Innovations In Clinical Trial Design Research Articles

Cardiovascular Pharmacogenomics: Current Status and Future Directions—Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular

Bayesian clinical trials at the University of Texas M. D. Anderson Cancer Center

The Bayesian approach is being used increasingly in medical research. In particular, it has become a standard in designing clinical trials at the University of Texas M. D. Anderson Cancer Center. / To address the extent and nature of Bayesian trials conducted at M. D. Anderson, we reviewed the protocols registered in the Protocol Document Online System between 2000 and early 2005. We summarize our findings and give details for three innovative trials that typify those in which a Bayesian approach has played a major role at the center. Of 964 protocols reviewed, 59% were conducted solely at M. D. Anderson and the rest were multicenter trials. Bayesian designs and analyses were used in about 20% (195/964) of the protocols that we reviewed. Of the 520 protocols identified as phase I or II drug trials, about 34% were Bayesian. Most of the 195 Bayesian trials were designed by M. D. Anderson statisticians. The Bayesian design features most commonly used were the continuous reassessment method in phase I (toxicity) trials, adaptive randomization in phase II trials, and designs to monitor efficacy and toxicity simultaneously. We also provide an insider's view regarding some practical considerations that have made the design and implementation of so many Bayesian trials possible. We reviewed only a subset of all M. D. Anderson protocols, but did not exclude any available in electronic form. The large number of Bayesian trials conducted at M. D. Anderson testifies to the receptivity to the Bayesian approach within the center, including principal investigators, regulatory review committees, and patients. Statisticians who take a Bayesian perspective can successfully work to establish a culture of innovation in clinical trial design.

Drug development in advanced colorectal cancer: Challenges and opportunities

Despite recent advances in treatment options, advanced colorectal cancer (ACC) remains a leading cause of cancer death worldwide, and new therapies are needed to improve the grim prognosis of this disease. Drug development in ACC faces the challenges of a constrained pipeline, a paucity of patients enrolled in clinical trials, and an outdated "one drug fits all" model of clinical research. This article discusses potential innovations in clinical trial design--including enrichment strategies, novel patient populations, and the use of randomization in the phase 2 setting--to optimize the testing of new therapies. It concludes with a selection of promising agents and pathways under investigation in ACC.

Neuroprotection in Parkinson’s disease: Myth or reality?

Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder with no cure. Therapies that delay or halt disease progression are urgently needed, but finding such therapies has been difficult. In this article, we review historical and recent clinical trial work in the field of neuroprotection. Several issues have arisen during the search for disease-modifying therapies, including challenges in selecting appropriate therapeutic targets, assessing potential therapies, and selecting the proper patient population to study. Advances in the understanding of PD pathogenesis are presented as they relate to selecting potential therapeutic targets, and issues with preclinical testing are described. We review recent innovations in clinical trial design, including futility studies and delayed-start designs that promise to make clinical testing more efficient. It is hoped that ongoing work in this field will lead to treatments that delay the progression of PD.

The simple model versus the super model: translating experimental traumatic brain injury research to the bedside.

Despite considerable investigation in rodent models of traumatic brain injury (TBI), no novel therapy has been successfully translated from bench to bedside. Although well-described limitations of clinical trails may account for these failures, several modeling factors may also contribute to the lack of therapeutic translation from the laboratory to the clinic. Specifically, models of TBI may omit one or more critical, clinically relevant pathophysiologic features. In this invited review article, the impact of the limited incorporation of several important clinical pathophysiologic factors in TBI, namely secondary insults (i.e., hypotension and/or hypoxemia), coma, and aspects of standard neurointensive care monitoring and management strategies (i.e., intracranial pressure [ICP] monitoring and ICP-directed therapies, sedation, mechanical ventilation, and cardiovascular support) are discussed. Comparative studies in rodent and large animal models of TBI (which may, in some cases, represent super models) are also presented. We conclude that therapeutic breakthroughs will likely require a multidisciplinary approach, involving investigation in a range of models, including clinically relevant modifications of established animal models, along with development and application of new innovations in clinical trial design.

Prototype antiepileptic drug clinical development plan.

Antiepileptic drug (AED) development has been generally difficult owing to many factors: regulatory requirements for demonstration of efficacy and safety, subject availability, traditional trial designs, and physicians' beliefs about epilepsy and its treatment. The U.S. Food and Drug Administration (FDA) regulations require a new drug to be shown safe and effective for its intended use before it can be marketed. The unambiguous proof required is a formidable hurdle for AED development. We report a recent clinical development plan highlighting innovations in clinical trial design that have addressed these requirements, discuss alternative endpoints, and compare the results of various trial designs at various stages of development. This model clinical development plan includes trials relevant to all three clinically relevant contexts in which an AED might be used: as an adjunct to an existing regimen, as a substitution for much of an existing AED regimen, and as monotherapy.