LIFELAX - diet and LIFEstyle versus LAXatives in the management of chronic constipation in older people: randomised controlled trial

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 01/10/04. The contractual start date was in June 2003. The draft report began editorial review in October 2009 and was accepted for publication in February 2010. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

none

Copyright statement

© 2010 Queen’s Printer and Controller of HMSO. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2010 Queen’s Printer and Controller of HMSO

Introduction

As a medical problem, constipation is often trivialised. 1 However, chronic constipation has a considerable impact upon the individual and all of the health-care resources associated with managing the condition. The effect of chronic constipation on quality of life (QoL) is considerable,2,3 and the burden on health-care resources, in terms of visits to health-care practitioners, and medications, is substantial. 4 In England and Wales, constipation generated some 450,000 general practitioner (GP) consultations per year in 1991–2,5 at an estimated cost of £4.5M per year. 6 The net ingredient cost in 2005 of prescriptions for laxatives was approximately £50M per year in England alone. 7

Defining constipation and ‘normal’ bowels

Constipation is ‘variably defined’8 by patients and medical professionals and is a common complaint of industrialised societies. 9 Patients perceive ‘regularity’ to be an important variable in determining good health. 10 In Scouting for Boys,11 Baden Powell declared that in order ‘to make yourself strong and healthy it is necessary to begin with your inside’, and recommendations for this included ‘making the stomach work to feed the blood’ with exercises such as the ‘cone’, or ‘body bending’, and ‘twisting’. In order to ‘make the bowels active to remove the remains of food and dirt from the body’ he suggested ‘body bending’ and ‘kneading the abdomen’, and suggested his scouts ‘drink plenty of good water’ and had, what he referred to as, a ‘regular daily rear’.

The frequency and consistency of stools are important in defining constipation and ‘normal bowels’, both in lay and clinical definitions. Regarding ‘frequency’, clinicians consider passing a stool anywhere from three times a day to three times a week as being ‘normal bowel function’. 12 Regarding ‘consistency’, as this is linked to transit time through the gut it is considered by clinicians to be a useful indicator of normal bowel function. 13–15 In everyday life, however, constipation means different things to different people. 16,17 Even to health-care professionals constipation remains a largely subjective diagnosis. 18 As the experiences of the STOOL (Stepped Treatment Of Older adults on Laxatives) trial and its associated qualitative study show, both constipation and normal bowel function are so difficult to define that it is entirely understandable that there is often a mismatch between what patients and health-care professionals mean when they use the term ‘constipation’ (p. 67). 19

Prevalence rates of constipation among older people

Given the lack of consensus on the definition of constipation in the clinical world, and the variation in definition and perceptions of constipation among lay people, it is not surprising that there is little agreement on the prevalence rates of the condition. UK estimates of prevalence rates of constipation in the general population range from 2% to 51.5%. 13,15,32–34 In the epidemiological study in North America mentioned earlier, prevalence rate estimates range from 1.9% to 27.2%. 24

Regardless of this lack of consensus over actual prevalence rates, there is agreement that the rates do increase with age5,35,36 (Table 1). In the HTA-commissioned systematic review of the effectiveness of laxatives in the elderly, the authors assert that approximately one-fifth of older people living in the community have symptoms of constipation. 1

Impact of constipation on QoL in older people

Given the prevalence and burdensome nature of chronic constipation, the literature surrounding the impact it has upon QoL and standardised assessments to measure this is surprisingly sparse. 38 Many of the early studies attempting to investigate the overall burden of chronic constipation on QoL made use of general assessments such as the Gastrointestinal Symptom Rating Scale and the Psychological General Well-Being Index. 3 These assessments have been limited, however, to observational studies and cross-sectional comparisons.

Psychological General Well-Being Index scores (which assess anxiety and depression, perceived health, vitality, and overall well-being) were significantly lower (poorer) for people with constipation than the published scores for a general population sample. 3 In a cross-sectional, population-based survey of individuals of at least 65 years of age completing the Medical Outcomes Study Short Form General Health Survey, those with chronic constipation reported poorer role functioning and pain scores compared with those without constipation. 2 A similar pattern was shown in a mailed survey that assessed health-related QoL (HRQoL) (using the Short Form questionnaire-36 and Short Form questionnaire-12 items) among a Canadian population with self-reported functional constipation (Rome II criteria), when compared with Canadian norms. 39 In interviews with frail older people living at home, constipation was considered by 11% to be a major problem adversely affecting their QoL. 21 Although there is a paucity of them, studies that report the relationship between QoL and constipation show that people with constipation generally have impaired QoL compared with the general population.

Management of constipation in older people

The most common method to treat constipation in older people (> 50 years) is to use laxatives. However, there is little evidence to support either their clinical effectiveness or cost-effectiveness. 1 Readers interested in the evidence (or lack thereof) for the use of laxatives in the management of constipation in older people are encouraged to read the Health Technology Assessment (HTA)-commissioned review,1 Gallagher, O’Mahony and Quigley’s recent review40 and the STOOL trial report. 19

While there is little evidence supporting the use of laxatives in the treatment of constipation in older people, there is also little evidence-based guidance on what constitutes effective management of constipation in older people more generally. 1,41 The HTA review concludes that laxatives may not be an appropriate method for treating constipation for all people, and that change in general diet may be sufficient to treat and/or prevent the condition. However, the authors concede that there is a lack of good-quality evidence showing that dietary interventions are effective.

Petticrew et al. 1 proposed a stepped approach to the management of constipation, which first considered dietary and lifestyle changes then (if unsuccessful) considered dietary supplements, and then (if both of the previous interventions failed) considered the use of a prescribed cost-effective laxative treatment.

Taking into account the findings of the review, the advisory panel to the HTA proposed a further step in the constipation management strategy. This step involved prescribing a single class of laxative (bulk, stimulant or osmotic laxative) in the first instance and then, if this failed to resolve the constipation, adding in a second laxative from another class (e.g. stimulant plus bulk). In light of this, the HTA commissioned two independent randomised controlled trials (RCTs) – STOOL and LIFELAX.

The STOOL trial19 was commissioned to investigate the clinical effectiveness and cost-effectiveness of laxatives prescribed for older people from the three classes (bulk, stimulant or osmotic laxative) and for different management strategies of combining the classes.

LIFELAX was commissioned to compare the clinical effectiveness and cost-effectiveness of practice-based educational interventions to change the diets of older people who have constipation with traditional medical management using laxatives.

Impact of diet and lifestyle on constipation

Interest in the role of dietary fibre has existed from the Victorians, who believed that bran stimulated colonic movements. By the 1900s, fibre had received some attention for its role in relieving constipation, and in the 1930s dietary fibre was being investigated for its laxative properties. 42

Epidemiological evidence suggests that diseases of the large bowel, commonly seen in industrialised countries, are linked with decreasing fibre intake. 43 Findings from the recent European Prospective Investigation into Cancer and Nutrition study have suggested that where there is a low average fibre intake, doubling total fibre intake from foods could reduce the risk of colorectal cancer by 40%. 44

Intake of dietary fibre is just one of a number of factors that influence bowel frequency. 45 The most common causes of constipation in primary care are related to diet, fluid intake and psychological factors. 8 Although there is ‘no compelling medical evidence that inadequate fluid intake results in constipation’, it is generally agreed, both by the medical profession and the general public, that low levels of fluid intake are associated with constipation. 10

Constipation is more common in women than men and its prevalence increases with age. 46 In constipated older people, a lifetime of environmental risk factors, such as poor intake of dietary fibre, chronic use of laxatives and ignoring periods of high motility, rural living and colder temperatures are likely to have been causes of constipation. 45,47 Others have found evidence for gender (female), ageing, low energy intake, inactivity, number of medications taken, low income and low education level, as well as depression, physical and sexual abuse being factors associated with constipation. 48

Constipation is rarely seen in developing countries and it has been related to the low-fibre diet consumed in the typical industrialised society. 43 From this brief introduction it is apparent that the impact of diet and lifestyle on constipation is multifactorial. A more detailed consideration of the evidence of these factors and summary of the evidence, as was incorporated into the LIFELAX diet and lifestyle advice, follows.

Fibre and constipation

‘Fibre supplementation is generally the cornerstone of prophylaxis against constipation.’29 Increasing stool weight and improving bowel movement are two of the primary physiological functions of the large bowel49 in which dietary fibre has a role to play. Dietary fibre can be defined as a ‘plant-derived material’ that is ‘resistant to digestion by human alimentary enzymes’;50 it affects the large bowel more than any other dietary component. 51 Dietary fibre’s relationship with the gastrointestinal (GI) tract includes roles of being a substrate for bacterial fermentation, water holding, cation exchange and adsorptive functions. 50 These mechanisms cause an increase in stool output and dilute the colon’s contents. 51 The increase in faecal bulk depends upon the type of fibre ingested (e.g. wheat produces high faecal bulk compared with pectin). 52

Adding sources of insoluble fibre to the diet significantly increases stool weight. 49 Wheat bran and oat bran, which are composed of differing amounts of insoluble fibre (> 90% and 50–60%, respectively), have similar effects on daily stool output, although they work by a different mechanism. Oat bran, which consists of more soluble fibre, results in greater bacterial growth than wheat bran, whereas the insoluble fibre of wheat bran provides more slowly fermentable polysaccharides to maintain the microbial population during transit through the large intestine. Neither oat bran nor wheat bran should be thought of as the superior ‘treatment’ for constipation, as both have important (if different) roles to play.

Results from a double-blind controlled trial to measure the effects of wheat bran in the treatment of constipation suggest that bran was effective in improving bowel frequency and large bowel transit time, and that a daily dose of 20 g of bran in addition to a high-fibre diet is beneficial to patients with chronic non-organic constipation. 53 Gear et al. 54 also concluded that a high intake of dietary fibre is associated with more rapid transit times.

Non-starch polysaccharides (NSPs) refers to all fibre in the diet. Recommendations as to the amount of NSP the average adult diet should contain suggest at least 18 g per day. 55 The Dietary and Nutritional Survey of British Adults56 found that fibre intake was significantly greater in individuals from higher social classes, higher in men who did not smoke or drink and higher in older women. The National Diet and Nutrition Survey (NDNS)57 of people aged ≥ 65 years reported, nonetheless, that the mean NSP intakes for free-living men and women (13.5 g for men and 11.0 g for women) were significantly below the dietary reference value, with intake decreasing with age. There was a positive association between the number of bowel movements and NSP intake in free-living men and women in the NDNS;57 for women, this increased bowel movement with increased NSP intake was regardless of laxative use. Analysis from the Nurses’ Health Study58 found a higher dietary fibre intake to be associated with a decreased prevalence of constipation.

Though a systematic review concluded that neither strong nor consistent evidence existed regarding the effectiveness of using dietary fibre for constipation in older adults, this, the authors conceded, was due, in part, to weak study design. 59

Fluid and constipation

Whether or not fluid relieves constipation is a disputed fact. Health practitioners regularly recommend increased fluid intake to alleviate constipation, but the role of fluid has been challenged. Lindeman et al. 60 found no association between fluid intake and frequency of chronic constipation in the elderly, while Chung et al. 61 did not observe any significant increase in stool output by healthy volunteers when fluid intake was increased. There is, however, evidence which does suggest that increased fluid intake has a role in alleviating constipation. Klauser et al. 62 found that a relatively short period of fluid deprivation decreased stool frequency and stool weight in young healthy male volunteers. Positive associations between fluid intake and bowel movements were reported for women aged ≥ 65 years in the NDNS,57 while no relationship between fluid intake and bowel movement frequency was seen in men and women living in institutions. It is important that when individuals are advised to increase their fibre intake they are also advised to increase their fluid intake. 63

Probiotics, prebiotics and constipation

Probiotics and prebiotics both have a beneficial impact on gut microflora. 64 Prebiotics have an osmotic effect on the gut, as long as they are not fermented; when they are fermented by the endogenous flora they increase gas production. 64

Gut bacteria, of which 400–500 species exist in the human large intestine, carry out fermentation, which metabolises endogenously produced and dietary residues. 65 Dietary carbohydrates that have not been digested in the upper GI tract are the main substrates for gut bacterial growth, in addition to amino acids, bacterial secretions, lysis products, sloughed epithelial cells and mucins, which are metabolised to produce short-chain fatty acids (SCFAs). 65 In summary, the positive influences of gut microflora is that they prevent colonisation by harmful bacteria, have roles such as improving lactose tolerance, providing SCFAs as energy substrates, neutralising toxins, stimulating the intestinal immune system and having a role in reducing blood lipid levels.

Probiotics, defined as viable non-pathogenic microorganisms, which, on ingestion, exert a positive influence on host health or physiology,66 are either bacteria or yeast. 67 In a recent study,68 350 healthy elderly subjects consuming one, two and three 125-g servings per day of Bifidobacterium SP/DN-173010, had marked reduced transit time (22%, 40% and 47% reduction of initial values). This effect was still present for 2–6 weeks after the end of the product consumption.

Constipation was explored in a recent review of probiotics in human studies;69 the authors reported that few studies were of double-blind design and had adequate washout periods. Sample size was often limited and outcome markers were non-comparable, including both bowel frequency and transit time. They concluded, however, that probiotics do have a probable effect on gut transit time and on stool frequency, although this is species and strain specific rather than genus dependent.

Described as non-digestible food ingredients, prebiotics stimulate selectively the growth and activity of bifidobacteria and lactobacilli, which benefit health. 70 Non-digestible oligosaccharides are found in plant cells naturally and are also manufactured food components, they are non-digestible (in the upper GI tract) and are prebiotics; two well-studied and well-established prebiotics are inulin and oligofructose, which are fermented by the beneficial flora (bifidobacteria and also lactobacilli) The major food sources of both inulin and oligofructose in the typical Western diet are wheat (70%) and onions (25%). 71 Evidence indicates that these fructans are digested in the large intestine, increasing microbial mass and producing SCFAs,72 which also increases the stool mass, beneficial for bowel health. 51

The laxative effect of prebiotics was shown by Gibson et al. ,73 in whose study oligofructose and inulin significantly increased stool output, possibly due to an increase in biomass. In constipated patients, low-digestible carbohydrates, with a low molecular weight, had a positive effect on intestinal transit time in constipated patients. 74 An earlier study75 examined the effect of fructo-oligosaccharides – found naturally in onion, asparagus root, artichokes and wheat – on gut health. Increases in bifidobacteria – believed to be beneficial to the host – following fructo-oligosaccharide ingestion, were found to relieve both constipation and loose stools, as well as improving blood lipid profiles.

The definition of dietary fibre alludes to the fact that it consists of ‘remnants of edible plant cell polysaccharides and associated substances resistant to hydrolysis by human alimentary enzymes’. 76 Dietary fibre improves laxation by increasing stool weight from the fibre in the stools and also by bacterial cells (which have high water content). Higher faecal water content increases the ease of stool passing. Cherbut76 described how inulin and oligofructose, found in a number of vegetables, fruits and whole grains, both fit into the current concept of dietary fibre and contribute to a well-balanced diet.

Kleessen et al. 77 observed that inulin and lactose improved the clinical signs of constipation on elderly constipated individuals whose bowel movements increased from one or two per week to 7.5 times per week with a 40 g/day intake of lactose and eight to nine stools per week with either a 20 g/day or 40 g/day dose of inulin. The elderly tend to experience an increase in bifidobacteria and a decrease in enterococci and enterobacteria numbers with inulin, which had a better laxative effect than lactose. Use of prebiotics that change the elderly patient’s intestinal microflora, as seen in Kleessen et al. ’s77 elderly population, may be of benefit to the wider elderly population.

Exercise and constipation

There is perceived to be a lack of convincing data relating physical activity (or a lack thereof) to constipation. 29 Propulsive movements in the large intestine are increased by exercise. 78 Although it is thus assumed that increased activity stimulates bowel motility, an investigation on healthy young men failed to confirm this;79 however, mild exercise accelerated mouth–caecum transit time for a liquid-based meal by 20–25%. 80

In patients with chronic idiopathic constipation, 4 weeks of regular moderate physical activity did not alleviate slow transit constipation. 81 The authors of this study suggested that more vigorous activity, for a longer time period, might have shown more positive results, but compliance in an elderly population may have been reduced with a requirement for increased vigour.

In women aged 36–61 years, increased physical activity was related to a reduced prevalence of constipation;58 taking part in physical activity daily was independently associated with a 44% lower risk of constipation, while physical activity two to six times per week was associated with a 36% lower risk when compared with less than once daily. 58

A daily walking programme, within 30 minutes after a meal has been recommended, with stationary exercises for those who cannot walk. 29 The authors29 suggested that abdominal and pelvic floor strengthening exercises may be useful.

Position for defecation

In industrialised societies the preferred position for defecation is seated, while in Asia and Africa the main position is squatting. In a study carried out in individuals with normal bowel habits, the squatting position required less time and less straining for faeces depletion than any other sitting position. 82 In the squatting position the rectoanal junction is straightened, whereas in the seated position more straining is required to push the faeces through the right rectoanal junction. 82 The strain required to defecate in a seated position may lead to repeated Valsalva manoeuvres (forcibly exhaling against the closed airway) and may result in defecation syncope and death, while the squatting position is associated with reduced amounts of straining. 83

Summary of diet and lifestyle advice for the LIFELAX trial

• Most people experience constipation at some point.

• ‘Normal’ bowel movement frequency is from three times/day to three times/week.

• Signs of constipation include:

  1. – hard stools that are difficult to pass

  2. – frequency of stools decreasing

  3. – cramp-like pains in lower abdomen.

• Constipation may be caused by:

  1. – not eating enough fibre (fruit, vegetables and cereals)

  2. – not drinking enough fluid

  3. – poor bowel habits (ignoring the ‘call to stool’)

  4. – medicines (antacids, codeine, iron tablets, some antidepressants).

• Constipation is made worse by:

  1. – dehydration

  2. – inactivity

  3. – painful anal conditions (e.g. haemorrhoids).

• Constipation can be eased by:

  1. – eating regularly

  2. – eating more fibre-rich foods (fruit, vegetables and cereals)

  3. – drinking eight to ten cups of water/juice/soft drinks per day

  4. – keeping active/regular exercise.

• Toileting:

  1. – sitting in a comfortable position

  2. – spreading your legs slightly apart and leaning forward

  3. – relaxing and taking your time.

Behaviour change

The nutritional evidence-based guidelines that underpinned both the standardised and personalised intervention arms were the same, and it was in the style and mode of delivery that the arms varied. Not all of the findings of the studies we used to inform the intervention were appropriate for both arms. Full discussion of the literature reviewed, and the theoretical approaches and models used to inform the behaviour change interventions used in LIFELAX, can be found in Chapter 3, which details the development of the intervention.

We were seeking to develop two notionally different interventions in LIFELAX. One of the arms (standardised) needed to sit firmly within the current nursing model in the UK84 and be suitable for delivery within a routine appointment time. The other arm (personalised) was informed by techniques that had been shown to be effective in interventions of behaviour change in similar topic areas with similar samples to ours.

In studies of individual behaviour change strategies, particularly those relating to dietary change and exercise,85–87 personalised interventions have been shown to be more effective than standard, non-customised approaches. Personalised interventions, however, are typically more resource intensive than non-individualised approaches. 88

Summary

Although it is often viewed as a trivial complaint, constipation is undoubtedly a major concern to both patients and the health-care system. For an intuitively simple condition, defining constipation continues to prove difficult. Among health professionals, there is little consensus on a formal definition of constipation. The Rome II (and more recently the Rome III) criteria were an attempt to formalise the assessment of constipation yet as we have seen, they are complex and few practitioners use them in practice. Rather, in clinical practice, constipation tends to be a subjective diagnosis. Frequency of bowel movement is an important factor in the assessment of constipation yet there is no consensus on how often the ‘normal’ bowel opens. Clinicians do agree, however, that there is a wide variation between individuals in the ‘normal’ frequency of bowel movements, ranging from three times per day to three times per week but many patients have expectations of a daily bowel movement.

Lay perceptions of constipation are far removed from the Rome II criteria though, as with health-care professionals, frequency of bowel movements is a key component of the definition of constipation for the majority of older people.

The Petticrew et al. 1 review found that there is little known about the clinical effectiveness and cost effectiveness of laxative treatment for constipation, although dietary and lifestyle changes may help in the prevention and treatment of constipation, there is also little clear evidence about the cost effectiveness of such management strategies.

Collectively the STOOL19 and LIFELAX trials were designed to provide such evidence. It is sad to report that given the recruitment difficulties in both trials, clinical trials to evaluate the clinical effectiveness and cost effectiveness of these treatments remain to be done in the UK.

Embedded qualitative process evaluation

Randomised controlled trials and process evaluation studies are complementary research methodologies. 89 Although the former excel in producing outcomes data, the latter provide procedural information, such as the fit between the study protocol and how the research is practically carried out. 89,90 Oakley90 describes the typical functions of embedded process evaluations in detail:90

Process evaluations within trials explore the implementation, receipt, and setting of an intervention and help in the interpretation of the outcome results. They may aim to examine the views of participants on the intervention; study how the intervention is implemented; distinguish between components of the intervention [and] investigate contextual factors that affect an intervention. Process evaluation can help to distinguish between interventions that are inherently faulty (failure of intervention concept or theory) and those that are badly delivered (implementation failure).

(p. 413)

Process evaluations are therefore particularly useful within RCTs of complex interventions, when it may be difficult to identify the active components of the interventions from contextual ‘noise’. 91 Examples of RCTs incorporating qualitative process evaluations include the Southampton Heart Integrated care Project (SHIP) in which the evaluation contributed towards interpretation of the research findings, and the Birmingham Rehabilitation Uptake Maximisation Study (BRUM), in which the evaluation provided insights regarding reasons for non-adherence. 92–94

Within the LIFELAX RCT, a qualitative process evaluation was used to collect data on the development and implementation of both the RCT and its interventions. Whereas in previous studies, process evaluations have largely functioned as auxiliary studies, supplementing the research findings of their host trials, in LIFELAX the process evaluation took a subtly, yet fundamentally broader, role by examining the process of HTA in action, through the medium of an RCT. In this respect the research questions were designed not to ask ‘how closely does implementation of the interventions fit the protocol?’ but ‘how is the protocol constructed and practically enacted, and what are the implications for the types of knowledge produced?’ The process evaluation was thus fully integrated into the RCT, rather than playing a complementary role; its results contributed information about the process of evaluation, the barriers faced by the trial team, the manner in which some of these barriers were circumvented, and the overarching structural problems that eventually prevented the trial’s completion.

Understanding the process of evaluation is important, for we actually know little about the practical conduct of HTA through RCTs, although there is a large and expanding body of literature that details either the RCT’s methods or the results of their application. In one specific field of HTA – the development and evaluation of ‘telehealthcare’ systems – May et al. have undertaken a series of studies95–98 that have examined the evaluation of a relatively unstable health technology using RCTs and other methods, and have developed a model of the social and technical process of HTA that defines the contingent points on the journey between ideation (i.e. the emergence of ideas about the value of a new technology) and normalisation (i.e. the point at which it becomes possible for it to be embedded in clinical practice). 99 Of specific interest here is the way that evaluation acts as a mediating set of practices between these two points on the ‘innovation journey’: specifically, the production of evidence supports – or hinders – the uptake of a new technology.

Evaluation is not a discrete asocial activity, nor is it self-evident. At the very outset, we place the kinds of evaluations that define the specific utility of health technologies within the frame of the larger ‘proto-discipline’ of HTA. HTA is one of the major research enterprises of our time. Broad in scope, and defined by its emphasis on formal – mainly quantitative – methods and its focus on clinical effectiveness and cost-effectiveness, HTA is directed at the production of evidence about the efficacy and utility of techniques and technologies of health-care delivery treatment modalities and ways of working. As a field of practice, HTA is orientated around the production of evidence that meets particular criteria of adequacy100,101 – its formal proof, as it were, is to be found in the outcomes of the RCT, systematic review and meta-analysis. The questions that inform it tend to arise directly from the thrust of health-care policy, and the outcomes of HTA practitioners’ work are specifically intended to mediate between policy and practice. So within the field of HTA, it is method that is prioritised either in the production of primary outcomes data or in the synthesis of existing knowledge. 102 The expository literature of HTA reflects the priority given to methods, not theories, by locating them in a rhetoric of political and social neutrality, and emphasising applied investigatory technique over broader political questions. None of this is intended to imply that practitioners of HTA are unaware of the political implications of their work or the wider social implications of their practice – the reverse is certainly the case. But HTA emulates the neutral rhetorical form of the wider field biomedical science, constructing apparently methodologically secure quantitative facts. So it has, at the outset, a first line of defence against wider political critique – it is given as quantitative science rather than politics.

In this broad context, HTA can be seen as the development of a field of research practice that accords well with contemporary notions of the place of ‘research’ in the complex political and social contexts of the advanced economies. For example, it fits well with the model of Gibbons et al. of ‘mode 2’ knowledge production through its connectedness with ‘user’ communities, its multidisciplinarity and because of the permeability of the institutional structures in which it is located. 103 Certainly the evaluation of new systems of working and of the delivery of treatments is not simply directed at establishing their fitness for specific tasks, but about adjudicating on their superiority over others. More than this, it is focused on evidence production: HTA is thus one of a number of regulatory systems of practice available to governments and others in the advanced economies to constrain the conduct of health professionals and health-care institutions. It can be understood as a form of institutional surveillance that governs the conduct of practice, defines the directions of innovation, and defines potential new fields of clinical organisation and practice. As Tanenbaum104 has observed, the thrust towards outcomes studies within the field of HTA (and across biomedicine more generally) can also be seen to represent a powerful and authoritative social movement.

Relevant work to conceptualise HTA to date has mainly been directed either at practical problems of recruitment into trials,105–111 or at macrolevel analyses of the relationship between policy formation and evidence production. 104,112 More localised critiques have investigated the assumptions that underpin outcomes themselves or the methods by which they are reached. 95 Much less work has investigated the specifics of HTA as a field of practice, the sociotechnical networks in which knowledge about efficacy is defined and generated, negotiations about criteria for its adequacy or the procedures through which these are enacted in concrete practices. The paucity of literature in this field is surprising, given the importance of the RCT as an HTA method. The process evaluation was necessary to provide a more detailed understanding of the organisation of RCTs, and to assist in the development of a robust theoretical model of HTA practice.

Overview

LIFELAX was designed as a pragmatic113 three-armed cluster (randomisation at the level of the individual general practice) RCT to compare laxative treatment (current practice) of chronic constipation in older people with both standardised, non-personalised dietary and lifestyle advice (delivered in a single, short consultation) and personalised dietary and lifestyle advice (delivered in one long consultation – or two shorter consultations – with telephone reinforcement) in the management of chronic constipation in older people. LIFELAX was to be conducted in north-east England and was to recruit patients aged ≥ 55 years, registered with practices participating in the trial, with a current diagnosis of functional constipation (operationalised as either having a recorded diagnosis of functional constipation or having received three or more prescriptions for laxatives in the preceding year). Due to poor levels of practice uptake and lower than expected levels of patient recruitment, it was necessary to approach the HTA for an extension to the LIFELAX trial and these eligibility criteria were revised in the subsequent protocol amendments. In Chapter 4, which details the implementation of the LIFELAX trial, we describe the protocol revisions in depth. Here we will describe the design of the trial as it was in the original protocol, agreed with the HTA and submitted to the Multi-Centre Research Ethics Committee (MREC). The original protocol (version 2, 4 October 2004) and the final version (version 5, 24 July 2006) can be found in Appendix 1.

Objectives

The primary objectives for the study were to investigate the clinical effectiveness and cost-effectiveness of:

1. laxatives versus dietary and lifestyle advice

2. standardised versus personalised dietary and lifestyle advice.

Health technologies being assessed

Training strategies for health professionals

An orientation and training programme was developed for the practices recruited to the study. All practices had an on-site training visit to discuss aspects of the treatment protocol and how it was to be delivered in the practice. In addition, a dietitian with experience in health promotion delivered in-practice training on how to deliver the dietary and lifestyle intervention to patients, as follows:

• Standardised dietary and lifestyle intervention All primary health-care professionals (GPs, practice and district nurses, and health visitors) in the practice were invited to a single 1-hour session to introduce the programme and the patient resource pack.

• Personalised dietary and lifestyle intervention All primary health-care professionals in the practice were invited to an initial 1-hour session to introduce the programme and the patient pack. Practice staff involved in delivering the intervention to patients were invited to take part in two further 45-minute sessions on the delivery of a personalised pack and motivational interviewing techniques.

The choice of number and duration of training sessions was based on experience in other similar studies, and represented a balance between minimising the demands on busy health professionals’ resources, while having sufficient time to motivate doctors and nurses and to equip them with the knowledge and skills required to deliver the interventions to patients. Our personal experience, reinforced by the literature,121 suggested that in-practice delivery of training of this nature is more cost-effective than delivery at a single central location.

Study participants

Sampling design and implementation

QoL and clinical outcomes

The primary outcome, and the criterion upon which the sample size calculations were based, was patient-reported condition-specific QoL at 3 months post recruitment. Our preferred measure of QoL was the constipation-specific Patient Assessment of Constipation-Symptoms (PAC-SYM)/ Patient Assessment of Constipation-Quality of Life (PAC-QOL),127 which had been demonstrated to have good validity and reliability. Permission to use this instrument was granted by the owners of the scale (Janssen Pharmaceuticals, Titusville, NJ, USA) after agreement that anonymised patient data (i.e. questionnaire responses) would be submitted to them for the purposes of further refinement of their scales and development of population norms. However, this measure is not utility based. For the purposes of the economic evaluation, a measure of the utility placed by patients on their health state was required. The condition-specific measure of QoL was therefore supplemented by the generic utility-based European Quality of Life-5 Dimensions (EQ-5D). 128,129 Secondary outcomes included bowel movement frequency, the presence/absence of the other Rome II criteria for constipation, patients’ own perceptions of whether or not they were constipated, patient satisfaction with bowel function, adverse effects of treatment; relapse/reconsultation rates, and fluid and fibre intake. In addition, the cost implications of the condition and its treatment (e.g. GP consultations, purchase of prescribed and OTC medication) was assessed, as part of the economic evaluation.

Economic evaluation

Design of the integrated qualitative process evaluation

Recruitment strategy

Practices enrolled in LIFELAX were recruited to the process evaluation by a three-step process. Initially, information relating to the process evaluation was included in LIFELAX recruitment packs distributed by the trial team. When a practice had been identified as suitable for inclusion, a letter was sent to the practice manager or senior partner in accordance with previous methods of contact with that practice. The letter included a brief summary of the process evaluation and forewarned the staff that a researcher (BH) would contact the practice by telephone within several days. In addition, senior staff were asked to cascade the content of the letter to the practice nurses as per local custom. The final step in this recruitment strategy was to telephone the relevant member of senior staff and/or practice nurses to arrange an interview. In some instances it was not possible to speak to relevant members of staff on any given occasion, and repeated telephone calls were necessary. However, the availability of staff was hard to predict, and even when a time and date for a return telephone call had been made in advance, staff were not always available to speak on the telephone or asked to reschedule the call. Consequently, if staff had not expressed an interest in participating in the process evaluation after approximately four telephone calls to a practice, it was decided not to pursue the recruitment further at that site. The rationale for this decision was to both maximise the productive use of research time, and avoid undermining relationships between the practice and the trial team, and thus jeopardising the RCT.

During the opening phases of the RCT, the recruitment of practices ran behind intended targets. Consequently, at this point in the process evaluation, staff from all recruited practices were approached to take part in an interview. Towards the end of the trial, when recruited practices were distributed across the country, we purposively sampled practices according to their randomised allocation status and geographical location. Practices situated more than approximately 60 minutes drive from Newcastle, UK, were offered only a telephone interview rather than the option of a telephone or face-to-face encounter. Practices randomised to either of the two diet and lifestyle arms of the trial [behaviour change counselling (BCC) or brief intervention] were specifically targeted, as these conditions required the most input from practice staff. Unfortunately, relatively few practice staff were recruited to the process evaluation.

In following the research strategy outlined above it became apparent that in many practices the practice manager rather than a senior partner mediated between the trial team and the practice. While senior partners ultimately made the decision for their practice to participate in the RCT, their general involvement in the trial was limited, although possibly also included the screening of patients for contraindications and comorbidity. Only two senior clinicians were recruited to the process evaluation. With regard to senior practice staff, including practice managers, we observed that during interviews these staff usually struggled to discuss the research beyond the reason for the inclusion of their practice in the RCT. While these explanations were of interest to the research team, the senior staff viewed their lack of practical involvement in the trial as a limit for the scope and value of the interview. Therefore, we found it difficult to reach many senior staff and after a period of time questioned the value of pursuing interviews with this group. It would be inaccurate to claim therefore that saturation of data occurred within the sample, although meaningful data were nevertheless collected.

At their recruitment to the RCT, participants were informed about the purpose of the process evaluation, and the possibility that they might be asked to partake in an interview. All participants were given the opportunity to have their preferences recorded if they preferred not to be contacted. At the initial stages of the LIFELAX trial all participating patients who had not objected to being contacted were sent a recruitment pack for the process evaluation. This included an information sheet and a response slip. Once response slips had been obtained from the participants, those willing to be contacted by the research team were telephoned to arrange a time and place for an interview. In the latter stages of the trial, due to the over-representation of participants within the brief intervention arm, we approached all participants recruited to the trial with the exclusion of those randomised to this condition. As it was not possible to conduct repeat interviews with individual participants – due to concerns by the ethics committee of potential harassment – we recorded the stage of participation in the trial for each individual. The rationale for this approach was that different phases of the research might present new issues for participants, and that the meaning of the research might also vary along the continuum of involvement. Participants were interviewed from 5 weeks post recruitment to the trial, through to the time of completing a final 12-month questionnaire. Nevertheless, retrospective analysis of the data set did not reveal notable thematic differences across the participants’ stage of participation. Appendix 5 contains a consolidated standards of reporting trials (CONSORT) checklist for the process evaluation and an adapted flow chart of participant recruitment.

Maintaining the relationship

It is by understanding the problem and the patient, and by sharing this understanding, that the health-care professional will be working towards fulfilling the aim of the first component one of the model: effective consultation. It is by using an educational style that allows the patient to build upon their existing abilities to manage the problem, rather than by telling the patient what to do, that the spirit of the Pendleton approach is upheld. The standardised intervention focused on enabling the practitioners to have the most up-to-date knowledge and information on constipation. One general PIL was developed for the standardised arm of the trial. The aim was to enable the practitioner to understand what constipation meant to their patient and to explore the options for management. The practitioner had 10 minutes in which to see patients and to set goals for changes to their diet and lifestyle.

The personalised intervention arm drew on a range of models of behaviour change. It is the development of the resources, training and materials for the personalised intervention arm that is the main focus of the remainder of this chapter.

Theories and models of behaviour change

There is a wide range of conceptual models of behaviour change, such as Bandura’s Social Cognitive Learning Theory, Becker’s Health Belief Model, Azjen and Fishbein’s Theory of Reasoned Action, Prochaska and DiClemente’s Stages of Change Theory (discussed in greater depth in the section entitled Motivational interviewing, below) that can be applied to the primary health-care setting. 139–141 When designing the interventions for LIFELAX we reviewed evidence from interventions, theories, techniques and counselling styles that had been used to encourage individual (patient) behaviour change. From the outset we were minded to produce interventions that would use techniques and skills already familiar to health-care professionals and that would be easily communicable to them so as to reduce any potential barriers and patient dissatisfaction that are documented to arise from poor communication. 142

Interventions for behaviour change in healthy eating

From a review of literature indexed in MEDLINE, Web of Science and CSA Illumina on the effectiveness of interventions to promote healthy eating in the general population, it was apparent that there was a number of specific characteristics common to the successful interventions. 140 According to the review, any intervention, whether the focus was on diet alone or on diet and exercise, should be based on a model of behaviour change (i.e. it should be theory and goal driven) rather than simply on the provision of information. Successful interventions tended to be the ones that emphasised personal contact and were related to specific behavioural change strategies. Tailoring the intervention to the patient by using individualised personalised materials or using trained personnel to deliver a case by case intervention was also shown to be beneficial. Opening a dialogue between the health-care professional and patient that allowed for feedback on changes in behaviour (i.e. multiple contacts over an extended time period) was also found to be advantageous.

Physical activity interventions in primary care

In a review of primary prevention and secondary prevention interventions (12 and 24 studies, respectively),143 the authors identified several components of an intervention to promote physical activity that are likely to improve success (some of which had also been identified as being associated with successful interventions for dietary change), these include:

1. using behavioural approaches (individualised goal setting and problem-solving, self-monitoring, feedback and reinforcement)

2. supervised exercise

3. provision of exercise equipment.

The concept of ‘self-efficacy’ was highlighted and shown to be closely linked to a stage of self-change in physical activity. Individuals at the different stages of preparedness to change have different ‘degrees of exercise specific self-efficacy’. 144 Individually tailored reports and self-help manuals matched to the patient’s stage of motivational readiness to start physical activity were found to increase physical activity significantly more than standard self-help materials. 145 A brief negotiation intervention, based on motivational interviewing, was found to be more effective than attempts to persuade or coerce. 146

Interventions for elderly people living in the community

The decision to exclude non-community dwelling older adults from the LIFELAX study had been taken at the design stage as it was felt in residential care people would have less control over what they ate, and therefore that there would be less opportunity for them to make lifestyle changes. As elderly people living alone in the community account for 80% of the lowest single household income groups147 it was important that the diet and lifestyle changes promoted by the interventions were not costly to the individual. There is a paucity of literature on interventions that are focused on community-based nutrition. From a review of 23 such studies, none of which was from the UK (21 from the USA, one in Australia and one in France), we concluded that there was limited evidence for the effectiveness of healthy eating interventions in the elderly. 147 However, the review did find that the strategies of individual feedback and goal-setting highlighted previously142 were beneficial and were associated with a positive intervention. 147 The review restated the fact that the elderly community dwelling population is a heterogeneous group and that more research is required to identify suitable approaches at different age groups, social class and health status. 147

Primary care as a setting

Motivational interviewing

While motivational interviewing holds ‘substantial promise for health behaviour change’, is patient centred, can be tailored to the patients degree for readiness of change and is an effective means for working with patients who are ambivalent or not ready for change, it should be added as a note of caution that few controlled studies measuring the efficacy of motivational interviewing exist, and little is known about how to structure sessions. 161

Motivational interviewing is ‘a directive, client centred counselling style for eliciting behaviour change by helping clients to explore and resolve ambivalence’. 162 Motivational interviewing has four principles:163

1. expressing empathy

2. developing discrepancy

3. rolling with resistance

4. supporting self-efficacy.

Table 7 shows the characteristics of what is and what is not a characteristic of motivational interviewing.

TABLE 7 - The characteristics of motivational interviewing

Adapted from Miller and Rollnick. 163

Motivational interviewing	Opposite to motivational interviewing
Collaboration Partnership conducive to change	Confrontation Ignoring patient’s perspective
Evocation Intrinsic motivation to change is drawn from patient’s own goals	Education Aim of the practitioner is to educate the patient for change to occur
Autonomy Patient-led self-direction	Authority Practitioner tells patient what to do

Motivational interviewing is not defined as a technique per se but rather by ‘its spirit as a facilitative style for interpersonal relationship(s)’. 162 This ‘spirit’ involves collaboration between health-care professional and patient. The health-care professional elicits the motivation to change from the patient, through drawing on their patient’s own perceptions, goals and values, while the responsibility for change remains with the patient. 163 The focus of the motivational interview is to examine and resolve ambivalence, defined as a key obstacle to change, in a patient-centred and directive manner. 162

Although not explicitly based on any specific theory of behaviour change, motivational interviewing has been linked with the Transtheoretical Model of Change,164 which assists by ‘providing a framework for understanding the change process itself’, whereas motivational interviewing provides ‘a means of facilitating this change’. 161 The combination of motivational interviewing with the Transtheoretical Model has been described as an ‘optimal patient encounter’. 142

Because the notion of a readiness to change is important in all motivational interviewing approaches, including ‘brief motivational interviewing’, it is necessary to have a working understanding of the Transtheoretical Model (Figure 1). 165

FIGURE 1.

The Transtheoretical Model. Adapted from Prochaska and DiClemente. 165

Adapted from Prochaska and DiClemente. 165

Debate as to the merits of the Transtheoretical Model as a predictive or descriptive model is beyond the scope of this report; suffice to say that this is a model with which health-care professionals are familiar, and it provides a useful lexicon to describe people as they undergo a behaviour change intervention. The rationale behind this model is that behaviour change does not happen in one step. People tend to progress through different stages on their way to successful behaviour change. People also progress through the stages at different rates. Expecting behaviour change from someone who is still in the ‘pre-contemplation’ stage is unlikely because, when in this stage, the individual is not ready to change. Decisions as to when to move through the stages (i.e. when a stage is complete) must be made by the patient, as opposed to being imposed by the health-care professional. In each of the stages there is a different set of issues and tasks that relate to changing behaviour. The health-care professional can use different tools and techniques at each stage.

The focus of traditional medical consultations regarding behaviour change is ‘advice giving’. As discussed above, this paternalistic approach is not always the most effective mechanism and may be met with resistance and disagreement between patient and practitioner. 166 In behaviour change interventions, ambivalence to change is an often encountered problem. Ambivalence to change can be characterised as a conflict between two courses of action (patient and counsellor). It is difficult to resolve as each party has benefits and costs associated with the behaviour change. 166 This is particularly true when a directional (e.g. advice giving) approach, with unequal partners, is adopted, rather than a negotiated strategy. Motivational interviewing, although it uses a non-directive counselling approach, is a negotiated approach and does focus explicitly on ambivalence and the resolution of it. 167 The practitioner can positively or negatively influence their patient’s resistance to change and the outcome of the consultation. Negotiations in which the patient expresses his/her perceptions of the costs and benefits of change have been shown to promote the patient’s motivation to change. 166 Behaviour change interventions that tailor advice to the patient’s readiness to change should ensure closer agreement between patient and practitioner, encounter less resistance and improve the effectiveness of the intervention. 166 The most successful use of motivational interviewing is when the patient is given individual, personalised feedback. 168

While we knew that some of the practice staff involved in the LIFELAX intervention delivery would have a specific interest or experience in constipation or GI conditions, there was good evidence to suggest that motivational interviewing could also be successfully used by health-care professionals that were non-specialist in a specific field. 169

Despite these theoretical benefits of motivational interviewing, we were aware that the most limiting factor in using motivational interviewing in a medical or public health setting is time,170 in particular the length of time available in the ‘normal’ appointment slot for either GPs or practice nurses. For LIFELAX, therefore, we recognised that a briefer format of motivational interviewing would be required. Within the time constraints of the normal encounter with a practice nurse, we felt that there might not be sufficient time to fully explore the patient’s ambivalence. We were also aware that asking health-care professionals to adopt the LIFELAX intervention protocols may require some adjustment from the traditional prescriptive methods of patient education (i.e. provision of advice) to becoming more facilitative and collaborative. 170 Health-care professionals delivering the interventions in the trial would be required to leave their traditional ‘expert’ role and allow the patient to become the expert. 167

Brief motivational interviewing

Brief motivational interviewing techniques have been used with success in brief interventions in primary care in a range of topics, for example perinatal drug use,171 to improve dietary adherence in adolescents172 and psychiatric patients’ attitudes to their care, motivation to change, compliance and outcome. 173 There are a number of key elements that characterise a successful brief intervention and these should be apparent to anyone observing such a consultation. These elements are represented by the acronym FRAMES. 174

• Feedback Systematic assessment and feedback of individual findings.

• Responsibility Emphasising the individual’s personal responsibility for change, that this change is a free choice and a personal decision

• Advice Advice giving consists of two negative factors: first, it provides the patient with information (usually using tactics of fear induction), and, second, it uses persuasion (why a patient should do what you tell them).

• Menu The variety of ways in which change could be accomplished.

• Empathy Style of counselling.

• Self-efficacy Intervention should contain elements to strengthen the individual’s self-efficacy.

Despite ‘advice’ being a key element, it is important to recognise that ‘brief motivational interviewing’ consultations are not in the traditional advice-giving mould; advice is not given without the patient’s permission, and when advice is given it needs to be accompanied by encouragement for patients to make their own decisions. 161

Brief motivational interviewing was developed for use in a medical setting, where most patients do not enter in a state of readiness to change. 175

An implication of the Transtheoretical Model is that, before attempting to give people the skills and resources needed to change their behaviour, it may be more effective to assess their readiness to change. A person’s preparedness to change can be assessed accurately by the use of a questionnaire;176 however, this is likely to prove to be impractical in a routine clinical setting. Other useful tools to assess readiness to change, including an agenda setting chart (Figure 2), a ‘pros and cons’ chart (Figure 3) and a readiness-to-change ruler (Figure 4), have also been developed. 177 In LIFELAX we produced an agenda-setting chart that allowed patients to address constipation-specific factors (known to impact on bowel health), such as exercise, diet and fluid, as well as three open options where the patient could identify their own priority areas. In the intervention, patients were encouraged to identify their own priority items and set achievable goals when they were ready (Figure 5). 178 We understood that patients might well have had a rigid mental picture as to the consultation that they should expect when they underwent the intervention. We were aware that changing the consultation process and associated behaviours might not be easy; however, we felt that the simplicity of the agenda-setting chart, and its ability to help patients express choice and take the lead in target-setting, would make it a useful instrument. 178

FIGURE 2.

LIFELAX agenda setting chart.

FIGURE 3.

LIFELAX pros and cons chart.

	Staying the same	Changing
Pros	I wouldn’t have to change a thing	I could do without my laxatives
Cons	I’d still need my laxatives every day	I would have to change my diet

FIGURE 4.

Scaling tools.

FIGURE 5.

Setting aims and plans.

In order for behaviour to change, a person needs be motivated to change their behaviour and feel confident to do so. Motivation can be defined as the individual’s expectations of the costs and benefits of change, whereas confidence may be described as their ability to master the demands of assistance. Bandura’s Self-Efficacy Model and the distinction between outcome and efficacy expectation provide a theoretical framework to use motivation and confidence. 179 Exploring the importance of changing a behaviour with the patient is an important exercise. For this exploration, a ‘pros and cons’ chart was developed (see Figure 3). Using this chart it is possible to explore and record the positives of making a behaviour change and staying the same. Below is a worked example.

Confidence to change can be assessed simply by asking two questions:180

1. ‘If on a scale of 1–10, where 1 is not at all motivated to eat more fruit and 10 is 100% motivated to eat more fruit, what number would you give yourself at the moment?’

2. ‘If you were to decide to eat more fruit now, how confident are you that you would succeed? If, on a scale of 1–10, 1 means that you are not at all confident and 10 means you are totally confident that you could eat more fruit, what number would you give yourself now?’

After the topic (eating more fruit) had been raised, the aim of the next stage would be to identify arguments for change (motivation) and practical steps to make the change (confidence); this could be done through scaling questions

• First, by asking the patient why they scored as they did rather than a lower number:

  1. – ‘Why have you given yourself a score of 6 and not 1?’

• Second, by asking the patient what would need to be in place for them to move to a higher number:

  1. – ‘What would have to happen for your motivation score to move up from 6–9?’ ‘How could your confidence score move up from 5–8 or even 9?’

This information would then be incorporated into the ‘setting aims and plans’ sheet (Figure 5) as part of the ‘contract’ between the patient and health-care professional during the LIFELAX personalised intervention counter between the patient and health-care professional. Patients would take a copy of this away and a copy would also be retained in the practice for future reference in terms of follow-up telephone calls and follow-up visits.

Counselling

Counselling is defined as a ‘cooperative mode of interaction between the patient and primary care physician or related health-care staff members to assist patients in adopting behaviours associated with improved health outcomes’. 181 Improved behavioural outcomes in dietary counselling are thought to be associated with a number of factors, including the use of dietary assessment, enlisting family involvement, providing social support, using group counselling, emphasising food interaction (tasting, testing and cooking), encouraging goal setting and using advice appropriate to the patient group. 182

In a review of 21 studies, focusing on the counselling effect on changes in fat, fruit, vegetable and fibre intake, higher-intensity interventions, (more than one 30-minute contact) were found to be more effective than lower-intensity interventions. 181 Counselling interventions using self-help material and interactive communication alongside brief provider advice seemed to produce medium changes. Elsewhere, behavioural counselling to increase fruit and vegetables consumption have also been shown to be effective. 183 The PILs were designed to enable respondents to think about their current practice and to compare this with recommendations. For example, the PIL on ‘Fluid and constipation’ contained a fluid counter, the ‘Fibre and constipation’ PIL contained a fibre counter, and the ‘Activity and constipation’ PIL, an activity counter.

Behaviour change counselling

In addition to the principles of (brief) motivational interviewing, and the models and theories that underpin (brief) motivational interviewing (the Transtheoretical Model, and Bandura’s Self-Efficacy model), the personalised diet and lifestyle arm of LIFELAX also drew heavily on the BCC model. BCC184 is a set of consulting strategies derived from the patient-centred method,185 health behaviour change184 and motivational interviewing. 163 See Table 8 for a summary of the characteristics of BCC. As we described above, motivational interviewing is a directive, patient-centred counselling style for increasing intrinsic motivation by helping patients explore and resolve ambivalence. Being ‘patient-centred’ involves a number of factors:

• It is an active process that involves both patient and practitioner.

• There is a core partnership between patient and practitioner.

• It is not directional advice giving.

• Careful listening – listening to the patient to learn from them.

• The patient has greater control in decision-making.

• The practitioner and the patient reach joint decisions together.

TABLE 8 - The characteristics of BCC

Adapted from Rollnick et al. 184

Goals	Establish rapport, identify goals, exchange information Choose strategies/goals based on individual’s readiness Build on motivation for change
Style	Practitioner – patient both active Seldom confrontational Use of an empathic style, information is exchanged
Skills	Ask open-ended questions Summaries Ask permission Encourage patient choice and responsibility Provide advice Reflective listening

Behaviour change counselling, like motivational interviewing and brief motivational interviewing, has been developed for brief health-care consultations to help the individual talk through the ‘why’ and ‘how’ of change. The practitioner’s main task is to understand how the person is feeling and his/her plans for change. 40

As in motivational interviewing and brief motivational interviewing, establishing rapport is an essential component of BCC consultations. Once rapport is established, two-way information exchange tends to occur more readily. Establishing the patient’s readiness for change and what behaviour to focus on are also parts of the BCC approach. Establishing and agreeing goals and strategies for behaviour change should involve the patient setting realistic aims and plans that can be achieved. The consultation is an active process that involves both the patient and the practitioner; it should be collaborative, rather than prescriptive, and should be non-confrontational. By the professional asking permission to discuss a topic during a consultation, the patient will not feel it has been forced upon them.

Empathy – which can be defined as: ‘the ability to share someone else’s feelings or experiences by imagining what it would be like to be in their situation’186 – is a further core skill of the BCC process. This includes empathic listening, an active listening process, and demonstration that the professional is indeed listening, by replying and reflecting to what the patient has just said. For example:

‘Being constipated makes me feel lethargic, I can’t be bothered doing anything and I am scared of leaving the house.’

‘Your constipation makes it difficult for you to be more active – that must be hard.’

The BCC interviewing style is one that ‘quiet and curious’ – allowing the patient to do more talking, using open-ended questions, rather than closed questions. 184 Empathic listening, reflection and summaries are useful in rapport building and also ensure that aims are understood by both patient and practitioner. The practitioner provides structure to the consultation but decision-making should be shared184 (Figure 6 – suggested BCC consultation ‘flow’) and should be the patient’s choice as well as their responsibility. In BCC, as in motivational interviewing, it is vital that practitioners avoid falling into a paternalistic, directional advice-giving trap. Evidence suggests that this generally does not induce behaviour change. 184 When advice needs to be given, a more positive form of advice giving is giving a number of options, with the patient choosing the most suitable one.

FIGURE 6.

The BCC consultation ‘flow’.

The key principles that underpinned the LIFELAX personalised intervention

• Individualised goal identification.

• Realistic goal setting.

• Practitioner listening to the patient.

• The intervention being directed by the patient.

• Setting and following up the patient’s individual goals, using a range of novel tools: the agenda-setting chart, the scaling tools, the ‘pros and cons’ sheet and the goal-setting sheet.

• Monitoring of patient’s progress using specifically developed PILs containing tools, such as a fluid counter, fibre counter, measures of physical activity.

• A user-friendly and accessible practitioners’ manual that had all necessary trial information, and set out clearly and concisely what was required in the intervention.

• Training materials and resources.

From visiting practices and speaking to practitioners, the study team established that there was a scarcity of independent constipation, diet and lifestyle PILs, with the majority being produced by drug companies and laxative producers. A comprehensive suite of materials and resources was developed to enhance the LIFELAX interventions. We worked closely with patients and health-care professionals to develop many of the tools and the information materials needed. For example, we used cognitive interviewing techniques to test the acceptability and comprehensibility of the PILs (from text to pictures) and thereby to ensure their relevance and acceptability to the target audience. 119

High-quality training and reference manuals for health-care professionals were produced for both the standardised and personalised diet and lifestyle intervention arms. These contained the entire set of information (see Chapter 1, Impact of diet and lifestyle on constipation) that health-care professionals would need about constipation and bowel health, as well as full details of the delivery style and techniques for the appropriate arm.

Training of practice staff was envisaged to take place over a number of visits (one to two) for the standardised arm and (two to three) for the personalised arm. The training sessions were conducted by the project dietitian and nutritionist. As we were aware that we might be asking practitioners to change their consulting behaviour, this training drew heavily on the behaviour change techniques we were passing on for LIFELAX. However, after much discussion within the team it was agreed that there would be no formal assessment of the any health-care professional’s preparedness to change their own consulting behaviour.

The time available to train health-care professionals in the intervention techniques was always an issue in this trial; however, the importance of training cannot be over emphasised. 167 We needed to be flexible and to tailor our training to fit in with the practice schedule. There is evidence that training based upon two or three 1- to 1.5-hour training sessions and role play demonstrations is successful. 177 We were told by the practices involved in developing the interventions that practice nurses would not readily enter into or enjoy role play, especially if senior colleagues were to be involved or observing. As a result of this, we elected to produce training DVDs in place of the role play. Evidence suggests, too, that outside of the training sessions few of the health-care professionals were willing to practice the training and techniques. 177 For this reason, we felt that the DVD would serve as a useful resource and aide-memoire.

Our experiences of practice training varied from practices that set aside the majority of a day for training to ones that required us to fit in with lunch breaks. Having project staff (a research dietitian) that were sympathetic to and understood the dynamics of working in a primary care environment was seen as an advantage.

We felt it important that staff should have a positive experience from the training, and worked to create sessions that were informative, interesting and with clear useable learning outcomes. We felt that our training DVD helped to avoid the embarrassment of role play and the unfeasibility of offering staff ‘refresher’ courses.

Novel ways for engaging practice staff and assessing their knowledge of the condition were used, for example we used the quiz show formats of ‘Who Wants to Be a Millionaire’ and ‘The Weakest Link’ rather than a more formal assessment or lecture. A lecture would imply they may not know how to deal with constipation, whereas the quiz format was a two-way process that facilitated discussions and information exchanges.

Summary

In designing both the standardised and personalised diet and lifestyle interventions for LIFELAX there were a number of theoretical models that we could have potentially chosen on which to base our materials, methods and resources. The standardised approach made use of the existing nursing model in use in primary care as the basis for those appointments. For the personalised intervention arm, we reviewed a number of trials that had successfully used a number of different models and techniques to deliver behaviour change with respect to diet, physical activity and other aspects of lifestyle. We drew on the recommendations from those papers and from other practising health-care professionals to produce training, training materials and literature, the likes of which were not otherwise available to practitioners in the UK.

Copies of the resource packs, PILs and training DVD are available for purchase from the central trial team.

Introduction

In this chapter we will describe the challenges encountered during the implementation of LIFELAX. These challenges arose both with the recruitment of practices and of patients. The planned recruitment model described in Chapter 2 (which formed the original study protocol) and the account of the reality presented here differ widely. Various reasons for the challenges will be documented in this chapter and the embedded Process Evaluation Study (see Chapter 6) offers a further interpretation on this account.

In summary, some 1114 practices in total were approached and invited to participate. Of these, 44 (just under 4% – 13 short of our target of 57) agreed to participate and were randomised. However, only 19 practices (43% of those randomised – 33% of the target of 57) recruited participants to the trial; 16 practices withdrew post randomisation and six practices were unable to recruit during the time frame available. Figure 7 presents the CONSORT diagram for the trial.

FIGURE 7.

LIFELAX CONSORT diagram. a, Although not all consented participants received the allocated intervention they were eligible for a baseline assessment; therefore n = 154 is used in the analyses of baseline data. b, Not all withdrawals were complete withdrawal from all follow-up assessments; consequently, some participants supplied questionnaire data and not diary data, and some participants agreed to telephone follow-up only.

A total of 154 participants were recruited to LIFELAX. Initial calculations showed that in order to recruit the required number of participants (approximately 1800) for the trial we would need to recruit 57 GP practices (31 patients per practice on average). This would seem now to be a vast underestimate, given the poor levels of participant uptake we experienced.

Preparation and implementation of the trial protocol

For the findings of clinical trials such as LIFELAX to be generalisable across primary care (i.e. to have external validity), it is important for the amount of research and the proportion of research-active primary care staff, in particular GPs, to increase. 187 Increased participation in primary care trials is a priority in the UK,188 even although such trials have always been more challenging to researchers than trials in alternative environments, such as the more controlled and more research-orientated secondary care. Added to this ‘standard’ challenge of primary care research, LIFELAX also coincided with a period of considerable change within the NHS, both in terms of the emergence of a new research governance and ethics framework and the implementation of new GP contracts.

Regulatory approval

Although LIFELAX began after the publication of the EU Clinical Trials Directive, it was prior to the Directive’s enactment into UK law. This meant that although the LIFELAX trial appeared to meet the criteria for a clinical trial of an investigative medicinal product (ctIMP) we were able to apply for a Doctors’ and Dentists’ Exemption (DDX) certificate when obtaining regulatory approval from the Medicines and Healthcare products Regulatory Agency (MHRA). This meant that we did not need to submit a full application for a Clinical Trial Authorisation (CTA) to the MHRA. In common with all other trials at the time, the DDX was issued and was then ‘rolled over’ into a CTA on 1 May 2004. (With hindsight it would seem that the study could have made the case to the MHRA that the study was a trial of management strategies, rather than specific drugs. However, the general advice we received was that if there was any possibility of a study being a ctIMP the DDX/clinical trial exemption route should be followed to avoid the additional paperwork associated with obtaining a CTA.)

MREC approval

An overview of the time line for the trial is shown in Table 9. The initial ethics application was submitted to the allocated MREC in December 2003, at which time the subsequent approval of the LREC associated with each participating site was required, unless a ‘no local investigator’ (NLI) status was agreed by the MREC. To reduce the burden on the multiple GPs who were to be recruited to this study, we asked the MREC to consider NLI status for LIFELAX. Unfortunately, NLI status was not granted. The MREC reviewed the application on 22 January 2004. A number of minor changes were requested in the patient information sheets. The MREC delegated authority to their ‘lead reviewers’ for this application to approve these amendments once they had been received. The formal letter conferring the favourable opinion of the MREC was issued on 12 March 2004.

The LIFELAX trial team had concerns over the burdensome nature of the recruitment protocol submitted to MREC as part of the approval process. This method had been approved by another MREC for the STOOL trial. 19 The approval process for STOOL had taken 15 months, and we were concerned that any deviation in LIFELAX from an already approved method might lead to unnecessary delay. [At this time there were many changes in the research ethics committee (REC) approval process. Many of the recruitment strategies that had been acceptable in earlier studies were deemed to be no longer so. It is in the context of this changing landscape and inconsistencies across RECs that LIFELAX operated.]

LREC approval

As LIFELAX was not able to operate as a NLI study, an extra level of approval was required before recruitment could begin. LRECs treated each general practice recruited into the study as a separate ‘site’ and required the submission of a separate SSA, accompanied by the CV of the GP taking on the role of principal investigator (PI) for that site, before they would consider that site for approval. The process was made additionally burdensome to GPs as it required that each local PI should apply for an LREC number, complete and sign the relevant form and send it to the appropriate LREC. These requirements created a number of difficulties: many GPs did not have readily available CVs of the type required; many GPs were unfamiliar with the new LREC forms and processes and did not have sufficient time to carry out these tasks; and others felt that they did not wish to be designated as responsible for a study that ‘wasn’t theirs’ and felt that responsibility for the study lay with the research team.

To facilitate this process we designed a short CV template that would allow GPs to provide us with the minimum amount of information required for LREC to carry out the SSA. Having heard anecdotal evidence/horror stories of trials that needed SSAs spending > 7 months on this part of the approval process alone, we made an approach to our MREC, the local COREC manager and the Director of NoReN (the local primary care research network) with an innovative solution.

The COREC guidelines at the time stated that if two or more GP practices had contracted to conduct research collaboratively, whether through a consortium or under the direct management of the PCT, they could be collectively identified as a single site and, in such cases, one of the investigators should be appointed as the PI for the site. Our solution to the local approvals dilemma proposed that NoReN (an inclusive organisation for all north-east general practices, not requiring any practice to ‘opt in’) should form the consortium with the other recruiting practices in the area, with the clinical director of NoReN (GR, already a coinvestigator on the study) acting as the PI for the purpose of the SSA. 189 This solution was accepted, and notification that the various LRECs had approved LIFELAX to run in the ‘Area 1’ PCTs came via MREC on 10 November 2004.

Although LIFELAX pioneered this approach, allowing us to speed up the SSA process in the areas covered by NoReN, we were not entirely happy with it as a model outside the NoReN area. Although successful in Cumbria with the CumbReN network (again with the CumbReN director acting as PI for the consortium), there was a concern that should the trial seek to recruit further afield the directors of other GP research networks might not agree to take responsibility as PI for the sites within their network’s geographical area. In light of this concern we again approached MREC and asked them to reconsider the ‘NLI’ status of LIFELAX. At the time of this final approach, the ‘NLI’ status for trials had ceased to exist. By this time, the LREC approval process required site-specific information (SSI) to be submitted to LREC as part of the local approval process or, in certain circumstances, an SSI exemption could be claimed. After consultation with the local COREC manager and the agreement of the COREC policy officer to support the MREC decision to support the SSI exemption, should it be granted, an approach to MREC for SSI exemption was made in October 2005. We argued that the LIFELAX was a ‘low-risk’ study, the prescribing of laxatives was in line with normal practice (with no stipulation on class or dosage) and that the behaviour change techniques were often used in routine practice.

After agreeing that LIFELAX was a ‘low-risk’ study, MREC considered that it could be an ‘SSI-exempt’ trial (favourable opinion 12 October 2005), which meant that sites no longer needed a GP to act as a PI and that no application to LREC for approval of sites (or consortia thereof) needed to be made.

PCT selection and R&D approval

LIFELAX as a business

An RCT is a huge investment in time, money and people. For a long time it has been acknowledged that in order to succeed, trials need to be marketed and trial managers need to think like marketers. 191 Trial management involves lateral thinking, good communication, ethical marketing and common sense. 192 From the start of the trial, LIFELAX was looked upon as being very much a small business. We understood that we would need to find GPs and convince them to ‘buy into’ the study. However, when businesses market a product they are attempting to convince customers that they will gain benefits directly from their purchase of the product. In LIFELAX the marketing task was somewhat different in that we were seeking to gain a commitment from senior GPs to allow their practice to engage in the study, when they themselves would apparently make no direct material gain by doing so. Therefore, from the outset, it was vital for LIFELAX to identify the potential gains and benefits that would accrue from participation in the trial.

Although not specifically stated at the time that LIFELAX was being ‘marketed’, the subsequent publication of the Strategies for Trial Enrolment and Participation Study (STEPS) report193 and the influential ‘Marketing and clinical trials: a case study’194 allow us to retrospectively assess LIFELAX’s marketing strategies against these proposed models for success (Figure 8).

FIGURE 8.

The 12-component reference model. Adapted from Francis et al. 194

Adapted from Francis et al. 194

Developing ‘brand values’ (Ia)

Brand values define what a brand is and what it is not. Without this, it is impossible to communicate a coherent and persuasive perception of a trial’s ‘promise’ – i.e. what the trial intends to deliver to medicine, doctors, patients, etc. We worked closely with professional designers and graphic artists to develop the LIFELAX brand. We had our own distinct logo, font and colour scheme that featured on all of our trial related materials to render them easily identifiable. The ‘promise’ of our logo was life and vitality.

Gaining legitimacy/prestige (Ib)

Trials need legitimacy – they need to be positively’ tagged’ by association with prestigious individuals and institutions. LIFELAX was ‘tagged’ to the Newcastle University ‘brand’ (using the recognised crest) and to NoReN/NYReN (PCRN-NE) and its Clinical Director, Professor Greg Rubin. Legitimacy and prestige provide persuasive credibility, which is key to gaining access to decision-makers who decide whether a trial should be supported and maintain engagement. Practice senior partners and staff, particularly those in north-east England, would have been familiar with, and respectful of, both Newcastle University and NoReN/NYReN.

Signalling worthiness (Ic)

It is vital to signal to likely participants that ‘this trial will create greater value than the costs (time, effort or money) involved’. In LIFELAX we negated the ‘money’ cost by securing the SfS funding. This effectively meant that all LIFELAX-related ‘costs’ incurred by practices would be reimbursed. We were also able to present the training in the behaviour change techniques as a benefit to practice staff (training in such techniques is both costly and difficult to source) that would be generalisable and applicable beyond the LIFELAX study. By highlighting the benefits that changes to diet and lifestyle have on a range of conditions (not just constipation) we hoped to show the value of participation. The aim was to roll out the training in the behaviour change techniques to all participating practices at the end of the trial so this ‘value’ would be available to all.

Providing simple, complete processes (IIa)

Trials require participants to undertake work – for example, identifying, approaching and recruiting patients, delivering the intervention and completing study documentation – that is additional to their normal duties. Providing them with simple, complete processes reduces the opportunity and financial costs of participation and increases the chances that involvement will be affordable and manageable. We offered assistance with electronic queries to search for patients. We (following the protocol amendment) undertook the consent, recruitment and follow-up processes.

Devising strategies for overcoming resistance (IIb)

Potential participants frequently raise objections. Trials should have standard and persuasive answers to these. Having a persuasive answer for each objection increases the probability of ‘making a sale’. This is an interesting premise for LIFELAX. Due to the ‘opt in’ nature of the practice recruitment process, we intuitively felt that post-enrolment resistance would be low. We were not ‘cold calling’ practices and trying to convince them to join. However, as shall be seen later in this chapter, resistance to participation (barriers) were identified. The strategies we devised to overcome them are also discussed below.

Adopting an explicit marketing plan (IIc)

The marketing of a trial is too important and too complicated to be done informally. A formal marketing plan is required and should include a definition of target market segments (groups that need to buy in to the trial) and the trial’s unique selling points (USPs). LIFELAX may not score highly in this component as we did not as such. We were aware that the ‘way in’ and ‘sign up’ for practices usually has to be via the senior GPs, rather than the practice nurses, managers. We actually targeted all three in our approach, as we describe below. So in this respect it can be argued that we did adopt a marketing plan, We identified the trial’s USP for each of the categories to highlight the benefits of supporting the study.

Engaging active sponsors, champions and change agents (IIIa)

Selling a trial to prospective participants requires persuasion. This requires enrolling sponsors (public advocates), champions (activists) and change agents (facilitators). Trial managers need a network of supporters to spread the message. Persuasion is more likely to occur if the advocate is respected and known personally to the prospective participant. LIFELAX did have local champions (via NoReN/NYReN). However, we failed in our early attempts to recruit public advocates and our patient representatives’ activities were confined to TSC duties (though they were extremely supportive of the study).

Delivering a multiaudience, multilevel message (IIIb)

Trials need to convey sales messages through publicity, presentations, training materials, etc. These should be tuned to the distinctive needs of target groups – for example, surgeons are likely to be persuaded by different messages to administrators or nursing staff. Speaking in the language of the person being targeted and addressing their particular pattern of motivation is more likely to succeed than a ‘one size fits all’ approach. In LIFELAX we understood the importance of this. Our presentations (contents and style) were tailored to fit with our target audience (GPs, nurses or practice managers).

Achieving buy-in (in public) (IIIc)

Public buy-in requires that intended participants announce their commitment to join the trial in a setting where others hear them. This is important because when someone states, in public, that they are willing to undertake an action, then they are more likely to abide by their commitment than if they take a silent decision – that can be forgotten easily. This was not done in LIFELAX. With benefit of hindsight, we wonder whether techniques such as regular publication of lists of signed up practices might have acted as a signal of commitment. Anecdotal evidence of the lack of awareness in practices signed up to the study suggests that in some cases the senior partner did not even announce commitment to, and elicit support from, the rest of the practice team, leading to a lack of awareness of the study and them feeling that they were ‘pressed’ men and women.

Ensuring positive ‘moments of truth’ (IVa)

People evaluate organisations (including trial management teams) on the basis of their experiences at moments of truth. For example, if a doctor has a technical question about entering a patient into a trial, she will gain a strong impression of the trial management team’s competence by the way that the query is handled. In LIFELAX we had a clear and efficient way of handling queries so that accurate and timely responses were given. We set up a dedicated ‘LIFELAX.queries@…’ e-mail address so that practice staff could e-mail queries and questions to us directly. This account was checked routinely and the message passed to the most appropriate member of the trial team for response.

Providing frequent positive reinforcement (IVb)

Positive reinforcement for existing participants should be an important part of a trial’s participant retention strategy. It is more expensive to recruit new participants than to retain existing participants. We feel that we largely achieved this in LIFELAX. Those practices that underwent training and became active recruiting sites remained committed to the trial until the end.

Facilitating incorporation into routines (IVc)

Activities that become embedded as routines are more likely to be done than one-offs. Trial procedures should be incorporated into the routines of units undertaking the work. Due to the ‘stand alone’ nature of the patient search and mail out, it is difficult to see how this aspect of LIFELAX could be incorporated into practice routine. With regard to the intervention, we were concerned that nurses who saw participants on an infrequent basis might feel less confident in engaging with the techniques. Recognising this, we attempted to show how the principles and techniques of behaviour change taught in LIFELAX could be incorporated into routine practice, and so LIFELAX should not be seen as study-specific training.

With reference to the 12 components above, we are able to demonstrate that the LIFELAX marketing strategy used does fit closely to the proposed STEPS model for success, although we did not apply it explicitly in designing and conducting the study (the STEPS publications193,194 appeared in 2007).

Baseline characteristics of the LIFELAX participants

Here we report on the baseline data collected via the self-completion questionnaire and the face-to-face interview. Daily diaries were also completed for 6 months from the date of the start of the intervention. Diary data will be reported separately (below) from the two baseline measures. Further reporting on the effects on HRQoL at baseline can be found in the economic evaluation section below.

Baseline postal questionnaire

PAC-SYM

The PAC-SYM is a 12-item scale measuring stool, rectal and abdominal symptoms. Respondents report the severity of each symptom on a scale from 0 to 4, (with ‘4’ representing the greatest severity). An overall score (PAC-SYM global score) is computed by taking the average item response across the 12 symptoms. The three subscale scores are computed in the same manner, based on the symptom groupings (abdominal – four items; rectal – three items; stool – five items); algorithms for data imputation in the case of missing data mean that subscale scores can be calculated when one or two items in the subscale are missing. The mean scores and standard deviations for the PAC-SYM subscales and global score can be found in Table 11.

TABLE 11 - Mean scores (and standard deviation) for the PAC-SYM subscales and global scales

SD, standard deviation.

PAC-SYM	n	Minimum	Maximum	Mean	SD
Abdominal	123	0.00	3.75	1.07	0.92
Rectal	119	0.00	4.00	0.74	0.92
Stool	122	0.00	3.25	1.38	0.94
Global	120	0.00	3.17	1.10	0.79

Figure 9 shows a histogram of the distribution of responses on the PAC-SYM global scale. This provides some evidence that there was a ceiling effect (patients scoring the lowest possible score at baseline, and therefore with no ‘capacity’ to capture improvement over time) in the study population.

FIGURE 9.

Distribution of patient assessment of constipation – symptoms (PAC-SYM) responses.

In the development of the PAC-SYM,127 Cronbach’s alpha for the total PAC-SYM score was reported as being 0.98. Subscale Cronbach’s alphas were 0.80 for stool symptoms, 0.84 for abdominal symptoms and 0.87 for rectal symptoms. Our findings were consistent with these figures with Cronbach’s alpha for the global score being 0.91 and the subscale alphas being 0.84 for stool symptoms, 0.87 for abdominal symptoms and 0.81 for rectal symptoms; all of these values exceed the criterion of 0.70, indicative of adequate internal consistency reliability at the group level. 208

The PAC-SYM mean scores suggest that the level of constipation symptoms experienced by our sample was low. This is supported by evidence from the objective measure of bowel movement frequency collected in the daily diary. The mean number of daily bowel movements was 1.5. This again supports the findings of the STOOL report19 that patients did not define themselves as having constipation, once a preferred pattern of bowel movements was established, regardless of whether it took the use of regular laxatives to achieve this.

PAC-QOL

The PAC-QOL questionnaire was developed as a patient-reported outcome measure to evaluate the impact of constipation on QoL over time. 38 In development work, the PAC-QOL scales have been established as being internally consistent (Cronbach’s alpha > 0.80 on each of them). Our findings were consistent with this. Cronbach’s alpha for the 28 items forming the global score was 0.93. For the subscales (dissatisfaction – five items; physical discomfort – four items; psychosocial discomfort – eight items; worries or concerns – 11 items) the Cronbach’s alphas were: dissatisfaction 0.86; physical discomfort 0.89; psychosocial discomfort 0.87; worries or concerns 0.93 – again, all in excess of the threshold level of 0.7 indicative of adequate internal consistency at the group level. 208

The correlations of the PAC-SYM and the PAC-QOL global scores at baseline were in line with what we would expect, with there being a greater impact upon QoL with increased symptoms (r = 0.76, p < 0.01).

The box plot shown in Figure 10 offers some suggestion that the groups were not evenly balanced with respect to constipation-related QoL at baseline.

FIGURE 10.

Box plot of the PAC-QOL overall scores.

Baseline face-to-face questionnaire

Use of prescription laxatives

In our sample, over 30% of respondents had been taking a prescription laxative for 10 years or longer, and 90% had been taking a prescription laxative for more than a year. A breakdown of the duration for which respondents had been taking laxatives can be seen in Figure 11.

FIGURE 11.

Number of years taking prescribed laxatives.

Nearly 90% of our participants had used a prescription laxative in the previous 7 days, with in excess of 41% of them being prescribed a stimulant laxative by their GP; 30% had been prescribed a second laxative and 5% of our sample was prescribed a third.

Half of the respondents had never taken an OTC laxative and approximately 15% had been taking them for 10 years or more.

Postal questionnaire follow-up response rates

The self-completion questionnaire was sent at three time points (3, 6 and 12 months). At 3 months the response rate was 80%; at both 6 and 12 months it was 85%. This suggests that, despite length of the questionnaire, the time taken to complete it and the added burden of the daily diary at the first two time points, respondent fatigue was not an issue.

Economic evaluation

Introduction

Within the LIFELAX trial the process evaluation provided a unique opportunity to investigate the stages of development and implementation of an RCT in ‘real time’ as events occurred. We observed that the trial team’s activities centred on two key ‘technologies’. The first was the development of the RCT itself, which – in common with other forms of research – required the investment of expertise, finance, clinical and bureaucratic support, and the sustained collaboration of a number of contributors. The second technology at stake was the development of training packages and materials for the diet and lifestyle interventions, and subsequent deployment of this training by the trial team, in particular the research dietitian and nutritionist, to an audience of practice nurses. The research dietitian and nutritionist delivered the training packages with the intention that the nurses would later deploy target skills and materials with patients in the practice. An important observation was that the underlying factors that supported each technology differed, such that while the trial team were able to overcome a number of barriers to the deployment of the RCT, many of the factors influencing the nurses’ reception of the training packages were beyond the trial team’s control.

In the first section of the chapter we discuss the key barriers that taxed the implementation of the RCT, and the trial team’s efforts to implement the trial in primary care practices. At the time of LIFELAX, the organisations on which the trial depended were in a stage of transition with regard to their interpretation of Research Management and Governance (RM&G) guidelines. Consequently, there was some ambiguity across these organisations about how the RM&G guidelines should be implemented and this had a number of effects on the trial team’s capacity to deploy the trial. In particular, the trial team received different instructions across PCTs regarding how the trial should be implemented. In most cases practices contemplating involvement in the trial were faced with the prospect of additional work on behalf of the trial team. In this regard, the LIFELAX RCT – in common with almost all forms of research – did not offer an immediate advantage to primary care practices. Indeed, quite the reverse was true. In this context, the trial team worked hard to find innovative solutions to potential barriers and reduce the amount of work required of NHS staff, while maximising the attractiveness of the research topic and experimental interventions. These issues, and the approach adopted by the trial team, have been described in more detail in Chapter 4, specifically with regard to assessing strategies against those proposed in the STEPS report,193 and other literature. 194 We draw primarily on interview data to describe the ‘technology of the RCT’, as transcripts of the trial team meetings provide a less concise and at times less explicit account of key issues. (In LIFELAX trial team meetings, many problems associated with RM&G guidelines or MREC decisions emerged over successive meetings. The trial team shared some understanding of the history of RM&G guidelines and MREC stipulations, and therefore the contexts underpinning particular problems were not always made explicit. In interviews, however, these issues were articulated overtly and unambiguously by the interviewees as they attempted to inform the ethnographer.)

In the latter half of the chapter we describe the ‘second technology’ of LIFELAX, namely the development and deployment of training packages for practice nurses. In the first instance, the trial team developed a training package in BCC techniques, and the production of diet and lifestyle materials (information sheets, a video and behaviour change manual). The second activity was the delivery of BCC training by the research dietitian and nutritionist to nurses in the BCC arm of the trial. The intention of the trial team was that the nurses receiving training in BCC would then deploy these skills with recruited participants in their own practice. Due to the pragmatic design of the trial, the interactions between the nurses and participants were unobserved by the trial team. In this chapter, we describe the perceived utility and reported use of the BCC materials and training through the accounts of practice nurses, GPs and practice managers enrolled in the trial. The reports from primary care staff suggested that the topic of the trial was not seen as a clinical priority when considered alongside targets identified in the GMS contract, and that diet and lifestyle approaches were informally considered part of the current skill set and training of practice nurses. In attempting to find meaning in the trial’s interventions, the practice nurses suggested that community nurses might benefit from the BCC techniques, as these staff were viewed as being more likely to work with patients suffering chronic constipation. Finally, we report how the interventions were perceived by participants through their interactions with enrolled nurses.

Making sense of participation in the context of chronic illness

Some of the barriers to the success of the LIFELAX trial, as explained earlier in the chapter, were due to a range of issues concerning RM&G guidelines and MREC rulings, and a notable lack of interest in the research across primary care sites. However, the participants’ accounts of their experience also offer a useful perspective regarding how the trial was deployed, and the significance of the interventions for patients suffering chronic constipation. The meaning of the trial for participants was shaped by their individual ‘illness trajectories’ or, specifically, the manner in which participation met ongoing, idiosyncratic priorities regarding their illness. 222 Specifically, although some participants had reached personally satisfying treatment decisions prior to the trial, others were actively seeking new solutions to the management of their chronic constipation. Participants in the two ‘active’ diet and lifestyle arms of the trial experienced an interaction with one of the practice nurses. Consequently, in these arms, the participants’ perception of the research was shaped by how the nurses conveyed – deliberately or subconsciously – their own views of the trial. It was difficult therefore to discern through a single interview with a given participant, sometimes a considerable time after the consultation with the nurse, how these factors independently affected the participants’ experiences. Nevertheless, three key topics were central to all accounts. These were: (1) reported motivations for participation; (2) experience of interacting with a nurse in the research consultation (in applicable arms); and (3) understanding of the outcomes of participation in the RCT.

Discussion

The assessment of complex interventions can be a challenging process. 228 In the process evaluation, we observed two ‘complex interventions’: (1) diet and lifestyle training for practice nurses, but, more specifically, (2) the practical conduct of an HTA RCT. In light of the trial’s premature closure, data from the qualitative evaluation help to explain some of the processes that led to the trial’s closure, and how they might be avoided in future RCTs. Although we can comment on the structure and implementation of LIFELAX (and offer recommendations for future implementation of HTA research), the relative importance of clinical topics such as ‘chronic constipation’ and the merit of ‘BCC’ per se are less clear. Specifically through the process evaluation we observed the confluence of several ‘trajectories’ or processes:

• The implementation of a pragmatic RCT in an ‘unsettled environment’ of research governance interpretation and ethical judgements.

• The response of practice staff to involvement in an RCT concerning a condition not prioritised in GMS contracts.

• The response of practice nurses to proposed changes in their work patterns.

• The responses of practice staff to the problematisation of chronic constipation: practice nurses perceived chronic constipation to be a condition already successfully managed by laxatives.

• The response of the nurses to BCC training as delivered by dietitians or nutritionists.

• The response of participants to involvement in a pragmatic RCT (including management of expectations and research-related tasks, such as the daily diary).

• The response of participants in the diet and lifestyle arms to the combined stimuli of the LIFELAX trial and an interaction with a practice nurse.

In this report we have attempted to describe the interaction of these processes on the success of the LIFELAX trial. Nevertheless, RM&G and ethics issues aside, it is not possible to isolate the factors from one another. For example, had the training been delivered to community nurses the response of these staff may have differed from that of the practice nurses in LIFELAX.

As the embedded process evaluation study was ethnographic, qualitative research techniques were employed, and it was therefore not appropriate to set out our research questions in hypothetical form. However, at the outset, we attempted to address the following specific questions:

1. Formation How are ideas about the appropriateness of health technologies and their clinical applications formed and mobilised in practice; how are the interests of consumers and other users defined and incorporated in the organisation of the trial?

The process evaluation explains some of the reasons for the early closure of LIFELAX and we draw a number of conclusions about the structural processes of HTA assessment from these data. However, it is not possible to make claims about specific public health topics, such as the significance of chronic constipation for primary care medicine. We did observe that practice nurses and managers perceive chronic constipation to be successfully managed by laxatives, and that roughly one-half our sample of participants also considered themselves either not to suffer from constipation or that they successfully managed their symptoms through the routine use of laxatives. However, the nurses also explained that they did not work with patients presenting primarily for chronic constipation. The ‘problem’ of chronic constipation may largely be one of economics for senior practice staff, or an issue of concern for community nurses, or an issue for some, but certainly not all, patients.

If we consider the ‘lessons learnt’ for future HTA trials, it is important to understand how and why the LIFELAX trial was commissioned considering the response of practices. A systematic review underpinning the commissioning of LIFELAX, identified both chronic constipation and diet/lifestyle interventions as pertinent topics in primary care. This finding, taken on face value, appears to be at odds with the outcome of the process evaluation. However, the cost of laxatives and the dependence of patients on medication were issues that concerned some practice staff in interviews. Nevertheless, the relative priority of this problem when compared with others in the practice was not high.

Most of the trial team’s efforts were invested in ensuring that the RCT was successfully embedded in individual practices and across PCT sites. However, the response of practice staff to the trial’s topic and interventions were identified only after the RCT had been deployed. These issues may have been identified through a prior feasibility study, if one had been funded. A small pilot study was conducted during the development of training materials. However, this work was focused on the development of BCC materials and not on the feasibility of a larger trial.

1. Integration How are specific clinical and methodological problems within an RCT identified and resolved within professional groups and networks; how is the trial integrated into the existing organisation of clinical service provision, and what professional and organisational dynamics are involved in this integration; how is participation in the RCT negotiated and understood by subjects?

This is a multifaceted question and, as such, we have addressed it in the current chapter via several different means. With regard to the clinical and methodological problems of the LIFELAX trial, the trial team engaged in a considerable amount of negotiation and bureaucratic work in order to integrate the trial in clinical environments, and to meet RM&G and MREC requests. We have discussed this process through the NPM constructs of interactional workability and contextual integration. Notably, we found that the RCT relied heavily on cooperative networks. Cooperation and a shared understanding of goals (congruence) were achieved through the social skills of the trial manager and his ability to negotiate access to resources with relevant personnel across NHS organisations at both a national, and local (PCT) level. This observation highlights the necessary (though potentially underacknowledged) skills required of trial managers in the current climate of primary care research.

Due to the decision of the MREC regarding SSAs and access to patient data, the evolving nature of RM&G guidelines, and various interpretations of these guidelines across PCT sites, the trial team were under pressure to continually develop creative and workable solutions to emerging problems. This formed a barrier to the satisfactory and timely achievement (disposal) of essential milestones – such as recruitment – in the delivery of the trial. A review of the practical implementation of MREC decisions and RM&G guidelines in primary care is also necessary in order to identify how to promote quality research while meeting ethical standards.

We addressed the research question ‘how is participation in the RCT negotiated and understood by subjects?’ through the NPM constructs of interactional workability and relational integration. Specifically, we found that some participants reported a lack of understanding or congruence between themselves and the practice nurse regarding the value of the research. For some participants, their encounter with the practice nurse was a demoralising experience as the nurse appeared to view the trial’s interventions as a poor use of time. Moreover, for most of the participants who sought medical interventions, the BCC or standardised advice consultations failed to help them dispose of problems related to health, diet or lifestyle issues. When describing their experiences in the RCT, the participants reported that the daily diary exercise was the most salient part. Most of the participants therefore struggled to make sense of the mechanics of the trial and how such a diary might usefully contribute to the amelioration of their, or others, chronic constipation. Therefore, whether participants viewed their constipation as problematic or not, both groups reported that they struggled to see how the trial would lead to results that would benefit suffers of chronic constipation. This finding may result from the intrinsically confusing experience of trial participation as reported in the literature,229–231 an issue more specific to the LIFELAX trial, such as the practice nurses’ perceptions of the research and their subsequent behaviour with participants, or a combination of factors.

1. Implementation How are the production of results negotiated and organised within networks of researchers; how are its results mediated to the wider community and how is this negotiated and organised, both formally (through report writing and presentation), and informally how are the mechanisms and results of the trial understood by subjects?

Following the premature closure of the LIFELAX RCT it was not possible to collect data relating to the development and publication of outputs from the trial. However, we have discussed the manner in which the participants attempted to understand the mechanisms and results of the trial through the context of their own illness trajectories and the NPM constructs of interactional workability and relational integration.

1. What lessons can be learned that will improve the organisation and conduct of HTA RCTs in the UK – and further afield? The study holds important implications for the organisation and conduct of HTA. It is important that its results can inform and develop both policy and practice?

A number of issues regarding the development and implementation of RCTs have been identified through the conduct of the process evaluation. The problem of the trial’s topic, setting and training packages may have been identified had a prior feasibility study been conducted. At the time of the LIFELAX trial the HTA did not fund pilot studies of this nature, although the HTA have now changed their policy in this regard. However numerous system wide problems – such as the changing RM&G guidelines and research briefs that did not match GMS contracts – also taxed the capacity of the trial to be successful. Following the results of the process evaluation, and the input of several of the reviewers of this report, we suggest the following:

• Improved means and methods of communication are required between governance bodies, MRECs and researchers regarding the best way to conduct RCTs that are ethically, methodologically, and practically sound.

• There is a need for a clear and consistent means of applying for RM&G approval across PCTs.

• There is a clear need for pilot studies prior to the design and implementation of HTA RCTs. The pilot study should:

  1. – Assess the feasibility of all aspects of the intended research but specifically ensure that the assumptions underpinning the study are correct. These assumptions may be multiple but should ensure that: (1) there is an identified need for a technological intervention; (2) the intended beneficiaries also perceive a need for intervention and are in equipoise regarding the proposed interventions and control; and (3) the definition of the need or problem is commensurate between researchers, users and beneficiaries.

  2. – Pilot studies should assess whether the interventions will enable the intended users and/or beneficiaries to achieve relevant goals (such as disposal of symptoms).

  3. – Pilot studies should assess whether the intended interventions fit within existing patterns of work, and where they do not, assess the likely disruption and acceptability to intended users.

  4. – Pilot studies designed to assess the feasibility of the research should be conducted prior to any significant investment in the development of an RCT.

Conclusions

Through application of the NPM we were able to identify a number of factors that contributed to the premature closure of the LIFELAX RCT. Evaluation of the trial raises a number of important considerations for the deployment of other trials of complex interventions in primary care. In particular, the administrative difficulties encountered by the LIFELAX trial team, regarding the application of RM&G guidelines and research ethics, were indicative of the unsettled climate at the time of the trial, also experienced and reported by other researchers. 19,215 Nevertheless, research should be conducted to explore how the processes of implementing RCTs in primary care can be practically facilitated, and how procedures may be standardised and streamlined. In addition, it is important for funders such as the HTA to commission studies using appropriate forms of assessment. RCTs may not always be the most suitable method, particularly in the initial stages of development for new and complex technologies.

The trial team developed innovative solutions to practical problems of implementation. This work illustrated the importance of social, as well as technical, competence in the delivery of a multicentred RCT. However, there is a significant gap in the literature exploring how RCTs are practically accomplished. While the process evaluation contributed towards addressing this shortfall, further research is needed to explore the practical conduct of RCTs in different contexts in order to better understand the processes underpinning the formation of medical evidence.

Conventionally, when a large project fails, stakeholders attempt to identify the causal factors for this outcome. However, in the LIFELAX RCT, there was no central agent of blame for the trial’s failure. A number of significant problems accumulated across the life of the research to prevent the RCT from moving forwards. These structural problems included the contemporaneous climate of uncertainty regarding interpretation of ethical and RM&G governance, changing priorities in primary care expressed though the GMS contract, and a general lack of enthusiasm or commitment for research in primary care. Specifically, the clinical environment in which the LIFELAX trial was situated was largely indifferent to the research. Although the trial team worked hard to develop workable solutions to these problems, the numerous and unforeseeable issues encountered by the trial team exhausted the capacity of LIFELAX to be a workable trial.

Pilot studies

At the time of commissioning, the HTA did not fund pilot studies. If a rehearsal (external) pilot trial or feasibility study had been conducted first then it is likely that the full LIFELAX trial would either never have been commissioned or if it had, it would have had a major methodological overhaul. We are pleased that pilot and feasibility studies are now part of the HTA commissioning process.

Choice of data collection methods

Our findings suggest that the range of data collection methods we employed in LIFELAX were acceptable for use in a population of this age with constipation. The self-completion questionnaire response rates in excess of 80% suggests that despite the length of the questionnaire, the time taken to complete it and the added burden of the daily diary, at the first two time points at least respondent fatigue was not an issue.

Analyses of the response rates and item response rates suggest that the daily diary was not troublesome to participants. We would propose that a diary of this nature to collect information about bowel function and medication is not burdensome to complete and is a satisfactory way of gathering such information.

Defining ‘eligibility’ for studies of constipation

The experiences of both the STOOL Trial19 and LIFELAX would suggest that being able to define ‘constipation’ in a way that is both measurable and acceptable to all stakeholders is vital to future research in this field. When people do not think that they have a particular condition then it seems unlikely that they would be interested in or motivated to participate in research into that condition.

Though a common complaint of industrialised societies,9 there is much variability in definition of constipation, both within the medical literature and between patients and medical professionals. 8 Some attempts as at a definition have used the frequency of bowel movements. 20,21 Clinical definitions do exist within the Rome II22 and III23 criteria for functional constipation.

In the Rome II criteria for functional constipation,22 two or more of the following symptoms must have present for at least 12 consecutive weeks in the previous 12 months for a diagnosis of constipation:

• straining in more than one in four defecations

• lumpy or hard stools in more than one in four defecations

• sensation of incomplete evacuation in more than one in four defecations

• manual procedures (e.g. digital evacuation or support of the pelvic floor) in more than one in four defecations; and

• fewer than three defecations per week.

In the Rome III criteria a somewhat less restrictive time frame has been introduced. 23

Practitioners, however, appear unlikely to apply the above criteria in their clinical practice and constipation is typically a subjective diagnosis. 18 Nonetheless, a level of consensus does exist among clinicians over the wide variation between individuals in the normal frequency of bowel movements (from three times per day to three times per week being normal). 12 The perceptions of older people reported by a small number of previous studies suggest that lay definitions of constipation differ from professional criteria. 14,16,17 From the STOOL report it is apparent that frequency and ‘ease’ of bowel movements, however, are key components of constipation for the majority of older people. 19

Our belief is that while there is such a lack of agreement – both within clinicians and patients, and between the two parties – as to what constipation is then recruiting to studies of ‘patients with chronic constipation’ will remain difficult. If objective criteria such as Rome II/III, or the number of laxatives prescribed in a given time frame are met with the circular argument from patients of ‘I take laxatives which produce my desired frequency of bowel movements, and therefore I am not constipated’ it would seem there is a hurdle that is particularly troublesome to overcome.

Difficulty implementing the LIFELAX trial

LIFELAX fulfilled all the criteria of a ‘marketable trial’. 232 LIFELAX was designed as a pragmatic113 three-armed cluster RCT to compare laxative treatment (current practice) of chronic constipation in older people with both standardised, non-personalised dietary and lifestyle advice (delivered in a single, short consultation) and personalised dietary and lifestyle advice (delivered in a long consultation, or two shorter consultations, with telephone reinforcement) in the management of chronic constipation in older people. LIFELAX was to be conducted in north-east England and was to recruit patients aged ≥ 55 years, registered with practices participating in the trial, with a current diagnosis of functional constipation.

Like the STOOL trial, LIFELAX was not successful in recruiting patients to the trial and experienced difficulty in encouraging general practices to fully engage with the research.

Though largely anecdotal and based upon the experiences and beliefs of the wider research team and collaborating GPs since the turn of the century, the climate of research has changed and there are now considerable barriers to complex trials of ‘routine’ interventions.

Ethics committees reacted (some would say over-reacted) to a number of landmark documents including the report of the Alder Hey enquiry,198 the European Human Rights Act199 (and its implementation) and preparation for the enactment of the EU Clinical Trials Directive. As a result, the guidelines to which ethics committees adhered became more prescriptive and committees became more risk aware and averse, and took measures to mitigate risk where possible. The publication of the Research Governance Framework for Health and Social Care200 created further challenges with guidance and decisions taken at a local level often appearing to be contradictory to national advice. Ethics committees and NHS Trusts, faced with the introduction of a more prescriptive and bureaucratic framework, were unable to respond to the increasing workload generated. Our experiences in these respects are echoed by other researchers conducting multicentre research involving primary care at a similar time. 201–203

In addition to the inevitable delays created by these developments, the necessity for participants to ‘opt in’ to LIFELAX and the apparent removal of direct contact with the research team until much later in the research process was one of the major issues of concern to both the research team and the TSC. This model has major implications for health services research in the future204 and by implementing such a model, one immediately decreases the likelihood of participation and increases the risk of participation bias. 205 Communication between a committed trial team and the participant is crucial to the success of a trial. Opportunities for those most familiar with the study design and processes (i.e. the research team) to explain the trial or discuss any aspect of participation diminish once the GP practice becomes the primary contact point for information in the early stages of the trial.

We are pleased that, since LIFELAX, many of the proposed measures to streamline the research process are slowly being implemented. The Integrated Research Application System is now running and continues to be revised. This will simplify the entire ethics and research governance approval process, especially for multicentre studies. The Research Passport (its imminent introduction was heralded during the set-up of LIFELAX), when available, will add to innovations such as the Central Sign-off Process for NHS R&D approval, and will hopefully further reduce the bureaucracy of the research process.

Insight from process evaluation

Through application of the NPM233 we were able to identify a number of factors that contributed to the premature closure of the LIFELAX RCT. However, it is important to note that within the constraints set by the commissioning brief – including the topic of the trial and nature of the interventions – the trial team could not have produced a successful outcome. Evaluation of this trial raises a number of important considerations for the deployment of other trials of complex interventions in primary care. In particular the bureaucratic difficulties encountered by the LIFELAX trial team, regarding the application of RM&G guidelines and research ethics, were indicative of the unsettled climate at the time of the trial, also experienced and reported by other researchers. 19,215 Nevertheless, research should be conducted to explore how the processes of implementing RCTs in primary care can be practically facilitated, and how procedures may be standardised and streamlined.

The trial team developed innovative solutions to practical problems of implementation. This work illustrated the centrality of socially-mediated processes across the lifespan of the RCT. There is a significant gap in the literature exploring how RCTs are practically accomplished. While the process evaluation contributed towards addressing this shortfall, further research is needed to explore the practical conduct of RCTs in different contexts in order to better understand the processes underpinning the formation of medical evidence.

Conventionally, when a large project fails, stakeholders attempt to identify the causal factors for this outcome. However, in the LIFELAX RCT, there was no central agent of blame for the trial’s failure. A number of significant problems accumulated across the life of the research to prevent the RCT from moving forward. These structural problems included the contemporaneous climate of uncertainty regarding ‘correct’ interpretation of ethical and RM&G governance, changing priorities in primary care expressed though the GMC contract, and a general lack of enthusiasm or commitment for research in primary care. Specifically, the clinical environment in which the LIFELAX trial was situated was largely indifferent to the research. Although the trial team worked hard to develop workable solutions to these problems, the numerous and unforeseeable issues encountered by the trial team exhausted the capacity of LIFELAX to be a workable trial.

Recommendations

The issues raised in this report are many and complex, some are condition and time bound (RM&G framework), and, as such, we are reluctant to make stringent recommendations as there may be little usefulness in doing so. However, there are a number of key learning points that we can highlight in the belief that these can be of use to researchers planning an RCT of a complex intervention in the future.

• Our experience suggests that the topic under investigation needs to be relevant to both the people delivering the intervention and those receiving the intervention.

• Rather than launching straight into conducting a full-scale intervention and trial, work needs to be undertaken to ascertain whether such a trial is feasible (we are pleased that pilot and feasibility studies are now part of the commissioning process for the HTA).

• The inclusion criteria need to be clear and comprehensible to both the people identifying participants and the participants themselves.

• If a ‘train-the-trainer’ approach is to be used for intervention delivery, there needs to be confidence that the trainees are fully supportive and motivated rather than participating because their institution has agreed to take part.

Although it is unclear whether ‘payment’ or financial incentives would make a future intervention a success, attention needs to be paid to the current funding arrangements and priority topic areas for the health-care practitioners with whom researchers will be working. Topics within the QOF have a much higher profile, interest and importance.

Contribution of authors and other team members

Publications

Lake A. Constipation in the older patient. Com Nutr 2004;4:23–5.

Lake A, Speed C, Brookes A, Heaven B, Adamson AJ, Moynihan P, et al. Development of a series of PILs for constipation using a range of cognitive interview techniques: LIFELAX. BMC Health Serv Res 2007;7:3.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Health Technology Assessment reports published to date

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   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

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8. Preschool vision screening.

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9. Implications of socio-cultural contexts for the ethics of clinical trials.

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10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

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12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

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    By Petticrew M, Watt I, Sheldon T.

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    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

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2. Screening for ovarian cancer: a systematic review.

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   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

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5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

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6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

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7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

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   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

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10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

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11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

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17. The costs and benefits of paramedic skills in pre-hospital trauma care.

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18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

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19. Systematic reviews of trials and other studies.

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20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

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   A review by Briggs AH, Gray AM.

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9. A review of the use of health status measures in economic evaluation.

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    A review by Robert G, Milne R.

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    By O’Meara S, Cullum N, Majid M, Sheldon T.

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    By Williams JE, Louw G, Towlerton G.

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    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Riemsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA, Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant LD, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost-effectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

39. Psychological interventions for postnatal depression: cluster randomised trial and economic evaluation. The PoNDER trial.

    By Morrell CJ, Warner R, Slade P, Dixon S, Walters S, Paley G, et al.

40. The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

    By Rogowski R, Burch J, Palmer S, Craigs C, Golder S, Woolacott N.

41. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care.

    By Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al.

42. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

    By Gray AJ, Goodacre S, Newby DE, Masson MA, Sampson F, Dixon S, et al. , on behalf of the 3CPO study investigators.

43. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

    By Ara R, Pandor A, Stevens J, Rees A, Rafia R.

44. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation.

    By Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, et al.

45. Methods to identify postnatal depression in primary care: an integrated evidence synthesis and value of information analysis.

    By Hewitt CE, Gilbody SM, Brealey S, Paulden M, Palmer S, Mann R, et al.

46. A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care.

    By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

47. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

    By Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R.

48. Rehabilitation of older patients: day hospital compared with rehabilitation at home. A randomised controlled trial.

    By Parker SG, Oliver P, Pennington M, Bond J, Jagger C, Enderby PM, et al.

49. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

    By Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.

50. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation.

    By Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al.

51. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness.

    By Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al.

52. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al.

53. The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.

    By Bond M, Mealing S, Anderson R, Elston J, Weiner G, Taylor RS, et al.

54. Gemcitabine for the treatment of metastatic breast cancer.

    By Jones J, Takeda A, Tan SC, Cooper K, Loveman E, Clegg A.

55. Varenicline in the management of smoking cessation: a single technology appraisal.

    By Hind D, Tappenden P, Peters J, Kenjegalieva K.

56. Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal.

    By Lloyd Jones M, Holmes M.

57. Rituximab for the treatment of rheumatoid arthritis.

    By Bagust A, Boland A, Hockenhull J, Fleeman N, Greenhalgh J, Dundar Y, et al.

58. Omalizumab for the treatment of severe persistent allergic asthma.

    By Jones J, Shepherd J, Hartwell D, Harris P, Cooper K, Takeda A, et al.

59. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma.

    By Boland A, Bagust A, Hockenhull J, Davis H, Chu P, Dickson R.

60. Adalimumab for the treatment of psoriasis.

    By Turner D, Picot J, Cooper K, Loveman E.

61. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

    By Holmes M, C Carroll C, Papaioannou D.

62. Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

    By Mowatt G, Boachie C, Crowther M, Fraser C, Hernández R, Jia X, et al.

63. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    By Bond M, Hoyle M, Moxham T, Napier M, Anderson R.

64. Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

    By Stevenson M, Lloyd-Jones M, Papaioannou D.

65. The effects of biofeedback for the treatment of essential hypertension: a systematic review.

    By Greenhalgh J, Dickson R, Dundar Y.

66. A randomised controlled trial of the use of aciclovir and/or prednisolone for the early treatment of Bell’s palsy: the BELLS study.

    By Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al.

67. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    By Jones J, Takeda A, Picot J, von Keyserlingk C, Clegg A.

68. Infliximab for the treatment of ulcerative colitis.

    By Hyde C, Bryan S, Juarez-Garcia A, Andronis L, Fry-Smith A.

69. Rimonabant for the treatment of overweight and obese people.

    By Burch J, McKenna C, Palmer S, Norman G, Glanville J, Sculpher M, et al.

70. Telbivudine for the treatment of chronic hepatitis B infection.

    By Hartwell D, Jones J, Harris P, Cooper K.

71. Entecavir for the treatment of chronic hepatitis B infection.

    By Shepherd J, Gospodarevskaya E, Frampton G, Cooper K.

72. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal.

    By Stevenson M, Pandor A.

73. Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

    By Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E.

74. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

    By Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al.

75. Mifamurtide for the treatment of osteosarcoma: a single technology appraisal.

    By Pandor A, Fitzgerald P, Stevenson M, Papaioannou D.

76. Ustekinumab for the treatment of moderate to severe psoriasis.

    By Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A.

77. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

    By Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al.

78. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

    By Chen Y-F, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JSR, et al.

79. Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY) – a pharmacoepidemiological and qualitative study.

    By Wong ICK, Asherson P, Bilbow A, Clifford S, Coghill D, R DeSoysa R, et al.

80. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

    By Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al.

81. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation.

    By Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z, et al.

82. Randomised preference trial of medical versus surgical termination of pregnancy less than 14 weeks’ gestation (TOPS).

    By Robson SC, Kelly T, Howel D, Deverill M, Hewison J, Lie MLS, et al.

83. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

    By Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al.

84. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

    By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al.

85. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial.

    By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, Shackley P, et al.

86. Communication of carrier status information following universal newborn screening for sickle cell disorders and cystic fibrosis: qualitative study of experience and practice.

    By Kai J, Ulph F, Cullinan T, Qureshi N.

87. Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation.

    By Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al.

88. Development of a toolkit and glossary to aid in the adaptation of health technology assessment (HTA) reports for use in different contexts.

    By Chase D, Rosten C, Turner S, Hicks N, Milne R.

89. Colour vision testing for diabetic retinopathy: a systematic review of diagnostic accuracy and economic evaluation.

    By Rodgers M, Hodges R, Hawkins J, Hollingworth W, Duffy S, McKibbin M, et al.

90. Systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives: a short report.

    By Bond M, Wyatt K, Lloyd J, Welch K, Taylor R.

91. Are adverse effects incorporated in economic models? An initial review of current practice.

    By Craig D, McDaid C, Fonseca T, Stock C, Duffy S, Woolacott N.

1. Multicentre randomised controlled trial examining the cost-effectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE).

   By Turnbull LW, Brown SR, Olivier C, Harvey I, Brown J, Drew P, et al.

2. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation.

   By Thompson Coon J, Hoyle M, Green C, Liu Z, Welch K, Moxham T, et al.

3. The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation.

   By Fleeman N, McLeod C, Bagust A, Beale S, Boland A, Dundar Y, et al.

4. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

   By Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TRL, et al.

5. Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

   By Campbell MK, Skea ZC, Sutherland AG, Cuthbertson BH, Entwistle VA, McDonald AM, et al.

6. A randomised 2 × 2 trial of community versus hospital pulmonary rehabilitation for chronic obstructive pulmonary disease followed by telephone or conventional follow-up.

   By Waterhouse JC, Walters SJ, Oluboyede Y, Lawson RA.

7. The effectiveness and cost-effectiveness of behavioural interventions for the prevention of sexually transmitted infections in young people aged 13–19: a systematic review and economic evaluation.

   By Shepherd J, Kavanagh J, Picot J, Cooper K, Harden A, Barnett-Page E, et al.

8. Dissemination and publication of research findings: an updated review of related biases.

   By Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al.

9. The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.

   By Hemingway H, Henriksson M, Chen R, Damant J, Fitzpatrick N, Abrams K, et al.

10. Comparison of case note review methods for evaluating quality and safety in health care.

    By Hutchinson A, Coster JE, Cooper KL, McIntosh A, Walters SJ, Bath PA, et al.

11. Clinical effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes: systematic review and economic evaluation.

    By Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, et al.

12. Self-monitoring of blood glucose in type 2 diabetes: systematic review.

    By Clar C, Barnard K, Cummins E, Royle P, Waugh N.

13. North of England and Scotland Study of Tonsillectomy and Adeno-tonsillectomy in Children (NESSTAC): a pragmatic randomised controlled trial with a parallel non-randomised preference study.

    By Lock C, Wilson J, Steen N, Eccles M, Mason H, Carrie S, et al.

14. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.

    By Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FGR, Gillespie I, et al.

15. A randomised controlled multicentre trial of treatments for adolescent anorexia nervosa including assessment of cost-effectiveness and patient acceptability – the TOuCAN trial.

    By Gowers SG, Clark AF, Roberts C, Byford S, Barrett B, Griffiths A, et al.

16. Randomised controlled trials for policy interventions: a review of reviews and meta-regression.

    By Oliver S, Bagnall AM, Thomas J, Shepherd J, Sowden A, White I, et al.

17. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review.

    By McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N.

18. A systematic review of outcome measures used in forensic mental health research with consensus panel opinion.

    By Fitzpatrick R, Chambers J, Burns T, Doll H, Fazel S, Jenkinson C, et al.

19. The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation.

    By Loveman E, Jones J, Hartwell D, Bird A, Harris P, Welch K, et al.

20. Antenatal screening for haemoglobinopathies in primary care: a cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial.

    By Dormandy E, Bryan S, Gulliford MC, Roberts T, Ades T, Calnan M, et al.

21. Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.

    By Black C, Sharma P, Scotland G, McCullough K, McGurn D, Robertson L, et al.

22. A randomised controlled trial of cognitive behaviour therapy and motivational interviewing for people with Type 1 diabetes mellitus with persistent sub-optimal glycaemic control: A Diabetes and Psychological Therapies (ADaPT) study.

    By Ismail K, Maissi E, Thomas S, Chalder T, Schmidt U, Bartlett J, et al.

23. A randomised controlled equivalence trial to determine the effectiveness and cost–utility of manual chest physiotherapy techniques in the management of exacerbations of chronic obstructive pulmonary disease (MATREX).

    By Cross J, Elender F, Barton G, Clark A, Shepstone L, Blyth A, et al.

24. A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.

    By McKenna C, Burch J, Suekarran S, Walker S, Bakhai A, Witte K, et al.

25. Avoiding and identifying errors in health technology assessment models: qualitative study and methodological review.

    By Chilcott JB, Tappenden P, Rawdin A, Johnson M, Kaltenthaler E, Paisley S, et al.

26. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A.

    By Shaw L, Rodgers H, Price C, van Wijck F, Shackley P, Steen N, et al. , on behalf of the BoTULS investigators.

27. Weighting and valuing quality-adjusted life-years using stated preference methods: preliminary results from the Social Value of a QALY Project.

    By Baker R, Bateman I, Donaldson C, Jones-Lee M, Lancsar E, Loomes G, et al.

28. Cetuximab for the first-line treatment of metastatic colorectal cancer.

    By Meads C, Round J, Tubeuf S, Moore D, Pennant M, Bayliss S.

29. Infliximab for the treatment of acute exacerbations of ulcerative colitis.

    By Bryan S, Andronis L, Hyde C, Connock M, Fry-Smith A, Wang D.

30. Sorafenib for the treatment of advanced hepatocellular carcinoma.

    By Connock M, Round J, Bayliss S, Tubeuf S, Greenheld W, Moore D.

31. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

    By Jones J, Colquitt J, Shepherd J, Harris P, Cooper K.

32. Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

    By Greenhalgh J, Bagust A, Boland A, Saborido CM, Fleeman N, McLeod C, et al.

33. Alitretinoin for the treatment of severe chronic hand eczema.

    By Paulden M, Rodgers M, Griffin S, Slack R, Duffy S, Ingram JR, et al.

34. Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

    By Fleeman N, Bagust A, McLeod C, Greenhalgh J, Boland A, Dundar Y, et al.

35. Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix.

    By Paton F, Paulden M, Saramago P, Manca A, Misso K, Palmer S, et al.

36. Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

    By Simpson EL, Rafia R, Stevenson MD, Papaioannou D.

37. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

    By Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, et al.

38. The safety and effectiveness of different methods of earwax removal: a systematic review and economic evaluation.

    By Clegg AJ, Loveman E, Gospodarevskaya E, Harris P, Bird A, Bryant J, et al.

39. Systematic review of the clinical effectiveness and cost-effectiveness of rapid point-of-care tests for the detection of genital chlamydia infection in women and men.

    By Hislop J, Quayyum Z, Flett G, Boachie C, Fraser C, Mowatt G.

40. School-linked sexual health services for young people (SSHYP): a survey and systematic review concerning current models, effectiveness, cost-effectiveness and research opportunities.

    By Owen J, Carroll C, Cooke J, Formby E, Hayter M, Hirst J, et al.

41. Systematic review and cost-effectiveness evaluation of ‘pill-in-the-pocket’ strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy.

    By Martin Saborido C, Hockenhull J, Bagust A, Boland A, Dickson R, Todd D.

42. Chemoprevention of colorectal cancer: systematic review and economic evaluation.

    By Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF, et al.

43. Cross-trimester repeated measures testing for Down’s syndrome screening: an assessment.

    By Wright D, Bradbury I, Malone F, D’Alton M, Summers A, Huang T, et al.

44. Exploring the needs, concerns and behaviours of people with existing respiratory conditions in relation to the H1N1 ‘swine influenza’ pandemic: a multicentre survey and qualitative study.

    By Caress A-L, Duxbury P, Woodcock A, Luker KA, Ward D, Campbell M, et al.

45. Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant.

    By Yates L, Pierce M, Stephens S, Mill AC, Spark P, Kurinczuk JJ, et al.

46. The impact of communications about swine flu (influenza A H1N1v) on public responses to the outbreak: results from 36 national telephone surveys in the UK.

    By Rubin GJ, Potts HWW, Michie S.

47. The impact of illness and the impact of school closure on social contact patterns.

    By Eames KTD, Tilston NL, White PJ, Adams E, Edmunds WJ.

48. Vaccine effectiveness in pandemic influenza – primary care reporting (VIPER): an observational study to assess the effectiveness of the pandemic influenza A (H1N1)v vaccine.

    By Simpson CR, Ritchie LD, Robertson C, Sheikh A, McMenamin J.

49. Physical interventions to interrupt or reduce the spread of respiratory viruses: a Cochrane review.

    By Jefferson T, Del Mar C, Dooley L, Ferroni E, Al-Ansary LA, Bawazeer GA, et al.

50. Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR).

    By Peek GJ, Elbourne D, Mugford M, Tiruvoipati R, Wilson A, Allen E, et al.

51. Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation.

    By Waugh N, Cummins E, Royle P, Clar C, Marien M, Richter B, et al.

52. Barrett’s oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin.

    By Fayter D, Corbett M, Heirs M, Fox D, Eastwood A.

53. Towards single embryo transfer? Modelling clinical outcomes of potential treatment choices using multiple data sources: predictive models and patient perspectives.

    By Roberts SA, McGowan L, Hirst WM, Brison DR, Vail A, Lieberman BA.

54. Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment.

    By Chambers D, Paulden M, Paton F, Heirs M, Duffy S, Craig D, et al.

55. Systematic review and economic modelling of the effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence.

    By Imamura M, Abrams P, Bain C, Buckley B, Cardozo L, Cody J, et al.

56. A multicentred randomised controlled trial of a primary care-based cognitive behavioural programme for low back pain. The Back Skills Training (BeST) trial.

    By Lamb SE, Lall R, Hansen Z, Castelnuovo E, Withers EJ, Nichols V, et al.

57. Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.

    By Takeda A, Cooper K, Bird A, Baxter L, Frampton GK, Gospodarevskaya E, et al.

58. A pragmatic randomised controlled trial to compare antidepressants with a community-based psychosocial intervention for the treatment of women with postnatal depression: the RESPOND trial.

    By Sharp DJ, Chew-Graham C, Tylee A, Lewis G, Howard L, Anderson I, et al.

59. Group cognitive behavioural therapy for postnatal depression: a systematic review of clinical effectiveness, cost-effectiveness and value of information analyses.

    By Stevenson MD, Scope A, Sutcliffe PA, Booth A, Slade P, Parry G, et al.

60. Screening for hyperglycaemia in pregnancy: a rapid update for the National Screening Committee.

    By Waugh N, Royle P, Clar C, Henderson R, Cummins E, Hadden D, et al.

61. Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03B/oil-in-water emulsion-adjuvanted (AS03B) split-virion versus non-adjuvanted wholevirion H1N1 influenza vaccine in UK children 6 months to 12 years of age.

    By Waddington CS, Andrews N, Hoschler K, Walker WT, Oeser C, Reiner A, et al.

62. Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and chest physiotherapy in clinical practice: implications for management of pandemic influenza and other airborne infections.

    By Simonds AK, Hanak A, Chatwin M, Morrell MJ, Hall A, Parker KH, et al.

63. Evaluation of triage methods used to select patients with suspected pandemic influenza for hospital admission: cohort study.

    By Goodacre S, Challen, K, Wilson R, Campbell M.

64. Virus shedding and environmental deposition of novel A (H1N1) pandemic influenza virus: interim findings.

    By Killingley B, Greatorex J, Cauchemez S, Enstone JE, Curran M, Read R, et al.

65. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: a Cochrane review.

    By Jefferson T, Jones M, Doshi P, Del Mar C, Dooley L, Foxlee R.

66. Intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation.

    By Hummel S, Simpson EL, Hemingway P, Stevenson MD, Rees A.

67. Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems.

    By Main C, Moxham T, Wyatt JC, Kay J, Anderson R, Stein K.

68. Relapse prevention in UK Stop Smoking Services: current practice, systematic reviews of effectiveness and cost-effectiveness analysis.

    By Coleman T, Agboola S, Leonardi-Bee J, Taylor M, McEwen A, McNeill A.

69. A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence.

    By Pennant M, Takwoingi Y, Pennant L, Davenport C, Fry-Smith A, Eisinga A, et al.

70. Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis.

    By Connock M, Tubeuf S, Malottki K, Uthman A, Round J, Bayliss S, et al.

71. Capecitabine for the treatment of advanced gastric cancer.

    By Norman G, Soares M, Peura P, Rice S, Suh D, Wright K, et al.

72. Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia.

    By Dretzke J, Barton P, Kaambwa B, Connock M, Uthman O, Bayliss S, et al.

73. The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.

    By Main C, Pitt M, Moxham T, Stein K.

74. Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer.

    By Greenhalgh J, McLeod C, Bagust A, Boland A, Fleeman N, Dundar Y, et al.

75. Everolimus for the second-line treatment of advanced and/or metastatic renal cell cancer: a critique of the submission from Novartis.

    By Pitt M, Crathorne L, Moxham T, Bond M, Hyde C.

76. Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer.

    By Whyte S, Pandor A, Stevenson M, Rees A.

77. Dronedarone for the treatment of atrial fibrillation and atrial flutter.

    By Maund E, McKenna C, Sarowar M, Fox D, Stevenson M, Pepper C, et al.

78. Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours.

    By Dretzke J, Round J, Connock M, Tubeuf S, Pennant M, Fry-Smith A, et al.

79. Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

    By Brown T, Boland A, Bagust A, Oyee J, Hockenhull J, Dundar Y, et al.

80. Systematic review of the links between human resource management practices and performance.

    By Patterson M, Rick J, Wood S, Carroll C, Balain S, Booth A.

Health Technology Assessment programme

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Director, Medical Care Research Unit, University of Sheffield