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Background: For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published from January 2010 to November 2020. Methods: Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50–0.86), 1–12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04–2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54–1.10), 1–12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3–5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83–2.60)], immune-mediated AEs [1.75 (0.33–7.49)], and all-cause discontinuation due to AEs [1.21 (0.58–2.61)]. Conclusions: Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Objective Current advice for patients being discharged from hospital suggests a body mass index of 18.5 to 24 kgm−2, although this aspirational target may often not be achieved. We examined the relationship between body mass index on discharge from hospital and subsequent mortality over a maximum follow-up of 3.8 years. Design We conducted a survival analysis using linked hospital records data with national hospital episode statistics and national death certification data. Participants & Setting The analysis included adult patients who were admitted to University Hospitals Birmingham NHS Foundation Trust for a period of over 24 h during 2011, excluding day cases and regular day case attenders. Main outcome measures The relationship between body mass index and mortality at medium term was estimated separately in both men and women, after accounting for case-mix. Results For both males and females, the relationship between body mass index at discharge and the loge hazard of death was strongly non-linear (p = 0.0002 for females and p −2, with a sharp increase in risk for lower body mass index. Conclusions There was little evidence to support current aspirational body mass index targets in the discharge population. Hospitals should ensure adequate nutrition especially among those with a reduced body mass index.

Newly marketed pharmaceuticals command increasingly high prices, particularly in oncology where single treatment cycles can be very costly, even though data at market approval are usually inadequate to describe thoroughly their effectiveness and cost-effectiveness. Both manufacturers and payers have shown interest in solutions to achieve rapid access for patients – known as ‘market-access agreements’. Although the literature offers a variety of definitions, these agreements can be roughly grouped under two main types: financial-based and performance-based. Financial-based schemes focus on the budget impact of a new drug and usually consist of price/dose discounts. Performancebased schemes involve collecting clinical evidence once a new drug has been marketed in a healthcare system and lead to payment only for patients responding to therapy, an objective which is methodologically and practically challenging while not without political appeal. The underlying strategy is to help reduce the likelihood of payers adopting technologies that turn out not to be cost-effective, while at the same time helping manufacturers increase market access time and take profit. Market-access agreements can also be considered an opportunistic way for manufacturers to keep official prices high such as maintaining a common European price, while granting health authorities confidential rebates, thus preventing parallel trade and undermining effective external reference pricing. The English and Italian health services have been the first countries to introduce market-access agreements on specific drugs. These contracts are now called Managed Entry Agreements (MEA) in Italy and Patient Access Schemes (PAS) in England and Wales. We focus on the area of oncology, where many new drugs are costly and fall under these arrangements. Italy

Summary Objectives To explore the relationship between in-hospital mortality following adult cardiac surgery and the time since primary clinical qualification for the responsible consultant cardiac surgeon (a proxy for experience). Design Retrospective analysis of prospectively collected national registry data over a 10-year period using mixed-effects multiple logistic regression modelling. Surgeon experience was defined as the time between the date of surgery and award of primary clinical qualification. Setting UK National Health Service hospitals performing cardiac surgery between January 2003 and December 2012. Participants All patients undergoing coronary artery bypass grafts and/or valve surgery under the care of a consultant cardiac surgeon. Main outcome measures All-cause in-hospital mortality. Results A total of 292,973 operations performed by 273 consultant surgeons (with lengths of service from 11.2 to 42.0 years) were included. Crude mortality increased approximately linearly until 33 years service, before decreasing. After adjusting for case-mix and year of surgery, there remained a statistically significant ( p = 0.002) association between length of service and in-hospital mortality (odds ratio 1.013; 95% CI 1.005–1.021 for each year of ‘experience’). Conclusions Consultant cardiac surgeons take on increasingly complex surgery as they gain experience. With this progression, the incidence of adverse outcomes is expected to increase, as is demonstrated in this study. After adjusting for case-mix using the EuroSCORE, we observed an increased risk of mortality in patients operated on by longer serving surgeons. This finding may reflect under-adjustment for risk, unmeasured confounding or a real association. Further research into outcomes over the time course of surgeon's careers is required.

Although physiotherapy possesses examples of researchers and trials that are rigorous, broadly as a profession physiotherapy needs to address urgently the methodological quality of trials. This in turn will enable greater trust in trial and systematic review findings. As a minimum, all physiotherapy trials should be based on a trial protocol that explicitly addresses components of possible systematic bias (a priori specification of a primary outcome, randomization and concealment of allocation, blinding, intention-to-treat analysis, and avoidance of loss to follow-up) and the appropriate selection of outcome measures. Established physiotherapy researchers can facilitate this by providing consensus for minimum core sets of outcome measures for specific populations. The issues identified in this article have a wider reach than physiotherapy researchers; informing all disciplines that are without external regulation; as well as funding bodies, policymakers and commissioners.

Adding pindolol to serotonergic antidepressant treatment offers a potential strategy for producing a more rapid onset of action and an enhanced antidepressant effect. This review investigated whether pindolol enhances the efficacy of serotonergic antidepressant treatment in adult patients with depressive disorders at sequential time points up to 6 weeks. Search strategy: Cochrane Collaboration Depression, Anxiety and Neurosis-Controlled Trials Register plus unpublished trial data. Study selection: Randomised trials including depressed patients, comparing serotonergic antidepressants + pindolol with serotonergic antidepressants + placebo and using depressive symptom clinical outcomes scales. Data extraction: Clinical response at time points up to 6 weeks as defined by >50% depression scale score reduction was extracted for each trial as possible. Eleven studies were identified including unpublished data. The pooled odds ratios for dichotomous response to treatment at time points from 1 to 6 weeks were 2.39 (95% CI 1.40—4.06), 2.39 (1.74—3.29), 1.94 (1.46—2.58), 1.59 (1.16—2.18), 1.42 (0.87—2.31) and 1.28 (0.91—1.81). Time-to-event analysis showed a greater response with pindolol augmentation versus placebo (P = 0.04). There was significant heterogeneity between studies at some time points. Dropout rates did not significantly differ between treatment arms. This review suggests an overall beneficial clinical effect of pindolol augmentation, most clearly up to 4 weeks of treatment.

Objective To explore whether or not gender predicts consultant activity rates. Design Using data from the Hospital Episode Statistics for England 2004/2005, we explored inpatient activity rates of male and female hospital consultants, with and without adjustment for case-mix differences. As a sensitivity analysis we also explored outpatient attendances for male and female hospital consultants. Setting Data from the Hospital Episode Statistics for England. Main outcome measures Finished consultant episodes per year, with and without adjustment for case-mix differences, age and gender of consultant, contract held, hospital trust, specialty of practice, and clinical excellence awards, discretionary points and distinction awards. Results Including only consultants on full-time or maximum part-time contracts, men have significantly higher activity rates than women, after accounting for age, specialty and hospital trust. Conclusions The reasons for the different activity rates of male and female consultatns are unclear, but the implications of these results for the planning of the medical workforce are important.

Objectives: To explore variation in the National Health Service (NHS) activity rates of consultant surgeons, and examine whether activity is dependent upon the type of contract held and/or bonus payments, after accounting for age and other consultant and hospital characteristics. Methods: NHS Hospital Episode Statistics (HES) for England were used in combination with workforce data in five surgical specialties in 1998/99 and 1999/2000. Descriptive statistics were used to explore variation in activity rates. A multi-level model was used to analyse the relationship between NHS contract and bonus payments, and activity. Results: There is considerable variation in activity rates of English NHS consultant surgeons, with and without adjustment for casemix. Interquartile variation shows that the top 25% of consultants have activity rates 60 to 85% higher than the bottom 25%. A multi-level model indicates that consultant surgeons with a 'maximum part-time' contract have significantly higher activity rates than those with a full time contract (129 more finished consultant episodes (FCEs) per year, 95% CI 97-160). Consultant surgeons who hold discretionary salary points undertake significantly more activity than those without (95 FCEs, 95% CI 62-128). Those with a distinction award (a type of bonus payment) have a tendency towards higher activity rates, but this does not reach statistical significance (48 FCEs, 95% CI -4 to 103). Conclusions: 'Maximum part-time contract' status is associated with higher absolute activity rates among NHS surgeons. Rich data sources like HES merit careful exploration and increased use as an essential first step in measuring and managing variations in specialists' performance.

Objectives: To identify the effect of a complex intervention (educational outreach visits by pharmacists) designed to change general practitioners' (GPs') prescribing on each step of a hypothesised pathway of change leading to the final primary trial outcome of change in prescribing. Method: The study was undertaken in six health authorities in the North of England and six in London. We described three steps leading to this outcome: the general practices agreeing to participate; GPs in each practice attending the outreach visit conducted by the pharmacists; and the GPs' prescribing practice being influenced by these visits. The outcomes of each step were assessed using a combination of quantitative and qualitative methods. Results: Of the 102 practices randomly selected, 75 (73.5%) agreed to participate. The odds of all the doctors attending the outreach meeting in small practices (i.e. 1-2 partners) was 6.7 (95% CI: 4.4-23.5) compared with other practices (i.e. > 3 partners). Although the pharmacists reported that they had established a good rapport at 100 (72%) first visits and had agreed management plans for 110 (79%) of these visits, they were confident that the practice was likely to alter its prescribing in only 41% of these visits. Pharmacists' and GPs' satisfaction with the outreach visits did not necessarily lead to prescribing changes after the practice visit, and the GPs' knowledge of the guidelines promoted by the pharmacists did not necessarily translate into changes in clinical practice. The main barriers to the implementation of guidelines identified by the pharmacists at the follow-up visits were organisational difficulties, the GPs' scepticism of the evidence presented to them and the doctors' lack of interest in changing their prescribing behaviour. Conclusions: Although our study is limited by a post hoc rather than a pre hoc design, it provides a pragmatic approach to understanding the factors influencing the pathway of change in prescribing behaviour in response to academic outreach visits.

Objectives: To report on the updating of two evidence-based guidelines. Methods: Development of multi-disciplinary evidence-based guidelines within the North of England Evidence Based Guideline Development Programme. Results: The guideline updating groups were multi-disciplinary although the balance of disciplines was different from the original development groups; the convening of the updating groups allowed refinement of both the skills within the groups and the overall size of the groups. As both groups were starting with a previous version of the guideline, defining the scope of the guideline was more straightforward and faster than when developing the guideline de novo. The process of evidence identification for both guidelines was again by systematic review. Updating the guidelines influenced recommendations in two ways: new evidence required new recommendations; and supplementary evidence in an existing area allowed refinement of recommendations. Overall savings within the guideline updating process (compared with initial development) were modest. The major costs of both the initial guideline development and the updating process were staff costs, which were identical for the two processes. Conclusions: There is little other experience to set alongside this paper. There is a need for further sharing of experiences and the development of explicit methods for informing decisions on when and how to update evidence-based guidelines.

The undergraduate medical curriculum is in a labile state, with rapid developments in evidence-based interventions and a shift in emphasis ‘from gaining knowledge to a learning process that includes the ability to evaluate data as well as to develop skills to interact with patients and colleagues’.1 In addition Government-led initiatives to widen participation to medical schools and increasing student numbers2 mean that medical education programmes need to develop alternative learning and teaching resources and strategies to ensure that students from increasingly diverse backgrounds with different learning needs are able to achieve core outcomes. In this editorial we advocate evidence-based curriculum development that also addresses constraints on time and resources: cost-effective curriculum development.

The design and interpretation of experimental studies to examine the effectiveness and efficiency of implementation strategies intended to change professional practice are gaining increasing attention. It has been argued that variations of the simple randomised design are most appropriate in this setting. The principles of block designs and their applicability in this field are reviewed critically, as are the choice of outcomes and approaches to economic analysis. We conclude that more complex designs are not superior per se, and that the design, choice of implementation method and topic, and analysis of such experiments should reflect the circumstances of the study.

This paper examines a recent rationing crisis in the UK National Health Service (NHS) in which a patient was denied treatment for a life threatening illness on the basis of cost. Rationing is inevitable in health care, as resources which can be allocated to health are finite and demand is essentially infinite. The new managerial relationships which constitute the purchaser/provider split contribute to rationing becom ing more explicit. The NHS is socialist in that it socialises the financial risk of illness.Questions about the form which rationing should take are funda mentally political rather than empirical. Yet the media purvey a version of reality which is best understood as myth. The paper con cludes by raising these crucial questions in the context of the politics of the left.

This paper presents an overview of some of the pitfalls and suggests ways of improving the quality of research into rehabilitation after stroke. The aims of rehabilitation are outlined and methodological problems inherent in this area discussed, including spontaneous recovery, multidimensional outcomes, definition of treatment and placebo effects. Major weaknesses found in the rehabilitation literature are identified and recommendations for improvement made, including the need for comparable controls, adequate numbers, appropriate outcome measures, clear definition of therapy, generalizability, and a concern for the cost-effectiveness of stroke rehabilitation packages. The field of rehabilitation is still relatively new and idiosyncratic in form and content. Thus it still provides opportunities for research into its relative effectiveness before current practices in rehabilitation become entrenched in medical practice and folklore. Adequate funding support for improved, multicentre clinical trials in rehabilitation is essential.

Cervical cancer is the second most common female cancer worldwide, mainly affecting women aged between 35 and 55 years. It has important consequences in terms of life-years lost. The high-risk types of human papilloma virus (HPV) are a recognised cause of cervical cancer. HPV vaccine is the first available against a cancer. The European Medicines Agency has approved two HPV vaccines. The quadrivalent vaccine protects against HPV types 6, 11, 16 and 18, and the bivalent vaccine only against types 16 and 18. Types 16 and 18 are responsible for about 73% of all cervical cancer cases in Europe. The low-oncogenic HPV types 6 and 11 mainly cause genital warts (90%), low-grade neoplasia and recurrent respiratory papillomatosis. To our knowledge, HPV vaccines are the most expensive of all available vaccines, their manufacturers claiming the high prices reflect a major research and development investment and relatively complex manufacturing processes. Vaccination advisory bodies have passed a recommendation in favour of HPV vaccination in most EU countries. Both the bivalent and the quadrivalent vaccines are used in Italy for the prevention of cervical cancer. The Italian National Health Service, a public service funded by general taxation, has three institutional tiers: the Department of Health; Regional Health Authorities; and Local Health Authorities. Since 2001, a Constitutional Law has increased regional autonomy (so-called ‘regionalisation’ or ‘devolution’) in healthcare policy, which leads the Regional Health Authorities to develop different economic strategies. Most Regional Health Authorities run tender schemes to exploit potential competition between the two vaccines manufacturers. The regions of Lombardy and Piedmont recently held tenders, both of which were awarded to the bivalent vaccine manufacturer which offered its vaccine for E34.47 per dose while the most recent one (Veneto region) went to the quadrivalent vaccine at E32.75. This price illustrates the steep decline which started in 2007 with the first regional tender for HPV vaccines. The current tender prices indicate substantial savings for the Italian National Health Service, as the ex-factory prices per dose negotiated by AIFA (the Italian agency for drugs) are E95 for bivalent vaccine and E104 for quadrivalent vaccine. The Italian experience demonstrates that tendering may be associated with worthwhile price reductions even where competition is limited, with only two manufacturers offering products for sale. It appears that the same has been achieved with tendering in other EU countries like Sweden and the UK, although tender prices are considered commercial in confidence in these countries. Some indication of prices paid in the UK may be gained from The Department of Health’s Commercial Medicines Unit, which provides mean prices paid for pharmaceutical products. Differences between the two vaccines can be addressed through adding a ‘quality score’ in tender clauses (as in the recent UK tender and in three regional tenders in Italy), in an attempt to maximise cost-effectiveness rather than simply minimise cost. Economic theory suggests that tendering procedures may achieve important savings when purchasing power is high on the demand side, where there are potential suppliers for similar products (shifting the balance of power to the buyer) and where there is perfect information. A further tangible benefit of tendering is when it increases the transparency of prices, at least in the countries where they are publicly available and discounts become directly observable between different contracting authorities. If low prices achieved through tendering are sustained over time, highly centralised and long duration tenders could force some manufacturers out of the market, generating dominant positions. This could erode competition and lead to future price increases. Such a negative scenario depends largely on the size of the tender setting, and in countries like Italy the

The Reverend Bayes (1702-1761) has become well known for his Theorum, and developed a following of statisticians and their hangers-on who declare themselves to be ‘Bayesians’. Does his contribution merit the enthusiasms of his followers? Or is his legacy overhyped? Bayes did not publish any mathematical work during his lifetime under his own name, and indeed his major attributed work was apparently found by a friend on his desk after his death and remained unpublished until 1764. Although probably at least in large part his own work, and decent work at that, the major objection to Bayes' legacy in the early 21st century is the effect that it has had on those who currently declare themselves to be his followers. This effect has a number of manifestations. First, Bayesians appear to have an absolute right to disapprove of any conventional approach in statistics without offering a workable alternative—for example, a colleague recently stated at a meeting that ‘... it is OK to have multiple comparisons because Bayesians' don't believe in alpha spending’. [Alpha spending is the statistical discipline which governs the interpretation of multiple endpoints in clinical trials. Alpha is ‘spent’ on the primary outcome, and when this is non-significant it denotes all other statistical tests to be hypothesis generating rather than hypothesis proving.] Other interested parties (such as the pharmaceutical industry) demonstrably do not believe in alpha spending in clinical trials when it suits them (e.g. when the primary outcome of a randomized trial is neutral but some apparently statistically significant results exist with a secondary outcome). The Bayesian trust in sensible people making sensible decisions based upon their prior beliefs in these circumstances seem at best naive. Second, Bayesians appear to build an army of straw men—everything it seems is different and better from a Bayesian perspective, although many of the concepts seem remarkably familiar. For example, a very well known Bayesian statistician recently surprised the audience with his discovery of the P value as a useful Bayesian statistic at a meeting in Birmingham. Third, Bayesians possess enormous enthusiasm for the Gibbs sampler—a form of statistical analysis which simulates distributions based on the data rather than solving them directly through numerical simulation, which they declare to be inherently Bayesian—requiring starting values (priors) and providing posterior distributions (updated priors). However, rather than being of universal application, the Gibbs sampler is really only advantageous in a limited number of situations for complex nonlinear mixed models—and even in those circumstances it frequently sadly just does not work (being capable of producing quite impossible results, or none at all, with depressing regularity). While a step forward, the world is not a different place once populated by Gibbs samplers. And some of those who were involved in the development and evaluation of the Gibbs sampler are arch frequentists (so defined by Bayesians as a pejorative term for all those who work with numbers who are not Bayesians!). Finally, the social and sartorial objections to Bayesianism are perhaps paramount—sporting a depressingly drab and amorphous uniform of socks and sandals, facial hair and shades of drab green. Coupled with the sellotape repaired glasses and other worldly gleam in the eye, the collective noun for Bayesians is obvious: a posterior. Bayes (probably) wrote some insightful things, some of which are still relevant now. But once you strip away the hype, his contribution was modest and not the rational basis for a new statistical orthodoxy, or indeed a new religion.