Study Monitoring in Emergency Care Trials: Lessons from the Resuscitation Outcomes Consortium Continuous Chest Compressions Trial.

OBJECTIVE: Clinical trial investigators often assemble internal study monitoring committees (SMCs) to measure individual or group adherence with trial performance benchmarks. We examined the processes and results of study monitoring in an international trial of out-of-hospital cardiac arrest. METHODS: We studied SMC operations for the Resuscitation Outcomes Consortium (ROC) Continuous Chest Compressions (CCC) trial, which compared continuous with interrupted chest compressions upon survival after out-of-hospital cardiac arrest. The SMC defined trial performance benchmarks, which included compliance with the intervention, cardiopulmonary resuscitation (CPR) process data availability and timely data completion. Trial investigators received monthly performance reports. We determined rates of trial noncompliance and suspension from the trial. RESULTS: ROC-CCC enrolled a total of 23,711 subjects in the primary analysis population. Across 113 enrolling agencies, the SMC monitored performance for a total 2,367 agency-months. Emergency medical services agencies were on probation for a total of 178 (7.5%) agency-months. Fifty-five agencies were placed on probation at least once, of which 78% improved their performance and were approved for continued participation in the trial. A total of 12 agencies were suspended from trial participation. Data monitoring resulted in high-quality CPR (mean chest compression fraction = 0.80), 87% CPR process availability and timely data completion (75th and 95th percentiles prehospital data = 22 and 57 days; hospital data = 58 and 118 days). CONCLUSIONS: Study monitoring procedures may play an important role in ensuring the performance quality in acute care clinical trials.

Reporting on data monitoring committees in neonatal randomised controlled trials is inconsistent.

AIM: To evaluate the reported use of data monitoring committees (DMCs), the frequency of interim analysis, prespecified stopping rules and early trial termination in neonatal randomised controlled trials (RCTs). METHODS: We reviewed neonatal RCTs published in four high-impact general medical journals, specifically looking at safety issues including documented involvement of a DMC, stated interim analysis, stopping rules and early trial termination. We searched all journal issues over an 11-year period (2003-2013) and recorded predefined parameters on each item for RCTs meeting inclusion criteria. RESULTS: Seventy neonatal trials were identified in four general medical journals: Lancet, New England Journal of Medicine (NEJM), British Medical Journal and Journal of American Medical Association. A total of 43 (61.4%) studies reported the presence of a DMC, 36 (51.4%) explicitly mentioned interim analysis, stopping rules were reported in 15 (21.4%) RCTs and seven (10%) trials were terminated early. The NEJM most frequently reported these parameters compared to the other three journals reviewed. CONCLUSION: While the majority of neonatal RCTs report on DMC involvement and interim analysis, there is still scope for improvement. Clear documentation of safety-related issues should be a central component of reporting in neonatal trials involving newborn infants.

Stopping guidelines for an effectiveness trial: what should the protocol specify?

BACKGROUND: Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials. MAIN TEXT: To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions: 1. How should the relative importance of the treatment benefits and hazards be assessed? 2. For decisions to stop a trial for benefit: (a) What would be the minimum clinically important difference for the study population? (b) How should the probability that the benefit exceeds that difference be assessed? (c) When should the interim analyses include data from other trials? (d) Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines? 3. Should less evidence be required to stop the trial for harm than for benefit? 4. When should conventional stopping guidelines for futility be used for comparative effectiveness trials? CONCLUSION: Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.

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Independent data monitoring committees: preparing a path for the future.

Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

Stopping guidelines for harm in a study designed to establish the safety of a marketed drug.

In a study designed to establish the safety of a marketed drug, interim analyses performed to detect harm can protect trial participants and the wider public before the final analysis occurs. Monitoring for harm within a safety study is different from monitoring for benefit, so techniques commonly used in an efficacy study of an experimental drug may not apply. We propose potentially more suitable techniques in this setting, including a novel spending function and conditional power. These techniques have reasonable operating characteristics in a simulation. The appropriate technique to implement will depend on circumstances of specific to the individual safety study.

An opinion and practice survey on the structure and management of data and safety monitoring boards.

There is little to no empirical data available on how data and safety monitoring boards (DSMBs) are structured and how they operate. The purpose of this study was to provide data on this. To accomplish this goal, we administered a random survey on current structure and management practices and opinions as reported by principal investigators (PIs) and biostatisticians. We also surveyed Institutional Review Board (IRB) community members, as proxies for the public, as to their opinions on how DSMBs should be structured and managed. A final purpose was to compare opinions about what should be taking place to what is actually happening.

[Malpractice in the treatment of supracondylar humeral fractures in children - experience of the arbitration office of the Northern German Medical Boards]. / Fehler bei der Behandlung suprakondylärer Humerusfrakturen bei Kindern - Erfahrungen der Norddeutschen Schlichtungsstelle.

INTRODUCTION: Arbitration offices ("Schlichtungsstellen") in Germany are expert panels for the extrajudicial resolution of malpractice claims. The performance of arbitration panel proceedings ("Schlichtungsverfahren") is based on the German medical and insurance jurisdiction. In Germany, and in the United States likewise, malpractice claims involving children concern in most cases fracture treatment followed by appendicitis. Out of 242 panel proceedings with the background of fracture treatment in children malpractice was confirmed in 144 cases (60%). The overall ratio: number of confirmed malpractices to number of all proceedings is 30%. There are remarkable differences between the natural occurrence of the different fracture localisations and the fracture localisation related claims. This ratio amounts for example: clavicula 7 : 1, forearm 2 : 1, femur 1 : 5, elbow region (articular) 1 : 5, humerus supracondylar 1 : 3. METHOD: 32 arbitration panel proceedings concerning alleged malpractice in the treatment of supracondylar humeral fractures in children were evaluated in regards to diagnosis of fracture type and degree of dislocation, conservative and operative fracture treatment, complications, and malpractice related permanent disabilities. RESULTS: In 20 cases (63%) malpractice was confirmed. The different failures could be classified in: 1) Incorrect interpretation of the X-ray findings, classified as fractures without or with minimal displacement, no reduction, healing with intolerable dislocation; n = 3. 2) Insufficient closed or open fracture reduction, stabilisation and healing with intolerable dislocation; n = 10. 3) Correct primary closed or open reduction, unstable osteosynthesis (loss of pin fixation of the ulnar epicondylus), secondary postoperative rotatory dislocation, cubitus varus; n = 3. 4) Delayed detection of a compartment syndrome of the forearm, no or delayed fasciotomy; n = 3, in two cases resulting in severe Volkmann's contracture. 5) Extensive skin necrosis caused by uncontrolled tourniquet under operation. All malunited fractures, except one, led to cubitus varus, often combined with a restriction (extension/flexion) of the mobility of the elbow joint. No cubitus valgus was found in our series. In eight cases a cubitus varus was treated by valgus osteotomy later on. In other cases this procedure was planned. Adverse events which could not be proven as caused by malpractice, included fracture consolidation in minimal tolerable displacement, n = 3; delayed recurrence of the normal mobility of the elbow joint, n = 2; traumatic cubitus varus caused by primary damage of the humero-ulnar epiphysis, n = 3; pin track infection, n = 1; nerve injuries, n = 10. The concomitant nerve injuries concerned: n. medianus 3, n. ulnaris 2, n. radialis 1, nn. radialis and ulnaris 3, nn. medianus and ulnaris 1. In all these cases the claim was based only or together with other reproaches on the nerve injury, but in no case could a malpractice be confirmed. However it should be mentioned that in some cases a iatrogenic nerve injury could not be excluded definitively. Therefore we always recommend the exploration and documentation of the function of the arm nerves at admittance and immediately after treatment. The applied methods of osteosynthesis were pin fixation, crossed or unilateral radial, n = 30; radial screw, n = 1; elastic stable intramedullary nailing fixation (ESIN), n = 1; fixateur externe (reoperation), n = 1. In no case the method of osteosynthesis was proven as inapplicable or as the cause for the adverse event. Permanent disabilities were considered to be slight in 12 cases (deficient mobility of the elbow joint) and severe in two cases (Volkmann's contracture). Physiotherapy was not found to be beneficial for the restitution of normal mobility of the elbow joint after supracondylar fracture. In at least 7 cases painful physiotherapy was applied, although the X-ray films clearly demonstrated the displaced fracture as the cause of the restricted mobility. In 5 casuistic representations of adverse events after treatment of a supracondylar humeral fracture, the final decision of the arbitration board on the basis of expert reports is illustrated. CONCLUSION: The results are discussed in order to avoid mistakes in the treatment of supracondylar humeral fracture in children. The appropriate treatment requires exact assessment of the degree and direction of the fracture dislocation, clear definition of the cases in which active treatment, i.e. closed or open reduction and stabilisation, is obligatory, and experience in the operative treatment. A beginning compartment syndrome of the forearm should be detected early by the initial symptoms and immediately treated by fasciotomy.

A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials.

BACKGROUND: Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of Data Monitoring Committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials. METHODS: We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination. RESULTS: 110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included; 68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%); 62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods. CONCLUSIONS: Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.

[Clinical safety and patient oriented care: descriptive study of 113 Spanish hospitals and similarities in other European countries]. / Seguridad clínica y orientación al paciente: estudio descriptivo en 113 hospitales españoles y similitudes en otros países europeos.

OBJECTIVES: This study describes the stage of development of the Spanish acute care hospitals quality improvement systems. It also presents data on their achievement of some specific requirements related to clinical safety and patient oriented care. Additional data from seven other European countries are included, in order to provide a comparative reference for the analysis of results. MATERIAL AND METHODS: Cross-sectional descriptive study developed in acute care hospitals with more than 100 beds from 8 European countries. Data was gathered using an on-line questionnaire that had more than 500 close questions. In order to validate the responses, a sample of the hospitals that had answered the questionnaire received an evaluation by external assessors. RESULTS: A total of 113 public and private Spanish hospitals participated in the study, which represented 34% of the total group that met the inclusion criteria. Another 276 hospitals from 7 other countries also answered the questionnaire. The results associated with quality management, clinical safety and patient oriented care from both groups are presented. CONCLUSIONS: Improvements must be made in those areas where Spanish hospitals have a lower developmental level than the rest of the participating countries: public dissemination of results from external quality assessments, development of some key mechanisms to promote clinical safety and patient involvement in organisational management.

Management and interpretation of data obtained from clinical trials in pain management.

Conducting a clinical trial involves various stages of planning and implementation. The three major components involved in clinical trials are the management of data, the quality control to ensure data integrity, and the interpretation of the data at the conclusion of the trial. Although each process is distinct and involves different levels of effort and knowledge to implement, all processes are intimately linked. Data management techniques include the process of data entry and the implementation of an organized, comprehensive approach to quality control. Some guidelines for quality control screening are recommended to address various common issues related to clinical data, such as missing data, invalid cases, subject "outliers," and violation of distributional assumptions relevant to statistical analyses. In order to aid in interpreting the data, conditions that need to be met to make causal inferences are discussed. Taking into account baseline characteristics of the patient sample is also discussed as an extension to maintaining the internal validity of the study. Additionally, some common threats to statistical conclusion validity, including Type I error inflation and the problem of overpowered tests, are highlighted. Finally, the concept of the effect size as an important complement to statistical significance and how the various types of effect size measures can be interpreted within the context of a clinical trial are discussed.

The use of interim data and Data Monitoring Committee recommendations in randomized controlled trial reports: frequency, implications and potential sources of bias.

BACKGROUND: Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). Data Monitoring Committees (DMCs) often undertake such analyses, but their widening role may lead to extended use of interim analysis or recommendations that could potentially bias trial results. METHODS: Systematic search of eight major publications: Annals of Internal Medicine, BMJ, Circulation, CID, JAMA, JCO, Lancet and NEJM, including all randomised controlled trials (RCTs) between June 2000 and May 2005 to identify RCTs that reported use of interim analysis, with or without DMC involvement. Recommendations made by the DMC or based on interim analysis were identified and potential sources of bias assessed. Independent double data extraction was performed on all included trials. RESULTS: We identified 1772 RCTs, of which 470 (27%; 470/1772) reported the use of a DMC and a further 116 (7%; 116/1772) trials reported some form of interim analysis without explicit mention of a DMC. There were 28 trials (24 with a formal DMC), randomizing a total of 79396 participants, identified as recommending changes to the trial that may have lead to biased results. In most of these, some form of sample size re-estimation was recommended with four trials also reporting changes to trial endpoints. The review relied on information reported in the primary publications and methods papers relating to the trials, higher rates of use may have occurred but not been reported. CONCLUSION: The reported use of interim analysis and DMCs in clinical trials has been increasing in recent years. It is reassuring that in most cases recommendations were made in the interest of participant safety. However, in practice, recommendations that may lead to potentially biased trial results are being made.

Ensuring trial validity by data quality assurance and diversification of monitoring methods.

Errors in the design, the conduct, the data collection process, and the analysis of a randomized trial have the potential to affect not only the safety of the patients in the trial, but also, through the introduction of bias, the safety of future patients. Trial monitoring, defined broadly to include methods of oversight which begin when the study is designed and continue until it is reported in a publication, has a role to play in eliminating such errors. On-site monitoring can be extremely inefficient for the identification of errors most likely to compromise patient safety or bias study results. However, a variety of other monitoring strategies offer alternatives to on-site monitoring. Each new trial should conduct a risk assessment to identify the optimal means of monitoring, taking into account the likely sources of error, their consequences for patients, the study's validity, and the available resources. Trial management committees should consider central statistical monitoring a key aspect of such monitoring. The systematic application of this approach would be likely to lead to tangible benefits, and resources that are currently wasted on inefficient on-site monitoring could be diverted to increasing trial sample sizes or conducting more trials.

Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode.

OBJECTIVES: To provide an accurate estimation of the magnitude of effect of lithium in short-term efficacy studies conducted in patients with moderate to severe manic episode. METHODS: All placebo-controlled randomized studies submitted to the Medicines Evaluation Board (MEB) in which lithium was used as the third study arm were selected for the meta-analysis. The studies were part of registration files submitted to the MEB between the years 1997 and 2005. In addition, Medline and EMbase searches were conducted with the key words 'manic' ('mania' for the EMbase search) and 'placebo' in order to identify additional placebo-controlled studies of lithium. This search was updated until March 1, 2006. Two effect size indicators were used based on the primary outcome measure of each study: Cohen's standardized effect size based on the difference in mean change from baseline, and numbers needed to treat (NNT) based on the difference in treatment response defined as >or=50% improvement from baseline on day 21. RESULTS: Six studies were identified. They involved a combined total of 470 patients in the lithium groups and 562 in the placebo groups. The overall standardized effect size was 0.40 [95% confidence interval (CI): 0.28, 0.53] and the overall NNT for response was 6 (95% CI: 4, 13). In the placebo groups response rates varied from 21% to 47%. CONCLUSIONS: The results indicate that lithium is an effective drug in the treatment of moderate to severe manic episode. The variability in placebo response indicates that a placebo control arm in efficacy studies among patients with moderate to severe manic episode is necessary.

The brain tumor board: lessons to be learned from an interdisciplinary conference.

BACKGROUND: The aim of this study is to analyze the work of the interdisciplinary Brain Tumor Board (BTB) which was established at Freiburg University Hospital in 1998. PATIENTS AND METHODS: From January 1998 to December 2003, a total of 1,516 patients were discussed in 259 meetings of the BTB. The protocols of the BTB were analyzed retrospectively. RESULTS: In 79% of the patients, the diagnosis was based on histological findings or a typical radiological appearance of a lesion, or both. This group was composed of 4 subgroups: 28% benign skull base tumors (19% meningiomas, 4% pituitary adenomas, 3% acoustic schwannomas, 2% others), 24% primary brain tumors of glial origin (8% glioblastomas, 12% gliomas other than glioblastomas, 5% oligoastrocytomas or oligodendrogliomas), 19% brain metastases, and 8% other brain or skull base tumors. In 13% of the cases, the exact diagnosis was still unknown when the patient was presented. 8% of the presentations were motivated by nontumorous interdisciplinary problems (e.g. arterio-venous malformations). The recommendations given by the BTB included: 23% further diagnostic procedures (11% non-invasive examinations, 12% stereotactic biopsies), 57% active antitumoral therapy (22% resection, 17% fractionated radiotherapy, 13% radiosurgery, 5% chemotherapy, <1% embolization), 20% no treatment (14% watchful waiting, 6% supportive care). 91% of the BTB recommendations were realized within 3 months. CONCLUSION: Interdisciplinary care seems to be particularly necessary in patients with benign skull base tumors, gliomas and brain metastases. Decisions made in a small interdisciplinary group of experts have a high potential of subsequently being realized.

Reported use of data monitoring committees in the main published reports of randomized controlled trials: a cross-sectional study.

BACKGROUND: We describe a review of published main reports of randomized controlled trials (RCTs), in order to measure the frequency of reported use of data monitoring committees (DMCs) and factors associated with reported DMC use. METHODS: Twenty-four higher impact general and specialist medical journals were handsearched for main reports of RCTs in order to provide a cross-sectional sample of trials published in the year 2000. Additionally, the same general medical journals were handsearched for 1990 to allow a comparison across time. RESULTS: Of 662 RCTs published in 2000, 120 (18%) explicitly reported using a DMC, while 107 (16%) reported planned interim analyses. Overall, about a quarter (24%) reported at least one of these. A higher proportion of trials reported using a DMC in 2000 than 1 990 (70/282, 25% versus 21/204, 10%) in the general medical journals. Logistic regression models suggested the more important variables associated with increased reported DMC use were: later year of publication, publication in general medical journal, survival-based endpoint, multicentre trial, increasing number of patients recruited, at least one arm involving a placebo, at least one arm involving a drug, factorial design and USA involvement in the trial. CONCLUSIONS: In 2000, about a quarter of main RCT reports mention use of a DMC. Actual use of DMCs is likely to be somewhat greater. Reporting use of a DMC was more likely for larger and longer trials among other factors. We believe the factors affecting reported use affect actual use. It is recommended that when a DMC oversees a trial, brief details should be explicitly included in the main trial paper. Standard nomenclature for DMCs is recommended.

Acceptability and profile of the clinical drug trials underway in Finnish university hospitals in the 1990s: applications reviewed by ethics committees.

There is scarce information in literature about the decisions made by ethics committees concerning the clinical studies they have reviewed. A retrospective, detailed review of 666 applications, their amendments and the ethics committees' statements was undertaken. All protrocols of clinical studies on medicinal products submitted to and reviewed by the ethics committees of two university hospitals during the years 1992, 1994, 1996 and 1998 were investigated. Most of the studies were international (50%), multicenter (71%), phase III trials (41%) on a new clinical entity, (38%). Validity of the clinical drug study applications was acceptable in more than half of the cases (364; 55%), while 91 (14%) were approved with advisory comments, 153 (23%) had to be amended, 35 (5%) were left pending and 23 (3%) were rejected. Most of the questions pertained to informed consent and the study protcol. In accordance with precious results, our findings support the opinion that the submitted documents need to be improved, especially with regard to informed consent and study protocols, in order to gain better Good Clinical Practice (GCP) compliance. Well-defined, documented operating procedures of the ethics committees would have facilitated the practical issues in the review process.