Do Contemporary Randomized Controlled Trials Meet ESMO Thresholds for Meaningful Clinical Benefit?

Paggio, Joseph C Del; Azariah, Biju; Sullivan, Richard; Hopman, Wilma M.; James, Francis V.; Roshni, S.; Tannock, Ian F.; Booth, Christopher M.

doi:10.1093/annonc/mdw538

Cited by 69 publications

(49 citation statements)

References 15 publications

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“…About a third of “positive” randomised controlled trials of cancer drugs report treatment effects that are considered to be clinically meaningful according to the European Society of Medical Oncology Magnitude of Clinical Benefit Scale 514. Moreover, there is no association between magnitude of benefit and drug price 15.…”

Section: Introductionmentioning

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

133

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: Introductionmentioning

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

133

100

View full text Add to dashboard Cite

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“…14 Studies analyzing clinical benefit of FDA-approved drugs using these frameworks have concluded that most drugs did not have meaningful clinical benefit. [33][34][35] Although these frameworks can be used to quantify benefits, clinicians would require an in-depth and detailed understanding of the intricacies of the framework algorithms to understand the possibilities that lead to a specific score (ASCO-VF) or grade (ESMO-MCBS), which may make the output less accessible to clinicians or decision-makers with respect to the underlying magnitude of survival benefit of oncology drugs. RMST is an easily interpretable way to describe the magnitude of benefit because it is measured in the natural unit of time (eg, months), which makes interpretation of the magnitude directly accessible to clinicians and decisionmakers.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Rahmadian

Santos

Parshad

et al. 2020

Journal of the National Comprehensive Cancer Network

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Background: Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies. Methods: Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders. Results: Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32–1.77) and 2.99 months for PFS (95% CI, 2.65–3.33). Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09–1.13) and 1.42 for PFS (95% CI, 1.36–1.48). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders. Conclusions: Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer.

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“…-American Society of Clinical Oncology, ASCO) [26], а среди препаратов, изучавшихся в 226 рандомизированных контролируемых исследованиях (РКИ), клинически значимая польза в соответствии с критериями Европейского общества медицинской онкологии (англ. -European Society of Medical Oncology, ESMO) наблюдалась лишь в 70 (31%) исследованиях [27]. Причем в реальной медицинской практике польза от применения этих препаратов, согласно результатам ряда исследований, может быть значительно меньше, чем в РКИ, в связи с более пожилым возрастом больных и наличия у них большего числа коморбидностей по сравнению с тщательно отобранными участниками клинических исследований [28][29][30][31].…”

Section: соотношение стоимости и терапевтической пользы инновационныхunclassified

Economic challenges of oncological diseases’ pharmacotherapy

2020

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Oncological diseases rank high in the structure of population morbidity and mortality. They entail considerable direct and indirect economic costs. In the past decades, the cost of oncotherapy has increased significantly, which is largely conditioned by high prices of antitumor drugs, which on average increased by ten times in the past ten years. At the same time, many innovative medications have only minor advantages over cheaper old medications because they are registered based on the data on the achievement of the surrogate endpoint – extension of progression-free survival. The high cost of oncotherapy is associated with financial toxicity that affects negatively the patients’ quality of life, their adherence to treatment and consequently survival. To reduce the cost of oncotherapy, it is necessary to conduct pharma-economic analysis, the results of which can serve as the basis to negotiate price-cutting with the manufacturers, as well as to use high-quality generics and biosimilars as effective and safe as their originals, and to monitor effectiveness and safety of all antitumor drugs within the pharmacovigilance framework.

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Do Contemporary Randomized Controlled Trials Meet ESMO Thresholds for Meaningful Clinical Benefit?

Cited by 69 publications

References 15 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

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Economic challenges of oncological diseases’ pharmacotherapy

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