Combining model-based clinical trial simulation, pharmacoeconomics and value of information to optimize trial design

The Bayesian decision-analytic approach to trial design uses prior distributions for treatment effects, updated with likelihoods for proposed trial data. Prior distributions for treatment effects based on previous trial results risks sample selection bias and difficulties when a proposed trial differs in terms of patient characteristics, medication adherence, or treatment doses and regimens. The aim of this study was to demonstrate the utility of using pharmacometric-based clinical trial simulation (CTS) to generate prior distributions for use in Bayesian decision-theoretic trial design. The methods consisted of four principal stages: a CTS to predict the distribution of treatment response for a range of trial designs; Bayesian updating for a proposed sample size; a pharmacoeconomic model to represent the perspective of a reimbursement authority in which price is contingent on trial outcome; and a model of the pharmaceutical company return on investment linking drug prices to sales revenue. We used a case study of febuxostat versus allopurinol for the treatment of hyperuricemia in patients with gout. Trial design scenarios studied included alternative treatment doses, inclusion criteria, input uncertainty, and sample size. Optimal trial sample sizes varied depending on the uncertainty of model inputs, trial inclusion criteria, and treatment doses. This interdisciplinary framework for trial design and sample size calculation may have value in supporting decisions during later phases of drug development and in identifying costly sources of uncertainty, and thus inform future research and development strategies

Choice of oral anticoagulant prescribed by general practices in Wales: Application of Dirichlet regression and linked data

AIMS: There has been sustained growth in the prescribing of direct oral anticoagulants (OACs) in primary care in the UK. Given the different indications, properties and prices of OACs, variation between prescribers is expected; however, a high level of variation may be evidence of inappropriate or suboptimal prescribing. This study examined the variation in the relative use of OACs in primary care in Wales. METHODS: Data on total defined daily doses of all community‐dispensed OACs in 2019 were linked at the GP practice level with disease registers, patient demographic data and GP and patient numbers. The relative use of each OAC, as a fraction of all OACs prescribed, was analysed using Dirichlet regression to quantify the association between prescribing patterns and practice and area‐level characteristics. RESULTS: Across 417 GP practices, the mean (range) in the relative prescribing of warfarin was 37% (6%–64%), apixaban was 32% (2%–65%), rivaroxaban 23% (0%–66%), dabigatran 3% (0%–23%) and edoxaban 6% (0%–59%). Statistical modelling provided strong evidence that prescribing patterns are associated with a GP practice's health board and also their nearest major hospital. Compared to the null model, a model including health board resulted in a 15% fall in Akaike information criterion, increasing to 20% with the addition of nearest major hospital and 27% including further covariates. CONCLUSION: Systematic variation in OAC prescribing, by health board and based on nearest hospital, indicates that factors other than patient clinical characteristics and preferences may be influencing prescribing decisions

Effects of minimum unit pricing for alcohol on different income and socioeconomic groups: a modelling study

Background: Several countries are considering a minimum price policy for alcohol, but concerns exist about the potential effects on drinkers with low incomes. We aimed to assess the effect of a £0·45 minimum unit price (1 unit is 8 g/10 mL ethanol) in England across the income and socioeconomic distributions. Methods: We used the Sheffield Alcohol Policy Model (SAPM) version 2.6, a causal, deterministic, epidemiological model, to assess effects of a minimum unit price policy. SAPM accounts for alcohol purchasing and consumption preferences for population subgroups including income and socioeconomic groups. Purchasing preferences are regarded as the types and volumes of alcohol beverages, prices paid, and the balance between on-trade (eg, bars) and off-trade (eg, shops). We estimated price elasticities from 9 years of survey data and did sensitivity analyses with alternative elasticities. We assessed effects of the policy on moderate, hazardous, and harmful drinkers, split into three socioeconomic groups (living in routine or manual households, intermediate households, and managerial or professional households). We examined policy effects on alcohol consumption, spending, rates of alcohol-related health harm, and opportunity costs associated with that harm. Rates of harm and costs were estimated for a 10 year period after policy implementation. We adjusted baseline rates of mortality and morbidity to account for differential risk between socioeconomic groups. Findings: Overall, a minimum unit price of £0·45 led to an immediate reduction in consumption of 1·6% (−11·7 units per drinker per year) in our model. Moderate drinkers were least affected in terms of consumption (−3·8 units per drinker per year for the lowest income quintile vs 0·8 units increase for the highest income quintile) and spending (increase in spending of £0·04 vs £1·86 per year). The greatest behavioural changes occurred in harmful drinkers (change in consumption of −3·7% or −138·2 units per drinker per year, with a decrease in spending of £4·01), especially in the lowest income quintile (−7·6% or −299·8 units per drinker per year, with a decrease in spending of £34·63) compared with the highest income quintile (−1·0% or −34·3 units, with an increase in spending of £16·35). Estimated health benefits from the policy were also unequally distributed. Individuals in the lowest socioeconomic group (living in routine or manual worker households and comprising 41·7% of the sample population) would accrue 81·8% of reductions in premature deaths and 87·1% of gains in terms of quality-adjusted life-years. Interpretation: Irrespective of income, moderate drinkers were little affected by a minimum unit price of £0·45 in our model, with the greatest effects noted for harmful drinkers. Because harmful drinkers on low incomes purchase more alcohol at less than the minimum unit price threshold compared with other groups, they would be affected most by this policy. Large reductions in consumption in this group would however coincide with substantial health gains in terms of morbidity and mortality related to reduced alcohol consumption. Funding: UK Medical Research Council and Economic and Social Research Council (grant G1000043)

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship

Microdiscectomy compared with transforaminal epidural steroid injection for persistent radicular pain caused by prolapsed intervertebral disc: the NERVES RCT

Background Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment. Objective To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months’ duration. Interventions Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection. Design A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration. Setting NHS services providing secondary spinal surgical care within the UK. Participants A total of 163 participants (aged 16–65 years) were recruited from 11 UK NHS outpatient clinics. Main outcome measures The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland–Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England. Results Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect –4.25 points, 95% confidence interval –11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland–Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year. Limitations Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment. Conclusions To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients