Evolution of the Randomized Clinical Trial in the Era of Precision Oncology

Abstract

The randomized clinical trial (RCT) in oncology has evolved since its widespread adoption in the 1970s. In recent years, concerns have emerged regarding the use of putative surrogate end points, such as progression-free survival (PFS), and marginal effect sizes. OBJECTIVE To describe contemporary trends in oncology RCTs and compare these findings with earlier eras of RCT design and output. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of systemic therapy RCTs in breast, colorectal, and non-small cell lung cancer published in 7 major journals between 2010 and 2020. This strategy replicates prior work and allows for comparison of trends with RCTs published between 1995 to 2004 and 2005 to 2009. MAIN OUTCOMES AND MEASURES Data on RCT design, funding, results, and reporting were extracted from the published RCT report. Findings from the current period (2010-2020) were compared with data from RCTs published from 1995 to 2004 and 2005 to 2009. Descriptive and bivariate statistics were used to analyze temporal trends. RESULTS The cohort included 298 RCTs (132 [44%] breast, 111 [37%] non-small cell lung cancer, 55 [19%] colorectal cancer). Experimental treatment included molecular inhibitor (171 of 298 [57%]), cytotoxic (83 of 298 [28%]), hormone (15 of 298 [5%]), and immune (24 of 298 [8%]) therapies. Sixty-nine percent (206 of 298) of RCTs were of palliative intent. The most common primary end point is now PFS; this has increased substantially over time (from 0% [0 of 167] to 18% [25 of 137] to 42% [125 of 298]; P < .001). Of 298 RCTs, 265 (89%) are now funded by industry (previously 95 of 167 [57%] and 107 of 137 [78%]; P < .001).Fifty-eight percent (173 of 298) of trials met their primary end point. Among positive trials, median improvement in overall survival and PFS was 3.4 and 2.9 months, respectively. More than one-third (117 of 298 [39%]) of reports used a professional medical writer; this increased substantially during the study period (from 3 of 27 [11%] in 2010 to 12 of 18 [67%] in 2020; P < .001).CONCLUSIONS AND RELEVANCE This cohort study suggests that contemporary oncology RCTs now largely measure putative surrogate end points and are almost exclusively funded by the pharmaceutical industry. The increasing role of medical writers warrants attention. To demonstrate that new cancer treatments are high value, the oncology community needs to consider the extent to which study end points and target effect size provide meaningful benefit to patients.

Potential negative impact of reputed regulators’ decisions on the approval status of new cancer drugs in Latin American countries: A descriptive analysis

“…It has led to the relaxation of MA rules to quickly allow entrance of new cancer therapies into the worldwide market. Two main regulatory concepts have been used to facilitate this: i. the extended use of surrogate endpoints at registration time [26], and ii. the reliance on the regulatory decisions taken by reputed regulators [27][28][29].…”

“…Two main regulatory concepts have been used to facilitate this: i . the extended use of surrogate endpoints at registration time [ 26 ], and ii . the reliance on the regulatory decisions taken by reputed regulators [ 27 – 29 ].…”

“…The European Medicines Agency and the US Food and Drug Administration must be aware that their regulatory decisions directly influence decisions elsewhere. The bar to approve new cancer drugs should be raised to protect patients globally [ 2 , 26 , 54 ]; this will require a paradigm shift from the industry driven early access approach to a new one prioritising the approval of clinically meaningful cancer drugs. A way to go further in that direction is by the regulators´ systematic demand of overall survival and quality of life, ideally both, as primary endpoints in oncologic clinical trials [ 1 , 35 , 54 , 55 ].…”

Characteristics and Research Waste Among Randomized Clinical Trials in Gastric Cancer

“…Additionally, Jairam et al 34 found that among phase 3 oncology clinical trials, RCTs of targeted systemic agents were more likely to be externally funded. Del et al 11 reported that, over time, there has been an increase in the proportion of RCTs with industry funding. Our analyses found that 77 RCTs (29.4%) were externally funded.…”

Beyond the lessons learned from the COVID-19 pandemic: opportunities to optimize clinical trial implementation in oncology

“…Another important challenge for cancer research has been the definition of endpoints capturing relevant outcomes in each research setting as timely as possible, in order to provide the patient with rapid access to innovative therapeutics. Ideally, surrogate endpoints with strong correlation with clinically meaningful outcomes should serve this purpose, but few comply to this definition ( 70 , 71 , 72 ). As an example, after granted accelerated approval for several Immune Checkpoint Inhibitors, FDA announced that four indications were voluntarily withdrawn, and six others were under review since reported results from confirmatory trials have not verified clinical benefit ( 73 ).…”