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Kumar H, Fojo T, Mailankody S. An Appraisal of Clinically Meaningful Outcomes Guidelines for Oncology Clinical Trials. JAMA Oncol. 2016;2(9):1238–1240. doi:10.1001/jamaoncol.2016.0931
In the past decade, several new therapies have been approved for patients with cancer, with incremental improvements in outcomes.1 Although any advance in the treatment of cancer is welcome, for many of these therapies, the effect on survival has been marginal; consequently, the high costs associated with their administration has caused concern among patients and physicians.1,2 Recognizing the need to raise standards for cancer clinical trials and define clinically meaningful outcomes, the American Society of Clinical Oncology (ASCO) Cancer Research Committee convened 4 disease-specific working groups to provide meaningful goals for future clinical trials.3 The goals chosen were deliberately modest, in recognition that more ambitious goals would be seen as unrealistic and unachievable. More important, these goals were not intended for regulatory approvals or insurance coverage; rather, they were proposed so that patients and physicians could demand better outcomes from cancer clinical trials.
In a previous review of therapies approved by the US Food and Drug Administration between 2002 and 2014 for solid tumors, only 30 of the 71 therapies (42%) can be considered to have achieved the modest clinically meaningful improvements suggested by the ASCO working groups.1
The ASCO Clinically Meaningful Outcomes Working Group perspective was first published on March 17, 2014.3 To assess the number of therapies approved that meet the standards of the ASCO clinically meaningful improvements, from October 1, 2015, to March 20, 2016, we reviewed all oncologic therapies approved by the US Food and Drug Administration since the publication of these guidelines. For each approval, we obtained information on the clinical trial supporting the approval as well as the improvements in progression-free survival (PFS) and overall survival (OS) found in these trials. The ASCO working groups recommended OS and PFS goals for clinical trials in pancreatic, lung, colon, and breast cancer.3 For other tumor types, we tried to adhere to the spirit of the ASCO guidelines and defined clinically meaningful improvements as a relative improvement of 25% and an absolute increase of 2.5 months in PFS and/or OS compared with that achieved with standard treatments. Most oncologists would agree that these values are concordant with those proposed by ASCO for the 4 cancers they considered. This study was based on previously published reports and did not analyze primary human data or samples and was therefore exempt from institutional review board approval.
Between April 1, 2014, and February 29, 2016, the US Food and Drug Administration approved 47 therapies for the treatment of cancer. Ten therapies (21%) received accelerated approval based on data from a single-arm clinical trial, precluding quantification of the improvements in OS and/or PFS compared with standard treatments. The ASCO working groups recommended OS and PFS goals for cancer clinical trials, and with these (or comparable) values as the metric, 25 of the 47 therapies (53%) met the standards for PFS, while only 9 therapies (19%) met the standards for OS (Table).
ASCO and other professional organizations are increasingly recognizing the importance of establishing clinically meaningful thresholds for cancer therapies and the word value is appearing in more narratives. Despite this change, nearly 2 years after the initial publication of the ASCO working group guidelines, only 19% of the therapies approved meet the modest OS goals established by the ASCO committees. And although some may argue that all or nearly all the trials we summarize were begun before the publication of the ASCO guidelines, while most approvals met statistically significant end points, they represent modest improvements in clinically relevant outcomes. Furthermore, 22% of the therapies received accelerated approval based on single-arm studies and represent drugs that address an unmet medical need. Future confirmatory studies will be necessary to establish their effect on clinically meaningful outcomes.4
Although we recognize the importance of incremental gains in oncology, we must also accept that the concept of building on incremental gains by combining marginally effective regimens has not brought the substantive progress for patients with cancer that we need to achieve. Thus, we believe these data reinforce the need for continued engagement of all stakeholders in ensuring that we do better for our patients. The pharmaceutical industry; academics; and professional societies, such as ASCO, the European Society for Medical Oncology, and the American Association for Cancer Research; as well as scientific journals, practicing oncologists, regulatory agencies, and patient advocacy groups must continue to demand more from trials of cancer therapy.
Corresponding Author: Sham Mailankody, MBBS, Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1233 York Ave, New York, NY 10065 (firstname.lastname@example.org).
Published Online: June 9, 2016. doi:10.1001/jamaoncol.2016.0931.
Author Contributions: Drs Kumar and Mailankody had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: Kumar, Mailankody.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Kumar, Mailankody.
Study supervision: Mailankody.
Conflict of Interest Disclosures: None reported.