Best practice guidance for the use of strategies improved retention in randomised trials developed from two consensus workshops

OBJECTIVE: To develop best practice guidance for the use of retention strategies in randomised clinical trials (RCTs). DESIGN: Consensus development workshops. SETTING: Two UK Clinical Trials Units. PARTICIPANTS: 66 statisticians, clinicians, RCT coordinators, research scientists, research assistants, and data managers associated with RCTs. METHODS: The consensus development workshops were based on the consensus development conference method used to develop best practice for treatment of medical conditions. Workshops commenced with a presentation of the evidence for: incentives, communication, questionnaire format, behavioural, case management and methodological retention strategies identified by a Cochrane review and associated qualitative study. Three simultaneous group discussions followed, focused on: a) how convinced the workshop participants were by the evidence for retention strategies, b) barriers to the use of effective retention strategies, c) types of RCT follow-up that retention strategies could be used for, and d) strategies for future research. Summaries of each group discussion were fed back to the workshop. Coded content for both workshops were compared for agreement and disagreement. Agreed consensus on best practice guidance for retention was identified. RESULTS: Workshop participants agreed best practice guidance for the use of small financial incentives to improve response to postal questionnaires in RCTs. Use of 2nd class post was thought to be adequate for postal communication with RCT participants. The most relevant validated questionnaire was considered best practice for collecting RCT data. Barriers identified for the use of effective retention strategies were: the small improvements seen in questionnaire response for the addition of monetary incentives, and perceptions among trialists that some communication strategies are outdated. Furthermore, there was resistance to change existing retention practices thought to be effective. Face to face and electronic follow-up technologies were identified as retention strategies for further research. CONCLUSIONS: We developed best practice guidance for the use of retention strategies in RCTs and identified potential barriers to the use of effective strategies. The extent of agreement on best practice is limited by the variability in the currently available evidence. This guidance will need updating as new retention strategies are developed and evaluated

Long-term outcomes with intensive induction chemotherapy (carboplatin, bleomycin, vincristine and cisplatin/bleomycin, etoposide and cisplatin) and standard bleomycin, etoposide and cisplatin in poor prognosis germ cell tumours: A randomised phase II trial (ISRCTN53643604).

Background Up to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%-85%).Aim To assess long-term outcomes and late toxicity associated with CBOP/BEP.Methods Patients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis.Results Eighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not.Conclusion Although not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted.Trial registration ISRCTN 53643604

Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study

Background/aims: In multi-site clinical trials, where trial data and conduct are scrutinised centrally with pre-specified triggers for visits to sites, targeted monitoring may be an efficient way to prioritise on-site monitoring. This approach is widely used in academic trials, but has never been formally evaluated. // Methods: TEMPER assessed the ability of targeted monitoring, as used in three ongoing phase III randomised multi-site oncology trials, to distinguish sites at which higher and lower rates of protocol and/or Good Clinical Practice violations would be found during site visits. Using a prospective, matched-pair design, sites that had been prioritised for visits after having activated ‘triggers’ were matched with a control (‘untriggered’) site, which would not usually have been visited at that time. The paired sites were visited within 4 weeks of each other, and visit findings are recorded and categorised according to the seriousness of the deviation. The primary outcome measure was the proportion of sites with ≥1 ‘Major’ or ‘Critical’ finding not previously identified centrally. The study was powered to detect an absolute difference of ≥30% between triggered and untriggered visits. A sensitivity analysis, recommended by the study’s blinded endpoint review committee, excluded findings related to re-consent. Additional analyses assessed the prognostic value of individual triggers and data from pre-visit questionnaires completed by site and trials unit staff. // Results: In total, 42 matched pairs of visits took place between 2013 and 2016. In the primary analysis, 88.1% of triggered visits had ≥1 new Major/Critical finding, compared to 81.0% of untriggered visits, an absolute difference of 7.1% (95% confidence interval −8.3%, +22.5%; p = 0.365). When re-consent findings were excluded, these figures reduced to 85.7% versus 59.5%, (difference = 26.2%, 95% confidence interval 8.0%, 44.4%; p = 0.007). Individual triggers had modest prognostic value but knowledge of the trial-related activities carried out by site staff may be useful. // Conclusion: Triggered monitoring approaches, as used in these trials, were not sufficiently discriminatory. The rate of Major and Critical findings was higher than anticipated, but the majority related to consent and re-consent with no indication of systemic problems that would impact trial-wide safety issues or integrity of the results in any of the three trials. Sensitivity analyses suggest triggered monitoring may be of potential use, but needs improvement and investigation of further central monitoring triggers is warranted. TEMPER highlights the need to question and evaluate methods in trial conduct, and should inform further developments in this area

Radiotherapy for malignant gliomas in the elderly

While fractionated external beam radiotherapy remains the principal treatment in patients with histologically verified malignant glioma, its use in older patients and in patients with adverse prognostic features has not been subject to randomized studies. Hypofractionated partial brain irradiation offers a short, well-tolerated treatment with a palliative benefit for patients with a predicted median survival of less than 6 months. To assess its true efficacy in terms of survival and quality-of-life gain requires a formal randomized comparison with supportive care either alone or in combination with palliative chemotherapy and with radical radiotherapy. On present evidence, palliative radiotherapy remains the appropriate treatment for older patients and those with adverse prognostic features, but the final choice should be based on the patient’s wishes moderated by the clinician’s perception of the gain of treatment