There is substantial discordance among the design and conduct of clinical trials, FDA drug approval, and the current view of OS as the ultimate measure of clinical benefit. However, the recent ODAC recommendation [37] to withdraw the breast cancer indication from the bevacizumab label despite a modest and statistically significant PFS effect has raised questions regarding the magnitude of effect that should be considered clinically significant as well as whether assessment of PFS should be based on median values or hazard ratios. What Matters Most in the End 1st Peter 4:7-11 Introduction When the end of life comes it brings clarity. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. europarl.europa.eu. By Will Story Rivera . Frequency of significant improvements in OS and PFS/TTP of (A): All trials (n = 73); (B): Trials reporting OS (n = 5) or PFS/TTP (n = 27) as the primary endpoint; (C): First‐line trials (n = 48); and (D): Trials of second‐line plus other lines of therapy (second‐line+) (n = 23). (B): Plot of number of patients per arm in phase III trials. In the end, what matters most is ensuring rapid access to safe and effective oncology treatments. The study found that the longer survival times corresponded to greater use of systemic therapy for MBC; 75% of patients diagnosed in 1991–1992 were administered therapy whereas >90% of patients diagnosed in 1994–2001 received therapy. Therefore, OS was found to be an appropriate primary endpoint when the median PPS interval was short; however, it was not considered to be an optimal endpoint when the PPS interval was >12 months, because of the greater likelihood that the effect would be diluted by subsequent lines of therapy. I would really like to have another chance to talk with my sister and hear her sing “Ten Thousand Angels”. The study found that the longer survival times corresponded to greater use of systemic therapy for MBC; 75% of patients diagnosed in 1991–1992 were administered therapy whereas >90% of patients diagnosed in 1994–2001 received therapy. "In the end, what matters most in this election is not going to be who spends more or who comes up with the cleverest catch phrase. Given the emergence of molecular pathology and personalized medicine, there is an even greater urgency for collaboration between researchers and regulators. and you may need to create a new Wiley Online Library account. These findings suggest that OS is not used by investigators as a primary endpoint and most trials are not powered to detect OS benefits. 1). 5:21). These results are limited by a small sample size; however, the findings indicate that clinicians were divided between PFS/TTP and OS as the most important endpoint, underscoring the intrinsic clinical value of PFS/TTP. All rights reserved. Two types of approval exist for drugs or biological products: regular approval and accelerated approval (AA). Few trials were designed with the capacity to detect OS effects. Start dates were not available in three studies and these were excluded from all point‐in‐time analyses. Therefore, clinical trial design, and specifically the selection of the primary endpoint, is pivotal because it defines how the clinical benefit will be measured, determines the size of the trial, and determines the length of follow‐up required. Trastuzumab in combination with paclitaxel (Taxol®; Bristol‐Myers Squibb, New York) was approved for first‐line disease based on a phase III registration trial demonstrating an independently reviewed longer TTP and a statistically significant greater 12‐month survival rate for patients receiving trastuzumab and chemotherapy [3]. When outcomes from all phase III trials (n = 73) were reviewed, only a small proportion of trials demonstrated an OS gain (12%, n = 9) (Fig. In total, 73 trials, corresponding to 152 trial arms, met the eligibility criteria for this review and were included in the analysis. Of the 23 second‐line+ trials, five (22%) reported longer OS times whereas 10 (43%) reported longer PFS/TTP (Fig. Patients in the trastuzumab and paclitaxel subgroup had a longer TTP with a trend toward longer survival [28]. When asked what magnitude of effect would make treatment worthwhile, clinicians indicated that an absolute gain in OS of 2–6 months would be warranted to justify treatment. Of the trials reporting OS as a primary endpoint (n = 5), only one trial (20%) reported a significant OS gain [27] (Fig. Published. Follow/Fav What Matters Most in the End. 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Data included: agent approved, year of approval, description of indication, type of approval (AA versus regular), trial design (phase III versus phase II), and endpoint used as the basis for FDA approval. Learn more. In 1996–2003, a period governed by early AA policy, two applications were granted AA for second‐line+ disease and two applications were granted regular approval, one for second‐line+ and one for first‐line disease (Table 2). Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, Cancer Diagnostics and Molecular Pathology, Health Outcomes and Economics of Cancer Care, New Drug Development and Clinical Pharmacology, Precision Medicine Clinic: Molecular Tumor Board, I have read and accept the Wiley Online Library Terms and Conditions of Use, U.S. Department of Health and Human Services, U.S. Food and Drug Administration. In total, 28 Canadian breast cancer oncologists responded to the survey. europarl.europa.eu. In light of the entire canon of Scripture, the only kind of righteousness that avails for eternal life is the righteousness of Christ that is imputed to us by faith alone (2 Cor. Similar observations were recently published by Saad et al. by Susan Marsh. There is an urgent need to reassess standards for clinical benefit in MBC and to establish guidelines for study design and conduct and drug approval. Abstract :: These findings suggest that, in contrast to regulatory policy, OS may be a more appropriate endpoint for second‐line trials, in which the PPS interval is shorter (8.5 months, second‐line disease), whereas PFS and TTP may be more appropriate endpoints in first‐line disease, in which the PPS interval is longer (12.9 months). Finding out what matters most at the end of life Presented by The John A. Hartford Foundation. June 8, 2020 by John P. Weiss Leave a Comment . 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