Cancer Drugs Reimbursed with Limited Evidence on Overall Survival and Quality of Life: Do Follow-Up Studies Confirm Patient Benefits?

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Abstract

Background and Objective Cancer drug costs have increased considerably within healthcare systems, but many drugs lack quality-of-life (QoL) and overall survival (OS) data at the time of reimbursement approval. This study aimed to review the extent of subsequent literature documenting improvements in OS and QoL for cancer drug indications where no such evidence existed at the time of reimbursement approval. Methods Drug indications with claims of added therapeutical value but a lack of evidence on OS and QoL that were reimbursed between 2010 and 2020 in Sweden were included for review. Searches were conducted in PubMed and ClinicalTrial.gov for randomized controlled trials examining OS and QoL. Results Of the 22 included drug indications, seven were found to have at least one trial with conclusive evidence of improvements in OS or QoL after a mean follow-up of 6.6 years. The remaining 15 drug indications either lacked subsequent randomized controlled trial data on OS or QoL (n = 6) or showed no statistically significant improvements (n = 9). Only one drug demonstrated evidence of improvement in both OS and QoL for its indication. Conclusions A considerable share of reimbursed cancer drug indications continue to lack evidence of improvement in both OS and QoL. With limited healthcare resources and an increasing cancer burden, third-party payers have strong incentives to require additional post-reimbursement data to confirm any improvements in OS and QoL. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-023-01285-4.

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Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC

Suresh S. Ramalingam, Johan Vansteenkiste, David Planchard … (2019)

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported.

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A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results

Tessa Kennedy-Martin, Sarah E Curtis, Douglas E Faries … (2015)

Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1023-4) contains supplementary material, which is available to authorized users.

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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

Courtney Davis, Huseyin Naci, Evrim Gurpinar … (2017)

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.