Walking the line – Regulations and the tenets of outbreak clinical research

By guest contributors Piero Olliaro and Josephine Bourner

Outbreak clinical research presents special challenges, the most pressing one being speed. Long-lasting pandemics are, luckily, the exception: the typical epidemic – and there are several – is short-lived, so starting studies as early as possible is crucial to enrol meaningful numbers of patients into the study and return answers to the research community and patients with minimal delay.  

However, we often only manage to catch the tail of an outbreak, when cases are dwindling, leaving critical questions hanging. Examples of failed attempts abound in recent years, notably the 2009 H1N1 pandemic and the 2014-16 West-African Ebola epidemic, alongside some successes, such as the COVID-19 RECOVERY trial and the PALM007 trial during the 2018-2020 Ebola outbreak in the Democratic Republic of the Congo.

Smaller, geographically-confined epidemics are even worse off. Mpox (formerly monkeypox) is one of them. While endemic in Central and West Africa, it only gained notoriety with the 2022 Clade IIb PHEIC (public health emergency of international concern). The first cases were detected in May, and the peak was reached in August 2022 – over 80% of Clade IIb mpox cases occurred in just four months – at which in point most studies were only just starting to enrol patients, followed by a sharp decline in cases, which are still lingering on. Studies have so far collectively failed to generate a robust evidence-base for therapeutic interventions, and, lest another surge in case numbers, none will likely be conclusive. This is ever so disappointing given that the mpox outbreak has occurred in substantial numbers and for a protracted period – over 90,000 and over 18 months to-date – so it wasn’t because of a shortage of cases or time that the research output is limited.

For most emerging infectious diseases, outbreaks are the only opportunity for robust evidence generation for new interventions to take place. Between outbreaks, few cases of these diseases are reported, making it challenging to collect sufficient data to evaluate interventions in a meaningful way. Researchers therefore need the research ecosystem to work, and there was a legitimate expectation that the lessons learnt about what works and what doesn’t with Ebola and COVID-19 would make that happen. Sadly, such has not been the case.

In our paper “Mpox: the alarm went off. Have we gone back to sleep?” – a natural segue to the “Waking up to monkeypox” paper – we describe the clinical research landscape during the Clade IIb mpox outbreak and show how the failure to launch studies in a timely manner was largely caused by the time needed to attend to ill-adapted regulations and bureaucracy, and partly to mobilise funds that were not ready. Developing and agreeing on trial endpoints and design was relative quick, considering it was a new form of the disease.  So, above all, it is the medical research ecosystem that requires reform.

Which is the problem addressed in a related paper “Experiences and challenges with the new European Clinical Trials Regulation”, where we examine a critical part of the research ecosystem and delve into the regulatory hurdles of conducting clinical research during outbreaks in Europe.

Using examples of three clinical trials that took place during the COVID-19 pandemic and mpox PHEIC, we explore the impact of the EU Clinical Trials Regulation (CTR EU 536/2014) and identify three key challenges that hindered the timely generation of evidence to support much-needed therapeutic advancements for these diseases: Conflicting application requirements; Long clinical trial application review and approval timelines; Technical hurdles.

But lessons-learnt exercises are only useful if they generate workable solutions to make things better – and is these are acted upon. So, alongside describing these challenges, we also propose several ways forward to ensure that future research responses to outbreaks are not hindered by the same barriers. While the regulations in question are specific to clinical research in the European Union, lessons and proposals can be generally relevant and applicable.

Regulations should favour, not thwart collaborative, independent, efficient clinical research. Such an obvious general principle is however unfortunately overlooked by a bureaucratic approach to clinical research – a situation which is all the more damaging in health emergencies. Action needs to be taken quickly, and before another health emergency strikes. We don’t know when the next outbreak will occur and how long- or short-lived – and how deadly – it might be. While outbreaks are the space within which to efficiently generate robust evidence for new interventions, the time between outbreaks should be used for preparation. The work should not stop. In this current inter-outbreak period researchers are spending time trying to overcome methodological hurdles in preparation for the next outbreak, but we also need other actors in the research ecosystem to prepare the ground for future studies to be launched quickly. The delay between outbreaks taking hold, studies being launched, results being communicated and translated into practice needs to be shortened, but this can only happen if all actors optimise their role.

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