On the science and ethics of Ebola treatments

ebola_micrograph_0by Joanna Monti-Masel

We have recently seen much ethical hand-wringing around use of the two new and experimental treatments for Ebola, ZMapp and TKM-Ebola. Unfortunately, people are worried about the wrong things.

The first two patients to be treated were Americans. Prior to this came the old (and historically justified) fear of testing potentially dangerous new treatments on vulnerable populations in developing countries rather than on privileged first world patients. The first ever treatment was not given to an African doctor because of this concern [1]. After Westerners were treated, complaints rose about giving infected Westerners access to a new drug while infected Africans went without. These two concerns are obviously mutually exclusive. People are concerned, they are just not sure about what, sometimes even voicing both concerns in the same article [2].

An important worry for any drug is that it might have damaging side effects. But if there were ever a disease for which this is not a big deal, it is Ebola. It seems extraordinarily unlikely that the drug could make matters any worse for an Ebola patient than they are already. No drug, approved as well as unapproved, is ever completely “safe.” The question is whether patients given the drug tend to do better, worse, or the same as those not given the drug, both in the short term and the long term. In the case of Ebola, I think we can reasonably ignore any concerns about the “safety” of the treatments and focus on figuring out whether they are effective.

To learn about effectiveness, we need to test these treatments on Africans, in the midst of a terrifying epidemic. Science isn’t just something that happens in laboratories, to be brought to the clinic when ready. To find out whether a treatment will work on real patients in clinics, there is only one way to do it: we need to test it on real patients in clinics. Those patients and clinics are in Africa. Today’s circumstances, with an abundance of patients, are exactly those in which the trials need to happen. And given the terrifying spread of this particular outbreak, the sooner we start, the better. The question is not whether this is the best or most ethical way to do a trial. This is the only way to do a trial, so let’s get on with it.

The WHO has given an ethical green light [3] to the use of these experimental therapies, with the caveat that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’ (access to an unapproved drug outside of a clinical trial).” They mention a number of ethical issues, but leave out the one that troubles me. The unethical behavior here, which was just given a green light by the WHO, is not doing an experiment, but doing an experiment without using a control group. There should be no compassionate use exceptions. Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them.

Five patients have received the ZMapp serum so far. Two US missionaries recovered, a Spanish priest died, and reports are not yet in for two Liberian doctors. Unfortunately, the supply is now exhausted, and we must wait until more is manufactured. Another experimental treatment, TKM-Ebola, also now has a green light for use in patients [4]. I don’t know how many people we can treat with the quantity of TKM-Ebola available today. I hope it is many more than the five we could treat with ZMapp.

At least five patients have received a potentially effective treatment, but nobody has yet been assigned to a control group. This is the ethical travesty, and it needs to stop.

With 1013/1848 = 55% of reported Ebola patients dying during this outbreak, you may think that we don’t need a control group. Surely we will notice if the death rate goes down from there [5]. But this is not as easy as you might think. Some of those infected patients haven’t died yet, but will die later, so the true death rate is likely a little higher than 55%. And neither the typically more privileged patients who receive the therapies, nor the care they receive during their treatment are likely to be representative of the average Ebola patient suffering and perhaps dying at home in their village.

A control group is not only essential for good science backed by rigorous statistics, but it is also ethically sound. Many people are understandably concerned about deliberately withholding potentially life-saving treatment and giving a placebo instead. But this is a moot point; we have no choice about withholding treatment. There isn’t enough of it to go around. The fairest way to distribute it is by lottery. This fairest plan also happens to be the best scientific plan. The question is whether we capitalize on our inability in the service of science by implementing a well-designed lottery, or whether we squander it instead with a less systematic lottery of who gets treated and who misses out.

This situation has an important and telling precedent. The very first randomized clinical trial ever published [6] in 1948 investigated whether antibiotics are effective against tuberculosis with Ebola-like death rates. Just like today, there was a shortage of a new drug, streptomycin. In the aftermath of World War II, Britain received only a very limited supply from American manufacturers. The Medical Research Council controlled this shipment, and seized the opportunity to dictate to doctors that if they wanted access to the drug for their patients, the only way to get it was by taking their chances within a randomized trial. Thus began a golden era of effective medical science [7], led by a strikingly novel and extraordinarily effective gold standard. What is more, to everyone’s surprise, the streptomycin treatment had limited effectiveness against tuberculosis. Patients improved initially, but then the bacteria evolved resistance to the drug and patients deteriorated again. This phenomenon of drug resistance had never been seen before. The randomized trial allowed this failure to be quickly recognized, leading to the improved and effective treatment protocols we have today.

We have so few doses available, and it is unethical to waste them in unsystematic tests that lack a control group. The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo. And then it should have given its second dose to Africa on the condition that it be randomly distributed to one out of two preselected patients in the same manner. This would have been the ethical thing to do.

If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a “statistically significant” fashion, from that tiny but well designed trial, that the drug works. We think of randomized trials as huge affairs. And it is true that to detect subtle differences, we do need huge trials. But when the improvements are not subtle, trials can be quite small. Sixteen patients (eight per group) would be enough to have a 95% chance of detecting the effectiveness of a miracle drug. Even if the drug were slightly less miraculous, dropping the death rate from 60% to 30%, the 10-patient trial that we could and should have done with existing resources would have had a 42% chance of detecting the drug’s effectiveness. Our unsystematic trial of five patients will tell us much less, squandering this opportunity to make best use of the limited supply of ZMapp that we had.

Even if the treatment is only moderately effective, we still want to prove this and use the treatment with confidence that we are doing good. The more patients we can test, the better our chances of spotting moderately effective treatments. The limit should be our ability to manufacture the drug quickly enough, not our failure to throw together a randomization procedure. Randomization procedures are not difficult; all you need is a coin or dice. Let’s not make this harder than it needs to be.

What we should learn from the history of randomized trials is that the biggest danger with randomization comes from the urge to cheat. It is only natural for doctors to have special sympathy for particular patients, and to rig the game so that their favorite patients end up in the treatment group rather than the placebo. This is the real historical reason that trials were made “double blind” so that neither patient nor doctor knows who gets what. There is a lot of talk about the power of the placebo effect, and it is important for some conditions such as pain, but for most diseases the placebo effect is overrated. A placebo won’t stop you dying of Ebola just because you believe in it. But a double blind design is still an important precaution to make it impossible for well-meaning doctors to rig the allocations.

This overwhelming temptation is why we should enforce randomization at the source. We should ship treatments out in randomized kits, where each “treatment” is labeled only with a color-coded key. This should be the only way that treatment can be had; no compassionate use exemptions, instead you receive a kit at random. The kits can come in more than two colors, to make it harder for doctors to guess which is which. And if a patient dies before finishing all doses, or seems to need an extra dose, doses can be exchanged between kits of the same color. A condition for receiving treatment kits is that you report back, for each kit, whether the patient(s) who received it lived or died. That’s all you need to report; it’s not complicated. Modern clinical trials are complicated, but the subtleties don’t matter for a life-and-death condition like Ebola. Let’s not make things more complicated than they need to be.

One final concern is that many Africans are suspicious of Western doctors and experiments, and that their fears will keep them away. That’s fine, at least for now. That’s what the ethical principle of autonomy is about, crystallized in the notion of informed consent. And yes, African patients can be informed. The message we need to give them is simple:

This drug might work. We have some good reasons to hope so, but we don’t know. We don’t think the dangers of the drug are anything like as bad as the disease you already have, and it might save your life. If you sign up, whether you get the drug is like tossing the coin, except you won’t be told which way the coin landed, and we your doctors won’t know either. In any case, we will do our best to take care of you, but this disease is hideous, and with or without treatment, you might die. If you sign up, you will also be helping us learn for sure whether the drug works, when we see whether people who get it do better. It’s up to you.

A Western education is neither necessary nor sufficient for understanding this simple message, which encapsulates what a randomized trial of an experimental treatment means. We should cut through the excessive paperwork of the “informed consent ritual” that few Westerners understand [8], and stick to the essentials.

Plenty of infected Africans will probably refuse to take part in the trial. That’s okay, because we don’t have enough treatments to go around anyway. I suspect that the brave doctors and nurses in Africa who have risked their lives caring for Ebola patients will believe in the system enough to volunteer for a chance at life-saving treatment. Indeed, in recognition of their bravery, I would put health care providers in the front of the queue to sign up for the trial. But neither they nor anyone else should get access to our very limited stocks outside of a trial. Nobody should have more than a 50% chance of getting the treatment rather than a placebo.

Let’s hope that both treatments can be manufactured quickly, that both work, and that this outbreak is contained soon. And that during the next outbreak, we can move on to testing the two treatments against one another rather than against a placebo, to see which of the two works better.

_____

Joanna Masel is an evolutionary biologist at the University of Arizona, where she teaches a class in Evidence-Based Medicine. Her research investigates the robustness and evolvability of biological systems and the nature of different types of competition in both biology and economics.

[1] Opting Against Ebola Drug for Ill African Doctor, by Andrew Pollack, The New York Times, 12 August 2014.

[2] Ebola, research ethics, and the ZMapp serum, by Laura Seay, Washington Post, 6 August 2014.

[3] Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD), World Health Organization, 12 August 2014.

[4] FDA eases restrictions on experimental Ebola drug as CDC warns of ‘inevitable’ spread to US, RT.com, 8 August 2014.

[5] Ebola prizes revisited, by Eric Crampton, Offsetting Behavior, 5 August 2014.

[6] Streptomycin Treatment of Pulmonary Tuberculosis, British Medical Journal, 30 October 1948.

[7] Controlled trials: the 1948 watershed, British Medical Journal, 31 October 1998.

[8] Informed consent: how much and what do patients understand?, by M.E. Falagas et al., American Journal of Surgery, September 2009.

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22 replies

  1. I nice article which I agree with (assuming all facts and figures are correct).

    However, isn’t it true that it doesn’t strictly have to be 50%? If there were enough of the drug, and if we were motivated by a suspicion that it did work, might we not design a trial where 80% of patients, say, get the drug while 20% get a placebo and still be able to detect its effectiveness?

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  2. Great article, I totally agree with most of it. A few things to point out though:

    “The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo.” I’m not sure how much of the new treatments are available. If the supply is so low that we can only potentially treat a handful of people, then I guess this holds up. If we could potentially treat anything more than about twenty people, then both Americans should have been treated, because A) Having a single person as a control group doesn’t constitute a good test B) Treating one extra patient doesn’t diminish the amount of treatment available to the extent to effect further trials, and C) It’s unclear whether further trials will ever take place on a larger scale, so it’s too risky to withhold treatment for the sake of a set of trials that we don’t know will take place. But if it’s the case that there is only enough of the treatment availabe to treat about 20 or less people, then the treatment is precious enough that we should make efforts to begin a trial immediately, as the author states.

    Second, the author mentions that there have been concerns by the people in Ebola stricken regions about the intentions and ability of healthcare workers. This raises concerns when testing a new drug. If the new treatment does have disastrous side effects, even if the side effects are minor in comparison with the effect that they have on death rates, this might cause the uneducated population to become even more hostile to treatment. It’s hard to predict something like that.

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  3. Since Ebola occurs in non-human animals with physiology similar enough to humans to do reasonable control group experiments on them, I disagree on the primary ethical objection the author presents. And, if we can learn enough from animal control studies, beyond what’s already been done, maybe we can then decide just what control studies are needed on humans and how tightly crafted they should be.

    An experimental post-infectious medical treatment is different from an experimental vaccine on ethical issues like this.

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  4. I think this comes down again to the amount of medicine that we currently have available. Right now, there isn’t enough available to treat the whole population of infected people anyway, so there are going to be people who don’t have access to treatment. So having a control group doesn’t actually deny anybody treatment. And animal testing, at the moment, would result in using our limited resources in trials where nobody has the potential to be cured. And waiting until some later date to do animal testing isn’t helping anybody at the moment. When would these studies begin? After the outbreak is over? We don’t know when that will happen, and without some action taken, it won’t. The place to start seems to be with human trials.

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  5. @Disagreeable_I: If we have 100 patients in a trial, we have the highest power (greatest chance of detecting that a drug works) if split the patients 50:50 rather than 80:20 or in some other way. In particular, if the treatment drops the death rate from 60% to 30% a 50/50 patient trial has a 88% chance of discovering this, while a 80/20 patient trial only has a 69% chance. If there are only 50 doses available, a trial that enrols 100 placebo patients does have slightly more power than one that enrols only 50 (rising from 88% to 97%, with corresponding power to detect smaller treatment effects too), but at some point it becomes a question of diminishing returns limited primarily by the number of patients in the smaller group.

    @Michael: There were only 5 doses of ZMapp, so there was no question in my mind that all 5 would be used somehow. By flipping a coin to use the first, we would have set an example that a coin should be flipped for the next 4 doses too. That alone might have been enough to tell us something (although given that the Spanish patient died, in retrospect it wouldn’t have, but if we got a few more doses we would be back in business). And I think the best approach on multiple counts, including minimizing hostility, is to treat infected healthcare workers before “regular” patients, and to be entirely non-coercive with respect to enrolling in the trial.

    @SocraticGadfly: The only way to find out whether non-human physiology is similar enough to humans is to do an experiment on humans. Historically, a huge proportion of promising treatments have disappointingly failed to transfer successfully to humans. And the experimental vaccine shares many of the same constraints, in particular that there is not enough of it to go around to everyone in high danger of exposure. It’s more ethical to do safety trials on an African nurse with a lot to gain that it is to do safety trials on a “healthy volunteer” in the US with nothing to gain except a fee. There are a lot of ethical concerns about the sort of vulnerable “volunteers” who do phase I trials for money in the US.

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  6. Animal trials have already happened BTW. It was human trials that we were waiting on. In the “normal” course of things, they would have started with human volunteers on the US, looking for dosage and major side effects. But after those were done, they still would have had to wait for the next outbreak before they could do a trial to test effectiveness. The only way to test that is in real patients.

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  7. I agree with the “availability” premise. That said, other than having people for whom we can’t give the medicine be given nothing, there really is no “control group” other than doing a monitored quarantine or whatever we do for the treated group.

    In that sense, it’s a “default” action, though, not a deliberate one.

    So, to be more precise? If we have more prophylactic medicine, I disagree on the author’s ethical objection. There’s a difference between a prophylactic treatment like antibiotics and a preventative like a vaccine.

    That said, some sort of randomizer is the only legitimate way to decide who gets the vaccine and not. Any other method is unwarranted.

    Beyond that, I’m going to call BS on the larger idea.

    If the medicine is really that limited right now, we don’t have enough doses to have an adequately sized treatment group, or therefore an adequately sized control group. Therefore, there’s no statistically significant results that can come out of this right now anyway.

    So, to be a bit blunt, this is all really at the “mental masturbation” point right now anyway.

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  8. A tiny note — Given some of the results of monoclonal antibody trials in the past, it is in fact more than theoretically possible that an untested drug from this category could make things worse, even in the case of Ebola. (“It seems extraordinarily unlikely that the drug could make matters any worse for an Ebola patient than they are already.”) Had it been associated with the same sorts of problems as e.g. the TGN1412 trials turned up (where healthy volunteers who got tiny — vastly sub-clinical — doses were almost killed), it seems likely raised the mortality rate to around 100%. That may or may not be a good reason for exercising extreme caution in the distribution of untested drugs from this category. But it remains a fact that even in the case of a disease with a extraordinarily high mortality rate, an experimental drug can in fact make things worse.

    The notes on the use of statistical significance testing are, I think, a little misleading; it is important to consider our actual informational state. It is true that “If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a ‘statistically significant’ fashion, from that tiny but well designed trial, that the drug works.”

    But that isn’t the informational state we are in fact ever in. Consider: If we know for example that most potential drugs *don’t* work — that is, if we know, going into the trial, that most untested treatments aren’t in fact miracle drugs — than even a very successful trial, in terms of statistical significance, does not give us good reason to think that the drug in question really works. It is true, as noted, that IF the drug works, there is a good chance that we will get statistically significant results, but it is well understood that given even relatively low background chances of a drug trial being successful, a statistically significant result doesn’t raise the probability of that the drug really works to a reasonable level (that is, most trials in which we get statistically significant results will be trials of drugs that don’t in fact work). That is something important to consider, I think, when considering whether to engage in an RTC in a particular case (that is, we should think about how much we would really learn about the drug in question’s actual effectiveness, rather than just the power of the trial in the abstract). In this case, the various problems, both ethical and practical, with trying to run a tiny but relatively pure RTC, might speak against doing so. Or they might not — but if not, it is worth thinking through why not rather carefully, I think. Just a thought!

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  9. Jonathan, I agree that a Bayesian approach would be better, I was keeping it simple with the conventional frequentist statistics I used. But I think the prior probability that the drugs work is higher in this case than for most trials. Biologics tend to do better than small drug molecules, and infectious diseases are one of the best possible scenarios for generalizing from animals (in some cases monkeys, so not even too distant from us) to humans. Yes, there could be harms, but I believe the probability that there is also some benefit, for this particular cateogory of drugs, is extremely high. The benefit may or may not outweigh the harm, of course, but it is more ethical to trial these drugs on patients to whom the benefit applies than to our usual human guinea pigs to whom it doesn’t.

    A monoclonal antibody like TGN1412 attacking not just any target but a host immune component is in a class of its own both in terms of danger and in terms of difficulty of generalizing from one species to another – I don’t believe any of the Ebola drugs fall into this category. An important lesson from TGN1412 was the need for slow one subject at a time rollout, but that is likely to happen here anyway.

    Within a Bayesian framework, it should also be possible to make do with a somewhat smaller control group by beginning with a prior for the treated and untreated death rates centered on 60%, with greater uncertainty around this for the treated group. But this sort of statistical design is tricky for people to agree on, hence my calculations stuck to more conventional approaches. (For the record, I calculated power by applying a likelihood-ratio (G-) test to simulated contingency tables.) Chances are that if we distribute drugs within a randomized framework as fast as we can manufacture them, then we will get an unambiguous answer well before the shortage ends. A rapid 60% baseline death rate means high power no matter how we do the stats. But if we distribute first and try to do a trial later, any preliminary evidence, however methodologically flawed, in favor of the drug will create an ethical barrier to doing the trial at that later stage.

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  10. Intensive autopsying and tissue sample preservation of the dead patients, aimed at finding signs of damage from the experimental drugs, should also be required. The is also an onerous emotional burden on the patient’s loved ones, but foregoing the opportunity to save people from a failed drug would be unethical.

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  11. Intensive autopsies in Africa run the risk of infecting those doing the autopsies, a more serious life and death matter than the emotional burden on loved ones. This should only be done when conditions are sufficiently safe and containment capabilities are not overstretched dealing with live patients and safe disposal of dead bodies. And even if there is detectable damage from drugs, if patients in the treatment group are more likely to survive than patients in the control group, the damage would insufficient reason to stop giving out the drug. The most important thing we need to know right now is whether the drugs change survival rates.

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  12. Oh, I understand the ethics of paid volunteers. You’re getting, in fair degree, alcoholics and addicts who might have, for those reasons, adverse reactions, etc., to be honest. I’m not saying we should rule out human trials, just do more of what we can with animals before moving onward. Plus, as I noted, 5 people being doses (and 5 controls) isn’t an actual controlled trial worth anything anyway.

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  13. A major point I wanted to make is that just 5 doses and 5 controls is worth something in this case, contrary to conventional wisdom. For a true “miracle drug” (which we don’t have, because one treated patient died) it would have had 69% power. Statistics has some interesting nonlinearities in it, and it requires remarkably few patients to get results against a baseline of 60% death. Most trials we do don’t have that kind of baseline.

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  14. Thanks for the reply!

    One quick thought: You write that “the prior probability that the drugs work is higher in this case than for most trials” and that “if we distribute first and try to do a trial later, any preliminary evidence, however methodologically flawed, in favor of the drug will create an ethical barrier to doing the trial at that later stage.” I’m concerned that in this case that the general requirement that we only hold RTCs where something resembling “clinical equipoise” obtains might be being skirted…

    Put somewhat crudely, it is generally accepted that RTCs are only permissible if there is no good reason to prefer, clinically, one arm of the trial to the other. If one thought that there were real risks to the treatment, and no good evidence of effectiveness, this would hold, even in the case of a disease like Ebola. On the other hand, if we have any reasonably good reason to think that the drugs are effective and reasonably safe, an RTC against a placebo is clearly impermissible in this case, even if the drugs have never been tested directly, etc.

    If you are right that the prior probability of the drugs working is higher in this case than for most trials, and that the risks are relatively low, then given the high mortality rate associated with not-treating, it might be that an RTC is simply ethically impermissible in any event, and we are simply forced to use matched-case and historical controls, however problematic those might be, if we want to behave ethically.

    The idea that we should refrain from gathering evidence that might result in a shift towards RTCs against placebos being ethically impermissible, though, seems to push in the wrong direction.

    One might of course reject clinical equipoise as a requirement for RTCs (I think a good case can be made that strict equipoise can’t be a requirement when one is thinking about cost-effectiveness analyses, for example), but if so, then a different kind of reason has to be given for why it would permissible to withhold the treatment when we merely have good reasons to think it will work before it has been deployed but impermissible to withhold it when we have good reasons to think it will work after it has been deployed…

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  15. Excellent article providing clarity and a sensible/scientific perspective which cuts through the madness and volatility enveloping Tekmira stock. Heads Up: Hope you don’t mind me tweeting your article!
    Yours Aye,
    Bill Christie. @BAMPOTSCOT

    $TKMR “We have so few doses available & it is unethical to waste them in unsystematic tests that lack a control group”https://scientiasalon.wordpress.com/2014/08/14/on-the-science-and-ethics-of-ebola-treatments/ …

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  16. The reason ethicists ask for clinical equipoise is that if we lack it, we would be sacrificing members of the group getting the likely inferior option to the cause of science. Instead we should give everyone the best alternative. But we can’t do that right now, because the likely better option is the treatment, and there isn’t enough of the treatment to go around. So the clinical equipoise objection simply doesn’t apply in this unusual case (which has a precedent with streptomycin). But if we wait, the equipoise objection will eventually come into force, and will make a trial very difficult in the future. This makes it especially urgent to do a well designed trial now.

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  17. Bingo. Without a Bayesian approach … which you can’t really do on an initial study, anyway, right? … we don’t know even where to guess at on the effectiveness probability of ZMapp, especially if animal trials don’t “translate” well.

    So, I don’t see how we can put a 69 percent figure on statistical significance. Or whatever percentage, if ZMapp is not a miracle drug.

    So, when we have enough ZMapp, for our first clinical trial, to do an adequately sized one, call me back. Per Jonathan, I’m not an immunologist, nor do I play one on teevee, but I’m assuming RTC = real time control? If I’m following the discussion correctly, and your side in particular, right. Again, let’s get ZMapp produced in some amount greater than now, then do traditional placebo controls on a larger sample. Again, it’s mental masturbation, IMO, before that.

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  18. An excellent presentation of the ethical and practical issues in trying to develop a scientific response rapidly to an epidemic.
    A lot of people are saying in the media, ‘hey, if there’s this magic pill, let’s get it to the people in Africa!’ without any idea of what they are asking for or the processes involved.
    Part of the problem is that the agencies that assumed public responsibility for our response to the epidemic have not presented the matter in terms that most people understand.
    Hopefully articles like this can receive greater attention.
    (Side note: It is also disgusting the way some xtian fundamentalists have tried to appropriate this whole issue as yet another demonstration of god’s ‘wrath against gays.’ But that’s another discussion. I do wish, more generally, that people would just give the medical scientists and technicians the time and space – and money – they need to get on finding a cure, and leave their own self-righteousness in the closet.)

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  19. You make a good point and I agree with you. There is sometimes a fine line between compassionate use which I believe should be used when there is already some evidence of efficacy and the clinical situation is dire e.g. bedaqualine for XDR TB and the need for a trial when efficacy data is lacking and the situation is a bit less dire e.g. trials of new regimens for MDR TB.

    I wonder what your opinion would be if there was no shortage of these drugs and we would use them liberally in West Africa if we wanted to? Personally I would still think it ethical to do a placebo controlled RCT but do it quickly and efficiently. What do you think?

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  20. When there is no drug shortage, it seems ethically questionable to give placebos rather than a drug that seems likely to be effective. But remember that new drugs can not only be ineffective, they can also be harmful. There have been some meta-analyses in oncology as to whether, on average, you are better off getting allocated to the new treatment or the placebo/previous best treatment. Fortuitously, it comes out as 50:50. If this had not happened, we would have a real ethical dilemma, either that placebos are unethical, or that experimental treatments are unethical. But it just so happens that prior experience suggests that complete equipoise is the rational stance. Ethically very convenient, but that is what the available data says.

    That said, I think the situation with Ebola treatments is weighted towards treatment. There are better than average animal models, resistance is less of an issue than for slow viruses like HIV, and the potential benefits are so large. If there were no drug shortages, the question of whether to do a RCT would be a truly agonizing ethical dilemma. If you do it, you willfully deny patients of a likely effective treatment. If you don’t, you risk falsely concluding that an ineffective or harmful treatment works (eg because evolution is driving death rates down anyway) or that a marginally effective treatment doesn’t (eg because evolution is driving death rates up), either way with consequences for a much larger number of people. That’s not an ethical decision I want to make. That’s is one of the reasons I think it is urgent to do a trial as quickly as possible, while the drug is still in short supply and there are no legitimate ethical barriers because not everyone can get it anyway. And why it is such a shame that we didn’t do this for the first 6 treated patients (it turns out to be 6 patients not 5 as in my original post), setting an example from the very beginning. If we wait too long, the ethical pressures against a placebo group will become overwhelming.

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  21. I would like to thank Joanna Masel for a thoughtfully written piece, and the commentators afterward for responding in such a restrained manner on behalf of good and useful dialogue.

    From my relatively uneducated standpoint (in comparison with many of those who have written here) I wondered if there is any study under way on those who have survived particularly this wave of Ebola to see if antibodies and the process of how they were produced in the survivors might yield useful results in producing a cure / treatment? Also if anyone has been found to have been exposed to the illness but not contracted it because of pre-existing immunity?

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  22. Studies on survivors are a sensitive matter culturally, many are having a hard enough time already being accepted back into their communities. Nonetheless, one paper that may answer some of your questions in the context of a much earlier Ebola outbreak is at http://www.ncbi.nlm.nih.gov/pubmed/307455. I doubt that pre-existing immunity is common, but many infections may be subclinical, i.e. the body successfully fights off the virus before things deteriorate to the point of “getting sick”. Those who have already had subclinical infections are likely to be immune. I don’t think we know how common subclinical infections are for this particular outbreak. There is no evidence that subclinical cases are infectious, people seem to be infectious only after they start having symptoms.

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