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Original Investigation
March 25, 2021

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

Author Affiliations
  • 1Department of Medical Oncology, Thunder Bay Regional Health Sciences Centre and Northern Ontario School of Medicine, Thunder Bay, Canada
  • 2Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Queen’s University, Kingston, Canada
  • 3Kingston General Health Research Institute, Kingston, Canada
  • 4Department of Public Health Sciences, Queen’s University, Kingston, Canada
  • 5Department of Oncology, Queen’s University, Kingston, Canada
  • 6Department of Epidemiology and Biostatistics, University of California at San Francisco
JAMA Oncol. 2021;7(5):728-734. doi:10.1001/jamaoncol.2021.0379
Key Points

Question  What are the characteristics that define modern randomized clinical trials (RCTs) in oncology, and do they differ from characteristics of RCTs from the preceding decades?

Findings  In this cohort study of 298 RCTs, progression-free survival was the predominant end point of oncology RCTs, and median survival gains remain modest. Almost all RCTs are now funded by industry; this is accompanied by a substantial increase in use of professional medical writers.

Meaning  The oncology community needs to consider new approaches to study design to ensure that treatments offer important benefits to patients; parallel to this, the current funding model for cancer clinical trials requires urgent attention.


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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    3 Comments for this article
    Professor and HOD - Medical oncology
    Govind Babu K, DM Med. oncology | Rajiv Gandhi Health University ,Bangalore,India
    very true interpretation.As practising oncologists its so difficult to accept all these pharma funded trial conclusions!
    In defense of medical writers
    R Michelle Sauer Gehring, PhD, ELS | UTHealth
    I take issue with this article's concern over the use of professional medical writers. I myself would be considered a professional medical writer, and I work in academia. The majority of professional medical writers are members of professional societies and adhere to strict ethical codes of conduct. We work hard to ensure a fair, balanced and clear reporting of the data. The "findings" of this article indicate that there is a greater DISCLOSURE of the use of medical writers, not that their use has increased. This is due, in large part, to the efforts of medical writers who have consistently pushed for more transparency. I would encourage the authors to review the joint position statements and policies of professional medical writer organizations.
    Misinterpretation of data on use of medical writers in published studies of oncology RCTs
    Monica Nicosia, PhD | Self-employed | Nicosia Medical Writer LLC
    Del Paggio and colleagues misinterpreted their findings on the use of medical writers in published studies of oncology RCTs. The bar graph in Figure 3 (titled, "Temporal Trends in Use of Medical Writers and Industry Funding of Randomized Clinical Trials (RCTs) of Breast, Colorectal, and and Non-Small Cell Lung Cancer Published in 7 Major Journals, 2010-2020") does not show "...a substantial increase in use of medical writers during the study era." Rather, as Dr Gehring pointed out in her comment, it shows an increase in the percentage of articles disclosing the involvement of professional medical writers. This is most likely due to efforts by journals, medical writers, and other publication professionals to enforce the ethical disclosure of medical writer and editor contributions to manuscript development. Ironically, a good professional medical writer would have noted this data misinterpretation and queried the authors with suggestions on how to fix the discrepancy. It's interesting that this misinterpretation appears to have fallen under the radar of the JAMA Oncol reviewers and editors.

    I find it disturbing that the authors use their misinterpreted data to make the unsupported statement that, "There is reason to be concerned that medical writers may unduly influence the interpretation of trials." Where are the data that show this alleged undue influence which maligns an entire profession? Many people don't seems to understand what medical writers do and what is beyond our control. Professional medical writers can help time-pressed authors write manuscripts that objectively, accurately, and cogently report the results of their research. We help authors abide with journal editorial policies and instructions for manuscript preparation as well as with other good publication practices such as the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Any medical writer worth their salt will adhere to publication best practice and to the code of conduct and ethical principles of the American Medical Writers Association and other professional organization. As medical writers we can make suggestions but the authors have the final say.
    CONFLICT OF INTEREST: I am a self-employed, professional medical writer