Good Medicine for Children BNF Prescribing Excellence Conference 2004

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Good Medicine for ChildrenBNF Prescribing
Excellence Conference 2004

• What are the challenges
• for the next 5 years?

Robert M. Ward, MD, FAAP, FCP Professor,
Pediatrics Co-Director, Pediatric Pharmacotherapy
Program University of Utah Chair, American
Academy of Pediatrics Committee on Drugs
1997-2001
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Ultimate Challenge Safe and Effective Drugs for
the Pediatric Population

• AAP Committee on Drugs. Guidelines for the
  Ethical Conduct of Studies to Evaluate Drugs in
  Pediatric Populations - Pediatrics 199595286

There is a moral imperative to formally study
drugs in children so that they can enjoy equal
access to existing as well as new therapeutic
agents.
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Challenge Proactive Education of the Public

• Many adults and the press dont seem to realize
  that children become sick with serious illnesses
  similar to adults and require drug treatment
• Drug treatment will occur either with or without
• careful study of dosages
• observation of the outcome
• reporting of results
• Off-label treatment usually indicates inadequate
  study

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Ethical BoundaryEnthusiasm vs Evidence

• All new drugs that are quite effective in adults
  will eventually be used to treat children.
• Is it more ethical to treat children with
  medications based only on adult data or to enroll
  them in carefully designed, pediatric studies
  with careful analysis of dosage, effectiveness,
  and adverse events that describe how to use the
  drug for all children with that disorder?

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Lessons from U.S. Regulatory Efforts To Increase
Pediatric Drug Studies

• Those who cannot remember the past
• are condemned to repeat it
• George Santayana, The Life of Reason,
• vol 1, 1905.

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Decreasing Pediatric LabelingIn the U.S.

• 75 of drugs lacked adequate pediatric labeling
  since 1969 despite efforts to increase pediatric
  study
• 1991 1996 1997 1998
• New Molecular
• Entities Approved 17 40 27 30
• With Pediatric
• Labeling 9 15 9 6
• 56 37 33 20

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Ineffective U.S. Efforts to Increase Pediatric
Study of Drugs

• 1994 Final Rule
• Encouraged pediatric studies labeling
• Voluntary
• Extrapolate efficacy to children from adults
  without additional study if the disease process
  is similar
• Few pediatric studies
• Few labels changed in a helpful way
• Results Safety and effectiveness in pediatric
  patients have not been established

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U.S. Efforts to Increase the Pediatric Study of
Drugs

• 1998 Final Rule FDA may require pediatric
  studies of marketed drugs and biologicals if it
• would provide a meaningful therapeutic benefit
• would be used in a substantial number of
  pediatric patients
• could pose significant risks without ped
  labeling
• Waivers granted if
• there are too few pediatric patients for study
• the study poses risk to pediatric patients
• the drug offers no therapeutic benefit
• Overturned in court, but renewed by Congress

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Congress Replaces 1998 Rule With a Law (AAP
Pivotal Role)

• Pediatric Research Equity Act, 2003
• For new active ingredient, indication, dosage
  form, dosing regimen, or route of administration
• The product must study be studied in all relevant
  pediatric populations for the claimed indications
  
• Deferral of pediatric studies if product is ready
  for release for adults
• Waiver if not effective in pediatrics, not used
  in significant number, or not a significant
  improvement over existing treatments
• Sunsets in 5 years unless renewed

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Successful U.S. Efforts to Increase the
Pediatric Study of Drugs

• FDA Modernization Act of 1997 (FDAMA)
• Provided incentives of 6 month extension of
  market exclusivity for pediatric studies if the
  information relating to the use of a new drug may
  produce health benefits in that population
• Only applied to new drugs with patent protection
• FDA specifies required studies in a Written
  Request (safety, efficacy, pK)
• Prioritized list of drugs needing pediatric study
• Advisory subcommittee for dispute resolution

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Challenges with FDAMA

• FDA Modernization Act of 1997 (FDAMA)
• Prioritizing a list of new drugs for pediatric
  study
• Large effort, little effect
• How do you rank need for treatment of different
  pediatric illnesses?
• Dermatology vs cardiovascular collapse
• Common childhood illnesses vs inborn errors of
  metabolism
• Almost every study yielded helpful information
  for pediatric therapy, so prioritization didnt
  add much value or stimulus to a volunteer program
  

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Best Pharmaceuticals for Childrens Act (BPCA) -
1/2002

• Renewed much of FDAMA improved FDAMA
• 6 months exclusivity
• Reinstated User Fees to fund the extra work
• Established an Office of Pediatric Therapeutics
  at the FDA (after 9/11 was combined with
  bioterrorism)
• Provided for dissemination of results of studies
• Provided a means to study older, generic drugs
  without patent protection through a NIH
  foundation

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New Challenges as Pediatric Drug Studies Increase

• Large regulatory workload
• Not enough sites/investigators
• Study design pediatric vs adult
• Unique medical issues
• Ethical issues
• Public misperceptions of
• Off-label treatment data to support current
  treatments
• Risk to children in studies
• Inform physicians of new data
• Workload for MD volunteers

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Not Enough Investigators and Sites

• University of Utah Pediatric Pharmacology
  Program, clinical trials since 1999
• 4 certified coordinators office staff
• Medical director - pediatric clinical
  pharmacologist
• Infrastructure to conduct trials of many types of
  medications for many faculty (hypertension to PDA
  in prematures)
• Funded years 1-2 by Childrens Hospital
  Foundation, but now sustains itself with industry
  NIH funding

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Challenge of Successful RegulationIncreased
Workload

• FDAMA Workload for FDA
• 663 Requested pediatric studies
• 286 Written Requests issued by the FDA
• 242 Written Request amendments
• 107 Exclusivities issued for 97 different drugs
• 70 Label Changes
• 41,359 Subjects in requested studies
• 5 Guidances
• www.fda.gov/cder/pediatric/

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Challenge for Regulatory Agency May Require
Support from RCP

• Unfunded Mandate to the FDA
• Few Pediatricians and Pediatric Subspecialists at
  the FDA
• Large increase in workload combined with a freeze
  on new hires and creating new advisory committees
• Create Sub-committees
• Pediatric staff worked overtime - all the time
• Developing Written Requests for pediatric studies
  required pediatric expertise that was not
  available in all areas
• BPCA increased revenues
• BPCA increased pediatricians at the FDA

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Challenge Increased Workload

• European Pediatricians
• Many meetings with physicians, drug
  manufacturers, and regulatory agencies outside
  your usual responsibilities
• Time to explain to the public how children remain
  second-class patients without more study of drugs
  to provide rational treatment
• Time to speak with the press who may be seeking
  information or your name and affiliation for a
  story that is already written critical of
  studying drugs in pediatrics

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Public Misperception of Pediatric Study of Drugs

• Drug studies are often perceived by the public to
  place children at increased risk
• All drug treatment, in a study or in clinical
  care, carries risk
• Close monitoring and controls associated with
  drug studies reduce risk
• Treatment outside of a study doesnt increase our
  knowledge systematically to improve future
  therapy
• Lack of study creates greater risk because
  current prescribing for pediatrics is often
  based on small studies in limited populations

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Public Understanding of Unlicensed (Off-label)
Treatment

• Press sometimes portrays unlicensed drug use as
  illegal or substandard treatment
• Parents and press (maybe even physicians) need
  education about what licensing (labeling) means
  doesnt mean
• The only way to have licensed pediatric drug
  treatment is through careful controlled study
  in pediatric subjects
• No data, no license

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AAP Committee on Drugs

• Uses of Drugs Not Described in the Package
  Insert (Off-Label Uses) - Pediatrics 2002110181
  
• Off-label use does not imply an improper use
  and certainly does not imply an illegal use or a
  contraindication based on evidence.
• Indeed, the practice of medicine may require a
  practitioner to use drugs off-label to provide
  the most appropriate treatment for a patient.

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Help Educate the PressHeadlines vs Healthcare
Gains

• Akron Ohio Beacon Journal - Alice Dembner,
  2/21/2001
• Experimenting on children-the deadly risks

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Help Educate the PressHeadlines vs Healthcare
Gains

• Wall Street Journal - Rachel Zimmerman, 2/5/2001
• Pharmaceutical firms win big on plan to test
  adult drugs on kids

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Increased Pediatric Drug StudyIssues for
Pediatrics to Address

• Ethical issues
• Placebos - when are they appropriate
• Conflict of interest among investigators and
  subjects
• Consent/assent
• Child friendly/appropriate study designs
• Which drugs deserve pediatric study
• Regulatory oversight of adverse events
• Serious adverse events require prompt reporting
  and evaluation

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Physicians Must Support Safe, Ethical Study of
Drugs in Children

• Adverse events will occur during studies--just as
  they occur during our usual drug therapy
• European physicians must support the highest
  standards for ethical safeguards and scientific
  study of drugs in the pediatric population
• Children must never become a commodity in drug
  studies.
• Policies and position statements should help the
  regulatory agencies develop appropriate pediatric
  safeguards and guidances that provide safe and
  effective drugs for children

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Medical Challenges Unanticipated Difficulties -
Oncology

• Endpoint of 5-year survival endpoint could not be
  studied through FDAMA before patent expiration
• 1 year after FDAMA was signed, no pediatric
  oncology written requests had been requested or
  issued
• Parent groups wanted pediatric studies now and
  threatened to legally disassemble FDAMA
• AAP sponsored meeting of NCI, FDA, Parent Support
  Groups, PhRMA (industry), Childrens Oncology
  Group (COG), St. Judes

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Challenges Unanticipated Difficulties - Oncology

• New FDA end-point reduction in tumor size vs 5
  year survival to measure efficacy
• Meetings every 3 months Pediatric oncologists in
  industry, NCI, FDA and COG to increase the study
  of new drugs in children
• NCI agreed to implement screening new drugs
  against pediatric tumor cell lines
• FDA issued Written Requests without waiting for
  companies to approach them about studies
• Appoximately 8 oncology drugs began pediatric
  study

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Increased Information from FDAMAFor Pediatric
Drug Therapy

• Important information resulted from the first 40
  moieties labeled
• 33 (12/40) of the last products labeled had
  significant changes in doses or risk
• 70 (28/40) of the last products labeled through
  FDAMA extended age and safety profile
• Propofol excess mortality for PICU sedation
• Gabapentin dosage inadequate for specific ages

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Challenge Dissemination of New Findings to the
Medical Community

• How do we communicate new indications, new
  dosing, new adverse events to physicians??
• No assurance that these will be published, and
  publication may take many months
• AAP is developing an internet-based Continuing
  Medical Education program to disseminate new
  information to physicians while providing credit
  for CME-needed for license renewal
• May feature label changes at annual meeting

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Pediatric Study ChallengesRequire Pediatric
Assistance

• Special therapeutic areas may require creative
  endpoints to apply to children
• Pulmonology measurement of pulmonary function in
  young children is difficult
• Dosage forms dont fit pediatric patients
• Analgesics for the preverbal infant child - may
  require special, creative endpoints or better
  validation of current analgesia evaluation tools

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Ultimate ChallengeUltimate Goal

• The first child treated with a new drug receives
  that treatment based on data that describe the
  optimal dosage and potential side effects
  developed prospectively during the drug approval
  process in similar aged patients.

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Examples of Significant Label Changes for
Pediatric Patients

• Tamoxifen females 2-10 yrs with McCune-Albright
  syndrome precocious puberty.
• Pravastatin, atorvastatin, simvastatin boys
  post menarchal girls, heterozygous familial
  hypercholesterolemia
• Atomoxetine ADHD down to 6 year (first
  non-stimulant drug labeled for ADHD)
• Vinorelbine No meaningful activity against a
  variety of solid tumors in pediatric patients
• Betamethasone cream, ointment corticosteroid
  responsive dermatoses NOT RECOMMENDED in
  pediatric patients lt12-17 years of age HPA axis
  suppression, skin atrophy