Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first-line add-on therapies for seizures in Dravet syndrome: A network meta-analysis.

OBJECTIVES: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS. METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs. RESULTS: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter. SIGNIFICANCE: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS. PLAIN LANGUAGE SUMMARY: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.

Determining the Relationship Between Seizure-Free Days and Other Predictors of Quality of Life in Patients with Dravet Syndrome and Their Carers from FFA Registration Studies.

INTRODUCTION: Dravet syndrome (DS) is a rare, lifelong epileptic encephalopathy characterised by frequent and severe seizures associated with premature mortality. Typically diagnosed in infancy, patients also experience progressive behavioural, motor-function and cognitive decline. Twenty percent of patients do not reach adulthood. Quality of life (QoL) is impaired for both patients and their carers. Reducing convulsive seizure frequency, increasing convulsive seizure-free days (SFDs) and improving patient/carer QoL are primary treatment goals in DS. This study explored the relationship between SFDs and patients' and carers' QoL to inform a cost-utility analysis of fenfluramine (FFA). METHODS: In FFA registration studies, patients (or their carer proxies) completed the Paediatric QoL inventory (PedsQL). These data were mapped to EuroQol-5 Dimensions Youth version (EQ-5D-Y) to provide patient utilities. Carer utilities were collected using EQ-5D-5L and mapped to EQ-5D-3L to align patient and carer QoL on the same scale. Linear mixed-effects and panel regression models were tested and Hausman tests identified the most appropriate approach for each group. On this basis, a linear mixed-effects regression model was used to examine the relationships between patient EQ-5D-Y and clinically relevant variables (age, frequency of SFDs per 28 days, motor impairments and treatment dose). A linear panel regression model examined the relationship between SFDs and carer QoL. RESULTS: After adjustment for age and underlying comorbidities, the patient regression model showed that SFDs per 28 days was a significant predictor of QoL. Each additional patient-SFD increased utility by 0.005 (p < 0.001). The carer linear panel model also showed that increasing SFDs per 28 days was a significant predictor of improved QoL. Each additional SFD increased carer utility by 0.014 (p < 0.001). CONCLUSION: This regression framework highlights that SFDs are significantly correlated with both patients' and carers' QoL. Treatment with effective antiseizure medications that increase SFDs directly improves QoL for patients and their carers.

Decision-makers' preferences for approving new medicines in Wales: a discrete-choice experiment with assessment of external validity.

BACKGROUND: Few studies to date have explored the stated preferences of national decision makers for health technology adoption criteria, and none of these have compared stated decision-making behaviours against actual behaviours. Assessment of the external validity of stated preference studies, such as discrete-choice experiments (DCEs), remains an under-researched area. OBJECTIVES: The primary aim was to explore the preferences of All Wales Medicines Strategy Group (AWMSG) appraisal committee and appraisal sub-committee (the New Medicines Group) members ('appraisal committees') for specific new medicines adoption criteria. Secondary aims were to explore the external validity of respondents' stated preferences and the impact of question choice options upon preference structures in DCEs. METHODS: A DCE was conducted to estimate appraisal committees members' preferences for incremental cost effectiveness, quality-adjusted life-years (QALYs) gained, annual number of patients expected to be treated, the impact of the disease on patients before treatment, and the assessment of uncertainty in the economic evidence submitted for new medicines compared with current UK NHS treatment. Respondents evaluated 28 pairs of hypothetical new medicines, making a primary forced choice between each pair and a more flexible secondary choice, which permitted either, neither or both new medicines to be chosen. The performance of the resultant models was compared against previous AWMSG decisions. RESULTS: Forty-one out of a total of 80 past and present members of AWMSG appraisal committees completed the DCE. The incremental cost effectiveness of new medicines, and the QALY gains they provide, significantly (p < 0.0001) influence recommendations. Committee members were willing to accept higher incremental cost-effectiveness ratios and lower QALY gains for medicines that treat disease impacting primarily upon survival rather than quality of life, and where uncertainty in the cost-effectiveness estimates has been thoroughly explored. The number of patients to be treated by the new medicine did not exert a significant influence upon recommendations. The use of a flexible-choice question format revealed a different preference structure to the forced-choice format, but the performance of the two models was similar. Aggregate decisions of the AWMSG were well predicted by both models, but their sensitivity (64 %, 68 %) and specificity (55 %, 64 %) were limited. CONCLUSIONS: A willingness to trade the cost effectiveness and QALY gains against other factors indicates that economic efficiency and QALY maximisation are not the only considerations of committee members when making recommendations on the use of medicines in Wales. On average, appraisal committee members' stated preferences appear consistent with their actual decision-making behaviours, providing support for the external validity of our DCEs. However, as health technology assessment involves complex decision-making processes, and each individual recommendation may be influenced to varying degrees by a multitude of different considerations, the ability of our models to predict individual medicine recommendations is more limited.

Societal views on NICE, cancer drugs fund and value-based pricing criteria for prioritising medicines: a cross-sectional survey of 4118 adults in Great Britain.

The criteria used by the National Institute for Health and Clinical Excellence (NICE) for accepting higher incremental cost-effectiveness ratios for some medicines over others, and the recent introduction of the Cancer Drugs Fund (CDF) in England, are assumed to reflect societal preferences for National Health Service resource allocation. Robust empirical evidence to this effect is lacking. To explore societal preferences for these and other criteria, including those proposed for rewarding new medicines under the future value-based pricing (VBP) system, we conducted a choice-based experiment in 4118 UK adults via web-based surveys. Preferences were determined by asking respondents to allocate fixed funds between different patient and disease types reflecting nine specific prioritisation criteria. Respondents supported the criteria proposed under the VBP system (for severe diseases, address unmet needs, are innovative--provided they offered substantial health benefits, and have wider societal benefits) but did not support the end-of-life premium or the prioritisation of children or disadvantaged populations as specified by NICE, nor the special funding status for treatments of rare diseases, nor the CDF. Policies introduced on the basis of perceived--and not actual--societal values may lead to inappropriate resource allocation decisions with the potential for significant population health and economic consequences.

Reimbursement decisions of the All Wales Medicines Strategy Group: influence of policy and clinical and economic factors.

BACKGROUND: There have been several explorations of factors influencing the reimbursement decisions of the National Institute for Health and Clinical Excellence (NICE) but not of other UK-based health technology assessment (HTA) organizations. OBJECTIVE: This study aimed to explore the factors influencing the recommendations of the All Wales Medicines Strategy Group (AWMSG) on the use of new medicines in Wales. METHODS: Based on public data, logistic regression models were developed to evaluate the influence of cost effectiveness, the quality and quantity of clinical evidence, disease characteristics (including rarity), budget impact, and a range of other factors on the recommendations of AWMSG and its subcommittee, the New Medicines Group (NMG). RESULTS: Multivariate analyses of 47 AWMSG appraisals between 2007-9 correctly predicted 87% of decisions. The results are suggestive of a positive influence on recommendations of the presence of probabilistic sensitivity analyses (PSAs) but, counter-intuitively, a statistically significant negative influence of evidence from high-quality randomized controlled trials (RCTs) [odds ratio 0.059; 95% CI 0.005, 0.699]. This latter observation may be attributed to our strict definition of high quality, which excluded the use of surrogate endpoints. Putative explanatory variables, including cost effectiveness, budget impact, underlying disease characteristics and 'ultra'-orphan drug status were not statistically significant predictors of final AWMSG decisions based on our dataset. Univariate analyses indicate that medicines with negative recommendations had significantly higher incremental cost-effectiveness ratios than those with positive recommendations, consistent with the pursuit of economic efficiency. There is also evidence that AWMSG considers equity issues via an ultra-orphan drugs policy. CONCLUSIONS: Consideration of decision uncertainty via PSA appears to positively influence the reimbursement decisions of AWMSG. The significant negative impact of the presence of high-quality RCTs, and the lack of a significant positive impact of other expected factors, may reflect issues in the plausibility of supporting evidence for medicines that received negative recommendations. Furthermore, it serves to emphasize the difficulties in applying the usual hierarchies of evidence to the HTA process, and in particular to the appraisal of high-cost specialist medicines close to market launch.