Indirect treatment comparison of oral versus injectable azacitidine as maintenance therapy for acute myeloid leukemia.

Aim: Evaluate the relative efficacy of oral versus injectable azacitidine (AZA) maintenance therapy in acute myeloid leukemia (AML) after complete remission. Materials & methods: Systematic literature review identified QUAZAR AML-001, HOVON 97 AML, UK NCRI AML16 and QoLESS-AZA-AMLE (sensitivity analysis) trials. Network meta-analysis and matching-adjusted indirect comparisons assessed survival outcomes. Results: In the network meta-analysis, combining the HOVON 97 and UK NCRI trials, oral AZA (QUAZAR) was associated with significantly improved overall survival (OS) versus injectable AZA (hazard ratio: 0.744; 95% credible interval: 0.557-0.998). After matching-adjusted indirect comparisons, to address differences in patient characteristics across trials, OS improvements were maintained with oral versus injectable AZA (hazard ratio: 0.753; credible interval: 0.563-0.998). Conclusion: In AML, maintenance therapy with oral AZA was associated with improved OS versus injectable AZA.

Older people with acute myeloid leukemia (AML) may have remission with or without blood count recovery, after first-line chemotherapy; however, remission is short lived and overall survival is limited (7­12 months). Ongoing treatment (maintenance therapy) after response to initial chemotherapy may prolong remission. Maintenance therapy with azacitidine (AZA) given by injection beneath the skin (subcutaneous) or into a vein (intravenous) can extend disease-free survival compared with no further treatment and best supportive care. However, treatment with intravenous AZA may only extend overall survival in certain patients. ONUREG^® is a novel formulation of AZA that can be taken by mouth (orally), remains in the body for longer periods and has the potential for significant clinical benefits compared with intravenous AZA. Presently, there are no studies directly comparing outcomes of maintenance therapy with oral and injectable AZA in older people with AML. In this analysis, we used an indirect treatment comparison method including four clinical trials to explore the survival benefit associated with ONUREG and injectable AZA when used as maintenance therapies after response to initial chemotherapy in older people with AML. Findings showed ONUREG significantly improved overall survival compared with injectable AZA, with an almost 26% reduction in the risk of death. These results suggest that maintenance therapy with ONUREG significantly improves overall survival compared with injectable AZA in older people with AML who may have remission with or without blood count recovery, after first-line chemotherapy.

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.

Risk of Developing Comorbidities Among Women with Endometriosis: A Retrospective Matched Cohort Study.

BACKGROUND: Endometriosis has been associated with higher rates of various chronic conditions, but its epidemiological data are fragmented and dated. We sought to compare the incidence of developing commonly occurring comorbidities among patients with and without endometriosis in a large, contemporary patient cohort that reflects real-world clinical practice. MATERIALS AND METHODS: A cohort of women aged 18-49 with incident endometriosis was extracted from the 2006-2015 de-identified Clinformatics® DataMart commercial insurance claims database (OptumInsight, Eden Prairie, MN). Endometriosis was identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 617.x on ≥1 inpatient or emergency department claim or ≥2 outpatient claims. Nonendometriosis control patients were exactly matched 4:1 to cases based on state, insurance plan type, and age (±1 year). Based on a literature review and expert consultation, 22 comorbidities were identified for analysis. The risk of developing a comorbidity post-index date was analyzed with stratified Cox proportional hazards models. RESULTS: There were 26,961 cases and 107,844 controls. Mean age was 36 years. The adjusted risk of developing a comorbid condition among endometriosis cases was statistically significantly higher than the matched controls for all 22 comorbidities (p ≤ 0.001) and was at least twice as large for nine comorbidities (infertility/subfertility, ovarian cyst, uterine fibroids, pelvic inflammatory disorder, interstitial cystitis, irritable bowel syndrome, constipation/dyschezia, ovarian cancer, and endometrial cancer). CONCLUSION: The incidence of developing many comorbidities was significantly higher among endometriosis patients compared with matched women without endometriosis. Additional research is needed to establish the implications for healthcare resource use.

Changes in Healthcare Spending After Diagnosis of Comorbidities Among Endometriosis Patients: A Difference-in-Differences Analysis.

INTRODUCTION: We sought to characterize changes in healthcare spending associated with the onset of 22 endometriosis-related comorbidities. METHODS: Women aged 18-49 years with endometriosis (N = 180,278) were extracted from 2006-2015 de-identified Clinformatics® DataMart claims data. For 22 comorbidities, comorbidity patients were identified on the basis of having a first comorbidity diagnosis after their initial endometriosis diagnosis. Controls were identified on the basis of having no comorbidity diagnosis and were matched 1:1 to comorbidity patients on demographics and baseline spending. Total medical and pharmacy spending was measured during 12 months before and after each patient's index date (first comorbidity diagnosis for comorbidity patients, and equal number of days after earliest endometriosis claim for controls). Pre-post spending differences were compared using difference-in-differences linear regression. Total and comorbidity-related cumulative spending per patient for all endometriosis patients were calculated annually for the 5 years following endometriosis diagnosis. RESULTS: The number of endometriosis patients with each comorbidity varied between 121 for endometrial cancer and 16,177 for fatigue. Healthcare spending increased significantly with the onset of eight comorbidities: breast cancer, ovarian cancer, pregnancy complications, systemic lupus erythematosus/rheumatoid arthritis/Sjogren's/multiple sclerosis, infertility, uterine fibroids, ovarian cyst, and headache [p < 0.001 except for headache (p = 0.045)]. Spending decreased significantly for fatigue, cystitis/UTI, and eczema [p < 0.001 except for fatigue (p = 0.048)] and was not statistically different for the other 11 comorbidities. Difference-in-differences estimates were significantly higher for comorbidity patients for all comorbidities except eczema (p ≤ 0.003). Mean 5-year total cumulative spending was $58,191 per endometriosis patient, of which between 11% and 23% was attributable to comorbidity-related medical claims. CONCLUSION: For all but one of the 22 comorbidities associated with endometriosis, comorbidity onset was associated with a relative increase in total healthcare spending. FUNDING: AbbVie Inc.

Effects of non-medical switching on outcomes among patients prescribed tumor necrosis factor inhibitors.

OBJECTIVE: To evaluate health care use and outcomes among patients who experienced a non-medical switch of their prescribed anti-tumor-necrosis-factor biological agent (anti-TNF) for cost containment reasons. METHODS: Retrospective evaluation of Humedica electronic health records of patients ≥18 years old with anti-TNF treatment for immune conditions. Using natural language processing, stable patients who experienced a non-medical switch (for cost reasons) of their anti-TNF between 2007 and 2013 were identified (NMS cohort, n = 158) and matched to patients who did not (control cohort, n = 4804). Rates of office visits, emergency department visits, and hospitalizations at 30, 90, and 365 days following were evaluated. Medication-related adverse events, defined as subsequent medication change due to a side effect and/or efficacy-related reason were also compared. RESULTS: Adjusted rates of office visits were higher among the NMS cohort than the control cohort at 30 (46.4% vs. 31.7%, p < .001), 90 (71.0% vs. 57.0%, p < .001), and 365 days (87.8% vs. 76.8%, p < .001). Rates of emergency department use and hospitalization were comparable between cohorts. The NMS cohort had higher adjusted rates of medication-related adverse consequences (both increased side effects and diminished efficacy) than the control cohort at 30 (13.8% vs. 4.0%, p = .003), 90 (31.6% vs 9.6%, p < .001), and 365 days (54.7% vs. 20.3%, p < .001). Compared with controls, the NMS cohort had higher adjusted rates of subsequent medication change within 1 year (27.82% vs. 13.9%, p = .001). CONCLUSION: Non-medical switching among patients prescribed anti-TNFs was associated with increased health care use, medication-related side effects, and reports of diminished efficacy.

Economic evaluation of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic genotype 1 hepatitis c virus infection.

OBJECTIVES: To estimate clinical outcomes and cost-effectiveness of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (OMB/PTV/r + DSV ± RBV) compared with treatment regimens including pegylated interferon (PegIFN) for patients with chronic genotype 1 hepatitis C virus (HCV) infection. METHODS: An Excel spreadsheet Markov model tracking progression through stages of liver disease was developed. Costs and patient utilities for liver disease stages were taken from published studies. Rates of disease progression were based on studies of untreated HCV infection and long-term follow-up of those achieving sustained virologic response (SVR) after drug treatment. Impact of OMB/PTV/r + DSV ± RBV and other drug regimens on progression was estimated through SVR rates from clinical trials. Analyses were performed for treatment-naive and treatment-experienced patients. Impact of alternative scenarios and input parameter uncertainty on the results were tested. RESULTS: For genotype 1 treatment-naive HCV patients, for OMB/PTV/r + DSV ± RBV, PegIFN + ribavirin (PegIFN/RBV), sofosbuvir + PegIFN/RBV, telaprevir + PegIFN/RBV, boceprevir + PegIFN/RBV, lifetime risk of decompensated liver disease was 5.6%, 18.9%, 7.4%, 11.7%, and 14.9%; hepatocellular carcinoma was 5.4%, 9.2%, 5.7%, 7.0%, and 7.4%; and death from liver disease was 8.7%, 22.2%, 10.4%, 14.8%, and 17.6%, respectively. Estimates of the cost-effectiveness of OMB/PTV/r + DSV ± RBV for treatment-naive and treatment-experienced patients indicated that it dominated all other regimens except PegIFN/RBV. Compared with PegIFN/RBV, the incremental cost-effectiveness ratios were £13,864 and £10,258 per quality-adjusted life-year (QALY) for treatment-naive and treatment-experienced patients, respectively. The results were similar for alternative scenarios and uncertainty analyses. LIMITATIONS: A mixed-treatment comparison for SVR rates for the different treatment regimens was not feasible, because many regimens did not have comparator arms; instead SVR rates were based on those from recent trials. CONCLUSIONS: OMB/PTV/r + DSV ± RBV is a cost-effective oral treatment regimen for chronic genotype 1 HCV infection compared with standard treatment regimens and is estimated to reduce the lifetime risks of advanced liver disease.

Physician response to financial incentives when choosing drugs to treat breast cancer.

This paper considers physician agency in choosing drugs to treat metastatic breast cancer, a clinical setting in which patients have few protections from physicians' rent seeking. Physicians have explicit financial incentives attached to each potential drug treatment, with profit margins ranging more than a hundred fold. SEER-Medicare claims and Medispan pricing data were formed into a panel of 4,503 patients who were diagnosed with metastatic breast cancer and treated with anti-cancer drugs from 1992 to 2002. We analyzed the effects of product attributes, including profit margin, randomized controlled trial citations, FDA label, generic status, and other covariates on therapy choice. Instruments and drug fixed effects were used to control for omitted variables and possible measurement error associated with margin. We find that increasing physician margin by 10% yields between an 11 and 177% increase in the likelihood of drug choice on average across drugs. Physicians were more likely to use drugs with which they had experience, had more citations, and were FDA-approved to treat breast cancer. Oncologists are susceptible to financial incentives when choosing drugs, though other factors play a large role in their choice of drug.

Risk-benefit analysis of adalimumab versus traditional non-biologic therapies for patients with Crohn's disease.

BACKGROUND: Adalimumab is indicated for the treatment of moderately to severely active Crohn's disease (CD). A systematic analysis of risks and benefits of adalimumab versus traditional non-biologic therapies for patients refractory to non-biologic therapy is lacking. METHODS: A base-case analysis compared expected benefits of adalimumab therapy with a 12-week stopping rule for non-responders versus non-biologic therapies using data from clinical trials (CHARM, CLASSIC I). Adverse events (AEs) recorded in clinical trials (CHARM, CLASSIC I, CLASSIC II, GAIN, open-label extensions) were compiled. Sensitivity analyses incorporated all observed benefits of adalimumab and placebo (CHARM, CLASSIC I, GAIN) and observed AEs from a systematic literature review of non-biologic therapies (MEDLINE search of randomized trials 1990-2007). Distributional information from maintenance clinical trial observations and benefit model predictions were used in a probabilistic simulation. Incremental net benefits were estimated based on utility estimates from the literature. RESULTS: Average time in remission (i.e., CDAI <150) over 1 year of therapy was 39.9% for adalimumab versus 6.6% for traditional non-biologic therapies. Adalimumab was associated with fewer expected hospitalizations, better fistula closure rates, and lower AE rates. These findings were robust in sensitivity analyses. In the probabilistic simulation, with serious AEs as a composite of risks, adalimumab provided greater benefits with fewer AEs versus non-biologic therapies (P < 0.01). Adalimumab demonstrated greater incremental net quality-adjusted life-years (0.12) versus non-biologic therapies. CONCLUSIONS: Adalimumab demonstrated greater benefits and lower rates of AEs versus traditional non-biologic therapies for patients with moderately to severely active CD who were refractory to non-biologic therapies.

Cost-effectiveness of adalimumab for the maintenance of remission in patients with Crohn's disease.

OBJECTIVE: Adalimumab is a fully human, monoclonal antibody clinically effective for the treatment of active Crohn's disease. The cost-effectiveness of adalimumab versus conventional, nonbiologic pharmacotherapies is unknown. This study evaluated the cost-effectiveness of adalimumab versus conventional, nonbiologic pharmacotherapies in the maintenance of Crohn's disease. METHODS: Trial data from two randomized controlled studies [Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) and CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC I)] were analyzed within a cost-utility framework using a 1-year horizon from the perspective of the National Health Service (UK). The treatment efficacy and use for the adalimumab arm were based on observations from CHARM. A regression model used data from CLASSIC I to predict efficacy in patients who received nonbiologic pharmacotherapy. Unit costs of drugs, hospitalization, and other medical resources were derived from the literature. Primary standard gamble-calculated data were used to derive health-utility estimates. RESULTS: Compared with conventional, nonbiologic pharmacotherapy, adalimumab seemed to be cost-effective for the treatment of patients with severe disease and moderate-to-severe disease. The 56-week incremental cost-effectiveness ratio was 16 064 UK pounds/quality-adjusted life-year and 33 731 UK pounds/quality-adjusted life-year for severe and moderate-to-severe groups, respectively. Sensitivity analyses showed that the findings were robust. In the treatment of patients over their lifetimes, the incremental cost-effectiveness ratio was 6550 UK pounds/quality-adjusted life-year and 17 873 UK pounds/quality-adjusted life-year for patients with severe Crohn's disease and those with moderate-to-severe Crohn's disease, respectively. CONCLUSION: Adalimumab maintenance therapy seems to be cost-effective versus conventional, nonbiologic therapies for the maintenance of remission in patients with active Crohn's disease.