Risk-adapted monitoring is not inferior to extensive on-site monitoring: Results of the ADAMON cluster-randomised study.

Background According to Good Clinical Practice, clinical trials must protect rights and safety of patients and make sure that the trial results are valid and interpretable. Monitoring on-site has an important role in achieving these objectives; it controls trial conduct at trial sites and informs the sponsor on systematic problems. In the past, extensive on-site monitoring with a particular focus on formal source data verification often lost sight of systematic problems in study procedures that endanger Good Clinical Practice objectives. ADAMON is a prospective, stratified, cluster-randomised, controlled study comparing extensive on-site monitoring with risk-adapted monitoring according to a previously published approach. Methods In all, 213 sites from 11 academic trials were cluster-randomised between extensive on-site monitoring (104) and risk-adapted monitoring (109). Independent post-trial audits using structured manuals were performed to determine the frequency of major Good Clinical Practice findings at the patient level. The primary outcome measure is the proportion of audited patients with at least one major audit finding. Analysis relies on logistic regression incorporating trial and monitoring arm as fixed effects and site as random effect. The hypothesis was that risk-adapted monitoring is non-inferior to extensive on-site monitoring with a non-inferiority margin of 0.60 (logit scale). Results Average number of monitoring visits and time spent on-site was 2.1 and 2.7 times higher in extensive on-site monitoring than in risk-adapted monitoring, respectively. A total of 156 (extensive on-site monitoring: 76; risk-adapted monitoring: 80) sites were audited. In 996 of 1618 audited patients, a total of 2456 major audit findings were documented. Depending on the trial, findings were identified in 18%-99% of the audited patients, with no marked monitoring effect in any of the trials. The estimated monitoring effect is -0.04 on the logit scale with two-sided 95% confidence interval (-0.40; 0.33), demonstrating that risk-adapted monitoring is non-inferior to extensive on-site monitoring. At most, extensive on-site monitoring could reduce the frequency of major Good Clinical Practice findings by 8.2% compared with risk-adapted monitoring. Conclusion Compared with risk-adapted monitoring, the potential benefit of extensive on-site monitoring is small relative to overall finding rates, although risk-adapted monitoring requires less than 50% of extensive on-site monitoring resources. Clusters of findings within trials suggest that complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings. Risk-adapted monitoring in only a sample of patients appears sufficient to identify systematic problems in the conduct of clinical trials. Risk-adapted monitoring has a part to play in quality control. However, no monitoring strategy can remedy defects in quality of design. Monitoring should be embedded in a comprehensive quality management approach covering the entire trial lifecycle.

Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials.

BACKGROUND: The concept of risk assessment for clinical trials has been discussed before, but no comprehensive structured procedure leading to risk-adapted quality management has been published so far. Such a procedure is of particular interest for noncommercial trials in order to optimally use the sparse resources. PURPOSE: To provide a structured procedure for risk analysis in clinical trials. To propose strategies for on-site monitoring adapted to the risks identified. RESULTS: The risk analysis refers to the risk of noncompliance with the main objectives of Good Clinical Practice. It takes into account risks of the study intervention compared to the risks a patient would run if treated outside a protocol as well as further potential risks regarding patient safety, patient rights, or the credibility of results. The risk analysis is based on detailed questionnaires, which are used to draw up (a) an on-site monitoring strategy recommendation, (b) a list of trial-specific tasks to be covered by on-site monitoring, and (c) a specification of further quality management measures e.g., central monitoring measures. The resulting risk-adapted monitoring strategies focus on the trial's critical aspects, and differ in terms of the recommended extent of on-site activities. LIMITATIONS: The effectiveness of the proposed risk analysis and risk-adapted monitoring has not yet been confirmed. However, the ADAMON project (prospective cluster-randomised study of trial-specific adapted strategies for on-site monitoring in combination with additional quality management measures) has been started in Germany to investigate whether a trial-specific, risk-adapted, reduced on-site monitoring strategy is as effective as an intensive monitoring strategy with regard to the occurrence of serious or critical audit findings. Twelve clinical trials planning to recruit more than 3200 patients participate in this investigation. CONCLUSIONS: Our proposal will provide sponsor-investigators and other noncommercial sponsors with an instrument that may facilitate risk analysis and the implementation of targeted quality management measures.

Serum hyaluronate correlates with histological progression in alcoholic liver disease.

OBJECTIVES: Chronic alcohol consumption may lead to the development of liver cirrhosis. Serum concentrations of hyaluronate were suggested as a predictor in chronic liver disease, but its power to distinguish between severity of fibrosis and inflammation had not been assessed. In order to evaluate hyaluronate as a marker to detect early stages of alcoholic liver disease and to establish a possible correlation with hepatic histology, serum concentrations were measured by radioimmunoassay in 87 patients with biopsy-proven fatty liver, fatty liver and mild fibrosis, fatty liver and inflammation, severe fibrosis and inflammation, and cirrhosis, and in 12 non-alcoholic control subjects. In addition, serum hyaluronate was determined in 40 non-cirrhotic alcoholic patients with either a normal serum aspartate aminotransferase (AST) or an AST elevated at least two-fold. RESULTS: Serum hyaluronate increased significantly with advanced stages of alcoholic liver disease, while levels in patients with fatty liver were elevated only slightly without reaching significance. Hyaluronate correlated well with histological stage and was highly sensitive for detecting fibrosis in general and perivenular fibrosis as an indicator of progression to cirrhosis. Hyaluronate levels were not influenced by AST levels. CONCLUSION: Serum hyaluronate is a good predictor of the presence of even moderate hepatic fibrosis in alcoholic liver disease, justifying its clinical use to assess morphological alterations of the liver in alcoholics.

Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries.

BACKGROUND: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. METHODS: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). RESULTS: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. CONCLUSIONS: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.