Clinical Trials: Rethinking How We Ensure Quality

Landray, Martin J; Grandinetti, Cheryl; Kramer, Judith M.; Morrison, Briggs W.; Ball, L.; Sherman, Rachel E.

doi:10.1177/0092861512464372

Cited by 20 publications

(15 citation statements)

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“…Several publications suggest that reliable results can be generated in real-world settings in large trials as long as randomisation and avoidance of systematic bias is guaranteed. 4 , 3 , 26 Two publications 27 , 28 suggest that data corrections triggered by source data verification only minimally affect trial outcomes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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BackgroundAccording 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.MethodsIn 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).ResultsAverage 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.ConclusionCompared 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 t...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…number of hours per visit) within risk category: 1. site experience with clinical trials 2. presence of an electronic database at site 3. whether site is coordinating lead site of the study An additional risk assessment is required if the trial undergoes substantial amendments 1–3 conducted according to the Swiss Clinical Trial Organization Guidelines for Good Operational Practice V2.0. Scheme adapted from Hurley et al [ 23 ]. a Including indicators on vulnerability of study population, setting of recruitment, critical eligibility criteria, additional risks of therapy, trial procedures that are unusually complex, etc.…”

Section: Methodsmentioning

confidence: 99%

“… 1–3 conducted according to the Swiss Clinical Trial Organization Guidelines for Good Operational Practice V2.0. Scheme adapted from Hurley et al [ 23 ]. a Including indicators on vulnerability of study population, setting of recruitment, critical eligibility criteria, additional risks of therapy, trial procedures that are unusually complex, etc.…”

Section: Methodsmentioning

confidence: 99%

Generating evidence on a risk-based monitoring approach in the academic setting – lessons learned

Niederhäusern

Orleth

Schädelin

et al. 2017

BMC Med Res Methodol

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BackgroundIn spite of efforts to employ risk-based strategies to increase monitoring efficiency in the academic setting, empirical evidence on their effectiveness remains sparse. This mixed-methods study aimed to evaluate the risk-based on-site monitoring approach currently followed at our academic institution.MethodsWe selected all studies monitored by the Clinical Trial Unit (CTU) according to Risk ADApted MONitoring (ADAMON) at the University Hospital Basel, Switzerland, between 01.01.2012 and 31.12.2014. We extracted study characteristics and monitoring information from the CTU Enterprise Resource Management system and from monitoring reports of all selected studies. We summarized the data descriptively. Additionally, we conducted semi-structured interviews with the three current CTU monitors.ResultsDuring the observation period, a total of 214 monitoring visits were conducted in 43 studies resulting in 2961 documented monitoring findings. Our risk-based approach predominantly identified administrative (46.2%) and patient right findings (49.1%). We identified observational study design, high ADAMON risk category, industry sponsorship, the presence of an electronic database, experienced site staff, and inclusion of vulnerable study population to be factors associated with lower numbers of findings. The monitors understand the positive aspects of a risk-based approach but fear missing systematic errors due to the low frequency of visits.ConclusionsWe show that the factors mostly increasing the risk for on-site monitoring findings are underrepresented in the current risk analysis scheme. Our risk-based on-site approach should further be complemented by centralized data checks, allowing monitors to transform their role towards partners for overall trial quality, and success.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-017-0308-6) contains supplementary material, which is available to authorized users.

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“…The Clinical Trials Transformation Initiative (CTTI) has recently reemphasized the importance of prospectively building quality into the scientific and operational design of clinical trials (“quality-by-design”; see Figure 1 ), rather than relying only on retrospective monitoring, inspection, or scientific review. 11 , 12 This approach evolved from concepts used in pharmaceutical manufacturing. It adapts the idea of prospectively designing quality into manufacturing processes, rather than testing for it at the end, to the clinical research environment.…”

mentioning

confidence: 99%

Enhancing clinical evidence by proactively building quality into clinical trials

et al. 2016

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Background:Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight.Methods:The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials (“quality-by-design”), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach.Conclusion:The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial’s quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors.

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Clinical Trials: Rethinking How We Ensure Quality

Cited by 20 publications

References 1 publication

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

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

Generating evidence on a risk-based monitoring approach in the academic setting – lessons learned

Enhancing clinical evidence by proactively building quality into clinical trials

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