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Moving the needle: strengthening ethical protections for people who inject drugs in clinical trials
  1. Daniel Wolfe
  1. Correspondence to Daniel Wolfe, Open Society Foundations, 224 West 57th St, New York, NY 10019; Daniel.wolfe{at}opensocietyfoundations.org

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Those researching HIV prevention measures for people who inject drugs (PWID) face a dilemma. Regions where baseline HIV prevalence and onward transmission via injecting is sufficiently high to power HIV prevention trials are also those where repressive laws, policies and practices raise concerns about the ethics of research subject protection. Dawson et al, outlining criteria to address ethical challenges in HIV prevention research among PWID, recommend that all trial participants be offered sterile injecting equipment and urge additional strategies to limit research and background risks.1 In light of ethical questions opened by recent clinical trials involving PWID, including several the authors cite favourably, these cautions are timely.

Dawson et al urge weighing of costs and benefits of PWID participation in research trials as an essential part of the ethical calculus. Overdose is a particular risk in any trial that uses abstinence from opioids as a precondition for participation or as an outcome of interest, and a risk that institutional review boards and researchers frequently ignore. Given the increased likelihood of fatal overdose for those who return to injection following a period of abstinence, provision to all trial participants of naloxone—the overdose antidote that WHO recommends be prescribed for opioid injectors and to those likely to witness an overdose2 —would seem an ethical minimum. Trial design should also include rigorous measures to assess overdose among participants who drop out and after trial conclusion. Dawson et al note favourably that a study of long-acting naltrexone among PWID in Russia resulted in an additional treatment option for drug-dependent patients. This trial did not carefully assess post-trial overdose, instead defining return to injection as the outcome of interest, and assuming that those who dropped out had resumed opioid use.3 With such trial designs, genuine weighing of cost/benefit of the kind urged by the authors is difficult.

The authors highlight community consultation as an essential strategy for risk mitigation. In settings where PWID are subjected to intense state surveillance and criminal or administrative penalties, usefulness of this approach can be limited by conditions often invisible to researchers or institutional review boards. For example, HIV research has been conducted in Vietnamese drug detention centres,4 settings where former detainees report participation in trials without information about the nature of the experiment, and where visitors, including government representatives, are misinformed about conditions such as limited food, forced labour and abusive punishments.5 Researchers working in such settings, or those reviewing research subject protections for trials proposed there, may wish to interview former detainees in a setting where no government authorities are present or take other measures to ascertain whether research is inadvertently supporting coercive or exploitative recruitment practices for HIV prevention trials.

The question of whether local standards or internationally accepted best practice should be used in assessing ethical trial design among PWID remains thorny. Dawson et al argue compellingly that use of local standards may lead to maximum local benefit and adoption of the intervention, and that the perfect (eg, internationally accepted standard of care) should not be the enemy of the good (eg, new intervention being tested). This division between local and international standards, however, seems ethically cloudy in an era of globalised clinical trials, when evidence from studies conducted in one country is routinely used to secure regulatory approval in others.6 The Russian study of injectable naltrexone, for example—which compared the effects of monthly injections of the medication to a placebo—may have faced ethical scrutiny for its use of placebo in the USA, where standard of care for opioid dependence is treatment with methadone or buprenorphine. Nonetheless, Russian data were submitted to the US Food and Drug Administration to secure approval of long-acting naltrexone injection for opioid dependence.7 Similarly, a study of tenofovir for prexposure prophylaxis (PrEP) of HIV transmission among PWID in Thailand did not offer needle and syringes to those in either the treatment or placebo arm,8 and thus would fail the standard proposed by Dawson et al. Despite this ethical lapse, the trial was used by the US Centers for Disease Control and Prevention to endorse PrEP as a potential HIV prevention measure for PWID, and has been cited in subsequent analyses about potential scale-up of the intervention in the USA.9 It is interesting to consider how or whether trial design would be altered if researchers conducting studies using local standards were restricted from using their data for regulatory approval outside that local context.

Creating ethical standards so rigid that they deprive local populations of an opportunity to benefit from research is clearly a different risk, and one that Dawson et al rightly suggest should be avoided. That said, the question of when a study falls far enough below the ethical standard as to no longer contribute substantially to scientific advancement is a vexing one that Dawson et al resolve somewhat arbitrarily. Methadone and buprenorphine, for example, have been determined to reduce HIV risk among opioid injectors,10 ,11 and prescription of these medications is arguably as essential as provision of sterile injecting equipment to researchers seeking to assess the added value of new HIV prevention interventions for PWID. At the same time, as we have seen, provision of these medicines has been prohibited by authorities either during the trial or after the trial's conclusion.12 ,13 One answer to this ethical quandary would be to restrict HIV prevention research to countries that permitted use of these standard medications during and after the trial. Another approach, favoured by Dawson et al, is to avoid insistence on standards that cannot be met in countries of research interest. Here it would be better to acknowledge that such decisions are based on pragmatism rather than on ethical assessment alone.

References

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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