LBPS #307298 VOL 18, ISS 4
COMMENTARY ON “ACCOUNTING FOR INTERIM SAFETY MONITORING OF AN ADVERSE EVENT UPON TERMINATION OF A CLINICAL TRIAL” Yi Tsong
QUERY SHEET This page lists questions we have about your paper. The numbers displayed at left can be found in the text of the paper for reference. In addition, please review your paper as a whole for corrections. Q1: Au: Is Vioxx a trademarked product? Should we add TM? Q2: Au: Please rephrase “serves practically as frailty” to clarify meaning Q3: Au: Please provide page range.
TABLE OF CONTENTS LISTING The table of contents for the journal will list your paper exactly as it appears below: Commentary on “Accounting for Interim Safety Monitoring of an Adverse Event Upon Termination of a Clinical Trial” Yi Tsong
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Journal of Biopharmaceutical Statistics, 18: 1–2, 2008 Copyright © Taylor & Francis Group, LLC ISSN: 1054-3406 print/1520-5711 online DOI: 10.1080/10543400802071329
COMMENTARY ON “ACCOUNTING FOR INTERIM SAFETY MONITORING OF AN ADVERSE EVENT UPON TERMINATION OF A CLINICAL TRIAL” Yi Tsong Office of Biostatistics, CDER, FDA, Silver Spring, Maryland, USA
Risk assessment and management of new drugs have been the focus of the regulatory critical path in the last few years. In the wake of safety problems associated with Vioxx, drug sponsors and regulatory authorities became more active in safety assessments with phase III clinical trials. The conventional setting of risk AQ1 assessment is based on testing the superiority hypothesis of rate differences (or of relative risk, odds ratio) between the test treatment, PT , and the properly chosen reference treatment, PC , on the safety endpoint: H0 PT ≤ PC vs. Ha PT > PC
(1)
The sponsor and regulatory authority declare that there is a higher risk of adverse events when treating with PT if the null hypothesis is rejected. Otherwise, failing to reject hypothesis (1), leads to the conclusion of “no evidence” to conclude that adverse event are more associated with the test treatment than with the control treatment. With such a setting, the sponsor often emphasizes the “no evidence” part of the conclusion and the regulatory authority will emphasize the “lack of power” part of the conclusion. When a clinical trial is designed to assess the safety of a test treatment for a specific adverse event in an outcome trial, it is natural to consider a noninferiority hypothesis test setting with a prespecified “no worse than” margin, > 0, such that H0 PT − PC ≥ vs. Ha PT − PC <
(2)
This setting is more attractive to study investigators and regulatory authorities because of better power control and proper indications of testing results. Once the noninferiority hypothesis is rejected, the evidence for “test treatment is no worse in safety than the control treatment” is shown. Michael J. Dallas proposes, in this issue, a procedure to test the noninferiority hypothesis (2) for a specific rare serious event at the termination of a trial, in the setting of a clinical trial with safety monitoring that may stop the clinical trial at interim stages due to a larger-than-expected event Address correspondence to Yi Tsong, Office of Biostatistics, CDER, FDA, Silver Spring, Maryland, USA; E-mail:
[email protected] 1
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TSONG
rate. In other words, the trial is monitored and terminated if the following null hypothesis is rejected at an interim stage: H0 PT − PC < vs. Ha PT − PC ≥
(3)
where ≥ 0 is a margin set for terminating the trial at monitoring stages. Since (3) serves practically as frailty for testing (2), Dallas proposes to adjust the p-value of testing (2), or the confidence level of the confidence interval of AQ2 PT − PC , at terminal stages for power loss due to futility tests. However, there are two important points to be taken into consideration when applying the futility adjustment in this problem. First, a data safety monitoring board (DSMB) may often stop a trial due to unexpected safety concerns that are unrelated or partially related to the adverse reaction studied, with a stopping rule that is difficult to specify before the trial. Even with a prespecified stopping rule, it is often difficult to expect a DSMB to apply the stopping rule strictly. In some situations, a DSMB may keep the trial going if the decision is at the borderline. Second, in most safety assessments, the objective is to assess the risk difference in terms of the confidence interval PT − PC . Since variances in the estimate of PT − PC are different under the corresponding null hypotheses (1)–(3), the p-value of the test may be adjusted for the null hypothesis involved. However, variance in the estimate of PT − PC should be independent from the null hypothesis and the confidence interval should be the same regardless of what hypothesis is involved in hypothesis testing. REFERENCES Dallas, M. J. (2008). Accounting for the interim safety monitoring of an adverse event upon termination of a clinical trial. Journal of Biopharmaceutical Statistics 18.
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