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

RE: Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration We appreciate the important contribution of Tibau et al. (1) in evaluation of the magnitude of clinical benefit of US Food and Drug Administration (FDA)–approved anticancer agents. The authors report the proportion of FDA-approved indications meeting the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.0 threshold of scores for substantial clinical benefit (A and B for curative treatments or 4 or 5 for noncurative treatments, which the authors have used as a threshold for “meaningful clinical benefit”). In the discussion, the authors describe the ESMO-MCBS thresholds as “arbitrary” and then subsequently refer to them as the “ESMO-MCBS criteria for meaningful benefit.” These descriptions perpetuate two misconceptions regarding the ESMO-MCBS grading that we want to correct. First, the thresholds for substantial benefit are not “arbitrary.” The thresholds for designation of substantial benefit were derived in a careful approach involving extensive statistical modeling (2), field testing, and peer review for reasonableness (3,4) and are subject to ongoing revision in accordance with the standards for accountability for reasonableness (5). Second, the ESMO-MCBS distinguishes high-benefit from low-benefit studies, but it does not set a threshold for “clinical meaningfulness” (2–4). Indeed, studies demonstrating slightly lesser gains and achieving slightly lower scores, such as a grade of 3 in the noncurative/palliative setting, may provide benefit that is less than substantial, but that may still be considered “clinically meaningful.” While it is the prerogative of the study authors to arbitrarily define a threshold for meaningful benefit at the same level as the ESMO-MSBS thresholds for substantial benefit, this is not uncontroversial. Israeli health care researchers who retrospectively applied the ESMO-MCBS to reimbursement decisions by the Israeli health technology assessment (HTA) committee found that in the noncurative setting, most medications attaining a score of 3 or higher were approved for reimbursement whereas those with a score lower than 3 were very rarely approved. This Israeli study suggests that in a country with a developed economy and health care system and a refined HTA process, ESMO-MCBS scores of 3 or higher were correlated with the judgment by the HTA that a new therapy provides enough meaningful benefit to justify reimbursement in a resource-limited environment (6). This observation does not diminish from the impact of the reported findings, which show that the threshold for licensing by the FDA is often far less than “substantial benefit” (1), but it adds a cautionary message regarding to the use of the term “meaningful clinical benefit.” Notes Affiliations of authors: Cancer Pain and Palliative Medicine Service, Department of Medical Oncology, Shaare Zedek Medical Center, Jerusalem, Israel (NIC); Laboratory of Biostatistics, School of Health Sciences, National and Kapodistrian University of Athens and Frontier Science Foundation-Hellas, Athens, Greece (UD); Methodology Direction, EORTC Headquarters, Brussels, Belgium (JB); ESMO Head Office, Lugano, Switzerland (NJL, JYD); Medical Oncology Department, Ioannina University Hospital, Ioannina, Greece (GP); Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain (JT); Division of Oncology, Medical University Vienna, Vienna, Austria (CZ); Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium (MJP); Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (EGEdV). References 1 Tibau A , Molto C , Ocana A et al. , Magnitude of clinical benefit of cancer drugs approved by the US Food and Drug Administration . J Natl Cancer Inst. 2018 ; 110 ( 5 ): djx232 . 2 Dafni U , Karlis D , Pedeli X et al. , Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules . ESMO Open. 2017 ; 2 : e000216 . Google Scholar CrossRef Search ADS PubMed 3 Cherny N , Dafni U , Bogaerts J et al. , ESMO-Magnitude of Clinical Benefit Scale Version 1.1 . Ann Oncol. 2017 ; 28 : 2340 – 2366 . Google Scholar CrossRef Search ADS PubMed 4 Cherny NI , Sullivan R , Dafni U et al. , A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) . Ann Oncol. 2015 ; 26 : 1547 – 1573 . Google Scholar CrossRef Search ADS PubMed 5 Daniels N. Accountability for reasonableness . BMJ. 2000 ; 321 : 1300 – 1301 . Google Scholar CrossRef Search ADS PubMed 6 Hammerman A , Greenberg-Dotan S , Feldhamer I , Birnbaum Y , Cherny NI. The ESMO-Magnitude of Clinical Benefit Scale for novel oncology drugs: Correspondence with three years of reimbursement decisions in Israel . Expert Rev Pharmacoecon Outcomes Res. 2018 ; 18 : 119 – 122 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
ISSN
0027-8874
eISSN
1460-2105
D.O.I.
10.1093/jnci/djy029
Publisher site
See Article on Publisher Site

Abstract

We appreciate the important contribution of Tibau et al. (1) in evaluation of the magnitude of clinical benefit of US Food and Drug Administration (FDA)–approved anticancer agents. The authors report the proportion of FDA-approved indications meeting the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.0 threshold of scores for substantial clinical benefit (A and B for curative treatments or 4 or 5 for noncurative treatments, which the authors have used as a threshold for “meaningful clinical benefit”). In the discussion, the authors describe the ESMO-MCBS thresholds as “arbitrary” and then subsequently refer to them as the “ESMO-MCBS criteria for meaningful benefit.” These descriptions perpetuate two misconceptions regarding the ESMO-MCBS grading that we want to correct. First, the thresholds for substantial benefit are not “arbitrary.” The thresholds for designation of substantial benefit were derived in a careful approach involving extensive statistical modeling (2), field testing, and peer review for reasonableness (3,4) and are subject to ongoing revision in accordance with the standards for accountability for reasonableness (5). Second, the ESMO-MCBS distinguishes high-benefit from low-benefit studies, but it does not set a threshold for “clinical meaningfulness” (2–4). Indeed, studies demonstrating slightly lesser gains and achieving slightly lower scores, such as a grade of 3 in the noncurative/palliative setting, may provide benefit that is less than substantial, but that may still be considered “clinically meaningful.” While it is the prerogative of the study authors to arbitrarily define a threshold for meaningful benefit at the same level as the ESMO-MSBS thresholds for substantial benefit, this is not uncontroversial. Israeli health care researchers who retrospectively applied the ESMO-MCBS to reimbursement decisions by the Israeli health technology assessment (HTA) committee found that in the noncurative setting, most medications attaining a score of 3 or higher were approved for reimbursement whereas those with a score lower than 3 were very rarely approved. This Israeli study suggests that in a country with a developed economy and health care system and a refined HTA process, ESMO-MCBS scores of 3 or higher were correlated with the judgment by the HTA that a new therapy provides enough meaningful benefit to justify reimbursement in a resource-limited environment (6). This observation does not diminish from the impact of the reported findings, which show that the threshold for licensing by the FDA is often far less than “substantial benefit” (1), but it adds a cautionary message regarding to the use of the term “meaningful clinical benefit.” Notes Affiliations of authors: Cancer Pain and Palliative Medicine Service, Department of Medical Oncology, Shaare Zedek Medical Center, Jerusalem, Israel (NIC); Laboratory of Biostatistics, School of Health Sciences, National and Kapodistrian University of Athens and Frontier Science Foundation-Hellas, Athens, Greece (UD); Methodology Direction, EORTC Headquarters, Brussels, Belgium (JB); ESMO Head Office, Lugano, Switzerland (NJL, JYD); Medical Oncology Department, Ioannina University Hospital, Ioannina, Greece (GP); Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain (JT); Division of Oncology, Medical University Vienna, Vienna, Austria (CZ); Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium (MJP); Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (EGEdV). References 1 Tibau A , Molto C , Ocana A et al. , Magnitude of clinical benefit of cancer drugs approved by the US Food and Drug Administration . J Natl Cancer Inst. 2018 ; 110 ( 5 ): djx232 . 2 Dafni U , Karlis D , Pedeli X et al. , Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules . ESMO Open. 2017 ; 2 : e000216 . Google Scholar CrossRef Search ADS PubMed 3 Cherny N , Dafni U , Bogaerts J et al. , ESMO-Magnitude of Clinical Benefit Scale Version 1.1 . Ann Oncol. 2017 ; 28 : 2340 – 2366 . Google Scholar CrossRef Search ADS PubMed 4 Cherny NI , Sullivan R , Dafni U et al. , A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) . Ann Oncol. 2015 ; 26 : 1547 – 1573 . Google Scholar CrossRef Search ADS PubMed 5 Daniels N. Accountability for reasonableness . BMJ. 2000 ; 321 : 1300 – 1301 . Google Scholar CrossRef Search ADS PubMed 6 Hammerman A , Greenberg-Dotan S , Feldhamer I , Birnbaum Y , Cherny NI. The ESMO-Magnitude of Clinical Benefit Scale for novel oncology drugs: Correspondence with three years of reimbursement decisions in Israel . Expert Rev Pharmacoecon Outcomes Res. 2018 ; 18 : 119 – 122 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Mar 12, 2018

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