Lessons Learned from Growth Studies with Orally Inhaled and Intranasal Corticosteroids CS

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Lessons Learned from Growth Studies with Orally
Inhaled and Intranasal Corticosteroids (CS)

• Peter Starke, M.D., FAAP
• Division of Pulmonary and Allergy Drug Products
• Stephen E. Wilson, Dr.P.H., CAPT USPHS
• Division of Biometrics II
• March 24, 2005

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Outline

• Background and presumptions
• Growth studies
• Longitudinal growth studies
• Design issues and limitations
• Regulatory history and class labeling
• Results of longitudinal growth studies with
  intranasal and orally inhaled drug products
• Issues and conclusions

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Growth Studies Background and Presumptions

• Growth is an indicator of systemic exposure
  and of the potential to cause systemic toxicity
• Growth suppression is well known side effect of
  systemic CS use
• Class effect All CS given in sufficiently high
  doses
• Thought to be due to direct bone effect
• May also act through secondary mediators/hormones
• We believe that growth is the most sensitive
  indicator of systemic effect
• We have seen a growth effect even when an HPA
  axis study by cosyntropin stimulation was
  negative

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Growth Studies 2 Types

• Knemometry
• 2 to 4 week studies
• Methodological issues
• Consistency of results
• Primarily a research tool
• Longitudinal growth Long-term
• Designed to measure growth velocity over a 1 year
  treatment period
• Patient population -- need for chronic treatment
• Cannot have need for concurrent therapy with a
  drug that may influence growth

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Longitudinal Growth Studies Population

• Performed during relatively constant growth rate
  period between 3 to 9 -11 years

Source http//www.cdc.gov/growthcharts
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Longitudinal Growth Studies Measurements

• Growth rate measured by serial stadiometry
• Recommended periods
• Baseline 3 months
• On-treatment 1 year
• Follow-up 3 months
• Growth Guidance
• Draft Nov, 2001
• Now being finalized
• http//www.fda.gov/cder/guidance/index.htm

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Longitudinal Growth Studies Design Issues and
Limitations

• Technically difficult to perform
• Require large numbers of children
• Long baseline and treatment periods
• Measurement and compliance issues
• Statistical issues / recommendations
• Not superiority, equivalence, or non-inferiority
  trials
• Presumption of growth effect -- designed to best
  characterize that effect (i.e., the difference in
  treatment effect between active and placebo)
• N affects the 95 CI around the growth effect
• The size of the growth effect that is clinically
  relevant is unknown or not fully known

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Regulatory History

• 1996-97
• Two longitudinal growth studies were performed to
  better characterize the systemic risks prior to
  consideration of taking beclomethasone
  dipropionate (BDP) nasal spray over-the-counter
• Results of other growth studies submitted for
  orally inhaled products BDP, TAA, budesonide,
  and FP
• 1998 Joint Pulmonary-Allergy and
  Metabolic-Endocrine Advisory Committee
  recommended class labeling for all orally
  inhaled and intranasal corticosteroids
• AC recommendations implemented

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Recommended Class Labeling Precautions section

• General and Pediatric Use subsections
• Orally inhaled / Intranasal corticosteroids may
  cause a reduction in growth velocity in pediatric
  patients
• Pediatric Use subsection
• Growth effect may occur in the absence of
  laboratory evidence of hypothalamic-pituitary-adre
  nal axis suppression
• Potential for post-treatment "catch-up" growth
  has not been addressed
• Titrate to lowest effective dose for each patient
  and monitor growth routinely
• If reported, cases of growth suppression should
  be noted in the ADVERSE REACTIONS section

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Intranasal Beclomethasone Dipropionate (BDP)
Growth Study (CP93-048) Design

• Design
• Randomized, double blind, placebo controlled,
  parallel group, prospective, one year
• Inclusions
• Prepubertal children with allergic rhinitis
• Age 6-9.5 yrs
• Arms
• Intranasal BDP 168 mcg BID n49
• Placebo (vehicle) BID n49
• Information from Joint Pulmonary-Allergy and
  Metabolic-Endocrine Advisory Committee
  presentation of Dr. Saul Malozowski, 1998

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Intranasal BDP Growth Study (CP93-048) Results

• Results
• BDP 5.1 1.5 cm/yr
• Placebo 5.8 1.3 cm/yr
• Delta -0.7 cm/yr
• Statistically significant difference between
  treatment groups in mean annual growth rates
• In the same study, no significant differences
  were observed between treatment groups for mean
  basal cortisol or ACTH-stimulated plasma cortisol
  levels

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Intranasal BDP Growth Study (CP93-048) Results
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Intranasal Drugs (Growth rate in cm/year)
1 Data from studies in product labels
budesonide, fluticasone propionate, and
mometasone furoate monohydrate 2 Highest approved
dose 3 Lowest approved dose 4 Only approved dose
for 2-11 year age range (Approved dose ?12 y
200 mcg )
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Orally Inhaled Drugs (Growth rate in cm/year)
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Issues

• Difficult to perform and to review
• Growth studies are not designed to evaluate
• Reversibility of growth or HPA axis effects
• Changes gt1 year or effects on final adult height
• We have not identified a clinically relevant
  effect size

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Conclusions

• We use growth as a stand-alone measure
• Sensitive indicator of systemic effects
• HPA-axis and growth study results may be
  discordant
• Surrogate for systemic exposure and potential to
  cause systemic toxicity
• We believe the results are applicable to all age
  groups
• Class effect labeling
• All orally inhaled intranasal corticosteroids
• Results of submitted studies are added to labels,
  but the class labeling is not removed

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