Evaluating Patient-Centered Outcomes in the Randomized Controlled Trial and Beyond: Informing the Future with Lessons from the Past

Abstract

In the era of molecular oncology, patients still define a useful therapy as one that allows them to live longer and helps them to live better. Although patient outcomes have clearly improved as a result of randomized controlled trials (RCT), it is critical that contemporary trials retain the perspective of these fundamental patient-centered outcomes. Trends in study design, results, and interpretation of oncology RCTs from the past provide a useful framework in which to consider how the research community may approach trial design in the future. Although the RCT remains the standard for establishing efficacy, this article also considers how population-based outcome studies can provide insight into effectiveness of new therapies and explores how the results of RCTs translate into benefit in the general population. Clin Cancer Res; 16(24); 5963-71. Ó2010 AACR.Although patient outcomes have improved as a result of clinical trials conducted since the 1970s, in the contemporary era, patients still define a useful therapy as one that improves the quality, or increases the quantity, of survival. Despite considerable change in the treatment and outcome of patients with cancer, it is critical that investigators, clinicians, and policy makers not lose sight of these fundamental patient-centered outcomes. Furthermore, although the randomized controlled trial (RCT) remains the gold standard for establishing efficacy of new therapies, increased effort is required to understand how the results of RCTs influence clinical practice and to assess the benefit of new treatments in the general population. This article explores how the RCT in oncology has evolved over time and proposes issues that require consideration in the design and interpretation of future trials. The article also considers how population-based outcome studies can provide insight into the uptake of new medical therapies and explores how the results of RCTs translate into benefit in the "real world." Evolution of Design and Outcomes of Oncology Randomized Controlled TrialsA recent overview of 321 RCTs of systemic therapy in breast, colorectal, and non-small cell lung cancer (NSCLC), published between 1975 and 2004, provides insight into the methods, results, and outcomes of oncology trials over time (Table 1; ref. 1). RCTs in oncology have become larger and increasingly involve multiple international centers. Although the median sample size of RCTs has increased from 100 to 446 patients per study, the total duration of study accrual for these trials has remained relatively stable since the 1970s. During the study period, encouraging changes occurred in the statistical methodology and endpoints in RCTs. The primary endpoint of oncology RCTs has shifted away from response rate to survival and other time-to-event endpoints. The proportion of trials using intention-to-treat (ITT) analyses has also increased. Despite these improvements, in the most recent decade (1995 to 2004), one third of systemic therapy RCTs published in high-impact and widely read journa...

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