Risk Based Monitoring – Does Clinical Trial monitoring in a dynamic Central Intelligence-led Adaptation (CIA) mode ensure superior levels of accuracy, quality & safety?

Opening up Pandora's box...

Discussing the above topic is essentially impossible without appreciating the origins and reasons for safeguarding clinical trials. As such, I will devote the following five short paragraphs to the poignant reasons for regulating clinical trials, in addition to proffering a concise definition of Good Clinical Practice (GCP), before discussing monitoring in general (in the context of adopting Risk Based Monitoring (RBM)) along with the positive effect RBM can have on clinical trial patient safety and data quality.

Why should clinical trials be regulated?

To put it succinctly, adhering to GCP regulations provides a minimum level of ensurance that clinical research is conducted with integrity in a scientifically sound and ethical manner, and that the obtained results will be credible. Equally important; it also safeguards the rights and safety of the trial participants. In other words, clinical trial regulations aim to safeguard the rights and well being of trial participants as well as that of future patients, while simultaneously providing organisations with clear guidance on how to conduct clinical trials in a universally accepted format and on how to demonstrate compliance with regulatory requirements that are legally and ethically acceptable.

Despite the international community agreeing on this ethical and scientific framework of standards (GCP) for the design and conduct of clinical research, the inherent complexity of this framework leaves many aspects up to alternative interpretation, revision and debate, as is evidenced by relatively recent breaches in the consensus of how to apply such ethical standards to research in developing countries (e.g. placebo-controlled trials to reduce maternal to child transmission of HIV-1 in Africa and Asia in 1994 or the Trovan study in Nigeria in 1996).

Unfortunately, a large number of historical events (including very recent ones), teach us that the development of pharmaceutical products can neither be self-regulated, nor can it rely on a code of practice that does not address future developments. Simply put, without strictly enforced rules and up-to-date regulations, people (trial participants, and future patients / users of medicinal products) as well as organisations and company reputations will get damaged.

Events and tragedies that raised the initial questions of safety and efficacy, include a series of articles by Samuel Hopkins Adams (1906), the Nuremberg trials (1947), the Thalidomide incident (1956 – 1962), and the Tuskegee Syphillis Experiment which prompted the Belmont report (1932 – 1972). These early events led to the development of certain regulations and guidelines (e.g. the Pure Food and Drug Act by US congress in 1906 and The Declaration of Helsinki by the WMA in 1964), which ultimately evolved into the code of practice that most countries and organisations conducting clinical trials now subscribe to. This code of practice is known as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) – Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (GCP) or, in short: ICH-GCP.

However, it is clear that continued vigilance and improvements to such guidelines are warranted given the recent examples of circumstances, different interpretations, or fraud that ultimately resulted in non-compliance with acceptable code of conduct and behaviour (e.g. East German clinical trial scandal (1970s – 1990), the aforementioned clinical studies in developing countries (during the mid-nineties), and the Ranbaxy scandal (2005 – 2013)). Nevertheless, implementing ill-considered and far reaching changes in safeguards (i.e. monitoring) without appreciating the origins and reasons for enforcing measures that protect the integrity of clinical trials may result in enormously destructive unintended consequences.

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Why should clinical trials be monitored?

For those not familiar with monitoring and its purpose, it is perhaps useful to remind ourselves with a GCP definition of the importance of this aspect of running clinical trials. ICH-GCP E6 1.38 defines monitoring as: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), GCP, and the applicable regulatory requirement(s).

In addition, ICH-GCP (section 5.18.1) states that 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 applicable regulatory requirement(s).

Needless to say that proper monitoring is absolutely crucial to the success of any clinical trial.

Who is monitoring clinical trials and is there more to monitoring than meets the eye?

As established in the previous section, Clinical Trial Monitoring is one of the most important activities in clinical research. Which is why it is not surprising that many organisations seek to develop collaborative and synergistic processes within the GCP framework that will enhance the quality and predictive powers of monitoring.

In a classical arrangement, the clinical trial monitor or Clinical Research Associate (CRA) is assigned by the sponsor and is tasked with the responsibility to check for protocol compliance and patient safety. Invariably, this is accomplished through regular on-site monitoring visits combined with Source Document Verification (SDV) and monitoring reports. However, there are other layers of monitoring that are tasked with detecting non-compliance and safety issues. Given the move towards a more integrated approach spread over several layers of the organisation, it is perhaps useful to raise awareness of those departments and individuals that share some of this monitoring responsibility as well as the way they interact and how they evaluate and verify data.

The individuals involved in aspects of monitoring include the monitor / CRA, independent Data Safety Monitoring Committee (DMC), and the Independent Ethics Committee (IEC) – called Institutional Review Board (IRB) in the USA. Based on their responsibilities in clinical research as defined by Good Clinical Practices, they can be categorised as follows:

1. GCP, protocol, SOP, and regulatory Compliance Monitoring including Source Data Verification (SDV): The Monitor / CRA 
2. Overall Safety Monitoring: The Independent Data Safety Monitoring Committee  
3. Safety and Ethical Monitoring: The Independent Ethics Committees  

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GCP, protocol, SOP, and regulatory Compliance monitoring including Source Data Verification (SDV)

One of the duties and responsibilities of the monitor / CRA (who is invariably assigned by the sponsor) is to determine that the source data is available and that the data submitted reflects the source data (e.g. medical files, lab reports, etc...). In addition, the monitor is obliged to verify that safety information such as Adverse Events (AE / SAE / SUSARs) have been accurately reported in a timely fashion, that the study is conducted according to protocol, and that local regulatory requirements have been adhered to. Monitors are in essence the eyes and ears for the sponsor at a clinical trial site. As such, the monitor must ensure that the study is fully compliant given that the monitor forms the main link between investigator and sponsor (often the manufacturer, but not always). Thus site interaction in the form of on-site visits are an accepted procedure which is currently essential.

Overall Safety Monitoring

The independent Data Safety Monitoring Committee (DMC) – otherwise known as Data Safety Monitoring Board, provides an additional layer of safety and data monitoring during the conduct of a clinical trial. Given the often highly complex and scientific nature of trial data in various formats from multiple sites and disparate sources, such as medical records, or lab reports containing erroneous or missing values, these departments are predominantly staffed with highly experienced medical staff or scientists to ensure that data is interpreted and analysed correctly. The effectiveness of DMCs are in part reliant upon clear standard operational procedures and trial rules for safety detection and reporting.

Safety and Ethical Monitoring

The Independent Ethics committees (IEC) or Institutional Review Board (IRB) has a responsibility to monitor the safety of subjects of a study at a site they approve for conducting a specific study. They exercise that responsibility by providing an opinion regarding the suitability of the investigator as well as the site for the conduct of a trial, and whether or not the study is ethically acceptable in its aims, its protocols and for the subject population of that site (i.e. they have to approve a study before it can be initiated at the site). The IEC / IRB then periodically review these ongoing clinical trials, in order to provide public assurance that the protection of the rights, safety, and well-being of human subjects involved in a trial are safeguarded and that the research conducted continues to be appropriate. These IEC / IRB committees have the responsibility to review proposed clinical trials in a timely manner. However, the effectiveness of their review depends significantly on the quality of safety reports, and other documentation that is submitted by the investigator.

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Can Risk Based Monitoring preserve Good Clinical Practice (GCP) principles and enhance compliance, safety and accuracy?

In essence, monitoring is a quality control tool which allows sponsors and other stakeholders to determine whether study activities are being carried out as planned and that the research conducted continues to be safe and appropriate; all in an effort to identify deficiencies with the purpose to correct them.

Despite GCP guidelines 5.18.3 stating that “the sponsor should determine the appropriate extent and nature of monitoring” and that “statistically controlled sampling may be an acceptable method for selecting the data to be verified,” it also states that “In general there is a need for on-site monitoring, before, during, and after the trial” and that only “in exceptional circumstances the sponsor may determine that central monitoring... assures appropriate conduct of the trial in accordance with GCP”. As such, most clinical trials have often relied (and continue to rely) on a brute-force approach to the verification of source data (SDV) through on-site monitoring.

However, the ICH GCP monitoring guidelines, that were finalised in 1996, were established on the assumption that clinical research would be predominantly paper-based. Two decades later, the increasing utilisation of Electronic Data Capture (EDC), rapid communications (i.e. e-mail and video conferencing, etc...), comprehensive lab reports, electronic source data, and improved data analytics, allow sponsors to have far greater visibility into study conduct and data in real-time than previously thought possible. In addition, it is clear that clinical research today has become a lot more complex given the sheer volume of data generated on a daily basis.

In summary, clinical research and available technologies have evolved tremendously. As such, it would seem logical (and necessary) that monitoring approaches follow suit, whilst obeying the spirit of the GCP guidelines, in order to keep up with technological advances and avoid becoming irrelevant.

This train of thought is echoed in a relatively recent Food and Drug Administration (FDA) guidance document on risk-based monitoring and the release of the final version of the European Medicines Agency (EMA)'s Reflection Paper on Risk-Based Quality Management in Clinical Trials. These two documents mark an important milestone in efforts to introduce and develop the risk-based monitoring concept. Given that data quality is absolutely paramount in determining study success and ensuring patient safety, it is not surprising that these newly suggested recommendations have brought about a transition period within the industry that will ultimately see the adoption of standardised risk-based techniques in monitoring trials.

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What is the difference between classical on-site monitoring and risk based monitoring?

Risk will become a focal point...

In contrast to on-site monitoring, risk assessment and Central Statistical Monitoring (CSM), otherwise known as intelligent risk-based monitoring (RBM), makes use of a central intelligence operation that validates and analyses clinical trial data and site metrics in order to determine whether clinical sites should receive more extensive quality review through on-site monitoring visits (something I referred to as “Central Intelligence-led Adaptation (CIA) mode” in the title).

Several benefits can be derived from a dynamic CIA mode monitoring operation, given that statistical and graphical checks can determine the presence of outliers or unusual patterns in the data. Early on, and throughout the trial, comparisons can be made between sites to evaluate performance. In addition, CIA mode monitoring will be capable of highlighting possible fraudulent data, miscalibrated or faulty equipment. Ultimately, this approach to monitoring allows issues to be be identified and resolved while the trial is ongoing.

Some reports even suggest that many SDV related queries can be picked up by RBM with some additional centralised edit-checks put in place (though it is dependent on the data that is available in a database), while other publications state that a more varied approach to monitoring can identify failings that would likely be missed with either on-site or centralised review alone. As such, both on-site monitoring as well as RBM will be required to ensure the quality of trial conduct.

However, adopting such alternative monitoring practices industry-wide cannot be accomplished overnight given that procedures to remotely review clinical data, statistical sampling of data to verify source data (SDV), and targeted monitoring practices need to be implemented and integrated properly across many layers of an organisation (and include People, Ethos, Processes, and Technology). Nevertheless, the transition period for adoption of RBM practices is progressing rapidly as many companies see a cost benefit in addition to increased quality of data and patient safety.

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