Acceptability of Using Real-World Data to Estimate Relative Treatment Effects in Health Technology Assessments: Barriers and Future Steps.

OBJECTIVES: Evidence about the comparative effects of new treatments is typically collected in randomized controlled trials (RCTs). In some instances, RCTs are not possible, or their value is limited by an inability to capture treatment effects over the longer term or in all relevant population subgroups. In these cases, nonrandomized studies (NRS) using real-world data (RWD) are increasingly used to complement trial evidence on treatment effects for health technology assessment (HTA). However, there have been concerns over a lack of acceptability of this evidence by HTA agencies. This article aims to identify the barriers to the acceptance of NRS and steps that may facilitate increases in the acceptability of NRS in the future. METHODS: Opinions of the authorship team based on their experience in real-world evidence research in academic, HTA, and industry settings, supported by a critical assessment of existing studies. RESULTS: Barriers were identified that are applicable to key stakeholder groups, including HTA agencies (eg, the lack of comprehensive methodological guidelines for using RWD), evidence generators (eg, avoidable deviations from best practices), and external stakeholders (eg, data controllers providing timely access to high-quality RWD). Future steps that may facilitate future acceptability of NRS include improvements in the quality, integration, and accessibility of RWD, wider use of demonstration projects to highlight the value and applicability of nonrandomized designs, living, and more detailed HTA guidelines, and improvements in HTA infrastructure relating to RWD. CONCLUSION: NRS can represent a crucial source of evidence on treatment effects for use in HTA when RCT evidence is limited.

Outbreak of STEC O157:H7 linked to a milk pasteurisation failure at a dairy farm in England, 2019.

In November 2019, an outbreak of Shiga toxin-producing Escherichia coli O157:H7 was detected in South Yorkshire, England. Initial investigations established consumption of milk from a local dairy as a common exposure. A sample of pasteurised milk tested the next day failed the phosphatase test, indicating contamination of the pasteurised milk by unpasteurised (raw) milk. The dairy owner agreed to immediately cease production and initiate a recall. Inspection of the pasteuriser revealed a damaged seal on the flow divert valve. Ultimately, there were 21 confirmed cases linked to the outbreak, of which 11 (52%) were female, and 12/21 (57%) were either <15 or >65 years of age. Twelve (57%) patients were treated in hospital, and three cases developed haemolytic uraemic syndrome. Although the outbreak strain was not detected in the milk samples, it was detected in faecal samples from the cattle on the farm. Outbreaks of gastrointestinal disease caused by milk pasteurisation failures are rare in the UK. However, such outbreaks are a major public health concern as, unlike unpasteurised milk, pasteurised milk is marketed as 'safe to drink' and sold to a larger, and more dispersed, population. The rapid, co-ordinated multi-agency investigation initiated in response to this outbreak undoubtedly prevented further cases.

Prodromal symptoms of multiple sclerosis in primary care.

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Healthcare resource utilisation and direct medical cost for individuals with 5q spinal muscular atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive, neuromuscular disorder. Recent advances in treatment require an updated assessment of burden to inform reimbursement decisions. OBJECTIVES: To quantify healthcare resource utilisation (HCRU) and cost of care for patients with SMA. METHODS: Cohort study of patients with SMA identified in the Swedish National Patient Registry (2007-2018), matched to a reference cohort grouped into four SMA types (1, 2, 3, unspecified adult onset [UAO]). HCRU included inpatient admissions, outpatient visits, procedures, and dispensed medications. Direct medical costs were estimated by multiplying HCRU by respective unit costs. Average annual HCRU and medical costs were modelled for SMA versus reference cohorts to estimate differences attributable to the disease (i.e., average treatment effect estimand). The trajectory of direct costs over time were assessed using synthetic cohorts. RESULTS: We identified 290 SMA patients. Annualised HCRU was higher in SMA patients compared with reference cohorts. Highest risk ratios were observed for inpatient overnight stays for type 1 (risk ratio [RR]: 29.2; 95% confidence interval [CI]: 16.0, 53.5) and type 2 (RR: 23.3; 95% CI: 16.4,33.1). Mean annual direct medical costs per patient for each year since first diagnosis were greatest for type 1 (€114,185 and SMA-attributable: €113,380), type 2 (€61,876 and SMA-attributable: €61,237), type 3 (€45,518 and SMA-attributable: €44,556), and UAO (€4046 and SMA-attributable: €2098). Costs were greatest in the 2-3 years after the first diagnosis for all types. DISCUSSION AND CONCLUSION: The economic burden attributable to SMA is significant. Further research is needed to understand the burden in other European countries and the impact of new treatments.

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.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 10.

In this latest update we discuss the transportability of comparative effectiveness evidence across countries. We highlight results of a survey indicating that European HTA agencies are reluctant to accept real-world data from other countries, review recent benefit assessments indicating a potential softening of a requirement for the use of local real-world data in Germany, and outline a recent review presenting approaches that can correct for a lack of transportability.

Estimating the prevalence of diagnosed Alzheimer disease in England across deprivation groups using electronic health records: a clinical practice research datalink study.

OBJECTIVE: Estimate the prevalence of diagnosed Alzheimer's disease (AD) and early Alzheimer's disease (eAD) overall and stratified by age, sex and deprivation and combinations thereof in England on 1 January 2020. DESIGN: Cross-sectional. SETTING: Primary care electronic health record data, the Clinical Practice Research database linked with secondary care data, Hospital Episode Statistics (HES) and patient-level deprivation data, Index of Multiple Deprivation (IMD). OUTCOME MEASURES: The prevalence per 100 000 of the population and corresponding 95% CIs for both diagnosed AD and eAD overall and stratified by covariates. Sensitivity analyses were conducted to assess the sensitivity of the population definition and look-back period. RESULTS: There were 448 797 patients identified in the Clinical Practice Research Datalink that satisfied the study inclusion criteria and were eligible for HES and IMD linkage. For the main analysis of AD and eAD, 379 763 patients are eligible for inclusion in the denominator. This resulted in an estimated prevalence of diagnosed AD of 378.39 (95% CI, 359.36 to 398.44) per 100 000 and eAD of 292.81 (95% CI, 276.12 to 310.52) per 100 000. Prevalence estimates across main and sensitivity analyses for the entire AD study population were found to vary widely with estimates ranging from 137.48 (95% CI, 127.05 to 148.76) to 796.55 (95% CI, 768.77 to 825.33). There was significant variation in prevalence of diagnosed eAD when assessing the sensitivity with the look-back periods, as low as 120.54 (95% CI, 110.80 to 131.14) per 100 000, and as high as 519.01 (95% CI, 496.64 to 542.37) per 100 000. CONCLUSIONS: The study found relatively consistent patterns of prevalence across both AD and eAD populations. Generally, the prevalence of diagnosed AD increased with age and increased with deprivation for each age category. Women had a higher prevalence than men. More granular levels of stratification reduced patient numbers and increased the uncertainty of point prevalence estimates. Despite this, the study found a relationship between deprivation and prevalence of AD.

The epidemiology of Shiga toxin-producing Escherichia coli O26:H11 (clonal complex 29) in England, 2014-2021.

OBJECTIVES: We aimed to describe the genomic epidemiology of the foodborne gastrointestinal pathogen, Shiga toxin-producing Escherichia coli (STEC) serotype O26:H11 belonging to clonal complex 29 (CC29) in England. METHODS: Between 01 January 2014 and 31 December 2021, 834 human isolates belonging to CC29 were sequenced at the UK Health Security Agency, and the genomic data was integrated with epidemiological data. RESULTS: Diagnoses of STEC O26:H11 in England have increased each year from 19 in 2014 to 144 in 2021. Most isolates had the Shiga toxin subtype profiles stx1a (47%), stx1a,stx2a (n = 24%) or stx2a (n = 28%). Most cases were female (57%), and the highest proportion of cases belonged to the 0-5 age group (38%). Clinical symptoms included diarrhoea (93%), blood-stained stool (48%), and abdominal pain (74%). Haemolytic Uraemic Syndrome (HUS) was diagnosed in 40/459 (9%) cases and three children died. All isolates causing STEC-HUS had stx2a either alone (n = 33) or in combination with stx1a (n = 7). CONCLUSIONS: STEC O26:H11 are a clinically significant, emerging threat to public health in England. Determining the true incidence and prevalence is challenging due to inconsistent national surveillance strategies. Improved diagnostics and surveillance algorithms are required to monitor the true burden, detect outbreaks and to implement effective interventions.

Real-world evaluation of ocrelizumab in multiple sclerosis: A systematic review.

Across its clinical development program, ocrelizumab demonstrated efficacy in improving clinical outcomes in multiple sclerosis, including annualized relapse rates and confirmed disability progression. However, as with any new treatment, it was unclear how this efficacy would translate into real-world clinical practice. The objective of this study was to systematically collate the published real-world clinical effectiveness data for ocrelizumab in relapsing remitting multiple sclerosis and primary progressive multiple sclerosis. A search strategy was developed in MEDLINE and Embase to identify articles reporting real-world evidence in people with relapsing remitting multiple sclerosis or primary progressive multiple sclerosis receiving treatment with ocrelizumab. The search focused on English language articles only but was not limited by the country in which the study was conducted or the time frame of the study. Additional manual searches of relevant websites were also performed. Fifty-two studies were identified reporting relevant evidence. Real-world effectiveness data for ocrelizumab were consistently favorable, with reductions in relapse rate and disease progression rates similar to those reported in the OPERA I/OPERA II and ORATORIO clinical trials, including in studies with more diverse patient populations not well represented in the pivotal trials. Although direct comparisons are confounded by lack of randomization of treatments, outcomes reported suggest that ocrelizumab has a similar or greater efficacy than other therapy options. Initial real-world effectiveness data for ocrelizumab appear favorable and consistent with results reported in clinical trials, providing clinicians with an efficacious option to treat patients with multiple sclerosis.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 7.

This month we focus on papers that provide insights into the potential for target trial emulation to be used in health technology assessment, the role of real-world evidence (RWE) in informing additional elements of value and the importance of RWE to European joint clinical assessments.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 6.

In this latest update we highlight recent publications from the US FDA and a Canadian Health Technology Assessment collaboration which provide insights into the future role of real-world evidence in market access in terms of health technology management.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 8.

In this latest update we highlight the publication of a draft real-world evidence framework by the UK National Institute for Health and Care Excellence, and describe a press release from Germany's Institute for Quality and Efficiency in HealthCare outlining how real-world evidence submissions are not following their guidelines. We also discuss whether the lack of adherence to guidelines is due to ignorance of these guidelines on the part of manufacturers, the difficulty in achieving best practices or a failure of guidelines to comprehensively describe best practices.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to HTA: part 5.

In the latest update we focus on recent publications which have provided insights into the importance of focusing on the development and consideration of a body of real-world evidence, and an approach to evaluating the complex area of treatment sequencing.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 4.

In this month's round up, we discuss a number of recent publications and guidelines addressing the use of real-world evidence to evaluate the clinical benefit of health technology assessments and what the publications mean practically for manufacturers.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 9.

In this latest update we highlight a recent International Society of Pharmacoeconomics and Outcomes Research Good Practice Report on machine learning (ML) for health economics and outcomes research. We specifically discuss use cases of ML that offer opportunities in the generation of evidence using real-world data, including improvements in the identification of study cohorts, confounder identification and adjustment and estimating treatment effect heterogeneity. Barriers to the wider adoption of ML methods are also discussed.

R WE ready for reimbursement? A round up of developments in RWE relating to health technology assessment: part 2.

In this round up, we cover how COVID-19 has been beneficial for improved access to real-world data, as well as how real-world data can be used to address health inequity, an area of increasing interest for health technology assessment.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to HTA: part 3.

In this round up, we discuss a number of recent publications that have utilized real-world evidence to explore the value that innovative treatments have brought to patients.