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 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.

Could Canadian patients be prevented from accessing experimental Ebola drugs, too? You bet they could!

Ok, so I'm a tad bit lazy. Sections of the post below are actually a few months old and I'm re-posting them here, because of the current debate about access to the experimental drug deployed in the case of the two Ebola missionaries in the United States. 

First things first though, on the current debate: There has been a bit of a storm in a teacup about the question of whether or not it is just to provide an experimental treatment for Ebola to two sick missionaries who returned home to the United States from West Africa while denying it to dying Africans. Art Caplan has provided a reasonable analysis of the issues in a Washington Post OpEd. I disagree with him on the reasons for why the agent cannot be produced now in larger quantities and shipped to West Africa (poor start-up company and all that jazz). There is no reason to accept an artificial scarcity (i.e. human regulation made) as a kind of natural law, inevitable and beyond our control. Still, Caplan is right, it would be difficult to provide the medication locally in West Africa where it's needed, due to the relatively fragile nature of the experimental agent (it needs special handling, be kept in a freezer and whatnot). And yes, imagine the drug actually was a dud, potentially doing more harm then good. The same professional do-gooders shouting now racism and demanding delivery of the medication to Africa would turn around before you can say 'ouch' and excitedly shout 'exploitation' and 'African guinea pigs' and, yes, 'racism', because that charge usually sticks. 

From the published reports about the experimental agent it's unclear - to me - at what stage in the R&D process it is. It seems to me - I might be mistaken here - that the drug hasn't undergone phase 1 clinical trials (i.e. how dangerous to human health is it?). From the experience with the two missionaries it seems at least as if it ain't too toxic. Still, two folks count for all scientific intent and purposes as an anecdote. Not a big surprise though, that proper trials have not been undertaken, given how quick people die, and in what locations they usually die. Doing placebo-controlled studies - no doubt the methodological gold standard under the circumstances - also seems a dicey proposition seeing the high mortality rate among infected people. 

Fundamentally though, the question is whether knowledgable patients suffering from catastrophic illnesses should be permitted to access experimental drugs. Ebola is just the latest disease triggering this debate. It turns out, the situation the African patients find themselves in isn't that different to the situation faced by Canadians suffering from other catastrophic diseases.  It's here where my mentioned older post kicks in...

Imagine you suffer from a catastrophic kind of illness, an illness that’s invariably going to kill you in the near future. Everything that you and your doctor know about the illness suggests that your death will be anything but peaceful. Doctors can deal with some of your symptoms and palliative care can address some of the pain you are experiencing. But that’s about it.

Sadly this scenario isn’t unrealistic. Many Canadians face this sort of situation today.

During a scheduled visit to your specialist doctor you learn that there’s a brand-new drug currently being tested that might just save your life, if it worked that is. The doctor has already inquired with the researchers testing the drug in a phase-three clinical trial and you would be eligible to participate in that trial.

Phase-three clinical trials are trials at which stage in the drug research and development process we know what its safety profile looks like and we have pretty good evidence to think that it’s effective to some extent. That is so because during earlier trials, involving initially animals and eventually other patients, sufficient evidence has been accumulated to justify letting the phase-three trial go ahead. Now the doctors are trying to recruit a fairly large number of patients in order to establish whether the drug is as good as they thought it is. The nature of your disease is such though that there is no standard therapy around to assist your struggle for survival. The trial design in such cases demands that the experimental agent is tested against a placebo control, a dummy pill. That’s done because we need to know, before doctors can confidently prescribe the drug to patients like yourself, that the drug is doing better than what is the status quo – ie no drug. It’s always possible that an experimental drug actually does worse than the dummy pill.

Now, ask yourself, if you were that patient: Would you be willing to participate in a last-chance clinical trial where you’d have a 50:50 chance of getting a dummy pill? You know already what the dummy pill would achieve: your death. Would you trust the investigators to pull the plug quickly enough for you to survive if they discovered that the experimental drug actually works? In case you want to get a better handle on how it feels to be faced with this sort of decision, check out this blog (adriennes.blog.com) by a Toronto-based melanoma patient.

Many people suffering catastrophic illnesses flat-out refuse to participate in research that’s designed as I have described it. Their argument is not about the trial methodology, it is sound. Their argument is about the ethics of providing dying people with a coercive offer: join my clinical research project on my conditions or die a predictably horrible death.

The good news is that the story doesn’t end here. It has been recognized by regulators both in Canada and elsewhere that such coercive offers to people fighting for their very survival are incompatible with the fundamental values of liberal democracies. We must not reduce patients suffering catastrophic illnesses to mere means to achieve our research objectives. While that’s nothing much other than an honorable principle, there’s also a more pragmatic reason for this. I’ll get to that in a moment.

Health Canada actually permits people who suffer catastrophic illnesses to access drugs that are in the clinical trials system, and they can do so without actually participating in the clinical trials I mentioned earlier. The agency runs a Special Access Program for these sorts of patients. The program permits patients to access the experimental agent without trial participation. 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. One of the ethical reasons for this I have just mentioned. The pragmatic reason for this solution is this: it was discovered during the early days of the AIDS epidemic, when no life-preserving medication existed, that patients who are coerced into placebo controlled trials will simply cheat in order to get access to the actual experimental drug. HIV-infected people enrolled in ostensibly placebo-controlled trials and then took their drugs to chemists to find out who did and who didn’t get the active agent. They then started sharing the actual drug and dumped the placebo. That, of course, rendered the trial pretty useless. True volunteers would have accepted the uncertainties and volunteered to test whether the experimental agent is any better than the placebo control.

The problem patients with catastrophic disease who wish to access experimental drugs through our Special Access Program face today in Canada is two-fold: Health Canada leaves it up to pharmaceutical companies to decide whether or not they provide drugs to eligible patients. Manufacturers who have trouble recruiting sufficient numbers of patients into their trials could deny patients access to the experimental drug to encourage them to join the trial on their conditions. They might also have other reasons for refusing to provide catastrophically-ill patients with access to an experimental drug. Either way, we are back to square one: a coercive situation. This problem occurs more frequently in Canada than you might think. Here is a heart wrenching appeal (http://www.youtube.com/watch?v=olwDT7NPSsM) from one such patient, who has since died. A Toronto paper contacted me about another case recently, both cases interestingly involved pharmaceutical multinational Bristol Myers Squibb refusing to provide an experimental drug that the company is testing in a phase-three clinical trial right now. This issue should be addressed by Health Canada as a matter of urgency. The other problem is that manufacturers are permitted to charge for their experimental drug. That is unreasonable. It costs typically cents to produce such medicines – I am not talking research and development costs but actual production costs. There is no reason whatsoever why pharmaceutical companies should profit from experimental drugs. They should be compelled by Health Canada to provide such agents to clinically eligible patients, while the clinical trials are ongoing and the drug isn’t formally approved as a for-pay prescription medication. If Health Canada were to address these shortcomings of the present Special Access Program it would ensure that catastrophically ill patients are given a fairer shot at actually accessing these experimental drugs.

Udo Schuklenk holds the Ontario Research Chair in Bioethics and Public Policy at Queen’s University, he tweets @schuklenk

Fighting for survival in the clinical trials' system

This weekend's column in the Kingston Whig-Standard.

 Imagine you suffer from a catastrophic kind of illness, an illness that’s invariably going to kill you in the near future. Everything that you and your doctor know about the illness suggests that your death will be anything but peaceful. Doctors can deal with some of your symptoms and palliative care can address some of the pain you are experiencing. But that’s about it.

Sadly this scenario isn’t unrealistic. Many Canadians face this sort of situation today.

During a scheduled visit to your specialist doctor you learn that there’s a brand-new drug currently being tested that might just save your life, if it worked that is. The doctor has already inquired with the researchers testing the drug in a phase-three clinical trial and you would be eligible to participate in that trial.

Phase-three clinical trials are trials at which stage in the drug research and development process we know what its safety profile looks like and we have pretty good evidence to think that it’s effective to some extent. That is so because during earlier trials, involving initially animals and eventually other patients, sufficient evidence has been accumulated to justify letting the phase-three trial go ahead. Now the doctors are trying to recruit a fairly large number of patients in order to establish whether the drug is as good as they thought it is. The nature of your disease is such though that there is no standard therapy around to assist your struggle for survival. The trial design in such cases demands that the experimental agent is tested against a placebo control, a dummy pill. That’s done because we need to know, before doctors can confidently prescribe the drug to patients like yourself, that the drug is doing better than what is the status quo – ie no drug. It’s always possible that an experimental drug actually does worse than the dummy pill.

Now, ask yourself, if you were that patient: Would you be willing to participate in a last-chance clinical trial where you’d have a 50:50 chance of getting a dummy pill? You know already what the dummy pill would achieve: your death. Would you trust the investigators to pull the plug quickly enough for you to survive if they discovered that the experimental drug actually works? In case you want to get a better handle on how it feels to be faced with this sort of decision, check out this blog (adriennes.blog.com) by a Toronto-based melanoma patient.

Many people suffering catastrophic illnesses flat-out refuse to participate in research that’s designed as I have described it. Their argument is not about the trial methodology, it is sound. Their argument is about the ethics of providing dying people with a coercive offer: join my clinical research project on my conditions or die a predictably horrible death.

The good news is that the story doesn’t end here. It has been recognized by regulators both in Canada and elsewhere that such coercive offers to people fighting for their very survival are incompatible with the fundamental values of liberal democracies. We must not reduce patients suffering catastrophic illnesses to mere means to achieve our research objectives. While that’s nothing much other than an honorable principle, there’s also a more pragmatic reason for this. I’ll get to that in a moment.

Health Canada actually permits people who suffer catastrophic illnesses to access drugs that are in the clinical trials system, and they can do so without actually participating in the clinical trials I mentioned earlier. The agency runs a Special Access Program for these sorts of patients. The program permits patients to access the experimental agent without trial participation. 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. One of the ethical reasons for this I have just mentioned. The pragmatic reason for this solution is this: it was discovered during the early days of the AIDS epidemic, when no life-preserving medication existed, that patients who are coerced into placebo controlled trials will simply cheat in order to get access to the actual experimental drug. HIV-infected people enrolled in ostensibly placebo-controlled trials and then took their drugs to chemists to find out who did and who didn’t get the active agent. They then started sharing the actual drug and dumped the placebo. That, of course, rendered the trial pretty useless. True volunteers would have accepted the uncertainties and volunteered to test whether the experimental agent is any better than the placebo control.

The problem patients with catastrophic disease who wish to access experimental drugs through our Special Access Program face today in Canada is two-fold: Health Canada leaves it up to pharmaceutical companies to decide whether or not they provide drugs to eligible patients. Manufacturers who have trouble recruiting sufficient numbers of patients into their trials could deny patients access to the experimental drug to encourage them to join the trial on their conditions. They might also have other reasons for refusing to provide catastrophically-ill patients with access to an experimental drug. Either way, we are back to square one: a coercive situation. This problem occurs more frequently in Canada than you might think. Here is a heart wrenching appeal (http://www.youtube.com/watch?v=olwDT7NPSsM) from one such patient, who has since died. A Toronto paper contacted me about another case recently, both cases interestingly involved pharmaceutical multinational Bristol Myers Squibb refusing to provide an experimental drug that the company is testing in a phase-three clinical trial right now. This issue should be addressed by Health Canada as a matter of urgency. The other problem is that manufacturers are permitted to charge for their experimental drug. That is unreasonable. It costs typically cents to produce such medicines – I am not talking research and development costs but actual production costs. There is no reason whatsoever why pharmaceutical companies should profit from experimental drugs. They should be compelled by Health Canada to provide such agents to clinically eligible patients, while the clinical trials are ongoing and the drug isn’t formally approved as a for-pay prescription medication. If Health Canada were to address these shortcomings of the present Special Access Program it would ensure that catastrophically ill patients are given a fairer shot at actually accessing these experimental drugs.

Udo Schuklenk hold the Ontario Research Chair in Bioethics and Public Policy at Queen’s University, he tweets @schuklenk

A study that should not have been done

Here is a piece Sean Philpott and I have published today in the Hastings Center Forum.

The New England Journal of Medicine in February published the results of a deeply flawed clinical trial in South Africa. The SAPIT (Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy) trial was designed to determine the most effective way to treat patients infected with HIV and tuberculosis. But it raises a number of disturbing questions about the oft-debated and vexing issue of appropriate standards of care in clinical trials undertaken in developing countries like South Africa. It also raises serious concerns about the quality of ethical review undertaken in those countries, and it highlights some surprising deficiencies in existing U.S. regulations regarding when ethical review should be undertaken by American IRBs.

In 2007 almost two million people died of TB and over nine million people were newly infected. TB-related morbidity and death is profound among people living with HIV/AIDS; nearly 7 percent of new cases and over a quarter of all TB-related deaths occur among people living with HIV/AIDS. Doctors treating TB in this population face a difficult challenge. Serious side effects can occur with concurrent HIV and TB treatment, leading some clinicians to suggest that antiretroviral therapy for HIV be delayed for several weeks after treatment for TB is started. But serious side effects are also a risk of delaying ART therapy. Guidelines state that ART therapy should be started as soon as possible, but there is disagreement over when that should be.
In the SAPIT trial, 642 individuals co-infected with HIV and TB were randomized to receive one of three treatments: early integrated ART (started during the intensive phase of TB therapy), late integrated ART (started during the continuation phase of TB therapy), or sequential ART (started after completion of TB therapy).
Individuals randomized to the two integrated arms received ART within three months of study entry. Antiretroviral treatment of individuals randomized to the sequential treatment arm, however, was delayed on average for almost nine months. For several unlucky study participants, ART was delayed even longer; mean time to initiation of ART in this group was six to 11 months (260±71 days), regardless of CD4 cell count, an indicator of HIV disease progression, at study entry. This matters, as patients with CD4 cell counts lower than 200 cells per cubic millimeter face a significantly increased risk of death.
Forty-four months after the first SAPIT participants were enrolled, the study’s Data Safety Monitoring Board stopped the sequential treatment arm and required that all of its participants be started on ART immediately. In its interim analysis, the DSMB had found that participants in the sequential treatment arm had a much higher rate of death than participants in the integrated treatment arms.
The majority of these deaths occurred among patients with CD4 counts below 200 cells per cubic millimeter at study entry. Twenty-seven of 213 participants, or 12.7 percent, in the sequential therapy arm died during the abbreviated treatment and observation period, of whom 21 had CD4 counts of less than 200 per cubic millimeter at study entry, while only 25 of 429, or 5.8 percent, in the integrated therapy arms died over the course of the study. Integrated HIV and TB treatment thus reduced the likelihood of death among study participants by more than twofold.
The trial conclusively showed that integrated HIV and TB treatment is more effective than sequential treatment. The question is whether obtaining that data justified the 10 or more preventable deaths that occurred among trial participants. Even before the study began, years of observational data had shown that the risk of HIV-related death among patients not receiving ART therapy was highest during the first few weeks of TB treatment, calling into question the need to conduct a randomized, controlled trial in which ART was delayed by as long as 11 months for some study participants.
The side effects of concurrent HIV and TB treatment can often be managed by observant clinicians; given this, the WHO Global TB/HIV Working Group recommended as far back as 2003 that “any decision on treatment should be individualized, based on response to anti-TB therapy, side-effects, and readiness for ART.” More recently, based primarily on data from the SAPIT trial, WHO urged that ART be given within eight weeks of starting TB treatment in co-infected individuals.
Current treatment guidelines recommend that patients infected with both TB and HIV should start ART as soon as possible. Where CD4 testing is routinely available, these guidelines recommend starting ART when CD4 cell counts drop below 350 cells per cubic millimeter, and they require ART once cell counts drop below 200 cellsper cubic millimeter. Where routine CD4 testing is not available, these guidelines suggest that HIV-infected individuals with TB should start ART immediately.
In a recent article in The Lancet, several of the SAPIT investigators argued that “an estimated 10,000 deaths could be prevented every year by the initiation of ART in HIV/tuberculosis co-infected patients with CD4-cell counts below 500 cells per cubic millimeter.” However, the level of care provided to participants in the sequential treatment arm of the SAPIT trial fell considerably below this standard. The level of treatment provided to these volunteers even violated existing domestic standards of care for patients in South Africa, which recommend starting patients with CD4 cell counts of less than 200 per cubic millimeter on ART after just two months of TB treatment.
Although the SAPIT investigators noted that trial participants’ primary care physicians were free to start them on ART as necessary – in keeping with the 2003 recommendations of the WHO Global TB/HIV Working Group – this ignores the reality of public sector HIV care and treatment in South Africa. It is unlikely that most of the study participants even had a primary care doctor, let alone a physician who would initiate ART despite the restrictions imposed by the SAPIT protocol. Who then could have started these patients on life-preserving treatment if not the clinician-investigators on the study? Individualized treatment decisions based on medical need were not made in the sequential arm of the study, despite the ethical obligation of study clinicians to ensure the safety and well being of individual study participants.
Aggravating these problems, the trial design violated the golden rule of ethical study design and conduct: No clinical equipoise existed between the trial arms. Given decades of research showing that untreated patients with CD4 cell counts of less than 200 cells per cubic millimeter are at great risk of HIV-related complications and death, coupled with observational data showing that this risk is even higher during the first few weeks of TB treatment for co-infected individuals, the sequential treatment arm never should have been considered a viable treatment strategy. Patients randomized into the sequential arm were knowingly subjected to substandard clinical care.
The fundamental ethical (and legal) issue is this: the SAPIT study caused foreseeable harms and preventable deaths for a substantial number of impoverished and poorly educated South African trial participants. In doing so, the trial violated the Declaration of Helsinki’s requirements on standards of care of the then-applicable 2000 revision:

The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

For the South African researchers involved with the SAPIT trial, the Declaration of Helsinki is not only a moral exhortation but also a legally binding obligation. South Africa’s Good Clinical Practice Guidelines require that all investigators “follow fully the guidelines set out” in the Declaration of Helsinki, in addition to other national research ethics guidelines.
Organizations such as the Welcome Trust in the U.K. and the National Institutes of Health in the U.S. have directed millions of dollars to train members of African ethical review committees, and yet this trial was reviewed and approved by a committee in South Africa. The failure of this research ethics committee to recognize the clinical, ethical, and legal deficiencies in this study is shameful and, we hope, will be investigated by the relevant South African authorities.
Another issue is worth noting. As published in the New England Journal of Medicine, the study boasts a large number of authors. This is not an uncommon practice for large clinical trials like SAPIT. The authors of the article are located in South Africa and the U.S., and some authors list both South African and U.S. institutional affiliations. It is unfortunate, however, that U.S. research ethics guidelines (at least as interpreted by the American institutions involved) did not require these authors to submit the study protocol for ethical review by committees in the U.S.
If, as these institutions suggest, the study investigators were not acting on behalf of the U.S. institutions or were not engaged in what these universities define as human subjects research, it is worth asking why these institutions are listed on the published research papers. If they want to share in the academic glory associated with a study published in a prestigious journal like the New England Journal of Medicine, then they have the obligation to ensure that the trial meets accepted standards of ethical conduct and the responsibility to protect the rights and safety of all study participants. Further review might have made an appreciable difference to the ethical design and conduct of this study.
Sean Philpott is an assistant professor of bioethics at Union Graduate College and a former science and ethics officer for the Global Campaign for Microbicides. Udo Schüklenk holds the Ontario Research Chair in Bioethics at Queen's University, Canada, and is the joint editor-in-chief of BIOETHICS. 

Beware: AIDS microbicide makes you more vulnerable to HIV infection

An HIV prevention trial was halted in various Southern African countries and in India. The BBC reports that the investigators discovered that instead of reducing the risk of HIV infection the microbicide in question actually increased the risk. In other words, more participants (it being a microbicide, all women, of course) became infected in the active agent arm then in the placebo controlled arm of the trial.

There are several interesting questions with regard to this trial, none of which was flagged in the BBC news report:

1. The women who participated in the trial, by definition were HIV negative when they enrolled. They became infected (almost certainly due to unsafe sex) during the trial. The question is whether these infections constitute a trial related injury that ought to be subject to compensation. Many of them might well have had a therapeutic misconception, that is they might have thought that the stuff they got in the clinic gave them some (a lot - complete?) protection against HIV.
   
2. Indeed, one wonders whether these women will be provided with access to HAART when this could be clinically beneficial to them.
3. Sexy as the idea of an HIV microbicide is, none of the trials undertaken so far have led anywhere. As a non-expert I wonder whether this is a dead-end type concept that is never going to work. You might say, reasonably so, that only further research will tell. The trouble is that we will only find out when women become infected during a trial. That's arguably a pretty high price to pay, even if the women were volunteers and even if they gave truly informed first person consent.