Sunday, 7 June 2015

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).

Tuskegee Syphilis experiment 1932 - 1972 - President Bill Clinton publicly apologised to five of the eight survivors of this experiment | photo of survivor Herman Shaw with President Clinton who said, “It is not only in remembering that shameful past that we can make amends and repair our nation, but it is in remembering that past that we can build a better present and a better future. And without remembering it, we cannot make amends and we cannot go forward.” The president also stated that the Tuskegee men were betrayed and lied to. Their rights were trampled upon.

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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