Pediatric Drug and Medical Device Development NIHNICHD CTSA meeting

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Pediatric Drug and Medical Device
DevelopmentNIH/NICHDCTSA meeting

• Dr. Dianne Murphy
• Director, Office of Pediatric Therapeutics, OC,
  FDA

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Topics

• Legislation Driving Pediatric Development
• Labeling as a Research Goal
• Biologics, Drugs and Devices each with its own
  set of laws and regulations
• Orphan Products its process
• Ethics Pediatrics is different
• Monitoring, Audits and Inspections
• New Driver European Legislation

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Acronyms

• FDAAA Food Drug Administration
  Amendments Act
• BPCA Best Pharmaceuticals for Children Act
• -WR Written Request (FDA issues)
  -PPSR Proposed Pediatric Study
  Request (sponsor submits)
• PREA Pediatric Research Equity Act
• PeRC Pediatric Review Committee
• FDAMA Food Drug Administration
  Modernization Act
• PIP Pediatric Investigational Plan

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A Decade of USA Pediatric Regulations/Legislation

• FDAMA Pediatric Exclusivity 1997
• Pediatric Rule Regulation 1998 (enjoined 2002)
• January 2002 FDAMA Exclusivity sunsets
• January 2002 Best Pharmaceuticals for Children
  Act (BPCA)
• December 2003 Pediatric Research Equity Act
  (PREA)
• October 2007 Sunset for BPCA PREA
• Sept. 2007 Food Drug Administration Amendments
  Act (FDAAA)

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The Goal Labeling

• The FDA and the American Academy of Pediatrics
  have sought pediatric clinical trials of the same
  caliber as those required for adults for products
  being used in children.
• The trials should result in labeling information.

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What That Means

• The data must be collected in a manner that will
  meet FDA standards
• The trial must be conducted in a manner that will
  meet FDA standards
• NIH and the Investigator functionally become the
  Sponsor for the submission.
• However, the label is owned by the product
  manufacturer and new information must be
  negotiated with the owner for inclusion in the
  label

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How a Drug Product might be studied in the
pediatric population

• Incentive Program (BPCA Exclusivity,
  On-patent)
• -Written Request Process (if sponsor accepts)
• -Declined WRs can be sent to NIH
• Requirement Program (PREA-adult indication)
• Off-patent or generic process (List and
  contracting process coordinated by NICHD)
• Orphans Program
• None of the above usually for product to treat
  pediatric disease or condition.

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FDA On-Patent BPCA Drug Process

• Background Research/Extensive Literature Review
• Sponsor
• Proposed Pediatric Development of Written Request
  by
• Study Request (PPSR) Reviewing Division
• Reviewed by PeRC
• FDA WR Issued(if declines
  NIH)
• Sponsor Completes Studies
• or FDA Exclusivity Determined by
• Exclusivity Board
• Action on Application

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ExtrapolationIf the disease and the expected
response to therapy are sufficiently similar in
adults and pediatrics ORbetween pediatric
subgroups
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Pediatric Study Decision Tree

• Reasonable to assume (pediatrics vs adults)
• similar disease progression?
• similar response to intervention?

NO TO EITHER
YES TO BOTH
Reasonable to assume similar concentration-respons
e (C-R) in pediatrics and adults?

• Conduct PK studies
• Conduct safety/efficacy trials

NO
NO
YES
Is there a PD measurement that can be use to
predict efficacy?

• Conduct PK studies to achieve levels similar to
  adults
• Conduct safety trials

YES

• Conduct PK/PD studies to get C-R for PD
  measurement
• Conduct PK studies to achieve target
  concentrations based on C-R
• Conduct safety trials

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Regulatory Environment for Pediatrics Within FDA
USA

• Pediatric process is different from that for
  adults in the following ways
• development of clinical trials Centralized
  activity, as of November 2007
• transparency of data Posting of negative
  results and information on negative studies in
  labeling

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Regulatory Environment for Pediatrics Within FDA
USA

• Pediatrics is NOT different as far as the
• scientific review,
• submission requirements and
• labeling process
• What is finally accepted as the labeling
  information must still be negotiated with the
  sponsor and is managed by the technical division

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New Pediatric Labeling Through December 2008

• Total BPCA PREA new Pediatric labeling N270
• BPCA Labeling changes N 159
• Expanded age n 95
• Safety and efficacy not established n
  50
• New/enhanced safety information n 45
• Specific dosing change/adjustment n 27
• Pediatric formulation n 16
• Extemporaneous formulation n 8
• PK differences (pediatrics vs. adults) n
  7
• Products with Safety Reporting N 88

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Differences FDA Centers

• LAW Federal Food, Drug and Cosmetic (FDC)
• Act of 1938 as outlined in Title 21 of the
  Code of Federal Regulations (CFR)
• CDER 21 CFR 312
• CDRH 21 CFR 812
• CBER 21 CFR 601
• CFSAN FDC Sections 409 and 412 (infant formula
  21 CFR 106 and 107)
• All have sections on Responsibilities for
  Investigators

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What is an Orphan Product?

• A product intended to treat a rare disease or
  condition affecting fewer than 200,000 persons in
  the United States
• or
• A product which will not be profitable within 7
  years following approval by the U.S. Food Drug
  Administration.

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The U.S. Orphan Drug Act Signed in 1983

• Established the public policy that the Federal
  Government could/would assist in the development
  of products for the diagnosis, prevention or
  treatment of rare diseases or conditions.

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To Obtain Designation

• Sponsor submits designation request to FDA/OOPD
• OOPD Staff Reviews Requests
• Criteria
• Is population lt200,000 in the U.S. (prevalence)?
• Is there rationale for the use of the drug in the
  proposed indication/disease/condition?

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OOPD and Pediatric Drug Development

• Pediatric Patients have long been recognized as
  therapeutic orphans
• Pediatric patients as a medically unique
  population for purposes of designation
• lt 200,000 pediatric patients in the US affected

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OOPD and Pediatric Devices

• OOPD manages the Humanitarian Use Device (HUD)
  Designation Program
• HUD designation is first step in obtaining a
  Humanitarian Device Exemption (HDE)
• Recent FDAAA legislation has lifted the HDE ban
  on making a profit for pediatric devices

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Why Humanitarian Device Exemptions?

• Premarket approval applications for new medical
  devices ordinarily must show that products are
  safe and effective.
• For very rare diseases, FDA will approve such
  devices if manufacturers demonstrate the safety
  and probable benefit to patients.

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OOPD and Pediatrics

• In Summary, OOPD supports the development of
  products for the pediatric population through
• Designations
• Humanitarian Use Device Program
• Grants

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Contacts

• 1. Request for HUD Designation
• Office of Orphan Products Development
  http//www.fda.gov/orphan/HUDS
• Contact Debra Lewis 301-827-0059
• 2. HDE application
• CDRH/ODE http//www.fda.gov/cdrh/ode/guidance/138
  1.pdf
• Contact Stephen Rhodes 240-276-4036

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Ethics and Pediatrics

• Children cannot volunteer for research
• Need either the prospect of direct benefit
  (50.52) or exposure to only a minor increase over
  minimal risk (50.53) otherwise, ask questions
• Subpart D Additional Protections for Children
  (21 CFR 50) is different than Subpart D of 312
  Responsibilities of Sponsors and Investigators

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21 CFR 50 56

• IRB Regulations for FDA
• 21 CFR 50 is Protection of Human Subjects
• 21 CFR 56 is Institutional Review Boards
• FDA does NOT have a waiver of parental
  permission, except for emergency situations under
  21 CFR 50.24
• 45 CFR 46 incorporates both IC and IRB
• Includes waiver of parental permission

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Quality

• Monitoring is the responsibility of the sponsor
  and investigator. You need to have evidence that
  it is independent (not involved in the trial),
  risk-based, and is responsive to problem
  identification.
• Maybe 1 of clinical investigations are visited
  by FDA
• Audits by FDA Bigger picture of conduct of
  overall program, not usually for just 1 study
• Inspections by FDA Data Audit may be part of it
  but usually it is an overview of a number of
  programs such as Genetic Studies.

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Resources

• BIMO- Google Bioresearch Monitoring and it will
  take you to FDAs page with Guidance and
  references
• Good Clinical Practices, E-6
• www.fda.gov/cder/guidance/index.htm
• www.fda.gov/cber/guidelines.htm
• Know your FDA regulations

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Pediatric Clinical Trials

• Why are pediatric trials more difficult?
• Why are pediatric trials often global?

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HOW ARE PEDIATRIC TRIALS MORE DIFFICULT?

• Many age subsets require studies, not just one
  study covers all of pediatrics
• Kids tend to be healthy and the products are not
  as often for chronic use
• Small populations mean many centers are required
  to enroll an adequate number of patients and
  studies often are international
• Special facilities, equipment, nurses,
  laboratories, and expertise are needed
• Children cannot consent. Often both parental
  permission and the childs assent are needed
• Healthy adults can volunteer for a study,
  children cannot
• You enroll not only a child- the entire family is
  involved

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Why Pediatric Drug Development is Global

• SMALLER PART OF THE POPULATION Children by
  definition occupy a lifespan for a shorter period
  of time than an adult. There are fewer of them.
• PROTECTED FROM STUDIES" Children cannot
  volunteer themselves the way adults can and
  children without a disease or condition are not
  usually involved in trials.
• LITTLE COMMERCIAL MOTIVATION for companies to
  answer questions by performing additional
  pediatric studies. Thus, there are fewer
  pediatric studies in a products development
  lifespan.
• fewer patients and a need for
• more experienced sites

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Principles of InteractionsEMEA and FDA

• Objectives
• Regular exchange of scientific and ethical
  information on pediatric development programs in
  Europe and the U.S.
• To avoid exposing children to unnecessary trials
• To inform each other of the scientific rationale
  when there are differences in approach
• To inform design/conduct of ongoing/future trials
  based on information obtained from previously
  conducted studies.

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EMEA-USA Pediatric Cluster

• TIME August 2007-December 2008
• EMEA Identified PIPS over 329
• USA and EMEA Topics for Discussion 126
• In Depth Discussions 55

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FDA and EMEA Triggers for Scientific Discussion

• Ethical or data integrity issues
• Safety concerns
• Different pediatric indications for development
• Pediatric study feasibility issues
• Pediatric studies completed (to avoid
  duplication)
• Outcome of pediatric studies, including negative
  studies.
• Marketing approval differences

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Drug Development Process
Phase 3 Efficacy-Safety
Phase 1 Dosing/Tolerability
Post-Marketing Requirements
Phase 2A Exposure-Response
Phase 2B Dose-Ranging
Pre-IND Meeting
EOP2A Meeting
EOP2 Meeting
Pre-NDA Meeting
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VISION

• That the goals of ICH E-11 be fully attained.
  Namely, that children receive therapeutics that
  have been evaluated in an appropriate, timely and
  ethical manner.
• To do this, we must work together.

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New FDA homepage www.fda.gov
Pediatric Therapeutics
MedWatch
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http//www.fda.gov/oc/opt/default.htm
http//www.fda.gov/oc/opt/default.htm
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