Subversion of allocation concealment in a randomised controlled trial: a historical case study.

BACKGROUND: If the randomisation process within a trial is subverted, this can lead to selection bias that may invalidate the trial's result. To avoid this problem, it is recommended that some form of concealment should be put into place. Despite ongoing anecdotal concerns about their susceptibility to subversion, a surprising number of trials (over 10%) still use sealed opaque envelopes as the randomisation method of choice. This is likely due in part to the paucity of empirical data quantifying the potential effects of subversion. In this study we report a historical before and after study that compares the use of the sealed envelope method with a more secure centralised telephone allocation approach in order to provide such empirical evidence of the effects of subversion. METHODS: This was an opportunistic before and after study set within a multi-centre surgical trial, which involved 654 patients from 28 clinicians from 23 centres in the UK and Ireland. Two methods of randomly allocating subjects to alternative treatments were adopted: (a) a sealed envelope system administered locally, and (b) a centralised telephone system administered by the trial co-ordination centre. Key prognostic variables were compared between randomisation methods: (a) age at trial entry, a key prognostic factor in the study, and (b) the order in which 'randomisation envelopes' were matched to subjects. RESULTS: The median age of patients allocated to the experimental group with the sealed envelope system, was significantly lower both overall (59 vs 63 years, p < 0.01) and in particular for three clinicians (57 vs 72, p < 0.01; 33 vs 69, p < 0.001; 47 vs 72, p = 0.03). No differences in median age were found between the allocation groups for the centralised system. CONCLUSIONS: Due to inadequate allocation concealment with the sealed envelope system, the randomisation process was corrupted for patients recruited from three clinicians. Centralised randomisation ensures that treatment allocation is not only secure but seen to be secure. Where this proves to be impossible, allocation should at least be performed by an independent third party. Unless it is an absolute requirement, the use of sealed envelopes should be discontinued forthwith.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of different knee prostheses: the Knee Arthroplasty Trial (KAT).

BACKGROUND: In the late 1990s, new developments in knee replacement were identified as a priority for research within the NHS. The newer forms of arthroplasty were more expensive and information was needed on their safety and cost-effectiveness. OBJECTIVES: The Knee Arthroplasty Trial examined the clinical effectiveness and cost-effectiveness of four aspects of knee replacement surgery: patellar resurfacing, mobile bearings, all-polyethylene tibial components and unicompartmental replacement. DESIGN: This study comprised a partial factorial, pragmatic, multicentre randomised controlled trial with a trial-based cost-utility analysis which was conducted from the perspective of the NHS and the patients treated. Allocation was computer generated in a 1 : 1 ratio using a central system, stratified by eligible comparisons and surgeon, minimised by participant age, gender and site of disease. Surgeons were not blinded to allocated procedures. Participants were unblinded if they requested to know the prosthesis they received. SETTING: The setting for the trial was UK secondary care. PARTICIPANTS: Patients were eligible for inclusion if a decision had been made for them to have primary knee replacement surgery. Patients were recruited to comparisons for which the surgeon was in equipoise about which type of operation was most suitable. INTERVENTIONS: Patients were randomised to receive a knee replacement with the following: patellar resurfacing or no patellar resurfacing irrespective of the design of the prosthesis used; a mobile bearing between the tibial and femoral components or a bearing fixed to the tibial component; a tibial component made of either only high-density polyethylene ('all polyethylene') or a polyethylene bearing fixed to a metal backing plate with attached stem; or unicompartmental or total knee replacement. MAIN OUTCOME MEASURES: The primary outcome was the Oxford Knee Score (OKS). Other outcomes were Short Form 12; EuroQol 5D; intraoperative and postoperative complications; additional surgery; cost; and cost-effectiveness. Patients were followed up for a median of 10 years; the economic evaluation took a 10-year time horizon, discounting costs and quality-adjusted life-years (QALYs) at 3.5% per annum. RESULTS: A total of 116 surgeons in 34 centres participated and 2352 participants were randomised: 1715 in patellar resurfacing; 539 in mobile bearing; 409 in all-polyethylene tibial component; and 34 in the unicompartmental comparisons. Of those randomised, 345 were randomised to two comparisons. We can be more than 95% confident that patellar resurfacing is cost-effective, despite there being no significant difference in clinical outcomes, because of increased QALYs [0.187; 95% confidence interval (CI) -0.025 to 0.399] and reduced costs (-£104; 95% CI -£630 to £423). We found no definite advantage or disadvantage of mobile bearings in OKS, quality of life, reoperation and revision rates or cost-effectiveness. We found improved functional results for metal-backed tibias: complication, reoperation and revision rates were similar. The metal-backed tibia was cost-effective (particularly in the elderly), costing £35 per QALY gained. CONCLUSIONS: The results provide evidence to support the routine resurfacing of the patella and the use of metal-backed tibial components even in the elderly. Further follow-up is required to assess the stability of these findings over time and to inform the decision between mobile and fixed bearings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45837371. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the orthopaedic industry. It will be published in full in Health Technology Assessment; Vol. 18, No. 19. See the NIHR Journals Library website for further project information.

Case study: a patient-clinician collaboration that identified and prioritized evidence gaps and stimulated research development.

OBJECTIVE: To assess the effect of a research prioritization partnership that aimed to influence the research agenda relating to urinary incontinence (UI). STUDY DESIGN AND SETTING: Research often neglects important gaps in existing evidence so that decisions must be made about treatments without reliable evidence of their effectiveness. In 2007-2009, a United Kingdom partnership of eight patient and 13 clinician organizations identified and prioritized gaps in the evidence that affect everyday decisions about treatment of UI. The top 10 prioritized research questions were published and reported to research funders in 2009. A year later, new research or funding applications relating to the prioritized topics were identified through reviews of research databases and consultation with funding organizations, elements of the research community, and organizations that participated in the partnership. RESULTS: Since dissemination of the prioritized topics, five studies are known to have been funded, three in development; five new systematic reviews are under way, one is being updated; five questions are under consideration by a national research commissioning body. CONCLUSION: The partnership successfully developed and used a methodology for identification and prioritization of research needs through patient-clinician consensus. Prioritization through consensus can be effective in informing the development of clinically useful research.

Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).

CONTEXT: Vitamin D or calcium supplementation may have effects on vascular disease and cancer. OBJECTIVE: Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people. DESIGN AND SETTING: The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom. PARTICIPANTS: Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture. INTERVENTIONS: Participants were randomly allocated to daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention. MAIN OUTCOME MEASURES: All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated. RESULTS: In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85-1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79-1.05), cancer mortality (HR = 0.85; 95% CI = 0.68-1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92-1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94-1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92-1.24), cancer mortality (HR = 1.13; 95% CI = 0.91-1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91-1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant. CONCLUSIONS: Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence.

A framework for the evaluation of new interventional procedures.

OBJECTIVES: The introduction of new interventional procedures is less regulated than for other health technologies such as pharmaceuticals. Decisions are often taken on evidence of efficacy and short-term safety from small-scale usually observational studies. This reflects the particular challenges of evaluating interventional procedures - the extra facets of skill and training and the difficulty defining a 'new' technology. Currently, there is no framework to evaluate new interventional procedures before they become available in clinical practice as opposed to new pharmaceuticals. This paper proposes a framework to guide the evaluation of a new interventional procedure. PROPOSED FRAMEWORK: A framework was developed consisting of a four-stage progressive evaluation for a new interventional procedure: Stage 1: Development; Stage 2: Efficacy and short-term safety; Stage 3: Effectiveness and cost-effectiveness; and Stage 4: Implementation. The framework also suggests the types of studies or data collection methods that can be used to satisfy each stage. CONCLUSIONS: This paper makes a first step on a framework for generating evidence on new interventional procedures. The difficulties and limitations of applying such a framework are discussed.

The introduction of new interventional procedures in the British National Health Service--a qualitative study.

OBJECTIVES: To investigate how interventional procedures (IPs) are introduced into the British National Health Services and identify areas for improvement in the current process. METHODS: Qualitative study using one to one semi-structured interviews. Using the framework approach, the data generated from 14 participants were analysed with coding of emergent themes. Data were analysed separately for providers and commissioner organisations. RESULTS: Variations were observed in how IPs are introduced from both the provider and commissioner perspectives. Patterns of approaches allowed the development of models reflecting practice at each type of organisation: very structured in some places to, unstructured or almost non-existent in others. Factors affecting the decision to introduce a procedure include: immediate costs and benefits, numbers of people affected, training requirements, NICE guidance, nature of procedure, support from colleagues, incentives, public or policy-maker pressure, and aims of the institution. Monitoring was seen as a key area for improvement by many. CONCLUSIONS: These variations indicate that the process of introducing new IPs in the NHS can be improved. Factors affecting decision-making and problems have been identified. The results of our study could inform and help shape future processes of managing and the introduction of new procedures into the NHS.

Reaching a consensus and ranking research priorities in urinary incontinence.

Gaps in the evidence base in healthcare are common, and this is also the case for the management of urinary incontinence. The James Lind Alliance helped patients and clinicians to identify and then prioritise gaps in the evidence base for managing this condition, producing a list of 10 research priorities. This article outlines the process involved in reaching this consensus.

Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a common condition with up to 20% of patients from Westernised countries experiencing heartburn, reflux or both intermittently. It is unclear whether medical or surgical (laparoscopic fundoplication) management is the most clinically and cost-effective treatment for controlling GORD. OBJECTIVES: To compare the effects of medical management versus laparoscopic fundoplication surgery on health-related and GORD-specific quality of life (QOL) in adults with GORD. SEARCH STRATEGY: We searched CENTRAL (Issue 2, 2009), MEDLINE (1966 to May 2009) and EMBASE (1980 to May 2009). We handsearched conference abstracts and reference lists from published trials to identify further trials. We contacted experts in the field for relevant unpublished material. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing medical management with laparoscopic fundoplication surgery. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from articles identified for inclusion and assessed the methodological quality of eligible trials. Primary outcomes were: health-related and GORD-specific QOL, heartburn, regurgitation and dysphagia. MAIN RESULTS: Four trials were included with a total of 1232 randomised participants. Health-related QOL was reported by four studies although data were combined using fixed-effect models for two studies (Anvari 2006; REFLUX Trial 2008). There were statistically significant improvements in health-related QOL at three months and one year after surgery compared to medical therapy (mean difference (MD) SF36 general health score -5.23, 95% CI -6.83 to -3.62; I(2) = 0%). All four studies reported significant improvements in GORD-specific QOL after surgery compared to medical therapy although data were not combined. There is evidence to suggest that symptoms of heartburn, reflux and bloating are improved after surgery compared to medical therapy, but a small proportion of participants have persistent postoperative dysphagia. Overall rates of postoperative complications were low but surgery is not without risk and postoperative adverse events occurred although they were uncommon. The costs of surgery are considerably higher than the cost of medical management although data are based on the first year of treatment therefore the cost and side effects associated with long-term treatment of chronic GORD need to be considered. AUTHORS' CONCLUSIONS: There is evidence that laparoscopic fundoplication surgery is more effective than medical management for the treatment of GORD at least in the short to medium term. Surgery does carry some risk and whether the benefits of surgery are sustained in the long term remains uncertain. Treatment decisions for GORD should be based on patient and surgeon preference.

Prioritizing research: Patients, carers, and clinicians working together to identify and prioritize important clinical uncertainties in urinary incontinence.

AIMS: Research often neglects important gaps in existing evidence. Throughout healthcare, clinicians and patients face avoidable "clinical uncertainties" daily, making decisions about treatments without reliable evidence about their effects. This partnership of patients and clinicians aimed to identify and prioritize "clinical uncertainties" relating to treatment of urinary incontinence (UI). METHODS: UK clinician and patient organizations whose remit includes UI were invited to participate. Participating organizations consulted memberships to identify "uncertainties" affecting treatment decisions. "Uncertainties" were also identified in published research recommendations. Prioritization involved two phases: shortlisting of "uncertainties" by organizations; patient-clinician prioritization using established consensus methods. Prioritized "uncertainties" were verified by checking any available relevant up-to-date published systematic reviews. RESULTS: Thirty organizations were invited; 8 patient and 13 clinician organizations participated. Consultation generated 417 perceived "uncertainties," research recommendations 131. Refining, excluding and combining produced a list of 226. Prioritization shortlisted 29 "uncertainties," then a "top ten" (5 submitted by clinicians, 4 by patients, 1 from research recommendations). CONCLUSIONS: The partnership successfully developed and tested a systematic and transparent methodology for patient-clinician consultation and consensus. Through consensus, unanswered research questions of importance to patients and clinicians were identified and prioritized. The final list reflects the heterogeneity of populations, treatments and evidence needs associated with UI. Some prioritized "uncertainties" relate to treatments that are widely used yet whose effects are not thoroughly understood, some to access to care, some to precise surgical questions. Research needs to address the uncertainties range from systematic reviewing to primary research.

Minimal access surgery compared with medical management for chronic gastro-oesophageal reflux disease: UK collaborative randomised trial.

OBJECTIVE: To determine the relative benefits and risks of laparoscopic fundoplication surgery as an alternative to long term drug treatment for chronic gastro-oesophageal reflux disease (GORD). DESIGN: Multicentre, pragmatic randomised trial (with parallel preference groups). SETTING: 21 hospitals in the United Kingdom. PARTICIPANTS: 357 randomised participants (178 surgical, 179 medical) and 453 preference participants (261, 192); mean age 46; 66% men. All participants had documented evidence of GORD and symptoms for >12 months. INTERVENTION: The type of laparoscopic fundoplication used was left to the discretion of the surgeon. Those allocated to medical treatment had their treatment reviewed and adjusted as necessary by a local gastroenterologist, and subsequent clinical management was at the discretion of the clinician responsible for care. MAIN OUTCOME MEASURES: The disease specific REFLUX quality of life score (primary outcome), SF-36, EQ-5D, and medication use, measured at time points equivalent to three and 12 months after surgery, and surgical complications. MAIN RESULTS: Randomised participants had received drugs for GORD for median of 32 months before trial entry. Baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) in the surgical and medical randomised groups, respectively. Of those randomised to surgery, 111 (62%) actually had total or partial fundoplication. Surgical complications were uncommon with a conversion rate of 0.6% and no mortality. By 12 months, 38% (59/154) randomised to surgery (14% (14/104) among those who had fundoplication) were taking reflux medication versus 90% (147/164) randomised medical management. The REFLUX score favoured the randomised surgical group (14.0, 95% confidence interval 9.6 to 18.4; P<0.001). Differences of a third to half of 1 SD in other health status measures also favoured the randomised surgical group. Baseline scores in the preference for surgery group were the worst; by 12 months these were better than in the preference for medical treatment group. CONCLUSION: At least up to 12 months after surgery, laparoscopic fundoplication significantly increased measures of health status in patients with GORD. TRIAL REGISTRATION: ISRCTN15517081.

Marketing and clinical trials: a case study.

BACKGROUND: Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. METHODS: Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. RESULTS: The case study demonstrates that trials need various categories of people to buy in - hence, to be successful, trialists must embrace marketing strategies to some extent. CONCLUSION: The performance of future clinical trials could be enhanced if trialists routinely considered these factors.

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

BACKGROUND: Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). METHODS: In-depth semi-structured telephone interviews were conducted in 2003-04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. RESULTS: The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. CONCLUSION: This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies.

BACKGROUND: A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. METHODS: The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. RESULTS: Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. CONCLUSION: Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Persistent urinary incontinence and delivery mode history: a six-year longitudinal study.

OBJECTIVE: To investigate the prevalence of persistent and long term postpartum urinary incontinence and associations with mode of first and subsequent delivery. DESIGN: Longitudinal study. SETTING: Maternity units in Aberdeen (Scotland), Birmingham (England) and Dunedin (New Zealand). POPULATION: Women (4214) who returned postal questionnaires three months and six years after the index birth. METHODS: Symptom data were obtained from both questionnaires and obstetric data from case-notes for the index birth and the second questionnaire for subsequent births. Logistic regression investigated the independent effects of mode of first delivery and delivery mode history. MAIN OUTCOME MEASURES: Urinary incontinence-persistent (at three months and six years after index birth) and long term (at six years after index birth). RESULTS: The prevalence of persistent urinary incontinence was 24%. Delivering exclusively by caesarean section was associated with both less persistent (OR=0.46, 95% CI 0.32-0.68) and long term urinary incontinence (OR=0.50, 95% CI 0.40-0.63). Caesarean section birth in addition to vaginal delivery, however, was not associated with significantly less persistent incontinence (OR 0.93, 95% CI 0.67-1.29). There were no significant associations between persistent or long term urinary incontinence and forceps or vacuum extraction delivery. Other significantly associated factors were increasing number of births and older maternal age. CONCLUSIONS: The risk of persistent and long term urinary incontinence is significantly lower following caesarean section deliveries but not if there is another vaginal birth. Even when delivering exclusively by caesarean section, the prevalence of persistent symptoms (14%) is still high.

Low back pain: influence of early MR imaging or CT on treatment and outcome--multicenter randomized trial.

PURPOSE: To establish whether early use of magnetic resonance (MR) imaging or computed tomography (CT) influences treatment and outcome of patients with low back pain (LBP) and whether it is cost-effective. MATERIALS AND METHODS: In a multicenter randomized study, two imaging policies for LBP were compared in 782 participants with symptomatic lumbar spine disorders who were referred to orthopedists or neurosurgeons. Participants were randomly allocated to early (393 participants; mean age, 43.9 years; range, 16-82 years) or delayed selective (389 participants; mean age, 42.8 years; range, 14-82 years) imaging groups. Delayed selective imaging referred to imaging restricted to patients in whom a clear clinical need subsequently developed. Main outcome measures were Aberdeen Low Back Pain (ALBP) score, Short Form 36 (SF-36) score (for multidimensional health status), EuroQol (EQ-5D) score (for quality-adjusted life-year [QALY] estimates), and healthcare resource use at 8 and 24 months after randomization. Data were evaluated with analysis of covariance, ordinal logistic regression analysis, and chi(2) and Mann-Whitney tests. RESULTS: Both groups showed improvement in ALBP score, but this was greater in the early group (adjusted mean difference between groups, -3.05 points [95% CI: -5.16, -0.95; P =.005] and -3.62 points [95% CI: -5.92, -1.32; P =.002] at 8 and 24 months, respectively). Scores for SF-36 (bodily pain domain) and EQ-5D were also significantly better at 24 months. Clinical treatment was similar in both groups. Differences in total costs reflected cost of imaging. Imaging provided an adjusted mean additional QALY of 0.041 during 24 months at a mean incremental cost per QALY of $2,124. CONCLUSION: Early use of imaging does not appear to affect treatment overall. Decisions about the use of imaging depend on judgments concerning whether the small observed improvement in outcome justifies additional cost.

The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design.

BACKGROUND: In randomized trials there may be no overriding reason whether or not to have a placebo control. PURPOSE: We assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention. METHODS: We undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design. RESULTS: From 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85). CONCLUSIONS: We conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial.

Assessing the learning curve effect in health technologies. Lessons from the nonclinical literature.

INTRODUCTION: Many health technologies exhibit some from of learning effect, and this represents a barrier to rigorous assessment. It has been shown that the statistical methods used are relatively crude. Methods to describe learning curves in fields outside medicine, for example, psychology and engineering, may be better. METHODS: To systematically search non-health technology assessment literature (for example, PsycLit and Econlit databases) to identify novel statistical techniques applied to learning curves. RESULTS: The search retrieved 9,431 abstracts for assessment, of which 18 used a statistical technique for analyzing learning effects that had not previously been identified in the clinical literature. The newly identified methods were combined with those previously used in health technology assessment, and categorized into four groups of increasing complexity: a) exploratory data analysis; b) simple data analysis; c) complex data analysis; and d) generic methods. All the complex structured data techniques for analyzing learning effects were identified in the nonclinical literature, and these emphasized the importance of estimating intra- and interindividual learning effects. CONCLUSION: A good dividend of more sophisticated methods was obtained by searching in nonclinical fields. These methods now require formal testing on health technology data sets.