To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs).
Electronic databases. Handsearching of selected books. Personal contacts with experts in the field.
...Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions.
Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial.
Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.
BACKGROUND: Enhanced recovery protocols (ERPs) have the potential to streamline care and improve short-term outcomes for surgical patients. However, for patients undergoing modern iterations of ...complex abdominal wall reconstruction (AWR), little literature exists on the effectiveness of these protocols. STUDY DESIGN: In this retrospective study we reviewed our institutional experience with complex AWR throughout a 2-year period with 1 year immediately before and 1 year after implementation of our ERP. Patients undergoing primarily minimally invasive complex AWR who were compliant with 11 elements of our ERP were compared with patients who received surgery before implementation of the protocol or did not meet these criteria. Baseline patient characteristics and patient outcomes including hospital length of stay, narcotic usage, and readmission were compared across groups. Multivariable regression models were used to estimate the associations of our ERP protocol with outcomes adjusting for surgical approach. RESULTS: Median length of stay for the overall cohort (n = 132) was 3 days (interquartile range 1 to 4). Morbidity and mortality rates were 22.6% and 0.7%, respectively. ERP patients were less likely to have a complication (ERP compliant 8.7% n = 46 vs non-ERP 30.2% n = 86, p < 0.01), had a shorter median postoperative length of stay (median 1 vs 3 days, p < 0.01), and received fewer morphine equivalents (median 30.8 vs 45 mg, p < 0.01). Readmission rate for ERP patients did not differ significantly vs non-ERP patients (6.5% vs 11.8%, p = 0.34). CONCLUSIONS: Use of ERPs in patients undergoing complex AWR may provide benefits for both patients and hospitals.
Formal monitoring of data from randomised controlled trials (RCTs) is becoming more common. Wide variation exists in the structure and organisation of data monitoring committees (DMCs), with little ...guidance on how they should operate. We used various strategies to consider the behavioural, procedural, and organisational aspects of data monitoring in RCTs: systematic reviews of DMCs and small group processes in decision making; surveys of reports of RCTs, recently completed and ongoing RCTs, and the policies of major organisations connected with RCTs; detailed case studies of four DMCs that faced difficult decisions; and interviews with experienced DMC members. The findings aided the development of a template for a charter for DMCs. We summarise the findings and outline the key considerations at every stage of the data monitoring process. Widespread use of a charter for the structure and organisation of DMCs would promote a systematic and transparent approach, and enable them to operate more effectively and efficiently.
Abstract Background Right ventricular failure (RVF) is associated with significant morbidity after left ventricular assist device (LVAD) surgery. Hemodynamic, clinical, and 2-dimensional ...echocardiographic variables poorly discriminate patients at risk of RVF. We examined the utility of 3-dimensional echocardiography (3DE) right ventricular (RV) volumetric assessment to identify patients at risk for RVF. Methods and Results RVF was defined as the need for inotropic infusion for >14 days after LVAD surgery or the need for biventricular assist device support. Preoperative RV volumes and ejection fraction (EF) were measured, blinded to clinical data, from transthoracic 3DE full volume data sets in 26 patients. Baseline variables and 3DE RV indices were compared between patients with and without RVF. Twenty-four patients received continuous-flow LVADs, and 2 required biventricular support devices. Ten patients required prolonged inotropes after LVAD placement. Baseline characteristics associated with RVF included higher right atrial pressure, higher right atrial pressure to pulmonary capillary wedge pressure ratio, and lower cardiac index and RV stroke work index (RVSWI). Echocardiographic indices associated with RVF included 3DE indexed RV end-diastolic and end-systolic volumes (RVEDVI and RVESVI) and RV ejection fraction (RVEF). The relationship between 3DE quantification of RV volumes and the development of RVF was independent from RVSWI: RVEDVI: odds ratio (OR) 1.16, 95% confidence interval (CI) 1.00–1.33 ( P = .04); RVESVI: OR 1.14, 95% CI 1.01–1.28 ( P = .03). Conclusions Quantitative 3DE is a promising method for pre-LVAD RV assessment. RV volumes assessed by 3DE are predictive of RVF in LVAD recipients independently from hemodynamic correlates of RV function.
In judging whether or not to continue enrolling patients into a randomised clinical trial, most datamonitoring and ethics committees (DMECs) rely on the p value for the difference in effect between ...the study groups. In the 1990s, two randomised controlled trials—one in patients with lung cancer and one in those with head and neck cancer—were instead monitored by Bayesian methods. We assessed the value of this approach in the monitoring of these clinical trials.
Before the trials opened, participating clinicians were asked their opinions on the expected difference between the study treatment (continuous hyperfractionated accelerated radiotherapy CHART) and conventional radiotherapy. These opinions were used to form an “enthusiastic” and a “sceptical” prior distribution. These prior distributions were combined with the trial data at each of the annual DMEC meetings. If, during monitoring, a result in favour of CHART was seen, the DMEC was to decide whether the results were sufficiently convincing to persuade a sceptic that CHART was worthwhile. Conversely, if there was apparently no or little difference, the DMEC was asked whether they thought the results sufficiently convincing to persuade an enthusiast that CHART was not worthwhile.
At each of the annual meetings, the DMEC concluded that there was insufficient evidence to convert either sceptics or enthusiasts, and that the trials should therefore remain open to recruitment. Neither trial was closed to recruitment earlier than planned. However if a conventional (p-value-based) stopping rule had been used, the lung-cancer trial would probably have been stopped.
This Bayesian approach to monitoring is simple to implement and straightforward for members of the DMEC to understand. In our opinion, it is more intuitively appealing than conventional approaches.
Use of conventional magnetic resonance imaging (MRI) for target definition may expose glioblastomas (GB) to inadequate radiation dose coverage of the nonenhanced hypercellular subvolume. This study ...aimed to develop a technique to identify the hypercellular components of GB by using high b-value diffusion-weighted imaging (DWI) and to investigate its relationship with the prescribed 95% isodose volume (PDV) and progression-free survival (PFS).
Twenty-one patients with GB underwent chemoradiation therapy post-resection and biopsy. Radiation therapy (RT) treatment planning was based upon conventional MRI. Pre-RT DWIs were acquired in 3 orthogonal directions with b-values of 0, 1000, and 3000 s/mm(2). Hypercellularity volume (HCV) was defined on the high b-value (3000 s/mm(2)) DWI by a threshold method. Nonenhanced signified regions not covered by the Gd-enhanced gross tumor volume (GTV-Gd) on T1-weighted images. The PDV was used to evaluate spatial coverage of the HCV by the dose plan. Association between HCV and PFS or other clinical covariates were assessed using univariate proportional hazards regression models.
HCVs and nonenhanced HCVs varied from 0.58 to 67 cm(3) (median: 9.8 cm(3)) and 0.15 to 60 cm(3) (median: 2.5 cm(3)), respectively. Fourteen patients had incomplete dose coverage of the HCV, 6 of whom had >1 cm(3) HCV missed by the 95% PDV (range: 1.01-25.4 cm(3)). Of the 15 patients who progressed, 5 progressed earlier, within 6 months post-RT, and 10 patients afterward. Pre-RT HCVs within recurrent GTVs-Gd were 78% (range: 65%-89%) for the 5 earliest progressions but lower, 53% (range: 0%-85%), for the later progressions. HCV and nonenhanced HCV were significant negative prognostic indicators for PFS (P<.002 and P<.01, respectively). The hypercellularity subvolume not covered by the 95% PDV was a significant negative predictor for PFS (P<.05).
High b-value DWI identifies the hypercellular components of GB and could aid in RT target volume definition. Future studies will allow us to investigate the role of high b-value DWI in identifying radiation boost volumes and diagnosing progression.
Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate ...cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP.
Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP.
A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82–1.65); failure-free survival HR=0.51 (95% CI 0.39–0.67); progression-free survival HR=0.65 (95% CI 0.48–0.88); metastasis-free survival HR=0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR=1.02 (0.70–1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.
This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.
Clinicaltrials.gov: NCT00268476.
Because of censoring, standard methods of plotting individual survival times are invalid. Therefore, graphic display of time-to-event data usually takes the form of a Kaplan–Meier survival plot. ...Kaplan–Meier plots, however, make differences between groups seem larger than they really are. To overcome these limitations, we developed a technique for producing scatter plots with survival data and applied it to data from a randomized trial of patients with renal cancer. As of June 21, 2001, 25 of the 347 patients with kidney cancer in the Medical Research Council RE01 randomized treatment trial for whom data were available had been censored, and the remainder had died. Values of the censored survival times were imputed by assuming a log-normal distribution in survival times and by drawing a random sample given that that each patient with censored data survived at least to the point of censoring. The combined original and imputed data were then examined by use of dot plots and scatter plots. In the RE01 trial, median survival of patients treated with interferon was 3.0 months (95% confidence interval = 0.3 to 5.5 months) longer than that in patients treated with medroxyprogesterone acetate. The Kaplan–Meier analysis showed clear separation between treatment groups and between prognostic groups. In contrast, comparisons of individual observed and imputed survival times between groups of patients showed considerable overlap and gave a more realistic idea of the modest between-group differences than Kaplan–Meier comparisons. These graphs of the distribution of survival times for individuals in each study group, which are simple to produce, may usefully complement Kaplan–Meier plots.
Learning from errors in nursing practice Meurier, C.E.; Vincent, C.A.; Parmar, D.G.
Journal of advanced nursing,
July 1997, Letnik:
26, Številka:
1
Journal Article
Recenzirano
Little attention is paid to the issue of errors in nursing practice. Staff are reluctant to discuss or publicize them. However, as clinical audit and quality management become more important and ...established in the health service, there is now a greater need to investigate and monitor the incidence of errors. The purpose of this study was to examine the causes and consequences of errors as well as the potential for errors to initiate changes in practice. One hundred and twenty‐nine nurses answered a 22‐item questionnaire relating to an error they had made. Nurses reported that the most common causes of errors were lack of knowledge or information, work overload, stressful atmosphere and lack of support from senior staff. Nurses were found to have recourse to a number of coping strategies in the aftermath of the error. Accepting responsibility and planful problem‐solving were found to lead to positive changes in practice, whereas distancing and self‐controlling strategies were associated with defensive changes, particularly with a tendency not to divulge the error. The findings also showed that errors had the potential to effect learning. The study suggests the need for staff to be encouraged to accept responsibility for their error within the framework of support. Strategies should be developed so that errors can be managed in a more constructive manner.
Summary Background The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings ...reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. Methods RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b–T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3–6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. Findings Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1–10·8). Overall survival at 10 years was 71% (95% CI 66–75) in each group (hazard ratio HR 0·99, 95% CI 0·77–1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 57% in the control group and 170 43% in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38–48) in the control group and 55% (50–61) in the escalated-dose group (HR 0·69, 95% CI 0·56–0·84; p=0·0003). Interpretation At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. Funding UK Medical Research Council.
PDF
