New Medicines, New Initiatives the US Perspectives

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New Medicines, New Initiativesthe US Perspectives
Murray M. Lumpkin, M.D. Deputy Commissioner
International and Special Programs US Food and
Drug Administration Annual Meeting Faculty of
Pharmaceutical Medicine London, UK 29 November
2007
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Paediatric Drug Development and FDA Paediatric
Initiatives
Murray M. Lumpkin, M.D. Deputy Commissioner
International and Special Programs US Food and
Drug Administration Annual Meeting Faculty of
Pharmaceutical Medicine London, UK 29 November
2007
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OVERVIEW OF PRESENTATION

• Statement of Problem
• Historical Overview
• Examples of What we have learned
• European and US Activities

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The Problem At the end of the 20th Century

• There is inadequate information regarding
  Pediatric use for almost 3/4 of prescription
  medications.
• Gilman Clinical Pharmacokinetics 1992

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OFF-LABEL USENational International Problem

• Approximately 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 paediatric use 1984-1989 Survey,
  1991-2001 Repeat Survey
• 38 of new drugs potentially useful in
  paediatrics were labeled for children when
  initially approved 1991-1997, FDA statistics
• Wilson,JT Pediatrics 104, No3. Sept. 1999

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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 adultsNEJM 34718 (October 31, 2002)
1462-70
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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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THE PROBLEMN1

• Ignorance is poor public policy and yet
• it best describes what has been the status of
  our understanding of how best to use therapeutics
  in the paediatric population.
• Each child becomes an experiment of 1. There is
  no methodical data accrual to guide safe and
  efficacious drug administration and few if any
  controlled trials to test the current prescribing
  hypotheses or benefit/risk profile.

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Past Misadventures in Paediatric 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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Kearns et al., NEJM 349 1160
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(No Transcript)
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HISTORY LESSONS

• Products must be safely manufactured
• Products must tell you what is in them
• Products should not harm you
• Products should do what they say they will do
• Products to be used in children should in most
  cases be studied in children

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Biologics Control Act of 1902

• Diphtheria antitoxin was made by inoculating
  horses with increasingly concentrated doses of
  diphtheria bacteria, then bleeding the animals to
  obtain their blood serum, which was bottled as
  antitoxin
• Possibilities for contamination were vast in the
  production process
• In 1901, thirteen children in St. Louis died
  after receiving diphtheria antitoxin contaminated
  with tetanus spores
• This tragedy spurred Congress into passing the
  Biologics Control Act.

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1906 Pure Food and Drugs Act

• Medicines from the 19th century contained
  dangerous substances
• Mrs. Winslow's Soothing Syrup
• "For children teething. Greatly facilitates the
  process of Teething will allay ALL PAIN and
  spasmodic action, and is SURE TO REGULATE THE
  BOWELS. Depend on it, Mothers, it will give rest
  to yourselves and RELIEF AND HEALTH TO YOUR
  INFANTS.
• Contained alcohol and morphine sulfate Causing
  coma, addiction death in infants
• Pure Food and Drugs Act prohibited interstate
  commerce in adulterated or misbranded drugs

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1938 Food, Drug and Cosmetic Act

• Elixir of Sulfanilamide introduced in September
  1937
• Compounded with an untested solvent, diethylene
  glycol (chemically related to antifreeze)
• Caused 107 deaths including many children
• President Roosevelt signed the Food, Drug and
  Cosmetic Act on June 25, 1938
• Firms had to prove to FDA that any new drug was
  safe before it could be marketed

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1962 Kefauver-Harris Amendment

• 1960 a New Drug Application was filed with FDA
  for Kevadon (thalidomide), which had been
  marketed in Europe since 1956
• FDA felt that the data were incomplete to support
  the safety (concern was neurotoxicity)
• 1961 the drug was pulled off the market in Europe
  because of congenital anomalies
• Over 20,000 Americans received thalidomide under
  the guise of investigational use
• 1962 Kefauver-Harris Amendment that manufacturers
  had to prove efficacy as well as safety

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Amendments 1960s

• Kefauver-Harris Amendments - the most significant
  changes in the Food, Drug and Cosmetic Act
• Premarket efficacy and safety
• Good manufacturing practices
• Prescription drug advertising

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The Knowledge Gap in Paediatric Therapeutics

• How did we get to this state of ignorance?
• Why was it acceptable that a population that is
  growing, developing and inherently highly
  variable would not be studied while the more
  stable, not growing, and less variable adult
  population was?

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The Knowledge Gap Possible Reasons

• Ethical concerns
• Limited populations for certain diseases
• Difficulties in conducting trials in paediatrics
  logistical to technical reasons
• Lack of infrastructure in all arenas
• Belief dosing could be determined by weight based
  calculations (little adults)
• Lack of accepted endpoints and validated
  paediatric assessment tools
• Limited marketing potential compared to adults

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HOW ARE PAEDIATRIC TRIALS MORE DIFFICULT

• Many age subsets require studies, not just one
  study covers all of pediatrics
• Children tend to be healthy and the products are
  not as often for chronic use
• Small populations mean many centres 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 only a child but the entire family is
  involved

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FDA and Paediatric Health

• These crises involved children, but resulting
  laws actually benefited adults
• Information on use of therapeutics in children
  remained inadequate
• Finally, in the late part of the 20st century,
  political action, especially from paediatricians,
  resulted in laws being enacted to address
  specifically drug use in children

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Change in Perspective

• Change from Protecting children from clinical
  trials to Protecting children with clinical
  trials
• Standards for authorisation and usage children
  are not second-class citizens.

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Acronyms

• FDAMA Food and Drug Administration
  Modernization Act (1997)
• BPCA Best Pharmaceuticals for
  Children Act (2002)
• PREA Pediatric Research Equity Act
  (2003)
• FDAAA - FDA Amendments Act (2007)

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Benchmarks Pediatric Drug Development

• 1977 AAP statement concerning the need to
  conduct trials in children
• 1979 FDA labeling recognises children as not
  little adults unintended consequences
• 1994 FDA requires sponsors to update
  label introduces" extrapolations

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Benchmarks Pediatric Drug Development

• 1996 - FDA proposes paediatric rule
• 1997 Congress passes FDAMA
• Exclusivity Provision
• Incentives / voluntary
• 1998 FDA publishes Paediatric Rule
  (mandatory)

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Benchmarks Pediatric Drug Development

• 2002 Congress passes Best Pharmaceuticals
  for Children Act (BPCA)
• Voluntary Incentive reauthorised
• Added off-patent study process
• Required public posting of results
• Required 1 year public review of ADRs
• Created the Office of Pediatric Therapeutics
• 2003 Court overturned Pediatric Rule

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Benchmarks Pediatric Drug Development

• 2003 Congress passes Pediatric Research Equity
  Act
• Required the study of drugs AND biologics except
  in certain circumstances
• Created full pediatric advisory committee
• 2006 Developed Paediatric Cluster with EMEA
• 2007 Both BPCA and PREA set to expire on 01 Oct
• The legislative effort is in full swing
• This time as part of an omnibus FDA law
• This time not federal budget neutral
• 2007 Both BPCA and PREA re-authorised for 5
  more years

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Process for the Study of On-Patent Drugs
Industry submits a Proposed Pediatric Study
Request (PPSR)
FDA determines public health benefit to support
pediatric studies
yes
Industry agrees to conduct studies
FDA issues (WR) Written Request
yes
Industry declines to conduct studies
no (BPCA)
Industry has 180 days to respond
Referral to Foundation for NIH
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Goal of BPCA
On-Patent Process and Off-Patent Process New
Paediatric Information in Label Dissemination

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2003 Pediatric Research Equity Act (PREA)

• Became law December 3, 2003
• Legislation mimics Pediatric Rule of 1998
• Requires paediatric studies for certain
  applications
• Retroactive for all applications back to April 1,
  1999

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PREA vs. BPCA

• PREA
• Studies are required
• Orphan drugs designated exempt
• Studies limited to drug/indication under
  development
• Waivers / deferrals
• 10-1-07 Sunset
• RENEWED

• BPCA
• Studies are voluntary
• Includes orphan drugs and orphan drug indications
• Studies on whole moiety
• Public Summary of Data
• Public 1 year safety review
• 10-1-07 Sunset
• RENEWED

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Results
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Paediatric Exclusivity Stats (December 2006)

• Exclusivity Initiative (BPCA)
• Proposed Paediatric Study Requests 492
• Written Requests Issued 336
• Exclusivity granted 125
• Products with studies submitted 144
• New labels 122!!!

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Paediatric Exclusivity Stats (December 2006)

• Studies Requested 782
• Efficacy/Safety (34) 260
• PK/Safety (28) 220
• PK/PD/Safety (8) 64
• Safety (16) 118
• Other (14) 120
• of studies with patients specified 502
• of patients 45,700

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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 paediatric safety issue
• Many of the studies have raised more issues
• Long term safety and effects on growth, learning
  and behaviour continue to be understudied
• Neonates still remain mostly unstudied as to the
  safety and efficacy of the therapies being used
  to treat them

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What Paediatric Trials Have Taught(what we were
doing before we knew better)

• Unnecessary Exposure to Ineffective Drugs
• Ineffective Dosing of an Effective Drug
• Overdosing of an Effective Drug
• Undefined Unique Paediatric AEs
• Effects on Growth and Behaviour

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Exclusivity Summary of On-Patent Drugs(2006)

• Efficacy or Safety NOT ESTABLISHED 24
• Dosing Changes/Recommendations 25
• New/Enhanced Safety Information 35
• New Paediatric Formulation/prep 12 / 6
• New Lower Age Limit 82

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Inability to Demonstrate Effectiveness

• Temozolomide Recurrent brain stem glioma,
  astrocytoma other tumours
• Vinorelbine No meaningful clinical activity in
  46 patients with recurrent solid tumours
• Fludarabine Data insufficient to establish
  efficacy in
• any childhood malignancy
• Tolterodine 2 randomised trials involving 710
  children 5-10 years old

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Inability to Demonstrate Effectiveness (contd)

• Glyburide/Metformin Combination not superior to
  either component
• Leflunomide 68 of drug vs 89 of comparator
  demonstrated improvement in polyarticular JRA
• Irinotecan Trial halted in untreated
• rhabdomyosarcoma because of high rate of
  progressive disease
• Sumatriptan 5 trials in 12-17 year olds when
  compared to placebo
• Zolmitriptan 12-17 year olds in placebo
  controlled trial

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Inability to demonstrate effectiveness (contd)

• Sirolimus Though SE were established for gt13yo
  at low or moderate immunologic risk, SE for
  lt13yo or in paediatric renal transplant
  recipients at high immunologic risk have not been
  established.
• Gemcitabine No meaningful clinical activity
  observed in a phase 2 trial in 22 patients with
  relapsed ALL and 10 with AML
• Linezolid Because of variable CSF levels in
  patients with shunts, use of the product for
  empiric treatment of paediatric patients with CNS
  infections is not recommended

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Inability to demonstrate effectiveness (contd)

• Ertapenem Approved down to 3 months but not
  recommended in the treatment of meningitis due to
  lack of sufficient CSF penetration
• Rosiglitazone There was an insufficient number
  of patients to establish statistically whether
  the mean treatment effects were similar or
  different

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Ineffective Dosing of an Effective Therapy

• Higher dosing required for adolescents taking
  fluvoxamine and children lt5 years taking
  gabapentin
• Higher clearance of benazepril in hypertensive
  children
• Double the clearance rate of remifentanil in
  neonates

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Overdosing of an Effective Therapy

• Dosing of fluvoxamine in girls 8-11 years of age
• Reduced clearance of leflunomide in pediatric
  patients lt40 kg
• Decreased clearance of famotidine in infants 0-3
  months of age and of lamivudine for HIV in 1 week
  old neonates

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Undefined Unique Paediatric Adverse Effects

• Occurrence of rare seizures in patients without a
  prior history of seizures when exposed to
  sevoflurane
• Increase of suicidal ideation with
  ribavirin/intron A

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New Adverse Events

• Accutane bone demineralisation
• Elidel increase in infections, fever
  diarrhoea
• Gabapentin emotional lability, hostility and
  thought disorder
• Propofol increased mortality in PICU sedation
  study serious bradycardia when used with
  Fentanyl
• Antidepressants - suicidality signal

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Effects on Growth and Developmental Behavior

• Tolterodine Hyperactive behaviour and attention
  disorder occurred 3 times as frequently in
  treated vs. placebo population
• Gabapentin Neuropsychiatric AEs identified in
  3-12 year olds, including aggressive behaviour
  and school problems

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Growth and Development

• Fluoxetine 19-week trial, effects on ht wt
  were statistically significant
• Venlafaxine 18 vs 3.6 in placebo had wt loss
  height increase 0.3 vs 1cm in placebo.

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Growth and Development

• Atomoxetine weight percentile decreased over 18
  months of treatment and appeared to be correlated
  with poor metabolisers
• Ribavirin/Intron Hepatitis C trial - decrease
  in rate of linear growth during 48 weeks of
  treatment. Reversal in 24 wks post-treatment

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What Have We Learned?

• Historically drugs have been used in children
  WITHOUT the same level of evidence as has been
  obtained for adults and these data confirm such a
  approach is not good public health policy
• Children are even more dynamic and variable than
  anticipated
• This legislation is having a positive impact on
  development of therapies for children
• These paediatric initiatives have identified some
  gaps in how much we dont know
• Trials have raised new ethical issues

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ONGOING LESSONS LEARNED

• PK is more variable, even within the paediatric
  population, than anticipated
• Adverse reactions that are paediatric specific
  will not be defined without paediatric studies
• Trial designs are being modified as we learn from
  submitted studies
• Ethical issues have to be reassessed from the
  paediatric perspective
• Safety studies, of sufficient duration and longer
  term follow-up studies, remain problematic

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Ethical Issues

• Pediatric Advisory Subcommittee Meetings have
  addressed
• Patients vs. subjects in pediatric trials
  (11/15/99)
• Placebo controlled trials (9/11/00)
• Vulnerable pediatric populations (4/24/01)
• Consensus statements http//www.fda.gov/cder/pedi
  atric/index.htmadvisory

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General Principles ICH E-11

• Paediatric patients should be given medicines
  that have been properly evaluated for their use
  in the intended population
• Product development programs should include
  paediatric studies when pediatric use is
  anticipated
• Paediatric development should not delay adult
  studies nor adult availability
• Shared responsibility among companies, regulatory
  authorities, health professionals, and society as
  a whole
  

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You dont know what you dont know.

• Paediatric 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.

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EMEA US FDA Interactions

• Challenge is to assure children do not become
  commodities
• All WRs shared under our confidentiality
  arrangement
• PIPs now being shared with US FDA
• Paediatric cluster form under our
  implementation plan EDUCATION
• Draft guidances shared for comments

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FDA Web Page
Link to Peds page