CHAPTER TWO LITERATURE REVIEW
2.3 THE DEBATE ABOUT CARE IN HIV VACCINE TRIALS
2.3.2 STANDARDS OF CARE
Some commentators (UNAIDSa) argued that sponsors and investigators should ensure that HIV vaccine trial participants have ART-access, even in settings where it was not available, because participants in clinical trials should receive the ‘standard of care’. This term (originally from the medico-legal context) migrated into the research ethics arena and referred to the care to be offered to control-group participants when new interventions were being tested (Heise et al., 2008; NBAC, 2001). The term standard of care framed intense debate about the conditions under which it was ethically acceptable to test new interventions against placebo when an effective intervention already existed or, put another way, when it was ethically acceptable to provide some participants with no treatment when effective treatment already existed.
Central to the concept of standard of care is that for any particular medical condition there is a set of recognized treatment and care interventions that constitute the standard of care for that particular condition (Holm & Harris, 2008). The standard of care acts as the baseline against which other treatment regimens can be compared in a clinical trial (Holm & Harris, 2008). However it has been recognised that the concept of standard of care is more ambiguous than it first appears, and that a number of standards exist under the rubric of standard of care (Macklin, 2008) or put another way the term can be indexed to various points of reference (Heise et al., 2008). More specifically, there is the de facto standard which is the actual set of practices for medical patients in a community (often determined
empirically) and the normative or de jure standard of what should be provided to patients as determined by medical experts. The latter can be (in itself) the local de jure standard as defined by national treatment norms and guidelines, national regulatory authorities and national experts in a particular country or it can be the global de jure standard as defined by global experts and authorities such as WHO and encompassing the best proven interventions available anywhere in the world (London, 2001; McGrory, Philpott, Hankins, Paxton & Heise, 2010). The latter standard of the best treatment available anywhere in the world is sometimes referred to as the universal standard (NCOB, 2002).
The case that opened up the debate about the standard of care for control-arm participants (Holm & Harris, 2008) was the perinatal HIV transmission trials in developing countries that compared a short-course antiretroviral regimen (zidovudine) to placebo instead of to a more expensive and logistically more complex longer-course regimen previously shown to be effective (Bayer, 2000; NCOB, 2002). Critics of placebo-control argued that no participant taking part in a trial supported by United States (US) funds should be denied the standard of care available there, and that known effective treatment should not be withheld from participants. In support of this argument the Declaration of Helsinki (WMA, 1996, II.3) was cited - ‘In any medical study, every patient, including those of a control group, if any, should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of placebo where no proven …method exists.’
Defenders of placebo control noted that the standard of care available in high-income countries was at that time unaffordable in low-resource-settings and logistically difficult to implement as a part of routine antenatal care (Holm & Harris, 2008) – on the latter point it required mothers to cease breastfeeding, use formula and risk infant diarrhoea (cf. van der Graaf & van Delden, 2009). They argued that in resource -poor settings, it was acceptable to test a simpler cheaper regimen against placebo, where the standard of care available in high- income countries was not available or sustainable in the low-resource setting, and the objective was to develop safe and effective interventions that were responsive to critical health needs and priorities in that setting (Bayer, 2000). Defenders of placebo-control argued that comparing a shorter cheaper regimen to a longer, more expensive regimen would not represent a research question of high value in many low-resource settings, and that it was
critical to ensure that trials addressed concerns that were locally relevant and were designed to benefit the actual population from which participants were drawn (Holm & Harris, 2008).
Effectively defenders of placebo-control argued that incorporating the global de jure standard in this case would render the research question locally irrelevant (DAIDS, 2010) or would provide information that was not useful to patients in that setting (Holm & Harris, 2008) or would ensure that the results were of more value to the researcher than the researched community (van der Graaf & van Delden, 2009). This debate illuminated that while commentators agreed that control-arm participants should get ‘standard of care’ they did not agree about the best moral guide for determining the standard (McGrory et al., 2010). Resnik (2014) argued that debate illuminated underlying disagreement about what it means to not exploit participants.
This ethical controversy about the standard of care to be offered to control-arm participants in perinatal transmission studies involved collaborative research between investigators and participating communities from low-resource settings on the one hand, and sponsors from high-income countries on the other. It also involved allegations that the existence of effective ART made a central feature of the trial unethical (that is, use of placebos), as well as counter- charges of ethical imperialism and insensitivity to realities in low-resource settings. It was argued early on that the placebo-control debate underscored the need to seriously consider the implications for HIV vaccine trials in developing countries with inadequate ART-access (Bloom, 1998).
The controversy in these perinatal transmission studies centered on the question ‘when is it acceptable to compare a new treatment against placebo when a proven therapeutic method exists’ and the terminology ‘standard of care’ referred to the standard against which new interventions are to be tested. In HIV vaccine trials, commentators extrapolated the term standard of care to the issue of HIV treatment in under-resourced contexts, asking the question: ‘when is it acceptable to provide less than best proven treatments to participants who acquire HIV while enrolled in trials’? The debate in HIV vaccine trials came to focus on three levels of HIV treatment, more specifically the debate focused on whether participants should receive HIV treatment and care (i) at the ‘best proven’ treatment standard or (ii) at the
local standard or (iii) at the ‘highest attainable’ standard? (Guenter et al., 2000; Macklin, 2008; UNAIDS, 2000a; UNAIDS, 2000b).
Some commentators argued participants should receive the ‘best proven’ treatment available internationally including ART according to best scientific evidence available at the time of the trial (Guenter et al., 2000; Levine, 1999; UNAIDS, 2000a) or put another way according to ‘what is available to participants in the same or similar trials in industrialized countries’ (Macklin, 2008, p. 284) and participants should not be consigned to receive the often inadequate prevailing care in low-resource settings (Lurie & Wolfe, 1999; Macklin, 2008). Some commentators countered that the ‘best proven’ standard was problematic insofar as it confined the focus to the equivalency of drug regimens between participants from high-income and low-income settings (Benatar & Singer, 2000; Benatar, 2002). It was argued that this was somewhat arbitrary and de-emphasized other care components, such as access to equivalent facilities or personnel with equivalent qualifications or expertise (Benatar
& Singer, 2000; Benatar & Singer, 2010).
Critics also argued that applying the ‘best proven’ standard in HIV vaccine trials would mean that sponsor-investigators would be saddled with financing and providing ART for extended periods, which would exhaust limited funds or overwhelm study budgets (Grant et al., 2006).
It was also argued that it would require clinical skills not available in research teams and require scarce monitoring infrastructure (Guenter et al., 2000). Critics asserted that study sponsors would be deterred and the progress of trials would be adversely affected (cf.
Macklin, 2006a). Still others argued that the ‘best proven’ standard could be exposed as untenable by invoking it in other trials, for example, application of that standard in trials exploring whether aspirin would reduce death from heart attacks or strokes would require needy participants to be provided with angioplasty or coronary artery bypass surgery (Bloom, 1998).
At the other end of the spectrum, some argued that participants in HIV vaccine trials should receive the ‘local standard’ – that which would be routinely available to them in the public sector in their country. It was asserted that participants would not be made worse off by their
available in their setting, and to which they consented (Resnik, 2014; UNAIDS, 2000a). Critics argued that this position would consign participants to the inadequate treatment delivered to patients in the public-sector health systems of low-income countries, take advantage of the negative conditions prevailing in many resource-poor settings, violate the Declaration of Helsinki (Lurie & Wolfe, 1999; UNAIDSa) and fail to provide participants with important benefits (Resnik, 2014).
Other commentators promoted yet another standard for participants in HIV vaccine trials who acquired HIV- the so-called ‘highest attainable’ standard (UNAIDS, 2000b). The ‘highest attainable standard’ was viewed as the standard of medical services available for patients in the local setting combined with the additional resources brought by the sponsor into the research setting (Guenter et al., 2000; UNAIDSa; UNAIDS, 2000b). Harris (1998) asserted that it could not follow from the fact that researchers cannot do everything that they are permitted to do nothing. He argued that researchers could not move from the impossibility of providing everything to the conclusion that participants should get inadequate prevailing local care. He noted the question must be what should reasonably be provided by researchers taking into account all the circumstances of the study? (Harris, 1998). While ‘highest attainable’ might be viewed as somewhat vague, it clearly expressed the spirit that sponsors and researcher should take steps to improve care services for participants, by for example, building infrastructure and capacity to deliver strengthened services (Guenter et al., 2000).
This approach to the issue of treatment-access tended to foreground participants’ access to ART for HIV needs specifically.