The current outbreak of Ebola in west Africa has prompted a fair amount of debate around the ethics of epidemic control, containment, and intervention. Some of this discussion looks at what kind of intervention (use of experimental treatment? compassionate use? randomised One of these impotence buy viagra australia drugs that can treat acne effectually, and prevent its reoccurrence also. Yes, at the fingertips of the person, but comes and attacks. overnight cheap viagra Sometimes, we are so busy with our work that we don’t feel the need to consulting midwayfire.com levitra no prescription the physician. An adolescent with unhappiness can remain for an incredible measure of nervousness for his or her bad times so that he or she has enough viagra prices check availability to spend without going bankrupt. clinical trial?) is ethically appropriate in the context of such an outbreak. Here’s a link to a blog posting that considers what the writer describes as the “fetishisation” of science and data gathering in situations of crisis.
What do people think?
These questions remind me of the ones posed by Greg Egan in his 1995 short story Blood Sisters (PDF).
Several early Egan stories provide compelling illustrations of some very tricky bioethical questions. It’s testimony to his talent as an author that he clearly elucidates the problems without trying to preach solutions.
My favorite Egan line?
Nicholas Evans (at the blog post linked–it’s hard to find the actual name of the owner of that blog, apart from the twitter widget!) sees arguments against compassionate use access as imposing the priorities of science over the priorities of saving lives, and as continuing a colonial and racist history of using black bodies “for the benefit of all.”
This second point is extremely important, as he says, especially in light of the direction taken by the comments on Monti-Masel’s post arguing against compassionate use access. Monti-Masel reduces the question to informed consent, when in this context trust and justice (both in the sense of fair sharing in benefits, and in the sense of voice/control) are in question.
I’m not sure that Nicholas’s argument on the first point is as differentiated and fair to competing concerns as it might be. Compounding the public health disaster of an infectious disease outbreak with a potential public health disaster of an untested treatment going wrong is a genuine concern for everyone. Breast cancer advocates famously followed the lead of HIV/AIDS activists in demanding access to not-yet-proven treatments, and it didn’t work for bone marrow transplant for breast cancer the way it did for antiretrovirals for AIDS.
David Healy at the Data-based Medicine project has an interesting line of thought. He argues that placebo-controlled RCTs are designed to scrutinize treatments that we already think work—they shouldn’t be used to do the work of proving that things work when we don’t know at first whether they do or not. He ties this in some way I can’t fully reproduce to how regulators require RCTs for licensing, and drug companies and researchers pursue drugs that require large RCTs to prove marginal benefit. That’s another critique of the “fetishization” of RCTs.
I find it helpful to think about Bayesian reasoning, and the role of ethics in determining levels of confidence considered sufficient for proof, in these contexts. People’s understanding of what is “scientific” in clinical trials is often rule-driven (“must use placebo-controlled RCT” and “must meet threshold of P<0.05" and "must test in non-human primates first"), whereas the level of proof we need is related to the prior probabilities we can assign the hypothesis tested, the appropriate animal model for a given disease and therapeutic approach. An observational trial with matched controls and some degree of real world messiness may deliver the degree of confidence needed—the safety we are looking for—without randomization. The reminder often invoked here is that the link between smoking and cancer was based on observational data. With a case fatality rate as high as 90%, and a treatment that in animal models has shown survival of 4 out of 6 infected rhesus macaques –well, someone with the technical statistical know-how could calculate what kind of confidence you could get from using other kinds of non-randomized controls (historical, etc.). If there are pressing social and ethical concerns about randomizing in a specific context (as there was at a certain point with AART and there may be here), and a hypothesis unlikely enough that you’d have substantial confidence based on non-randomized first-in-human or Phase I results (even though those aren’t trials designed for capturing efficacy), “good science” and ethics may license other approaches.
It would be nice if our scientific reasoning could be nimble enough on these issues that we could have some conversational space left over for the trust and justice issues. Evans is making very important points about the historical context. We need serious work on governance and benefit-sharing–any solution that focuses on technical issues about trial design and misses that will miss the mark.
This is somewhat off the top of my head–I’m not following closely enough to know if folks have been making careful proposals based on Bayesian trial design, or distinguishing stages of clinical trials, or where the benefit-sharing conversation is at.
If you believe Hróbjartsson and Gøtzsche placebos have no discernible effect on physiological conditions so it would be unethical to conduct placebo controlled trials on seriously ill people.
I, however, don’t believe them.
Nonetheless I agree with Lynette that you don’t need too much evidence of efficacy and safety to propose a non-placebo trial to people who have such a terrible prognosis. Nonetheless, the question of informed and empowered consent is a biggie. How empowered can consent be if the prognosis you are expected to take on faith from experts is like a gun pointed at your head?
Hi All,
So first, thanks for linking through to my post!
Second, I acknowledge that I was incensed at the time of writing, and thus may not have been as sensitive to competing considerations as is otherwise desirable. I’ve been mulling over the type of positive response I’d want to provide—positive in the sense of saying “we ought to X,” rather than what I ended up posting, which was strictly negative. I’ve discussed this very briefly elsewhere in a post co-authored with my wife, Kelly Hills; this seems an apt place to build on this idea.
I think that a Bayesian analysis would be an incredible advancement of this debate. I’m all in favour of the RCT as the “gold standard” of clinical research, when looking at premarket authorization as well as other applications. I think that in the standard realm of testing in which we want safety, efficacy/non-inferiority, and (in some jurisdictions, like my homeland of Australia) cost-effectiveness, RCTs give us good information.
However, there are other important considerations that we need to take into account, including ethical. First up, the logistics required for an RCT are considerable—even for small RCTs. In the context of an epidemic in a nation that is , I think that there are consdierable disadvantages to attempting an RCT inside an epidemic, both from an ethical perspective on the part of of participants (such as I’ve raised in my blog post), but also insofar as we are committed to achieving beneficial results from our study.
For me, the most important consideration is attending to the central aim of applying these interventions. In this case, it is relief of suffering due to Ebola. With this in mind, while I’m sensitive to needing to make sure the drug(s) being administered are safe, it is necessary to view that from within the perspective of the clinical situation. The countries in question—particularly the initial trio of Liberia, Guinea, and Sierra Leone—are already well past breaking point. Adding to the burden through an RCT is likely (though how likely is a question for the Bayesians) to pressure that infrastructure even more. Even a case series study will allow us to track adverse events—a cohort study will have more power and get us important and actionable data, even without the power and prestige of an RCT.
Still, even if we could pull off an RCT, I think there are good, independent reasons to advocate for a different design. In the context of the West African nations affected by Ebola, I think we should put strong weight on studies that—in consultation with decision makers in those countries—are most likely to provide relief in the current outbreak, and in future outbreaks (because this Ebola outbreak is most certainly not the last). A cohort study with a strong epidemiological and public health presence would allow us to build up a strong set of comparisons between different intervention strategies, and begin building a cost-effectiveness profile for Ebola management in low SES countries (and Guinea, Sierra Leone, and Liberia are some of the lowest—their entire government budgets are orders of magnitude lower than US health expenditure). In the context in which the find themselves, I can’t see how (for example) ZMapp would be a choice of stockpiled drug in the future, at least until other priorities like running water, power, and so on are managed. Too often our C-E analysis focuses on variables like drug stockpiling. C-E of more modest interventions is also important in these contexts.
I hope that provides some added information to my views, and helps qualifies some of my assertions. I think that there are lots of good types of research we can do that allow the rigorous testing of these experimental agents. But I think that has to be moderated not just by considerations of public trust in these incredibly fraught healthcare scenarios, but by considerations of needs in terms of the types of data the affected populations can use to create better health outcomes.
Nick
Hi Nick.
As a fellow tertiary educated Australian I can certainly empathise with your intent here. I also applaud your wisdom in setting C-E against the opportunity cost of more modest interventions that may have a greater benefit in the medium to long term. But as an Aboriginal Australian I feel pretty wary about imposing external ideas of appropriate health measures upon someone else without doing everything possible to involve the recipients in the planning and delivery of such services. In practical terms that may not be feasible when we’re dealing with very sick people who need immediate assistance but I think yesterday’s armed attack on a Liberian hospital demonstrates the dangers of trying to impose external perspectives upon a community without gaining some kind of broad based consensus that will give as many people as possible a stake in both the process and the outcomes. The ‘decision makers’ in the affected communities are everyone. Or at least they should be.
I have a little background in population genetics and it’s application to forensic science but I think Bayesian analysis in the context of large scale, real world interventions that can’t be isolated and objectified is elitist nonsense. Even if you can explain the process you will never get a broad based consensus on what factors constitute a priori probability nor how to weigh them. It will always come down to the experts with the biggest swinging slide-rules imposing their view on everyone else. Of course if you believe in Bayesian analysis that is what you must go with, just like if I put it all down to demonic possession that will dictate the actions I must take. Just don’t imagine that the gospel according to Reverend Bayes will be anything other than more neo-colonialist gibberish to those who don’t see its relevance to their lived experience.
I know this is all pie-in-the-sky moralising in the face of an emergency that obviously requires rapid action. I just don’t want you to think that your hoped for (or expertly calculated) ends can ever morally justify your means. Consequentialism is not a system on which to base moral policy making. It is a technocratic tool of oppression – even if the dictatorship is a ‘benevolent’ one.
Hi cabrogal,
So I think that I agree with near-on everything you wrote—or, at least, I agree with what I understood of your writing, which I know is a separate thing.
I’m absolutely, 100% on board with involving—privileging—members of the affected communities as the holders of the relevant sets of experiences and needs in the outbreak. My suggestion about a cohort study, or a C-E that focuses on interventions at a different price-point than ZMapp or any other experimental serum was to point to potential (western) researchers that concerns about statistical power in studies (which Monti-Masel, in particular, is concerned with) can be achieved, with better effect, and without appealing to the RCT as something that is lexically prior to all other study designs. Too often, I think that researchers today are guided by what they are told is the best type of study to get published, and not the types of study that answer questions worth asking. What those questions are, isn’t up to me to answer.
(I’m also open to the idea that in this outbreak, research may just not be a priority—at all—for the people whose perspectives ought to matter most.)
In discussion with anyone from Liberia, Guinea, Nigeria, or Sierra Leone, I think it would absolutely be lunacy to approach this problem from the perspective of Bayesian analysis. Unfortunately, I don’t know anyone from those areas—though I’d like to, because I’m acutely aware that the circles in which I travel are very (though not exclusively) white, rich, male, and western-tertiary educated. Insofar as that’s the field I play in, however, speaking to “not the RCT” has been a moderately productive strategy in the last 24 hours.
Far from pie-in-the-sky moralizing, I see this as a chance to engage people within my sphere (see: the above predominantly white, rich, male, western-tertiary educatedness of that sphere) to encourage them out of some familiar and problematic moves. That’s all I can do right now, so I do it (largely through cranky blog posts and noisy arguments on social media).
I think the only thing that—as far as I understand you—I disagree on consequentialism being (solely) a technocratic tool of oppression. But I’m also aware that my account of consequentialism diverges in some pretty important ways from typical accounts of consequentialism. The most important one for my purposes here is that the values that best promote the best life for a person aren’t easily or readily aggregated; someone who is a serious consequentialist always has to inquire deeply into the people about which they are talking.
Which leads me to a question after my ramble: given that “what the Liberians/Guineans/Sierra Leonese/Nigerians decide is important to them, on their terms” should be a central part of any decisions made by westerners, where do you think we should go from there? I ask because that is usually where I stop—I’m out of my depth here once I break from some of the simplistic arguments I’ve made on my blog (and my central area of research is bioterrorism, which doesn’t really help me much!).
Nick
Hi Nick,
Some people are writing good stuff on the neglected public health aspect of the crisis. (Alison Thompson here, for example.)
One thing worth reflecting on is the way that “trust-building” moves can themselves also be very time consuming and have opportunity costs, just like appropriate RCTs. Who in Western Africa should take the time, now, to help the wealthy world feel good about our terms of engagement? “Nothing about us without us” may not be the whole solution.
Much of what “we” are doing in far-flung areas is setting the stage for this storm, something of which you are acutely conscious. The people on the ground in the response can only begin to say “let’s build trust” if we who are more distant are doing something about e.g. the WHO’s budget for response to this kind of disaster being cut in half in a few short years, or the relative focus on public health vs. catastrophic insurance in the global move for universal healthcare (Dan Wikler and others with the “Making fair choices” report on Universal Health Coverage (UHC)), or pouring buckets of ice on our heads for the relatively unsexy cause of getting healthcare and basic infrastructure to people who need it, or thinking about the background economic reality that, as Piketty sums it up in Capital in the 21st Century, 20% of African capital is owned outside of Africa–the only continent in this position–making Africa the only continent remaining in the fundamentally colonial position of people working day in and day out to enrich the rest of the world.
I’m working on the topic of solidarity this year (my comments about the different places people need to be doing different work relates to that concept), and in the back of my mind thinking about “biocitizenry,” which is a concept about which many people have theories and definitions–but the one face I’m seeing in it right now is “the medicalization of solidarity.” A generation or two ago, people could wave around the Universal Declaration of Human Rights, and sing “you may say I’m a dreamer,” and this was what “naive idealism” looked like. In this generation, the permissible naive idealism is: “how dare they not provide the poorest countries in the world this incredibly expensive drug for which there is no appropriate infrastructure?” On one level, this is very sad and strange, and worthy of critique. On another level, I’m impressed with the way it has, if nothing else, brought us back to conversation and action on global solidarity. But it’s such a convoluted route back to that conversation that the folks policy-making have an interesting challenge on their hands. Can they leverage this moment of attention from the wealthy world, and the strange way it is focused on incredibly expensive, unproven miracle drugs, into better health and community infrastructure?
-Lynette