# Presentation: 107114

## 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,**_** **
**	****8 studies; previously reviewed by FDA advisory review panel**
_**CHPA Meta-Analysis**__**, **_
**	****7 of the 8 studies included in the CP meta-analysis**

## 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**Report **_**EMC140**_**,  Wyeth Consumer Healthcare:  3 previously unpublished studies conducted between 1967 and 1983**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**

## Slide 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.**

## 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.**

## 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.**

## 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**

## 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.**

## CHPA Meta-Analysis

**7 studies: Crossover design.**
**Primary Endpoint: Reduction in NAR in 0-60 minutes. **

## 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.**

## 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.**

## 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.**

## 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.**

## 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)

## Additional slides

## The Studies and Cross-references

**The Studies and Cross-references**

## 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**

## "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 baseline between 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%)."

**"****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 baseline**_** ****between 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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