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He P.,Genentech | Su Z.,Deerfield Institute
Contemporary Clinical Trials Communications | Year: 2015

The semi-parametric proportional hazards model is widely adopted in randomized clinical trials with time-to-event outcomes, and the log-rank test is frequently used to detect a potential treatment effect. Immuno-oncology therapies pose unique challenges to the design of a trial as the treatment effect may be delayed, which violates the proportional hazards assumption, and the log-rank test has been shown to markedly lose power under the non-proportional hazards setting. A novel design and analysis approach for immuno-oncology trials is proposed through a piecewise treatment effect function, which is capable of detecting a potentially delayed treatment effect. The number of events required for the trial will be determined to ensure sufficient power for both the overall log-rank test without a delayed effect and the test beyond the delayed period when such a delay exists. The existence of a treatment delay is determined by a likelihood ratio test with resampling. Numerical results show that the proposed design adequately controls the Type I error rate, has a minimal loss in power under the proportional hazards setting and is markedly more powerful than the log-rank test with a delayed treatment effect. © 2015 The Authors.

He P.,Genentech | Lai T.L.,Stanford University | Su Z.,Deerfield Institute
Contemporary Clinical Trials | Year: 2015

Time to event is the clinically definitive endpoint in Phase III trials of new treatments of cancer, cardiovascular and many other diseases. Because these trials involve relatively long follow-up, their protocols usually incorporate periodic interim analyses of the data by a Data and Safety Monitoring Board/Committee. This paper gives a review of the major developments in the design of these trials in the 21st century, spurred by the need for better clinical trial designs to cope with the remarkable advances in cancer biology, genomics and imaging that can help predict patients' sensitivity or resistance to certain treatments. In addition to this overview and discussion of related issues and challenges, we also introduce a new approach to address some of these issues. © 2015 Elsevier Inc. All rights reserved.

Lin Y.,Takeda Development Center Americas Inc. | Zhu M.,Abbvie Inc. | Su Z.,Deerfield Institute
Contemporary Clinical Trials | Year: 2015

Randomization is fundamental to the design and conduct of clinical trials. Simple randomization ensures independence among subject treatment assignments and prevents potential selection biases, yet it does not guarantee balance in covariate distributions across treatment groups. Ensuring balance in important prognostic covariates across treatment groups is desirable for many reasons. A broad class of randomization methods for achieving balance are reviewed in this paper; these include block randomization, stratified randomization, minimization, and dynamic hierarchical randomization. Practical considerations arising from experience with using the techniques are described. A review of randomization methods used in practice in recent randomized clinical trials is also provided. © 2015 Elsevier Inc. All rights reserved.

Stuntz M.,Deerfield Institute
Cardiology (Switzerland) | Year: 2016

Objectives: Abdominal aortic aneurysm (AAA) is a pathological condition characterized by an abnormal, localized dilatation of the lower part of the aorta. Due to a lack of data on the natural history of AAA and risk of death from other cardiovascular diseases attributable to AAA, the true number of AAA-attributable deaths may be higher than currently estimated. This study aims to produce more realistic estimates of the burden of AAA. Methods: A disease-modeling software, DisMod II, was used to assess the AAA burden via a multistate life table. Inputs included population, all-cause mortality, size- and sex-specific AAA prevalence, and relative risk of death estimates for persons with AAA compared with persons without AAA. Results: There were 2,347,339 prevalent cases of AAA in the USA in 2013 (95% CI: 2,131,964-2,524,116), resulting in 41,371 deaths attributable to AAA (95% CI: 34,090-49,234). Females constituted 21.1% of prevalent cases and 45.2% of deaths, compared with males constituting 78.9% of prevalent cases and 54.8% of deaths. Conclusions: This work shows that the burden of mortality attributable to AAA is more than twice the current estimates from the American Heart Association. Females account for a disproportionately high percentage of deaths despite constituting a low percentage of prevalent cases. © 2016 The Author(s) Published by S. Karger AG, Basel

Daniel G.W.,Engelberg Center for Health Care Reform at Brookings | Caze A.,Deerfield Institute | Romine M.H.,Engelberg Center for Health Care Reform at Brookings | Audibert C.,Deerfield Institute | And 2 more authors.
Health Affairs | Year: 2015

New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation. © 2015 Project HOPE-The People-to-People Health Foundation, Inc.

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