Statistical Review for Hylaform

1
Statistical Review forHylaformPMA P030032

• General and Plastic Surgery Devices Panel
• November 21, 2003
• Phyllis M. Silverman, M.S.
• Division of Biostatistics, OSB

2
Outline

• Study Design Strengths
• Patient Accountability
• Study Hypotheses and Sample Size
• Primary Efficacy Results
• Secondary Efficacy Analysis
• Poolability
• Per-Protocol Analysis
• Safety
• Concerns
• Conclusion

3
Study Design Strengths

• Prospective
• Randomized
• Concurrently controlled
• Multiple evaluators
• Validated grading scale
• Masked evaluations
• Balanced treatment groups

4
Patient Accountability

• 261 Patients randomized / 255 completed 12
  weeks (130/133 Hylaform, 125/128 Zyplast)
• 7 Hylaform and 8 Zyplast patients did not have
  12-week IPR scores and were excluded from the
  primary efficacy analysis (in addition to the 6
  withdrawals)
• Per-protocol population consisted of 115 Hylaform
  and 109 Zyplast patients

5
Study Hypotheses and Sample Size

• Study designed to test both non-inferiority and
  superiority
• Non-inferiority window (delta) was 0.5 points on
  a 6-point scale
• Superiority requirement was a full 1.0 point
  advantage
• Sample size provided 80 power for
  non-inferiority and 95 power for superiority

6
Primary Efficacy Results

• Unadjusted Mean of median IPR scores at 12 weeks
  was 2.3 for Hylaform and 2.2 for Zyplast
• Lower bound of 97.5 C.I. for adjusted difference
  (Zyplast Hylaform) was 0.38
• Hylaform less than ½ point inferior
• Analysis based on ITT population
• Analysis adjusted for baseline differences and
  within patient correlation
• Superiority criteria not met

7
Secondary Efficacy Analyses

• Proportion of patients who experienced at least a
  1-point improvement at 12 weeks was 9.5 for
  Zyplast and 4.1 for Hylaform - not
  statistically significant for this sample size
• Investigator live severity score and
  investigator and patient global assessments were
  extremely close between Hylaform and Zyplast
  (i.e.1/10 pt)

8
Poolability

• Subgroup analyses performed for smoking history,
  and sun exposure
• Pooling of these subgroups acceptable
• No treatment by site interaction
• Pooling across sites acceptable

9
Per-Protocol Analysis

• 18 Hylaform and 19 Zyplast patients excluded for
  major protocol deviations
• 115 Hylaform and 109 Zyplast in per-protocol
  population
• Lower bound of 97.5 C.I. for adjusted difference
  (Zyplast-Hylaform) was -0.36
• Non-inferiority criteria met for per-protocol
  population

10
Safety

• Incidence of adverse events identical in each
  group (88)
• Most were mild
• Study not sized to detect subtle differences
  between treatments
• Safety profile addressed by clinical reviewer

11
Concerns

• Performance of Hylaform in all skin types
• 94 of study subjects were women
• 80 were Caucasian
• Duration of correction is short

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Number () of Folds Returned to Baseline
Hylaform Zyplast
2 Weeks 95 (38.2) 54 (21.9)
4 Weeks 138 (56.1) 63 (26.3)
8 Weeks 175 (68.9) 112 (46.7)
12 Weeks 178 (73.3) 151 (65.1)
denominators vary slightly depending on visit denominators vary slightly depending on visit denominators vary slightly depending on visit
13
Conclusion

• Well-designed and analyzed clinical study
• Data support the non-inferiority of Hylaform to
  Zyplast for treatment of nasolabial folds
• Superiority criteria not met
• Longevity should be evaluated from a clinical
  perspective