Impact of disease progression on health-related quality of life of advanced ovarian cancer patients - Pooled analysis from the PRIMA trial.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.

Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial.

Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo. Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019). Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9-8.9] and 4.1 [95% CI, 2.2-5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5-8.6] and 3.5 [95% CI, 1.7-5.6] months, respectively) in the HRd and ITT populations. Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure. Trial registration: ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016. Plain language summary: Background: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients' quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA.Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses:● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life.● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects.Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib - they are known as homologous recombination deficiency (HRd) patients.● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo.● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo.Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients' quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.

Preapproval Information Exchange: Perspectives of U.S. Population Health Decision Makers on Preferences for Early Engagement with Investigational Therapies.

BACKGROUND: Preapproval information exchange (PIE) is the communication of clinical and health care economic information (HCEI) on therapies in development between U.S. population health decision makers (PHDMs) and drug manufacturers before regulatory approval. Early access to HCEI can help PHDMs plan budgets, inform formulary coverage decisions, and accelerate policy development to improve patient access to innovative health technologies. While recent FDA guidelines and proposed legislation aim to clarify definitions and execution of PIE, the level of U.S. PHDMs' awareness and preferences for early engagement with investigational therapies is unclear. OBJECTIVES: To (a) assess U.S. PHDMs' current knowledge and perceptions of PIE and (b) identify their preferences for PIE, in order to shape future development of related guidelines and policy. METHODS: An expert panel of 5 U.S. PHDMs representing national and regional payers from integrated health plans, pharmacy benefit management, and specialty pharmacy organizations participated in a 2-round modified Delphi process. A targeted literature review of PIE was used to develop a web-based survey administered to the panel. Survey responses were grouped by consensus, with ≥ 80% agreement or disagreement as the threshold in round 1. In round 2, content experts moderated an inperson meeting where panelists deliberated and then revoted on round 1 nonconsensus topics. RESULTS: In the round 1 survey, the panelists reached consensus on 35 of 54 (65%) multiple-choice questions. In the round 2 face-to-face discussion, 19 nonconsensus questions were debated. One question was removed due to duplication, and consensus was achieved on 16 additional questions, with 2 items of nonconsensus remaining. Overall, consensus was achieved on 51 of 53 topics (96%). There was full consensus by the panelists that PIE should encompass new molecular entities and new indications of marketed therapies. Panelists completely agreed on the need for a legislative "safe harbor" for PIE. Four of five panelists reported that the value of PIE was high to PHDMs, and they expressed a strong preference for peer-to-peer conversations with manufacturers' medical or outcomes liaisons for PIE. The main topic of nonconsensus was the optimal timing of PIE. CONCLUSIONS: This panel of U.S. PHDMs achieved consensus on the value of PIE to proactively budget, make informed formulary decisions, and develop pharmaceutical policy to facilitate patient access to new therapies. The PHDM panel's preferences for PIE should be considered in legislative discussions and planning for future PIE by PHDMs and manufacturers. The full contribution of PIE to improving the U.S. health system can best be realized under a safe harbor that allows U.S. PHDM and manufacturer experts to engage in robust scientific and economic discourse. Additional research and broad stakeholder engagement is needed to advance the development of formal U.S. PIE guidelines. DISCLOSURES: This study was funded by GlaxoSmithKline (GSK). Brixner, Oderda, and Biskupiak are principals of Millcreek Outcomes Group, a consultancy that received funding from GSK to conduct this study. Marciniak and Woodward are employees of GSK and own stock in GSK. Seifter was employed by GSK at the time of this study. Neumann served as external health policy advisor for this study and has consulted or served on advisory boards with Merck, Bayer, Pacira, Novo Nordisk, Amgen, Abbvie, Boston Health Economics, Vertex, Precision Health Economics, the Congressional Budget Office, CEA Registry Sponsors, Axovant, Veritech, Janssen, Parateck, Avexis, GSK, Celegene, Bluebird, Roche, Sage, Sarepta, Biogen, and Ipsen. Neumann also reports grants from Amgen, Lundbeck, Gates, NPC, Alzheimer's Association, and NIH.

The costs of treating acute heart failure: an economic analysis of the SURVIVE trial.

OBJECTIVE: To estimate the incremental cost per life year gained with levosimendan relative to dobutamine in treatment of acute heart failure based on the Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial. METHODS: SURVIVE enrolled 1,327 patients (levosimendan 664, dobutamine 663) from nine nations with 180-day survival from date of randomisation as the primary endpoint. Hospital resource utilisation was determined via clinical case reports. Unit costs were derived from hospital payment schedules for France, Germany and the UK, and represent a third-party payer perspective. Cost-effectiveness analysis was performed for a subset of the SURVIVE patient population selected in accordance with current levosimendan labeling. RESULTS: Mortality in the levosimendan group was 26 versus 28% for dobutamine (hazard ratio 0.91, 95% confidence interval 0.74-1.13, p=0.40). Initial hospitalisation length of stay was identical (levosimendan 14.4, dobutamine 14.5, p=0.98). Slightly lower rates of readmission were observed for levosimendan relative to dobutamine at 31 (p=0.13) and 180 days (p=0.23). Mean costs excluding study drug were equivalent for the index admission (levosimendan euro5,060, dobutamine euro4,952; p=0.91) and complete episode (levosimendan euro5,396, dobutamine euro5,275; p=0.93). CONCLUSION: At an acquisition cost of euro600 per vial, there is at least 50% likelihood that levosimendan is cost effective relative to dobutamine if willingness to pay is equal to or greater than euro15,000 per life year gained.

Budget impact model of tobramycin inhalation solution for treatment of Pseudomonas aeruginosa in cystic fibrosis patients.

BACKGROUND: Pseudomonas aeruginosa (PA) is the most common airway pathogen in cystic fibrosis (CF) patients. The objective of this analysis was to determine the costs of managing PA infection in CF patients with a chronic regimen of tobramycin inhalation solution (TIS). METHODS: A budget impact model of CF patients was developed to evaluate the costs of TIS from a US managed-care organization (MCO) perspective. The Microsoft Excel model compared TIS treatment plus standard care with standard care alone over a 4-year time horizon and included the cost of drugs, medical care, and annual probabilities of hospitalization and IV anti-pseudomonal (anti-PA) antibiotics administration. RESULTS: For an MCO with 5,000,000 members, 389 members 6 years of age or older were estimated to have CF, and 218 (56%) had PA infection. Assuming that use of TIS increased from 20% to 25%, the 1-year budget increased $231,251 or from $0.049 to $0.053 per member per month (PMPM). The net drug budget increase was $243,919, while medical costs associated with exacerbation management decreased $12,669 over the first year. Increasing utilization of TIS, from 20% to 40% over 4 years resulted in an incremental overall budget increase of $925,002, a 3% decrease in hospitalizations, and a 4% decrease in administrations of IV anti-PA antibiotics. These reductions translated to a medical care cost saving of $50,676 over 4 years. Limitations of this study include that the clinical data for the model are from clinical trials conducted in 1996 and the estimation of TIS use for CF patients with chronic PA infections can be impacted by TIS adherence. CONCLUSION: Model results suggest that increasing the use of TIS decreases medical care costs due to decreased hospital admissions and the use of IV anti-PA antibiotics at the expense of higher drug costs.

Cost effectiveness of adjunctive quetiapine fumarate extended-release tablets with mood stabilizers in the maintenance treatment of bipolar I disorder.

BACKGROUND: Bipolar I disorder (BPD I) is a recurrent illness that affects 1% of the US population and constitutes a large economic burden. However, few studies have investigated the cost effectiveness of maintenance treatment options for BPD I. OBJECTIVE: To determine the cost effectiveness of maintenance treatment with quetiapine fumarate extended-release (XR) tablets in combination with mood stabilizers (lithium or divalproex) in comparison with the following treatments: placebo in combination with lithium or divalproex; no maintenance treatment; lithium monotherapy; lamotrigine monotherapy; olanzapine monotherapy; and aripiprazole monotherapy. METHODS: The analysis was conducted from the societal and payer perspectives in the US, using a Markov model. The model simulated a cohort of 1000 stabilized BPD I patients and estimated the quarterly risk in three health states: euthymia, mania and depression. Efficacy data were derived from two randomized, double-blind trials comparing quetiapine + lithium/divalproex with placebo + lithium/divalproex for up to 2 years, as well as other published literature. Resource data were extracted from published literature. Drug costs, hospitalizations and physician visits were among the direct costs. Indirect costs included absenteeism, and mortality rates included suicide. Benefits and costs were discounted at 3% and the price reference year was 2009. Endpoints included number of acute mood episodes, hospitalizations due to an acute mood event and costs per QALY. Probabilistic sensitivity analysis (PSA) was conducted to evaluate uncertainty in the model inputs. RESULTS: Treatment with quetiapine XR + lithium/divalproex was associated with reductions in acute mania (46%), acute depression (41%) and related hospitalizations (44%) compared with placebo + lithium/divalproex, and similar reductions in events were observed relative to lithium monotherapy. In the base-case analysis from the payer perspective, the discounted incremental cost per QALY for quetiapine XR + lithium/divalproex compared with placebo + lithium/divalproex was $US22 959, and compared with lithium monotherapy was $US100 235, while all other comparators were dominated. PSA showed these results to be robust to select assumptions. CONCLUSIONS: Quetiapine XR + lithium/divalproex may be a cost-effective maintenance treatment option for patients with BPD I.

Cost-effectiveness of quetiapine with lithium or divalproex for maintenance treatment of bipolar I disorder.

BACKGROUND: Bipolar I disorder is a recurrent illness that affects 1% of the US population and constitutes a large economic burden. Few studies have investigated the cost-effectiveness of maintenance treatment options. The objective of this analysis was to assess the cost-effectiveness of quetiapine (QTP) in combination with lithium (Li) or divalproex (DVP) compared with that of Li or DVP alone for maintenance treatment of bipolar disorder. METHODS: The cost-effectiveness of maintenance treatment with QTP in combination with Li or DVP was compared with placebo (PBO) in combination with Li or DVP from a US direct costs perspective using a Markov model. The model simulated a cohort of 1,000 stabilized patients with bipolar I disorder and estimated the quarterly risk in three health states: euthymia, mania, and depression. Efficacy data were derived from two randomized, double-blind, placebo-controlled trials comparing QTP + Li/DVP with PBO + Li/DVP for up to 2 years. Resource data were obtained from published literature. Direct costs included drug costs, hospitalizations, and physician visits. Outcomes and costs were discounted at 3% and the price reference year was 2007. Endpoints included the number of acute mood episodes, hospitalizations due to an acute mood event, and costs per quality-adjusted life-years. A probabilistic sensitivity analysis (PSA) was conducted to evaluate uncertainty. RESULTS: In the base-case analysis, QTP + Li/DVP dominated PBO + Li/DVP. The PSA showed these results to be robust. In addition, treatment with QTP + Li/DVP was associated with reductions in acute manic episodes (46%), acute depressive episodes (41%), and related hospitalizations (44%) compared with PBO + Li/DVP. CONCLUSIONS: These analyses, based on two randomized clinical trials, suggest that QTP + Li/DVP is a cost-effective maintenance treatment option for patients with bipolar I disorder compared with Li or DVP alone.