What is the purpose of clinical trial monitoring?

Abstract

Background

The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language.

Methods

In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting.

Results

The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen.

Conclusion

From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials.

Background

The MRC-NIHR Trials Methodology Research Partnership (TMRP) Trial Conduct Working Group Data Quality and Monitoring (DQM) subgroup (hereafter “TMRP DQM”) comprises 13 people (authors of this paper) interested in improving the monitoring of clinical trials (four researchers, six trial managers, three other). Though location was not an exclusion when applications were requested for this subgroup, the current members are those involved in academic trials from the UK and Ireland, each involved in a variety of national and international trials. Despite each adapting our way of working from the guidance available, it was clear that we did not have a common monitoring strategy or understanding of terminology. We identified the need to go back to basics and define the purpose of monitoring. This will enable communication between researchers, regulators and trial teams and will give a strong easily explained foundation on which to build tools for clinical trial monitoring.

Clinical trial monitoring is an important aspect of clinical trial conduct. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) E6(R2) [1] gives a definition of the purpose of clinical trial monitoring

“5.18.1 Purpose

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).”

Though ICH GCP has used this underlying definition of the purpose of monitoring since 1996 [1], it is not written in accessible language and does not contain any explicit detailed guidance on monitoring activities [2]. Therefore, each clinical trial sponsor has taken this definition or the one in their own country’s legislation (for example [3]), interpreted it and created their own monitoring activities. This has led to wide variation in practices, as noted in several surveys of monitoring approaches [4,5,6].

Despite the recent shift towards a more risk-based approach, which has led to a re-focusing on monitoring, there remains little detailed guidance available on how it should be done. To facilitate the development of any guidance in the future, a clear understanding of the purpose of monitoring is essential.

This paper describes the process whereby the MRC-NIHR TMRP DQM extracted the purpose of monitoring, as described by pertinent sources, and from them defined the purpose of monitoring in accessible language. We hope that this paper can be used to formulate detailed guidance on how to monitor clinical trials.

Methods

We chose the sources from guidance provided by organisations that any one of the TMRP DQM referred to when deciding how to run trials. Table 1 gives the organisations included and their aims. Each author reviewed an organisation’s publicly available online or downloadable information to extract any material on the purpose of monitoring. We did not contact the organisations. The documents reviewed included guidance documents, minutes of workshops, toolkits, blogs and reports of questions and answers (Additional file 1). In a second round, the information related to the purpose of monitoring was distilled into non-repetitive statements by pairs of authors. In the final round, all authors independently compared the purpose of monitoring across all sources and in the ensuing consensus meeting five key principles for the purpose of monitoring emerged.

Table 1 Descriptions of the organisations publishing on monitoring from the organisation website

To obtain feedback on their value, we presented the five key principles covering the purpose of monitoring to delegates at the UKCRC Task and Finish Monitoring Group annual meeting 2021 (a national meeting of experts in conducting academic clinical trial monitoring in the UK) and asked “Are there any of these purposes of monitoring that you do not agree with?”, giving options to disagree with any principle or to answer “No, I agree with all 5 proposed principles”. In addition, delegates were asked to suggest any other potential “principles of monitoring” that we should consider (see Additional file 2).

We show the underlying text for these five principles and also give examples of which monitoring activities could happen within each of these principles. We also present the results of our poll of the annual meeting.

Results

The results of our synthesis for the purpose of monitoring are given in Table 2 and include five principles. The purpose of monitoring is keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. In our poll at a national meeting of those monitoring clinical trials in the UK, 93 attendees voted, with 85% (80/93) agreeing with all 5 proposed principles for the purpose of monitoring (Table 3). One poll respondent suggested adding building relationships with sites as a principle.

Table 2 Purpose of monitoring key principles synthesised from major worldwide organisations

Table 3 Results from poll about the principles of monitoring at national meeting of those monitoring academic clinical trials in the UK

Table 4 shows the clarification of our derivation of these principles by giving examples from the underlying sources. For example, the principle “having data we can trust” came in part from the CTTI statement “Ensuring that data quality is sufficient to answer study question”. In Additional file 3, we give the full text from all sources.

Table 4 Showing the link of the 5 principles of monitoring with the sources

We have given examples in Table 5 from sources and from our experience to show how each principle may be mitigated by monitoring. For example, if the principle of monitoring is to keep participants safe and respect their rights, then we should monitor to ensure the consent is valid.

Table 5 Examples of monitoring for each principle

Discussion

We have clarified the purpose of monitoring in accessible language from pertinent sources. This will enable communication between those carrying out clinical trial monitoring and facilitate the building of clinical trial monitoring tools on a strong easily communicated foundation.

Clinical trial monitoring is a crucial part of trial conduct, improving the safety of the participants, the quality of the data and the trial integrity. Clinical trial monitoring is conducted by monitors, quality assurance teams and by trial managers [5]. Guidance on trial monitoring is spread amongst different sources within and between organisations, is often in technical language and does not describe practicalities of how to achieve the monitoring aims. The differing specialities conducting monitoring and the disparity and high-level content of the sources mean there is scope for misunderstanding and communication errors. This could easily lead to poor quality monitoring which could jeopardise the protection of the rights and safety of patients and the data and trial integrity. Also, misunderstanding could lead to over-monitoring for no additional value, placing additional burden on research teams and sites and increasing the cost of undertaking research. It is difficult to have methodology research discussions, and therefore to deliver monitoring tools, without agreement of a common basis which multiple disciplines can all understand. It is difficult for grant committees to understand the value of monitoring research when there is no easily understandable consensus on why we need to do good clinical trial monitoring. The differing language and range of ideas on clinical trial monitoring are confusing and unhelpful. The variability in language and practices this range has caused, as evidenced by 13 people in the UK who were experienced in clinical trial monitoring finding it difficult to communicate and find common ground, is limiting progress in clinical trial monitoring. We have synthesised the sources to describe the purpose of monitoring in five key principles described in both technical and lay language (Table 2). We intend this to be a basis for making monitoring more accessible.

The purpose of monitoring principles presented in this paper are active, continual and responsive to monitoring findings. They are focussed on the conduct of a real trial rather than based on theory. They are aimed at monitoring to intervene and make trials better rather than certifying what has already been done. Monitoring is an integral part of trial conduct rather than an add-on. Our first three principles link with parts a, b and c of the ICH definition of monitoring (see methods) but the idea of improving trials or preventing problems before they happen is not part of the ICH definition. These are important aspects of monitoring, as finding an issue at one site early in the trial means that training can be given to the other sites and the overall trial is improved to the benefit of current and future patients. Stating improvement and prevention in our principles will help those running trials to address improvement to the trial and prevent poor conduct.

The FDA provided particularly valuable sources for this paper as they have strongly advocated risk-based monitoring and have had to be clear in their documents as they are extensively used worldwide.

Supplementary Table 2 lists the sources used. Although the thirteen authors all have experience of clinical trial monitoring in the UK and Irish academic setting, relevant and valuable sources of information may have been missed. The first selection of useful text from the individual documents within each source was done by one author and the second phase by groups of two or three. Only the final phase was completed by all authors together. These are limitations in the study but it also exemplifies how those devising monitoring policies for their trials and those carrying out monitoring activities must refer to multiple sources. The 86% vote of agreement with the five principles at the UK monitoring meeting corroborates the work done.

Though there is a limitation due to this work using world-wide English language sources, being led by UK and Ireland researchers and being corroborated in a UK national meeting, it is based on sources that are used by many. In future, it would be good to extend this to more of the clinical trial monitoring community world-wide.

Although building relationships with sites has been noted as a useful part of monitoring in publications [7,8,9], this did not come through from the sources reviewed and was only mentioned by one poll respondent at the national monitoring meeting. At present, we do not note it as one of the main five principles but further work may add principles.

As each group leading clinical trials has created their own monitoring strategy and language, there have been difficulties in communicating between groups [5]. Our principles clarifying the purpose of monitoring should improve communication and enable the monitoring community to start producing clear monitoring practical guidelines and to start sharing tools. These principles should be considered when undertaking risk assessments, developing monitoring plans and carrying out monitoring activities.

Conclusions

From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as (i) keeping participants safe and respecting their rights, (ii) having data we can trust, (iii) making sure the trial is being run as it was meant to be, (iv) improving the way the trial is run and (v) preventing problems before they happen.