Biomedical subjects

Brian L Wiens

Publications and source records attributed to Brian L Wiens.

7 recordsLinked to original sources

PubMed2007

Tree-structured gatekeeping tests in clinical trials with hierarchically ordered multiple objectives.

This paper discusses a new class of multiple testing procedures, tree-structured gatekeeping procedures, with clinical trial applications. These procedures arise in clinical trials with hierarchically ordered multiple objectives, for example, in the context of multiple dose-control tests with logical restrictions or analysis of multiple endpoints. The proposed approach is based on the principle of closed testing and generalizes the serial and parallel gatekeeping approaches developed by Westfall and Krishen (J. Statist. Planning Infer. 2001; 99:25-41) and Dmitrienko et al. (Statist. Med. 2003; 22:2387-2400). The proposed testing methodology is illustrated using a clinical trial with multiple endpoints (primary, secondary and tertiary) and multiple objectives (superiority and non-inferiority testing) as well as a dose-finding trial with multiple endpoints.

Antihypertensive Agents↗

PubMed2005

First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study.

PURPOSE: We evaluated the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients. PATIENTS AND METHODS: Patients were randomly assigned to either placebo or pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m(2) docetaxel. The primary end point was the percentage of patients developing febrile neutropenia (defined as body temperature >/= 38.2 degrees C and neutrophil count < 0.5 x 10(9)/L on the same day of the fever or the day after). Secondary end points were incidence of hospitalizations associated with a diagnosis of febrile neutropenia, intravenous (IV) anti-infectives required for febrile neutropenia, and the ability to maintain planned chemotherapy dose on time. Patients with febrile neutropenia were converted to open-label pegfilgrastim in subsequent cycles. RESULTS: Nine hundred twenty-eight patients received placebo (n = 465) or pegfilgrastim (n = 463). Patients receiving pegfilgrastim, compared with patients receiving placebo, had a lower incidence of febrile neutropenia (1% v 17%, respectively; P < .001), febrile neutropenia-related hospitalization (1% v 14%, respectively; P < .001), and use of IV anti-infectives (2% v 10%, respectively; P < .001). The percentage of patients receiving the planned dose on time was similar between patients receiving pegfilgrastim and patients who initially received placebo (80% and 78%, respectively), as would be expected of the study design. Pegfilgrastim was generally well tolerated and safe, and the adverse events reported were typical of this patient population. CONCLUSION: First and subsequent cycle use of pegfilgrastim with a moderately myelosuppressive chemotherapy regimen markedly reduced febrile neutropenia, febrile neutropenia-related hospitalizations, and IV anti-infective use.

Adult↗

PubMed2005

The fallback procedure for evaluating a single family of hypotheses.

In testing multiple hypotheses, control of the familywise error rate is often considered. We develop a procedure called the "fallback procedure" to control the familywise error rate when multiple primary hypotheses are tested. With the fallback procedure, the Type I error rate (alpha) is partitioned among the various hypotheses of interest. Unlike the standard Bonferroni adjustment, however, testing hypotheses proceeds in an order determined a priori. As long as hypotheses are rejected, the Type I error rate can be accumulated, making tests of later hypotheses more powerful than under the Bonferroni procedure. Unlike the fixed sequence test, the fallback test allows consideration of all hypotheses even if one or more hypotheses are not rejected early in the process, thereby avoiding a common concern about the fixed sequence procedure. We develop properties of the fallback procedure, including control of the familywise error rate for an arbitrary number of hypotheses via illustrating the procedure as a closed testing procedure, as well as making the test more powerful via alpha exhaustion. We compare it to other procedures for controlling familywise error rates, finding that the fallback procedure is a viable alternative to the fixed sequence procedure when there is some doubt about the power for the first hypothesis. These results expand on the previously developed properties of the fallback procedure (Wiens, 2003). Several examples are discussed to illustrate the relative advantages of the fallback procedure.

Data Interpretation, Statistical↗

PubMed2003

Testing for interaction in studies of noninferiority.

We consider the role of interaction tests in the context of active-controlled clinical trials that aim to demonstrate the noninferiority of an experimental treatment compared to a standard (control) treatment. When the subjects can be grouped into strata (e.g., study sites, gender, race, etc.), there may be a desire to determine whether the experimental treatment is noninferior to the standard in each of the strata. We present five possible analysis strategies to test for heterogeneity of relative treatment effects among strata. These strategies are either identical to or straightforward modifications of strategies that can be used to test for interaction when the objective of the study is to show differences rather than noninferiority. The various analysis strategies implicitly depend on different definitions of interaction. Power of the various tests will be low, a phenomenon that often occurs when testing for interaction. We present simulation results to quantify the power and type I error rates under different scenarios and an example to demonstrate the proposed tests. None of the analysis strategies is best under every parameter configuration. The tests may be best used in a descriptive or exploratory manner. Extensions to two-sided equivalence testing are also discussed.

Bias↗

PubMed2003

Assessing the impact of endpoint shopping on power in confirmatory clinical trials.

When planning a confirmatory study, one of the important aspects is choosing a primary endpoint and evaluating power to show a difference. Data from preliminary studies are generally used for such planning. It is natural to want to use the endpoint from the preliminary study that best differentiates between test drug and control as the primary endpoint in the confirmatory study. However this leads to the possibility of bias in estimation of the effect size in the preliminary study, and, hence, lower than anticipated power in the confirmatory study. In this paper we quantify the impact of such endpoint shopping on the power of confirmatory studies. We find the upper bound on bias and show that for low to moderate correlation it is not very conservative. We derive the asymptotic distribution of the treatment effect and propose a test forequal treatment effects for the data from the preliminary study when endpoints are correlated. We study properties of this test. We propose a strategy to use the data from the preliminary study to plan confirmatory studies with unbiased or conservative estimates of power.

Clinical Trials as Topic↗

PubMed2002

Choosing an equivalence limit for noninferiority or equivalence studies.

Studies that compare treatments with the purpose of demonstrating that the treatments are similar require an a priori definition of an equivalence limit, how different the treatments can be before the difference is of concern. Defining such an equivalence limit is one of the most difficult aspects of planning the study. Three principles are proposed for setting such limits, depending on the objective of the study: a putative placebo calculation, an approach based on clinically important differences, and methods based on statistical properties. All methods will be useful for many studies, but the study objective should determine the final choice of an equivalence limit. The statistician must play an integral role in determining the final equivalence limit. Advice is offered for helping the statistician participate in the decision on the equivalence limits.

Clinical Trials as Topic↗

PubMedDate not supplied

Randomization as a basis for inference in noninferiority trials.

Noninferiority testing in clinical trials is commonly understood in a Neyman-Pearson framework, and has been discussed in a Bayesian framework as well. In this paper, we discuss noninferiority testing in a Fisherian framework, in which the only assumption necessary for inference is the assumption of randomization of treatments to study subjects. Randomization plays an important role in not only the design but also the analysis of clinical trials, no matter the underlying inferential field. The ability to utilize permutation tests depends on assumptions around exchangeability, and we discuss the possible uses of permutation tests in active control noninferiority analyses. The other practical implications of this paper are admittedly minor but lead to better understanding of the historical and philosophical development of active control noninferiority testing. The conclusion may also frame discussion of other complicated issues in noninferiority testing, such as the role of an intention to treat analysis.

Clinical Trials as Topic↗