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Randomized Controlled Trial
. 2021 May 1;7(5):728-734.
doi: 10.1001/jamaoncol.2021.0379.

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

Joseph C Del Paggio  1 , John S Berry  2 , Wilma M Hopman  3   4 , Elizabeth A Eisenhauer  5 , Vinay Prasad  6 , Bishal Gyawali  2   4   5 , Christopher M Booth  2   4   5
Affiliations
Randomized Controlled Trial

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

Joseph C Del Paggio et al. JAMA Oncol. .

Abstract

Importance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Prasad reported grants from Arnold Ventures; royalties from Johns Hopkins Press, Medscape, and MedPage; consulting fees from UnitedHealthcare and New Century Health; speaking fees from eviCore and New Century Health; honoraria for grand rounds/lectures from universities, medical centers, nonprofits, and professional societies; and having Patreon backers for the Plenary Session podcast from Patreon outside the submitted work. Dr Booth is supported as the Canada Research Chair in Population Cancer Care. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Temporal Trends in Effect Size as per Power Calculation and Results Among Positive Superiority Trials for Randomized Clinical Trials of Systemic Therapy in Breast, Colorectal, and Non–Small Cell Lung Cancer Published in 7 Major Journals, 1995-2020
HR indicates hazard ratio.
Figure 2.
Figure 2.. Temporal Trends in Primary End Point and Industry Funding of Randomized Clinical Trials (RCTs) of Breast, Colorectal, and Non–Small Cell Lung Cancer Published in Major Journals Over 5 Decades, 1975-2020
Figure 3.
Figure 3.. Temporal Trends in Use of Medical Writers and Industry Funding of Randomized Clinical Trials (RCTs) of Breast, Colorectal, and Non–Small Cell Lung Cancer Published in 7 Major Journals, 2010-2020
See this image and copyright information in PMC

Comment in

References

    1. Booth CM, Cescon DW, Wang L, Tannock IF, Krzyzanowska MK. Evolution of the randomized controlled trial in oncology over three decades. J Clin Oncol. 2008;26(33):5458-5464. doi:10.1200/JCO.2008.16.5456 - DOI - PMC - PubMed
    1. Kay A, Higgins J, Day AG, Meyer RM, Booth CM. Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points. Ann Oncol. 2012;23(6):1646-1651. doi:10.1093/annonc/mdr492 - DOI - PubMed
    1. Hodi FS, O’Day SJ, McDermott DF, et al. . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. doi:10.1056/NEJMoa1003466 - DOI - PMC - PubMed
    1. Seruga B, Hertz PC, Wang L, et al. . Seruga B, Hertz PC, Wang L, et al. . Absolute benefits of medical therapies in phase III clinical trials for breast and colorectal cancer. Ann Oncol. 2010;21(7):1411-1418. doi:10.1093/annonc/mdp552 - DOI - PubMed
    1. Kumar H, Fojo T, Mailankody S. An appraisal of clinically meaningful outcomes guidelines for oncology clinical trials. JAMA Oncol. 2016;2(9):1238-1240. doi:10.1001/jamaoncol.2016.0931 - DOI - PMC - PubMed

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