Opportunity and accessibility: an environmental scan of publicly available data repositories to address disparities in healthcare decision-making.

BACKGROUND: Health disparities, starkly exposed and exacerbated by coronavirus disease 2019, pose a significant challenge to healthcare system access and health outcomes. Integrating health inequalities into health technology assessment calls for robust analytical methodologies utilizing disaggregated data to investigate and quantify the scope of these disparities. However, a comprehensive summary of population datasets that can be used for this purpose is lacking. The objective of this review was to identify publicly accessible health inequalities data repositories that are potential resources for healthcare decision-making and future health technology assessment submissions. METHODS: An environmental scan was conducted in June of 2023 of six international organizations (World Health Organization, Organisation for Economic Co-operation and Development, Eurostat, United Nations Inter-agency Group for Child Mortality Estimation, the United Nations Sustainable Development Goals, and World Bank) and 38 Organisation for Economic Co-operation and Development countries. The official websites of 42 jurisdictions, excluding non-English websites and those lacking English translations, were reviewed. Screening and data extraction were performed by two reviewers for each data repository, including health indicators, determinants of health, and health inequality metrics. The results were narratively synthesized. RESULTS: The search identified only a limited number of country-level health inequalities data repositories. The World Health Organization Health Inequality Data Repository emerged as the most comprehensive source of health inequality data. Some country-level data repositories, such as Canada's Health Inequality Data Tool and England's Health Inequality Dashboard, offered rich local insights into determinants of health and numerous health status indicators, including mortality. Data repositories predominantly focused on determinants of health such as age, sex, social deprivation, and geography. CONCLUSION: Interactive interfaces featuring data exploration and visualization options across diverse patient populations can serve as valuable tools to address health disparities. The data they provide may help inform complex analytical methodologies that integrate health inequality considerations into healthcare decision-making. This may include assessing the feasibility of transporting health inequality data across borders.

Justifying the source of external comparators in single-arm oncology health technology submissions: a review of NICE and PBAC assessments.

Background: The drive to expedite patient access for diseases with high unmet treatment needs has come with an increasing use of single-arm trials (SATs), especially in oncology. However, the lack of control arms in such trials creates challenges to assess and demonstrate comparative efficacy. External control (EC) arms can be used to bridge this gap, with various types of sources available to obtain relevant data. Objective: To examine the source of ECs in single-arm oncology health technology assessment (HTA) submissions to the National Institute for Health and Care Excellence (NICE) and the Pharmaceutical Benefits Advisory Committee (PBAC) and how this selection was justified by manufacturers and assessed by the respective HTA body. Methods: Single-arm oncology HTA submission reports published by NICE (England) and PBAC (Australia) from January 2011 to August 2021 were reviewed, with data qualitatively synthesized to identify themes. Results: Forty-eight oncology submissions using EC arms between 2011 and 2021 were identified, with most submissions encompassing blood and bone marrow cancers (52%). In HTA submissions to NICE and PBAC, the EC arm was typically constructed from a combination of data sources, with the company's justification in data source selection infrequently provided (PBAC [2 out of 19]; NICE [6 out of 29]), although this lack of justification was not heavily criticized by either HTA body. Conclusion: Although HTA bodies such as NICE and PBAC encourage that EC source justification should be provided in submissions, this review found that this is not typically implemented in practice. Guidance is needed to establish best practices as to how EC selection should be documented in HTA submissions.

Navigating the unknown: how to best 'reflect' standard of care in indications without a dedicated treatment pathway in health technology assessment submissions.

There is an urgent need for expedited approval and access for new health technologies targeting rare and very rare diseases, some of which are associated with high unmet treatment needs. Once a new technology achieves regulatory approval, the technology needs to be assessed by health technology assessment (HTA) bodies to inform coverage and reimbursement decisions. This assessment quantitatively examines the clinical effectiveness, safety and/or economic impact of the new technology relative to standard of care (SoC) in a specific market. However, in rare and very rare diseases, the patient populations are small and there is often no established treatment pathway available to define 'SoC'. In these situations, several challenges arise to assess the added benefit of a new technology - both clinically and economically - due to lack of established SoC to guide an appropriate comparator selection. These challenges include: How should 'SoC' be defined and characterized in HTA submissions for new technologies aiming to establish new treatment standards? What is usual care without an established clinical pathway? How should the evidence for the comparator 'SoC' (i.e., usual care) arm be collected in situations with low patient representation and, sometimes, limited disease-specific clinical knowledge in certain geographies? This commentary outlines the evidence generation challenges in designing clinical comparative effectiveness for a new technology when there is a lack of established SoC. The commentary also proposes considerations to facilitate the reliable integration of real-world evidence into HTA and decision-making based on the collective experience of the authors.

Increasing transparency in indirect treatment comparisons: is selecting effect modifiers the missing part of the puzzle? A review of methodological approaches and critical considerations.

Failure to adjust for effect modifiers (EMs) in indirect treatment comparisons (ITCs) can produce biased and uncertain effect estimates. This is particularly important for health technology assessments (HTAs), where the availability of new treatments is based on comparative effectiveness results. Much emphasis has been placed on advancing ITC methods to adjust for EMs, yet whether EMs are appropriately identified for the conduct of ITCs in the first place is unclear. To understand the extent of guidance and requirements for the selection of EMs for ITCs currently available and if and how this guidance is applied in practice, a series of pragmatic reviews of guidance documents from HTA and non-payer organizations, primary published ITC analyses, and prior HTA submissions in two indications (non-small cell lung cancer and psoriasis) was conducted. The reviews showed that current ITC guidance mainly focused on developing analytical methods to adjust for EMs. Some organizations, such as HTA bodies in the UK, France and Germany, recommended the use of literature reviews, expert opinion and statistical methods to identify EMs. No detailed guidance on the selection process or the appropriate literature review approach was found. Similar trends were identified through the database search and review of prior HTA submissions; only few published ITCs and submissions included information on the EM selection process which was either based on findings from the literature, trial subgroup analyses, or clinical input. No reference to a systematic selection approach was found. There is an urgent need to fill the guidance gap identified across the reviews by including a step in ITC guidelines on how EMs should be identified through systematic reviews, formal expert elicitation, and a quantitative assessment of the EM distribution. Researchers and manufacturers are also encouraged to improve transparent reporting and justification of their selection of EMs to allow for an independent review of the set of factors being considered for adjustment. Both will contribute toward reducing bias in the ITC results and ultimately increase confidence in decision-making.

Reconstructing the value puzzle in health technology assessment: a pragmatic review to determine which modelling methods can account for additional value elements.

Health technology assessment (HTA) has traditionally relied on cost-effectiveness analysis (CEA) as a cornerstone of evaluation of new therapies, assessing the clinical validity and utility, the efficacy, and the cost-effectiveness of new interventions. The current format of cost-effectiveness analysis, however, does not allow for inclusion of more holistic aspects of health and, therefore, value elements for new technologies such as the impact on patients and society beyond its pure clinical and economic value. This study aimed to review the recent modelling attempts to expand the traditional cost-effectiveness analysis approach by incorporating additional elements of value in health technology assessment. A pragmatic literature review was conducted for articles published between 2012 and 2022 reporting cost-effectiveness analysis including value aspects beyond the clinical and cost-effectiveness estimates; searches identified 13 articles that were eligible for inclusion. These expanded modelling approaches mainly focused on integrating the impact of societal values and health equity in cost-effectiveness analysis, both of which were championed as important aspects of health technology assessment that should be incorporated into future technology assessments. The reviewed cost-effectiveness analysis methods included modification of the current cost-effectiveness analysis methodology (distributional cost-effectiveness analysis, augmented cost-effectiveness analysis, extended cost-effectiveness analysis) or the use of multi-criteria decision analysis. Of these approaches, augmented cost-effectiveness analysis appears to have the most potential by expanding traditional aspects of value, as it uses techniques already familiar to health technology assessment agencies but also allows space for incorporation of qualitative aspects of a product's value. This review showcases that methods to unravel additional value elements for technology assessment exist, therefore, patient access to promising technologies can be improved by moving the discussion from "if" to "how" additional value elements can inform decision-making.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Economic and Humanistic Burden of Cerebral Vasospasm and Its Related Complications after Aneurysmal Subarachnoid Hemorrhage: A Systematic Literature Review.

INTRODUCTION: Cerebral vasospasm (VSP) is the leading risk factor of neurological deterioration (i.e., delayed cerebral ischemia [DCI] and cerebral infarction) after aneurysmal subarachnoid hemorrhage (aSAH) and a cause of morbidity and mortality. The objective of this systematic literature review is to summarize the economic and humanistic burden of VSP and its related complications after aSAH. METHODS: A predefined protocol was designed, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Systematic searches were conducted in MEDLINE, Embase, and Cochrane (in January 2021) to identify studies reporting economic and/or humanistic (i.e., health-related quality of life [HRQoL]) outcomes for patients with asymptomatic and symptomatic VSP after aSAH. Related conferences and additional sources were searched manually. Dual screening, data extraction, and qualitative analysis were conducted. RESULTS: Of 3818 abstracts identified for review, 43 full-text articles representing 42 single studies met the inclusion criteria and were included. Most studies (33) were observational; nine were randomized clinical trials (RCTs). Economic outcomes were reported in 31 studies, and alongside HRQoL outcomes in 4 studies; 7 studies reported HRQoL outcomes only. Forty studies were conducted in single countries, while only 2 RCTs were conducted in multiple countries. Patients diagnosed with VSP or DCI spent between 2.1 and 7.4 days longer in intensive care and between 4.7 and 17 days longer in hospital (total) compared with patients without VSP or DCI. A significantly higher cost burden of US$33,945 (2021 £26,712) was identified for patients with VSP and £9370 (2021 £13,733) for patients with DCI compared with patients without. Patients with DCI were also disadvantaged by being employed for 62 fewer days (during 24-month follow-up), with an estimated mean cost of £3821 (2021 £5600) for days off work. Poor HRQoL was associated with ≥ 1 days with VSP symptoms (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.4-5.3), symptomatic VSP (OR: 1.9, 95% CI: 1.0-3.6), and DCI (OR: 2.3, 95% CI: 1.3-4.2), although this was not consistent across all studies. Symptomatic VSP and DCI were identified as significant risk factors for depressed mood (OR: 2.2, 95% CI: 1.0-4.9) and global cognitive impairment (OR: 2.3) at 12 months, respectively. The severity of VSP was a critical predictor of post-aSAH economic and humanistic burden. Similar trends in economic and humanistic burden were identified in the general aSAH patient population. Study design and patient heterogeneity precluded direct metaanalysis of the results. CONCLUSION: A substantial direct and indirect economic burden is linked to VSP and its related complications after aSAH. Although limited evidence was identified for humanistic burden, these patients seem to suffer from poor HRQoL with long-lasting burden. Overall, there is an urgent need to understand better the concept of "burden of illness" of VSP and its related complications after aSAH.

Aneurysmal subarachnoid hemorrhage is a sudden, life-threatening emergency caused by bleeding in the subarachnoid space between the brain and skull. Vasospasm of the arteries surrounding the hemorrhage occurs in most patients and may lead to permanent brain damage. This study summarizes the published literature to describe the burden that patients may experience due to vasospasm and its related complications after aneurysmal subarachnoid hemorrhage, focusing on financial and life quality aspects. We show that the burden of vasospasm, and its related complications, is huge. Patients often experience reduced quality of life due to their poor health and are more likely to suffer from depression and intellectual impairment. There is also a substantial financial burden linked to vasospasm and its related complications, driven by the need for more intensive care, hospitalization, and higher investigative costs associated with the treatment and management of these patients. In addition, days off work and unemployment can cause a substantial indirect financial burden. Our study highlights the need for additional research to understand further the "burden of illness" of vasospasm and its related complications after aneurysmal subarachnoid hemorrhage.

ISPE-Endorsed Guidance in Using Electronic Health Records for Comparative Effectiveness Research in COVID-19: Opportunities and Trade-Offs.

As the scientific research community along with healthcare professionals and decision makers around the world fight tirelessly against the coronavirus disease 2019 (COVID-19) pandemic, the need for comparative effectiveness research (CER) on preventive and therapeutic interventions for COVID-19 is immense. Randomized controlled trials markedly under-represent the frail and complex patients seen in routine care, and they do not typically have data on long-term treatment effects. The increasing availability of electronic health records (EHRs) for clinical research offers the opportunity to generate timely real-world evidence reflective of routine care for optimal management of COVID-19. However, there are many potential threats to the validity of CER based on EHR data that are not originally generated for research purposes. To ensure unbiased and robust results, we need high-quality healthcare databases, rigorous study designs, and proper implementation of appropriate statistical methods. We aimed to describe opportunities and challenges in EHR-based CER for COVID-19-related questions and to introduce best practices in pharmacoepidemiology to minimize potential biases. We structured our discussion into the following topics: (1) study population identification based on exposure status; (2) ascertainment of outcomes; (3) common biases and potential solutions; and (iv) data operational challenges specific to COVID-19 CER using EHRs. We provide structured guidance for the proper conduct and appraisal of drug and vaccine effectiveness and safety research using EHR data for the pandemic. This paper is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Modeling Challenges in Cost-Effectiveness Analysis of First-Line Immuno-Oncology Therapies in Non-small Cell Lung Cancer: A Systematic Literature Review.

INTRODUCTION: The introduction of immuno-oncology (IO) therapies has changed the treatment landscape of non-small cell lung cancer (NSCLC). Numerous cost-effectiveness analyses (CEAs) and technology appraisals (TAs) evaluating IO therapies have been recently published. OBJECTIVE: We reviewed economic models of first-line (1L) IO therapies for previously untreated advanced or metastatic NSCLC to identify methodological challenges associated with modeling cost effectiveness from published literature and TAs and to make recommendations for future CEAs in this disease area. METHODS: A systematic literature review was conducted following Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched MEDLINE, Embase, EconLit (January 2009-January 2020), and select conferences (since 2016) for CEAs of 1L IO treatments in patients with recurrent or metastatic, epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC, published in English. TAs from England, Scotland, Canada, Australia, Germany, and France were also examined. Two reviewers screened the results and extracted the data. The quality of the CEAs was described using the Drummond checklist. RESULTS: In total, 46 records reporting on 38 unique models met protocol-defined criteria and were included. Five models adjusted for treatment switching or crossover in base-case analyses, and the remainder considered treatment switching or crossover to represent clinical practice and made no adjustment. Seven models used external real-world data for survival modeling or extrapolation validation. Six models that assumed long-term treatment benefit stopped at 3 or 5 years after initiation. Seven models used the observed time-on-treatment distribution from the trial, and eight used progression-free survival for treatment duration. All models compared one or more IO monotherapies or combination therapies with chemotherapy. Only one study directly compared different IO agents but did not consider the concordance issue across programmed death-ligand 1 (PD-L1) testing methods. Utilities were modeled by health state in 12 models, four applied a time-to-death approach, and ten explored both. None applied cure models. CONCLUSION: Variations in methodological challenges were seen across studies. Previous models took approaches that were followed in subsequent models, such as a 2-year stopping rule of IO duration or treatment-effect waning. Challenges such as heterogeneity in PD-L1 testing and survival extrapolation and validation using real-world data should be further considered for future models in advanced or metastatic NSCLC.

Framework for the synthesis of non-randomised studies and randomised controlled trials: a guidance on conducting a systematic review and meta-analysis for healthcare decision making.

INTRODUCTION: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. OBJECTIVES AND METHODS: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. RESULTS: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, 'high-bar evidence' when RCTs are the preferred source of evidence, 'medium,' and 'low' when NRS is the main source of inference). CONCLUSION: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology.

Short-Term Efficacy of Biologic Therapies in Moderate-to-Severe Plaque Psoriasis: A Systematic Literature Review and an Enhanced Multinomial Network Meta-Analysis.

INTRODUCTION: Many targeted, systemic therapies have been developed for treatment of moderate-to-severe psoriasis (PsO). A network meta-analysis (NMA) allows for comparison between treatments not directly compared in randomized controlled trials (RCT). This study's objective was to compare the short-term (10-16 weeks) clinical efficacy according to the Psoriasis Area and Severity Index (PASI) among approved biologic treatments for moderate-to-severe PsO using a novel (enhanced) NMA model. METHODS: A systematic literature review (SLR) of RCTs for patients with moderate-to-severe PsO was conducted. English publications in MEDLINE, Embase, and The Cochrane Library up to March 2019 were searched. An enhanced multinomial Bayesian NMA was performed to simultaneously adjust for baseline risk and utilize the conditional nature of the PASI (50, 75, 90, and 100) levels. The model relaxes typical constraints that all treatments must have the same ranks across PASI levels. RESULTS: The SLR resulted in 319 relevant publications, of which 72 publications from 73 RCTs reporting 10- to 16-week data for at least one PASI response level (30,314 total patients) were included. Interleukin (IL) inhibitors (risankizumab, ixekizumab, brodalumab, secukinumab, and guselkumab) were the best performing treatments for achieving all PASI levels. Etanercept was outperformed by the other subcutaneous tumor necrosis factor α inhibitors. Application of an enhanced NMA model that allowed treatment rankings to differ by PASI level tested the robustness of results of previous NMAs in PsO. CONCLUSION: The results of this model confirmed that IL inhibitors are likely the best short-term treatment choices for improving all PASI levels.

DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma.

INTRODUCTION: Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678). METHODS: At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH). RESULTS: Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001). CONCLUSION: Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.

Global prevalence of long-term neurodevelopmental impairment following extremely preterm birth: a systematic literature review.

OBJECTIVE: Neurodevelopmental impairment (NDI) is a major complication of extreme prematurity. This systematic review was conducted to summarize the worldwide long-term prevalence of NDI associated with extreme prematurity. METHODS: Embase and MEDLINE databases were searched for epidemiologic and observational/real-world studies, published in English between 2011 and 2016, reporting long-term prevalence of NDI (occurring from 1 year) among extremely preterm infants born at gestational age (GA) ≤28 weeks. RESULTS: Of 2406 articles identified through searches, 69 met the protocol NDI definition (24 North America, 25 Europe, 20 Rest of World). Prevalence of any severity NDI in North America was 8%-59% at 18 months to 2 years, and 11%-37% at 2-5 years; prevalence of moderate NDI in Europe was 10%-13% at 18 months to 2 years, 3% at 2-5 years, and 9%-19% at ≥5 years; prevalence of any NDI in Rest of World was 15%-61% at 18 months to 2 years, and 42% at 2-5 years (no North America/Rest of World studies reported any NDI at ≥5 years). A trend toward higher prevalence of NDI with lower GA at birth was observed. CONCLUSIONS: Extreme prematurity has a significant long-term worldwide impact on neurodevelopmental outcomes.

How well can we assess the validity of non-randomised studies of medications? A systematic review of assessment tools.

OBJECTIVE: To determine whether assessment tools for non-randomised studies (NRS) address critical elements that influence the validity of NRS findings for comparative safety and effectiveness of medications. DESIGN: Systematic review and Delphi survey. DATA SOURCES: We searched PubMed, Embase, Google, bibliographies of reviews and websites of influential organisations from inception to November 2019. In parallel, we conducted a Delphi survey among the International Society for Pharmacoepidemiology Comparative Effectiveness Research Special Interest Group to identify key methodological challenges for NRS of medications. We created a framework consisting of the reported methodological challenges to evaluate the selected NRS tools. STUDY SELECTION: Checklists or scales assessing NRS. DATA EXTRACTION: Two reviewers extracted general information and content data related to the prespecified framework. RESULTS: Of 44 tools reviewed, 48% (n=21) assess multiple NRS designs, while other tools specifically addressed case-control (n=12, 27%) or cohort studies (n=11, 25%) only. Response rate to the Delphi survey was 73% (35 out of 48 content experts), and a consensus was reached in only two rounds. Most tools evaluated methods for selecting study participants (n=43, 98%), although only one addressed selection bias due to depletion of susceptibles (2%). Many tools addressed the measurement of exposure and outcome (n=40, 91%), and measurement and control for confounders (n=40, 91%). Most tools have at least one item/question on design-specific sources of bias (n=40, 91%), but only a few investigate reverse causation (n=8, 18%), detection bias (n=4, 9%), time-related bias (n=3, 7%), lack of new-user design (n=2, 5%) or active comparator design (n=0). Few tools address the appropriateness of statistical analyses (n=15, 34%), methods for assessing internal (n=15, 34%) or external validity (n=11, 25%) and statistical uncertainty in the findings (n=21, 48%). None of the reviewed tools investigated all the methodological domains and subdomains. CONCLUSIONS: The acknowledgement of major design-specific sources of bias (eg, lack of new-user design, lack of active comparator design, time-related bias, depletion of susceptibles, reverse causation) and statistical assessment of internal and external validity is currently not sufficiently addressed in most of the existing tools. These critical elements should be integrated to systematically investigate the validity of NRS on comparative safety and effectiveness of medications. SYSTEMATIC REVIEW PROTOCOL AND REGISTRATION: https://osf.io/es65q.

Patient-Reported Outcomes and Economic Burden of Adults with Sickle Cell Disease in the United States: A Systematic Review.

PURPOSE: To systematically estimate the patient-reported outcomes (PROs) and economic burden of sickle cell disease (SCD) among adults in the United States (US). PATIENTS AND METHODS: Two systematic literature reviews (SLRs), one each for the PROs and economic topics, were performed using MEDLINE and Embase to identify observational studies of adults with SCD. Included studies were published between 2007 and 2018 and evaluated health-related quality of life (HRQL), function, healthcare resource utilization (HCRU), or costs. Given the high degree of clinical and methodological heterogeneity, findings were summarized qualitatively. RESULTS: The SLRs identified 7 studies evaluating the PROs and 15 studies evaluating the economic burden meeting the pre-specified selection criteria. The PRO evidence showed the prevalence of depression and anxiety to be 21-33% and 7-36%, respectively, in adults with SCD. The mean SF-36 physical summary scores ranged from 33.6 to 59.0 and from 46.3 to 61.5 for the mental summary scores. Overall HRQL for adults with SCD was poor and significantly worse in those with opioid use. Adult SCD patients were found to have varying rates of emergency department (ED) utilization (0.3-3.5 annual ED visits), hospitalizations (0.5-27.9 per patient per year), and/or readmission (12-41%). Key factors associated with significant HCRU were age, dental infection, and SCD-related complications. SCD specialized care settings and SCD intensive management strategy were reported to significantly decrease the number of hospitalizations. CONCLUSION: This systematic evidence synthesis found that disease burden measured by PROs and economic burden of SCD on adults in the US are substantial despite the availability of approved SCD treatments during 2007-2018. The use of hydroxyurea, optimal management with opioids, and employing intensive treatment strategies may help decrease the overall burden to patients and healthcare systems. Published data on costs associated with SCD are limited and highlight the need for more economic studies to characterize the full burden of the disease.

Moderately severe and severe acute pancreatitis : a systematic review of the outcomes in the USA and European Union-5.

BACKGROUND AND OBJECTIVES: The global incidence of hospitalisation due to acute pancreatitis (AP) has been rising in the recent decades. In the USA alone, there was a 13.2% increase between 2009 and 2012 compared with 2002-2005. There remains a lack of approved treatments to prevent disease progression, leaving many liable to developing complications that include multisystem organ failure (OF) and death. This therapeutic deficit raises questions about the scale of the current burden of illness (BOI) associated with severe forms of AP. The aim of the systematic literature review (SLR) was to assess clinical, humanistic, and economic outcomes associated with moderately severe AP (MSAP) and severe AP (SAP) in the USA and the European Union-5 (EU-5). METHODS: Systematic searches were conducted in MEDLINE and Embase to identify studies published in English (between 2007 and 2017) that reported on the BOI of MSAP and/or SAP. Manual searches of 'grey' literature sources were also conducted. RESULTS: The SLR identified 19 studies which indicated that 15%-20% of patients with AP progress to more severe forms of the disease, up to 10.5% of those with SAP require surgery for complications, and up to 40% die during hospitalisation. By contrast, there appears to be a lack of data on the extent to which SAP affects patients' quality of life. CONCLUSION: The available evidence clearly demonstrates that the current management for MSAP and SAP in the USA and EU-5 does not adequately meet patients' needs. Early identification and intervention for AP is crucial, given the evidence of high rates of morbidity and an associated economic burden that is considerable. Since many patients with the condition present to hospitals at a point when multisystem OF or death is highly likely, there is a particularly urgent need for effective treatment options to prevent disease progression.