Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration

Tibau, Ariadna; Molto, Consolación; Ocaña, Alberto; Templeton, Arnoud J.; Carpio, L.P. del; Paggio, Joseph C Del; Barnadas, Agustí; Booth, Christopher M.; Amir, Eitan

doi:10.1093/jnci/djx232

Cited by 77 publications

(67 citation statements)

References 26 publications

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“…New drugs that lower the risk of side effects of chemotherapy have also been developed (DeVita and Chu 2008). The majority of new drugs, however, are approved for advanced-stage cancers and not for first-line therapy (Tibau et al 2018).…”

Section: Measuring Innovation In Cancer Treatmentmentioning

confidence: 99%

Medical innovation, education, and labor market outcomes of cancer patients

Jeon

Pohl

2019

Journal of Health Economics

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Innovations in cancer treatment have lowered mortality, but little is known about their economic benefits. We assess the effect of two decades of improvements in cancer treatment options on the labor market outcomes of breast and prostate cancer patients. In addition, we compare this effect across cancer patients with different levels of educational attainment. We estimate the effect of medical innovation on cancer patients' labor market outcomes employing tax return and cancer registry data from Canada and measuring medical innovation by using the number of approved drugs and a quality-adjusted patent index. While cancer patients are less likely to work after their diagnosis, we find that the innovations in cancer treatment during the 1990s and 2000s reduced the negative employment effects of cancer by 63-70 percent. These benefits of medical innovation are limited to cancer patients with postsecondary education, raising concerns about unequal access to improved treatment options.

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Section: Measuring Innovation In Cancer Treatmentmentioning

confidence: 99%

Medical innovation, education, and labor market outcomes of cancer patients

Jeon

Pohl

2019

Journal of Health Economics

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“…The relevant endpoint for cancer therapy is its impact on overall survival, or in some cases, progression free survival of a cancer patient. Despite some isolated examples of success with inhibitors of HER2, EGFR, BCR/ABL, or ALK kinases, the inconvenient truth from numerous clinical trials tells us that the success of inhibitors of tyrosine or serine/threonine kinases in achieving clinically relevant endpoints is poor . In all listed cases, very potent and selective tyrosine kinase inhibitors (TKIs) have been developed and they mostly show efficient target inhibition, and in many cases initial therapeutic responses, but only BCR/ABL targeting in CML by first‐ and second‐generation TKIs results routinely in patient cure .…”

Section: Introductionmentioning

confidence: 99%

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Westermarck

2018

The FEBS Journal

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Therapies targeting tyrosine and serine/threonine kinases have raised enormous interest as potential cure for cancer patients in many common cancer types. However, except for the success story with BCR/ABL tyrosine kinase inhibitors in chronic myeloid leukemia (CML), critical review of results of a large number of clinical trials indicates that the clinical success with kinase inhibitors has been overall disappointing. These alarming results call for critical assessment of whether there is some fundamental flaw in the design of strategies to target phosphorylation-dependent oncogenic signaling for cancer therapy. This viewpoint debates on one potential, but thus far largely neglected, molecular explanation why inhibition of protein kinases is not sufficient for cancer cure. We note that the phosphorylation status, and thus the oncogenic potential of any given protein, is not regulated only by kinases, but rather by an intimate balance between kinases and their antagonist phosphatases. We further review the supporting functional evidence that for oncogenic transformation of human cells it is not enough to activate kinase signaling by activated kinases, if a group of counteracting tumor suppressor phosphatases is not inactivated. Based on these considerations, and a very recently emerged role of oncogenic function of a group of phosphatase inhibitor proteins as human oncoproteins, we propose that in order to efficiently inhibit phosphorylation-dependent signaling in cancer cells, and thus provide better therapeutic index, the kinase inhibitors should be combined with strategies to reactivate tumor suppressor phosphatases such as Protein Phosphatase 2A (PP2A).

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“…Using both the ESMO-MCBS and a modified version adapted for Health Technology Assessment (HTA) [12], an analysis of 5 years (2011-2016) of EMA cancer drug approvals showed that 89 and 79% of therapies did not meet the MCBS or modified threshold respectively [13]. A USA analysis, using the ESMO-MCBS threshold, showed that over the period of 2006-2016, only 43.8% of randomized controlled trials supporting FDA approvals for new cancer drugs met the MCB threshold [14].…”

Section: Clinical Benefitsmentioning

confidence: 99%

Biased by design? Clinical trials and patient benefit in oncology

2019

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trial design • drug development • drug registration • patient benefit • risks of bias Pivotal clinical trials: biased? A recent study by Naci et al. examined the design characteristics, risks of bias and reporting adequacies of pivotal randomized controlled trials of cancer drugs approved by the EMA in the period 2014-2016 [1]. During this period, 32 new cancer drugs were approved by the EMA on the basis of 54 pivotal trials-of these, 41 (76%) were randomized controlled trials and 13 (24%) were non-randomized or single arm trials. The study reported that 49% of trials were judged to be at high risk of bias based on aspects of their design, conduct or analysis. Furthermore, only 10 (26%) randomized controlled trials measured overall survival as a primary end point, with the majority of trials evaluating surrogate metrics such as progression free survival or response rates. Furthermore, there were also discrepancies between scientific publications and regulatory documentation, thereby raising concerns of reporting inadequacies and risks of bias in both sources of information. These findings raise serious questions regarding clinical trial design and the drug registration process, particularly with regards to patient benefits. The problem is not restricted to Europe alone; previous studies have also raised concerns with US FDA approvals. For example, a study that assessed all FDA approvals of novel drugs, across all areas of medicine in the period 2005-2012, reported wide disparities in pivotal trial characteristics across different therapeutic areas [2]. While overall 219 of 448 (48.9%) pivotal trials included a surrogate end point, for cancer it was 46 of 55 (83.6%). Pivotal trials in cancer were also less likely to be randomized, double-blinded or to not include a placebo or active comparator. Another notable finding was that most cancer approvals were on the basis of a single pivotal trial, whereas for other therapeutic areas, approvals were based on two to four pivotal trials. A different study examining FDA cancer drug approvals based on response rate showed that many cancer drugs are approved based on low or modest response rates, typically tested in single-arm studies [3]. It could be argued that the surrogate end points used in such pivotal trials are acceptable as they correlate to overall survival and/or quality of life in the long term [4]. However, the data to support such an argument is lacking [5]. A recent systematic review of the association between surrogate end points and overall survival in oncology showed that the vast majority (82%) are low or moderate in strength [6]. A study of FDA approvals of cancer drugs during 2008-2012, a period in which 67% of approvals were made on the basis of a surrogate end point, assessed whether subsequent data emerged to show an increase in overall survival [7]. With a median follow-up of 4.4 years, the study reported that of 36 drugs approved with surrogate end points, only five subsequently reported improved overall survival in a randomized controlled trial, 18...

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Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration

Abstract: The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.

Cited by 77 publications

References 26 publications

Medical innovation, education, and labor market outcomes of cancer patients

Medical innovation, education, and labor market outcomes of cancer patients

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Biased by design? Clinical trials and patient benefit in oncology

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