Real-World Evidence to Reinforce Clinical Trial Evidence in Health Technology Assessment: A Critical Review of Real-World Evidence Requirements from Seven Countries and Recommendations to Improve Acceptance.

BACKGROUND: Real-world evidence (RWE) can reinforce clinical trial evidence in health technology assessment (HTA). OBJECTIVES: Review HTA bodies' (HTAbs) requirements for RWE, real uses, and acceptance across seven countries (Brazil, Canada, France, Germany, Italy, Spain, and the United Kingdom) and outline recommendations that may improve acceptance of RWE in efficacy/effectiveness assessments and appraisals processes. METHODS: RWE requirements were summarized based on HTAbs' guidelines. Acceptance by HTAbs was evaluated based on industry experience and case studies. RESULTS: As of June 2022, RWE methodological guidelines were in place in three of the seven countries. HTAbs typically requested analyses based on local data sources, but the preferred study design and data sources differed. HTAbs had individual submission, assessment, and appraisal processes; some allowed early meetings for the protocol and/or results validation, though few involved external experts or medical societies to provide input to assessment and appraisal. The extent of submission, assessment, and appraisal requirements did not necessarily reflect the degree of acceptance. CONCLUSION: All the countries reviewed face common challenges regarding the use of RWE. Our proposals address the need to facilitate collaboration and communication with industry and regulatory agencies and the need for specific guidelines describing RWE design and criteria of acceptance throughout the assessment and appraisal processes.

Challenges for quality and utilization of real-world data for diffuse large B-cell lymphoma in REALYSA, a LYSA cohort.

ABSTRACT: Real-world data (RWD) are essential to complement clinical trial (CT) data, but major challenges remain, such as data quality. REal world dAta in LYmphoma and Survival in Adults (REALYSA) is a prospective noninterventional multicentric cohort started in 2018 that included patients newly diagnosed with lymphoma in France. Herein is a proof-of-concept analysis on patients with first-line diffuse large B-cell lymphoma (DLBCL) to (1) evaluate the capacity of the cohort to provide robust data through a multistep validation process; (2) assess the consistency of the results; and (3) conduct an exploratory transportability assessment of 2 recent phase 3 CTs (POLARIX and SENIOR). The analysis population comprised 645 patients with DLBCL included before 31 March 2021 who received immunochemotherapy and for whom 3589 queries were generated, resulting in high data completeness (<4% missing data). Median age was 66 years, with mostly advanced-stage disease and high international prognostic index (IPI) score. Treatments were mostly rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP 75%) and reduced dose R-CHOP (13%). Estimated 1-year event-free survival (EFS) and overall survival rates were 77.9% and 90.0%, respectively (median follow-up, 9.9 months). Regarding transportability, when applying the CT's main inclusion criteria (age, performance status, and IPI), outcomes seemed comparable between patients in REALYSA and standard arms of POLARIX (1-year progression-free survival 79.8% vs 79.8%) and SENIOR (1-year EFS, 64.5% vs 60.0%). With its rigorous data validation process, REALYSA provides high-quality RWD, thus constituting a platform for numerous scientific purposes. The REALYSA study was registered at www.clinicaltrials.gov as #NCT03869619.

Health economic evaluation of gene replacement therapies: methodological issues and recommendations.

Objective: To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations: Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

From investigational product to active reference: evolution of oral sumatriptan efficacy versus placebo for the treatment of acute migraine episodes and potential impact in comparative analyses.

Background: The relative efficacy and safety can vary among drugs over time. Sumatriptan, a first choice drug for acute migraine, can illustrate this phenomenon. Objective: To assess the evolution of the relative efficacy and tolerability of oral sumatriptan against placebo between its approval in 1991 and 2006. Methods: A systematic literature review of randomized controlled trials (RCTs) of adults suffering from acute migraine episodes was performed using Medline. Meta-analyses estimated odds ratios of the occurrence of pain-free at 2 hours and of any adverse event. Results: Out of the 67 RCTs identi.fied, pain-free at 2 hours and adverse events were reported in 25 and 28 studies, respectively. For pain-free, the relative effect of sumatriptan increases considerably over time, despite an increase in the absolute placebo effect. The odds ratio (95% CI) equaled 3.13 (1.67-5.86) around approval (1991-1994) and increased up to 4.14 (3.67-4.67) on the following decade. No specific variation was observed in the relative tolerability effect of sumatriptan over placebo over time. Conclusions: The relative effect of sumatriptan evolved substantially over time. This phenomenon may impact the results of network meta-analysis and indirect comparisons performed to evaluate the potential of a new drug, compared to widely prescribed older drugs.

Treatment patterns, comorbidities, healthcare resource use, and associated costs by line of chemotherapy and level of comorbidity in patients with newly-diagnosed Merkel cell carcinoma in the United States.

AIMS: To examine the characteristics of patients with newly-diagnosed Merkel cell carcinoma (MCC), analyze their treatment patterns and comorbidities after diagnosis, and evaluate the economic burden on the MCC patient population in the US. MATERIALS AND METHODS: This observational, non-interventional cohort study identified patients with MCC that were newly-diagnosed between January 1, 2010 through December 31, 2014, and whose data were either in the MarketScan Commercial Claims and Encounters (CCAE) or Medicare Supplemental and Coordination of Benefits databases. Standard descriptive statistics were used to describe patient demographics, clinical characteristics, treatment regimens, and healthcare resource use (HRU) and cost. RESULTS: Following MCC diagnosis, most patients in the study population (n = 2,177) received only surgery (34.5%) or surgery and radiotherapy without chemotherapy (22.0%), while 14.5% of patients received none of these treatments; 27.5% of patients received at least one line of chemotherapy as part of their treatment. Mean total healthcare costs per patient per year (PPPY), as well as mean inpatient, outpatient, and pharmacy costs, were significantly greater for patients who received chemotherapy compared with those who received other or no treatments. Higher HRU and mean costs were associated with increasing patient comorbidity burden, ranging from $62,401 PPPY in Deyo Charlson Comorbidity Index level 1 to $109,690 in level ≥3. LIMITATIONS: The study used claims databases that were limited to patients who are covered by large employer-sponsored insurance and/or Medicare and did not provide information regarding the rationale for treatment choice or resource use. CONCLUSIONS: The choice of treatment is a major factor in determining healthcare costs associated with MCC, with the highest costs in patients receiving chemotherapy. Patients with MCC often exhibit comorbidities, and both HRU and healthcare costs increase significantly with each comorbidity level.

Validation of disease states in schizophrenia: comparison of cluster analysis between US and European populations.

BACKGROUND: There is controversy as to whether use of statistical clustering methods to identify common disease patterns in schizophrenia identifies patterns generalizable across countries. OBJECTIVE: The goal of this study was to compare disease states identified in a published study (Mohr/Lenert, 2004) considering US patients to disease states in a European cohort (EuroSC) considering English, French, and German patients. METHODS: Using methods paralleling those in Mohr/Lenert, we conducted a principal component analysis (PCA) on Positive and Negative Syndrome Scale items in the EuroSC data set (n=1,208), followed by k-means cluster analyses and a search for an optimal k. The optimal model structure was compared to Mohr/Lenert by assigning discrete severity levels to each cluster in each factor based on the cluster center. A harmonized model was created and patients were assigned to health states using both approaches; agreement rates in state assignment were then calculated. RESULTS: Five factors accounting for 56% of total variance were obtained from PCA. These factors corresponded to positive symptoms (Factor 1), negative symptoms (Factor 2), cognitive impairment (Factor 3), hostility/aggression (Factor 4), and mood disorder (Factor 5) (as in Mohr/Lenert). The optimal number of cluster states was six. The kappa statistic (95% confidence interval) for agreement in state assignment was 0.686 (0.670-0.703). CONCLUSION: The patterns of schizophrenia effects identified using clustering in two different data sets were reasonably similar. Results suggest the Mohr/Lenert health state model is potentially generalizable to other populations.

Cost effectiveness of mirabegron compared with tolterodine extended release for the treatment of adults with overactive bladder in the United Kingdom.

BACKGROUND: Overactive bladder (OAB) is highly prevalent and is associated with considerable morbidity and reduced health-related quality of life. ß3-adrenergic receptor (ß3-AR) stimulation is a novel alternative to antimuscarinic therapy for OAB. OBJECTIVE: The objective of this analysis was to assess the cost effectiveness of the ß3-AR agonist mirabegron relative to tolterodine extended release (ER) in patients with OAB from a UK National Health Service (NHS) perspective. METHODS: A Markov model was developed to simulate the management, course of disease, and effect of complications in OAB patients over a period of 5 years. Transition probabilities for symptom severity levels and probabilities of adverse events were estimated from the results of the randomised, double-blind SCORPIO trial in 1,987 patients with OAB. Other model inputs were derived from the literature and on assumptions based on clinical experience. RESULTS: Total 5-year costs per patient were £1,645.62 for mirabegron 50 mg/day and £1,607.75 for tolterodine ER 4 mg/day. Mirabegron was associated with a gain of 0.009 quality-adjusted life-years (QALYs) with an additional cost of £37.88. The resulting incremental cost-effectiveness ratio (ICER) was £4,386/QALY gained. In deterministic sensitivity analyses in the general OAB population and several subgroups, ICERs remained below the generally accepted willingness-to-pay (WTP) threshold of £20,000/QALY gained. The probability of mirabegron 50 mg being cost effective relative to tolterodine ER 4 mg was 89.4 % at the same WTP threshold. CONCLUSIONS: Mirabegron 50 mg/day is likely to be cost effective compared with tolterodine ER 4 mg/day for adult patients with OAB from a UK NHS perspective.