Those of you who have followed the debates on AIDS clinical trial designs could be forgiven for thinking that humans must be unable to learn from history. I am not talking here about the current ongoing quarantine fiasco engulfing the USA. It's unworkable nonsense that has been condemned by pretty much every clinical expert under the sun. Panic is a bad guide for policy decision making. Perhaps next time the powers that are should try evidence based policy decision making. - Not terribly likely, unfortunately.
In any case, The Lancet has currently a debate going about the ethics of placebo controlled randomised clinical involving therapeutic and preventive experimental Ebola agents. The arguments pertinent to this have been - mostly - developed during the HIV/AIDS epidemic when it unfolded in the USA. Here is a review piece I had out a few years back on this subject. Remarkably, the arguments put forward in this context have not evolved at all since the late 1980s.
One the one hand you've those who are opposed to placebo controls in clinical trials involving post phase 1 experimental agents.
On the other hand you've the old battle axes from the US NIH bioethics department (Ezekiel Emanuel anyone?) reheating their undying support for benefit sharing in international health research and, of course, their undying support for placebo controlled randomised trials (presumably of post phase 1 experimental agents, but that ain't quite clear). It's the same arguments in favour of placebo controlled randomised trials involving catastrophically ill patients that are being regurgitated in the Ebola trials' debates. Its proponents write 'randomisation and placebo controls are the best means to control for confounding factors and determine whether interventions work or whether patients have recovered by chance.' Or, in another reheating of the same argument, writes David Shaw in a letter to the Lancet, 'but the best way to generate such data is in a randomised controlled trial'. It is entirely unclear what's meant by 'best' here. 'Best' presumably means a non-existent trial population on a planet where desperate patients and their loved ones have not killed health care workers and burned down treatment facilities. It's a planet, let's call it Emanuel-Shaw-landia, where catastrophically ill patients will be happily herded into placebo controlled trials. They are fully driven by a planetary sense of duty, no doubt. - On our planet, we know that such patients will do anything to subvert clinical trial designs they deem unfair. This is where our bioethicists might have taken on board lessons from the heydays of HIV/AIDS activism. Catastrophically ill patients rightly consider a 50:50 chance of getting a placebo a lousy deal. They will go to great length to share the active agents, thereby subverting the placebo controlled trial design, dosing regimes and whatnot. Remarkably none of the historical evidence we have on this count featured in any of the Ebola publications. Zilch. Why bother? Academic memories are truly remarkably short-term these days. Learning from experiences from a time when desperate, catastrophically ill patients responded to coercive offers involving places in purportedly ethical, placebo controlled trial designs by cheating on such large scale as to render a whole lot of research that occurred in those years useless? Na. Let's just stick to our story, the gold standard of placebo controlled randomisation, reality be damned.
In Western countries we have myriads of access schemes designed to ensure that whoever signs up today to participate in a placebo controlled randomised trial does so as a true volunteer, not a desperate patient who has run out of options in terms of accessing experimental agents legally by other means. One of those lessons we learned from HIV/AIDS. No word on any of this in current Ebola papers.
There's another issue that bothers me a bit about this debate. Much is made by everyone of the high mortality rate among patients infected with the virus. Things seem more complicated.
A recent paper in The Lancet reports this, 'evidence suggests that many Ebola infections are asymptomatic,1, 2 a factor overlooked by recent outbreak summaries and projections.3 Particularly, results from one post-Ebola outbreak serosurvey1 showed that 71% of seropositive individuals did not have the disease; another study2 reported that 46% of asymptomatic close contacts of patients with Ebola were seropositive. Although asymptomatic infections are unlikely to be infectious,2 they might confer protective immunity and thus have important epidemiological consequences.'
Much of the hype driving the reheating of the placebo debate is a result of projections likely overstating the future spread of the disease as well as the mortality rate associated with an infection. I wonder whether we will look back at short-cuts to informed consent, and the fast-tracking of ever more experimental agents as a terrible mistake. The little bit of data that we have from the USA suggests that early detection plus good clinical care can bring down the mortality very significantly. In fact, nobody who was treated competently and in a timely fashion died. This sheds a different light on trial justifications flagging the high mortality rate. Trial justifications flagging the high mortality rate that do not take into account that this rate is likely an artificial (ie human created, as opposed to disease created) result of the lack of efficient health care delivery essentially propose that economic reasons are good ethical justifications for clinical trial designs. After all, the mortality rates in question would have been caused by the economic conditions leading to the lack of timely and efficient clinical care for those who actually get sick from the Ebola virus. Perhaps bioethicists should focus again international justice issues. Not unlike in the days of HIV/AIDS, it's about prevention, prevention, prevention, treatment, treatment, treatment. Good clinical care will permit us to dramatically reduce the mortality rate among those getting seriously sick. Perhaps that's where our focus ought to be. Not on a regurgitation of the placebo debates of years-gone-by.
Or, if you really must, take note of the history of this debate. I thought that's a minimum requirement in the academy.
