The role of censoring on progression free survival: Oncologist discretion advised

Prasad, Vinay; Bilal, Usama

doi:10.1016/j.ejca.2015.07.005

Cited by 23 publications

(12 citation statements)

References 7 publications

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“…toxicity, low participation in follow-up, or the initiation of an alternative therapy [ 59 ]. This type of censoring is more common in the assessment of PFS compared with OS where censoring predominantly occurs as a result of a death [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund

et al. 2017

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BackgroundThe NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE.MethodsThis paper analyses the potential value delivered by the CDF according to six value criteria. This includes validated clinical benefits scales, cost-effectiveness criteria as defined by NICE and an assessment of real-world data. The analysis focuses on 29 cancer drugs approved for 47 indications that could be prescribed through the CDF in January 2015.ResultsOf the 47 CDF approved indications, only 18 (38%) reported a statistically significant OS benefit, with an overall median survival of 3.1 months (1.4–15.7 months). When assessed according to clinical benefit scales, only 23 (48%) and 9 (18%) of the 47 drug indications met ASCO and ESMO criteria, respectively. NICE had previously rejected 26 (55%) of the CDF approved indications because they did not meet cost-effectiveness thresholds. Four drugs—bevacizumab, cetuximab, everolimus and lapatinib—represented the bulk of CDF applications and were approved for a total of 18 separate indications. Thirteen of these indications were subsequently delisted by the CDF in January 2015 due to insufficient evidence for clinical benefit—data which were unchanged since their initial approval.ConclusionsWe conclude the CDF has not delivered meaningful value to patients or society. There is no empirical evidence to support a ‘drug only’ ring fenced cancer fund relative to concomitant investments in other cancer domains such as surgery and radiotherapy, or other noncancer medicines. Reimbursement decisions for all drugs and interventions within cancer care should be made through appropriate health technology appraisal processes.

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Section: Resultsmentioning

confidence: 99%

Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund

et al. 2017

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“…In this study, the primary domains responsible for the high risk of bias judgments were missing outcome data and measurement of the outcome (see box 2 for illustrative examples). In several trials, the proportions and reasons for missing outcome data differed, which probably resulted in unbalanced censoring60 and potentially favoured the experimental drug 61. Considerable differences in the toxicity profiles of drugs was another common issue.…”

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

135

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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“…Some patients censored initially on this arm were almost surely censored for toxicity. In an independent analysis, we have shown that the PFS benefit in BOLERO-2 can vanish if one alters the assumptions around censoring [28]. …”

Section: Introductionmentioning

confidence: 99%

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

Kemp

Prasad

2017

BMC Med

Self Cite

198

147

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BackgroundSurrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies.DiscussionIn this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked.We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm.ConclusionThe use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.

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The role of censoring on progression free survival: Oncologist discretion advised

Cited by 23 publications

References 7 publications

Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund

Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund

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

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

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