Lisa Schwartz describes the necessary conditions for the ethical provision of experimental Ebola drugs and vaccines.
The sudden outpouring of investigational drugs and vaccines in response to the Ebola crisis in West Africa is laudable. However, desperate emergencies do not mean we can forego caution. The World Health Organization (WHO) declared the outbreak of Ebola Virus Disease a Public Health Emergency on August 8, 2014 and struck an ethics committee that, on August 12, advised it is permissible to distribute experimental drugs and vaccines in response to the outbreak – even drugs and vaccines as yet untested in humans.
I believe the WHO was right to do this; speed is what is needed right now. However, the WHO was also rightly cautious in advising that these experimental interventions (for treatment or for prevention) should be used with care and under the vigilant scrutiny of, at the very least, observational research. Someone needs to be taking account of the results of these vast experiments, otherwise the risks taken by Ebola affected communities will be for naught.
Canada has offered an experimental vaccine, called VSV-EBOV, and Canadian based research laboratories have played a major role in the development of other early, untested medications – including the much talked about ZMapp. This is something that politicians say we ought to be very proud of, and so we should. But we must also be aware that there will likely be many such offers pouring in from experimental labs all over the world, mainly for the best reasons, but always with a mixture of hope and dread. What if the new intervention doesn’t work? Or worse, what if it harms, kills, or even accelerates the virus and its spread?
We need to be attentive to important cautionary cases and frightening realities. For example, in 2006 in Northwick Park Hospital, London, six healthy volunteers went into complete organ failure during the initial hours of a first-in-human Phase I clinical trial of a drug for the treatment of leukemia and autoimmune diseases such as rheumatoid arthritis. Fortunately none of the volunteers died, though some were permanently affected. The trial was done under impeccable clinical lab conditions; the research in animal models had not raised any concerns; and, for these reasons among others, no one predicted the disastrous result.
At the heart of the ethical concerns is trust. Research during global health emergencies has a blemished history. The use of Trovan during a severe meningitis outbreak in Northern Nigeria in 1996 is a case in point. Ethical problems point to how lack of transparency compromised consent. Investigations connected the experimental drug to the deaths of five children and severe impairment in numerous others. Accusations that the drug company put the interests of research and profits ahead of the children’s welfare eventually led Pfizer to offer some of the affected families a financial settlement.
Hard lessons learned from these cases demonstrate that clinical and social considerations may not be the only relevant factors in the current Ebola outbreak. As a result, global scrutiny is needed to help ensure that these factors are given proper weight in the face of potentially competing political and industry interests.
The relevant governance bodies in each of the geographical areas affected by the outbreak will need to be key collaborators in ensuring that ethical, scientific and legal requirements are upheld as the studies of these new Ebola interventions are rolled out. This means respecting core ethical principles while limiting exceptions, as the TCPS2 advises.
As well, innovative research designs should be considered in order to accelerate safe access to the drugs and vaccines under properly recorded scientific observation. For example, combined Phase I/II trials would help move patients more rapidly into active treatment arms. Stepped Wedge Cluster Randomized Control Trials that “involve sequential roll-out of an intervention to participants (individuals or clusters) over a number of time periods” could allow for the treatment of whole communities rather than small groups of individuals at a time.
Trials for the experimental Ebola drugs and vaccines should not be taken lightly. Three conditions must apply. First, informed consent and transparency about the uncertainties of these drugs and vaccines must be carefully made by the individuals and communities involved, so that political and private interests do not overshadow the welfare of participants. Second, proper scientific planning and ethics review should precede distribution of the experimental drugs and vaccines. Third, as far as possible, new and innovative research designs should be considered to permit safe and timely access to experimental interventions. We need to learn as much as possible about the drugs and vaccines so that they can be properly and safely marketed in the future.
The Ebola outbreak is a terrible disaster. People will be desperate for vaccination and treatment. This does not justify an experimental free-for-all, however, where no useful evidence can be collected from the first-in human clinical trials.
Correction 16-Aug-14: The original blog post incorrectly identified the hospital where six healthy volunteers went into complete organ failure as Norwich, UK. This has been corrected to Northwick Park Hospital, London.