Guidelines on standards of care in research: when is deviancy acceptable?

For years there have been overheated discussions about the standard of care provided to participants in health research, particularly in low-resource settings. Is it ever ethically justified to design a research study where participants in Benin with a standard of care inferior to what patients would routinely receive in (say) Baltimore, Maryland? There is no consensus on the issue, and even an influential international ethics document speaks out of both sides of its mouth on this one.

Every once in awhile, a study emerges that seems to offer (some) research participants inferior care, and the whole tumultuous debate is unleashed anew. This is what happened with the Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy (SAPIT) study in South Africa a couple of years ago. This randomized controlled trial randomized HIV-positive patients with tuberculosis to receive antiretroviral treatment earlier or later after starting TB treatment. The 'delayed arm' of the study seemed to violate WHO guidelines that recommended starting antiretroviral treatment in such patients as soon as possible after TB treatment was initiated. When the study was stopped due to heightened mortality in the delayed arm, commentators cried foul. The researchers, they claimed, should have followed the guidelines, and should have known what would happen in the delayed arm when they did not.

Seema Shah and Reider Lie have just published an interesting piece in the Journal of Medical Ethics on this topic, asking about when it can be justified to deviate from guidelines about standards of care and prevention. They remind us that guidelines, while useful, are not fixed and divine commandments: they may be based on insufficient evidence, they may change while a study is being conducted, they may be objects of controversy and disagreement. Not everyone is likely to agree with Shah and Lie's account of when deviations from clinical or prevention guidelines are ethically justified, or their interpretation of the SAPIT trial on the basis of their account, but they may have found tranquil angle to the passionate debate over standard of care in research. If such a thing exists.

The SAPIT trial on trial

HIV and TB, tragically, to go well together. TB is the most common opportunistic infection to arrive when HIV has compromised the body’s immune system. Especially in sub-Saharan Africa, patients who are diagnosed with TB are routinely tested for HIV, and often are found HIV-positive. To compound the misfortune, current effective treatments for TB and HIV are not entirely compatible: starting HIV-positive patients with tuberculosis on antiretroviral treatment can lead to a number of complications, both in terms of toxicities and in terms of adherence (i.e. dual treatment involves taking different drugs daily for a long time). It is important, therefore, to have a clear understanding of the optimal time at which to start antiretroviral treatment with TB patients.

This is what the SAPIT study (South African Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy) in South Africa attempted to do, and their results were recently published in the prestigious New England Journal of Medicine. But the means taken to answer this important question – the study design – has been a topic of heated debate inside and outside South Africa since March. The design of the study included a sequential arm in which HIV-positive patients would start antiretroviral therapy only after they completed TB treatment or retreatment, a period of six or eight months respectively. This is a long time without antiretroviral therapy, particularly for those patients with advanced disease and low CD4 counts. The results of the study indicate significantly higher mortality in the sequential arm in the study than other arms where antiretroviral treatment was initiated earlier.

The burning ethical question is: was it predictable that those in the sequential arm of the study would experience greater mortality than those in the other arms that started antiretroviral treatment earlier? If the answer is no, the SAPIT study generated new and useful information about late initiation of antiretroviral treatment in this population. If the answer is yes, then the study violated the principle of equipoise, as enshrined in numerous ethical guidelines and regulations.

The SAPIT researchers and their defenders argue that at the time the study took place, little was known about mortality rates for HIV-positive, TB patients who were not on antiretroviral therapy. Accusations about violating equipoise are, from this perspective, criticisms based on hindsight. But a recent article in the South African Medical Journal, authored by some 20 scientists and activists, is having none of it. The authors present the evidence on mortality among patients similar to those in the sequential arm of the SAPIT trial, as was available when the trial was being conducted, as well as (generally underwhelming) evidence about complications of combining TB and HIV treatment. Their findings strongly suggest that those in the sequential arm of the SAPIT trial were given less than the clinical ‘standard of care’.

It is not easy to predict the fallout of the study, now that it is a large blip on the ethics radar. Certainly the South African ethics committees that approved the study are feeling awkward, and the relationship between (some) AIDS researchers and advocates may be strained. The fact that US investigators seemed to be involved in the study (enough to be considered authors) without the study having been reviewed in the US, raises questions about either the regulation of global health research, or the ethics of authorship, or both. The SAMJ article suggests (diplomatically) that the South African ethics committees are simply overwhelmed, but it may more simply a matter of committees inadequately judging a complicated case.