Open collaborative development of a clinical research study decision tree risk assessment tool:

Clinical trials have become too expensive, cumbersome and burdened by over-regulation, and a one-size-fits all approach to the interpretation of clinical trial regulations and guidelines are cited as a significant part of the problem. Many regulatory agencies are now evaluating a risk-based approach to inform many operational aspects of running clinical trials. Both the EMA and the FDA have put out draft guidelines or opinion seeking papers on this issue, with the aim of revising their recommendations.

These discussion documents recognize that trials have varying levels of risk. For example, a clinical trial where patients are randomised to be given smoking cessation advice by a nurse trained in a new way compared to a nurse given the standard training is unlikely to require the same level of oversight as a trial of new born babies given a new and unregistered vaccine. In between such trials, in terms of risk, could be a trial assessing a new use for an existing therapy. The design, monitoring and oversight of these three examples (and all other trials) should be tailored, based upon a formal consideration of risk and complexity.

In the USA, the FDA Clinical Trials Transformation Initiative has established a working group to develop the concepts of Quality Risk Management and Quality by Design. While in the UK guidance has been issued by the MRC/DH/MHRA Risk Assessment Guidance. Both projects recognize that there is vast variety in the degree of risk across different trials. These include risks to the rights and wellbeing of the participants (e.g. due to the intervention, other protocol-mandated investigations, or threats to privacy) and to the reliability of the study results (e.g. due to poor design or conduct of study procedures). However, the efforts to promote risk assessment made by US, UK and EU regulators have largely been confined to trials of investigational medicinal products, particularly in high-income countries, and the limited risk-assessment tools produced have not been tested or tailored for use with other interventions or in other settings. Furthermore, efforts so far have been limited to the matter of clinical trial monitoring. Investigators and their teams seek a pragmatic mechanism to establishing the risk and complexity of their proposal trials so they can make sensible operational decisions on multiple aspects of the plans such as safety reporting, end point review, data monitoring and trial insurance, by way of a few examples.

The Ideal Solution

It is apparent that there is international agreement that the planning and implementation of clinical trials should include an assessment of their risk and complexity. However conducting a risk assessment is not easy and is daunting for investigators and their teams. To consider properly what is required and, more pertinently (in the quest to reduce costs and unnecessary burdening of research), what is not required, a deep understanding and considerable experience of clinical trials and the application of relevant guidelines is needed. It is clear from comments made by investigators on the website and from pilot qualitative research, that this is problematic and off-putting for investigators. There is an evident need for a framework and ultimately a tool that could guide researchers, or other stakeholders, in conducting a risk and complexity assessment of their specific protocol, and for this framework and tool to extend beyond trials of medicinal products into clinical trials of any intervention or action. The development of such a framework for assisting investigators in conducting a risk and complexity assessment of their trial is a clear extension and appropriate follow-on from the work that has already been conducted by the MRC/DH/MHRA because it would take the output from this work, the US’s Clinical Trials Transformation Initiative working group and other sources to generate and validate a framework.

The idea here is to collaboratively develop and test a tool.

A sophisticated and widely applicable web-based tool could be collectively built that would guide investigators and study teams through an assessment of the risk and complexity of their planned trial, and help them to develop an appropriate approach to trial design, conduct and monitoring. The first step in this is to build a framework and a pilot digital tool, which could be enhanced, tested and validated subsequently. Could this be done in an open and collaborative manner on this platform? Are you interested in being a partner in this?

The framework could be developed by drawing together the guidelines and publications that outline the requirement for risk-based clinical trials or describe different approaches to this task (bearing in mind that there are currently no real ‘guides’ on how to do this). In contrast to the perspective typically taken in the regulatory guidance the framework to be constructed will be broad, covering observational / sampling only studies through to randomised trials of a full range of health technologies (e.g. drugs, surgery, behavioural interventions, health care delivery models).

The aim is to develop a framework that would allow risks to be identified, particularly risks to the rights and wellbeing of the study participants, and to the reliability of the trial’s results.

Creating this framework would require open discussion and wide input to agree definitions and scope and resolve how standardisation.  For example, agreeing common principles such as ‘will the research provide a reliable answer to the question that is set?’ and ‘will it do so without causing harm?’. The framework for assessing this may then be developed from considerations such as:

  • Do you have a ‘good’ (answerable and novel) question?

  • What is your intervention (how might it cause harm)?

  • What are you doing that could cause harm (taking samples, asking sensitive questions)?

  • What will your data change (how will this happen)?

Then, again through this platform this community could test and revise iterations of the framework. The framework will be tested against several diverse types of clinical research study to confirm its validity and that a standardised approach will work.

The digital assessment tool is the ultimate goal and would be created from this. A pilot version for demonstration purposes will be possible within this project. Subsequently, it is hoped to extend this so that the tool becomes dynamic, taking the investigator through an assessment of their planned research and providing links to relevant resources, such as more detailed guidance, training tools and examples.