be involvement of the pediatric staff. There is no central process.
5. There is no tracking of outcomes except as Phase 4
6. Only approved applications have studies posted
7. There is no mandatory post approval safety review

Selected Pediatric Ethics Activities

• Pediatric Ethical Consults
  • Sept 2003 – July 2006: approx. 80 consults
  • Topics: pediatric safety, compliance with Subpart D, parental permission and child assent, exception from informed consent applied to parents, use of “healthy” children, international studies
• Subpart D (additional protections for children) Referrals under 21CFR 50.54
  • Pediatric Ethics Subcommittee of Pediatric AC: FACA review of protocols referred by local IRBs for approval by FDA Commissioner and/or HHS Secretary
  • Since 2004: 3 reviews (prior OHRP non-FACA reviews=14)

Subpart D Pediatric Advisory Committee and Ethics Subcommittee Meetings

• September 2004: Effects of single dose Dextroamphetamine in ADHD and functional imaging
• June 2005: Precursor Preference in Surfactant Synthesis of Newborns
• November 2005: Gonadotropin Releasing Hormone Agonist Test in Disorders of Puberty

BPCA: Pediatric Exclusivity Stats
 (As of March 2007)

Products For Which FDA Requested Studies N=341

Products for which studies were submitted N=150

Label changes N=12

BPCA RESULTS: March 2007
N= 128 Labels

• New dosing or dosing change N=25
• New or enhanced safety data  N=35
• Efficacy and Safety NOT established N=28
• New dosing instructions in younger pediatric population   N=83

 BPCA: Pediatric Exclusivity Stats
 (As of December 2006)

• Number of patients requested for studies N= 45,700
• Products with Safety Reviews Presented to PAC N= 65
  • http://www.fda.gov/oc/opt/pediatricsafety.html
• Summaries of Medical/Clinical Pharmacology
  • Summaries on fda.gov/cder/pediatrics N=73
  • www.fda.gov/cder/pediatric/summaryreview.htm

BPCA: Pediatric Exclusivity Stats
(As of December 2006)

• 65 products had safety reviews presented to Pediatric Advisory Comm.
• 73 summaries of Medical/Clinical Pharmacology posted on web.
• 56 products placed on the BPCA off-patent priority list

BPCA: What Have We Learned?

• For almost 1/3 to 1/5th of 120 products studied:
  • there was new dosing information,  or
  • it was not effective, or
  • it had a new pediatric safety issue
• Many of the studies have raised more issues
• Long term safety and effects on growth, learning and behavior continue to be understudied
• Neonates still remain mostly unstudied as to the safety and efficacy of the therapies being used to treat them

Pediatric Research Equity Act
(PREA)

• Codified elements of 1998 Pediatric Rule
• Applies to certain applications submitted for disease/condition that occurs in both adults and children
• Requires studies of adult indications in pediatric age groups unless waived or defer
• Is triggered for drugs & biological products seeking to make certain changes
  • New indication  
  • New dosing regimen
  • New active ingredient
  • New dosage form
  • New route

PREA STATS: 2002-2006

• Applications within scope    N=553
• Waivers, partial or complete   N=317
• Deferrals, partial or complete N=185
• Approved with completed studies  N=147
• Approved and NOT associated with Exclusivity    N=55
• New pediatric labeling based on studies performed in pediatrics  N=40

PREA: What have we learned?

• Important component is making sponsors think of how the product will be used in the pediatric population early in the drug development process.
• There is a difference in the quantity and in some aspects the quality of the studies we have seen performed when compared to studies obtained under BPCA.
• We need to do a better job of tracking these studies and the resultant labels.

You don’t know what you don’t know   

Pediatric Drug Development: It is like turning over rocks and discovering how much you did not know about what was under the rock. The next problem is how to communicate what is under the rock and how to answer questions that arise from looking.

You don’t know what you don’t know.

Pediatric Drug Development: It is like turning over rocks and discovering how much you did not know about what was under the rock. The next problem is how to communicate what is under the rock and how to answer questions that arise from looking.

Important Components
of a pediatric program

• Labeling needs to inform the reader about the pediatric trials
• Public dissemination of the studies is important, irrespective of approval status
• Having focused pediatric safety reviews ensure pediatric issues are addressed
• Having a strong ethics program is critical

Published Information

• Transparency: JAMA, Sept. 13, 2006-vol 296, No. 10
  • 253 studies: 45% published; +label change for 50%.  Efficacy and + study more likely published
• Economics of BPCA: JAMA, Feb 7,2007-vol 297, No. 5 (reviewed 59 agents)
  • Cost range: 20M-600k; 12M per WR
• Changes over Time: Tufts Center for the Study of Drug Development. Vol.9, No.2-March/April 07
  • Increase in complexity; 30M per WR; differences

We are making progress!
Special Population

Reauthorization of BPCA and PREA

• FDA thinks these have been successful in providing new pediatric information on how best to use therapies in pediatrics.
• GAO Report made no official recommendations but commented on the useful information that has been developed
• AAP and 15 other organizations strongly support reauthorization with 7 “improvements”.  Transparency, labeling speed, increase pediatric information, expand post marketing safety review, enhancing role of NIH, permanent authority to FDA to require studies and address “blockbuster” issue.

GAO Report: Strengths

• Economic incentives to conduct pediatric trials
• Availability of Summaries
• Broad scope of pediatric drug studies
• Use of dispute resolution as a negotiating tool in ensuring labeling changes
• Improved safety through focused pediatric safety reviews.

GAO: Changes they had heard suggested for BPCA

• Timing of Pediatric Exclusivity: 180 days
• Submission of studies at least 1 year prior to patent expiration
• Interest groups would like the Written Request to be public information and for FDA to announce when it receives study results submitted in response to a WR
• More effective ways to study off-patent drugs
• Use of current fees to study off-patent

Small populations require the world  as a village for clinical trials.

We look forward to working even more closely with our European colleagues as you move forward with your pediatric program.

Presentations

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