A Covid-19 coronavirus vaccine must first go through rigorous clinical trials – Leigh Fell

Thalidomide and the ‘Elephant Man’ trial help explain why any coronavirus vaccine must go through the proper process, writes Leigh Fell, chief executive of clinical research organisation Caritas Neuro Solutions

A member of the Italian Red Cross visits a patient during her round of home visits to Covid-19 positive patients in Bergamo (Picture: Marco Di Lauro/Getty Images)

Understandably and increasingly, people have been asking me questions about how treatments and vaccines for this novel strain of coronavirus will be developed and why it will take up to a year or more to come into general use. So I thought I would explain a little about the clinical trials process in order to help people understand.

Q. If there are potential treatments in the pipeline already, why can we not move straight to testing them in hundreds of patients who need it?

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Safety first! The clinical trials industry is one of the most strictly regulated sectors in the world and for good reason. Pharmaceutical products exist to save lives, not to put more at risk and therefore all newly discovered medicines must follow a very thorough process of testing. Even if all has gone well in the laboratory and animal trials, we can never ever be 100 per cent sure of how a new drug will react when we introduce it to the human body for the first time.

Rules and processes have been developed over time in response to previous disasters (I’m sure we’ve all heard of thalidomide) in order to prevent things like that from ever happening again. Therefore as an industry we have designed models of testing that ensure the lowest possible risk to participants. But we must never forget that that risk still exists every single time we make a new medicine and that the people who take part in these trials are incredibly brave.

If you need an example of what can go wrong, check out the “Elephant Man trial”, as featured in the BBC documentary The Drug Trial: Emergency at the Hospital. During that trial in London in 2006, six volunteers were dosed all at the same time and all six ended up having a severe reaction and multiple organ failure within hours of receiving the drug.

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Q. So what are Phase 1 trials? And how do we ensure safety?

Once a new compound has been fully tested in a laboratory and in animals, we can move to what are called “Phase 1” or “First-in-Human” trials.

These trials are very small with generally only 10-20 people participating., though in some of the Covid-19 trials I believe we might see up to around 50 participants. And typically these are healthy volunteers who do not have the disease.

The reason for this is that, at this early stage, the aim is to figure out exactly how the drug behaves in a normal human body. First and foremost, we are obviously on the lookout for any severe reactions or intolerable side effects – note, we expect all drugs to have some minor side effects such as mild headaches and nausea but these might be considered to be bearable if the clinical benefit outweighs the risk.

We also thoroughly review how the drug is being processed (metabolised) by our organs. We do this by looking at chemicals in the blood for what we call pharmacokinetics (the movement of the drug around the body), how it is absorbed into the blood, how it is broken down by the liver, what organs it reaches and how it leaves the body. And we look at pharmacodynamics (what effect is the drug having), is it acting in the way we expect and targeting the correct chemicals in the body?

Traditionally, in order to avoid situations such as the “Elephant Man Trial” mentioned above, we would dose one person at a time, leaving a few days before we dose the next person. We start off with a low dose for the first three participants, then review the data and start with a higher dose for the next three participants, continuing to do this in cohorts until we reach a dose that can no longer be tolerated. This is dubbed in the industry as a 3+3 design.

However recently there has been a shift to a new design which relies on very complicated (Bayesian) statistics. This means the data is analysed continuously as each participant is receiving the treatments and allows for quick decisions on dosage and safety rather than waiting until after three people have been dosed for example. This has enabled Phase 1 trials to be more reactive to events and therefore to treat more people and increase the dose more quickly while still maintaining safety review. For this reason, I would imagine that most of the Covid-19 trials will be using this methodology.

Q. So what are Phase 2 and Phase 3 trials?

Once we are confident the drug is safe to give to humans and we have decided on the optimum dose, we move to “Phase 2”, often called “Proof of Concept” trials. The participants in these studies will be real patients who have the disease. We are still (always) looking out for safety and side effects, but now also starting to look at efficacy – does the drug actually work?

These trials are slightly larger, potentially will have a couple of hundred participants and will be run in several medical centres, possibly in two or three different countries.

Note that at this point, it is still very early in development and therefore would still be unethical to give it to thousands of people before we have an idea of likely clinical benefit.

But assuming all goes well and the data analysis shows good results we then move to Phase 3 and this is when the really big trials begin.

Phase 3 trials will include many thousands of real patients. In hundreds of centres all around the world.

At this point we want to understand how the drug reacts in different demographics and populations of people and how effective it is at treating the disease.

Throughout all this, we are reviewing how it interacts with other medicines that people are taking and building up a really good picture of the “safety profile”. All the information you read in the information leaflet you get in your packet of medicine comes from the data that we gather throughout these trials.

Q. Can everyone take part in these trials?

Clinical trials of new medicines always have very strict entry criteria, again for safety reasons. For example, it might be considered too risky for someone who is pregnant to participate as, in the early stages, we don’t know how the drug might affect the unborn child (I refer you again to Thalidomide). As more data is collected though, a larger demographic of people will be able to participate especially in the Phase 3 trials.

Q. Why does it take so long to develop new medicines?

Under normal circumstances, it takes around 10 years to develop a new drug from start to finish (discovery to marketing authorisation) and the clinical (human) phases of testing would usually take at least five years. But with the current pandemic, scientists are aiming to complete the whole process in around a year. So how is it possible to speed it up so drastically?

The answer really is that, as with most things, it is a matter of applying resources. Clinical trials are hugely complex projects involving large teams of people of all different disciplines and immense volumes of work. Often navigating the paperwork and red tape is one of the most time-consuming aspects.

To give you an idea of the scale of the team, for any given trial we need doctors, nurses, pharmacists, data managers, lab technicians, scientists, statisticians, medical writers, project managers, drug and equipment suppliers, allied health professionals, programmers – as well as everyone who has oversight, from ethics committees to regulatory agencies, auditors and monitors. This list is by no means exhaustive.

In order to coordinate such a huge project, comprehensive instructions need to be written to cover every activity involved and absolutely everything that happens during the trial must be fully documented.

To complete all the activities quickly will require more manpower than usual, but inevitably as countries and organisations around the world have prioritised this particular disease area, the resources required will be made available.

For some types of illnesses (especially chronic long term illness such as cancer), patients can be on treatment regimes for months or even years and therefore the trials can last a long time. However, with Covid-19 being an acute (short-term) illness, treatments will likely last no longer than two weeks per patient, therefore allowing trial timelines to be shorter.

For the current novel coronavirus trials, it is anticipated that Phase 1 trials might take around six weeks. So given that the first trials have just begun, we might expect the earliest trials to report results by the start of May. Phase 2 trials will last slightly longer, potentially well into quarter three of this year after which large-scale Phase 3 trials will be able to start.

Lessons and information will be taken from previous similar trials for the like of the Sars virus which will help to speed things up and, of course, it is worth noting that ‘repurposing’ studies of already existing medication which could be used to treat novel coronavirus will be able to proceed quicker as the safety profile is already known.

There is also unprecedented levels of information sharing currently happening between scientists and organisations all around the world, which will also have a positive impact on timescales.

Q. Who is developing these medicines?

It is very common for initial discovery of new compounds to happen in academic settings such as universities. Once a compound is discovered it might be taken on by a small pharmaceutical or biotechnology company to carry out the early phases of testing. If successful then it will likely be acquired by a much larger pharmaceutical company in order to fund the large-scale later phases of development which, incidentally, will cost tens of millions.

In this case, already a number of companies have announced they are beginning clinical trials, including Swiss pharmaceutical giants Roche and smaller specialist vaccine and immunotherapy companies such as Moderna and Inovio. But there are many more and one thing we can be sure of is that they will all be racing to be first past the post – which is ultimately good news for patients.

In fact, a quick search of the clinical trials register (clinicaltrials.gov) brought up over 100 studies already planned or active.

Everything about this disease has been unprecedented (including the level of use of the word “unprecedented”). If we do indeed manage to create a completely new drug from scratch within a year, that will be a first but I truly believe it can be done. More importantly, it will be a testament to the human spirit and to everyone who is working so tirelessly and diligently to fight this. Therefore to close, I would like to extend my deepest gratitude to everyone involved.