An Analysis of Contemporary Oncology Randomized Clinical Trials From Low/Middle-Income vs High-Income Countries | Global Health | JAMA Oncology | JAMA Network
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    2 Comments for this article
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    Cancer care in low and middle-income countries vs wealthier countries
    Daniel Krell, M.D., ABFM | Retired family physician
    I am concerned that the findings and conclusions in the article do not reflect a significant confounding factor:

    Low and middle-income countries tend to have more homogeneous populations (ethnicity, income levels and disparities, etc.) than do wealthier countries. The inferior quality of care provided, in the U.S., consistently experienced by people of color, people without health insurance, and people in poverty is and has been, for years, well documented. This population, with inferior care and poorer prognoses, would skew downward the apparent benefits of therapy in RCT's.

    "Randomized clinical trials from LMICs are more
    likely to identify effective therapies and have a larger effect size than RCTs from HICs." My concern is that the relatively homogeneous populations of LMIC's receive more homogeneous levels of care than do populations in HIC's; the HIC benefits of a studied therapy are diluted by a significant portion of our population that receives inferior care, producing inferior outcomes. The discrepancies might not reflect "...funding and publication bias...", but health care disparities in our country.

    Daniel Krell, M.D.
    CONFLICT OF INTEREST: None Reported
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    Cancer Clinical Trials in Low - Middle Income Countries
    Arya Roy, MD | University of Arkansas For Medical Sciences
    We applaud Wells et al for their recent article in the JAMA Oncology (1), discussing differences in randomized control trials (RCT) conducted in High-income countries (HIC) when compared to low/middle-income countries (LMIC). However, we would like to bring attention to a couple of issues from an LMIC standpoint.

    The article described the skewed prioritization in research. Few RCTs are conducted in key issues that matter to the global cancer burden. Wells et al found that the proportion of RCTs relative to global deaths were higher for breast cancer, leukemia, lymphoma and were low for gastroesophageal cancer, liver, pancreas,
    and cervical cancer. We conducted a study on the cancer clinical trials that are registered in the Clinical Trial Registry of India from July 2007 to May 2017. We found that there is a disparity between the disease burden and the interventional trials in India. The highest number of interventional trials were conducted in breast cancer followed by lung cancer. There are fewer trials conducted in head and neck, gastrointestinal, gynecological cancers in India, although these are the most prevalent cancers in India (2). The problem is therefore pervasive in an LMIC setting as well.

    Wells et al note that studies from LMICs are published in journals with a lesser impact factor when compared to trials from HICs and this disparity persisted when they analyzed the publication rates of positive and negative oncology RCTs. When we analyzed the publication rates of the interventional trials conducted in India, we found that only 50% of the studies are published, and the chances of the publication of studies with negative results are dismal (3). We wish to highlight that any solution to the problems described by Wells et al should be locally generated through capacity building in LMICs and externally driven through a better understanding of the implicit bias against LMIC researchers.

    We wish to raise an alternative hypothesis to the finding that research published in LMICs is more impactful as measured by the effect size of the positive trials. Could it be an artifactual finding that describes the significant impact of some therapeutic strategies in LMIC when compared to HIC – for instance, impact of trastuzumab use in an LMIC (control arm consists of patients who are not receiving any targeted therapy) is much higher when compared to the impact of pertuzumab in HIC (control arm consists of patients who are receiving trastuzumab)?


    References

    1. Wells JC, Sharma S, Del Paggio JC, etal. An analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries. JAMA Oncology. Published online January 28, 2021. doi:10.1001/jamaoncol. 2020.7478
    2. Roy AM, Mathew A. Audit of Cancer Clinical Trials in India. J Glob Oncology. 2019; 5:1. doi: 10.1200/JGO.19.00156
    3. Thomas VM, John VM, Alexander SA, Roy AM, Mathew A. Publication rate and characteristics of cancer clinical trials in India. Journal of Cancer Policy. 2020; 26: 100248. https://doi.org/10.1016/j.jcpo.2020.100248


    Authors

    Arya Mariam Roy, MD; University of Arkansas for Medical Sciences, Little Rock, USA
    Aju Mathew, MD, MPhil; Assistant Professor, University of Kentucky Markey Cancer Center, Kentucky, USA, Consultant, MOSC Medical College Kolenchery, Kerala, India
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    January 28, 2021

    An Analysis of Contemporary Oncology Randomized Clinical Trials From Low/Middle-Income vs High-Income Countries

    Author Affiliations
    • 1Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Kingston, Ontario, Canada
    • 2Department of Oncology, Queen’s University, Kingston, Ontario, Canada
    • 3Department of Oncology, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
    • 4Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
    • 5Department of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon
    • 6Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
    • 7Institute of Cancer Policy, King’s College London, London, United Kingdom
    • 8Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
    JAMA Oncol. 2021;7(3):379-385. doi:10.1001/jamaoncol.2020.7478
    Key Points

    Question  To what extent do oncology randomized clinical trials (RCTs) reflect the global cancer burden?

    Findings  This systematic review–based cohort study of all 694 phase 3 RCTs published from 2014 to 2017 found that trials are conducted predominantly in high-income countries and study cancers that do not match the global burden of disease. Even though RCTs from low-middle and upper-middle–income countries are more likely to study new treatments that benefit patients, these RCTs are published in journals with lower impact factors.

    Meaning  Policy makers, research funders, and journals need to address these challenges with a range of measures including building capacity and capability in RCTs.

    Abstract

    Importance  The burden of cancer falls disproportionally on low-middle–income countries (LMICs). It is not well known how novel therapies are tested in current clinical trials and the extent to which they match global disease burden.

    Objectives  To describe the design, results, and publication of oncology randomized clinical trials (RCTs) and examine the extent to which trials match global disease burden and how trial methods and results differ across economic settings.

    Design, Setting, and Participants  In this retrospective cohort study, a literature search identified all phase 3 RCTs evaluating anticancer therapies published from 2014 to 2017. Randomized clinical trials were classified based on World Bank economic classification. Descriptive statistics were used to compare RCT design and results from high-income countries (HICs) and low/middle-income countries (LMICs). Statistical analysis was conducted in January 2020.

    Main Outcomes and Measures  Differences in the design, results, and output of RCTs between HICs and LMICs.

    Results  The study cohort included 694 RCTs: 636 (92%) led by HICs and 58 (8%) led by LMICs. A total of 601 RCTs (87%) tested systemic therapy and 88 RCTs (13%) tested radiotherapy or surgery. The proportion of RCTs relative to global deaths was higher for breast cancer (121 RCTs [17%] and 7% of deaths) but lower for gastroesophageal cancer (38 RCTs [6%] and 14% of deaths), liver cancer (14 RCTs [2%] and 8% of deaths), pancreas cancer (14 RCTs [2%] and 5% of deaths), and cervical cancer (9 RCTs [1%] and 3% of deaths). Randomized clinical trials in HICs were more likely than those in LMICs to be funded by industry (464 [73%] vs 24 [41%]; P < .001). Studies in LMICs were smaller than those in HICs (median, 219 [interquartile range, 137-363] vs 474 [interquartile range, 262-743] participants; P < .001) and more likely to meet their primary end points (39 of 58 [67%] vs 286 of 636 [45%]; P = .001). The observed median effect size among superiority trials was larger in LMICs compared with HICs (hazard ratio, 0.62 [interquartile range, 0.54-0.76] vs 0.84 [interquartile range, 0.67-0.97]; P < .001). Studies from LMICs were published in journals with lower median impact factors than studies from HICs (7 [interquartile range, 4-21] vs 21 [interquartile range, 7-34]; P < .001). Publication bias persisted when adjusted for whether a trial was positive or negative (median impact factor: LMIC negative trial, 5 [interquartile range, 4-6] vs HIC negative trial, 18 [interquartile range, 6-26]; LMIC positive trial, 9 [interquartile range, 5-25] vs HIC positive trial, 25 [interquartile range, 10-48]; P < .001).

    Conclusions and Relevance  This study suggests that oncology RCTs are conducted predominantly by HICs and do not match the global burden of cancer. Randomized clinical trials from LMICs are more likely to identify effective therapies and have a larger effect size than RCTs from HICs. This study suggests that there is a funding and publication bias against RCTs led by LMICs. Policy makers, research funders, and journals need to address this issue with a range of measures including building capacity and capability in RCTs.

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