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.

Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines recommend that patients with Staphylococcus aureus bloodstream infection (SAB) are treated with long courses of intravenous antimicrobial therapy. This serves to avoid SAB-related complications such as relapses, local extension and distant metastatic foci. However, in certain clinical scenarios, the incidence of SAB-related complications is low. Patients with a low-risk for complications may thus benefit from an early switch to oral medication through earlier discharge and fewer complications of intravenous therapy. The major objective for the SABATO trial is to demonstrate that in patients with low-risk SAB a switch from intravenous to oral antimicrobial therapy (oral switch therapy, OST) is non-inferior to a conventional course of intravenous therapy (intravenous standard therapy, IST). METHODS/DESIGN: The trial is designed as randomized, parallel-group, observer-blinded, clinical non-inferiority trial. The primary endpoint is the occurrence of a SAB-related complication (relapsing SAB, deep-seated infection, and attributable mortality) within 90 days. Secondary endpoints are the length of hospital stay; 14-day, 30-day, and 90-day mortality; and complications of intravenous therapy. Patients with SAB who have received 5 to 7 full days of adequate intravenous antimicrobial therapy are eligible. Main exclusion criteria are polymicrobial bloodstream infection, signs and symptoms of complicated SAB (deep-seated infection, hematogenous dissemination, septic shock, and prolonged bacteremia), the presence of a non-removable foreign body, and severe comorbidity. Patients will receive either OST or IST with a protocol-approved antimicrobial and are followed up for 90 days. Four hundred thirty patients will be randomized 1:1 in two study arms. Efficacy regarding incidence of SAB-related complications is tested sequentially with a non-inferiority margin of 10 and 5 percentage points. DISCUSSION: The SABATO trial assesses whether early oral switch therapy is safe and effective for patients with low-risk SAB. Regardless of the result, this pragmatic trial will strongly influence the standard of care in SAB. TRIAL REGISTRATION: ClinicalTrials.gov NCT01792804 registered 13 February 2013; German Clinical trials register DRKS00004741 registered 4 October 2013, EudraCT 2013-000577-77 . First patient randomized on 20 December 2013.

Requirements and tasks of cohorts and registers, the German KoRegIT project.

Epidemiological cohorts and registers (KoReg) are long lasting and complex research projects, which need systematic and extensive planning and steering. The aim of the KoRegIT project was to develop a generic catalogue of requirements to support the organisational- and IT-structure of KoReg. The catalogue of requirements comprises the top level (TL) tasks of the core processes. All TL were classified into the following project phases: 1. Development, 2. Operation, 3. Completion. According to the defined TL tasks, the appropriate use cases (UC) were identified. The catalogue currently specifies 45 TL tasks and 207 UC. The UC were elaborated by a short and standardized description of the task, the involved actors (human or external systems), the preconditions, which have to be fulfilled in order to realize this task, the normal flow of the task and the post conditions. The developed catalogue was reviewed by representatives of different KoReg in Germany. The draft catalogue of requirements was revised according to the reviewer's feedback and discussion. The revised and complete catalogue with all elaborated UC was reviewed again by further experts. The developed KoRegIT catalogue of requirements offers a supporting tool to set-up the organisational structures and processes of KoReg as well as the definition of the needed IT-infrastructure. In addition it can be used to optimize or to expand these structures.

Academic investigator-initiated trials and the challenge of sponsor responsibility: the Cologne Sponsor Model.

BACKGROUND: With the amendment to the German Drug Law in 2004, the conduct of clinical trials changed by at least two main aspects: (1) The principles of Good Clinical Practice (GCP) were implemented in the national legislation, and (2) for the first time, the function of the sponsor of a clinical trial and the clinical trial itself have become legally binding definitions. By that, legal differences between industrial and academic clinical trials no longer exist. Clinical trials initiated by investigators have to fulfil the same requirements while the entire sponsor responsibility has to be carried out by the Coordinating Investigator or his institution including implementation of a quality management system according to the GCP. PURPOSE: The Cologne Sponsor Model is an effective approach with settings, structures, basic features, action, and reporting lines, as well as funding for clinical trials initiated in an academic environment. RESULTS: The University of Cologne assumes the sponsor responsibility for clinical trials organised by the university researchers according to law. Sponsor's duties are delegated to a central operational unit of the sponsor - the Clinical Trials Center Cologne - which further delegates duties to the Coordinating Investigator. Clinical Trials Center Cologne was established in 2002 to support the performance of clinical trials at the university by offering comprehensive advisory and practical services covering all aspects of study planning and conduct. Furthermore, a specialised division of its quality management department acts as an independent sponsor's Quality Assurance Unit. The Clinical Trials Center Cologne has established a quality management system consisting of different components (1) to enable a reasoned decision to subsequent delegation, (2) for risk-based surveillance of trial conduct (audits, monitoring-checks, and reports), and (3) support and training of the Coordinating Investigator. LIMITATIONS: Double functions of persons and departments in the university environment sometimes make it difficult to define roles in such a model. Therefore, it is necessary to establish clear reporting lines and moreover to monitor regularly and carefully the roles and responsibilities. CONCLUSIONS: With the combination of central management and support, control and independence of the researchers, our model represents a 'risk-based' system that offers a sensible option that fulfils the requirements of legal regulations and GCP for trials organised within the university environment.

Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group.

PURPOSE: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy. PATIENTS AND METHODS: In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%. RESULTS: Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%). CONCLUSION: The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.

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.

Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial.

PURPOSE: To investigate whether combined-modality treatment (CMT) with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by extended-field radiotherapy (EF-RT) is superior to EF-RT alone in patients with early favorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Between 1993 and 1998, 650 patients with newly diagnosed, histology-proven HL in clinical stages IA to IIB without risk factors were enrolled onto this multicenter study and randomly assigned to receive 30 Gy EF-RT plus 10 Gy to the involved field (arm A) or two cycles of ABVD followed by the same radiotherapy (arm B). Results At a median observation time of 87 months, there was no difference between treatment arms in terms of complete response rate (arm A, 95%; arm B, 94%) and overall survival (at 7 years: arm A, 92%; arm B, 94%; P = .43). However, freedom from treatment failure was significantly different, with 7-year rates of 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%; P

Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease.

BACKGROUND: Faced with unsatisfactory results of treatment for advanced Hodgkin's disease, we investigated three combinations of chemotherapy. METHODS: From 1993 to 1998, 1201 eligible patients 15 to 65 years of age who had newly diagnosed Hodgkin's disease in unfavorable stage IIB or IIIA or stage IIIB or IV were randomly assigned to receive eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); or increased-dose BEACOPP, each followed by local radiotherapy when indicated. Enrollment in the COPP-ABVD group was stopped in 1996 owing to inferior results. RESULTS: For the final analysis, 1195 of 1201 patients could be evaluated: 260 in the COPP-ABVD group, 469 in the BEACOPP group, and 466 in the increased-dose BEACOPP group; the median follow-up was 72, 54, and 51 months, respectively. The rate of freedom from treatment failure at five years was 69 percent in the COPP-ABVD group, 76 percent in the BEACOPP group, and 87 percent in the increased-dose BEACOPP group (P=0.04 for the comparison of the COPP-ABVD group with the BEACOPP group and P<0.001 for the comparison of the increased-dose BEACOPP group with the COPP-ABVD group and with the BEACOPP group), and the five-year rates of overall survival were 83 percent, 88 percent, and 91 percent, respectively (P=0.16 for the comparison of the COPP-ABVD group with the BEACOPP group, P=0.06 for the comparison of the BEACOPP group with the increased-dose BEACOPP group, and P=0.002 for the comparison of the COPP-ABVD group with the increased-dose BEACOPP group). Rates of early progression were significantly lower with increased-dose BEACOPP than with COPP-ABVD or standard BEACOPP. CONCLUSIONS: Increased-dose BEACOPP resulted in better tumor control and overall survival than did COPP-ABVD.

Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin's lymphoma: final results of the German Hodgkin's Lymphoma Study Group Trial HD5.

PURPOSE: To investigate whether treatment results in intermediate-stage Hodgkin's lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks. PATIENTS AND METHODS: From January 1988 to January 1993, 996 patients in stage I or II Hodgkin's lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkin's lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy. RESULTS: Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each). CONCLUSION: Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkin's lymphoma and produce excellent long-term treatment results.