Efficient Source Data Verification Using Statistical Acceptance Sampling : A Simulation Study

Background: One approach to increase the efficiency of clinical trial monitoring is to replace 100% source data verification (SDV) by verification of samples of source data. An intuitive strategy for determining appropriate sampling plans (ie, sample sizes and the maximum tolerable number of transcription errors in the samples) is to use acceptance sampling methodology. Expanding upon earlier work in which the use of acceptance sampling strategies for sampling-based SDV was proposed, we describe an alternative acceptance sampling strategy that, instead of relying on sampling standards, evaluates all possible sampling plans algorithmically, thereby ensuring that selected sampling plans conform to prespecified criteria. Methods: Empirical trial data guided the design of the proposed strategy. In addition, extensive simulations, also based on the empirical data, were performed to assess the performance in terms of workload reductions and the post-SDV error proportion of applying the proposed strategy. Results: 13 different scenarios were simulated, but results of the default scenario show that the average pre-SDV error proportion per trial of.056 was reduced to.023 by inspecting only 40.5% of the case report form entries. Of the inspected data entries, almost half (18.0/40.5) was, on average, SDV-ed as part of the sampling process; remaining entries were inspected during full inspections after too many errors were observed in the samples. Conclusion: Our results suggest that major reductions in workload can be achieved, while maintaining acceptable data quality levels. However, the results also indicate that the proposed strategy is conservative and further improvement is possible

Predicting enrollment performance of investigational centers in phase III multi-center clinical trials

Failure to meet subject recruitment targets in clinical trials continues to be a widespread problem with potentially serious scientific, logistical, financial and ethical consequences. On the operational level, enrollment-related issues may be mitigated by careful site selection and by allocating monitoring or training resources proportionally to the anticipated risk of poor enrollment. Such procedures require estimates of the expected recruitment performance that are sufficiently reliable to allow centers to be sensibly categorized. In this study, we investigate whether information obtained from feasibility questionnaires can potentially be used to predict which centers will and which centers will not meet their enrollment targets by means of multivariable logistic regression analysis. From a large set of 59 candidate predictors, we determined the subset that is optimal for predictive purposes using Least Absolute Shrinkage and Selection Operator (LASSO) regularization. Although the extent to which the results are generalizable remains to be determined, they indicate that the prediction accuracy of the optimal model is only a marginal improvement over the intercept-only model, illustrating the difficulty of prediction in this setting. Keywords: Feasibility studies, Risk-based monitoring, Site performance prediction, Site questionnaires, Trial accrual, Trial recruitmen

The RISE study protocol: resilience impacted by positive stressful events for people with cystic fibrosis

Introduction For people with cystic fibrosis (CF), gaining access to elexacaftor/tezacaftor/ivacaftor (ETI) therapy, a new modulator drug combination, is perceived as a positive life event. ETI leads to a strong improvement of disease symptoms. However, some people with CF experience a deterioration in mental wellbeing after starting ETI therapy. The primary objective of this study is to investigate if and in which direction mental wellbeing of people with CF changes after starting ETI therapy. Our secondary objectives include, among others, investigation of underlying biological and psychosocial factors associated with a change in mental wellbeing of people with CF after starting ETI therapy. Methods and analysis The Resilience lmpacted by Positive Stressful Events (RISE) study is a single-arm, observational, prospective longitudinal cohort. It has a timeframe of 60 weeks: 12 weeks before, 12 weeks after, 24 weeks after and 48 weeks after the start of ETI therapy. The primary outcome is mental well-being, measured at each of these four time points. Patients aged ≥12 years at the University Medical Center Utrecht qualifying for ETI therapy based on their CF mutation are eligible. Data will be analysed using a covariance pattern model with a general variance covariance matrix. Ethics The RISE study was classified by the institutional review board as exempt from the Medical Research Involving Human Subjects Act. Informed consent was obtained by both the children (12–16 years) and their caregivers, or only provided by the participants themselves when aged ≥16 years

Predicting enrollment performance of investigational centers in phase III multi-center clinical trials

Failure to meet subject recruitment targets in clinical trials continues to be a widespread problem with potentially serious scientific, logistical, financial and ethical consequences. On the operational level, enrollment-related issues may be mitigated by careful site selection and by allocating monitoring or training resources proportionally to the anticipated risk of poor enrollment. Such procedures require estimates of the expected recruitment performance that are sufficiently reliable to allow centers to be sensibly categorized. In this study, we investigate whether information obtained from feasibility questionnaires can potentially be used to predict which centers will and which centers will not meet their enrollment targets by means of multivariable logistic regression analysis. From a large set of 59 candidate predictors, we determined the subset that is optimal for predictive purposes using Least Absolute Shrinkage and Selection Operator (LASSO) regularization. Although the extent to which the results are generalizable remains to be determined, they indicate that the prediction accuracy of the optimal model is only a marginal improvement over the intercept-only model, illustrating the difficulty of prediction in this setting

Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p p p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation

A computationally simple central monitoring procedure, effectively applied to empirical trial data with known fraud

OBJECTIVES: Central monitoring of multicenter clinical trials becomes an ever more feasible quality assurance tool, in particular for the detection of data fabrication. More widespread application, across both industry sponsored as well as academic clinical trials, requires central monitoring methodologies that are both effective and relatively simple in implementation. STUDY DESIGN AND SETTING: We describe a computationally simple fraud detection procedure intended to be applied repeatedly and (semi-)automatically to accumulating baseline data and to detect data fabrication in multicenter trials as early as possible. The procedure is based on anticipated characteristics of fabricated data. It consists of seven analyses, each of which flags approximately 10% of the centers. Centers that are flagged three or more times are considered "potentially fraudulent" and require additional investigation. The procedure is illustrated using empirical trial data with known fraud. RESULTS: In the illustration data, the fraudulent center is detected in most repeated applications to the accumulating trial data, while keeping the proportion of false-positive results at sufficiently low levels. CONCLUSION: The proposed procedure is computationally simple and appears to be effective in detecting center-level data fabrication. However, assessment of the procedure on independent trial data sets with known data fabrication is required

Series: Pragmatic trials and real world evidence : Paper 7. Safety, quality and monitoring.

Pragmatic trials offer the opportunity to obtain real-life data on the relative effectiveness and safety of a treatment before or after market authorisation. This is the penultimate paper in a series of eight, describing the impact of design choices on the practical implementation of pragmatic trials. This paper focuses on the practical challenges of collecting and reporting safety data and of monitoring trial conduct while maintaining routine clinical care practice. Current ICH guidance recommends that, all serious adverse events (SAEs) and all drug-related events must be reported in an interventional trial. In line with current guidance, we propose a risk based approach to the collection of non-drug related non-serious AEs, and even serious events not related to treatment based on the risk profile of the medicine/class in the patient population of interest. Different options available to support the collection and reporting of safety data whilst minimizing study-related follow-up visits are discussed. A risk-based approach to monitoring trial conduct is also discussed, highlighting the difference in the balance of risks likely to occur in a pragmatic trial compared to traditional clinical trials, and the careful consideration that must be given to the mitigation and management of these risks in order to maintain routine care

Safety of switching from vitamin K antagonist to non-vitamin K antagonist oral anticoagulant in frail elderly with atrial fibrillation : rationale and design of the FRAIL-AF randomised controlled trial

INTRODUCTION: Clinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with AF. METHODS AND ANALYSIS: The FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. TRIAL REGISTRATION NUMBER: EudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study)