When are breakthrough therapies cost-effective?

BACKGROUND: An increasing proportion of novel drug approvals use accelerated pathways, with notable growth in the US Food and Drug Administration-designated breakthrough pathway in recent years. Breakthrough therapy (BT) designation suggests that these therapies offer substantial potential to improve health outcomes but their value for money is not fully understood, as BTs typically cost more than non-BTs (NBTs). OBJECTIVE: To assess the economic value of BTs and factors associated with their reported value. METHODS: Using the Tufts Medical Center Cost-Effectiveness (CE) Analysis Registry, we (1) summarized the CE of BTs, as measured by cost per quality-adjusted-life-year (QALY); (2) compared the CE of BTs and NBTs in the United States; and (3) identified factors associated with BT CE using general estimating equation models across US willingness-to-pay (WTP) benchmarks ($50K-$150K/QALY). RESULTS: Between 2013 and 2018, the US Food and Drug Administration approved 279 drugs, designating 83 (32%) as BTs. Incremental costs and health gains (QALYs) were higher for BTs relative to NBTs ($29,000 vs $20,000 and 0.7 vs 0.2 QALYs, respectively), and BTs had more favorable CE ratios compared with NBTs (median values $38,000/QALY vs $50,000/QALY, respectively). For BTs, hepatitis C treatments had the most favorable CE ratios, which may be driven by the curative nature of some hepatitis C therapies. Furthermore, BT CE ratios for new molecular entities (NMEs) were about 40% lower than ratios for non-NME BTs on average, which may signal more value for money when the BT has a new active molecule. Regression analysis to identify trends driving CE found that BT drugs compared with active comparators (instead of best supportive care) were less likely to be cost-effective at standard US WTP thresholds (odds ratio [OR] = 0.1-0.6) and that BTs in the neoplasm space also trended less likely to be cost-effective (OR = 0.12-0.43). CE ratios reported by studies with industry funding were also more likely to be cost-effective than ratios from studies with other funding sources (OR = 4.3-4.5), though this finding was not significant at WTP thresholds over $50,000/QALY gained. CONCLUSIONS: Evidence from published, peer-reviewed CE studies suggests that BTs may confer greater health benefits than NBTs in terms of overall QALYs. Our analysis supports that the US Food and Drug Administration BT designation may be associated with increased value for money for these BTs. However, factors such as the disease area, NME status, and comparator (active vs standard of care) will also influence whether these therapies are cost-effective. DISCLOSURES: Dr Cohen reports grants or contracts from PhRMA Foundation, National Pharmaceutical Council, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Gilead Sciences, Regeneron, Pfizer, Merck, Johnson & Johnson, Vir Biotechnology, Moderna, Amgen, and Lundbeck; consulting fees from AbbVie, Biogen, IQVIA, Novartis, Partnership for Health Analytic Research, Pharmerit, Precision Health Economics, Sage, Sanofi, and Sarepta; and stock or stock options from Bristol-Myers Squibb, Johnson & Johnson, and Merck. Ms Kowal is an employee and stockholder of Genentech, Inc. Dr Yeh is an employee and stockholder of Roche, Inc.

Cost-Effectiveness of Brexanolone Versus Selective Serotonin Reuptake Inhibitors for the Treatment of Postpartum Depression in the United States.

BACKGROUND: Brexanolone injection (BRX) was approved by the FDA in 2019 for the treatment of adult patients with postpartum depression (PPD), but its cost-effectiveness has not yet been evaluated. OBJECTIVE: To estimate the cost-effectiveness of BRX compared with treatment with selective serotonin reuptake inhibitors (SSRIs) for PPD. METHODS: We projected costs (2018 U.S. dollars) and health (quality-adjusted life-years [QALYs]) for mothers treated with BRX or SSRIs and their children. A health state transition model projected clinical and economic outcomes for mothers based on the Edinburgh Postnatal Depression Scale, from a U.S. payer perspective. The modeled population consisted of adult patients with moderate to severe PPD, similar to BRX clinical trial patients. Short-term efficacy for BRX and SSRIs came from an indirect treatment comparison. Long-term efficacy outcomes over 4 weeks, 11 years (base case), and 18 years were based on results from an 18-year longitudinal study. Maternal health utility values came from analysis of trial-based short-form 6D responses. Other inputs were derived from the literature. RESULTS: The incremental cost-effectiveness ratio for BRX versus SSRIs was $106,662 per QALY gained over an 11-year time horizon. Drug and administration costs for BRX averaged $38,501, compared with $25 for SSRIs over the studied time horizon. Maternal total direct medical costs averaged $65,908 in the BRX arm, compared with $73,653 in the SSRI arm. BRX-treated women averaged 6.230 QALYs compared with 5.979 QALYs for the SSRI arm. Adding partner costs and utilities in a sensitivity analysis further favored BRX. Results were sensitive to the severity of PPD at baseline and the model time horizon. Probabilistic sensitivity analyses indicated that BRX was cost-effective at the $150,000-per-QALY threshold with 58% probability. CONCLUSIONS: Analysis using a state transition model showed BRX to be a cost-effective therapy compared with SSRIs for treating women with PPD. DISCLOSURES: This study was funded by Sage Therapeutics, Cambridge, MA. Eldar-Lissai, Gerbasi, and Hodgkins are employees of Sage Therapeutics and own stock or stock options in the company. Gerbasi also reports previous employment with Policy Analysis Inc. Cohen contributed to this work as an independent consultant. Meltzer-Brody has a sponsored clinical research agreement with Sage Therapeutics to the University of North Carolina, as well as a sponsored research agreement from Janssen to the University of North Carolina, unrelated to this work. Meltzer-Brody has also received personal consulting fees from Cala Health and MedScape, unrelated to this work. Johnson, Chertavian, and Bond are employees of Medicus Economics, which was paid fees by Sage to conduct the research for this study. Study findings do not necessarily represent the views of CEVR or Tufts Medical Center.

Are National Comprehensive Cancer Network Evidence Block Affordability Ratings Representative of Real-World Costs? An Evaluation of Advanced Non-Small-Cell Lung Cancer.

PURPOSE: The National Comprehensive Cancer Network (NCCN) developed the Evidence Blocks framework to assess the value of oncology regimens. This study characterizes the relationship between real-world costs and NCCN affordability ratings (ARs) for advanced non-small-cell lung cancer (aNSCLC) treatments. METHODS: Using the MarketScan and PharMetrics Plus databases, we identified patients treated between 2012 and 2017 with an aNSCLC regimen evaluated by the NCCN Evidence Blocks. We estimated adjusted mean total per-patient-per-month (PPPM) costs and drug costs for each regimen using a log-linked gamma generalized linear model. Weighted regression was used to examine the correlation between adjusted mean PPPM costs per regimen and NCCN AR. RESULTS: A total of 25,162 patients with aNSCLC (mean age, 63 years [standard deviation, 10 years]; 52% male) had identifiable regimens. Mean total PPPM cost by therapeutic class ranged from $16,824 for epidermal growth factor receptors to $41,815 for immunotherapy-based treatment. Epidermal growth factor receptor and anaplastic lymphoma kinase inhibitor treatment had lower ARs compared with generic chemotherapy. No therapy was listed as AR group 5 (least expensive). In pairwise comparisons, AR group 1 had significantly higher PPPM total costs compared with AR groups 2 and 4. There were no significant differences in PPPM total cost among AR groups 2, 3, and 4. CONCLUSION: Real-world aNSCLC treatment costs are often inconsistent with the NCCN ARs. Given that NCCN Evidence Blocks are intended to inform provider-patient discussions and other decision support resources, such as the NCCN Categories of Preference, our results suggest that the NCCN ARs require further refinement and validation.

Measuring the Value of New Drugs: Validity and Reliability of 4 Value Assessment Frameworks in the Oncology Setting.

BACKGROUND: Several organizations have developed frameworks to systematically assess the value of new drugs. OBJECTIVE: To evaluate the convergent validity and interrater reliability of 4 value frameworks to understand the extent to which these tools can facilitate value-based treatment decisions in oncology. METHODS: Eight panelists used the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Institute for Clinical and Economic Review (ICER), and National Comprehensive Cancer Network (NCCN) frameworks to conduct value assessments of 15 drugs for advanced lung and breast cancers and castration-refractory prostate cancer. Panelists received instructions and published clinical data required to complete the assessments, assigning each drug a numeric or letter score. Kendall's Coefficient of Concordance for Ranks (Kendall's W) was used to measure convergent validity by cancer type among the 4 frameworks. Intraclass correlation coefficients (ICCs) were used to measure interrater reliability for each framework across cancers. Panelists were surveyed on their experiences. RESULTS: Kendall's W across all 4 frameworks for breast, lung, and prostate cancer drugs was 0.560 (P= 0.010), 0.562 (P = 0.010), and 0.920 (P < 0.001), respectively. Pairwise, Kendall's W for breast cancer drugs was highest for ESMO-ICER and ICER-NCCN (W = 0.950, P = 0.019 for both pairs) and lowest for ASCO-NCCN (W = 0.300, P = 0.748). For lung cancer drugs, W was highest pairwise for ESMO-ICER (W = 0.974, P = 0.007) and lowest for ASCO-NCCN (W = 0.218, P = 0.839); for prostate cancer drugs, pairwise W was highest for ICER-NCCN (W = 1.000, P < 0.001) and lowest for ESMO-ICER and ESMO-NCCN (W = 0.900, P = 0.052 for both pairs). When ranking drugs on distinct framework subdomains, Kendall's W among breast cancer drugs was highest for certainty (ICER, NCCN: W = 0.908, P = 0.046) and lowest for clinical benefit (ASCO, ESMO, NCCN: W = 0.345, P = 0.436). Among lung cancer drugs, W was highest for toxicity (ASCO, ESMO, NCCN: W = 0. 944, P < 0.001) and lowest for certainty (ICER, NCCN: W = 0.230, P = 0.827); and among prostate cancer drugs, it was highest for quality of life (ASCO, ESMO: W = 0.986, P = 0.003) and lowest for toxicity (ASCO, ESMO, NCCN: W = 0.200, P = 0.711). ICC (95% CI) for ASCO, ESMO, ICER, and NCCN were 0.800 (0.660-0.913), 0.818 (0.686-0.921), 0.652 (0.466-0.834), and 0.153 (0.045-0.371), respectively. When scores were rescaled to 0-100, NCCN provided the narrowest band of scores. When asked about their experiences using the ASCO, ESMO, ICER, and NCCN frameworks, panelists generally agreed that the frameworks were logically organized and reasonably easy to use, with NCCN rated somewhat easier. CONCLUSIONS: Convergent validity among the ASCO, ESMO, ICER, and NCCN frameworks was fair to excellent, increasing with clinical benefit subdomain concordance and simplicity of drug trial data. Interrater reliability, highest for ASCO and ESMO, improved with clarity of instructions and specificity of score definitions. Continued use, analyses, and refinements of these frameworks will bring us closer to the ultimate goal of using value-based treatment decisions to improve patient care and outcomes. DISCLOSURES: This work was funded by Eisai Inc. Copher and Knoth are employees of Eisai Inc. Bentley, Lee, Zambrano, and Broder are employees of Partnership for Health Analytic Research, a health services research company paid by Eisai Inc. to conduct this research. For this study, Cohen, Huynh, and Neville report fees from Partnership for Health Analytic Research. Outside of this study, Cohen receives grants and direct consulting fees from various companies that manufacture and market pharmaceuticals. Mei reports a grant from Eisai Inc. during this study. The other authors have no disclosures to report. Study concept and design were contributed by Bentley and Broder, with assistance from Elkin and Cohen. Bentley took the lead in data collection, along with Elkin, Huynh, Mukherjea, Neville, Mei, Popescu, Lee, and Zambrano. Data interpretation was performed by Bentley and Broder, along with Elkin, Cohen, Copher, and Knoth. The manuscript was written primarily by Bentley, along with Elkin and Broder, and revised by Bentley, Broder, Elkin, Cohen, Copher, and Knoth. Select components of this work's methods were presented at ISPOR 19th Annual European Congress held in Vienna, Austria, October 29-November 2, 2016, and Society for Medical Decision Making 38th Annual North American Meeting held in Vancouver, Canada, October 23-26, 2016.

Validity and Reliability of Value Assessment Frameworks for New Cancer Drugs.

BACKGROUND: Several organizations have developed frameworks to systematically assess the value of new drugs. These organizations include the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review (ICER), and the National Comprehensive Cancer Network (NCCN). OBJECTIVES: To understand the extent to which these four tools can facilitate value-based treatment decisions in oncology. METHODS: In this pilot study, eight panelists conducted value assessments of five advanced lung cancer drugs using the ASCO, ESMO, and ICER frameworks. The panelists received instructions and published clinical data required to complete the assessments. Published NCCN framework scores were abstracted. The Kendall's W coefficient was used to measure convergent validity among the four frameworks. Intraclass correlation coefficients were used to measure inter-rater reliability among the ASCO, ESMO, and ICER frameworks. Sensitivity analyses were conducted. RESULTS: Drugs were ranked similarly by the four frameworks, with Kendall's W of 0.703 (P = 0.006) across all the four frameworks. Pairwise, Kendall's W was the highest for ESMO-ICER (W = 0.974; P = 0.007) and ASCO-NCCN (W = 0.944; P = 0.022) and the lowest for ICER-NCCN (W = 0.647; P = 0.315) and ESMO-NCCN (W = 0.611; P = 0.360). Intraclass correlation coefficients (confidence interval [CI]) for the ASCO, ESMO, and ICER frameworks were 0.786 (95% CI 0.517-0.970), 0.804 (95% CI 0.545-0.973), and 0.281 (95% CI 0.055-0.799), respectively. When scores were rescaled to 0 to 100, the ICER framework provided the narrowest band of scores. CONCLUSIONS: The ASCO, ESMO, ICER, and NCCN frameworks demonstrated convergent validity, despite differences in conceptual approaches used. The ASCO inter-rater reliability was high, although potentially at the cost of user burden. The ICER inter-rater reliability was poor, possibly because of its failure to distinguish differential value among the sample of drugs tested. Refinements of all frameworks should continue on the basis of further testing and stakeholder feedback.

The Cost-Effectiveness of Oral Nutrition Supplementation for Malnourished Older Hospital Patients.

BACKGROUND: Malnutrition, which is associated with increased medical complications in older hospitalized patients, can be attenuated by providing nutritional supplements. OBJECTIVE: This study evaluates the cost effectiveness of a specialized oral nutritional supplement (ONS) in malnourished older hospitalized patients. METHODS: We conducted an economic evaluation alongside a multicenter, randomized, controlled clinical trial (NOURISH Study). The target population was malnourished older hospitalized patients in the USA. We used 90-day (base case) and lifetime (sensitivity analysis) time horizons. The study compared a nutrient-dense ONS, containing high protein and ß-hydroxy-ß-methylbutyrate to placebo. Outcomes included health-care costs, measured as the product of resource use and per unit cost; quality-adjusted life-years (QALYs) (90-day time horizon); life-years (LYs) saved (lifetime time horizon); and the incremental cost-effectiveness ratio (ICER). All costs were inflated to 2015 US dollars. RESULTS: In the base-case analysis, 90-day treatment group costs averaged US$22,506 per person, compared to US$22,133 for the control group. Treatment group patients gained 0.011 more QALYs than control group subjects, reflecting the treatment group's significantly greater probability of survival through 90 days' follow-up, as reported by the clinical trial. Hence, the 90-day follow-up period ICER was US$33,818/QALY. Assuming a lifetime time horizon, estimated treatment group life expectancy exceeded control group life expectancy by 0.71 years. Hence, the lifetime ICER was US$524/LY. The follow-up period for the trial was relatively short. Some of the patients were lost to follow-up, thus reducing collection of health-care utilization data during the clinical trial. CONCLUSION: Our findings suggest that the investigative ONS cost-effectively extends the lives of malnourished hospitalized patients.

A quantitative risk-benefit analysis of changes in population fish consumption.

Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish contain methyl mercury (MeHg), which may harm the developing fetus. U.S. government recommendations for women of childbearing age are to modify consumption of high-MeHg fish, while recommendations encourage fish consumption among the general population because of nutritional benefits. To investigate the aggregate impacts of hypothetical shifts in fish consumption, the Harvard Center for Risk Analysis convened an expert panel (see acknowledgements). Effects investigated include prenatal cognitive development, coronary heart disease mortality, and stroke. Substitution of fish with high MeHg concentrations with fish containing less MeHg among women of childbearing age yields substantial developmental benefits and few negative impacts. However, if women instead decrease fish consumption, countervailing risks substantially reduce net benefits. If other adults (mistakenly and inappropriately) also reduce their fish consumption, the net public health impact is negative. Although high compliance with recommended fish consumption patterns can improve public health, unintended shifts in consumption can lead to public health losses. Risk managers should investigate and carefully consider how populations will respond to interventions, how those responses will influence nutrient intake and contaminant exposure, and how these changes will affect aggregate public health.

A quantitative analysis of fish consumption and coronary heart disease mortality.

Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish contain methyl mercury (MeHg), which may harm the developing fetus. U.S. government recommendations for women of childbearing age are to modify consumption of high-MeHg fish to reduce MeHg exposure, while recommendations encourage fish consumption among the general population because of the nutritional benefits. The Harvard Center for Risk Analysis convened an expert panel (see acknowledgements) to quantify the net impact of resulting hypothetical changes in fish consumption across the population. This paper estimates the impact of fish consumption on coronary heart disease (CHD) mortality and nonfatal myocardial infarction (MI). Other papers quantify stroke risk and the impacts of both prenatal MeHg exposure and maternal intake of n-3 PUFAs on cognitive development. This analysis identified articles in a recent qualitative review appropriate for the development of a dose-response relationship. Studies had to satisfy quality criteria, quantify fish intake, and report the precision of the relative risk estimates. Relative risk results were averaged, weighted proportionately by precision. CHD risks associated with MeHg exposure were reviewed qualitatively because the available literature was judged inadequate for quantitative analysis. Eight studies were identified (29 exposure groups). Our analysis estimated that consuming small quantities of fish is associated with a 17% reduction in CHD mortality risk, with each additional serving per week associated with a further reduction in this risk of 3.9%. Small quantities of fish consumption were associated with risk reductions in nonfatal MI risk by 27%, but additional fish consumption conferred no incremental benefits.

A quantitative analysis of fish consumption and stroke risk.

Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish contain methyl mercury (MeHg), which may harm the developing fetus. U.S. government recommendations for women of childbearing age are to modify consumption of high-MeHg fish to reduce MeHg exposure, while recommendations encourage fish consumption among the general population because of the nutritional benefits. The Harvard Center for Risk Analysis convened an expert panel (see acknowledgements) to quantify the net impact of resulting hypothetical changes in fish consumption across the population. This paper estimates the impact of fish consumption on stroke risk. Other papers quantify coronary heart disease mortality risk and the impacts of both prenatal MeHg exposure and maternal intake of n-3 PUFAs on cognitive development. This analysis identified articles in a recent qualitative literature review that are appropriate for the development of a dose-response relationship between fish consumption and stroke risk. Studies had to satisfy quality criteria, quantify fish intake, and report the precision of the relative risk estimates. The analysis combined the relative risk results, weighting each proportionately to its precision. Six studies were identified as appropriate for inclusion in this analysis, including five prospective cohort studies and one case-control study (total of 24 exposure groups). Our analysis indicates that any fish consumption confers substantial relative risk reduction compared to no fish consumption (12% for the linear model), with the possibility that additional consumption confers incremental benefits (central estimate of 2.0% per serving per week).

A quantitative analysis of prenatal intake of n-3 polyunsaturated fatty acids and cognitive development.

Although a rich source of n-3 polyunsaturated fatty acids (PUFAs) that may confer multiple health benefits, some fish also contain methyl mercury (MeHg), which may harm the developing fetus. U.S. government recommendations for women of childbearing age are to modify consumption of high-MeHg fish to reduce MeHg exposure, while recommendations encourage fish consumption among the general population because of the nutritional benefits. The Harvard Center for Risk Analysis convened an expert panel (see acknowledgements) to quantify the net impact of resulting hypothetical changes in fish consumption across the population. This paper estimates the impact of prenatal n-3 intake on cognitive development. Other papers quantify the negative impact of prenatal exposure to MeHg on cognitive development, and the extent to which fish consumption protects against coronary heart disease mortality and stroke in adults. This paper aggregates eight randomized controlled trials (RCTs) comparing cognitive development in controls and in children who had received n-3 PUFA supplementation (seven studies of formula supplementation and one study of maternal dietary supplementation). Our analysis assigns study weights accounting for statistical precision, relevance of three endpoint domains (general intelligence, verbal ability, and motor skills) to prediction of IQ, and age at evaluation. The study estimates that increasing maternal docosahexaenoic acid (DHA) intake by 100 mg/day increases child IQ by 0.13 points. The paper notes that findings were inconsistent across the RCTs evaluated (although our findings were relatively robust to changes in the weighting scheme used). Also, for seven of the eight studies reviewed, effects are extrapolated from formula supplementation to maternal dietary intake.