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How to conduct a clinical trial during a disease outbreak

11 Aug, 2015

Ebola Lang 2

A year after the WHO declared the Ebola outbreak to be a health emergency, new cases continue to emerge in Guinea and Sierra Leone. Oxford Professor of Global Health Research Trudie Lang is part of a team that has been carrying out clinical trials of potential Ebola therapies – some of the first to ever be conducted in the midst of an epidemic. In a follow up to a recent commentary piece for Nature, she shares some of her tips for designing and operating a clinical trial during a disease outbreak…

Clinical trials are cumbersome and difficult in any setting. They take a long time to set up, are highly regulated and are (although they don’t always need to be) expensive.

Within the context of an infectious disease outbreak, such as Ebola, meeting the existing challenges while trying to set up a trial within the narrow window where cases are available is very difficult. Indeed, during all previous disease outbreaks, including the recent MersCoV and H1N1 outbreaks, not a single trial was conducted and we are still left with no proven treatments or management strategies for these infections.

When Ebola hit West Africa last year, it soon became apparent that here was an opportunity to do what nobody had managed before – to carry out ethical, safe and scientifically robust clinical trials of promising new treatments and vaccines in the midst of an epidemic. For our team at the University of Oxford, the learning curve was steep, but we quickly gleaned some valuable lessons that we should all take forward for the next, inevitable, infectious disease outbreak.

Do as much as you can in advance of an outbreak

It took our team an unprecedentedly short 12 weeks to line up everything we needed to begin trialling our first experimental drug, the antiviral brincidofovir. This was thanks to a huge collaborative effort between multiple agencies. But we should have been quicker, and could have been if we’d had trial protocols agreed and approved before the outbreak started.

Research needs to be considered at the outset of an outbreak and then requires an agile and streamlined approach to getting the trials designed, set up and operated in order to obtain much needed data within a short window. Even better if that research can also be embedded within the medical humanitarian response.

This requires leadership from the WHO and a better grasp of the realities of research (and its requirements) from all the agencies involved.

Ask the right questions

Whether it is determining whether a drug or vaccine works in a disease, or evaluating how best to manage and care for the patients, you require a clinical trial.

The starting point – and the key to it all, in my view – is having a single clear question such as “Does drug A reduce mortality at day Y?” or “Does survival improve if fluids are given to all patients on admission to a centre?”.

Devise a clean and pragmatic protocol that will give you an answer quickly

Evaluating drugs during the Ebola outbreak taught us that the one thing you don’t have during an epidemic is time. With the rate of new cases now (thankfully) in decline, one of the biggest challenges we faced was devising a study protocol that could quickly tell us whether or not an intervention was working.

Having your research question is the first step, but developing a good research protocol is key to being able to answer that question accurately, safely and ethically. My mantra here is keep in simple, only measure anything that you really need in order to answer the question. If what you are doing or measuring (within the trial) is not going to contribute – then don’t do it.

Have a dress rehearsal

With the Wellcome Trust funded trials that we led in Liberia and Sierra Leone during the Ebola outbreak we went through a ‘trial walk-through’. This is an approach that I always take when trying to turn a question into an operating trial, especially in low-resource and challenging settings such as this.

It allows us to think about each patient and remember that they are the centre of all this. You have to consider what happens to them through their clinical care within that setting.

It works really well to literally map out what happens to each patient, when their blood samples are taken and where they go and what data are we collecting at what time points. It highlights logistical, ethical and design issues before we start, and gives us a chance to work out how to overcome them.

These could be questions such as “at what point can consent happen and where?”, “how will the samples be transported?” or “how do we verify patients are alive at days 7, 14 and 28 if they have returned home?” For all these practical challenges we have to find locally workable solutions, such as sending the participants home with a new mobile phone.

Walking through one of our trial protocols

As you can see from the image above, our ‘walk through’ wasn’t exactly high-teach, but it was a highly effective method of establishing what we needed in terms of clear operating procedures, trial staff and what points might be difficult.

Develop local research capacity

Clinical trials are rare in low-resource settings and indeed previous research experience was low in all the countries affected by the Ebola outbreak. We made a strong effort to train the local health-workers in basic research skills and awareness.

One of the partners in our efforts with this trial is The Global Health Network, which is an online science park that aims to improve and encourage research in places and situations where evidence is lacking. Using the Global Health Network, we are planning to hold research skills sharing workshops in Sierra Leone, Guinea and Liberia.

The aim here is to take the experience of working on the Ebola drug and vaccine trials and use it as a basis for showing the importance of research and encouraging the development of local research capacity.

Engage with the community

In the early stage of any planned research it is key to inform and involve the local community where the studies are being conducted.

In the case of Ebola trials this was incredibly difficult and sensitive due to the level of fear in the community and mistrust of the health service. For this trial we worked with the local agencies and thought carefully about how to explain the concepts that we needed to make sure were clearly understood in order that the trial was accepted.

Share your data

Data sharing is so important in order to generate the most benefit from clinical studies. Normally this is difficult because investigators are reluctant to share, and because they have all collected data in different ways. During the Ebola outbreak we achieved something quite special. We adapted the ISARIC data capture form into our trial-specific data forms, as did other trial teams, so the data could all be shared more easily, ready for new analysis to be conducted by other groups.

Remember the common goal

In an outbreak on this scale, with multiple agencies from different parts of the world established in different areas it was always going to be challenging to coordinate research on the ground.

We need to change from research being an afterthought in humanitarian crises, and instead get used to embedding research as a standard and expected element of the medical humanitarian response.

Expect the unexpected

Ebola LangAs with any trial, the team faced unexpected challenges and situations that we could not have anticipated. These included issues such as how to secure the drug supplies (in terms of getting them into country and also keeping them safe in the centre) and what would happen if one of the staff became sick.

The most important thing is to keep in mind the question you are trying to answer. That way you can work through each unexpected eventuality and consider it in terms of how it impacts the safety of the patient, the reliability of that specific data point, and whether there are there any ethical implications. Thinking through these three key elements will help guide you on whether – and what – action is needed.

Final Reflections

When we did get up and running, our experience in the treatment centres run by Medicins Sans Frontieres and GOAL, was an overwhelmingly positive one.

The teams that we sent out to run these trials did an incredible job in highly challenging settings that put them at considerable personal risk, and they should be recognised for their impressive and dedicated efforts.

We feel we have achieved something remarkable – we successfully set up two clinical trials in two countries (brincidovofir in Liberia and TKM-Ebola-Guinea in Sierra Leone) within the narrow window of a disease outbreak, and we managed to complete one of them and answer the question that was set.

This work proves that trials can be done in these difficult circumstances and hopefully raised awareness of the importance of trials to governments, donors and health agencies. Let’s hope that the lessons we’ve learned mean that next time we really are more research ready.

You can read Trudie Lang’s commentary piece in Nature’s special Ebola issue and find our more about the Wellcome Trust’s Ebola Research Fund on our website. More information can also be found on Ebola Clinical Trials platform website.

One Comment leave one →
  1. 11 Aug, 2015 9:42 am

    Reblogged this on Philandtropical and commented:
    Great achievement these trials.

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