Outcomes and endpoints in cancer trials: bridging the divide

Wilson, Michelle; Collyar, Deborah; Chingos, Diana T.; Friedlander, Michael; Ho, Tony W.; Karakasis, Katherine; Kaye, Stan B.; Parmar, Mahesh; Sydes, Matthew R.; Tannock, Ian F.; Oza, Amit M.

doi:10.1016/s1470-2045(14)70380-8

Cited by 76 publications

(52 citation statements)

References 92 publications

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“…ASCO 14 and others 25 have called for the use of OS in oncology trials, noting its importance in assessing value. However, evaluating OS may require a larger sample size than evaluations of disease-free survival or objective response.…”

Section: Discussionmentioning

confidence: 99%

Impact of industry collaboration on randomised controlled trials in oncology

Linker

Yang

Roper

et al. 2017

European Journal of Cancer

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Background Industry funders can simply provide money or collaborate in trial design, analysis, or reporting of clinical trials. Our aim was to assess the impact of industry collaboration on trial methodology and results of randomized controlled trials (RCT). Methods We searched PubMed for oncology RCTs published May 2013 to December 2015 in peer-reviewed journals with impact factor > 5 requiring reporting of funder role. Two authors extracted methodologic (primary endpoint; blinding of the patient, clinician, and outcomes assessor; and analysis) and outcome data. We used descriptive statistics and two-sided Fisher exact tests to compare characteristics of trials with collaboration, with industry funding only, and without industry funding. Results We included 224 trials. Compared to those without industry funding, trials with collaboration used more placebo control (RR 3·59, 95% CI [1·88–6·83], p<·0001), intention-to-treat analysis (RR 1·32, 95% CI [1·04–1·67], p=·02), and blinding of patients (RR 3·05, 95% CI [1·71–5·44], p<·0001), clinicians (RR 3·36, 95% CI [1·83–6·16], p=<·001), and outcomes assessors (RR 3·03, 95% CI [1·57–5·83], p=·0002). They did not differ in use of overall survival as a primary endpoint (RR 1·27 95% CI [0·72–2·24]) and were similarly likely to report positive results (RR 1·11 95% CI [0·85–1·46], p=0·45). Studies with funding only did not differ from those without funding. Conclusions Oncology RCTs with industry collaboration were more likely to use some high-quality methods than those without industry funding, with similar rates of positive results. Our findings suggest that collaboration is not associated with trial outcomes and that mandatory disclosure of funder roles may mitigate bias.

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Section: Discussionmentioning

confidence: 99%

Impact of industry collaboration on randomised controlled trials in oncology

Linker

Yang

Roper

et al. 2017

European Journal of Cancer

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“…The most informative and valuable studies are those providing robust evidence from well designed randomised controlled trials that a new drug has a significant effect on outcomes that are important to patients and that the magnitude of those effects, compared with other treatment options, are clinically meaningful. Although the goal of cancer treatment is to improve the quantity and quality of life,1 2 3 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4 5 6 7 8 9 10 11 or quality of life4 6 11 12 13 in all settings, and two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low 8…”

Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

466

415

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Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

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“…In addition, patients can report the impact of cancer on their daily life, as well as their perception of the disease [15]. Although PROs including HRQoL are now being recognised as direct measures of benefit to patients and as independent endpoints in cancer clinical trials, they are poorly reported in cancer trials or may even be excluded as measures [16]. For example, between 2008 and 2011, only 30% of Phase III breast cancer clinical trials included PRO measures as an endpoint [17].…”

Section: The Role Of Pros In Improving Patient Managementmentioning

confidence: 99%

Improving Outcomes in Patients with CRC: The Role of Patient Reported Outcomes—An ESDO Report

Cutsem

Gramont

Henning³

et al. 2017

Cancers

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Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient’s health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer.

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Outcomes and endpoints in cancer trials: bridging the divide

Cited by 76 publications

References 92 publications

Impact of industry collaboration on randomised controlled trials in oncology

Impact of industry collaboration on randomised controlled trials in oncology

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Improving Outcomes in Patients with CRC: The Role of Patient Reported Outcomes—An ESDO Report

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