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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Statistical Review and - CINRYZE

 

 Date:

Type/Application ID/Amendment #: STN 125267/18 Phase: 4

 Title: Cinryze

 Proposed Use (Indication): to evaluate the safety and efficacy of Cinryze (Cl inhibitor [human]) replacement therapy dose escalation to lower the RAE attack rate in inadequately controlled RAE patients

 Sponsor: LEV Pharmaceuticals

Product name(s)/Product Type:
Cinryze – C1 eserase inhibitor

 Review Team:
Charles Maplethorpe, M.D.
Nannette Cagungun

 From: Boris Zaslavsky, Ph.D.

Through: Ghanshyam Gupta, Ph.D.

cc: HFM-215/Henry Hsu
HFM-217/Ghanshyam Gupta
HFM-210/Steven Anderson
HFM-210/Robert Ball
HFM-215/Chronological File

Executive Summary: The sample size is estimated correctly for the one-sided test. The medical reviewer should decide whether the one-sided test is acceptable. If the two-sided test is recommended, the sample size should be increased to 32 patients.

Reviewer Title: Mathematical Statistician
Reviewer Signature:
Review Date:

Supervisory Concurrence:
Supervisor Title: Branch Chief

 Concur ______________ Not Concur ______________

Supervisory Signature:

Comments to the Draft Protocol

Protocol LEVP2008-1: Phase 4 Study to evaluate the safety and efficacy of Cinryze (Cl inhibitor [human]) replacement therapy dose escalation to lower the RAE attack rate in inadequately controlled RAE patients

The primary endpoint of the study is the estimate of the probability P that a patient meeting entry criteria and initiating the dose escalation algorithm will be classified as a success. Overall study success is defined as finding evidence consistent with P≥ 20%, where P≤ 5% is regarded as ignorable. Thus, the null hypothesis is that P ≤5% and the specific alternative hypothesis is that P≥ 20%. Based on this specification of hypotheses and a target type I error probability of one-sided 0.05 and a target power of 80% the following table defines the requi£red study size and provides the statistical operating characteristics:

The sponsor wrote:

 Null hypothesis (P = probability of individual patient success) P≤0.05
Alternative Hypothesis P> 0.05
Specific Alternative Hypothesis P≥0. 20
Target One Sided Type I Error Probability (alpha) < 0.05
Target Power >80%
Total Evaluable Patient Accrual Target  27 (computed from above using the binomial distribution)
Definition of  Hypothesis to be tested P≤0.05
Statistical  Significance level for testing hypothesis (one-sided) 0.05
Success (based on data collected) is the # successes for rejection in exactly 27 patients ≥4)

Statistical Operating Characteristics

True probability of success (P) Probability of study success
0.05 (null) 0.0437 (actual alpha)
0.10 0.282
0.15 0.593
0.20 (specific alternative) 0.818 (actual power)

Maximum half-width of exact 95% confidence interval for 27 patients equals ±21%

Minimum toxicity probability having Pr(occurring>1 time) ≥90% equals 9%

Comments to CBER:

The sample size of 27 patients is correct for the one sided Type I error 0.05.

Usual CBER standard is either two-sided 0.05 or one-sided 0.025 type I error. For the two-sided test, the sample size should be 32 patients or more.

I do not understand, why 4 out of 27 (4/27 = 0.148) is defined as success.