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Industry Funding of Oncology Randomised Controlled Trials: Implications for Design, Results and Interpretation

Published:August 31, 2021DOI:https://doi.org/10.1016/j.clon.2021.08.003

      Highlights

      • Industry funded trials tested systemic therapy more than Non-Industry funded trials.
      • Industry-funded trials were more likely to study palliative treatment.
      • Industry-funded trials were more likely to meet their primary endpoint.
      • Industry funded trials studied breast cancer more often.
      • No difference in clinical benefit between industry and non industry funded trials

      Abstract

      Aims

      Most randomised controlled trials (RCTs) in oncology are now funded by the pharmaceutical industry. We explore the extent to which RCT design, results and interpretation differ between industry-funded and non-industry-funded RCTs.

      Materials and methods

      In this cross-sectional analysis, a structured literature search was used to identify all oncology RCTs published globally during 2014–2017. Industry funding was identified based on explicit statements in the publication. Descriptive statistics were used to compare elements of trial methodology and output between industry- and non-industry-funded RCTs.

      Results

      The study sample included 694 RCTs; 71% were funded by industry. Industry-funded trials were more likely to test systemic therapy (97% versus 62%; P < 0.001), palliative-intent therapy (71% versus 41%; P < 0.001) and study breast cancer (20% versus 12%; P < 0.001). Industry-funded trials were larger (median sample size 474 versus 375; P < 0.001) and more likely to meet their primary end point (49% versus 41%; P < 0.001). Among positive trials, there were no differences in the magnitude of benefit between industry- and non-industry-funded RCTs. Trials funded by industry were published in journals that had a significantly higher median impact factor (21, interquartile range 7, 28) than non-industry-funded trials (impact factor 12, interquartile range 5, 24; P = 0.005); this persisted when adjusted for whether a trial was positive or negative.

      Conclusions

      The vast majority of oncology RCTs are now funded by industry. Industry-funded trials are larger, more likely to be positive, predominantly test systemic therapies in the palliative setting and are published in higher impact journals than trials without industry support.

      Key words

      Introduction

      Randomised controlled trials (RCTs) are the evidential backbone for improving patient outcomes in the global cancer community. In recent years, this has been challenged by a shift towards less rigorous trial designs, surrogate end points, marginal effect sizes of clinical benefit and, in some cases, the abandonment of RCTs altogether in favour of single-arm studies [
      • Fojo T.
      • Mailankody S.
      • Lo A.
      Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture.
      ,
      • Mailankody S.
      • Prasad V.
      Five years of cancer drug approvals: innovation, efficacy, and costs.
      ,
      • Tenhunen O.
      • Lasch F.
      • Schiel A.
      • Turpeinen M.
      Single-arm clinical trials as pivotal evidence for cancer drug approval: a retrospective cohort study of centralized European marketing authorizations between 2010 and 2019.
      ,
      • Kim C.
      • Prasad V.
      Strength of validation for surrogate end points used in the US Food and Drug Administration's approval of oncology drugs.
      ]. Since widespread adoption of the RCT in the 1970s, there has also been a shift in funding of cancer clinical trials. The proportion of systemic therapy RCTs in oncology funded by industry increased from 4% in 1975–1984, to 78% in 2005–2009, to 89% in 2010–2020 [
      • Kay A.
      • Higgins J.
      • Day A.G.
      • Meyer R.M.
      • Booth C.M.
      Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points.
      ,
      • Booth C.M.
      • Cescon D.W.
      • Wang L.
      • Tannock I.F.
      • Krzyzanowska M.K.
      Evolution of the randomized controlled trial in oncology over three decades.
      ,
      • Del Paggio J.C.
      • Berry J.S.
      • Hopman W.M.
      • Eisenhauer E.A.
      • Prasad V.
      • Gyawali B.
      • et al.
      Evolution of the randomized clinical trial in the era of precision oncology.
      ].
      Although it is clear that the pharmaceutical industry now has a major influence on the cancer research agenda, there are limited data to understand the implications of this paradigm. Prior work in other diseases show that industry trials are more likely to show favourable results than trials without industry support [
      • Lundh A.
      • Lexchin J.
      • Mintzes B.
      • Schroll J.B.
      • Bero L.
      Industry sponsorship and research outcome.
      ]. Our group has previously identified evidence of sponsorship bias: industry-funded cancer trials are more likely to be interpreted in a positive light by study authors independent of end point, effect size and statistical significance [
      • Booth C.M.
      • Cescon D.W.
      • Wang L.
      • Tannock I.F.
      • Krzyzanowska M.K.
      Evolution of the randomized controlled trial in oncology over three decades.
      ]. Only a handful of other studies have evaluated how industry involvement may influence oncology RCTs and many are over 10 years old [
      • Linker A.
      • Yang A.
      • Roper N.
      • Whitaker E.
      • Korenstein D.
      Impact of industry collaboration on randomised controlled trials in oncology.
      ,
      • Moy B.
      • Jagsi R.
      • Gaynor R.B.
      • Ratain M.J.
      The impact of industry on oncology research and practice.
      ,
      • Djulbegovic B.
      • Lacevic M.
      • Cantor A.
      • Fields K.K.
      • Bennett C.L.
      • Adams J.R.
      • et al.
      The uncertainty principle and industry-sponsored research.
      ,
      • Liang F.
      • Zhu J.
      • Mo M.
      • Zhou C.M.
      • Jia H.X.
      • Xie L.
      • et al.
      Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.
      ,
      • Pasalic D.
      • Tang C.
      • Jagsi R.
      • Fuller C.D.
      • Koong A.C.
      • Ludmir E.B.
      Association of industry sponsorship with cancer clinical trial accrual.
      ,
      • Peppercorn J.
      • Blood E.
      • Winer E.
      • Partridge A.
      Association between pharmaceutical involvement and outcomes in breast cancer clinical trials.
      ]. Djulbegovic et al. [
      • Djulbegovic B.
      • Lacevic M.
      • Cantor A.
      • Fields K.K.
      • Bennett C.L.
      • Adams J.R.
      • et al.
      The uncertainty principle and industry-sponsored research.
      ] found that industry-funded trials in myeloma were more likely to result in endorsement of new treatments over the control arms compared with non-funded trials. Pasalic and colleagues [
      • Pasalic D.
      • Tang C.
      • Jagsi R.
      • Fuller C.D.
      • Koong A.C.
      • Ludmir E.B.
      Association of industry sponsorship with cancer clinical trial accrual.
      ] found that industry-funded trials are more likely to complete accrual. Linker and colleagues [
      • Linker A.
      • Yang A.
      • Roper N.
      • Whitaker E.
      • Korenstein D.
      Impact of industry collaboration on randomised controlled trials in oncology.
      ] reported that industry-funded trials were more likely to use placebo, intention-to-treat analysis and blinding. Finally, Liang et al. [
      • Liang F.
      • Zhu J.
      • Mo M.
      • Zhou C.M.
      • Jia H.X.
      • Xie L.
      • et al.
      Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.
      ] showed that industry sponsorship was associated with concluding that a study drug was effective, although this finding was not seen in older studies.
      Importantly, the only contemporary studies [
      • Linker A.
      • Yang A.
      • Roper N.
      • Whitaker E.
      • Korenstein D.
      Impact of industry collaboration on randomised controlled trials in oncology.
      ,
      • Liang F.
      • Zhu J.
      • Mo M.
      • Zhou C.M.
      • Jia H.X.
      • Xie L.
      • et al.
      Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.
      ] focus only on trials published in high impact journals, which may identify factors associated with high impact publication rather than industry funding. Additionally, none of these modern studies has explored three critical elements to gauge the clinical utility and applicability of RCTs: whether industry funding is associated with differences in cancer type, treatment intent or use of surrogate end points. Given the increasing ubiquity of industry involvement in cancer clinical trials, we undertook the following study to understand how this may influence the study design, results and interpretation of RCTs.

      Materials and Methods

       Study Design and Search Strategy

      This was a secondary analysis of a previous sample of all phase III oncology RCTs published between 2014 and 2017. The study design and identification of the sample are described elsewhere [
      • Wells J.C.
      • Sharma S.
      • Del Paggio J.C.
      • Hopman W.M.
      • Gyawali B.
      • Mukherji D.
      • et al.
      An analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries.
      ]. A structured PUBMED literature search identified all phase III RCTs of cancer therapy (systemic, radiotherapy, surgery) published during 2014–2017. Studies were excluded if they reported only subset/pooled analyses, reported interim analyses or assessed cancer screening/prevention. Studies of supportive and palliative care (i.e. anti-emetics, growth factors) or integrative medicine (i.e. yoga, vitamins) were excluded.

       Data Abstraction and Classification

      A standardised data abstraction form was used to capture information regarding study funding, design, results and journal of publication. Data abstraction was carried out independently by two authors (JCW, SS). The senior author (CMB) carried out random duplicate abstraction throughout the process to validate the quality of data abstraction. At the completion of data collection, 30 studies were randomly chosen for double review; only 11/1020 variables (1%) were found to be discordant with the original assessment.
      The RCT funding source was identified by explicit statements of study support in the manuscript. Any study with industry funding/support was classified as ‘industry funded’. Studies were classified into country of origin based on the institutional affiliation of the first author; country of origin was used to further divide studies into low-middle-/upper-middle-income countries (collectively referred to as LMICs) or high-income countries (HICs) based on standard World Bank designations [
      The World Bank
      World Bank country and lending group.
      ].

       Outcomes and Statistical Analysis

      Journal impact factor was compared using the impact factor from 2016, as reported by the Journal Citation Reports Impact Factor []. For each RCT, treatment intent was classified as palliative or curative (which included neo/adjuvant and curative therapy). We also compared the primary end point effect size (i.e. hazard ratio) of ‘positive’ superiority RCTs between industry and non-industry trials. Version 1.1 of the European Society of Medical Oncology-Meaningful Clinical Benefit Score (ESMO-MCBS) was used to derive a grade based on the positive end point for systemic therapy [
      • Cherny N.I.
      • Dafni U.
      • Bogaerts J.
      • Latino N.J.
      • Pentheroudakis G.
      • Douillard J.Y.
      • et al.
      ESMO-Magnitude of Clinical Benefit Scale version 1.1.
      ]. Grades of A and B (curative setting) and 5 and 4 (palliative setting) were considered to have ‘substantial’ benefit.
      Statistical analysis was conducted using IBM SPSS version 26.0 for Windows (Armonk, New York, USA, 2019). Descriptive results (frequencies, percentages, medians and quartiles) were generated for the full study sample and comparisons were made between studies funded by industry and those without industry support. Categorical outcomes were compared using the Pearson chi-squared test or the exact test in the event of cells with fewer than five cases. Continuous data were compared using the Mann–Whitney U or the Kruskal–Wallis test. The initial analysis included all RCTs regardless of treatment modality. Secondary analyses were restricted to trials of systemic therapy; stratified analyses were carried out for trials with palliative intent and those with curative intent. P values less than 0.05 were considered significant; no adjustments for multiple comparisons were made.

      Results

       Results of the Search Strategy

      The search strategy identified 2275 publications. Reasons for exclusion were: subset or pooled analysis (n = 883), not phase III RCT (n = 250), not anti-cancer intervention (n = 217), protocol/interim analysis (n = 134) or additional reports of included study (n = 97) (see supplementary Figure S1). The final study sample included 694 RCTs.

       Design Characteristics of Randomised Controlled Trials

      Most RCTs were funded by industry (493/694, 71%). The characteristics of the study sample are presented in Table 1, Table 2. The most common cancers enrolled were breast (17%, 121/694), lung (15%, 104/694) and colorectal (8%, 58/694). Two-thirds (65%, 448/694) of RCTs were conducted in the palliative setting. Eighty-seven per cent (601/694) of trials tested systemic therapy (34% cytotoxic, 19% tyrosine kinase inhibitor, 8% monoclonal antibody, 6% hormone, 23% multi-agent, 10% other) and 13% (88/694) tested radiotherapy or surgery. Sixty per cent (416/694) of RCTs tested palliative-intent systemic therapies. The most common primary end points were progression-free survival (32%, 220/694), overall survival (31%, 215/694) and disease-/event-/relapse-free survival (DFS/EFS/RFS; 22%, 149/694).
      Table 1Characteristics of oncology randomised controlled trials (RCTs) published globally 2014–2017, stratified based on industry funding status
      All RCTsIndustry fundedNon-industry fundedP-value
      N = 694N = 493N = 201
      n (%)
      Site
      Breast121 (17)96 (20)25 (12)<0.001
      Lung104 (15)82 (17)22 (11)
      Gastrointestinal127 (18)85 (17)42 (21)
      Haematological123 (18)96 (20)27 (13)
      Other219 (32)134 (27)85 (42)
      Treatment intent
      Palliative448 (65)367 (74)81 (41)<0.001
      Curative
      Includes treatments given in the neoadjuvant, adjuvant and curative context.
      244 (35)126 (26)118 (59)
      Experimental arm
      Systemic601 (87)477 (97)124 (62)<0.001
      Radiation38 (6)1 (0.2)37 (18)
      Surgery16 (2)2 (0.4)14 (7)
      Systemic/radiation34 (5)10 (2)18 (9)
      Other
      Other experimental arms included surgery/radiation (n = 1) and other (n = 2) for industry funded; systemic/surgical (n = 5) and other (n = 3) for non-industry funded.
      5 (1)3 (1)8 (4)
      Study design
      Superiority610 (88)444 (90)166 (83)0.006
      Non-inferiority/equivalence84 (12)49 (10)35 (17)
      Primary end point
      Overall survival215 (31)154 (31)61 (30)<0.001
      DFS/EFS/RFS149 (22)84 (17)65 (32)
      PFS/TTF232 (33)198 (40)34 (17)
      Other
      Other primary end points included quality of life/toxicity (n = 14), response rate (n = 28) and other (n = 15) for industry funded; quality of life/toxicity (n = 7), response rate (n = 16) and other (n = 18) for non-industry funded.
      33 (5)57 (12)41 (20)
      DFS/EFS/RFS, disease-free survival/event-free survival/relapse-free survival; PFS/TTF, progression-free survival/TTF, time to failure.
      Includes treatments given in the neoadjuvant, adjuvant and curative context.
      Other experimental arms included surgery/radiation (n = 1) and other (n = 2) for industry funded; systemic/surgical (n = 5) and other (n = 3) for non-industry funded.
      Other primary end points included quality of life/toxicity (n = 14), response rate (n = 28) and other (n = 15) for industry funded; quality of life/toxicity (n = 7), response rate (n = 16) and other (n = 18) for non-industry funded.
      Table 2Results of all oncology randomised controlled trials (RCTs) published globally 2014–2017 stratified based on industry funding status
      All RCTsIndustry fundedNon-industry fundedP-value
      N = 694N = 493N = 201
      n (%)n (%)n (%)
      Total sample size
      Median (IQR)443 (246–718)474 (280–739)345 (184–650)<0.001
      Primary end point met
      Yes325 (47)243 (49)82 (41)0.042
      No369 (53)250 (51)119 (59)
      Hazard ratio for positive superiority RCTs
      Only reported for n = 262 positive superiority trials (203 yes and 59 no); hazard ratio not reported for 21/203 and 24/59 trials for the yes and no groups, respectively.
      Median (IQR)0.68 (0.64–0.75)0.68 (0.64–0.75)0.67 (0.57–0.75)0.744
      ESMO-MCBS grade
      Only reported for 166/262 positive superiority trials (143 industry funded and 23 not).
      Substantial benefit (A,B,4,5)55 (33)45 (32)10 (44)0.256
      Not substantial benefit (C,1,2,3)111 (67)98 (69)13 (57)
      Column percentages are rounded up so may total 101%. P-values are from the Pearson chi-squared test for categorical data and the Mann–Whitney U for continuous data.
      ESMO-MCBS, European Society of Medical Oncology-Meaningful Clinical Benefit Score; IQR, interquartile range.
      Only reported for n = 262 positive superiority trials (203 yes and 59 no); hazard ratio not reported for 21/203 and 24/59 trials for the yes and no groups, respectively.
      Only reported for 166/262 positive superiority trials (143 industry funded and 23 not).
      Elements of RCT design are shown in Table 1. Industry trials were disproportionately led by investigators in HICs than non-industry trials (industry: 95% HIC, 5% LMIC versus non-industry: 83% HIC, 17% LMIC, P < 0.001). The three most common tumour sites for industry trials were breast (n = 96; 20%), haematological (n = 96; 20%) and gastrointestinal (n = 85; 17%) cancers. The most common tumour sites for non-industry-funded trials were gastrointestinal (n = 42; 21%), haematological malignancy (n = 27; 13%) and head and neck (n = 25, 12%). Trials of breast cancer represented only 12% (25/201) of non-industry-funded trials. Industry-funded trials were more likely to test systemic therapies compared with trials without industry support (97% versus 62%) and were less likely to study radiotherapy or surgery (3% versus 38%, P < 0.001). The proportion of palliative-intent (74% industry trials versus 41% non-industry) and curative-intent trials (26% industry trials versus 59% non-industry) varied by funding source (P < 0.001).
      Although the use of overall survival as the primary end point was comparable between both groups (31% versus 30%), industry trials were more likely to use progression-free survival (40% versus 17%, P < 0.001) and were less likely to use DFS/EFS/RFS (17% versus 32%, P < 0.001) than non-industry trials. This was probably driven by the different proportion of palliative-intent/curative trials among the two funding sources as this difference disappeared with stratification by treatment intent (Table 3).
      Table 3Characteristics of systemic therapy oncology randomised controlled trials (RCTs) published globally 2014–2017, stratified by treatment intent and funding status
      Palliative intentCurative intent
      Industry fundedNot industry fundedP-valueIndustry fundedNot industry fundedP-value
      NumberN = 359N = 57N = 118N = 67
      n (%)n (%)n (%)n (%)
      Site
      Breast46 (13)5 (9)0.32850 (42)10 (15)0.004
      Lung74 (21)10 (18)3 (3)4 (6)
      Gastrointestinal61 (17)15 (26)18 (15)16 (24)
      Haematological74 (21)8 (14)22 (19)16 (24)
      Other104 (29)19 (33)25 (21)21 (31)
      Primary end point
      Overall survival133 (37)20 (35)0.58613 (11)14 (21)0.324
      DFS/EFS/RFS10 (3)2 (4)72 (61)37 (55)
      PFS/TTF181 (50)26 (46)14 (12)6 (9)
      Other
      Other primary end points for palliative intent and curative therapy are quality of life/toxicity (n = 9 and n = 4), response rate (n = 19 and n = 9) and other (n = 7 and n = 6) for industry funded; quality of life/toxicity (n = 1 and n = 2), response rate (n = 7 and n = 5) and other (n = 1 and n = 3) for non-industry funded.
      35 (10)9 (16)19 (16)10 (15)
      Total sample size
      Median (IQR)452

      (280–669)
      257

      (147–451)
      <0.001605

      (296–1554)
      441

      (263–815)
      0.022
      Primary end point met
      Yes187 (52)25 (44)0.24854 (46)28 (42)0.601
      No172 (48)32 (56)64 (54)39 (58)
      Hazard ratio for positive RCTs
      Only reported for n = 180 positive superiority trials (158 yes and 22 no); hazard ratio not reported for 12/158 and 6/22 trials for the yes and no groups, respectively. For curative intent, reported for n = 62 positive superiority trials (43 yes and 19 no); hazard ratio not reported for 9/43 and 9/19 trials for the yes and no groups, respectively.
      Median (IQR)0.68 (0.64–0.74)0.67 (0.60–0.75)0.8280.70 (0.62–0.75)0.74 (0.69–0.80)0.123
      ESMO-MCBS grade
      Only reported for positive superiority trials.
      Substantial benefit (A,B,4,5)31 (26)1 (8)0.29214 (58)6 (86)0.372
      Not substantial benefit (C,1,2,3)88 (74)11 (92)10 (42)1 (14)
      Column percentages are rounded up so may total 101%. P-values are from the Pearson chi-squared test or Fisher's exact test for categorical data and the Mann–Whitney U for continuous data.
      DFS/EFS/RFS, disease-free survival/event-free survival/relapse-free survival; ESMO-MCBS, European Society of Medical Oncology-Meaningful Clinical Benefit Score; IQR, interquartile range; PFS/TTF, progression-free survival/TTF, time to failure.
      Other primary end points for palliative intent and curative therapy are quality of life/toxicity (n = 9 and n = 4), response rate (n = 19 and n = 9) and other (n = 7 and n = 6) for industry funded; quality of life/toxicity (n = 1 and n = 2), response rate (n = 7 and n = 5) and other (n = 1 and n = 3) for non-industry funded.
      Only reported for n = 180 positive superiority trials (158 yes and 22 no); hazard ratio not reported for 12/158 and 6/22 trials for the yes and no groups, respectively. For curative intent, reported for n = 62 positive superiority trials (43 yes and 19 no); hazard ratio not reported for 9/43 and 9/19 trials for the yes and no groups, respectively.
      Only reported for positive superiority trials.

       Results of Randomised Controlled Trials

      Industry-funded trials had a larger median sample size (474, interquartile range [IQR] 280–739 versus 345, IQR 184–650; P < 0.001) and were more likely to meet their primary end point (49% versus 41%, P = 0.042) compared with non-industry-funded trials. This observation persisted when analysis was restricted to superiority trials (46% versus 36%, P = 0.024). The observed effect size (median hazard ratio) for the primary end point was comparable between both groups of trials (hazard ratio 0.68 and 0.67, P = 0.744). Among ‘positive’ trials, there was no significant difference in the proportion meeting ESMO-MCBS thresholds for substantial clinical benefit (32% versus 44%, P = 0.256).

       Stratified Analyses of Systemic Therapy Trials

      Systemic therapies were tested in 601 RCTs. As shown in supplementary Table S1, there were differences in diseases studied, with industry trials more likely to study breast cancer (20% versus 12%, P = 0.051) and less likely to study gastrointestinal cancers (17% versus 25%, P = 0.019). Differences in primary end points, median sample sizes and the proportion of ‘positive’ trials were similar to trends observed in the full study sample.
      Systemic therapy trials were further stratified by treatment intent (palliative versus curative/adjuvant/neoadjuvant) (Table 3). In the non-curative setting, industry trials were more likely to study lung, haematological and gastrointestinal cancers; in the curative setting, the most commonly studied cancers were breast, haematological and gastrointestinal. Curative-intent industry trials were more likely to study breast cancer than comparable non-industry-funded trials (42% versus 15%, P < 0.001). In both the palliative and curative setting, industry trials were larger. Primary end point selection in palliative and curative settings was comparable between industry and non-industry trials.

       Publication of Randomised Controlled Trials

      Trials funded by industry were published in journals that had a significantly higher median impact factor (21, IQR 7, 28) than non-industry-funded trials (impact factor 12, IQR 5, 24; P = 0.005) (Figure 1). Positive trials (median impact factor 21, IQR 7, 35) also had significantly higher impact factors than negative trials (impact factor 14, IQR 6, 25; P = 0.039). When stratified by positive/negative results, industry-funded RCTs were still published in higher profile journals; industry positive trials median impact factor 26 (IQR 11, 48) versus non-industry positive trials impact factor 12 (IQR 5, 27) and industry negative trials impact factor 18 (IQR 7, 26) versus non-industry negative trials impact factor 11 (IQR 5, 25; P < 0.001).
      Fig 1
      Fig 1Impact factor of published trials according to industry funding.

      Discussion

      In this study, we explored the design, results and publication of all industry-funded cancer RCTs published globally during 2014–2017. Several important findings have emerged. First, most cancer RCTs are now funded by industry testing cancer medicines. Second, industry-funded trials are more likely than non-industry-funded trials to test therapies in the palliative setting. Third, industry-funded trials focus on different cancer types than non-industry trials, with breast cancer being the most common. Fourth, industry-funded trials are larger and more likely to meet their primary end point. Fifth, industry studies are published in journals with a higher impact factor, which is even more pronounced if the trial is positive. Finally, among ‘positive’ RCTs, there is no significant difference in observed effect size between industry- and non-industry-funded RCTs or their end points meeting ESMO-MCBS thresholds for ‘substantial clinical benefit’. These collective findings are relevant given that most oncology trials are now industry funded and that this proportion continues to increase with time [
      • Kay A.
      • Higgins J.
      • Day A.G.
      • Meyer R.M.
      • Booth C.M.
      Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points.
      ,
      • Booth C.M.
      • Cescon D.W.
      • Wang L.
      • Tannock I.F.
      • Krzyzanowska M.K.
      Evolution of the randomized controlled trial in oncology over three decades.
      ,
      • Del Paggio J.C.
      • Berry J.S.
      • Hopman W.M.
      • Eisenhauer E.A.
      • Prasad V.
      • Gyawali B.
      • et al.
      Evolution of the randomized clinical trial in the era of precision oncology.
      ,
      • Peppercorn J.
      • Blood E.
      • Winer E.
      • Partridge A.
      Association between pharmaceutical involvement and outcomes in breast cancer clinical trials.
      ].
      Only a handful of studies have previously explored these issues. An older study analysing breast cancer trials from before 2003 confirmed our finding that industry-funded trials were more likely to report positive outcomes than non-industry-funded studies, although an analysis of 2006 trials published in major oncology journals failed to show this association [
      • Peppercorn J.
      • Blood E.
      • Winer E.
      • Partridge A.
      Association between pharmaceutical involvement and outcomes in breast cancer clinical trials.
      ,
      • Jagsi R.
      • Sheets N.
      • Jankovic A.
      • Motomura A.R.
      • Amarnath S.
      • Ubel P.A.
      Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research.
      ]. Liang et al. [
      • Liang F.
      • Zhu J.
      • Mo M.
      • Zhou C.M.
      • Jia H.X.
      • Xie L.
      • et al.
      Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication.
      ] analysed phase II and III trials published between 2014 and 2016 (also restricted to high impact journals) to explore factors associated with a positive conclusion by study authors. Only two factors were associated with a positive conclusion: a positive primary end point and industry funding. Linker and colleagues [
      • Linker A.
      • Yang A.
      • Roper N.
      • Whitaker E.
      • Korenstein D.
      Impact of industry collaboration on randomised controlled trials in oncology.
      ] evaluated 224 phase II and III trials published in only high impact journals between 2013 and 2015 and found that industry-funded trials were more likely to have high-quality methodology, as indicated by intention-to-treat analysis, placebo control and blinding; however, the analysis did not account for differences in end point, type of therapy, treatment intent, tumour type or journal impact factor. Unlike these studies, our sample was not restricted to high impact journals and captured exclusively phase III clinical trials. This is an important difference given our finding that industry RCTs are published in higher impact journals. Prior work examining systemic therapy trials published in high impact journals indicated an even higher proportion of industry-funded trials (89%) than our sample, providing further support of an association between impact factor and industry funding [
      • Del Paggio J.C.
      • Berry J.S.
      • Hopman W.M.
      • Eisenhauer E.A.
      • Prasad V.
      • Gyawali B.
      • et al.
      Evolution of the randomized clinical trial in the era of precision oncology.
      ].
      Importantly, 97% of industry-funded trials were trials testing systemic therapy, whereas <1% evaluated new approaches to surgery and radiotherapy. The observation that industry trials almost exclusively test medicines is not surprising. Prior work has found that 96% of trials across biomedical disciplines funded by industry involve either a drug or a device as opposed to a system or a behavioural change [
      • Bourgeois F.T.
      • Murthy S.
      • Mandl K.D.
      Comparative effectiveness research: an empirical study of trials registered in ClinicalTrials.gov.
      ,
      • Fabbri A.
      • Lai A.
      • Grundy Q.
      • Bero L.A.
      The influence of industry sponsorship on the research agenda: a scoping review.
      ]. This reflects the ‘pharmaceuticalisation’ of biomedicine in general [
      • Abraham J.
      Pharmaceuticalization of society in context: theoretical, empirical and health dimensions.
      ]. Our study also illustrates important differences in the cancer studied and treatment intent. Although industry trials were more likely to study breast cancer than non-industry trials, this varied by setting. Forty-two per cent of industry-funded trials for curative therapy include breast cancer compared with only 3% in lung and 19% in haematological malignancies.
      The disproportionate number of trials in breast cancer is consistent with prior work that found that the public health burden of specific cancers is not associated with the volume of research in that disease; breast cancer accounts for 10% of cancer mortality, yet 30% of published trials in Canada and the USA [
      • Patafio F.M.
      • Brooks S.C.
      • Wei X.
      • et al.
      Research output and the public health burden of cancer: is there any relationship?.
      ]. It remains unclear why industry disproportionately invests in studies of breast cancer. Lubitow and colleagues [
      • Lubitow A.
      • Davis M.
      Pastel injustice: The corporate use of pinkwashing for profit.
      ] have postulated that breast cancer is more easily marketable than other cancers, further increasing returns on investment. Other work has found that breast cancer medicines receive greater attention in the media and may be approved more quickly than medicines for other cancers [
      • Booth C.M.
      • Dranitsaris G.
      • Gainford M.C.
      • et al.
      External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer.
      ]. It is therefore not surprising that industry may be particularly interested in pursuing new treatments in breast cancer. This does raise important questions about the ability of industry to ultimately shape the research agenda for oncology. Given that the trend has been towards increasing industry funding with time, it is plausible that the amount of research dedicated to each cancer site will be dictated less by metrics such as disease prevalence and more by profitability. Our findings reflect an imbalance in research efforts that do not deliver equity across site-specific cancers; this requires discussion within the oncology community.
      Our data also show a predilection for industry to test new cancer medicines with palliative intent. Among systemic therapy trials, 75% of industry RCTs are non-curative in nature, whereas 54% of non-industry trials are in the curative context. It is probably not coincidental that most (~70%) Food and Drug Administration approvals in oncology are for palliative-intent treatment [
      • Martell R.E.
      • Sermer D.
      • Getz K.
      • Kaitin K.I.
      Oncology drug development and approval of systemic anticancer therapy by the U.S. Food and Drug Administration.
      ]. This is a marked change from a 2006 paper by Jagsi et al. [
      • Jagsi R.
      • Sheets N.
      • Jankovic A.
      • Motomura A.R.
      • Amarnath S.
      • Ubel P.A.
      Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research.
      ] that showed that 62% of industry trials focused on curative-intent therapy versus only 36% not funded by industry. This difference could potentially be explained by an increase in the rise of drug therapeutic classes such as tyrosine kinase inhibitors, which have not seen widespread use in the adjuvant setting but are widely used in the palliative setting. Our conclusion that palliative therapies are more common in industry-funded trials were observed in a recent review of National Comprehensive Cancer Network-recommended survival prolonging treatments for non-small cell lung cancer: 79% of industry trials cited in the guidelines are related to palliative therapies, whereas 58% of academic trials are related to curative-intent treatments [
      • Gyawali B.
      • Bouche G.
      • Pantziarka P.
      • Kesselheim A.S.
      • Sarpatwari A.
      Lung cancer survival gains: contributions of academia and industry.
      ].
      Our data provide evidence for a convergence of the private sector research agenda and regulatory capture, including a lowering of the evidential bar for market authorisation, particularly in the metastatic setting [
      • Davis C.
      Drugs, cancer and end-of-life care: a case study of pharmaceuticalization?.
      ]. There are several potential explanations for our observations around funding source and treatment intent. It is possible that adjuvant therapies are inherently less profitable than medicines in the advanced setting on a per-patient basis. Alternatively, the chance of a clinical trial being ‘positive’ in the adjuvant context might be lower than a trial in the palliative setting. Treatment for metastatic disease has the potential to be more lucrative if time on a drug exceeds the average duration of adjuvant treatment for the same disease. Another reason that clinical trials in the metastatic setting may appeal to industry is the high event rates, which means trials require fewer patients and can be completed more quickly with less follow-up. Given that adjuvant treatment has the potential to cure patients entirely, these treatments may be favoured by non-industry sponsors who have a public health perspective rather than a profit-seeking perspective.
      It is worth noting that although our study shows that industry trials are more likely to be ‘positive’, there was no observed difference in effects size, as indicated by the hazard ratio or the proportion of trials meeting the ESMO-MCBS threshold for substantial benefit. Our results illustrate that industry RCTs are published in higher impact journals than non-industry trials. This raises the possibility that industry trials have a disproportionate impact on clinical practice. Linker et al. [
      • Linker A.
      • Yang A.
      • Roper N.
      • Whitaker E.
      • Korenstein D.
      Impact of industry collaboration on randomised controlled trials in oncology.
      ] have suggested that trials with industry collaboration trials employ better methodology, such as placebo control, blinding and objective outcome assessors than those without. However, this is unlikely to be the only explanation for this imbalance and this issue warrants further discussion.
      Our study results should be interpreted in light of certain methodological limitations. Our sample of trials comes from a 4-year period (2014–2017) and only includes RCTs published in English; this may limit the generalisability of our results. We also did not distinguish trials that were sponsored by industry from those in which industry provided financial support (or drug) but the trial sponsor was another entity (such as a cooperative trials group). We did not explore whether trial sponsorship in itself was associated with differential design characteristics or results as the original dataset did not explicitly capture the study sponsor. Additionally, our sample was limited to only published studies and as such may capture results associated with publication and the findings may not be generalisable to the entirety of oncology clinical trials. Finally, our sample included only a minority of RCTs (13%) of radiotherapy and surgery; hence, our results may be less applicable to trials beyond systemic therapy.

      Conclusion

      In summary, we have found that most RCTs in oncology are funded by industry and they predominantly test new systemic therapies in the metastatic setting. Industry trials are larger and more likely to study breast cancer compared with non-industry studies. Although industry trials are larger and more likely to meet their primary end point than non-industry trials, there was no observed difference in the effect size or the proportion of trials identifying new treatments with substantial clinical benefit. Despite this, industry RCTs are published in higher impact journals. The primary goal of industry (i.e. to maximise profits) does not necessarily align with the primary goal of optimal clinical care for the population with cancer, which require clinical trials across all modalities (surgery, radiotherapy, palliative/supportive). The clinical trial research portfolio needs to be recalibrated to ensure that it reflects the burden of cancer-related suffering. Central to this concern is the over-emphasis on anticancer medicines relative to surgery and radiotherapy, which form the cornerstone of curative-intent cancer therapy for most solid tumours. There is a need for government research agencies and philanthropic organisations to provide funding for global RCTs to ensure a more balanced research agenda.

      Conflicts of interest

      The authors report no conflicts of interest.

      Funding

      There was no specific funding for this study.

      Acknowledgements

      C.M. Booth is supported as the Canada Research Chair in Population Cancer Care. R. Sullivan and D. Mukherji receive funding from the UK Research and Innovation GCRF grant Research for Health in Conflict ( R4HC-MENA ) ( ES/P010962/1 ).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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