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Phenylephrine Citizen Petition Statistical Evaluation of Effectiveness Submissions

Phenylephrine Citizen Petition Statistical Evaluation of Effectiveness Submissions. Nonprescription Drugs Advisory Committee Meeting Silver Spring, Maryland December 14, 2007 Stan Lin, PhD Division of Biometrics 4/OB/OTS. PEH 10 mg Effectiveness. Submissions Reviewed CP Meta-Analysis,

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Phenylephrine Citizen Petition Statistical Evaluation of Effectiveness Submissions

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  1. PhenylephrineCitizen PetitionStatistical Evaluation of Effectiveness Submissions Nonprescription Drugs Advisory Committee Meeting Silver Spring, Maryland December 14, 2007 Stan Lin, PhD Division of Biometrics 4/OB/OTS

  2. PEH 10 mg Effectiveness • Submissions Reviewed • CP Meta-Analysis, 8 studies; previously reviewed by FDA advisory review panel • CHPA Meta-Analysis, 7 of the 8 studies included in the CP meta-analysis

  3. PEH 10 mg Effectiveness • Submissions Reviewed • Report EMC140, Wyeth Consumer Healthcare: 3 previously unpublished studies conducted between 1967 and 1983 • Clinical study conducted by Schering-Plough in 2006

  4. Brief History • In 1976, the FDA published an ANPR in which the Advisory Review Panel on OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Products proposed phenylephrine (PEH) be classified as GRASE. • The Panel reviewed a total of 13 studies and concluded that 7 of the studies demonstrated PEH, 10 mg, to be effective in clearing the nasal airway (i.e., reducing nasal airway resistance,NAR). The other 6 studies did not show PEH to be effective at reducing nasal airway resistance.

  5. CP Meta-Analysis • The citizen petition (CP) was based on a meta-analysis of some of the studies previously reviewed by the 1976 advisory panel. However, the clinical endpoint used for the meta-analysis is the maximal reduction in nasal airway resistance measured periodically during the first two hours after administration of a single dose of phenylephrine hydrochloride (PEH) 10 mg.

  6. CP Meta-Analysis • Use of maximal reduction in nasal airway resistance is problematic • This endpoint was not mentioned in the studies reviewed by the panel, so • It was not the basis for the original design or analysis of the studies included in the meta-analysis. • May obscure differences throughout dosing interval.

  7. CP Meta-Analysis • This new endpoint is not appropriate to use for re-assessment of the efficacy of 10 mg PEH. • E.g., Trials might be designed differently

  8. Meta-Analysis • "All meta-analysis is post-facto. You only do it if you know you're going to win." –Bob Temple, Reg Briefing, 3/07 • Always a post-hoc re-assembly or re-analysis of already existing data. • Hypothesis formulating, but considered alone rarely provides confirmatory evidence (or lack of) without new data. • One issue of meta-analysis is the combinability of the results of studies • Data summarized should be sufficiently homogeneous.

  9. CHPA Meta-Analysis • 7 studies: Crossover design. • Primary Endpoint: Reduction in NAR in 0-60 minutes.

  10. CHPA Meta-Analysis • Evidence exists for treatment by study interaction at the different time points where NAR was measured. This indicates heterogeneity in the studies and/or their outcomes and potentially limits the poolability of data across the studies. • Note: Since these studies were included in the CP meta-analysis, heterogeneity affects that meta-analysis as well.

  11. CHPA Meta-Analysis • Of the 4 studies which showed efficacy of 10 mg PEH, 2 were conducted at the same site, the Elizabeth Biochemical Laboratory. • The same laboratory also studied efficacy of other doses of PEH.

  12. CHPA Meta-Analysis • All Elizabeth studies showed relatively stronger efficacy whatever dose was studied. Averaging these studies with other studies would mask a finding of no effect from the other studies. • With limited replication of positive findings from other sites, the lack of multicenter representation of the small studies at the Elizabeth Biochemical Laboratory limit the generalizability of its results.

  13. Summary: CP and CHPA Meta-Analyses • Neither analysis is conclusive for the effectiveness of PEH 10 mg. • The CP meta-analysis generates new hypothesis with the maximum reduction in NAR as endpoint of effectiveness. • Its effect discrimination properties. • New studies needed on the maximal reduction of NAR over time.

  14. Other Submissions • Neither the Schering-Plough study nor the Wyeth Report, EMC 140, contributes useful data on NAR for PEH 10 mg (basis of CP) • EMC 140: 1) AHR-G1A, Single blind, no Pbo Crtl, 8 subjects on PEH 10 mg 2) Study 7032, 8 subjects, 8-way crossover, no difference from placebo 3) AHR-4010-3, 1 of 6 centers measured NAR, 12 subjects. Showed significant difference in total NAR 30-180 min (not clearly explained how) • SP: 3-way crossover, single-center, SAR patients 6 hrs in chamber, 38/39 completed. No difference from pbo in primary endpoint of symptom scores. (NAR not measured)

  15. Additional slides

  16. The Studies and Cross-references

  17. Existing wording of the FR dated 8/23/94: phenylephrine HCl • On page 43410 under section (1), Oral, nasal decongestants – (i) For products containing phenylephrine hydrochloride identified in 341.20 (a) (1) is as follows: "Adults and children 12 years of age and over: 10 mg every 4 hours not to exceed 60 mg in 24 hours. Children 6 to under 12 years of age: 5 mg every 4 hours not to exceed 30 mg in 24 hours. Children 2 to under 6 years of age: 2.5 mg every 4 hours not to exceed 15 mg in 24 hours. Children under 2 years of age: consult a doctor." • Bitartrate listed 8/1/2006

  18. Efficacy and Safety of Oral Phenylephrine: Systematic Review and Meta-AnalysisPublished Online, 30 January 2007, www.theannals.com, DOI 10.1345/aph.1H679.The Annals of Pharmacotherapy: Vol. 41, No. 3, pp. 381-390. DOI 10.1345/aph.1H679 "Based on 8 unpublished studies that included 138 patients, phenylephrine 10 mg did not affect NAR more than placebo; the mean maximal difference in relative change from baselinebetween phenylephrine and placebo was 10.1%, [95% confidence interval, (-3.8%, 23.9%)]. Eight unpublished studies on phenylephrine 25 mg showed a significant reduction of maximal NAR compared with placebo of 27.6% (95% CI 17.5% to 37.7%)."

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