Pediatric Therapeutic Regulations and Trial Design

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Pediatric Therapeutic Regulations and Trial Design

• Dianne Murphy, MD
• Director, Office of Pediatric Therapeutics
• Office of the Commissioner, FDA
• November4-5th, 2008
• Copenhagen, Denmark

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Acronyms

• FDAMA Food and Drug Administration
  Modernization Act
• BPCA Best Pharmaceuticals for
  Children Act
• PREA Pediatric Research Equity Act
• WR Written Request (FDA issues)
• PPSR Proposed Pediatric Study Request
  (sponsor submits)

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AAP - 1977 Committee on Drugs

• 1. It is unethical to adhere to a system which
  forces physicians to use therapeutic agents in
  an uncontrolled experimental situation
  virtually every time they prescribe for
  children.
• 2. It is not only ethical, but also imperative
  that new drugs to be used in children be
  studied in children under controlled
  circumstances so the benefits of therapeutic
  advances will become available to all who need
  them

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Past Misadventures in Pediatric Therapy

• Oxygen (unique disease in preemies)
• - Significantly increased blindness
• Choramphenicol (metabolism)
• - Grey baby syndrome and death
• Postnatal steroids (development)
• - Increase in CP
• - Decrease in cortical brain growth

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Lack of Pediatric Information

• About 80 of listed medication labels disclaimed
  usage or lacked dosing information for children.
• Physicians Desk Reference 1973 1991 Surveys
• Only 20-30 of drugs approved by the FDA were
  labeled for pediatric use.
• 1984-1989 Survey, 1991-2001 Repeat Survey
• Only 38 of new drugs potentially useful in
  pediatrics were labeled for children when
  initially approved.
• 1991-1997, FDA statistics

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Kearns et al., NEJM 349 1160
7

• Recent data indicate that more children in the
  United States are taking prescription medications
  and that the annual percentage increase in
  spending on drugs is greater for children than
  for adults.
• NEJM 347(18)2002 1462-70.

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History 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

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The Food and Drug Administration Amendments Act
Sept. 2007

• FDAAA reauthorized the Best Pharmaceuticals for
  Children Act (BPCA) and the Pediatric Research
  Equity Act (PREA).
• New transparency mandates Entire Clinical Review
  posted
• Labeling required for both positive and negative
  studies
• Labeling and transparency mandates now apply to
  both BPCA and PREA
• Required coordination by Pediatric Committee
• Pediatric Safety reviews and public presentation
  extended to PREA products.
• FDAAA also enacted new pediatric medical device
  provisions.
• Significant new responsibilities for tracking and
  posting of certain information.

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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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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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PREA vs. BPCA

• PREA
• Studies are required
• Orphan drugs designated exempt
• Studies limited to drug/indication under
  development

• BPCA
• Studies are voluntary
• Includes orphan drugs and orphan drug indications
• Studies on whole moiety
• Written Request from FDA
• determines studies to be performed for
  exclusivity

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BPCA WR Highlights

• Questions FDA asks before Issuing a Written
  Request
• Is there a public health benefit?
• Is the risk/benefit appropriate?
• What information do we need?
• In what age groups do we need the information?
• What studies are needed to obtain this
  information?

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BPCA Highlights

• Is there a public health benefit?
• Serious life-threatening condition?
• How frequently does disease/condition occur?
• How often is this drug or others like it used in
  children?
• Offer a meaningful therapeutic benefit?
• Significant improvement in the treatment,
  diagnosis, or prevention of disease compared to
  already approved drugs?

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BPCA Highlights

• Is the risk/benefit appropriate?
• Risk Is there adequate safety data to move into
  pediatrics?
• Animal data?
• Adult data?
• Benefit Are there validated pediatric efficacy
  endpoints?
• Ethical considerations Subpart D (Code of
  Federal Regulations, 21CFR50.54, that gives
  additional protections for children involved in
  clinical trials).

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BPCA Highlights

• What information do we need?
• Historically, drugs have been used in children
  WITHOUT the same level of evidence as has been
  obtained in adults.
• In what age groups do we need the information?
• Need for age-appropriate pediatric formulations
• Neonates most understudied, greatest need.

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BPCA Highlights

• What studies are needed to obtain this
  information?
• Studies requested are driven by public health
  need and NOT by the approved adult indication
• Pediatric Study Decision Tree

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BPCA Highlights

• Public health benefit yes, appropriate risk
  benefit yes decision made on types of studies
  and age groups to study review by PeRC ?
  issuance of Written Request.
• A Written Request is a legal document that
  outlines studies requested by FDA.
• Exclusivity determination is made by FDA Board
  and is not an approval assessment
• Single WR may include uses that are both approved
  and unapproved.
• WR may include preclinical studies.

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BPCA 2007- Labeling Changes

• If FDA and applicant do not agree on labeling
  changes, the process for dispute resolution
  begins 180 days after the date of submission of
  the application
• Labeling must include all study results and FDA
  determination as to whether study demonstrated
  safe and effective use in children or was
  inconclusive (reflects current policy)
• The Toll-Free Number for Reporting Adverse
  Events on Labeling for Human Drug Products shall
  take effect January 1, 2008, unless an
  alternative is finalized before then.

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PREA Required Studies

• Required studies must be for the same indication
  as the adult application
• May be considered for exclusivity but more
  indications or other studies may be included in
  the Written Request
• PREA studies are now also going to a pediatric
  internal FDA committee (PeRC)
• for review

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PREA Substantial Number?

• PREA does not define a "substantial number." In
  the past, FDA generally has considered 50,000
  patients to be a substantial number of patients.
  The Agency, however, will take into consideration
  the nature and severity of the condition in
  determining whether a drug or biological product
  will be used in a substantial number of pediatric
  patients.

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PREA Meaningful Therapeutic Benefit

• a drug or biological product shall be considered
  to represent a meaningful therapeutic benefit
  over existing therapies if
• if approved, the drug or biological product could
  represent an improvement in the treatment,
  diagnosis, or prevention of a disease, compared
  with marketed products adequately labeled for
  that use in the relevant pediatric population or
• the drug or biological product is in a class of
  products or for an indication for which there is
  a need for additional options.

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PREA Criteria for Deferral

• FDA may defer submission of some/all required
  assessments until specified date after approval
  of drug or licensing of biological product
• Criteria for Deferral
• drug or biological product is ready for approval
  for use in adults before pediatric studies are
  complete
• pediatric studies should be delayed until
  additional safety or effectiveness data have been
  collected or
• there is another appropriate reason for deferral.

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PREA Criteria for Waiver full or partial

• full or partial waiver of required assessments
  with respect to specific pediatric age group if
  
• necessary studies impossible or highly
  impracticable (e.g., number of patients in age
  group so small or patients in age group
  geographically dispersed)
• evidence strongly suggests product ineffective or
  unsafe in all in that pediatric age group(s)
  or
• drug or biological product
• Not meaningful therapeutic benefit over existing
  therapies for pediatric patients in that age
  group and
• Not likely to be used in substantial number of
  pediatric patients in that age group.
• reasonable attempts to produce a pediatric
  formulation necessary for that age group have
  failed.

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PREA Specific Issues

• PREA studies are often tracked as Post Marketing
  Commitments
• If a waiver is because of a safety issue that
  information is to be included in label
• Reasons for not making a formulation are to be
  presented to FDA and discussed in the clinical
  review

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Important Componentsof a Pediatric Program

• Public Health needs should drive a process which
  is being indirectly funded by increased costs to
  governments and the public
• Labeling should inform the reader about pediatric
  trials conducted to determine safety, dosing and
  efficacy of a product or for devices, its proper
  use
• Public dissemination of the studies is important,
  irrespective of approval status
• A focused pediatric safety review ensures
  pediatric issues are addressed
• Having a strong ethics program is critical

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Pediatric Clinical Trials

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

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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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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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Extrapolation Unique to Pediatrics

• If course of the disease and effects of the drug
  are sufficiently similar in adults and pediatric
  patients, FDA may conclude that pediatric
  effectiveness can be extrapolated from adequate
  and well-controlled studies in adults, usually
  supplemented with other information obtained in
  pediatric patients, such as pharmacokinetic
  studies.
• A study may not be needed in each pediatric age
  group if data from one age group can be
  extrapolated to another age group.

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Pediatric Study Decision Tree (applies to BPCA
and PREA)

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

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Documentation of Extrapolation

• A brief documentation of scientific data
  supporting above conclusion shall be included
  in any pertinent reviews for the application.

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Results
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BPCA Exclusivity Accomplishments Through June 2008

• Written Requests issued N 360
• Products with safety reporting N 79
• Labeling changes N 149
• Expanded age n 90
• Safety and efficacy not established n
  46
• New/enhanced safety information n 43
• Specific dosing change/adjustment n 26
• Pediatric formulation n 15
• Extemporaneous formulation n
  7
• PK differences (pediatrics vs. adults) n 6

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BPCA What Have We Learned?

• For almost 1/3 to 1/5th of over 140 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
• A Focused pediatric post-marketing safety review
  will identify pediatric specific safety issues.
• Neonates still remain mostly unstudied as to the
  safety and efficacy of the therapies being used
  to treat them

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PREA What have we learned?

• There have been 76 new labels as of June 2008
  that were not associated with BPCA and were
  subject to PREA.
• 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.

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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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And together we might get this right!