Reporting harms more transparently in trials of cancer drugs

Gyawali, Bishal; Shimokata, Tomoya; Honda, Kazuo; Ando, Yumiko

doi:10.1136/bmj.k4383

Cited by 26 publications

(24 citation statements)

References 11 publications

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“…Finally, our assessments focused on the primary endpoints of randomised controlled trials; it remains possible that results for other outcomes could be at lower risk of bias. However, this is unlikely because pervasive limitations are well documented for secondary endpoints of cancer drug trials, including harms979899 and quality of life outcomes 100101. Therefore, we might not have fully captured other important shortcomings of randomised controlled trials that support cancer drug approvals.…”

Section: Discussionmentioning

confidence: 99%

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

Naci

Davis

Savović

et al. 2019

BMJ

Self Cite

137

100

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ObjectiveTo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DesignCross sectional analysis.SettingEuropean regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices.Eligibility criteriaPivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016.Main outcome measuresStudy design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents).ResultsBetween 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n=10) and measurement of the outcome (n=7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%) v 16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and non-preferred study endpoints, which were not disclosed as limitations in scientific publications.ConclusionsMost pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.

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Section: Discussionmentioning

confidence: 99%

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

Naci

Davis

Savović

et al. 2019

BMJ

Self Cite

137

100

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“…Comparative 'before and after' data on pulmonary function were not given in any of observational studies(2) which is consistent with the under-reporting of harms that has been found to be a feature of cancer trials. (24) The overriding limitation of this study is its small size with only 65 participants.…”

Section: Discussionmentioning

confidence: 96%

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multi-centre randomized clinical trial

Treasure

Farewell

Macbeth

et al. 2019

Preprint

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(348/of 350 allowed) Background: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised trial (RCT). Methods: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre 2-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen. The central trial management group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. Results: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 (Inter Quartile Range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no cross overs from control to treatment, and no treatment-related deaths or major adverse events. Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). Conclusions: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N=65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the five-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to <5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. Funding: Cancer Research UK funding Grant No. C7678/A11393 Trial registration: Clintrial.gov Registration number: NCT01106261 Date 19 th April 2010

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“…Chronic low-grade toxicities may be even more important affecting HRQoL for this group of patients [19]. In addition, recently published papers [18,20] elucidated that publications reporting the effectiveness and safety of cancer drugs often use subjective terms that downplay the seriousness of adverse events. A representative example is the SOLO2 trial, where olaparib did not improve the prespecified primary quality-of-life analysis, and this was interpreted as 'olaparib is not having a significant detrimental effect on QoL' and 'there were clinically meaningful patient-centred benefits despite the adverse effects' [18].…”

Section: Discussionmentioning

confidence: 99%

Olaparib treatment in older patients with ovarian cancer: need for ‘real-world’ data beyond clinical trials

Liposits

Wulff

Otland

et al. 2020

ecancer

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Background: Ageing is a risk factor for cancer. Worldwide, the number and proportion of adults aged ≥65 will increase, along with the incidence of ovarian cancer. Older adults are under-represented in randomised clinical trials (RCTs), and those who are enrolled have a good performance status and no major health issues. These patients are not representative of older patients seen in everyday clinical practice; therefore, age-specific data on efficacy and toxicity of olaparib in the 'real-world' setting are lacking. Methods: This observational study was conducted in the Central Jutland Region in Denmark. Data in unselected older (≥65) patients with known BRCA mutation receiving olaparib maintenance treatment for platinum-sensitive relapsed ovarian cancer were registered between 2015 and 2019. Toxicity and progression-free survival (PFS) were registered. No geriatric assessment has been performed. Results: In total, 20 consecutive patients ≥65 years were included with a median age of 75 years (range: 65-85). Most of the patients (18/20) had ECOG PS: 0-1. Treatment interruption and dose reduction occurred in 65% of the patients. Toxicities of any grade occurred in 18 (90%), whereas grade 3/4 toxicities occurred in 6 patients (30%). Treatment was terminated due to disease progression or unacceptable toxicity in 13 (65%) patients. The median PFS was 6 months (range: 2-31), and the median follow-up was 15 months (range: 3-30). Discussion: Our 'real-world' experience shows that unselected older patients represent a significant larger proportion in real life than in RCTs; furthermore, older patients in a real-world setting may experience more side effects possibly affecting the quality of life. The median PFS data suggest that older patients may not derive the same clinical benefit than their fit and younger counterparts. There is a need to enrol vulnerable/frail older patients into RCTs, ensuring that data will also be applicable in standard clinical settings. Incorporating geriatric assessment into these trials should be encouraged.

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Reporting harms more transparently in trials of cancer drugs

Abstract: Studies of cancer drugs often use terms that downplay the seriousness of adverse events. Bishal Gyawali and colleagues call for greater clarity and transparency

Cited by 26 publications

References 11 publications

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multi-centre randomized clinical trial

Olaparib treatment in older patients with ovarian cancer: need for ‘real-world’ data beyond clinical trials

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