U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy.

Use of the Fieller-Hinkley distribution of the ratio of random variables in testing for noninferiority.

We address the noninferiority assessment problem defined in terms of the ratio of population means in a parallel group design analysis of variance setting. The sample ratio as a point estimate of the corresponding population ratio has been considered. It has been shown that the Fieller-Hinkley distribution of the ratio of two correlated normally distributed random variables readily provide a technique for constructing confidence intervals comparable to the bootstrap percentile and Fieller's confidence intervals. A finite parameter space based level alpha test of an inferiority hypothesis formulated in terms of a fixed margin has been derived. We illustrate our approach using the forced vital capacity (FVC) data. We claim that it is easy to construct and straight forward to interpret our bootstrap equivalent confidence intervals that are used to assess noninferiority. We discuss appropriate methods for calculation of sample sizes.

New tests for null hypothesis of non unity ratio of proportions.

Testing for noninferiority and equivalence between an experimental therapy and a standard therapy in terms of the ratio of binomial proportions is considered. New tests based on the Fieller-Hinkley distribution of the ratio of random variables are proposed. Restricted maximum likelihood estimates of the null variances are used to derive the tests. Sample size determination is discussed. The proposed test procedure is extended to multiple tables. The tests are applied to numerical examples.