## Vaccines, Blood & Biologics

# 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

** C**oncur ______________ 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.