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)

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 03/48/01. The contractual start date was in July 2005. The draft report began editorial review in November 2008 and was accepted for publication in August 2009. 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

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Clinical background

The commissioned research

It was against this background that the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme sought to commission a new RCT of the effectiveness and cost-effectiveness of arthroscopic lavage for the treatment of patients with osteoarthritis of the knee. Given the widespread use, high cost and uncertain effectiveness of arthroscopic lavage for osteoarthritis of the knee, there was a clear need for further robust research if future policy and practice relating to the use of this intervention were to be based on reliable evidence. Given the results of the Moseley trial, the HTA programme sought to commission a similar placebo-controlled trial of arthroscopic lavage in the UK.

Recognising that there may be potential difficulties in mounting a placebo-controlled surgical trial (in terms of perceived acceptability of such a trial design), the HTA programme commissioned the research with an integrated, but discrete, feasibility study. Progression to a full-scale placebo-controlled trial would only go ahead if the feasibility study showed that this was appropriate. For a full-scale trial to be conducted successfully in the UK, it would be necessary to identify enough surgical teams willing to deliver arthroscopic lavage (and a placebo version of it) in the context of a randomised trial, and to be confident that a sufficient proportion of eligible patients would, when well informed, be willing to take part in such a trial.

This monograph presents the findings of the feasibility study.

The research project

Reflecting the commissioning brief, the feasibility study – known as KORAL (Knee Osteoarthritis: the Role of Arthroscopic Lavage) – developed in four distinct phases:

• Formal exploration of the acceptability of a placebo-controlled trial – the aim of this phase was to ascertain the acceptability of a proposed RCT comparing arthroscopic lavage with a placebo surgical procedure for the management of osteoarthritis of the knee to key stakeholder groups. This involved four components: focus groups with health professionals; focus groups (and interviews) with potential participants; interviews with chairpersons of the UK Multicentre Research Ethics Committees (MRECs); and, surveys of surgeons and anaesthetists.

• Obtaining ethics approval to mount a pilot RCT – having identified the components of a possible placebo procedure, we sought ethics approval to conduct a formal pilot study to assess the full feasibility of mounting a multicentre placebo-controlled trial to evaluate the effectiveness of arthroscopic lavage for osteoarthritis of the knee. As it sought to reflect the design of a full trial, the pilot was to include full consent and randomisation to a placebo surgical arm. This raised a number of significant ethical issues.

• The formal pilot – the aim of the pilot study was to assess the practical feasibility of mounting a multicentre placebo-controlled trial to evaluate the effectiveness of arthroscopic lavage for osteoarthritis of the knee. This included assessing the acceptability of proposed trial processes to patients and staff, to estimate the proportion of patients who would accept randomisation to the trial, and to examine the acceptability of the trial information material to patients. The pilot was designed as a two-centre, three-arm trial of: a) arthroscopic lavage (with or without debridement at the clinical discretion of the surgeon); b) placebo surgery; and c) non-operative (i.e. medical) management with specialist reassessment.

• The decision-making process as to whether to progress to full trial – based on the insights gained from the previous three phases and from external evidence, a decision was made jointly with the HTA programme on whether a full placebo-controlled trial should be mounted.

At the start of the project, the KORAL team convened a study day for the grant applicants, project staff and invited experts to further develop the study protocol. This study day (held in March 2005) benefited significantly from a presentation and discussion by Dr Nelda Wray, who was the chief investigator (and Dr Carol Ashton, a co-investigator) of the Moseley trial. 24 Professor Paul Dieppe (an acknowledged UK expert on osteoarthritis) also contributed.

The four phases of the feasibility study are described in Chapters 2–5. In Chapter 6, the implications of the project are discussed as a whole, finishing with a summary of the implications for practice and recommendations for further research.

Aim

The aim of this first phase of the research was to ascertain the acceptability of a proposed RCT comparing arthroscopic lavage with a placebo surgical procedure for the management of osteoarthritis of the knee to key stakeholder groups (in particular surgeons, anaesthetists, prospective participants and members of research ethics committees).

Objectives

• To ascertain what is the range of placebo procedures that could be considered for a trial comparing arthroscopic lavage with a placebo procedure.

• To describe the attitude of important stakeholder groups (in particular, surgeons, anaesthetists, prospective participants and members of ethics committees) to the use of a placebo procedure in the proposed evaluation.

• To clarify whether attitudes to the proposed trial differ depending on the type of placebo proposed and/or key trial design features.

This initial phase of research comprised four main components that sequentially allowed us to build a picture of the likely acceptability of a trial to evaluate the effectiveness of arthroscopic lavage in comparison with a placebo procedure:

• Component 1: Focus groups with health professionals – we conducted exploratory focus groups with health-professional stakeholders (surgeons and anaesthetists) to identify the range of placebo procedures that may be used, and to appraise their strengths and weaknesses from a clinical perspective.

• Component 2: Focus group and interviews with people with osteoarthritis – we also conducted exploratory focus groups and interviews with people with osteoarthritis of the knee to allow us to identify the types of judgements, beliefs and attitudes (including concern) that patients and prospective trial participants may hold in relation to a proposed trial; to identify features of the placebo procedure and trial design that could enhance the acceptability of the trial to potential participants; and to test and refine an initial draft of written information for potential participants. (The initial draft was developed taking into account the views expressed by the surgeons and anaesthetists on the most appropriate form of placebo surgery. It was designed with input from Arthritis Care.)

• Component 3: Interviews with chairpersons of UK MRECs – chairpersons of MRECs were interviewed by telephone. Their opinions were sought on the ethical issues raised by the research proposal. Twelve ethics committee chairpersons were invited to take part in the research.

• Component 4: Surveys of health professionals – Postal surveys of orthopaedic surgeons (all members of the British Association of Surgeons of the Knee; BASK) and anaesthetists (all members of the British Society of Orthopaedic Anaesthetists; BSOA) were conducted. The aim of these surveys was to investigate the distribution of attitudes towards the proposed trial and ascertain rates of expressed willingness among these groups to support the trial in their professional capacity.

The methods and findings of each component are described in separate sections below.

Full MREC approval was received for this phase of the study. To preserve independence with regard to any future ethics decisions about KORAL, the chairperson of the MREC who approved this part of the study was not interviewed for Component 3 of the study.

Component 1A – Focus groups with health professionals: the orthopaedic surgeons

Component 1B – Focus groups with health professionals: the anaesthetists

Component 2 – Focus group and interviews with people with osteoarthritis

Component 3 – Interviews with chairpersons of the UK Multicentre Research Ethics Committees

Component 4 – Surveys of health professionals

Comments on the acceptability phase

The findings from the acceptability phase of our study have shed light on the views of key stakeholder groups (including surgeons, anaesthetists, prospective participants and members of research ethics committees). The following is an overview of the key findings from both within and across the stakeholder groups.

Strengths of the acceptability phase of our study

Although we accessed the in-depth views of a relatively small number of stakeholders within the qualitative component of the acceptability phase of our study, we nevertheless gained valuable access to the multiple perspectives of a range of key people. The survey provided information about the views of larger numbers of surgeons and anaesthetists. As borne out by MREC chairpersons’ comments, by involving all key stakeholders early in the planning of such a trial we were able to explore important issues relating to: attitudes to the use of a placebo procedure in the proposed evaluation; the range of placebo procedures that could be considered for a trial comparing arthroscopic lavage with a placebo procedure; whether attitudes to the proposed trial differ depending on the type of placebo proposed and/or key trial design features; and initial suggestions for ensuring recruitment and other procedures are appropriate from a participant perspective.

Potential limitations of the acceptability phase of our study

Facts and arguments incorporated into our initial slide presentations (which were delivered at the start of focus groups) and our information leaflets about the acceptability phase (which were sent out to interviewees) were drawn on by several participants in subsequent discussions, and may have influenced the nature of stakeholders’ views. In addition, the KORAL clinicians who assisted in the facilitation of the health professional focus groups played an active part in discussions and may have influenced what other participants felt able and/or willing to say. However, we were careful to provide a balanced overview and to stress that we wanted to investigate whether, and why, a placebo-controlled trial would (or would not) be acceptable. Practical considerations led us to hold focus group discussions in centres where KORAL clinicians worked and at conferences where members of the relevant professional groups were already convened. We had little control over, and did not monitor, the extent to which participants represented clinicians with particular demographic, professional or work situation characteristics. However, this seems unlikely to have impaired our ability to identify the key issues relating to the proposed trial for health professionals. Within the focus groups and interviews a range of different views were expressed and there was often disagreement within the groups, particularly around the key ethical issues of our proposed trial.

Despite setting out to purposively select our sample for the patient interviews and focus groups, there was, inevitably, an element of convenience (or ‘opportunistic’) sampling in our study in that ultimately we had no control over who agreed to be interviewed from our initial sampling ‘framework’. It is possible that this may have influenced our findings; for example, responders’ views may have differed from those of non-responders. For example, our sample was generally positive with regard to the rationale for the proposed trial (with most stating that they would consider taking part) and the views of non-responders may have differed. However, we were reassured that despite the general acceptance of the need to find out more, there was variation in opinion within our patient group about how researchers should approach this and about whether or not it would be acceptable to investigate the effectiveness of arthroscopic lavage using placebo surgery (and a minority stated that they would be unwilling to take part for a variety of reasons).

We also observed relatively low response rates to our surveys (45% to the surgeon survey and 34% to the anaesthetist survey). It is possible that those who were particularly interested in the topic responded; however, we were reassured by the fact that a range of opinions was expressed (both positively and negatively) in the questionnaire responses. It is often the case that response rates to surveys of health professionals are low;50 in our case, this was not helped by the fact that only single mailings were authorised by the professional bodies, so we could not send out reminders about the questionnaire.

We also asked people to discuss a hypothetical trial. It is possible to speculate that views might have differed if stakeholders had been invited to enter and/or comment on a real trial involving placebo surgery. However, for reasons outlined above, the value of accessing opinions about key elements of the trial before actually proceeding is that researchers can attempt to ensure that the real trial is as acceptable as possible to prospective participants.

Ethical debate around placebo-controlled trials

The ethical aspects of placebo controls have been under intense global scrutiny in recent years. Following lengthy deliberation, both the World Medical Association and the Council of International Organisations of Medical Sciences have revised their guidance regarding placebo use in the past decade. Most of the debate has been around the question of whether it is ever acceptable to assign research participants to receive a placebo when a proven active treatment exists. In the context of the KORAL study, the evidence presented in the early chapters of this document showed that considerable debate remains as to the effectiveness of arthroscopic lavage for osteoarthritis of the knee and, therefore, that it cannot be described as proven active treatment. However, whilst it could be argued that this ethical question does not apply to the KORAL study, we recognised that it would be naive not to take account of the recent intense scrutiny of the ethics of placebo controls.

There has also been considerable debate in the literature as to the ethical acceptability of using placebo procedures in surgery. The use of a placebo in an non-pharmacological context is not new – as early as 1959, a placebo procedure was used in a trial of internal mammary artery ligation for angina pectoris where, in a trial of 17 participants, eight participants had their arteries tied (the Fieschi technique) and the other nine underwent only surgical incisions. 51 There was also a series of placebo-controlled trials of electro-convulsive therapy (ECT) in the late 1970s and early 1980s which compared active ECT with simulated treatment. 52–56 Patients in the simulated ECT groups received identical anaesthetic regimens to those receiving ‘active’ ECT.

The most recent debate on the ethics of placebo surgery was largely triggered by the Moseley trial,24 as described earlier, and trials of cellular-based therapies for Parkinson’s disease. 57,58 In the Parkinson’s trials those patients allocated to the placebo intervention had burr holes drilled in the frontal bone of the skull, but not penetrating the inner cortex of the skull. The principal areas of debate have been around whether placebo surgery fulfils two main ethical requirements for research: (1) that risks to participants are minimised; and (2) that risks to participants are reasonable in relation to anticipated benefits. 59

Several commentators have argued that placebo procedures are ethical for certain trials of surgery60 and have identified the Moseley trial as an exemplar of good practice in this field. 61–64 The main components of their arguments are that:

• Clinical trials are not designed to promote the medical best interests of enrolled patients, and often expose them to risks that are not outweighed by known medical benefits – accordingly the use of placebo surgery must be evaluated in terms of the ethical principles appropriate to clinical research.

• Surgical procedures of unproven benefit that are currently in routine use also pose a risk to patients.

• Placebo controls are especially appropriate for the evaluation of surgical innovation that has not previously been associated with robust scientific validation and where subjective symptoms of the patient are relied upon as outcome measures.

Others have argued strongly, however, that the use of placebo procedures cannot be justified in the surgical setting, as any surgical procedure carries risks of harm that are greater than those associated with no surgical interventions, – i.e. it fails to fulfil the criterion that risks to participants are minimised. 65,66

The most comprehensive consensus statement relating to the use of placebo surgery in research contexts was issued by the American Medical Association (AMA). 67 They suggested that four criteria should be met. In summary, these are that:

1. Surgical ‘placebo’ controls should be used only when no other trial design will yield the requisite data.

2. Particular attention must be paid to the informed consent process when enrolling participants in trials that use surgical ‘placebo’ controls.

3. The use of surgical ‘placebo’ controls may be justified when an existing, accepted surgical procedure is being tested for efficacy. It is not justified when testing the effectiveness of an innovative surgical technique that represents only a minor modification of an existing, accepted surgical procedure.

4. When a new surgical procedure is developed with the prospect of treating a condition for which no known surgical therapy exists, using surgical ‘placebo’ controls may be justified, but must be evaluated in light of whether the current standard of care includes a non-surgical treatment and the benefits, risks and side effects of that treatment.

Ethical issues specific to the KORAL study

The term ‘placebo’ is the common label used to describe any substance or procedure a patient accepts as medicine or therapy, but which has no known therapeutic activity. These ‘placebos’ can, therefore, describe a wide spectrum of substances and therapies from completely inert substances (such as a dummy pill) or more ‘active’ placebo procedures (such as the placebo procedure described in the KORAL study) when there are no inert procedures available to mimic the active intervention. These more ‘active’ placebos are designed to mimic the range of non-specific effects (both beneficial and detrimental) experienced by the patient whilst undergoing the active intervention.

For the KORAL study, therefore, this raised the question of whether the use of an ‘active’ placebo – placebo surgery in this instance – was ethical in this specific situation. On initial consideration, this approach would seem to violate the principle of non-maleficence (i.e. do no harm). On deeper examination of the issues, however, the situation is more complex. In this instance, not conducting the proposed trial also risks one of two further types of harm: dispensing with what is in fact an effective treatment or continuing to offer what is in fact an ineffective surgical procedure (and thus violating the principle of beneficence).

In medical practice, there is often a trade-off between short-term harms with the prospect of a longer term gain – for example, even a simple venepuncture is not without risk – but the risk is accepted if the importance of the test result outweighs the potential harm done. However, this short-term risk is accepted by the actual individual for his or her own longer term benefit, and much of the ethical complexity around the entire field of research ethics centres around the fact that this one-to-one relationship between persons accepting risk of harm and persons hoping for benefit is not necessarily direct. Rather, the weighing up of benefits and risks is done across a group of people. In the KORAL study, we were required to weigh up whether someone who is potentially not the direct beneficiary could reasonably be asked to take the risk related to placebo surgery. The project team believed that, in this case, it was reasonable. This judgement was based primarily on two main arguments:

1. The nature of the condition: Osteoarthritis is a chronic and generally progressive, or at least recurring, condition. Whilst there is no guarantee that an individual would directly benefit from the answers this study aimed to achieve, there was a reasonable likelihood he or she would benefit over the longer term. He or she would in future have the opportunity to receive the active treatment (if it were shown to be effective) or to not have an ineffective form of surgical intervention offered. As patients often live with the consequences of osteoarthritis for many years it can reasonably be anticipated that a sizeable proportion of the trial participants could potentially benefit from the results of this trial.

2. The results of the KORAL acceptability phase: The empirical findings from the acceptability phase of our study (see Chapter 2) indicated that such a study design was indeed acceptable to many of the patient group who would qualify for inclusion in the trial. These results, which appeared to suggest that patients were more likely to give a favourable view of the proposed design than surgeons or anaesthetists, were a powerful argument in favour of the study. In such a situation, it could even be argued that not to proceed to trial would be unacceptably paternalistic given these results. This needs to be tempered, however, with some thoughts as to why the patients appeared to find the study more acceptable than the relevant clinicians. The clinicians, whilst appreciating that the risks of an individual procedure may be low were much more likely than any individual patient to have encountered the more extreme consequences of what can go wrong, even with what appears to be a low-risk procedure (for example, life-threatening adverse events or severe wound infections unexpectedly arising in such circumstances). Therefore, the recourse to the immediate conclusion that this represents paternalism is not straightforward and should be tempered by the reasonable impact of professional experience and expertise. However, the fact that, in the KORAL study, there was a reasonable degree of acceptance among surgeons and anaesthetists that the trial did not ask for an unethical level of risk in proportion to the potential benefits of the trial was important.

These arguments, therefore, formed the basis on which the study team believed it was ethical to consider undertaking this research, and formed the basis for their formal application for ethics approval for a formal pilot study of the trial.

Whilst it was not used as an ethical argument, the fact that all groups in the Moseley trial (including the placebo group) reported significant symptom improvement after the procedure also provided some empirical evidence that, in this specific setting, patients might experience benefit from participation in the trial (although the mechanism of that benefit was not fully understood).

The principles of independent ethical review

Before we formally describe the ethics process for the KORAL study, it is useful to revisit the underlying importance of such an independent ethical review, as it provides important contextual information against which the experience of the KORAL study is interpreted (however, those with expert knowledge of this field may choose to move directly to the description of the KORAL experience below). Even with the best ethical intentions, any clinician or scientist, by virtue of individual experience may develop a skewed sense of the balance of risks and benefits involved in a field of research to which he or she is particularly devoted. An orthopaedic surgeon, accustomed to seeing the most severe effects that osteoarthritis can have on individuals, could understandably develop a skewed attitude to the risks and benefits based on his or her experience. Similarly, anaesthetists, accustomed to continually attempting to minimise risk for their patients, may understandably develop an attitude to the risks and benefits that might be skewed in the other direction. Subjecting the research proposal to independent scrutiny by a group of individuals with a much broader outlook safeguards against the risk that individuals may be asked to take risks in research that are out of proportion with the potential benefits even where the motivation of the researchers is beyond ethical question.

The need for appropriate informed consent on the part of the participants is ethically beyond question. 68 Having to present the detailed methods by which appropriate informed consent is proposed to be achieved is another safeguard for both patients and researchers alike.

Finally, an independent committee, in taking into account possible competing interests, can both protect patients from research that may be motivated by factors of which they should (at the very least) be made aware and protect the researchers from subsequent accusations of less than ethical or questionable professional motives for the study.

Application for ethics approval for the conduct of the pilot study

It was against this background of controversy relating to placebo-controlled trials that the KORAL team sought ethics approval to conduct a formal pilot study to assess the full feasibility of mounting a multicentre placebo-controlled trial to evaluate the effectiveness of arthroscopic lavage for osteoarthritis of the knee. As it sought to reflect the design of a full trial, the pilot was to include full consent and randomisation to a placebo surgical arm.

The pilot (full details of the design are presented in Chapter 4) was designed as a two-centre, three-arm trial with randomisation to one of:

• arthroscopic lavage (with or without debridement as the surgeon saw fit);

• placebo surgery; or

• non-operative (medical) management with specialist reassessment.

The components of the proposed placebo surgery were informed by the extensive discussions with the surgeons and anaesthetists (see Chapter 2). As with the arthroscopic lavage, the placebo surgery was to be performed as a day case and undertaken in an operating theatre under general anaesthesia.

Eligible patients were to be recruited from hospital clinics, and if they consented to participate, randomised to one of the three interventions. Participants were to be followed up at 2, 6, 12 and 24 months.

Multicentre Research Ethics Committee approval

An application was submitted for national MREC approval to conduct the pilot study in June 2006 (the application was submitted, as had been agreed, to the MREC that had approved the original acceptability study).

The Multicentre Research Ethics Committee members discussed the application at an initial meeting in June 2006 at which they gave the pilot a ‘provisional favourable response’ subject to receiving the full report of the initial feasibility phase (preliminary findings had been included, but final data were not available at the time of application submission) and some minor changes to the information sheet. The KORAL team provided this extra information and agreed to attend the following meeting of the MREC to address any outstanding queries.

At the next MREC meeting in August 2006 (which the KORAL Chief Investigator, MKC, attended) the MREC informed the team that a ‘provisional favourable response’ was assigned only to allow the application to be retained in the system and that the Committee had a number of major concerns about the project. There was extensive discussion about the place of general anaesthesia in such a study, concerns about centres that had stopped carrying out arthroscopic lavage on a routine basis taking part in the pilot and concerns about indemnity for non-negligent harm. They were also concerned about the extent to which this study would add to the original Moseley trial.

Following that meeting, the Committee’s written conclusion was that they were unable to give a favourable ethical opinion to the study. An extract from their letter, outlining the reason for this, is presented in Figure 1.

FIGURE 1.

Extract from MREC decision letter.

The KORAL team reviewed this ethical judgement closely and, following extensive discussions with the lead ethicist (RVC) and consultation with a wider group of ethicists, decided to appeal this decision. It was still felt, based on all of the arguments presented above, that the potential benefits to patients with osteoarthritis of the knee justified the risks associated with the study.

We were particularly concerned that approval for the trial hinged on the issue of whether patients would, or would not, have been routinely offered surgery had the trial not been in place. Two particular issues seemed to be important in the ethics committee’s ruling: (1) the inclusion of surgeons who would not normally offer arthroscopic lavage and (2) the inclusion of centres where arthroscopic lavage was being phased out and was no longer a routine treatment choice. In our opinion, surgeons who would never consider offering arthroscopic lavage would be highly unlikely to take part in the trial. Therefore, we could assume that, for patients recruited from surgeons who would take part in the trial, there was at least a theoretical possibility that they might have been offered lavage had the trial not been in place. For those centres that had stopped undertaking routine arthroscopic lavage, but that wished to take part in KORAL to find out whether lavage was truly effective/ineffective (i.e. to find out whether they were making the correct decision to phase out lavage), we believed that this was a further justification for proposing the research, rather than an ethical objection to it. In addition, the empirical evidence from the HES indicated that arthroscopic lavage was still being undertaken in significant numbers across a wide range of centres.

Essentially, it seemed to us that participation in the trial should be deemed either ethical or not, be based on sound ethical principles and not be based on where the patient lived. Consider a hypothetical patient who is eligible for inclusion into the trial living near a centre where lavage was falling out of favour and was no longer routinely performed, but where the clinicians had decided to take part in KORAL as mentioned above. Under the MREC ruling it would be unethical for this patient to be entered into the trial (even if fully informed and wishing to participate). However, if that patient moved to the catchment area of a hospital where lavage was still routinely undertaken this would indicate that, purely by moving house, entry to the trial would become ethical for that patient. This seemed inappropriate and appeared to have parallels with so-called ‘postcode’ lotteries for treatment whilst still leaving the question of the effectiveness of lavage unanswered.

As such, we appealed the MREC decision – an appeal was allowed and assigned to be heard by a different MREC. The KORAL Chief Investigator (MKC) and Lead Anaesthetist (BHC) attended the appeal meeting on behalf of the KORAL team. This meeting took place in November 2006, where the study documentation was reviewed in detail again and further clarification was provided by the KORAL team where necessary.

In the appeal we stressed again that in the absence of the proposed trial the evidence base available to surgeons would remain dominated by the original Moseley trial24 – a trial in which all the procedures were carried out by a single surgeon, in a single US centre, in an atypical group of patients. As indicated earlier, generalisation of the results from the Moseley trial to the practice of multiple surgeons in multiple centres in a different health-care setting has significant limitations.

In addition, we re-emphasised the 12 months of feasibility work that had contributed to the work-up of the pilot protocol, reiterating the findings and especially the acceptability of the trial to potential participants, and to a range of anaesthetists and surgeons, given appropriate informed consent.

Following this meeting, the appeal MREC ruled that they were content to give a favourable ethical opinion of the research subject to ‘receiving a significantly revised and extended patient information leaflet’. The appeal committee deemed that the ‘quality of the informed consent was crucial in this study’ and as such wished the patient information leaflet to be extensive, with particular emphasis to be placed on outlining any potential disadvantages of taking part.

This extensive revision of the patient information leaflet was undertaken by the KORAL team, following which full ethics approval for the pilot study was received in March 2007. A copy of the final version of the MREC-approved patient information leaflet is presented in Appendix 10.

Comments on the ethics process

Placebo-controlled trials give rise to complex ethical questions. These are intensified when it is proposed that an ‘active’ placebo be used to mimic the range of non-specific effects (beneficial and potentially detrimental) that a patient might experience under the active intervention. For some conditions, however, without such trials it will never be possible to know whether or not a specific procedure is more effective than placebo. As such, it may be ethically justified to use surgical placebo in some situations, provided the potential risks have been carefully evaluated and are outweighed by the potential benefits.

The ethical review process is a crucial safeguard for studies such as this. Understandably it can become long and complex. This has the drawback of postponing the answers to the research question proposed. Whilst bureaucratic delays to this process should be minimised, it is essential that the genuine ethical dilemmas be explored and debated fully.

Genuine informed consent is particularly important in the context of ‘active’ placebos, as patients must be fully aware that they are accepting certain risks of the treatment (in this case general anaesthetic) and will not receive any of the benefits (except for those based on the placebo effect itself).

In our case, the indemnity procedures were unduly complex. It would be helpful if the national arrangements for indemnity and non-negligent harm are clarified for all researchers involved in the conduct of clinical trials – particularly those trials that might involve a placebo arm – and perhaps NHS-wide indemnity procedures could be developed by the respective Health Departments.

Aim and objectives of the pilot study

The overarching aim of the pilot study was to assess the feasibility of mounting a multicentre placebo-controlled trial to evaluate the effectiveness of arthroscopic lavage for osteoarthritis of the knee. The design of the pilot was informed by the extensive qualitative feasibility work (presented in Chapter 2) and the specific ethical issues discussed in Chapter 3.

The specific objectives of the pilot study were to:

• examine whether the trial processes as planned were appropriate, feasible and acceptable to patients, clinicians and the trial office staff;

• quantify the throughput of eligible patients;

• quantify the number of patients approached and the proportion of patients who would accept randomisation to the trial (reasons for refusal were collated to examine whether they were influenced by the inclusion of a placebo procedure); and

• examine the acceptability of the trial information material to patients.

Design of the pilot

The pilot was designed as a two-centre, three-arm randomised trial comparing:

• arthroscopic lavage (with or without debridement at the clinical discretion of the surgeon)

• placebo surgery

• non-operative (medical) management with specialist reassessment.

Eligible patients were recruited from hospital clinics and, if they consented to participate, randomly allocated to one of the three interventions. Participants were to be followed up at 2, 6, 12 and 24 months. A schematic summarising the design of the pilot study is presented in Figure 2.

FIGURE 2.

Schematic representation of the design of the pilot study.

Descriptions of interventions used in the pilot

Eligibility criteria

Patients were eligible for inclusion if they were: (1) adults (18 years or older) with radiological evidence of osteoarthritis of the knee who might be considered for arthroscopic lavage; (2) fit for general anaesthetic – defined by the ASA grade 1 and 2; and (3) able to give informed consent.

Excluded patients were those for whom the orthopaedic surgeon judged that arthroscopic lavage was clearly indicated; for whom arthroplasty was clearly indicated; who had clear contraindication to general anaesthesia; who were unable to speak English; and who had an inability to complete follow-up questionnaires.

Obtaining consent

Potentially eligible patients were provided with the patient information sheet (see Appendix 10) in the outpatient clinic. The dedicated local recruitment co-ordinator discussed the study and went through the patient information sheet with the patients. If required, the patient was given time to decide whether or not to participate. If the patient wished to join the trial, the recruitment co-ordinator checked that the consent form had been understood, and obtained written consent (see Appendix 11).

The participant was also asked to complete a baseline questionnaire whilst at the clinic or, if necessary, at home (see Appendix 12).

If the potential participant did not wish to join the trial, the reason for this decision was explored. It was stressed that this information was sought for the benefit of the trial rather than to try to encourage participation.

Randomisation and allocation to trial group

Once consent was received, patients were randomised to one of the three trial groups using a fully automated computerised telephone randomisation provided by the Centre for Healthcare Randomised Trials (CHaRT), based in the Health Services Research Unit, Aberdeen, UK. CHaRT was the accredited clinical trials unit supporting the KORAL study. Allocation incorporated minimisation on centre and key prognostic factors including age group (≤ 50 or > 50 years), gender, extent of osteoarthritis (whether radiological evidence indicated ‘bone-on-bone’ or ‘non bone-on-bone’) and whether mechanical symptoms were present or not. For patients who presented with osteoarthritis in both knees (and for whom arthroscopic lavage might be considered for both knees), the knee indicated by the patient to be the most painful was the knee that was designated the study knee for the purposes of randomisation and subsequent study.

Outcome measures

The primary aim of the pilot was to assess the feasibility and acceptability of procedures for a full trial. However, if it transpired that a decision was made to proceed to full trial, it was hoped that any participant recruited to the pilot would be later integrated into the full trial; thus we planned to follow up pilot participants up at the timings proposed in the main trial (at time points equivalent to 2, 6, 12 and 24 months after surgery) using full trial paperwork.

The outcome measures proposed for the full trial were informed by a study investigating the priorities of patients with osteoarthritis of the knee which showed that the outcomes that mattered most to patients were limitations of activities and pain. 70 Further work71 on osteoarthritis outcome measures indicated that pain falls within the impairment component of the World Health Organization International Classification of Function (i.e. impairment, activities and participation)72 and that the recognised knee quality of life score – the Oxford Knee Score73 – contains items giving pure assessment of pain impairment and activity limitation. By including the Oxford Knee Score and the Short Form (12 questions; SF-12),74 the full trial would record measurements on all three components (impairment, activities and participation), whilst focusing on the patient’s perspective through the use of self-completion questionnaires.

Reflecting this approach the following outcome measures were chosen:

• Primary outcome measures: condition-specific pain and disability, as measured by the Oxford Knee Score; knee pain, as measured by a 10-cm visual analogue pain score (and the pain dimensions of the Oxford Knee Score and the SF-12 scales).

• Secondary outcome measures: general quality of life, as measured by SF-12; patient utility, as measured by the EuroQol-5 dimensions (quality of life instrument; EQ-5D);75 non-steroidal anti-inflammatory drug or analgesic use; use of other treatments outside the trial interventions; use and cost of health services; cost-effectiveness – as measured by the incremental cost per quality-adjusted life-year gained.

Questionnaires are reproduced in Appendix 12.

Sample size and feasibility

As this was a pilot study with the explicit aim of refining estimates of likely throughput of patients and the proportion of eligible patients who would consent in a given time period (both of which would inform a sample size calculation for a full trial), a formal sample size calculation at this stage was inappropriate.

Analysis plans

A single principal analysis was planned for the end of the pilot phase. Analysis was to consist primarily of descriptive statistics including throughput per month, proportion of eligible patients randomised, and reasons for refusing to take part in the trial. Reflecting the small sample size, no analysis was to be conducted by randomised group.

Pilot experience

Identification of patients

Referral letters to KORAL surgeons in Centre 1 were assessed for potentially eligible patients, and dedicated KORAL study clinics were set up. The centre’s lead surgeon led the majority of the clinics with support from the local KORAL recruitment co-ordinator. The first clinic took place in July 2007. During the period of recruitment (July–November 2007), eight KORAL clinics were held. Of the 49 patients who were given a clinic appointment, 40 attended (Figure 3). Twenty-seven patients were found to be ineligible. Nine of those had minimal pain and were discharged, four were referred for magnetic resonance imaging scan, three had mechanical symptoms (and were referred for arthroscopy), three were given review appointments for a later date, two were listed for knee replacements and two required hyaluronic acid injections. Two of the other ineligible patients had other chronic conditions, another had a meniscal tear and the final patient was referred to the pain clinic.

FIGURE 3.

Flow diagram of patients through the pilot. MRSA, methicillin-resistant Staphylococcus aureus.

Of the 13 eligible patients, nine were recruited into the pilot study in Centre 1. Six of these were randomised to some form of surgery (placebo or active) and three were randomised to non-surgical management. Reasons given by those four patients who declined were: one felt the research was important but was not for them; one indicated their pain had reduced since referral (but if it had remained at the same level they would have taken part); one had a new job and had ‘plenty to cope with already’; and one did not like the idea of the study.

Table 4 shows the baseline characteristics of the pilot participants. Four patients were male and five female. Of the nine patients recruited, eight completed a baseline questionnaire, comprising the Oxford Knee Score, SF-12 and EQ-5D. One participant, who took the questionnaire home to complete, failed to return it.

TABLE 4 - Baseline characteristics of trial participants

Characteristic	Description
Gender	4 male, 5 female
Age
Range	43–63 years
Mean	57 years
Median	61 years
Affected knee	6 right, 3 left
Oxford Knee Score
Range	13–31
Mean score (SD)	26.5 (6.2)
Median score (IQR)	29.0 (24.5 to 30.5)
EQ-5D
Range	0.66–0.80
Mean score (SD)	0.74 (0.06)
Median score (IQR)	0.76 (0.69 to 0.80)
SF-12 – physical
Range	33.9–49.8
Mean score (SD)	42.1 (6.1)
Median score (IQR)	43.1 (37.1 to 49.3)
SF-12 – mental
Range	29.2–61.1
Mean score (SD)	53.3 (11.2)
Median score (IQR)	57.5 (49.7 to 60.2)
Pain – visual analogue scale
Range	2–6
Mean score (SD)	3.88 (1.36)
Median score (IQR)	3.5 (3.0 to 5.0)

Baseline scores on the Oxford Knee Score ranged from 13 to 31 [possible scores range from 12 (least difficulties) to 60 (most difficulties)], with a mean score of 26.5 and a median score of 29. The range of EQ-5D scores was 0.66–0.80, with the mean score 0.74 [standard deviation (SD) 0.06] and median score 0.76 [interquartile range (IQR) 0.69 to 0.80]. Possible scores for EQ-5D range from –0.59 to 1.00 (with higher scores indicating better quality of life).

Seven people completed all questions contained within the SF-12 (possible scores range from 0 to 100, with higher scores indicating better quality of life). On the physical component summary scale, the range of scores was 33.9–49.8, the mean score 42.1 (SD 6.1) and the median score 43.1 (IQR 37.1 to 49.3). On the mental component summary scale, the range of scores was 29.2–61.1, mean score 53.3 (SD 11.2) and the median score 57.5 (IQR 49.7 to 60.2).

Patients were also asked to rate their pain ‘today’ on a visual analogue scale from 0 (no pain) to 10 (worst pain imaginable). The scores reported ranged from 2 to 6, with mean score 3.88 (SD 1.36) and median score 3.5 (IQR 3.0 to 5.0).

Comments on the pilot study

The pilot study showed that, in principle, a placebo-controlled trial in surgery can be conducted. It showed that a significant proportion of patients were willing to participate in a trial that would involve a placebo surgical arm, and that it was possible to undertake placebo surgery successfully and blind patients to their allocation.

The experience of the pilot, however, showed that, despite full MREC approval, the study required major discussion and negotiation before local clinical approvals could be obtained. Many of the arguments raised at MREC level were raised again at local level, and the fact that ethics approval had been granted did not mean that clinicians would automatically accept that the process was ethical. The ethics of a placebo-controlled trial in surgery remained contentious and there was a number of individuals (mainly anaesthetists) who retained strong negative perceptions of the ethics of the trial. However, we would anticipate that the wide airing the ethical arguments received through the process of securing consent for the pilot stage would make the process of obtaining ethics approval for a full trial less onerous.

Once clinics were under way, a significant percentage of eligible patients appeared willing to participate in the study – although once patients knew their allocation, some of those allocated to surgery became more concerned about the possibility of undergoing placebo surgery, and some withdrew. This suggested that higher than normal rates of postrandomisation withdrawal might have been expected in those randomised to some form of surgery should the study have progressed to full trial. However, the number of patients involved in the pilot was small, and as such strong conclusions cannot be made as to the true proportion of patients who would agree to participate and the proportion who might drop out of a full trial.

The issue of how, in a full trial, a placebo procedure would be funded in the context of different local commissioning arrangements remained unclear. This would have to be addressed on a case-by-case basis which is logistically cumbersome in a multicentre trial.

The decision-making process

Because of the multiphase nature of the study and the need to move rapidly between stages, a bespoke decision-making process for the project was set up with the NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC; formerly known as NCCHTA). At the start of the project it was agreed that special decision-making teleconferences would be held for the end of each of the distinct phases of the study to allow decisions to be made in a timely manner. At each teleconference a recommendation would be made as to whether the project should continue on to the next planned phase or the study should close. The grant holder team undertook to deliver specific project reports ahead of these teleconferences in addition to the standard progress reports required every 6 months. These decision teleconferences involved staff from the NETSCC, an independent scientific chairperson and the grant holder team. Final decisions were made by the NETSCC (in consultation with the independent scientific chairperson) and fed back to the grant holder team in writing.

The first decision teleconference was planned for the end of the feasibility phase. The aim of this teleconference was to review the findings of the (mainly qualitative) feasibility phase and to decide if there was sufficient support from those interviewed to allow the project to continue to a formal pilot phase.

The second teleconference was planned for the end of the formal pilot phase. The aim of this teleconference was to review the results of the pilot and to decide if the pilot experience, set against the current clinical climate, was conducive to progressing to a full-scale trial.

The second decision-making teleconference – end of the pilot phase

The second decision-making conference took place in January 2008. At this point data were available on: the experience of gaining ethics approval; the experience of gaining local approvals at the two pilot centres; the flow of patients from all eight KORAL clinics that had been held in Centre 1; all randomisations (and any subsequent withdrawals); the initial experience of all the non-surgical management patients; the experiences of the first two surgical procedures (one active and one placebo procedure); and information on the trends of arthroscopic lavage use in the UK over recent years.

This pilot study had shown that:

• The perceived ethics of a placebo-controlled trial in surgery remained contentious (even after ethics approval was received). There were a number of individuals (mainly anaesthetists) who retained strong negative perceptions of the ethics of the trial. However, given that the ethical principle of the trial had been given an extensive airing through the pilot study, one would expect that ethics approval for a continuation of pilot to full trial would be less onerous.

• Even when ethics approval had been received, approval at a local level was not straightforward. Many of the arguments considered at the ethics committee stage were raised again at local level. Had the study progressed to full trial, the experience of the pilot suggested that ensuring appropriate authorisations in multiple centres could have been a lengthy and time-consuming process.

• The issue of how, in a full trial, a placebo procedure would get funded in the context of different local commissioning arrangements was unclear.

• Eligible patients were open to the idea of participating in a placebo-controlled trial, and most of those approached were willing to consent.

• It was possible to undertake placebo surgery successfully and to blind patients to their allocation.

• Had the study progressed to full trial, however, higher than normal rates of post-randomisation withdrawal might have been observed in those randomised to some form of surgery – in the pilot two out of the six randomised to surgery withdrew citing increasing concerns about the possibility of receiving placebo surgery.

The decision whether to proceed to full trial was also informed by data on trends in the usage of arthroscopic lavage (and debridement) in the UK. Data were available from the HES13 for England and Wales, and data available from 1998–9 to 2005–6 are presented in Figure 4. These data showed that the use of arthroscopic lavage, and its associated procedures such as debridement, was steadily declining with a slightly more marked decrease after the publication of the Moseley trial in 2002.

FIGURE 4.

Hospital episode statistics on arthroscopic lavage and associated procedures.

Taking the results of the pilot experience and the trend data on the background usage of arthroscopic lavage together, the conclusion was made that whilst the KORAL pilot had shown that, in principle, a placebo-controlled trial in surgery could be conducted (and that conducting a full-scale trial in the field was likely to be possible), the anticipated time, energy and cost required to bring multiple centres on board against a background of falling use of the technique was not justified. An extract from the formal decision letter summarising these points is shown in Figure 5.

FIGURE 5.

Extract from the KORAL decision letter.

Thus, the decision was made not to proceed to full trial.

Close down

In light of the decision not to proceed to full trial, the KORAL study rapidly moved into a close down phase. Decisions on how to deal with randomised patients still active in the trial had to be made quickly. As the KORAL team knew that close down was always a possibility, close down plans for different scenarios had already been made within the group, which greatly facilitated the transition to close down. These plans were agreed with the MREC.

When the decision was made not to progress beyond the pilot stage, pilot participants fell into three distinct groups. Management of the patients differed according to their grouping:

1. Those who had already undergone surgery. Two participants had been randomised to, and had undergone, surgery (one placebo, one active) before the decision not to proceed to full trial. In line with the protocol and the information they were given before their entry into the trial, they were not subsequently informed of the type of surgery that they had undergone. Both patients were invited to attend (as per protocol) follow-up 3 weeks after their surgery; one attended and one did not (despite being offered more than one appointment). If a clinical need arises at some point in the future, plans have been put in place allowing them to be told, if necessary, what procedure they underwent.

2. Those who had been randomised to surgery, but had not yet undergone surgery. Two participants had been randomised to surgery (one to placebo surgery, one to active surgery), but at the time of the decision teleconference they had not yet received their surgery. In light of the decision not to proceed, it was agreed that these participants would not progress within the KORAL framework. This was agreed with the MREC. In Centre 1, these patients would not routinely have undergone arthroscopic lavage outside of the trial. It was agreed that these participants would be seen again by the surgeon at the outpatient clinic. At this appointment he would explain that the pilot had been stopped so they would not have surgery as part of KORAL. He would explain that the treatment options were now medical management or arthroscopic lavage (although the evidence for the latter was weak), and that the patient could choose between having arthroscopic lavage or medical management. One of the participants opted to proceed with surgery, subsequently underwent this surgery and was discharged from routine care. The other participant did not attend a number of clinic appointments to discuss the options, and was subsequently discharged.

3. Those who had been randomised to non-surgical management. Three participants had been randomised to non-surgical management, and this management was already under way before the decision teleconference. Because these patients were allocated to the non-surgical arm, they knew (by default) the group to which they had been allocated. They were invited to attend follow-up clinics 3 months after recruitment, as described in the pilot protocol.

Participants in all groups subsequently followed normal discharge procedures as appropriate.

Arthroscopic lavage – specific lessons from KORAL

Generic issues related to placebo-controlled trials in surgery

When, and how, should a placebo-controlled trial be mounted in a surgical context?

The KORAL study provided a number of insights into the question of when and how a placebo-controlled trial should be mounted in a surgical setting. Commentators agree that the ethical principles appropriate to all clinical research must be satisfied as a minimum when considering the acceptability and feasibility of a placebo-controlled design. These principles are that the study must: (1) have scientific merit, (2) be acceptable to participants in terms of the risk-to-benefit ratio of participation and (3) be respectful of the autonomy of participants to determine whether they should participate. 91 The results of the qualitative component within the KORAL study showed that these three factors were raised and discussed in depth for the particular case of arthroscopic lavage. The scientific merit of the proposed study – the evaluation of the true effectiveness of arthroscopic lavage – and the need for informed consent were readily accepted. Whether the proposed study design provided an acceptable balance of risks and potential benefits for participants, however, generated much wider debate.

The discussion of an acceptable risk-to-benefit ratio in a placebo-controlled study is not straightforward. As Horng and Miller61 argue, the risks must be considered in the context of alternative study designs to answer the research question: could an evaluation of arthroscopic lavage be conducted without the use of a placebo control and without compromising scientific rigour? In any trial of arthroscopic lavage, the subjective measure of pain is the primary outcome of interest. It is a well-recognised phenomenon that subjective outcomes are prone to bias when the allocation is known to the outcome assessor. 87 Any open trial that compared arthroscopic lavage with a control group that received no treatment or non-surgical treatment would thus have been prone to potentially biased results. This may go some way to explain the differences seen in the early studies of the effectiveness of arthroscopic lavage, where those open studies that compared arthroscopic lavage against no surgery (or non-surgical management) showed some evidence of benefit, whereas those studies that were conducted in a blinded manner showed none. This suggests that a placebo-controlled trial is most relevant in a surgical context when the primary outcome of interest is subjective (and thus prone to bias in other designs).

An additional consideration in the risk-to-benefit ratio for participants is the nature of the proposed placebo – how ‘risky’ the proposed placebo is perceived to be. A placebo must be able to mimic the intervention under evaluation, but must minimise the risks to those who might take part in the trial. Edwards et al. 92 suggest that perceptions of the acceptability of a placebo are likely to vary depending on the nature of the placebo in question. They suggest that when an active placebo is very intrusive or confers significant potential harm, participants need to display high levels of altruism to enter a trial. In the KORAL study there was consensus from all parties that, from a surgical perspective, the proposed placebo demonstrated not only high potential to mimic the active intervention but also low intrusiveness (three small skin incisions), and thus yielded high acceptability. The primary issue of concern was rather the perceived intrusiveness of the anaesthetic component of the placebo – the recommendation to have a general anaesthetic for those undergoing the placebo procedure. This raised concerns among many of the stakeholders within the study, and was the factor that caused most discussion with local decision-makers when seeking formal approval to conduct the KORAL pilot. It is interesting to note, however, that the subject experts, the anaesthetists, who contributed to our research viewed the use of a general anaesthetic in the placebo group as the option that did minimise the risk. They contended that the technique with which they would have more experience, a routine general anaesthetic, would be safer and that they would be less likely to make errors when administering it. We have discussed earlier how this assessment is borne out by the wider literature on expertise and errors.

Even when a placebo-controlled trial might be deemed to be an acceptable design, it must also be a feasible course of action. The experience of the KORAL study highlighted this issue well as, even when national approval for the study was gained, the trial faced a number of practical hurdles before it commenced. Inability to surmount any of these practical difficulties would have led directly to the failure of the study. The particular issues faced by KORAL highlighted that: (1) stakeholders in every trial centre need to be fully briefed about any proposed trial and any concerns need to be resolved prior to trial commencement; (2) arrangements need to be put in place to cover the costs of the placebo before any trial can go ahead; and (3) appropriate indemnity arrangements need be instituted. Whilst these issues were particularly relevant to KORAL, they are not unusual and are likely to be faced by any researcher planning a placebo-controlled trial. In particular, the crucial importance of local stakeholders (those who might be affected by the research) and gatekeepers (those who give formal permission for the organisation to be involved in the research) has been outlined by a number of authors,93,94 and the need to develop explicit recruitment and communication strategies has been identified.

These insights suggest, therefore, that the optimal place for a placebo-controlled trial in surgery is in situations in which the following conditions can be satisfied:

• Alternative designs would provide inferior (and potentially biased) results, particularly where the primary outcome is of a subjective nature and blinding cannot be sustained beyond the time of any placebo effect.

• A placebo surgical procedure and type of anaesthesia can be devised that adequately mimic the active intervention with a level of intrusiveness and risk that is acceptable to surgeons, anaesthetists, ethics committees and potential participants.

• Appropriate practical arrangements can be instituted in local centres to ensure that the delivery of such a design would be feasible.

• Sufficient numbers of potential participants (after assessment of clear descriptions and careful explanations in patient information leaflets of the advantages and disadvantages of taking part) judge for themselves that the risk-to-benefit ratio of participation is acceptable to them.

• Levels of compliance with the allocation are sufficiently high to sustain scientific rigour.

Overall conclusion

The KORAL feasibility study showed that, in principle, a placebo-controlled trial of arthroscopic lavage could be conducted in the UK, albeit with difficulty. It also showed, however, that the design remains controversial, and for some health professionals the use of placebo surgery can never be justified. It highlighted the importance of the surgeon–anaesthetist relationship in this context and how acceptance of the trial design by both parties is essential to successful participation. It also highlighted the importance of informed consent for trial participants and the strength and influence of individuals’ ethical perspectives in addition to collective ethics provided by MRECs. All these factors need to be accounted for in the planning of future placebo-controlled trials.

The wider conclusion from the KORAL study is that the optimal place for a placebo-controlled trial in surgery is likely to be for situations in which the strict conditions listed above can be satisfied.

Implications for practice

• A placebo-controlled trial of arthroscopic lavage could be conducted in the UK, albeit with difficulty.

• Those conducting trials in surgery must consider the surgeon–anaesthetist partnerships when planning clinical trials, especially trials including a placebo arm.

• People taking part in, and authorising the conduct of, trials have their own individual ethical perspectives which can influence their practice (in addition to the collective ethics assessment provided by MRECs). Researchers need to be aware of these, and work with them, when planning clinical trials – especially trials involving a placebo arm.

• Terminology referring to ‘placebos’, ‘shams’, ‘dummies’, etc. should be investigated and then standardised across trials – each has different connotations that may influence participation.

• The importance of including clear descriptions and careful explanations in patient information leaflets was reinforced in this study. All trials should ensure that any advantages and disadvantages of participation are explained as fully as possible.

• Patient information leaflets within placebo-controlled trials should explicitly state that whilst benefit might be seen within a placebo group, the underlying mechanism proposed for the placebo has no known scientific rationale to support benefit.

• National arrangements for indemnity and non-negligent harm should be clarified for all researchers involved in the conduct of clinical trials, particularly those trials that might involve a placebo arm.

• The HTA programme should consider the routine use of staged funding (with integrated rapid decision-making) for more complex research projects.

Implications for research

• Research is required into the impact of different terminology referring to placebos (e.g. placebo, sham, dummy) on understanding the role and function of a placebo.

• Research is required into the usefulness of formal decision aids to aid participant consent in the context of a placebo-controlled trial.

• Research is required into the impact of individual versus collective ethics on the conduct of placebo-controlled trials.

Contribution of authors

Marion Campbell (Director of Health Services Research Unit, lead methodologist) was the principal grant applicant, she led on the development of the study protocol, led the preparation of the report, was responsible for the overall conduct of the study and is guarantor of the study. Zoe Skea (study researcher, qualitative research) contributed to the development of the study design, and was responsible for the day-to-day management of the qualitative component of the study, led on the writing of the qualitative findings of the study and assisted in the wider preparation of the report. Alasdair Sutherland (Senior lecturer and Honorary Consultant in Orthopaedics, lead surgeon) contributed to the development of the study design, he also led on all surgical aspects of the trial including the conduct of focus groups and the surgical design and conduct of the pilot, led on the writing of the surgical aspects of the report and assisted in the wider preparation of the report. Brian Cuthbertson (Professor, lead anaesthetist) contributed to the development of the study design, led on all anaesthetic and other clinical aspects of the trial including the conduct of focus groups and the design of the pilot, led on the writing of clinical aspects of the report and assisted in the wider preparation of the report. Vikki Entwistle (Professor, qualitative methodology) contributed to the development of the study design, provided guidance to the qualitative component of the study, contributed to the conduct of the focus groups, and contributed to the writing of the qualitative findings of the study and the wider preparation of the report. Alison McDonald (Senior Trial Manager, trial management) contributed to the design of the study materials and to the organisation of study authorisations, co-ordinated liaison with study centres and assisted in the preparation of the report. John Norrie (CHaRT director, trialist) contributed to the design and conduct of the study, provided expert guidance on the contribution of clinical trials units to pilot studies and assisted in the preparation of the report. Robert Carlson (Senior lecturer, medical ethics) contributed to the design and conduct of the study, provided expert guidance on ethical arguments and the place of placebos within these frameworks, and contributed to the writing up of the ethics process and to the wider preparation of the report. Stephen Bridgman (Senior lecturer, local clinical leadership) contributed to the design and conduct of the pilot at a local level and contributed to the preparation of the report. The KORAL Study Group includes Seonaidh Cotton, Angela Donaldson, Ray Fitzpatrick, Adrian Grant, Alastair Grey, James Hutchison, Marie Johnston, David Murray, Craig Ramsay, David Rowley, Luke Vale and Carlos Wigderowitz. All were members of the KORAL Project Management Group and commented on drafts of the report.

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.

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10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

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

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    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, Reimsma 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, 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 costeffectiveness 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 placebocontrolled 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 costeffectiveness 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 costeffectiveness 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.

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