Conscientious objection, ethical problems in clinical research in public health emergencies, problems with ethics guidelines and other stuff

I know I know, I have not posted much since September last year. It's been an unusually busy time, professionally, so I must beg for your understanding that this blog has taken a backseat to other projects. I mostly want to alert you here to content I have published or that I have forthcoming. as well as the odd project that's going forward.

Let's start then with a heads-up on publications! I have done a lot of work on the issue of conscientious objection, mostly because I feared (I was right) it would be one of the tools in the armament of those determined to subvert the Canadian Supreme Court decision that decriminalised assisted dying. We have since discovered that buildings (hospitals) think they have conscience rights, even conscience rights that weigh heavier than the conscience rights of the doctors and other health care professionals working in them. Naturally, I am referring to Canada's legions of Catholic hospitals. Then there are health care professionals who think that saying 'I object on grounds of conscience' to the delivery of professional services that they are monopoly providers of, should kinda trigger all-out societal accommodation efforts, patients rights to service delivery be damned. I think both the hospitals as well as those doctors got it badly wrong, and I published a few papers designed to show why that is so.

Here's a paper in the Journal of Clinical Ethics, another one in the Journal of medical ethics, one in Bioethics [Open Access], a reply to various critics in the Journal of medical ethics and an Editorial in Bioethics, all on the conscientious objection issue.

I have also written a few other Editorials, on the ethics of access to unregistered medical interventions during infectious disease outbreaks, on baby boomers and assisted dying, and on the seemingly vacuous rhetoric of 'dignity' and 'vulnerability' that is liberally deployed in UNESCO's bioethics documents.

There are a few other papers in the production pipeline, one on treatment resistant depression and assisted dying is currently under review, and a piece on catastrophically ill patients right to access unregistered medical interventions, forthcoming in the Journal of Law, Medicine and Ethics.

I am currently busy organising an international workshop to be held at this lovely location in mid August, on recent revisions of the World Medical Associations Declaration of Helsinki and the Council for International Organisations of Medical Sciences research ethics guidelines. My own take on the CIOMS document was published in the Indian Journal of Medical Ethics.

Last week, in London, I spent a day with Ruth Chadwick, the other Editor of Bioethics, and our Editors at Wiley, to discuss how we will develop the journal to make it even more successful. Stay tuned for developments on that frontier. Oh, Ruth and I are also close to completing a new bioethics textbook that we are writing jointly. It's years late, which is probably inevitable when you have your plate full with research, teaching and other stuff, but we're close to completion of that project!

I also delivered on the teaching frontiers, creating a new first-year bioethics course for Queen's undergraduates. I have not taught undergraduates for oodles of years, so that was quite an experience. The teaching evaluations suggest that folks enjoyed it. But then, I would say that, wouldn't I?

Last but not least, in the end of March Ruth and I will be off to China to participate in a bioethics conference.

And that's a wrap.

Future Infectious Catastrophic Disease Outbreaks: Ethics of Emergency Access to Unregistered Medical Interventions and Clinical Trial Designs

The mass media excitement about Ebola has receded. The 2014-2015 West African outbreak has been brought under control not thanks to the deployment of successful treatment regimes, because there are none that are known to work. I participated recently in an international meeting of experts debating the ethical and methodological issues pertaining to trial designs for emerging infectious diseases like Ebola. It was both astounding and also immensely frustrating that to a large extent the controversies that exercised the minds of the delegates of this meeting exercised the minds of many an AIDS activist and clinical trials’ expert prior to the advent of highly active antiretroviral therapy, a good quarter of a century ago.[1] [2]Are placebo controls an ethically defensible methodological tool when patients face a terminal illness? Different alternative trial designs involving placebo controls, adaptive trial designs, and multi-stage approaches involving active controls were discussed during the meeting. The heated nature of some of these debates reminded me strongly of the passion that was on display during the early HIV trials. It turns out, despite decades of informed debate about these issues, a number of significant normative questions have not been settled.

A cluster of difficult ethical questions that engendered justifiably a lot of debate has to do with the use of placebo controls in trials involving patients facing a very high mortality risk (some in excess of 90%) and a fast-acting infection resulting in the death of these patient within 2-8 days after admission to a treatment centre. This scenario mirrors the sobering reality faced by a subset of Ebola Virus Disease patients. This issue was already highly contentious during the early HIV trials, and then patients and clinical investigators were faced with a virus that was nowhere near as fast-acting as the Ebola virus. The ethical conflict that arises here is this: We know that those randomized into the placebo arm face the same greater-than-90%-risk of death within a few days as those who receive the standard of care treatment. In some trial design the placebo control arm could be identical to the gold standard of (unsuccessful) clinical care provided in a particular clinical setting. Given that those who are randomized into the arm featuring the unregistered medical intervention might do better, or might do worse, or might do roughly as badly as those in the placebo control arm, the ethical question remains whether a trial design featuring a placebo control is ethically justifiable, given the almost certainty of imminent death faced by those randomized into the placebo arm. During the meeting I alluded to earlier a fairly contentious debate arose also over the question of whether trials producing less reliable results than placebo controlled trials might be acceptable under such circumstances.

What exacerbates the ethical challenges for those who undertake such trials is that their trial participants are arguably not true volunteers. Their – dying - trial participants are not given the opportunity to choose between participating in the placebo controlled randomized trial versus accessing the unregistered medical intervention on their own volition outside the trial process. It is perfectly conceivable that some patients might choose to participate in such trials in order to facilitate the development of a successful intervention capable of helping future patients like them. Or they might accept that there exists true clinical equipoise between the trial arms and they might be volunteering to be randomized under such circumstances. In the absence of alternative access routes to the unregistered medical intervention, we can never be certain that the patients agreeing to be randomized are not simply responding to what constitutes a coercive offer.

Clinical investigators colluding in this process, and arguably benefiting from it, are not absolved of their ethical responsibilities because they did not create the regulatory frameworks that gave rise to the problem. It is true that they did not create the regulatory framework under which they operate, but they undoubtedly benefit from its existence. We could respond to this kind of argument by pointing to the societal need for sound trial designs and the detrimental impact of permitting patients to access unregistered medical interventions outside the clinical trials’ system. The likely impact of permitting patients access, as a senior biostatistician attending the workshop rightly pointed out to me, would be a significant slowing-down in the trial recruitment process. Some trials might never be able to recruit sufficient patients, because most patients might be voting with their feet and opt to take their chances with the unregistered medical intervention. Surely that is not quite what is in the best interest of any society battling an emerging infectious disease such as Ebola. Does this justify coercing dying people into particular trial designs? I do not think so, but this is a contentious issue where reasonable, well-informed people can justifiably differ. A WHO panel looking at this question argued that while it would be ethically defensible to offer emergency access to unregistered medical interventions to Ebola patients, this should be subject to that emergency access not slowing down trial recruitment.[3] The panelists (not featuring a single expert or disease survivor from the affected countries) took a policy line here that mirrors US regulations. Other countries, including Canada and South Africa do not make this a threshold condition for emergency access. As it is with these sorts of panels, the advice it rendered on this controversial topic is not actually reasoned for, so policy makers and regulators as well as patient rights advocates aiming to balance the competing interests of access versus trial recruitment in a fair manner will be left wondering about the ethical reasons for this policy stance taken by the WHO panel, assuming there are any.

There are other ethical issues that arise in this context: Some experimental agents existed at the time only in insufficient quantities, for instance ZMapp, an unregistered medical intervention composed of monoclonal antibodies, was only available in very limited quantities. In light of this situation, is it acceptable to prioritize patients in comparable clinical circumstances who are willing to be randomized in a placebo controlled trial over patients clamoring for direct emergency access, given that the available quantities of this unregistered medical intervention would have been used up in the placebo controlled trial?

And here is another difficult question: While the AIDS activists of days gone by were highly educated about their disease and about the available unregistered medical interventions considered for expanded access programs, this is not quite the case with regard to the average West African Ebola patient. These patients were unlikely able to provide valid first person informed consent, because they were unable to demonstrate a reasonable person understanding of what was known about the unregistered medical intervention, about their options and so on and so forth. This is the case both because of educational limitations as well as disease progression. Are short-cuts to informed consent ethically justifiable under such circumstances? Given that time is of the essence and proxy consent might not be feasible due to family members being deceased or in a far-away village, are our informed consent requirements reasonable under such emergency circumstances?

The WHO panel suggests that evidence from nun-human primate experiments might be sufficient to justify offering a particular unregistered medical intervention for emergency access. Is that an ethically justifiable stance, given the high mortality rate and fast-acting nature of the infection?

Let me leave you with a final difficult question to ponder: Imagine you were running a medical NGO providing access to unregistered medical interventions to patients you care for in your emergency medical centre. By some fluke your unregistered medical intervention permits some of your patients to survive, but that survival comes at a high price, debilitating after-effects of the Ebola virus as well as of the unregistered medical intervention. Given concerns about your patients’ capacity to provide valid informed consent, should you accept responsibility for the patients’ future care and upkeep, given the lack of state infrastructure to assist these patients? If you accept responsibility for their care, say, by taking out an insurance package from some provider for them, you will expend a fair amount of donor monies on these patients (potentially for decades) that you cannot use to assist patients also facing life-threatening illnesses in other parts of the world. In other words, you face another ethical challenge, a resource allocation challenge. How should that medical NGO go about addressing this challenge?

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[1] U Schuklenk, C Lowry. 2009. Terminal illness and access to Phase 1 experimental agents, surgeries and devices: reviewing the ethical arguments. British Medical Bulletin 89: 7-22.

[2] U Schuklenk, C Hogan. 1996. Patient access to experimental drugs and AIDS clinical trial designs: ethical issues. Cambridge Quarterly of Health Care Ethics 5: 400-409.

[3] WHO. 2014. Ethical considerations for the use of unregistered interventions for Ebola virus disease.  WHO: Geneva 2014: p. 5.

The trouble with international ethics guidelines

In nearly regular intervals arguments flare up among bioethicists as well as political activists about the substantive guidance proffered in international ethics guidance documents such as the World Medical Association’s (WMA’s) Declaration of Helsinki or the Council for International Organisation of Medical Sciences’ (CIOMS’) research ethics guidance documents. Who doesn’t recall the arguments about standards of care in clinical trials undertaken in developing countries, or the post-trial benefits debate?[1] Monographs, anthologies, as well as an endless stream of graduate student theses focused on particular aspects of these debates. There is nothing wrong with these efforts. As someone who spends significant amounts of time vetting other people’s content, as a journal editor, academic supervisor and external examiner of graduate students’ theses I have read a lot of content dedicated to these debates over the years.

What has always struck me as strange is that virtually nobody seems to question the relevance of these documents. They are usually taken as authoritative statements, not dissimilar to consensus statements clinicians might publish in medical journals. And yet, it is far from clear that anyone should accept these declarations and guidelines as relevant documents of that kind.[2] Take the WMA’s Declaration of Helsinki as a case in point: it is interesting in so far as it has been one of the most bitterly fought over international research ethics guidance documents just a few years ago. It is still being revised in fairly frequent intervals, alas the old battle axes in this dispute have by and large moved on to other issues. There is little professional interest in substantive changes to what once were highly sensitive provisions in the Declaration.

At least the WMA has some claim to represent the world’s doctors. Still, the Declaration offers no justifications for its guidance, so it is unclear why anyone who undertakes biomedical research and isn’t a medical doctor should bother about it. It is also doubtful that the national medical associations debated in any meaningful way proposed revisions to the Declaration and instructed their delegates to the WMA’s General Assembly to vote in particular ways that actually represent the views of the members of these national associations. You might also wonder why a local GP’s views and vote ought to matter a great deal in matters research ethics in the first place. CIOMS remains a fairly smallish operator with even less of a claim to represent meaningfully people involved in biomedical research.[3] Its initial claim to fame was that it put itself forward to interpret the WMA Declaration of Helsinki. Once that – kind of - established its legitimacy this interpretation morphed into its own guidance document. At least CIOMS has a habit of trying to justify its guidance, as opposed to engaging merely in ex cathedra declarations like the WMA is wont to do.

The situation doesn’t get any better when one looks at international institutions such as the World Health Organisation (WHO). While undoubtedly United Nations insiders are clued in with regard to the status of myriad WHO documents, the wider public, and indeed policy makers outside the corridors of WHO offices, almost certainly do not. A case in point: After spectacularly failing in its response to the Ebola outbreaks WHO engaged in what can best be described as wild activism to show that it is doing something. It issued eventually an ethical guidance document that declared that it is OK to use unregistered experimental interventions on Ebola virus disease patients.[4] The authors of this document, celebrated as they were as experts on the subject matter, had mostly never published a word on either Ebola virus disease or, indeed, on the difficult subject of emergency access to experimental drugs in case of patients with catastrophic illnesses. The latter topic has been a matter of intense debate over the last few decades in bioethics. I should know, I have been involved in these debates. The WHO’s experts may have been nice people interested in this topic, who were known somehow to WHO people in charge of inviting someone ‘expert’, alas very few of their experts had any demonstrable expertise when they willingly pontificated publicly on WHO letterhead on this subject matter. Much like CIOMS, the authors of this guidance document ought to be commended for having made the effort to provide justifications for their recommendations.

The results of the WHO meeting were eventually reported the world all over as the WHO ‘approving’ the use of experimental drugs in patients with Ebola virus disease.[5] It turns out that the WHO has no jurisdiction to approve anything of that sort, and, equally as importantly, WHO never actually did approve what it was reported to have approved. The WHO documents produced by the people it invited to pontificate on this subject, state actually in small print that they merely reflect the views of the people who wrote them down, and that they are not the official view of WHO. Their views, in other words, ought to carry no more weight than the views of any other groups of academics who hang out together at conferences and draft papers in their spare time. This hasn’t stopped academics writing about this subject to mention the WHO documents as if they carried any meaningful regulatory or other weight.[6]

WHO is at the time of writing in the process of developing procedures for the selection and use of such experimental agents in Ebola virus disease patients.[7]  I suspect the status of these documents won’t be of more significant regulatory weight than that of any of its other Ebola crisis triggered documents. That is not to say that they will be bad documents. It appears to be the case that these documents will be an amalgam of best practice guidelines from nations that have many decades of regulatory experience with emergency access to investigational agents in patients with catastrophic illnesses. However, if, for instance, Liberia and the USA decided to establish an emergency access program for a particular therapeutic experimental agent, and they chose to ignore WHO (who is apparently keen to inject itself into these bilateral processes) what exactly would WHO be able to do about that? Nothing that I can think of.

What is the value of these sorts of guidance documents then? I think they are valuable as documents that drive debate among interested parties about the substantive controversial issues that they address. They might also be of value to organisations such as the International Committee of the Red Cross, Doctors without Borders, and others, who want guidelines for their own emergency access plans without spending too much time thinking about ethically defensible operational frameworks themselves. Last but not least, they might be useful to developing nations without the capacity to develop their own regulatory frameworks and who decide to resort to WHO guidance documents and protocols.

However, given these questions about the status and the legitimacy of these documents, if the old adage caveat emptor ever applied anywhere, it should apply to these guidelines, declarations and policies. Anyone choosing to adopt them ought to adopt them because they consider them ethically defensible, and not because they happen to come from WMA, CIOMS or indeed the WHO.

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[1] Schuklenk, U. 1998. Unethical Perinatal HIV Transmission Trials Establish Bad Precedent. Bioethics 12: 311-318.

 

[2] Schuklenk U. 2004. The Standard of Care Debate: Against the Myth of an ‘International Consensus Opinion’. Journal of Medical Ethics 30: 194-197.

[3] Schuklenk U. 2004. Ibid.

[4] WHO. 2014. Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD) Geneva, August 12, 2014. http://www.who.int/mediacentre/news/statements/2014/ebola-ethical-review-summary/en/ [Accessed March 16, 2015.] See also WHO. 2014. Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD) Geneva: Report of an advisory panel to WHO. Geneva, n.d. http://apps.who.int/iris/bitstream/10665/130997/1/WHO_HIS_KER_GHE_14.1_eng.pdf [Accessed March 17, 2015.]

[5] Eg Anonymous. 2015. WHO approves experimental treatment for Ebola. AlJazeera August 12, 2014. http://www.aljazeera.com/news/africa/2014/08/who-approves-experimental-treatment-ebola-2014812122023925143.html, McKay B, Loftus, P. 2014. Ebola Virus: Experimental Drugs Approved for Use in Fighting Outbreak in West Africa. Wall Street Journal August 13, 2014.   http://www.wsj.com/articles/experimental-drugs-are-approved-for-use-in-fighting-ebola-in-west-africa-1407884538 [Accessed March 17, 2015]

 

[6] Hayden EC, Reardon S. 2014. Should experimental drugs be used in the Ebola outbreak? Nature August 12 doi:10.1038/nature.2014.15698.

[7] WHO. 2015. Public consultation on emergency use assessment and listings procedures for medical products during public health emergencies. http://www.who.int/medicines/news/public_consult_med_prods/en/ [Accessed March 18, 2015.]

Placebo controlled trials, catastrophically ill patients and access to experimental drugs

Here's the long version of a piece I wrote on this topic for  The Conversation where it was published today (sans a few bits and pieces that I would have liked included). Interestingly enough, the site saw it fit to alert readers of my piece to an article expressing a different point of view. Fair enough, except, when you read said article you'll note that it doesn't link back to my piece.

In the last six months Colorado, Louisiana, Missouri, Michigan and, most recently, Arizona have passed “right to try” laws that allow terminally ill patients to access treatments that have only passed FDA Phase I clinical trials. All patients need is permission from a drug company and a prescription from a doctor.
 

Right to try laws are designed to ensure that terminally ill patients taking part in clinical trials are true volunteers and have no incentive to cheat the clinical trials system as has happened in the past.
 

Recently, these laws have been critiqued as misguided, and the ethics of allowing patients to use experimental drugs are still up for debate. These laws do not guarantee access to experimental treatments and patients may have to pay for them out of pocket.

Critics of these laws worry that alternative trial designs, or access to such experimental drugs outside the clinical trials system will significantly delay the development of effective therapies.
 

Right to try laws are ethically defensible because they give desperately ill patients a choice. They can decide to participate in placebo controlled clinical trials or to access experimental agents as a possible last-chance treatment. The clinical trial system demands that participants are true volunteers. But, without right to try laws, terminally ill patients have no choice but to access these experimental treatments through placebo controlled trials.

AIDS and the origins of ‘right to try’

Throughout the 1980s, AIDS activists and patients fought to change the clinical trials system. Dying from what was then a terminal illness, many people with AIDS insisted on the right to access experimental drugs that had successfully passed Phase I clinical trials.

Phase I trials are designed to establish the toxicity profile of a particular drug. A small group of volunteers (often not more than a handful) test the drug to find out whether it has serious side-effects. They don’t have to be patients, because the objective is to determine what negative effects, if any, the short-term use of the experimental agents could have.

The only option for AIDS patients in the 1980s was to join a post-Phase I placebo controlled trial or go without access to experimental agents that might give them a shot at survival. These drugs trials are typically double-blind. Double-blind means that neither the doctors nor the patients know who receives the experimental agent and who receives the placebo. This aims to eliminate any bias that might arise from patients or doctors knowing who receives what.
 

Taking part in clinical drug trials meant that AIDS patients faced the chance of being assigned to the placebo control group, and not the group receiving the experimental treatment. These patients understood perfectly well the steep odds against these drugs working. But at least there was a chance. The same cannot be said of placebos.

There is a sound methodological reason to test a new experimental agent against a placebo control when we have no gold standard of care. We need to know whether the new agent does better or worse than the existing standard of care. Even in cases where there is no effective or well-developed standard of care we are usually, but not always, justified in undertaking placebo controlled trials.
 

But, we expect patients participating in clinical trials to be true volunteers. Patients need to choose to participate and give first person voluntary informed consent.

AIDS patients charged that the clinical trials system was essentially coercive. To access experimental treatments, these patients were more or less forced to take part in these clinical trials. If they did not volunteer to participate in a placebo controlled trial, they couldn’t access experimental treatments.
 

Many patients grew frustrated with this system and, often in collusion with their doctors and pharmacists, lied and cheated to access particular clinical trials. They analyzed who got placebos and who got the experimental drugs, and shared the drugs. Patients dropped out of clinical trials they believed offered trial designs not conducive to their own survival. Controlled trials become nearly impossible under such circumstances.
 

Undoubtedly this made it harder to get a sense of what drugs worked and what didn’t and may have delayed the development of life-preserving anti-HIV medication.

Drug companies control access to experimental treatments. Taiyo FUJII/Flickr, CC BY

Right to try, but not right to access

Since the 1980s special access protocols have been implemented in the United States, Canada and other countries. These protocols meant to ensure that catastrophically ill patients can access experimental agents outside the clinical trials’ system.

At least in theory. In practice, things are different. Right to try laws do not guarantee the right to access experimental treatments. Even with laws in place, access is still controlled by drug manufacturers.
 

In Canada the government permits people with terminal illnesses to access drugs that are in the clinical trials system, and they can do so without having to participate in the trials. In return they promise to have their doctors monitor the impact of the drug carefully and report it back to the manufacturer or whoever runs the clinical trial.

Access to these treatments depends on the goodwill of pharmaceutical companies keen on recruiting patients into their clinical trials. Drug manufacturers effectively coerce terminally ill patients into their trials by refusing access to the experimental agents. Experimental drugs are sometimes released outside of clinical trials on so-called compassionate grounds, but that doesn’t always happen. Here is just one example of a since deceased cancer patient. Adrienne Cotton died earlier this year. She tried to access a particular experimental drug that was already in a phase 3 clinical trial (we had reasonable evidence that it worked against the cancer that was killing her from phase 2 clinical trials). The medication she was successfully denied access to by the drug's manufacturer has since received market approval as a cancer drug in Japan.
 

And who pays for these experimental treatments? For good reasons insurance plans in the US (or, in Canada, government programs assisting uninsured patients) will not pay for drugs that are untested and are not known to work. As a result of this patients in both Canada and the US must pay out of pocket for these experimental agents.
 

Pharmaceutical companies are free to charge whatever they wish for these agents, and so, arguably, are in a situation to exploit financially desperate dying patients. This also gives them an opportunity to deny patients access in order to coerce them into trial participation. Regulators need to look at this problem as a matter of urgency.

 

Ebola patients subjected to placebo controlled trials

FDA officials and influential former NIH staffers are currently falling over one another propagating placebo controlled trials to test experimental agents on Ebola virus infected patients in West Africa. It goes without saying that impoverished catastrophically ill patients there – in the real world – have no alternative other than to accept the deal on the table. There are methodologically sound alternative trial designs available that do not rely on placebos, yet – much like during the 1980s – the FDA remains intransigent to the human suffering caused by its edicts. Remarkably, trial designs that are not acceptable unless alternative access to the experimental agent is offered in a bunch of of US states are foisted so on desperate African trial participants if the FDA has its way.

The Ebola response shows that we are learning nothing from history

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.

Bioethics and the Ebola Crisis

As I write this the global north’s media hype about the Ebola outbreak in various West African nations is at its peak. Amidst wild speculations about the number of infected people there are also confirmed facts, such as about 3700 confirmed cases and about 1800 deaths.[1] No doubt numbers will increase. These cases occurred overwhelmingly in Liberia, Sierra Leone, Guinea and most recently Nigeria. It goes without saying that many more people have died of other preventable or treatable diseases in that same period of time in those same countries, yet the world’s gaze was transfixed on Ebola. Just for a reality check, in Nigeria about 215.000 people die per year entirely preventable deaths related to HIV/AIDS and another 300.000 die of Malaria.[2] Having said that, Ebola is a pretty terrible disease, even by the usual unpleasant standards of life-threatening diseases.

As can be expected of some mysterious disease emanating from the ‘dark continent’, a lot of attention seeking theatre accompanies the deadly performance of the actual virus. The actors are a mixed bunch of Christian missionaries busily trying to get their hands on the last available experimental agents while on private medical jet flights out of West Africa. As you would expect, toward the end of their performance they thanked their respective gods for their survival as opposed to state of the art medical care. Who else performed in the mass media’s bright lights? International organisations tried to grab the limelight. There were serious performers such as Doctors without Borders. They have treated patients in Ebola outbreaks for many years, without ever losing personnel in the process. Doctors without Borders provided us with sensible explanations for the ‘why now’ of the outbreak and the ‘why here’ with regard to where the outbreak is occurring. Essentially the outbreak is occurring in failing states with barely existing health care systems. Patients and their families – often with good reason – do not trust foreign or local medical staff. Quite understandably they are suspicious because mostly body bags leave government and other facilities tasked with attending to Ebola patients. Many of these people also don’t quite buy into the idea of viral causes of disease. Doctors without Borders asked for urgently needed specialist personnel from countries of the global north, staff able to undertake the necessary laboratory work, health care personnel for treatment, portable medical equipment necessary to isolate patients, and so on and so forth. That, of course, is so obvious, that it’s nearly boring. Theatre must be entertaining, and Doctors without Borders isn’t quite delivering on that front.

Steps in the WHO. After missing the outbreak for a fairly extensive period of time the world organisation responsible for global health decided that its first act after declaring this outbreak a pandemic, should be to host an expert meeting on experimental treatments and experimental preventative vaccines. It goes without saying that this haphazard meeting, convened within a week by WHO, and not really staffed by people who are experts on access to experimental agents, provided the necessary entertainment required by the media circuit. Endless media interviews were scheduled on the ethics of access to experimental agents all throughout August 2014, and it is here where the stage opened – finally – for bioethicists.

How did we perform? Did we stress that WHO’s choice of topic and the supposed urgency of its recommendation to provide access to experimental agents in Ebola regions amounted to pointless grandstanding in the face of a pandemic that requires a public health response, and not the tinkering with experimental agents? Some of us did, but it didn’t stop most of us from entertaining questions on the ethics of who should get experimental agents, whether it was ok that white religious activists with a health care background were prioritized over local dying health workers, and other reportedly important questions. In the rush to be seen to do something the WHO managed to convene said meeting without a single representative from a country affected directly by Ebola.

None of that mattered on the main stage of a pandemic veering out of control. Predictably riots broke out, patients ran away from hospitals or were violently freed out of isolation units by their worried families. Such on the ground mayhem would have also made for reasonably nice media theatre, alas, bioethicists decided to bring the full armament of analytical ethics to bear on crucial questions such as who should receive an experimental vaccine first. It is not that they were wrong in their concerns about the fact that these vaccines aren’t quite vaccines, they are chemicals that prevented infections in some monkeys. Even the drugs’ toxicity profiles were not established. So, in fairness there were ethical issues, but they were not the most pressing ethical issues. They were not particularly pressing because these vaccine candidates, even if they turned out to work, would not make a dent in the current pandemic. Did these issues occupy most of the mass media – bioethics collaborative performances? Sadly they did.

In supporting roles appeared health care professionals assembled by various nations, tasked with providing health care and laboratory services. They were doing the kind of work that Doctors without Borders has successfully undertaken for many years. Turns out our supporting actors are at the time of writing not quite ready for prime time, so as quickly as they drop in to West Africa, they are being airlifted due to some real or imaginary risk to them. The obvious point to be made here is perhaps this: Don’t send staff not up to the task, because the endless kerosene burned in private medical jets flying them forth and back is using up resources that could probably be put to better use. For instance, it could be used toward a down-payment for the creation of functioning primary care health care systems in the countries in question. Turns out, this allocation decision is an ethical decision, alas one not addressed by anyone currently pontificating on Ebola ethics.

What then are other relevant ethical questions to be addressed in the context of this pandemic? Here are a few that come to mind: What are the ethical obligations of citizens (and their representative governments) in the global north toward those affected now by this pandemic? Should they send health care personnel, possibly even military personnel, as the US President suggested in an interview? Or would it be sufficient to send a couple of experimental agents and wash their hands of the pandemic, as Canadian bioethicist Peter A. Singer seems to suggest in an interview. [3] Assuming that military or police force could assist in curbing the spread of the pandemic, under what circumstances and within which parameters should such deployments occur? What obligations of care do agencies have toward their staff? Do specialist technical public health workers in the global north have professional responsibilities to participate in Ebola related missions, given that they didn’t quite sign on for that sort of risk when they joined governmental agencies in the UK, Australia, Japan or elsewhere. What personal risks – if any – can they reasonably be expected to accept for themselves, both in terms of infection risk, but also in terms of violence that could occur if the local situation spins further out of control. Given that the existing health care infrastructure in the affected countries is disintegrating in front of our eyes, should others consider stepping in to provide the basic health services the local system was able to provide until – however insufficiently - the Ebola crisis hit?

There you go bioethics. Think of Ebola as primarily a public health challenge not a research ethics phenomenon and you might just be addressing questions that actually matter, ethically.

Udo Schuklenk

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[1] Centers for Disease Control (U.S.). 2014. 2014 Ebola Outbreak in West Africa. http://www.cdc.gov/vhf/ebola/outbreaks/guinea/ (Accessed September 8, 2014)

[2] United States Embassy in Nigeria. Nigeria Malaria Fact Sheet. http://photos.state.gov/libraries/nigeria/231771/Public/December-MalariaFactSheet2.pdf

[3] Hildebrandt, Amber. 2014. Why Canada must approach the Ebola outbreak as a natural disaster. CBC News Sept. 05. http://www.cbc.ca/news/canada/why-canada-must-approach-ebola-outbreak-like-a-natural-disaster-1.2754828 [Accessed September 8, 2014]