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

Associated data.

Supplemental material, 793379_supp_mat for Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study by Sally P Stenning, William J Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R Sydes and Sarah Meredith in Clinical Trials

Supplemental material, 793379_supp_mat_2 for Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study by Sally P Stenning, William J Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R Sydes and Sarah Meredith in Clinical Trials

Supplemental material, 793379_supp_mat_3 for Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study by Sally P Stenning, William J Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R Sydes and Sarah Meredith in Clinical Trials

Supplemental material, 793379_supp_mat_4 for Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study by Sally P Stenning, William J Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R Sydes and Sarah Meredith in Clinical Trials

Supplemental material, 793379_supp_mat_5 for Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study by Sally P Stenning, William J Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R Sydes and Sarah Meredith in Clinical Trials

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.

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.

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.

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.

Introduction

Clinical trial monitoring is defined by the International Conference on Harmonisation (ICH) as ‘The act of overseeing the progress of a clinical trial, and ensuring that it is conducted, recorded and reported in accordance with the protocol, Standard Operating Procedures, Good Clinical Practice (GCP), and the applicable regulatory requirements’, and aims to protect the rights and well-being of trial participants, while ensuring protocol compliance and data integrity. 1

Monitoring often relies on-site visits, an approach recommended in ICH GCP guidance: ‘In general there is a need for on-site monitoring …’ (section 5.18.3). 1 Through that guidance, and following high-profile data fraud cases, 2 on-site monitoring has become a standard means of ensuring GCP compliance since the 1990s, at least in industry-sponsored trials. Visit activities commonly include intensive document review, in particular, source data verification (SDV): the process of checking case report form data against source notes. While this may be done in a sample of patients, or on selected data items on all patients, many trials’ site visits aim to check 100% of trial data. 3 Intensive on-site monitoring has been highlighted as inefficient and associated with significant costs 4 – 9 which are passed down to patients and healthcare systems as drug development expenses. 2 , 4

A growing body of evidence shows that 100% SDV is of limited value. 10 – 13 Trialists 14 , 15 and regulators 16 – 18 have expressed support for ‘risk-based monitoring’, recognising that not all clinical trials require the same approach to quality control and assurance. This is reflected in the update of ICH GCP E6. 19

One risk-based approach is ‘triggered’ or ‘targeted’ on-site monitoring. It was suggested as a possible option for trials of investigational medicinal products classed as low or medium risk by the Medicines and Healthcare products Regulatory Agency, Medical Research Council (MRC), and UK Department of Health. 16 An initial risk assessment determines the key risks resulting from the intervention and the design of the trial and strategies to minimise those risks are specified. If triggered monitoring is selected, over the course of the trial sites are prioritised for visits based on central monitoring ‘triggers’: predefined indicators such as number of protocol deviations, case report form return rates, uncommon patterns of serious adverse event reporting or subjective assessments of site performance. Such targeted monitoring is also mentioned as a possible approach in the update to ICH GCP E6. 19

Although triggered monitoring approaches are not uncommon 3 and have clear potential benefits in terms of resource-use, there is no empirical evidence to show how well they work. TEMPER was designed to provide such evidence.

Study design

TEMPER is a prospective, matched-pair study assessing the value of triggered monitoring in distinguishing sites with important protocol or GCP compliance issues not identified centrally. Trials unit teams used triggers to identify sites to visit (‘triggered visit’). Each of these was matched with an ‘untriggered site’, and the paired sites were visited and monitored according to the trial’s monitoring plan. Site visit findings were categorised according to a standard classification based on a high-level summary ( Table 1 ). We compared the proportion of triggered and untriggered visits with ≥1 Major/Critical finding not identified through central monitoring or previous visits. The study design is summarised in Figure 1 . We developed a bespoke system, the TEMPER Management System (TEMPER-MS) to support implementation of the study. 20

Classification of monitoring findings in TEMPER.

TEMPER study design.

Ethics committee advice deemed no ethical review was required because the additional site visits were within the scope of each trial’s monitoring plan. To ensure visits were arranged and conducted as per normal practice, site staff were not explicitly informed about the TEMPER study or the reason for a monitoring visit.

Trial selection

Included trials were conducted and monitored by the MRC Clinical Trials Unit at University College London; sponsored by the UK MRC; employing a triggered monitoring strategy; investigational medicinal products risk category B (‘somewhat higher risk than standard medical care’) according to MRC/Department of Health/Medicines and Healthcare products Regulatory Agency risk classification. 16 Trials also needed to have started recruitment before 2012 and plan follow-up to continue until after 2014.

Triggers were based on those in use in the selected trials, with some additional quantification where thresholds of concern had not previously been defined. The triggers were mainly quantitative although subjective ‘general concerns’ could also be added to each site’s overall trigger score in response to, for example, worrying contact with a site or other more objective concerns not captured by the trial’s triggers. As risks and monitoring needs changed over time, some new triggers were added and/or thresholds modified (e.g. one trial demanded a higher threshold for data return ahead of an interim analysis). Table 2 summarises and exemplifies the trigger types used by trial at the completion of TEMPER.

Trigger types used during the course of TEMPER by trial.

CRF: case report form; SAE: serious adverse event.

Site selection

We scheduled regular ‘trigger meetings’ (3–6 monthly or more frequently if required) with trials unit teams to review trigger data. Sites’ trigger scores were calculated by the TEMPER-MS and reviewed by the trial teams to decide which sites to visit. Chosen sites usually had the highest total trigger scores, but general concerns sometimes led to other sites being prioritised. All trigger meeting discussions were documented.

To replicate real-life prioritisation by resource-limited trial teams, we asked teams to distinguish between sites that would definitely be visited in normal practice (‘triggered-and-usually-visited’); and those, usually with lower trigger scores, considered lower priority for a visit at that time (‘triggered-but-not-usually-visited’); both are grouped as ‘triggered visits’ for the primary analysis.

The TEMPER-MS matching algorithm proposed ‘untriggered’ sites to visit, minimising differences in (1) number of patients and (2) time since first patient randomised, while maximising differences in trigger score (see Appendix in Supplementary Material and Diaz-Montana et al. 20 ). The closest match was accepted, unless there were clearly documented reasons not to. For example, an untriggered site that had been visited very recently outwith TEMPER was replaced with the next closest match.

Site visits

To maximise similarity between triggered and untriggered monitoring visits, they were all conducted according to the trial’s monitoring plan with the same planned checks at all visits in addition to follow-up of any specific concerns raised by the trials unit team. These were broadly similar across the trials in the study: monitoring usually included SDV on a sample of patients and review of consent forms, pharmacy documents and facilities, and Investigator Site Files.

We aimed to conduct all visits within 3 months after the trigger meeting, with paired visits as close together as possible, and no more than 28 days apart. The triggered visit was planned before its untriggered match to help ensure that any changes to monitoring visit approach implemented by the trial team at the time of the triggered visit could be reflected in the paired visit. All monitors performed the same roles at site visits. Triggered visits were attended by TEMPER-specific and trial-specific monitors, untriggered visits only by TEMPER monitors. The same GCP and monitoring training was undertaken both by the trial team members attending visits and the monitors; the latter also received trial-specific training. A TEMPER-specific monitoring visit report ensured consistent reporting. Reports were written and followed-up according to each trial’s monitoring plan and trials unit procedures.

Data collection, finding classification and endpoint definition

Findings were classified as ‘Critical’, ‘Major’ or ‘Other’ (see Table 1 ), with their final grade taking account of any relevant response from the site to the monitoring report. All Critical and Major findings were further categorised as new or ‘already known prior to the monitoring visit’ (e.g. through central monitoring or self-reporting by the site). The latter were excluded from the primary outcome, but included in the monitoring report to allow follow-up to resolution by the trial team as required. The protocol provided detailed guidance on appropriate gradings (see Online Supplementary Material ). This was updated to incorporate new findings as they arose. Selected findings (related to consent and missed serious adverse events in particular), if repeated to a predefined level, could be ‘upgraded’ from ‘Other’ to ‘Major’ or from ‘Major’ to ‘Critical’. In these cases, one additional finding of the higher grade was added to the total findings for that visit.

Outcome measures

The primary outcome measure was the proportion of sites with ≥1 Major or Critical finding not already identified through central monitoring or a previous visit (‘new’ findings). Secondary outcomes were number of Major and Critical findings, proportion of sites with ≥ 1 Critical finding, number of Critical findings and category of Major/Critical findings.

Sample size

Sample size calculations, based on review of previous trials unit monitoring reports from trials using triggered monitoring, assumed ∼70% of triggered visits would produce ≥1 new Major/Critical finding. To detect an absolute reduction of ≥30% (from 70% to 40%) in untriggered sites, with 80% power and two-sided significance level of 5%, required ∼84 site visits in 42 matched pairs. We sought balanced numbers of visits across trials and required ≥50% of each trial’s triggered visits to be ‘triggered and usually visited’. Ten additional, unmatched visits were made to high recruiting sites not otherwise selected for visits, to allow further assessment of ‘high recruitment’ as a predictor of findings in secondary analyses.

The primary analysis was a two-group comparison of the proportion of sites with ≥1 new Major/Critical finding in the triggered versus untriggered groups. Analyses of total numbers of Major and Critical findings used one-sample t-tests of the within-pair differences. Prior to the first analysis, the TEMPER Endpoint Review Committee recommended a sensitivity analysis to exclude all findings related to re-consent, as these typically communicated minor changes in side-effect profile that could have been communicated without requiring re-consent. A second, exploratory analysis, excluded all consent-related findings because previous research suggested that these could likely be identified centrally. 21 , 22

In secondary analyses, using all 94 visits, and with additional information of potential prognostic value obtained from questionnaires completed by the Trials unit and site staff prior to the monitoring visits (see Online Supplementary Material ), the ability of individual triggers and site characteristics to predict on-site findings was assessed by comparing the proportion of visits with the outcome of interest (Eg ≥ 1 Major/Critical finding) at sites where a trigger had/had not fired. This utilised chi-square tests (with trend for ordered categories) or Fisher’s exact test as appropriate for univariate analyses and logistic regression for multivariate analyses.

Consistency

To reduce intra- and inter-observer bias, in addition to Monitor training and the use of the categorisation system, a Consistency Monitoring Group, comprising trials unit staff from the participating trials’ teams, discussed suitable gradings for findings. The Endpoint Review Committee comprised four experienced trialists from the trials unit with no direct link to the trials, and reviewed, for all visit reports and blind to whether the visit was triggered or untriggered, all Major and Critical findings and a selection of Other findings. They also performed cross-visit reviews of similar sorts of findings to ensure consistency of grading. The categorisation appendix and grading of relevant findings from previous visits were updated if required following Consistency Monitoring Group or Endpoint Review Committee discussions.

Three trials were included; all randomised, multicentre (>100 sites) cancer treatment trials with a time-to-event outcome measure (recurrence-free or overall survival), planned accrual of >1000 patients and paper-based data collection.

Site selection and matching

In total, 23 trigger meetings and 84 paired monitoring visits took place between 2013 and 2016 ( Figure 1 ). Triggered and untriggered sites had mean trigger scores of 4.0 (range of 2–6) and 0.8 (range of 0–3), respectively. The matching algorithm gave mean within-pair differences (triggered–untriggered) of -1.4 months (70.1 vs 71.5) in time since first randomisation and +8.5 (49.9 vs 41.4) in patients randomised.

Visit conduct

Three visits were >1 week outside the 3-month visit window. Five untriggered visits were >28 days after their triggered match, the longest gap being 4 months; the continued suitability of the untriggered match as a control was confirmed at the next trigger meeting. One untriggered visit was before its triggered match because of a short-notice postponement.

The median (interquartile range) number of trials unit staff attending triggered and untriggered visits was 3 (2–3) and 2 (2–2), respectively (Wilcoxon p < 0.01). Visit conduct within pairs was similar in most respects: full Investigator Site File checks were done at 25/42 triggered and 27/42 untriggered visits (p = 0.65), pharmacy facility checks at 25 and 29, respectively (p = 0.36), while the median (interquartile range) number of patients undergoing SDV was 4 (3–5) and 4 (3–5), respectively (paired t-test p = 0.08). However, more consent forms were checked at triggered (median (interquartile range): 44 (27–77)) than untriggered visits (35 (18–70)) (paired t-test p = 0.01).

Primary outcome: Major/Critical findings

Table 3 summarises all Major and Critical findings, and Table 4 summarises the primary outcome; 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 (CI) –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% CI 8.0%, 44.4%; p = 0.007)); while excluding all consent and re-consent findings reduced them further to 69.0% versus 45.2% (difference = 23.8% (95% CI 3.3%, 44.4%; p = 0.027)). Findings by trial are summarised in Table S1 in the Online Supplementary Material .

Summary of Major and Critical findings at TEMPER monitoring visits.

CRF: case report form; SDV: source data verification; SAE: serious adverse event.

Primary and secondary binary outcomes.

CI: confidence interval.

Secondary outcomes

Critical findings ( Online Supplementary Material Table S2 ) were almost solely from consent form and source data reviews. The majority (59%) were upgrades because of a cumulative number of Major findings, and the remainder were graded Critical in their own right. The proportion of visits with Critical findings was approximately halved in untriggered visits, but these differences were of borderline statistical significance ( Table 4 ).

The median number of new Major and Critical findings ( Table 5 ) was three at triggered visits and one at untriggered visits; the mean within-pair difference was 1.40 (95% CI –0.72, 3.53; p = 0.19) for all findings, 1.05 (95% CI 0.032, 2.06; p = 0.044) excluding re-consent findings and 0.48 (95% CI –0.12, 1.08; p = 0.12) excluding all consent findings (when the median number of findings was 1 and 0, respectively). The median number of new Critical findings was zero at all visits.

Secondary continuous outcomes.

Prognostic value of individual triggers

The ability of specific triggers to predict the presence of Major and/or Critical findings at the site visit was assessed across all outcomes ( Online Supplementary Material Tables S3 and S4 ). While the finding rates tended to be higher when the trigger had been fired at the time of site selection, only three triggers showed even a modest association with outcome (p < 0.05 for at least one outcome, no adjustment for multiple testing). These were ‘data query resolution time’, ‘protocol deviation’ and ‘general concern’. Multivariate analyses were carried out for each outcome measure, but resulted in univariate models only, namely, the trigger with the strongest association with that outcome measure in the univariate analysis.

High-recruiting sites were defined as the top 10% of trial sites ordered by recruitment at the time of the site visit. The prognostic value of high recruitment on outcomes was investigated excluding all consent findings, as the number of consent forms checked was directly related to number of patients. We found no evidence of higher finding rates at these sites.

Other site characteristics

Trials unit teams completed 90/94 pre-visit questionnaires. There was no clear evidence of a linear relationship between the trial team ratings and the presence of Major or Critical findings, including or excluding consent findings (data not shown).

Pre-visit site questionnaires were provided by 76/94 sites. There was no evidence of a linear association between the chance of ≥1 Major/Critical finding and the number of active trials either per site or per staff member. There was, however, evidence that the greater the number of different trial roles undertaken by the Research Nurse, the lower the probability of Major/Critical findings. To a lesser extent, the reverse was true for the principal investigator (see Online Supplementary Material Table S5 ).

We have shown that triggered monitoring, as used in these trials, did not satisfactorily distinguish sites with higher and lower levels of concerning on-site monitoring findings. The pre-specified primary comparison showed no significant difference between triggered and untriggered visits in the proportion with ≥1 Major/Critical finding not previously identified centrally. However, over 70% of on-site findings related to issues in recording informed consent, and 70% of these to re-consent; the pre-specified sensitivity analysis excluding re-consent findings demonstrated a clear difference in event rate. There was some heterogeneity between trials in the primary comparison, but much greater consistency in the sensitivity and secondary analyses. In addition, there was some evidence that the trigger process used could identify sites at increased risk of serious concern: around twice as many triggered visits had ≥1 Critical finding, in the primary and sensitivity analyses. Thus, we would suggest that triggered monitoring has promise, but clearly needs refinement.

The categorisation framework we used is, we believe, similar to those applied by regulators to the same findings. However, these typically identify a finding of importance in relation to an individual patient, when it is only by accumulation that these are likely to have serious impact on the trial as a whole. Risk-based monitoring is not looking for perfection in trial data or conduct, but to detect errors that really matter. We found no visit findings that raised serious issues that would apply across sites, involved serious trial-wide safety issues, or suggested any biases across trial arms which would impact credibility of the trials’ results.

The prevalence of sites with Major and Critical findings was higher than expected, echoing the experience of others. 23 However, the great majority of our findings, like others’, 24 related to documenting the consent process, for example, ensuring that correct versions are used, and signatures and dates are present and consistent with the timing of randomisation. The ‘quality by design’ concept 25 states the first course of action should be preventive; informed consent form templates used by academic clinical trials units should, therefore, be reviewed to see if their design can be improved and completion errors reduced. Timely central monitoring of consent forms with adequate anonymisation 22 may mitigate the effects of many consent form completion errors, particularly if trial treatment timelines mean that full consent forms – or at least selected items – can be reviewed before randomisation.

Re-consent was usually provoked by updates to drug safety information, of which participants (at least those still on treatment) should be aware. This can be a lengthy process and therefore difficult to monitor centrally. When re-consent is explicitly required, better central monitoring methods are possible, perhaps using site logs with lists of expected visit dates. However, although regulatory guidance is clear that participants must be informed about significant trial updates, the method is not specified. 19 Research Ethics Committees and Institutional Review Boards may prefer formal, documented informed re-consent, but this may not always be necessary. Waiting until the participant’s next trial visit may sometimes be inferior (certainly in terms of speed) to sending an immediate letter to the participants explaining the changes and asking them to contact their site only if they have concerns.

Beyond consent processes, the majority of other findings were identified from SDV activities. A growing body of evidence suggests intensive SDV is often of little benefit to randomised controlled trials, with any discrepancies found having minimal impact on the robustness of trial conclusions. 11 , 12 , 26 SDV for a sample of participants may be sufficient to detect systematic problems, 27 , 28 and focussing SDV only on key data items may be appropriate and rational.

We carried out exploratory analyses of the prognostic value of individual triggers to see if visits to sites at which a specific trigger had fired were substantially more likely to find Major or Critical findings than visits to sites at which this trigger was not fired. The sample size was sufficient to detect an absolute difference of approximately 30% in finding rates. Some triggers, including high or low serious adverse event rates, were rarely met so their prognostic value could not be assessed. Three triggers were of potential, though still at best modest value, given the multiple outcome measures assessed: the speed of data query resolution, protocol deviations and ‘general concern’. These triggers were not wholly independent, and it was not possible to combine them in a way that improved finding rate discrimination more than our triggered/not triggered visit categorisation. We note that high recruitment and poor case report form return rates, although commonly used as triggers 3 were not of clear prognostic value.

Analysis of site staffing and workload suggested that the fewer trial responsibilities held by the research nurse, the higher the chance of a Major/Critical finding, with a trend to the converse (mainly when findings relating to consent are excluded), in relation to the principal investigator. These findings suggest that, while an insufficiently supported and possibly overstretched investigator may impact adversely on trial conduct, an experienced, capable local Research Nurse, able to take responsibility for many elements of trial conduct, is key.

Ultimately, the sensitivity and specificity of triggered monitoring depends on the selection of triggers. We found Major and Critical findings at untriggered visits, suggesting it remains necessary to visit these sites unless central monitoring techniques can be improved or the discriminatory value of triggers can increase. We used the trials’ existing triggers – quantified more precisely where needed to facilitate ranking of sites – without any prior assessment of their potential value. The search for more discriminatory triggers should encompass work on Key Performance Indicators 29 and Central Statistical Monitoring. 30 Subjective assessments may be of value, but are perhaps more prone to inconsistency, particularly when staff turnover is high, and therefore, harder to generalise. We might also optimise current triggers, for example, with better (non-dichotomous) treatment of continuous variables or greater incorporation of temporal trends.

Planning, conducting and follow-up on monitoring visits is time-consuming and therefore costly, 2 , 8 , 9 so maximising cost-benefit is key. We did not routinely use triggers to guide the content of site visits which was perhaps not optimal. Refined triggers could target specific activities, for example, data quality issues could provoke SDV visits and general concerns could provoke additional training. Prospective study of trigger-defined visits is warranted.

Central monitoring enables review of information across sites and time without the time constraints of a site visit. Maximising these strengths would free more time at visits for targeted SDV and activities best done in-person, for example, process review, building rapport or training.

We acknowledge several limitations. TEMPER was conducted in only three trials of similar type although we see no reason to doubt its applicability to other trials. The trials unit staff present at triggered and untriggered visits were not blind to visit type. TEMPER monitors were at all visits, but trial team staff were only required to attend triggered visits. However, the additional staff at triggered visits often included new trial staff attending for training purposes and the planned activities were the same at all visits. The only notable difference in completed activity within pairs was the number of consent forms checked, which was higher in the triggered visits compared to the untriggered visits. While this could have increased the chance of findings at triggered visits, this appears not to have been the case, the difference in finding rates being greater when consent findings were excluded. Observation bias due to lack of blinding of monitoring staff was mitigated by consistent training on the trials and monitoring methods, the use of a common finding grading system and independent review of all Major and Critical findings which was blind to visit type.

The sample size was modest, but nonetheless adequately powered to detect the minimal differences in visit finding rates necessary to support the triggered monitoring strategy employed in these trials. TEMPER assessed the value of pre-existing triggers, rather than first exploring the best triggers. Evidence to support triggered monitoring comes largely from our sensitivity and exploratory analyses, although these were pre-planned, and recommended by an independent committee, which was blind to visit type.

Research into trial conduct rarely has the rigour we demand of clinical trials. The motivation to study this area comprises (1) the need to monitor trials effectively, minimising risk to patients’ rights and safety and protecting data integrity and (2) the need to do so in a cost-effective manner, noting that monitoring activities are a major component of trial conduct costs at the coordinating centre. TEMPER is one of the few studies to address monitoring strategies in a prospective manner, 23 , 31 , 32 and the first, we believe, to specifically evaluate triggered monitoring. Its results should help challenge and guide the future use of triggered monitoring.

Supplemental Material

Acknowledgments.

The authors acknowledge the teams working on the trials that took part in TEMPER, the Endpoint Review Committee and Consistency Monitoring Group, previous TEMPER Study Monitors and study team members, Matt Nankivell for conducting the independent validation analyses, staff at sites who participated in TEMPER study visits and Sharon Love and Director of MRC Clinical Trials Unit at University College London, Mahesh Parmar, for review of the final manuscript. The results were presented at the Joint 2017 International Clinical Trials and Methodology Conference (ICTMC) and Society for Clinical Trials (SCT) meeting, Liverpool, UK, May 2017.

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding: This work was supported by the Cancer Research UK (grant C1495/A13305 from the Population Research Committee); additional support was provided by the Medical Research Council (MC_EX_UU_G0800814) and the MRC London Hub for Trial Methodology Research (MC_UU_12023/24).

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22 Essential documents

• Published: February 2016
• Cite Icon Cite
• Permissions Icon Permissions

It is a legal requirement for sponsors and investigators to maintain essential documentation. This chapter outlines the ICH GCP E6 requirements for documentation before, during and after the study. It describes each document and its purpose in the study. The chapter also describes how to deal with additional documentation kept by sponsors and sites but not addressed in the guidelines e.g. correspondence, emails and notes to file, The organisation of the trial master file (TMF) is not defined in guidelines but many companies and institutions will have a filing system described in SOPs, most are numeric and an example content list is given. The TMF must be maintained and stored correctly and version control of documentation is vital to maintain the audit trail. The legislation does not distinguish between commercial and non-commercial/academic studies but researchers are expected to adhere to the principles of GCP and maintain the TMF requirements. Originally TMF were paper based but the eTMF is now widely used by commercial sponsors. The retention time for the TMF has changed on a number of occasions the EU Regulation clearly states that essential documentation must be kept for 25 years and must be readily available for inspection.

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• Our Mission
• Our Strategy
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Site Qualification and Training: Learn More

Site Qualification and Training Solutions

The following resources have been made available to simplify and enhance the clinical trial site qualification and training process.

For Assets available in additional languages, please click here .

GCP Training Mutual Recognition

One of the first solutions delivered by SQT was a set of Minimum Criteria to enable a voluntary mutual recognition process of GCP training across Member Companies. This allows clinical trial investigators and other site personnel to complete GCP training which may be recognized by other TransCelerate Member Companies, making it unnecessary to train separately for each participating company.

An explanatory overview video of GCP Training Mutual Recognition:

For additional information, please click to our  GCP Training Mutual Recognition page .

EDC System Training Mutual Recognition

In 2016, SQT developed a process to enable a voluntary mutual recognition of Electronic Data Capture (EDC) system training across companies. This addressed a pain point in the industry at that time by allowing previously completed EDC system training taken by investigator site personnel and monitors to be recognized by other companies, making it unnecessary to re-train separately for each company. Based on an evaluation performed by the SQT team in 2019, it was determined that the industry has evolved to address this gap that previously existed. Therefore, the decision was made to retire the EDC program.

Forms for Investigator Sites

Beginning in 2015, TransCelerate membership began to develop forms for Investigator Sites to be used by the R&D ecosystem. Several forms were created with a range of benefits. Today, these forms are governed by the TransCelerate community. If you have questions or feedback, please contact [email protected].

Please note that select Forms and Guidance Documents are governed and updated by the Society for Clinical Research Sites (SCRS). You may be redirected to the SCRS website upon clicking the link. If you have feedback, please email SCRS at [email protected] .

Nothing in these documents or forms should be construed to represent or warrant that persons using these documents or forms have complied with all applicable laws and regulations. All individuals and organizations using these documents or forms bear responsibility for complying with the applicable laws and regulations for the relevant jurisdiction.

Informational Program for Investigator Sites

In 2015, SQT developed a series of video modules to outline the basic components related to Principal Investigator oversight of clinical trials and the foundational concepts of Clinical Research in accordance with the ICH Guideline for Good Clinical Practice. These modules allow site staff with less experience to become more familiar with conducting clinical research. Following the public release of these modules, TransCelerate partnered with the Society for Clinical Research Sites (SCRS) to promote and maintain modules. In 2020, TransCelerate transitioned ownership of the modules to SCRS for continued promotion and governance. Today, SCRS continues to share these modules with the public at no monetary cost. To view these modules, please visit the SCRS website here.  If you have feedback about these modules, please email SCRS at [email protected] .

Your Easy Guide to Clinical Studies

Provides some background knowledge and basic definitions

Starts with a study idea

Ends after having assessed and evaluated study feasibility

Starts with confidence that the study is feasible

Ends after having received ethics and regulatory approval

Starts with ethics and regulatory approval

Ends after successful study initiation

Starts with participant recruitment

Ends after the last participant has completed the last study visit

Starts with last study visit completed

Ends after study publication and archiving

Set-Up ↦ Monitoring ↦ Site Initation Visit ↦ Preparation

What is it why is it important.

The Site Initiation Visit ( SIV) should be well prepared because it provides an important opportunity to train staff on study tasks and responsibilities .

In most cases, the SIV is performed by the monitor(s) who presents the planned monitoring procedures; while the SP-INV  or a delegate presents the study protocol .

The SP-INV can appoint other personnel to perform the SIV. However, the SP-INV must ensure that those performing the SIV are well-qualified and properly trained to perform this task.

What do I need to do?

As a SP-INV ensure that the monitor performs his or her tasks according to the monitoring plan .

If you are the study monitor, prepare the site for an upcoming SIV:

• Arrange a date for the SIV visit with the site and invite relevant staff
• Prepare an agenda with topics to discuss, including what processes and tasks to train
• Complete pre-study TMF and ISF filing . The ISF is handed over to the site at the SIV
• Ensure that IMP/MD is available at the study site and ready to use
• Confirm access to the study database needed for staff training
• Decide on who will be responsible for any staff training
• Prepare relevant study logs , such as the delegation log and a SIV training log
• Prepare a SD location list. In a multicentre study prepare an applicable list for each participating site

Prepare an easy-to-follow and relevant study presentation:

• Include diagrams or flow-charts. A clever designed image can replace highly complicated written procedures (e.g. the study design, safety reporting , analytical processes)
• A physician / Site-INV  or delegate can present and explain more complicated medical issues
• Make sure that the infrastructure needed for your presentation and training sessions is available at the site (e.g. a beamer, flip chart, video transmission, magnet board, material needed illustrate points)

In order to guarantee effective communication and training, use a local or common language. If needed, organise an interpreter who can participate at the SIV.

Where can I get help?

Your local CTU ↧ can support you with experienced staff regarding this topic

Basel, Departement Klinische Forschung, CTU, dkf.unibas.ch

Lugano, Clinical Trials Unit, CTU-EOC, www.ctueoc.ch

Bern, Clinical Trials Unit, CTU, www.ctu.unibe.ch

Geneva, Clinical Research Center, CRC, crc.hug.ch

Lausanne, Clinical Research Center, CRC, www.chuv.ch

St. Gallen, Clinical Trials Unit, CTU, www.kssg.ch

Zürich, Clinical Trials Center, CTC, www.usz.ch

External Links

• swissethics – Information on safety reporting
• swissmedic – Information on safety reporting

ICH GCP E6(R2) – see in particular guidelines

• 4.11 Safety reporting
• 5.18 Monitoring activities
• 8. Essential documents for the conduct of a clinical trial

ISO 14155 Medical Device – see in particular section (access liable to costs)

• 9.2.4.4 Initiation of the investigation site
• 10.8 Safety Reporting
• Annex E: Essential clinical investigation documents

ClinO – see in particular article

• Art. 37 – 43 Safety Reporting

HRO – see in particular article

• Art. 20 – 20 Safety notification
• ClinO – Clinical Trials Ordinance
• CTU – Clinical Trials Unit
• GCP – Good Clinical Practice
• ICH GCP – International Council for Harmonisation Good Clinical Practice
• IMD – Investigational Medical Device
• IMP – Investigational Medicinal Product
• ISF – Investigator Site File
• ISO – International Organisation for Standardisation
• SAE – Serious Adverse Event
• SD – Source Data
• SIV – Site Initiation Visit
• Site-INV – Site Investigator
• SP-INV – Sponsor-Investigator
• TMF – Trial Master File
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• Forms and Logs
• Non-Conformities
• Biobanking Staff
• Quality Control Indicators
• Data Monitoring
• Method Validation
• Research Transparency
• Staff Delegation
• Definition and Handling
• Purpose and Requirement
• Site Initiation Visit
• Study Initiation
• Master and Site File
• Safety Management Plan
• Emergency Unblinding
• Access Rights
• Statistical Analysis Plan
• Data Validation Plan
• Key Performance Indicator
• Prerequisite
• Preparation
• Sample Traceability
• Packaging and Shipment
• Data Accuracy
• Pre-Screening
• Screening and Consent
• Documentation
• Patient Information
• Sponsor and Site-Investigator
• Drug and Device Accountability
• Ongoing Tasks
• Consent of Vulnerable Participants
• Inspection Conduct
• Audit Conduct
• Audit Certificate
• ReportingTimelines
• Study Documentation
• Patient File
• Medicinal Product
• Medical Device
• Other Clinical Trials
• Research Projects
• Adverse Event
• Serious Adverse Event
• (Serious) Adverse Drug Reaction
• Suspected Unexpected Serious Adverse Reaction
• Advanced Therapies
• Adverse Event / Adverse Device Effect
• Serious Adverse Event and Device Effect
• Device Deficiency
• Serious Events
• Responsibility
• Adding Stakeholders
• Data Import
• Interim Lock
• Intermediate Data Export
• Re-Evaluation
• Risk Documentation
• Note to File
• Corrective and Preventive Actions
• Follow-Up Letter
• Close-Out Visit
• Database Lock
• Notification of Closure
• Lessons Learned
• Study Registries
• Scientific Publications
• Reporting and Liability
• Registry Update
• Study Closure
• Doument Archiving
• Document Destruction
• Data Formatting
• Data Transfer Agreement
• Risk Reporting
• Study Records
• For Further-Use
• Destruction
• Analytical Results

Please note: the Easy-GCS tool is currently under construction.

Introduction to the Monitoring in Clinical Trials, Pre-Study Site Selection Visit

• Post published: 31.07.2023

As per Good Clinical Practice (GCP) guideline “the purposes of trial monitoring are to verify that:

• a) The rights and well-being of human subjects are protected.
• b) The reported trial data are accurate, complete, and verifiable from source documents.
• c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).”.

Clinical Trial monitoring is achieved via conducting the monitoring visits to Clinical Trial Sites (hereinafter referred to as “Sites”) either face-to-face or remotely.

The visits are performed by monitors (Clinical Research Associates, CRAs).

According to GCP guideline:

• “a) Monitors should be appointed by the sponsor.
• b) Monitors should be appropriately trained and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
• c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).”.

The Sponsor of each Clinical Trial is responsible to develop a systematic, prioritized, risk-based approach to monitoring Clinical Trials. The Sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The Sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians). Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.

This article aims to briefly introduce the monitoring, describe the types of monitoring visits of Sites in Clinical Trials, and focus on a Pre-Study Site Selection Visit as a starting point in the monitoring process.

Depending on the timeframe (phase) in which each particular Clinical Trial Project is the following visits types are identified:

• Pre-Study Site Selection Visit (also known as Pre-Study Visit, Site Selection Visit, Site Qualification Visit)
• Site Initiation Visit
• Interim Monitoring Visit (also known as Routine Monitoring Visit)
• Close-out Visit.

Additionally, Co-Monitoring Visit(s) may be performed with the aim of either supporting the CRAs in their visit activities or assessing Site’s/CRAs’ adherence to Clinical Trial Protocol, GCP and other clinical research regulations. Co-Monitoring Visits are out of scope of this article.

Monitoring visits have typically one business day in duration, but depending on Clinical Trial complexity, amount of data to be reviewed and other factors their duration can be increased.

The main written documentation of each monitoring visit (irrespectively of its type) includes:

• Confirmation letter  – a letter/e-mail sent to Site well in advance of planned monitoring visit and which includes the details and activities to be done during the visit
• Visit report  – detailed description of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s)
• Follow-up letter  – a letter/e-mail sent to Site after the visit has been conducted and which includes the details of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s).

All confirmation, follow-up letters and Site Initiation Visit Report (per GCP requirements) are to be properly stored in Investigator Site File located at Sites.

Pre-Study Site Selection Visit (PSSV)

This is the starting point of interactions between Sponsor/CRO and Clinical Trial Site. It is performed after the Site Identification & Feasibility process has been completed.

The PSSV is performed to ensure that:

• A potential Principal Investigator (PI) is qualified and interested in conducting the clinical study
• The PI’s Site has adequate facilities, and resources to properly complete all required study activities
• Site has required pool of patients to complete enrollment.

Items to be reviewed/discussed may include, but are not limited to:

• Feasibility Questionnaire completed by Site
• Clinical Study Protocol/Synopsis and Clinical Study timelines
• Enrollment (recruitment) target, strategy, expectations, and availability of subject population
• Qualifications/ training, experience, interest and availability of the PI and Site Staff performing study related duties
• PI and Site Staff obligations, ICH-GCP / ISO 14155 guidelines (if applicable) and regulatory requirements
• Therapeutic area being investigated (including applicable standard of care)
• The PI’s/Site Staff’s regulatory inspection/audit experience, if any, and the outcome of the inspection/audit(s)
• IRB/IEC requirements, documentation, and approval timelines
• Site budget and execution of Clinical Trial Agreements
• Informed Consent Process and documentation requirements
• Source document and study record requirements, as well as Source Data definitions and Good Documentation Practice
• Monitoring visit process/schedule, PI and Site Staff availability, other competitive clinical trials with the same pathology run by Site
• The monitoring strategy including remote monitoring and remote Source Data Verification capacity and acceptance (if applicable)
• Electronic Data Capture (EDC) requirements, including vendor-specific experience, internet connectivity, and computer availability, if applicable
• Turn-around time for data entry and data query resolution
• Local country / Site-specific requirements for clinical study conduct (e.g., Site SOPs)
• Reporting and documenting safety events (e.g., Adverse Events, Serious Adverse Events, Adverse Events of Special Interest, SUSARs, pregnancy, study drug overdose etc.)
• Medical management of study subjects remotely, if appropriate
• Assessment of storage area and conditions for Investigational Medical Product (IMP) (includes Investigational Medical Device (IMD) and/or other study supplies/materials)
• IMP/IMD Accountability procedures (receipt, storage, dispensing, and record keeping)
• Laboratory sample handling procedures, including supplies, collection, and shipment.

During PSSV CRA ensures the adequacy of facilities where study subjects will be seen by visiting (touring) them (e.g., exam rooms for subject evaluation and treatment, laboratory and any special testing area, pharmacy (if applicable), any satellite sites (if applicable), working area for Site staff, data entry area etc.) CRA also ensures the adequacy of available equipment to be used in clinical study (including validity check for calibration/maintenance documentation).

As part of PSSV CRA requests/collects any required Site documentation which may include, but is not limited to:

• Confidentiality (Non-Disclosure) Agreement, if applicable
• Medical licenses (Institution and Site staff) and dated/signed Curriculum Vitae (CVs)
• Current GCP and ISO 14155 (if applicable) training certificates or certificates of relevant training(s) as listed on the corresponding CVs
• IRB/IEC membership list (roster), SOPs (if applicable) and statement of compliance
• Electronic Health Records related documentation, if used
• Completed dated/signed Project-specific forms and questionnaires required to qualify the Site, as applicable
• Local laboratory reference ranges, accreditation certificates and CV of Head of local laboratory if it will be used
• Dated/signed attendees log, Clinical Study Protocol, and Investigator Brochure acceptance pages.

The above documents may be collected as originals or copies, depending on Sponsor’s/country specific requirements.

On the basis of conducted PSSV and the review of all applicable documentation the Sponsor either approves Site’s participation in the given Clinical Trial or declines it.

If Site is approved CRA sends an appropriate Site Selection Letter and in case of disapproval – the appropriate Site Non-Selection Letter.

The above letters will thank PI and Site Staff for completion of Selection activities and will state the further actions to be completed (if Site is approved) or will explain the reason(s) for non-selection decision.

Carpathian Research Group capabilities

CRG as a CRO has extensive experience in conducting Pre-Study Site Selection Visits and choosing the most suitable Sites for successful Clinical Trial execution.

Information on all other Clinical Trial services that we provide could be found at  www.crg.global

You can contact us at  [email protected]

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