Calculating the Expected Value of Sample Information in Practice: Considerations from Three Case Studies

Investing efficiently in future research to improve policy decisions is an important goal. Expected Value of Sample Information (EVSI) can be used to select the specific design and sample size of a proposed study by assessing the benefit of a range of different studies. Estimating EVSI with the standard nested Monte Carlo algorithm has a notoriously high computational burden, especially when using a complex decision model or when optimizing over study sample sizes and designs. Therefore, a number of more efficient EVSI approximation methods have been developed. However, these approximation methods have not been compared and therefore their relative advantages and disadvantages are not clear. A consortium of EVSI researchers, including the developers of several approximation methods, compared four EVSI methods using three previously published health economic models. The examples were chosen to represent a range of real-world contexts, including situations with multiple study outcomes, missing data, and data from an observational rather than a randomized study. The computational speed and accuracy of each method were compared, and the relative advantages and implementation challenges of the methods were highlighted. In each example, the approximation methods took minutes or hours to achieve reasonably accurate EVSI estimates, whereas the traditional Monte Carlo method took weeks. Specific methods are particularly suited to problems where we wish to compare multiple proposed sample sizes, when the proposed sample size is large, or when the health economic model is computationally expensive. All the evaluated methods gave estimates similar to those given by traditional Monte Carlo, suggesting that EVSI can now be efficiently computed with confidence in realistic examples.Comment: 11 pages, 3 figure

The cost-effectiveness of opt-in and send-to-all HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway : The Equalscreen randomized controlled trial

OBJECTIVE: We assessed the cost-effectiveness of mailing a human papillomavirus self-sampling (HPV-ss) kit, directly or via invitation to order, compared with mailing reminder letters among long-term non-attenders in Norway. METHODS: We conducted a secondary analysis using the Equalscreen study data with 6000 women aged 35-69 years who had not screened in 10+ years. Participants were equally randomized into three arms: reminder letter (control); invitation to order HPV-ss kit (opt-in); directly mailed HPV-ss kit (send-to-all). Cost-effectiveness (2020 Great British Pounds (GBP)) was estimated using incremental cost-effectiveness ratios (ICERs) per additional screened woman, and per additional cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from extended and direct healthcare perspectives. RESULTS: Participation, CIN2+ detection, and total screening costs were highest in the send-to-all arm, followed by the opt-in and control arms. Non-histological physician appointments contributed to 67% of the total costs in the control arm and ≤ 31% in the self-sampling arms. From an expanded healthcare perspective, the ICERs were 135 GBP and 169 GBP per additional screened woman, and 2864 GBP and 4165 GBP per additional CIN2+ detected for the opt-in and send-to-all, respectively. CONCLUSIONS: Opt-in and send-to-all self-sampling were more effective and, depending on willingness-to-pay, may be considered cost-effective alternatives to improve screening attendance in Norway

Making Drug Approval Decisions in the Face of Uncertainty:Cumulative Evidence versus Value of Information

Background: The COVID-19 pandemic underscored the criticality and complexity of decision making for novel treatment approval and further research. Our study aims to assess potential decision-making methodologies, an evaluation vital for refining future public health crisis responses. Methods: We compared 4 decision-making approaches to drug approval and research: the Food and Drug Administration’s policy decisions, cumulative meta-analysis, a prospective value-of-information (VOI) approach (using information available at the time of decision), and a reference standard (retrospective VOI analysis using information available in hindsight). Possible decisions were to reject, accept, provide emergency use authorization, or allow access to new therapies only in research settings. We used monoclonal antibodies provided to hospitalized COVID-19 patients as a case study, examining the evidence from September 2020 to December 2021 and focusing on each method’s capacity to optimize health outcomes and resource allocation. Results: Our findings indicate a notable discrepancy between policy decisions and the reference standard retrospective VOI approach with expected losses up to $269 billion USD, suggesting suboptimal resource use during the wait for emergency use authorization. Relying solely on cumulative meta-analysis for decision making results in the largest expected loss, while the policy approach showed a loss up to$16 billion and the prospective VOI approach presented the least loss (up to $2 billion). Conclusion: Our research suggests that incorporating VOI analysis may be particularly useful for research prioritization and treatment implementation decisions during pandemics. While the prospective VOI approach was favored in this case study, further studies should validate the ideal decision-making method across various contexts. This study’s findings not only enhance our understanding of decision-making strategies during a health crisis but also provide a potential framework for future pandemic responses. This study reviews discrepancies between a reference standard (retrospective VOI, using hindsight information) and 3 conceivable real-time approaches to research-treatment decisions during a pandemic, suggesting suboptimal use of resources. Of all prospective decision-making approaches considered, VOI closely mirrored the reference standard, yielding the least expected value loss across our study timeline. This study illustrates the possible benefit of VOI results and the need for evidence accumulation accompanied by modeling in health technology assessment for emerging therapies.</p

Making Drug Approval Decisions in the Face of Uncertainty:Cumulative Evidence versus Value of Information

Background: The COVID-19 pandemic underscored the criticality and complexity of decision making for novel treatment approval and further research. Our study aims to assess potential decision-making methodologies, an evaluation vital for refining future public health crisis responses. Methods: We compared 4 decision-making approaches to drug approval and research: the Food and Drug Administration’s policy decisions, cumulative meta-analysis, a prospective value-of-information (VOI) approach (using information available at the time of decision), and a reference standard (retrospective VOI analysis using information available in hindsight). Possible decisions were to reject, accept, provide emergency use authorization, or allow access to new therapies only in research settings. We used monoclonal antibodies provided to hospitalized COVID-19 patients as a case study, examining the evidence from September 2020 to December 2021 and focusing on each method’s capacity to optimize health outcomes and resource allocation. Results: Our findings indicate a notable discrepancy between policy decisions and the reference standard retrospective VOI approach with expected losses up to $269 billion USD, suggesting suboptimal resource use during the wait for emergency use authorization. Relying solely on cumulative meta-analysis for decision making results in the largest expected loss, while the policy approach showed a loss up to$16 billion and the prospective VOI approach presented the least loss (up to $2 billion). Conclusion: Our research suggests that incorporating VOI analysis may be particularly useful for research prioritization and treatment implementation decisions during pandemics. While the prospective VOI approach was favored in this case study, further studies should validate the ideal decision-making method across various contexts. This study’s findings not only enhance our understanding of decision-making strategies during a health crisis but also provide a potential framework for future pandemic responses. This study reviews discrepancies between a reference standard (retrospective VOI, using hindsight information) and 3 conceivable real-time approaches to research-treatment decisions during a pandemic, suggesting suboptimal use of resources. Of all prospective decision-making approaches considered, VOI closely mirrored the reference standard, yielding the least expected value loss across our study timeline. This study illustrates the possible benefit of VOI results and the need for evidence accumulation accompanied by modeling in health technology assessment for emerging therapies.</p

Perspective and Costing in Cost-Effectiveness Analysis, 1974-2018

OBJECTIVE: Our objective was to examine perspective and costing approaches used in cost-effectiveness analyses (CEAs) and the distribution of reported incremental cost-effectiveness ratios (ICERs). METHODS: We analyzed the Tufts Medical Center's CEA and Global Health CEA registries, containing 6907 cost-per-quality-adjusted-life-year (QALY) and 698 cost-per-disability-adjusted-life-year (DALY) studies published through 2018. We examined how often published CEAs included non-health consequences and their impact on ICERs. We also reviewed 45 country-specific guidelines to examine recommended analytic perspectives. RESULTS: Study authors often mis-specified or did not clearly state the perspective used. After re-classification by registry reviewers, a healthcare sector or payer perspective was most prevalent (74%). CEAs rarely included unrelated medical costs and impacts on non-healthcare sectors. The most common non-health consequence included was productivity loss in the cost-per-QALY studies (12%) and patient transportation in the cost-per-DALY studies (21%). Of 19,946 cost-per-QALY ratios, the median ICER was $US26,000/QALY (interquartile range [IQR] 2900-110,000), and 18$US430/DALY (IQR 67-3400), and 8% were cost saving and DALY averting. Based on 16 cost-per-QALY studies (2017-2018) reporting 68 ICERs from both the healthcare sector and societal perspectives, the median ICER from a societal perspective ($US22,710/QALY [IQR 11,991-49,603]) was more favorable than from a healthcare sector perspective ($US30,402/QALY [IQR 10,486-77,179]). Most governmental guidelines (67%) recommended either a healthcare sector or a payer perspective. CONCLUSION: Researchers should justify and be transparent about their choice of perspective and costing approaches. The use of the impact inventory and reporting of disaggregate outcomes can reduce inconsistencies and confusion

Correction to : Perspective and Costing in Cost‑Effectiveness Analysis, 1974-2018

The article Perspective and Costing in Cost-Effectiveness Analysis

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer

BACKGROUND: First-line treatment with nivolumab plus ipilimumab (N+I) or nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), yet researchers have not concomitantly compared the cost-effectiveness of N+I and N+I+chemotherapy with chemotherapy alone. MATERIALS AND METHODS: Using outcomes data from the CheckMate 227 and CheckMate 9LA phase 3 randomized trials, we developed a Markov model with lifetime horizon to compare the costs and effectiveness of N+I and N+I+chemotherapy versus chemotherapy from the U.S. health care sector perspective. Subgroup analysis by programmed death-ligand 1 (PD-L1) expression levels (≥1% and <1%) and probabilistic analysis were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) of N+I versus chemotherapy was $239,072 per QALY, and$838,198 per QALY for N+I+chemotherapy versus N+I. The ICER of N+I versus chemotherapy was $246,584 per QALY for patients with PD-L1 ≥ 1$185,620 per QALY for those with PD-L1 < 1%. In probabilistic analysis, N+I had a 2.6% probability of being cost-effective at a willingness-to-pay threshold of $150,000 per QALY. The probability was 0.4% for patients with PD-L1 ≥ 1% and 10.6% for patients with PD-L1 < 1%. CONCLUSION: First-line N+I or N+I+chemotherapy for metastatic NSCLC was not cost-effective regardless of PD-L1 expression levels from the U.S. health care sector perspective

Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)-Positive Breast Cancer

IMPORTANCE: The neoadjuvant treatment options for ERBB2-positive (also known as HER2-positive) breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed. OBJECTIVE: To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years (range, 24-79 years in T-DM1 arm and 23-80 years in trastuzumab arm). The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020. EXPOSURE: There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1. MAIN OUTCOMES AND MEASURES: Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative. RESULTS: In the base-case analysis, costs ranged from $415 833 (strategy 3) to$518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70$0-200,000/QALY) and was associated with the highest net benefit. CONCLUSIONS AND RELEVANCE: These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with ERBB2-positive breast cancer compared with other treatment strategies considered

Treatment Sequencing Patterns and Associated Direct Medical Costs of Metastatic Breast Cancer Care in the United States, 2011 to 2021

IMPORTANCE: Advances in treatment of metastatic breast cancer (MBC) led to changes in clinical practice and treatment costs in the US over the past decade. There is limited information on current MBC treatment sequences and associated costs by MBC subtype in the US. OBJECTIVES: To identify treatment patterns by MBC subtype and associated anticancer and supportive drug costs from health care sector and Medicare perspectives. DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation analyzed data of patients with MBC obtained from the nationwide Flatiron Health database, an electronic health record-derived, deidentified database with data from community and academic practices across the US from 2011 to 2021. Participants included women aged at least 18 years diagnosed with MBC, who had at least 6 months of follow-up data, known hormone receptor (HR) and human epidermal growth factor receptor 2 (ERBB2) receptor status, and at least 1 documented line of therapy. Patients with documented receipt of clinical study drugs were excluded. Data were analyzed from June 2021 to May 2022. MAIN OUTCOMES AND MEASURES: Outcomes of interest were frequency of different drug regimens received as a line of therapy by subtype for the first 5 lines and mean medical costs of documented anticancer treatment and supportive care drugs per patient by MBC subtype and years since metastatic diagnosis, indexed to 2021 US dollars. RESULTS: Among 15 215 patients (10 171 patients [66.85%] with HR-positive and ERBB2-negative MBC; 2785 patients [18.30%] with HR-positive and ERBB2-positive MBC; 802 patients [5.27%] with HR-negative and ERBB2-positive MBC; 1457 patients [9.58%] with triple-negative breast cancer [TNBC]) who met eligibility criteria, 1777 (11.68%) were African American, 363 (2.39%) were Asian, and 9800 (64.41%) were White; the median (range) age was 64 (21-84) years. The mean total per-patient treatment and supportive care drug cost using publicly available Medicare prices was $334 812 for patients with HR-positive and ERBB2-positive MBC,$284 609 for patients with HR-negative and ERBB2-positive MBC, $104 774 for patients with HR-positive and ERBB2-negative MBC, and$54 355 for patients with TNBC. From 2011 to 2019 (most recent complete year 1 data are for patients diagnosed in 2019), annual costs in year 1 increased from $12 986 to$80 563 for ERBB2-negative and HR-positive MBC, $99 997 to$156 712 for ERBB2-positive and HR-positive MBC, and $31 397 to$53 775 for TNBC. CONCLUSIONS AND RELEVANCE: This economic evaluation found that drug costs related to MBC treatment increased between 2011 and 2021 and differed by tumor subtype. These findings suggest the growing financial burden of MBC treatment in the US and highlights the importance of performing more accurate cost-effectiveness analysis of novel adjuvant therapies that aim to reduce metastatic recurrence rates for early-stage breast cancer

Long-Term Outcomes of Prostate-Specific Membrane Antigen-PET Imaging of Recurrent Prostate Cancer

IMPORTANCE: Although prostate-specific membrane antigen positron emission tomography (PSMA-PET) has shown improved sensitivity and specificity compared with conventional imaging for the detection of biochemical recurrent (BCR) prostate cancer, the long-term outcomes of a widespread shift in imaging are unknown. OBJECTIVE: To estimate long-term outcomes of integrating PSMA-PET into the staging pathway for recurrent prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This decision analytic modeling study simulated outcomes for patients with BCR following initial definitive local therapy. Inputs used were from the literature and a retrospective cohort study conducted at 2 institutions. The base case analysis assumed modest benefits of earlier detection and treatment, and scenario analyses considered prostate-specific antigen (PSA) level at imaging and different outcomes of earlier vs delayed treatment. The analysis was performed between April 1, 2023, and May 1, 2024. EXPOSURES: (1) Immediate PSMA-PET imaging, (2) conventional imaging (computed tomography and bone scan [CTBS]) followed by PSMA-PET if CTBS findings were negative or equivocal, and (3) CTBS alone. MAIN OUTCOMES AND MEASURES: The main outcomes were detection of metastases, deaths from prostate cancer, and life-years and quality-adjusted life-years (QALYs) gained. RESULTS: The model estimated that per 1000 simulated patients with BCR (assumed median age, 66 years), PSMA-PET is expected to diagnose 611 (95% uncertainty interval [UI], 565-656) patients with metastasis compared with 630 (95% UI, 586-675) patients diagnosed using CTBS followed by PSMA-PET and 297 (95% UI, 202-410) patients diagnosed using CTBS alone. Moreover, the estimated number of prostate cancer deaths was 512 (95% UI, 472-552 deaths) with PSMA-PET, 520 (95% UI, 480-559 deaths) with CTBS followed by PSMA-PET, and 587 (95% UI, 538-632 deaths) with CTBS alone. Imaging with PSMA-PET yielded the highest number of QALYs, which were 824 (95% UI, 698-885) higher than CTBS. These results differed by PSA level at the time of testing, with the highest incremental life-years and QALYs and lowest number of deaths from prostate cancer among patients with PSA levels of at least 5.0 ng/mL. Finally, the estimates were sensitive to the expected benefit of initiating therapy for recurrent prostate cancer earlier in the disease course. CONCLUSIONS AND RELEVANCE: The results of this decision-analytic model suggest that upfront PSMA-PET imaging for the evaluation of BCR is expected to be associated with reduced cancer mortality and gains in life-years and QALYs compared with the conventional imaging strategy, assuming modest benefits of earlier detection and treatment