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Value of PFS as surrogate in NSCLC varies considerably
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The value of providing access to new treatments for non–small cell lung cancer based on improvements in PFS varied according to incremental treatment cost, the value of life and the correlation between PFS and OS, according to results of a modeling study.
“Since 1992, the U.S. FDA has provided accelerated approval of promising treatments for serious conditions on the basis of ‘surrogate’ endpoints to expedite patient access to potentially effective innovations,” Darius N. Lakdawalla, PhD, of the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California, and colleagues wrote. “While granting earlier access to new treatments, this strategy also risks introducing treatments that later proved ineffective.”
Darius N. Lakdawalla
Lakdawalla and colleagues evaluated data from 27 published phase 3 clinical trials in NSCLC to determine the net benefit or cost of providing early access to drugs based on a PFS benefit.
Researchers used data from these trials to model a hypothetical population of patients with NSCLC treated between PFS and OS evidence publication. The model utilized an equation to determine the social value of early access to treatment per patient each month. The equation was the product of three components: mean duration of delay between PFS and OS publications, net change in survival months — or the difference between clinical value of success and the clinical cost of failures — per patient treated, and the value of each survival month.
Overall, positive PFS predicted positive OS in 71% (n = 15) of the published NSCLC studies with a mean OS benefit of 1.25 months. Of the remaining 29% of studies, the mean OS reduction was 0.14 months.
Researchers described monetary values based on “value of a statistical life-year” (VSLY) — or the amount of money society would pay to save one life-year — in low ($100,000), medium ($200,000) and high ($300,000) patient benefit scenarios. Based on data from four studies with incremental treatment costs, researchers defined the medium-value parameter of drug cost as $22,000 per patient.
Results showed it was never socially valuable to grant access to every drug with a positive PFS regardless of VSLY and publication lag time; however, it was always valuable to approve drugs with 3 or more months of PFS benefit. Across the range of model parameters, granting access to drugs with a PFS benefit between 3 and 3.5 months was associated with an incremental social value ranging from $38,000 to more than $1 million per patient per month.
Early access to drugs with PFS greater than 1 or 2 months was valuable if VSLY equaled $200,000 or more, but not $100,000 or less.
Using the medium-value parameters of $200,000 for value of a life-year and $22,000 for incremental treatment cost, granting early access to any drug with a positive PFS was worse than waiting for OS data. Using these criteria, early access to drugs with any PFS improvement was associated with a loss of more than $170,000 per patient per month. However, early access based on a PFS benefit between 1 and 3.5 months produced more than $73,000 in incremental social value.
Lakdawalla and colleagues noted these data are limited by ability for patient crossover on the trials, which may result in an underestimate of OS benefits.
“Granting early access to novel therapies on the basis of PFS data can provide value to patients in need of life-extending therapy, but at the risk of reimbursing novel therapies that later prove ineffective or harmful,” Lakdawalla and colleagues wrote. “Decision-makers must carefully balance the risks and rewards of early access based on surrogate endpoints such as PFS. We showed how the optimal decision varies substantially with incremental treatment cost, the value of life, and the correlation between PFS and OS. When faced with cheaper therapies, higher values of life or stronger PFS–OS correlations, decision-makers ought to lower thresholds for PFS benefits, and vice versa.”
This model may need to be adjusted to consider the differences in targeted agents vs. chemotherapy, Yu Shyr, PhD, Leora Horn, MD and Lynne Berry, PhD, of Vanderbilt University in Nashville, Tennessee, wrote in an invited commentary.
“Correlation of PFS with OS may need to be reconsidered in patients receiving targeted agents; at the same time, such correlation may be less important in decision models for targeted therapy, due to increased value and decreased cost conferred even during PFS,” Shyr, Horn and Berry wrote. “In other words, minimum PFS benefit of 1 month, pointing to increased likelihood of OS benefit, may be necessary to justify the social cost of chemotherapy, while targeted drug development may benefit from a decision model that incorporates any superiority in PFS, with noninferiority in OS.” – by Cameron Kelsall
Disclosure: Researchers report employment and partner roles with Precision Health Economics. Horn reports grant support from and consultant roles with Astellas, Bayer, Bristol-Myers Squibb, Clovis Oncology, Genentech, Helix BioPharma, Merck and Xcovery.
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