Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Economic Evaluation of Cannabinoid Oil for Dravet Syndrome: A Cost-Utility Analysis.

INTRODUCTION: Cannabinoid oils are being increasingly used to treat Dravet syndrome, yet the long-term costs and outcomes of this approach are unknown. Thus, we examined the cost effectiveness of cannabinoid oil as an adjunctive treatment (added to clobazam and valproate), compared with adjunctive stiripentol or with clobazam and valproate alone, for the treatment of Dravet syndrome in children. METHODS: We performed a probabilistic cost-utility analysis from the perspective of the Canadian public health care system, comparing cannabinoid oil and stiripentol (both on a background of clobazam and valproate) with clobazam and valproate alone. Costs and quality-adjusted life-years (QALYs) were estimated using a Markov model that followed a cohort of children aged from 5 to 18 years through model states related to seizure frequency. Model inputs were obtained from the literature. The cost effectiveness of adjunctive cannabinoid oil, adjunctive stiripentol, and clobazam/valproate alone was assessed through sequential analysis. The influence of perspective and other assumptions were explored in scenario analyses. All costs are expressed in 2019 Canadian dollars, and costs and QALYs were discounted at a rate of 1.5% per year. RESULTS: The incremental cost per QALY gained with the use of adjunctive cannabinoid oil, from the health care system perspective, was $32,399 compared with clobazam and valproate. Stiripentol was dominated by cannabinoid oil, producing fewer QALYs at higher costs. At a willingness-to-pay threshold of $50,000, cannabinoid oil was the optimal treatment in 76% of replications. From a societal perspective, cannabinoid oil dominated stiripentol and clobazam/valproate. The interpretation of the results was insensitive to model and input assumptions. CONCLUSION: Compared with clobazam/valproate, adjunctive cannabinoid oil may be a cost-effective treatment for Dravet syndrome, if a decision maker is willing to pay at least $32,399 for each QALY gained. The opportunity costs of continuing to fund stiripentol, but not cannabinoid oil, should be considered.

Decision Models for Assessing the Cost Effectiveness of Treatments for Pediatric Drug-Resistant Epilepsy: A Systematic Review of Economic Evaluations.

BACKGROUND: Drug-resistant epilepsy affects about one-third of children with epilepsy and is associated with high costs to the healthcare system, yet the cost effectiveness of most treatments is unclear. Use of cannabis-based products for epilepsy is increasing, and the cost effectiveness of such strategies relative to conventional pharmacologic treatments must be considered. OBJECTIVE: The objective of this systematic review was to identify economic evaluations of cannabis-based treatments for pediatric drug-resistant epilepsy. We also sought to identify and appraise decision models that have been used in economic evaluations of pharmacologic treatments (i.e., antiepileptic drugs) in this population. METHODS: Electronic searches of MEDLINE, EMBASE, and the Cochrane library, as well as a targeted grey literature search, were undertaken (11 June 2018). Model-based full economic evaluations involving cannabis-based treatments or pharmacologic treatments for drug-resistant epilepsy in children were eligible for inclusion. Two independent reviewers selected studies for inclusion, and study quality was assessed by use of the Drummond and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. Study findings, as well as model characteristics, are narratively summarized. RESULTS: Nine economic evaluations involving children with drug-resistant epilepsy were identified; however, none involved cannabis-based treatments. All studies involved pharmacologic treatments compared with other pharmacologic treatments or non-pharmacologic treatments (i.e., ketogenic diet, epilepsy surgery, vagus nerve stimulation). Few studies have assessed the cost effectiveness of pharmacologic treatments in specific drug-resistant epilepsy syndromes, including Dravet and Lennox-Gastaut syndromes. Five included studies involved use of Markov models with a similar structure (i.e., health states based on seizure frequency relative to baseline). There was a wide range of methodological quality, and few studies fully addressed context-specific issues such as weight gain and treatment switching. CONCLUSION: Whether cannabis-based treatments for pediatric drug-resistant epilepsy represent good value for money has yet to be investigated. Economic evaluations of such treatments are needed and should address issues of particular importance in pediatric epilepsy, including weight gain over time, switching or discontinuation of treatments, effectiveness of interventions and comparators, and long-term effectiveness beyond the duration of available clinical studies. PROSPERO REGISTRATION: CRD42018099591.

Toward a Centralized, Systematic Approach to the Identification, Appraisal, and Use of Health State Utility Values for Reimbursement Decision Making: Introducing the Health Utility Book (HUB).

Cost-utility analysis (CUA) is a widely recommended form of health economic evaluation worldwide. The outcome measure in CUA is quality-adjusted life-years (QALYs), which are calculated using health state utility values (HSUVs) and corresponding life-years. Therefore, HSUVs play a significant role in determining cost-effectiveness. Formal adoption and endorsement of CUAs by reimbursement authorities motivates methodological advancement in HSUV measurement and application. A large body of evidence exploring various methods in measuring HSUVs has accumulated, imposing challenges for investigators in identifying and applying HSUVs to CUAs. First, large variations in HSUVs between studies are often reported, and these may lead to different cost-effectiveness conclusions. Second, issues concerning the quality of studies that generate HSUVs are increasingly highlighted in the literature. This issue is compounded by the limited published guidance and methodological standards for assessing the quality of these studies. Third, reimbursement decision making is a context-specific process. Therefore, while an HSUV study may be of high quality, it is not necessarily appropriate for use in all reimbursement jurisdictions. To address these issues, by promoting a systematic approach to study identification, critical appraisal, and appropriate use, we are developing the Health Utility Book (HUB). The HUB consists of an HSUV registry, a quality assessment tool for health utility studies, and a checklist for interpreting their use in CUAs. We anticipate that the HUB will make a timely and important contribution to the rigorous conduct and proper use of health utility studies for reimbursement decision making. In this way, health care resource allocation informed by HSUVs may reflect the preferences of the public, improve health outcomes of patients, and maintain the efficiency of health care systems.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

BACKGROUND: Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. METHODS: We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. DISCUSSION: Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no.: CRD42018099591 .

Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis.

BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment-resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality-adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration.

Quality of conduct and reporting in rapid reviews: an exploration of compliance with PRISMA and AMSTAR guidelines.

BACKGROUND: Rapid reviews are an accelerated evidence synthesis approach intended to meet the timely needs of decision-makers in healthcare settings. Quality of conduct and reporting has been described in the rapid review literature; however, no formal assessment has been carried out using available instruments. The objective of this study was to explore compliance with conduct and reporting guidelines in rapid reviews published or posted online during 2013 and 2014. METHODS: We performed a comprehensive literature search for rapid reviews using multiple bibliographic databases (e.g. PubMed, MEDLINE, EMBASE, the Cochrane Library) through December 31, 2014. Grey literature was searched thoroughly, and health technology assessment agencies were surveyed to identify additional rapid review products. Candidate reviews were assessed for inclusion using pre-specified eligibility criteria. Detailed data was collected from the included reviews on study and reporting characteristics and variables significant to rapid reviews (e.g. nomenclature, definition). We evaluated the quality of conduct and reporting of included rapid reviews using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklists. Compliance with each checklist item was examined, and the sum of adequately reported items was used to describe overall compliance. Rapid reviews were stratified to explore differences in compliance related to publication status. The association between compliance and time to completion or length of publication was explored through univariate regression. RESULTS: Sixty-six rapid reviews were included. There were heterogeneous nomenclature, research questions and approaches to rapid reviews. Compliance with AMSTAR and PRISMA checklists was poor. Published rapid reviews were compliant with individual PRISMA items more often than unpublished reviews, but no difference was seen in AMSTAR item compliance overall. There was evidence of an association between length of publication and time to completion and the number of adequately reported PRISMA or AMSTAR items. CONCLUSIONS: Transparency and inadequate reporting are significant limitations of rapid reviews. Scientific editors, authors and producing agencies should ensure that the reporting of conduct and findings is accurate and complete. Further research may be warranted to explore reporting and conduct guidelines specific to rapid reviews and how these guidelines may be applied across the spectrum of rapid review approaches.

How can we improve the recognition, reporting and resolution of medical device-related incidents in hospitals? A qualitative study of physicians and registered nurses.

BACKGROUND: To explore factors that influence and to identify initiatives to improve the recognition, reporting and resolution of device-related incidents. METHODS: Semi-structured telephone interviews with 16 health professionals in two tertiary care hospitals were conducted. Purposive sampling was used to identify appropriate study participants. Transcribed interviews were read independently by one individual to identify, define and organize themes and verified by another reviewer. RESULTS: Themes related to incident recognition were the hospital staff's knowledge and professional experience, medical device performance and clinical manifestations of patients, while incident reporting was influenced by error severity, personal attitudes of clinicians, feedback received on the error reported. Physicians often discontinued using medical devices if they malfunctioned. Education and training and the implementation of registries were discussed as important initiatives to improve medical device surveillance in clinical practice. CONCLUSIONS: Results from the telephone interviews suggest that multiple factors that influence participation in medical device surveillance activities are consistent with results for medical errors as reported in previous studies. The study results helped to propose a conceptual framework for a medical device surveillance system in a hospital context that would enhance patient safety and health care delivery.

Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation.

OBJECTIVE: To examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and vitamin K antagonists (VKA) at a standard adjusted dose (target international normalised ratio 2.0-3.0), acetylsalicylic acid (ASA), ASA and clopidogrel) for non-valvular atrial fibrillation and among subpopulations. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: A systematic literature search strategy was designed and carried out using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and the grey literature including the websites of regulatory agencies and health technology assessment organisations for trials published in English from 1988 to January 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials were selected for inclusion if they were published in English, included at least one antithrombotic treatment and involved patients with non-valvular atrial fibrillation eligible to receive anticoagulant therapy. RESULTS: For stroke or systemic embolism, dabigatran 150 mg and apixaban twice daily were associated with reductions relative to standard adjusted dose VKA, whereas low-dose ASA and the combination of clopidogrel plus low-dose ASA were associated with increases. Absolute risk reductions ranged from 6 fewer events per 1000 patients treated for dabigatran 150 mg twice daily to 15 more events for clopidogrel plus ASA. For major bleeding, edoxaban 30 mg daily, apixaban, edoxaban 60 mg daily and dabigatran 110 mg twice daily were associated with reductions compared to standard adjusted dose VKA. Absolute risk reductions with these agents ranged from 18 fewer per 1000 patients treated each year for edoxaban 30 mg daily to 24 more for medium dose ASA. CONCLUSIONS: Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding. People on antiplatelet drugs experienced more strokes compared with anticoagulant drugs without any reduction in bleeding risk. To fully elucidate the comparative benefits and harms of antithrombotic agents across the various subpopulations, rigorously conducted comparative studies or network meta-regression analyses of patient-level data are required. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO registry-CRD42012002721.

Rapid review: an emerging approach to evidence synthesis in health technology assessment.

BACKGROUND: Increasingly, healthcare decision makers demand quality evidence in a short timeframe to support urgent and emergent decisions related to procurement, clinical practice, and policy. Health technology assessment (HTA) producers are responding by developing innovative approaches to evidence synthesis that can be executed more quickly than traditional systematic review. These approaches, and the broader implications they bring to bear on health decision making and policy development, however, are generally neither well-understood nor well-described. This study intends to contribute to an emerging literature around methodological approaches to rapid review in HTA by outlining those developed and implemented by the Canadian Agency for Drugs and Technologies in Health (CADTH). METHODS: Since 2005, CADTH has developed and implemented a rapid review approach that synthesizes evidence to support informed healthcare decisions and policy. Rapid Response reports are tailored to the identified needs of Canadian health decision makers, representing a range of options with regard to depth, breadth, and time-to-delivery. RESULTS: Preliminary observations indicate that CADTH's approach to rapid evidence review is generally well-received by Canadian health decision makers; real-world case studies provide pragmatic examples of how health decision makers have used Rapid Response reports to support evidence-informed health decisions across Canada. CONCLUSIONS: Rapid review is becoming an increasingly important approach to evidence synthesis, both within and external to the field of HTA. Transparent reporting of the methods used to develop rapid review products will be critical to the assessment of their relevance, utility and effects in a range of contexts.

Case studies that illustrate disinvestment and resource allocation decision-making processes in health care: a systematic review.

OBJECTIVE: Technological change accounts for approximately 25 percent of health expenditure growth. To date, limited research has been published on case studies of disinvestment and resource allocation decision making in clinical practice. Our research objective is to systematically review and catalogue the application of frameworks and tools for disinvestment and resource allocation decision making in health care. METHODS: An electronic literature search was executed for studies on disinvestment, obsolete and ineffective technologies, and priority healthcare setting, published from January 1990 until January 2012. Databases searched were MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, Embase, The Cochrane Library, PubMed, and HEED. RESULTS: Fourteen case studies on the application of frameworks and tools for disinvestment and resource allocation decisions were included. Most studies described the application of program budgeting and marginal analysis (PBMA), and two reports used health technology assessment (HTA) methods for coverage decisions in a national fee-for-service structure. Numerous healthcare technologies and services were covered across the studies. We describe the multiple criteria considered for decision making, and the strengths and limitations of these frameworks and tools are highlighted. CONCLUSIONS: Disinvestment and resource allocation decisions require evidence to ensure their transparency and objectivity. PBMA was used to assess resource allocation of health services and technologies in a fixed budget jurisdiction, while HTA reviews focused on specific technologies, principally in fee-for-service structures. Future research can review the data requirements and explore opportunities to increase the quantity of available evidence for disinvestment and resource allocation decisions.

Funding source, trial outcome and reporting quality: are they related? Results of a pilot study.

BACKGROUND: There has been increasing concern regarding the potential effects of the commercialization of research. METHODS: In order to examine the relationships between funding source, trial outcome and reporting quality, recent issues of five peer-reviewed, high impact factor, general medical journals were hand-searched to identify a sample of 100 randomized controlled trials (20 trials/journal). Relevant data, including funding source (industry/not-for-profit/mixed/not reported) and statistical significance of primary outcome (favouring new treatment/favouring conventional treatment/neutral/unclear), were abstracted. Quality scores were assigned using the Jadad scale and the adequacy of allocation concealment. RESULTS: Sixty-six percent of trials received some industry funding. Trial outcome was not associated with funding source (p=.461). There was a preponderance of favourable statistical conclusions among published trials with 67% reporting results that favored a new treatment whereas 6% favoured the conventional treatment. Quality scores were not associated with funding source or trial outcome. CONCLUSIONS: It is not known whether the absence of significant associations between funding source, trial outcome and reporting quality reflects a true absence of an association or is an artefact of inadequate statistical power, reliance on voluntary disclosure of funding information, a focus on trials recently published in the top medical journals, or some combination thereof. Continued and expanded monitoring of potential conflicts is recommended, particularly in light of new guidelines for disclosure that have been endorsed by the ICMJE.