The Perspective and Experience of the USA

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The Perspective and Experience of the USA

• Elias H Sarkis, MD, DFAPA
• Sarkis Clinical Trials
• Sarkis Family Psychiatry
• 529 NW 60th Street
• Gainesville, FL 32607 USA

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The PROBLEM

• Medications have NOT been studied in children
• Therefore, children receive unapproved and
  unstudied drugs
• Or do not receive potentially beneficial
  medications

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Case Example

• 1930s
• SULFANILAMIDE
• Massengil Pharmaceuticals
• 107 deaths by diethylene glycol poisoning

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Gainesville, Florida
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The Problem is Well Documented

• TJong
• 238 patients, 218 (92) received 1 courses of
  an unapproved drug Dutch Hospital
• 5 weeks 1 medium care, 3 intensive care units
• Shah
• 78.7 of 355,409 patients - at least 1 drug was
  used off label during the year of 2004
• 31 tertiary care not-for-profit hospitals
• Turner
• 3/4 of all medications are not approved by the
  Food and Drug Administration

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Factors That Impede Research in Children

• Ethical
• Technical
• Business

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Ethical Factors

• Vulnerable population
• Subjecting children to Clinical Trials
• Lack of informed consent
• Guidelines are not specific enough in this
  terminology
• Central Moral Problem
• Encourage research to promote the well-being of
  all children while at the same time protecting
  individual research subjects

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Technical Challenges in Conducting Trials in
Children

• Difficult to recruit
• Difficult to retain
• Difficult to predict response, side effects, and
  long-term consequences
• Lack of trained pediatric researchers

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Business Factors

• Trials are more expensive in children
• Market for children is small
• Unforeseeable long-term consequences

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University of Florida
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Timeline

• 1979
• FDA established a section for drug labels about
  pediatric use
• 1994
• FDA encourages drug companies to provide data on
  children
• 1990 1996
• Drug sponsors promised to complete 71
  post-marketing pediatric studies
• Only 11 were completed

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Timeline (p 2)

• 1997
• FDA Modernization Act
• Six month patent extension if drug companies
  complete clinical trials on children
• 1998
• FDA issues the Pediatric Rule
• Obligatory assessments of safety and efficacy

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Timeline (p 3)

• 2000
• Pediatric Rule challenged in US Federal Court
• 2000
• Childrens Health Act passed
• 2001
• New safeguards under the jurisdiction of the
  Department of Health and Human Services

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Timeline (p 4)

• 2002
• Best Pharmaceuticals for Children Act
• Six month patent extensions
• 2003
• Pediatric Research Equity Act
• Makes the Pediatric Rule federal law and gives
  the FDA more power

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Timeline (p 5)

• 2007
• Best Pharmaceuticals for Children Amendment
• Pediatric Medical Device Safety and Improvement
  Act

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The Swamp University of Florida
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Results

• 800 pediatric studies
• 45,000 subjects
• New pediatric information in drug labeling for
  119 drugs

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Results

• Efficacy and Safety
• New Formulations
• Higher Doses
• Lower Doses
• Lack of Efficacy
• Toxicity
• Unintended Consequences

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Efficacy and Safety

• HIV Medications
• Ziagan (Abacavir Sulfate)
• Ages 3 months 12 years
• Zerit (Staudine)
• Age of brith
• Videx (Didanosine)
• Age 2 weeks
• Glucophage (Metformin)
• Age 10 years 16 years
• Vasotec (Enalapril)
• Age 1 month 16 year
• Suspension

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New Formulations

• Abacavir Sulfate
• Versed (Midazolam)
• Neurontin (Gabapentin)
• Atovaquone
• Proguanil HCl

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Dosing

• Higher Doses
• Neurontin (Gabapentin)
• Trileptal (Oxcarbazepine)
• Age 2 years 4 years
• Lodine (Etodolac)
• Juvenile Rheumatoid Arthritis

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Dosing (p 2)

• Lower Doses
• Buspar (Buspirone)
• Betapace (Sotalol HCl) (B-Adrenergic Blocker)
• Versed (Midazolam)
• Congenital heart defects
• Pulmonary hypertension

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Lack of Efficacy

• Buspar (Buspirone)
• Effexor (Venlafaxine)
• Luvox (Fluvoxamine)
• Age 12 years 17 years
• But effective for age 8 years 11 years

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Toxicity

• Betamethasone
• Suppresses hypopituitary adrenal axis
• Skin atrophy
• Alphagan (Brimonidine tartrate)
• Somnolence in age 2 6 years
• Imitrex (Sumatriptan)
• Loss of vision
• Strokes

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Toxicity (p 2)

• Anesthetics in Neonates
• Diprivan (Propofol)
• Age lowered to 2 months
• Concerns in pediatric intensive care units
• SAE with Fentanyl
• Ultane (Sevoflurane)
• Age lowered to 1 month
• New onset of seizures

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Unintended Consequences

• Poorly done studies and non-disclosures of
  negative trials have led to anti-depressant
  black box warnings
• Decreasing prescriptions
• Increasing REAL suicides

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Future Directions

• Inability to regulate and enforce existing laws
  and regulations
• Post-marketing surveillance
• Disclosure of all Clinical Trial Data
• Pediatric Pharmacology Research Units
• Children and Adult Psychiatry Trials Network
  (CAPTN)

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Of Mice and Men

• In many ways, rats and mice get greater
  protection as research subjects in the United
  States than do humans."
• --Arthur L. Caplin
• Medical ethics chairman at the
• University of Pennsylvania.
  
• The Gainesville Sun , October 3, 2007

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Of Mice and Men (p 2)

• A devastating report from the inspector general
  of the Department of Health and Human Services
  gives the Food and Drug Administration low marks
  for its efforts to oversee the safety of millions
  of people who participate in clinical trials.
  With only 200 inspectors to cover more than
  350,000 testing sites, the FDA audits only rarely
  and almost never follows up to ensure that
  corrective action is taken when problems are
  detected. "We are working to address these
  problems very aggressively," Janet Woodcock, the
  FDA's chief medical officer, told The New York
  Times last week.
• That might be reassuring if only an auditor
  general's report in 2000 hadn't pointed out
  similar problems. Congress might want to look
  into the FDA's apparent disregard for the
  wellbeing of human guinea pigs.
• The Gainesville Sun , October 3,
  2007

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