Will Ebola change the future of clinical trials?

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  • Author: Jennifer Rogers
  • Date: 28 Nov 2014
  • Copyright: Image appears courtesy of iStock Photo

The race is on to find a vaccine that will halt the spread of Ebola, with candidates being developed the UK, US, Canada, China, the Netherlands and Denmark. One of the frontrunners is the vaccine ChAd3, which is being developed jointly by GlaxoSmithKline (GSK) and the US National Institute of Allergy and Infectious Diseases (NIAID) [1]. Despite the research that is being done to develop a vaccine for Ebola, it is unlikely that a vaccine will be available for widespread administration until the middle of next year. This delay in getting a vaccine to the front line has been a source of frustration, with experts saying that this may be the only way to halt the spread of this outbreak [2]. In fact, the development of a vaccine for Ebola and the associated clinical trials that are necessary are moving at incredible speed. The clinical trial process typically takes many years and so to have a vaccine available next year would be a huge achievement. So what are the many hurdles that need to be jumped in the quest to get such an important vaccine out to those who need it so urgently? Why do clinical trials take so long? This is a question that has been asked many times. Clinical trials are specifically designed to test the safety and efficacy of a new treatment. This is hugely important because “new” doesn’t automatically mean “better” and, additionally, many treatments come with unwanted side effects that may prevent it from being brought to market. Clinical trials have been growing larger and larger as the regulations surrounding efficacy and patient safety have become tighter and tighter. But what are the tests a new treatment must go through, before it is deemed suitable to be brought to market.

thumbnail image: Will Ebola change the future of clinical trials?

Clinical trials are split into phases with the first phase, Phase I trials, aiming to test the safety of a new treatment. A small number of healthy volunteers will receive the treatment and they will be tested for side-effects. This will typically be the first time that a new treatment will be tried on humans and so there will always be an unavoidable element of risk. To minimise this risk, volunteers will usually begin by receiving a very small dose of the new treatment and this dose will slowly be increased if volunteers do not experience any side-effects (or if they experience only minor side-effects) and by continuing in this manner, researchers are able to determine the optimal dose.

Now, I’ve had people question me about the need of a Phase I trial in the case of Ebola. I am asked why we need to test the safety of these vaccines when the alternative is Ebola and that surely that is worse than any of the associated side-effects that may be experienced. Yes, it is true that sometimes the development of new treatments can be a fine balancing act between benefits and risks. Take for example, epilepsy: many anti-epileptic drugs (AEDs) come with extremely unpleasant side-effects, but for someone presenting with serious, debilitating seizures on a regular basis, the relative merits of AEDs may far outweigh the associated risks. But testing the safety of a new treatment isn’t just about determining whether there are any associated side-effects that need to be considered. Recall the Phase I trials of TGN 1412 at Northwick Park in March 2006. This trial comprised 8 healthy male volunteers, 2 of whom received a placebo with 6 being given the active treatment [3]. Every single one of the 6 who received the active treatment had severe and life-threatening reactions, including vital organ failure, and had to be treated in intensive care. The men all survived, but their health has been permanently compromised as a result of receiving TGN 1412 [4]. What happened to these 6 men is highly unusual, but the shocking nature of this event clearly demonstrates the overwhelming need for safety to be properly considered whenever a new treatment is developed. And Ebola vaccines are no exception to this.

In the UK, the Phase I clinical trial of ChAd3 started mid-September at the Jenner Institute at the University of Oxford with Ruth Atkins, a former nurse with the British National Health Service, being the first British volunteer to receive the experimental Ebola vaccine [5]. Results are expected from these in December this year [6]. The planned protocol for this study was that if the first volunteers vaccinated in the Oxford study showed a good response with no adverse reactions, the trial would be extended to The Gambia and a second West African arm of the study would then also begin in Bamako, Mali. The Oxford study planned to involve 60 healthy volunteers, while those in The Gambia and Mali would each involve 40. Each set of volunteers were to be split into groups of 20 that would receive different doses of the vaccine so researchers can evaluate the best dose to use in terms of both safety and activity [1]. GSK have begun manufacturing 10,000 additional doses of the vaccine at the same time, so that if the trials are successful, stocks could then be made available immediately.

Phase II trials test the new medicine on a larger group of people and this will be people who are ill. This is to get a better idea of whether it works and also to see how well it works in the short-term. Any treatments that make it through Phase I and Phase II will then move onto Phase III. This is where treatments are tested on a large-scale in many people who are ill. Phase III trials will often last a year or more and involve several thousand patients. If a treatment passes through Phases I to III, it is then that it will be given a marketing license and approved for widespread administration.

In the case of Ebola, GSK are planning to conduct the Phase II and Phase III trials in parallel, and will be in non-affected and affected countries, respectively [7]. Two Phase III trials have been proposed by GSK. The first of these is a fully randomised clinical trial in Liberia with two arms: the GSK vaccine and a control vaccine, which will involve up to 12,000 persons. The second Phase III trial will not use a placebo and will enrol up to 8,000 health care workers in Sierra Leone. The use of a placebo controlled trial has attracted a lot of criticism, with the ethical considerations of using a placebo in the case of Ebola being called into question [8]. Placebo controlled trials, however, remain the gold standard of clinical trials and are the best and quickest way to determine the efficacy of a new treatment. There is a treatment that has already been used in the battle against the Ebola outbreak. ZMapp, the most advanced of the experimental drugs at the time, was given to two Americans, Kent Brantly and Nancy Writebol, and also to William Pooley, the British nurse evacuated to the UK with Ebola. All three of these individuals survived and recovered from Ebola. So does three out of three mean that this treatment is an effective solution? Well, not necessarily. A WHO report released on 25th October stated that there had been, to date, 10,141 confirmed, probable, and suspected cases of Ebola reported in six affected countries (Guinea, Liberia, Mali, Sierra Leone, Spain, and the United States of America) and two previously affected countries (Nigeria, Senegal) and there had been 4,922 reported deaths [9]. This put the current mortality rate at just under 50%. So this means that even without treatment, we would expect over half of everyone infected with Ebola to recover. It should also be noted that a Spanish priest, Miguel Pajares, and a Liberian doctor, Abraham Borbor, have both died despite receiving the drug ZMapp. So how do we know whether ZMapp is doing anything? Well without proper comparison with a placebo, we don’t. Furthermore, Teresa Romero, the Spanish nurse who became the first person to contract Ebola outside of West Africa is reported to have received a variety of different experimental treatments, including an antiviral drug and the blood plasma from an Ebola survivor [10]. This variety of treatments means that we are unable to determine which of these, if any, aided her recovery. Without fully understanding which treatments work and which don’t, we risk sending vaccines to the front line which don’t actually do anything. And a placebo controlled trial remains the most effective way to determine efficacy.

So in answering the question as to whether Ebola will (or even should) change the future of clinical trials: the simple answer in my opinion is no. There are very good reasons as to why clinical trials are carried out in their current form. Each different phase that a new treatment must go through before widespread administration is immensely important in determining safety and efficacy. What this outbreak of Ebola has taught us, however, is that this process can be speeded up, turning something that would usually span years into one that lasts only months. So could Ebola change the way we carry out clinical trials in the face of a global epidemic, well that, perhaps.

1. http://www.gsk.com/en-gb/media/press-releases/2014/ebola-vaccine-trials-fast-tracked-by-international-consortium/
2. http://www.theguardian.com/world/2014/oct/16/ebola-vaccine-peter-piot-west-africa-epidemic
3. http://www.mhra.gov.uk/home/groups/comms-po/documents/websiteresources/con2023519.pdf
4. http://www.nhs.uk/Conditions/Clinical-trials/Pages/Problems.aspx
5. http://www.ox.ac.uk/news/2014-09-17-first-volunteer-receives-new-ebola-vaccine-uk-trial
6. http://www.who.int/mediacentre/multimedia/vpc-24-october-2104.pdf?ua=1
7. http://apps.who.int/iris/bitstream/10665/137184/1/WHO_EVD_Meet_EMP_14.2_eng.pdf?ua=1
8. Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy J, Heymann D, P Horby, Kaleebu P, Tamfum JM, Olliaro P, Piot P, Tejan-Cole A, Tomori O, Toure A, Torreele E and Whitehead J. (2014) Randomised controlled trials for Ebola: practical and ethical issues. The Lancet 384(9952): 1423-1424. DOI: 10.1016/S0140-6736(14)61734-7
9. http://apps.who.int/iris/bitstream/10665/137185/1/roadmapupdate25Oct14_eng.pdf?ua=1
10. http://www.bbc.co.uk/news/world-europe-29913739

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