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Ancillary Care: From Theory to Practice in International Clinical Research

Ancillary Care: From Theory to Practice in International Clinical Research Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 PUBLIC HEALTH ETHICS VOLUME 6 NUMBER 2 2013 154–169 154 Ancillary Care: From Theory to Practice in International Clinical Research Bridget Pratt , Monash University Deborah Zion, Monash University Khin Maung Lwin, Shoklo Malaria Research Unit Phaik Yeong Cheah, Shoklo Malaria Research Unit; Mahidol-Oxford Tropical Medicine Research Unit; University of Oxford Francois Nosten, Shoklo Malaria Research Unit; Mahidol-Oxford Tropical Medicine Research Unit; University of Oxford Bebe Loff, Monash University Corresponding author: Bridget Pratt, Michael Kirby Centre for Public Health and Human Rights, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, 99 Commercial Road, Melbourne VIC 3004, Australia. Tel.: +61 3 9903 0314; Email: Bridget.Pratt@monash.edu How international research might contribute to justice in global health has not been substantively addressed by bioethics. This article describes how the provision of ancillary care can link international clinical research to the reduction of global health disparities. It identifies the ancillary care obligations supported by a theory of global justice, showing that Jennifer Ruger’s health capability paradigm requires the delivery of ancillary care to trial participants for a limited subset of conditions that cause severe morbidity and mortality. Empirical research on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial was then undertaken to demon- strate whether and how these obligations might be upheld in a resource-poor setting. Our findings show that fulfilment of the ancillary care obligations is feasible where there is commitment from chief investigators and funders and is strongly facilitated by SMRU’s dual role as a research unit and medical non-governmental organization. Peter Singer argued that ‘a new, proactive research Introduction ethics .. . must ultimately be concerned with reducing International health research partnerships were identi- inequities in global health and achieving justice in fied as a ‘powerful tool’ for advancing health in low- and health research and health care’ (Benatar and Singer, middle-income countries (LMICs) and promoting 2000: 826). Progress has been made towards this object- global health equity by the Commission on Health ive with the development of concepts (Benatar and Research for Development in 1990 (CHRD, 1990: Singer, 2010) such as: xvii). Since then, the premise has been reiterated in World Health Organization reports and at global min-  responsiveness to local health concerns in host com- isterial summits on health research (Ministerial Summit munities and/or countries (NBAC, 2001; CIOMS, on Health Research, 2004; WHO Task Force on Health 2002; Nuffield Council on Bioethics, 2002; London, Systems Research, 2005; Global Ministerial Forum on 2005; World Medical Association, 2008), Research for Health, 2008).  ancillary care (i.e. health care that is not required for The idea that international health research should either the scientific validity of a study or redressing contribute to global health equity led to the identifica- study-related harms) (Belsky and Richardson, 2004; tion of a new role for research ethics—linking research Merritt et al., 2010), to advancing health and building research capacity in  post-trial benefits such as medical treatments or LMIC host communities. In 2000, Solomon Benatar and practices developed by a study (NBAC, 2001; doi:10.1093/phe/pht015 Advance Access publication on 13 June 2013 ! The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 155 CIOMS, 2002; Nuffield Council on Bioethics, 2002; a whole (Belsky and Richardson, 2004; Richardson, Emanuel, 2008; Macklin, 2008; World Medical 2007; Dickert and Wendler, 2009). Efforts have subse- Association, 2008) and quently been made to define the content of the duties research capacity strengthening in host communities supported by each model, particularly for researchers. and/or countries (NBAC, 2001; CIOMS, 2002; A two-step framework has also been developed to UNAIDS/WHO, 2007; Meslin, 2008). assist with the identification of baseline ancillary care obligations derived from the duty of rescue (Merritt This article builds on earlier research that considers et al., 2010). This framework can supplement either how, using such concepts, international clinical research the partial-entrustment or whole-person model should contribute to the reduction of global health (Merritt, 2011). inequalities. That research applied the principles of a Ancillary care obligations described by the partial-en- theory of justice drawn from political philosophy to de- trustment and whole-person models are not intended to termine what is owed by external research actors from connect international clinical research with global high-income countries to improve the health of individ- health equity. There has been minimal investigation uals in LMICs. Jennifer Ruger’s health capability into what guidance theories of global justice can offer paradigm, a theory that extends the work of Amartya on ancillary care provision in international clinical Sen and Martha Nussbaum, was relied upon because it research. At most, duties to remedy global injustice has features that make it particularly suitable for deriv- have been used to ground broad ancillary care obliga- ing guidance on such matters (Pratt et al., 2012a). In tions for medical researchers (London, 2005). These ‘ex- brief, the health capability paradigm demands that pansive arguments’ have been criticized for failing to international clinical research target health conditions identify why researchers should bear a greater burden that are major contributors to host communities’ gap in for reducing global health inequities than other citizens health status from the optimal global level, be conducted of high-income countries. Richardson (2007: 1957) in partnership with local researchers and build their notes ‘general appeals to justice are difficult to translate capacity to conduct clinical research on diseases of into obligations incumbent on researchers in particular.’ local concern on their own (Pratt et al., 2012a; Pratt It has further been asserted that an obligation to address and Loff, 2012). For the purposes of this article, it all ancillary care needs encountered over the duration should be assumed that the research discussed meets of international clinical trials would ‘strain budgets these criteria. and monopolize the scarce time of trained personnel’ Building on that work, our article derives ancillary (Participants in the 2006 Georgetown University care obligations from the health capability paradigm Workshop on the Ancillary-Care Obligations of and discusses empirical research undertaken in order Medical Researchers Working in Developing to describe how these obligations can be upheld. Countries, 2008: e90). Developing robust guidance for ancillary care demands Hyder and Merritt (2009) state that debate is required a normative model with the following features: a prin- about the precise ethical justification of ancillary care. In cipled basis for determining that researchers have ancil- the philosophical analysis section of this article, we lary care obligations, specification of the content of these derive guidance on ancillary care from the health cap- obligations and definition of the obligations’ upper and ability paradigm and briefly compare it to what is lower limits (Merritt, 2011). Thus far, a normative required by existing normative models. This supple- model has not been developed that relies on a theory ments’ existing work by showing that a theory of justice of global justice to identify ancillary care obligations. is able to ground ancillary care obligations and allocate The two normative models that have been proposed— specific obligations of justice to external research actors the partial-entrustment model and the whole-person from high-income countries, including governments, model—argue for the existence of special ancillary research funders, sponsors, and investigators. These care duties for researchers (and sponsors) above general ancillary care obligations do not require delivery of duties of rescue. The partial-entrustment model holds unlimited health care to participants during trials. that special ancillary care duties derive from a morally Instead, the health capability paradigm supports an significant feature of the researcher–participant rela- obligation to provide ancillary care for a limited tionship—the entrustment of aspects of participants’ subset of health conditions causing severe morbidity health to researchers —whereas the whole-person and mortality in host communities. model considers such duties to be based on the moral Constructing a normative model, however, is not significance of the researcher–participant relationship as sufficient to ensure obligations are met in the research Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 156 PRATT ET AL. setting in most cases. A recent consensus paper noted, The health capability paradigm establishes a univer- ‘empirical research ... about current ancillary-care pra- sal obligation to efficiently reduce shortfall inequalities ctices, should be undertaken to inform the debate and in individuals’ central health capabilities, particularly in countries where the shortfall from the optimal level is the development of appropriate guidelines’ (Partici- pants in the 2006 Georgetown University Workshop large (Ruger, 2010). Central health capabilities refer to on the Ancillary-Care Obligations of Medical Research- individual ability and freedom to achieve certain health ers Working in Developing Countries, 2008: e90). To functionings (i.e. avoiding preventable morbidity and translate ethical requirements into practice, empirical mortality). Reducing shortfall inequalities in health investigation is needed to identify where ancillary care status for an individual or population refers to dimin- obligations are observed and to identify contextual fac- ishing the gap in their health status from the optimal tors that facilitate or obstruct adherence. The findings of level (the highest level of health achieved worldwide in empirical research can inform the development of prac- terms of life expectancy, disease prevalence and inci- tical guidance for research actors on how to uphold dence and other variables). The paradigm envisions a these obligations, which, in turn, will promote greater shared health governance model where individuals, fulfilment (Pratt et al., 2012b). health goods and services providers and health-related There has been some empirical research conducted institutions work together to reduce these shortfalls (Ruger, 2010). that describes the provision of ancillary care in interna- tional research (Heise et al., 2008; Taylor et al., 2011). Underlying this model of governance are shared moral values and ‘voluntary commitments’. Voluntary Of these studies, none has investigated the alignment of current practice with the guidance of a normative model, commitment is defined as the process through which the ethical norm of health equity is internalized at the col- let alone provided information on how adherence to the model might be achieved. In the empirical section of this lective and individual levels. Ruger (2009: 271) states ‘[o]nce individuals internalize these ethical commit- article, we describe the results of case study research that examined whether the ancillary care obligations sup- ments, they freely embrace them and obligate them- ported by the health capability paradigm were upheld selves to conform to them, sacrificing some of their in the Shoklo Malaria Research Unit’s (SMRU) ongoing resources and autonomy to be regulated and to distrib- vivax malaria treatment trial. This was a retrospective ute those resources to others.’ Voluntary commitments are the glue holding the system of shared health govern- application of a newly created ethical standard, as the vivax malaria treatment trial was not designed to adhere ance together, leading individuals and institutions to voluntarily make choices and take positive measures to the obligations we derived from the health capability paradigm. The data show that SMRU investigators not to ensure health disparities are reduced worldwide. Once the norm of health equity is internalized at the only met their ancillary care obligations but also pro- vided health care beyond that required by the justice collective level, most actors will not have to be coerced to carry out their duties of justice, though regulatory model described here. We identify the factors instru- mental to SMRU investigators fulfiling their ancillary mechanisms may be introduced to encourage duty ful- filment. Ruger describes how commitment to the public care obligations. We do not compare SMRU’s provision of care to other normative models, as our aim is to norm of health equity could be created by WHO and states (Ruger, 2009; Ruger and Yach, 2009). Her theory determine whether obligations linking ancillary care delivery to global justice can be met. recognizes that this norm internalization will occur gradually over time, as health equity is not necessarily embraced by populations worldwide today. Under the shared health governance model, actors Philosophical Analysis within the health sector (which includes health research) Understanding the Health Capability Paradigm work towards fulfiling the universal moral duty to Jennifer Ruger’s health capability paradigm is both a reduce shortfall inequalities in health capabilities by theory of health justice and a framework for a system upholding specific duties that are consistent with and of global health governance founded upon shared eth- arise from their role in society. Unlike the majority ical commitment to equity in health. As such, it operates of cosmopolitan theories of justice, Ruger’s paradigm concurrently at theoretical and practical levels. It seeks provides a principle for assigning particular duties to to establish new norms and to investigate how they protect and maintain the central health capabilities to might be applied using current global health architec- specific parties. Without such a second-stage principle, ture as the starting point. ‘it would be difficult, if not impossible, to allocate Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 157 responsibilities among the multitudes and levels of in- population’s gap from the optimal health status is stitutions and actors’ (Ruger, 2009: 272). A theory of large, in accordance with their function. External re- justice would offer little justification for why specific search actors from high-income countries then have an obligation to perform international research in a actors ought to act in particular ways. According to the functional requirements principle, duties are distrib- manner that reduces global health disparities (Pratt uted to institutions or actors because the functions that et al. 2012a). We have previously described what this they typically assume make them particularly capable of entails in terms of selecting research targets, capacity- performing the duties (Ruger, 2009). The principle rec- building and post-trial benefits (Pratt and Loff, 2012). ognizes that institutions and individuals have respective Here, we take the position that this obligation further roles in addressing health issues that make them the includes providing ancillary care during research. pragmatic choice to carry out certain duties of justice. Assisting with the delivery of health care where state Institutions and actors’ mandated roles and activities health systems (public and private) are not doing so equip them with the skills, resources and authority to effectively can improve the health of the worst-off in discharge the duties. LMICs. Research actors’ obligation to provide ancillary care further corresponds to their specific research role Individuals and institutions are allocated obligations of justice that are consistent with their functions prior to (i.e. funder, sponsor or researcher). To conduct clinical research, investigators engage in societies internalizing the norm of health equity (i.e. in the absence of voluntary commitments). As a result, repeated interactions with trial participants in a medical until individuals and institutions within states embrace setting. As clinical researchers, they are likely to have the the norm, incentive measures such as government regu- skills and resources to make a restricted contribution to lation and oversight will probably be required to ensure address health conditions experienced by participants that they fulfil their obligations (Ruger, 2011). that are not dealt with by the local health system. The provision of health care unrelated to studies may be viewed as extraneous to the researchers’ role. Grounding Ancillary Care Obligations for However, physician-investigators will be especially Research Actors capable of facilitating the delivery of a limited amount In accordance with the functional requirements prin- of care to study participants in LMICs that they would ciple, the primary responsibility for promoting health not otherwise receive. This includes care required to capabilities is allocated to states. National governments ensure a trial’s scientific validity and (ancillary) care are in the best position to reduce the shortfall between that is not. their population’s health status and the optimal level. National governments, research funders and sponsors States must establish public health, health care and from high-income countries similarly acquire ancil- health research systems in order to ensure that their lary care obligations that align with their functions populations are able to obtain the goods and services (Table 2). Governments are obligated to use their necessary to guarantee central health capabilities— legislative powers to create a supportive policy environ- namely, public health goods and services; health care ment for the provision of ancillary care. Research fun- goods and services for prevention, diagnosis, treatment ders are obligated to finance the provision of ancillary and rehabilitation; social support services; adequate nu- care during trials. Funders acquire this obligation not trition and sanitary and safe living and working condi- simply because they are able to provide money but be- tions (Ruger, 2010). cause they have a mandate to allocate their funds to Where states do not reduce shortfalls in their citizens’ research activities, including collateral benefits of re- health capabilities from the optimal level, global actors search, and access to the channels to do so efficiently. have an obligation to assist such states, though states Funding organizations are generally most able to spend retain primary responsibility (Ruger, 2009). (As it is their money in ways that are consistent with their mis- pertinent to our case study, we also take the position sions. For example, Wellcome Trust does not support that where government persecution leads members of a post-trial access to efficacious study interventions be- state’s population to seek refuge in another country, the cause doing so falls outside its remit as a research country of refuge acquires a secondary obligation to funder. However, it does support the provision of col- ensure those individuals’ basic capabilities such as lateral benefits during research programs, including an- health, though the state of origin retains the primary cillary care, insofar as doing so does not adversely affect responsibility.) Global actors must support and facilitate the local research environment (Wellcome Trust, 2009). state efforts to promote health, particularly where a Sponsoring institutions have a responsibility to support Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 158 PRATT ET AL. their researchers accurately identify the ancillary care ends of justice (Pratt et al., 2012a). As noted by Merritt needs that they are likely to encounter in particular (2011), if achieving justice in global health requires the overseas research settings prior to trials commencing. production of scientific results from clinical trials, par- ties’ ancillary care obligations cannot be so extensive In instances where there is no longstanding collabor- ation or clear demographic information on disease that they usurp the necessary amount of resources (i.e. burden, sponsors should assist researchers to liaise human, financial and physical) to complete a particular with health care providers in host districts or commu- trial (Merritt, 2011). nities to gather information on the health conditions The health capability paradigm prioritizes addressing experienced by the local population. those health conditions that are major contributors to At present, external research actors from high-income the health gap between host communities and the opti- countries have ancillary care obligations that are mal level. It further emphasizes efficiency (Ruger, 2010) grounded by their role in research. These obligations and establishes obligations for global actors to assist will eventually be strengthened through voluntary com- where state systems are unable or choose not to de- mitments (the process of norm internalization). Once liver health care. Obligations are allocated on the individuals and institutions freely internalize a norma- basis of actors’ roles and technical skills (Table 2). tive ethical commitment to health equity, they are obli- International clinical researchers would, therefore, be required to meet only those ancillary care needs that gated to act in ways that align with their commitment (Ruger, 2012). This reinforces/strengthens all function- they have the training and expertise to deal with. This related duties that are consistent with the norm, includ- may mean that the ancillary care offered in similar trials ing the duty to fund and perform research that contrib- run by different research groups will vary. The paradigm utes to the reduction of shortfall inequalities in health in additionally holds that cost-effectiveness and appropri- LMICs, which, in turn, demands (among other things) ateness be considered when determining what interven- the provision of ancillary care. Thus, in time, the ancil- tion(s) to provide for a particular health condition lary care obligations of research actors from high- (Ruger, 2010). income countries will be grounded in both their ‘volun- From this, it may be inferred that international clin- tary commitment’ to changed norms and their function. ical researchers are obligated to provide ancillary care As a minimum, ancillary care obligations are owed to during trials for health conditions that meet the follow- ing selection criteria: trial participants. In some trials, investigators may have substantial interaction with participants’ families. This they are major contributors to the health gap of host may extend the obligations to them, but, in most situ- ations, the claimants of care will be trial participants communities, local, state-run health care providers (public and pri- because they are directly part of the research enterprise. Under the health capability paradigm, actors are obli- vate) are unable or choose not to offer treatment for gated to offer care to those in need who they are espe- the condition(s) and cially able to help in light of their functions. External  research personnel have the necessary expertise to research actors are best positioned to provide care to treat the condition(s). participants, as follow-up visits for trials give opportu- nities for continual medical examination and treatment. Where resources for ancillary care are limited, which It is, nonetheless, morally praiseworthy to extend care to will likely be the case for most international clinical re- participants’ families and communities. search projects, they should be allocated to treatments for diseases that cause significant morbidity and mor- tality in host communities in order to promote the re- Specifying the Content and Extent of Ancillary duction of global health disparities. Such diseases can be Care Obligations reasonably expected to be encountered frequently. The health capability paradigm establishes ancillary care Where rare diseases with severe implications for health obligations for external research funders, sponsors and occur, if resources permit and the diseases meet the investigators to clinical trial participants in LMICs. other selection criteria for ancillary care, international However, this duty cannot be the provision of unlimited clinical researchers should address them as well. ancillary care. There is an upper limit on the amount of However, treating diseases that are not driving host ancillary care that investigators are expected to deliver in communities’ health gap is secondary. Ancillary care is trial contexts. The health capability paradigm considers not a replacement for full health services. The ancillary international clinical trials to be necessary to realize the care provided should also consist of interventions that Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 159 Table 1. Different models’ articulation of the content of ancillary care obligations Health capability Duty of rescue Partial-entrustment Whole-person model paradigm model component model Scope of candidate Health condition is a Health condition Health condition All health ancillary care major contributor is severe and/or is entrusted to conditions needs to the health gap of urgent. researchers encountered. host communities. through consent process. Criteria to deter- An absence of others An absence of others Participants’ Participants’ mine whether a able to meet that able to meet dependence on dependence on (strong) obliga- health need. that health researchers researchers tion exists to Cost-effectiveness and need. (whether they (whether they meet a candidate appropriateness of Ability to meet the lack other lack other ancillary care available need without sources of help). sources of help). need interventions. incurring Cost (money, Cost (money, Researchers possess the ‘inordinate’ personnel, study personnel, study expertise and tech- costs. power). power). nical capacity to Researchers possess Participants’ Participants’ meet the need the expertise vulnerability vulnerability safely. and technical (how badly off (how badly off capacity to meet they would be if they would be if the need safely. they did not re- they did not Researchers’ freedom ceive help). receive help). from competing Duration of Duration of obligations. researcher– researcher– participant participant relationship. relationship. Participants’ Participants’ uncompensated uncompensated risks and risks and benefits. benefits. Note: Where there is alignment between two or more models, text is highlighted in bold. are cost-effective and appropriate for the research popu- conditions are causing significant morbidity and mor- lation. The health capability paradigm further recog- tality). The partial-entrustment model, in contrast, re- nizes that other global actors have obligations to quires awareness of what health conditions are likely to deliver health care to LMIC communities. If local med- be diagnosed through study-related tests. ical non-governmental organizations (NGOs) are de- livering care for certain conditions, the functional requirements principle does not demand researchers Empirical Research do so as well. The Case Study The health capability paradigm’s guidance regarding the content of ancillary care obligations is fairly consist- A case study was undertaken to determine the extent to ent with the partial-entrustment and whole-person which the ancillary care obligations supported by the models, though differences do exist, particularly with health capability paradigm are capable of being upheld respect to the scope of candidate ancillary care needs in practice and to identify the factors that make doing so (Table 1). To advance global justice, identifying the feasible. It was intended to demonstrate what is possible, scope of ancillary care needs requires a broad assessment though not necessarily common practice in interna- of the health situation of host communities (i.e. what tional clinical research. We selected SMRU and its Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 160 PRATT ET AL. ongoing vivax malaria treatment (VHX) trial as our case study because SMRU has been consciously designing its clinical trials to meet the health needs of its host com- munity for the past 25 years (Cheah et al., 2010). There was a high likelihood that one of its trials would involve the provision of ancillary care and provide us with data on how it was achieved. We describe both SMRU and its VHX trial below. SMRU was established in 1985 as a field unit of the Mahidol-Oxford Tropical Medicine Research Unit. It is located on the Thai–Myanmar border in Mae Sot, Thailand and conducts its research with Karen and Myanmar refugees, migrants and displaced persons. Myanmar (Burma) has a long history of ethnic conflicts and political instability. The Karen, one of the largest ethnic groups in Myanmar and northern Thailand, has been engaged in armed rebellion against the Myanmar military forces since 1949. This resulted in population being displaced from eastern Myanmar to Thailand in 1984. Since 1995, there has also been a new influx of Myanmar refugees and migrants, including the Karen, coming to Thailand in search of work. Accordingly, we take the position that Thailand acquires a secondary obligation to enable these migrant workers and dis- placed persons to access its health system and to provide care to the Karen and Myanmar refugee population living in camps, with Myanmar retaining primary responsibility for ensuring the population’s health cap- Figure 1. Map of the location of the SMRU office in Mae Sot, Thailand and the SMRU clinics along the Thai–Myanmar abilities. However, neither Myanmar nor Thailand fully border. meets its obligations. Consequently, SMRU established clinics over a 15-year period to fill the health care gap for the border population. It functions as both a research conditions (Yin, 2008). Data on SMRU’s VHX trial unit and health care provider. were collected using a triangulation approach that The VHX trial seeks to describe the epidemiology and relied on a mix of qualitative research methods—in- compare the efficacy of three treatments for vivax mal- depth interviews, direct observation and document ana- aria—chloroquine/primaquine, chloroquine and arte- lysis. Nineteen in-depth interviews were conducted with sunate (web reference: http://clinicaltrials.gov/ct2/ four types of VHX trial stakeholders—investigators (five show/NCT01074905). Trial sites are five SMRU interviews), Tak Province Border Community Ethics clinics—Mae La, Wang Pha, Mawker Thai, Mun Ru Advisory Board (T-CAB) members (four interviews), Chai and Mae Kon Ken—located within 1 h’s drive of trial participants (eight interviews) and funder repre- Mae Sot, Thailand (Figure 1). Across these five sites, sentatives (Wellcome Trust science portfolio advisors) there were roughly 410 VHX trial participants at the (two interviews). Examples of interview questions are time of our research. Each was randomized into one provided in Pratt et al. (2012b). Interview data were of the three treatment groups and was completing the supplemented by direct observation at four of the five trial’s 1-year follow-up period. Funding for the trial is VHX trial sites over a 5-week period in March and April provided by Wellcome Trust. 2011 and by an examination of trial-related documents such as VHX trial participants’ case report forms (Pratt Research Methods et al., 2012b). At trial sites, we first observed for the Case study methodology was selected because it enables standard examinations and treatments given to VHX exploration of how or why a complex social phenomena trial participants. When this baseline was determined, works and can bring out important contextual we then observed for the provision of any additional Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 161 Box 1. Conditions for which ancillary care is provided during the VHX trial 1. Abscess 2. Amoebic dysentery 3. Anaemia 4. Bronchiolitis 5. Bronchitis 6. Chronic gastric ulcer 7. Common cold Figure 2. Most common conditions for which ancillary care 8. Conjunctivitis is provided during the VHX trial as of April 2011 (based on 9. Dengue analysis of 200 case report forms). 10. Diarrhoea 11. External otitis 12. Fever (non-malarial) a picture of what non-malarial conditions were treated 13. Fungal infection during the trial. 14. Gastroenteritis All interviews were transcribed verbatim and trans- 15. Headache lated from Burmese to English (where required). To 16. Herpes simplex, STIs ensure the accuracy of translation, two interviews that 17. Insomnia had been fully transcribed in Burmese were sent to a 18. Joint pain, arthritis co-investigator who is fluent in Burmese and English 19. Kidney stone to translate. We compared his translation of the inter- 20. Leptospirosis view transcript to that of our transcriber and found 21. Neuropathy no significant discrepancies. Data were then analysed 22. Non-severe pneumonia according to the principles of thematic analysis 23. Oral thrush described in Braun and Clarke (2006), with co-coding 24. Otitis media performed independently by two researchers. Once 25. Pain themes were identified that pertained to the provision 26. Pharyngitis of ancillary care, we assessed whether the collated data 27. Scabies extracts from each provided evidence that the VHX trial 28. Scrub typhus met the health capability paradigm’s requirements 29. Severe abdominal pain (Pratt et al., 2012b). The results of that analysis are 30. Skin infection discussed below. 31. Sty 32. Tonsillitis 33. Typhoid fever Ancillary Care Provided During the VHX Trial 34. Ulcer Case report form analysis demonstrates that, beyond 35. Urinary tract infection vivax and falciparum malaria, VHX trial participants 36. Viral illness are treated for a wide variety of conditions (listed in 37. Worms Box 1). The most common conditions to be treated are 38. Wounds viral illness, non-malarial fever, worms, common cold, anaemia, headaches and gastroenteritis (Figure 2). Viral illness, fever, colds and headaches are treated with para- cetomol. Cases of worms are treated with mebendazole; examinations and treatments that deviated from this gastroenteritis with aluminium hydroxide and anaemia norm to identify ancillary care delivery. Case report with vitamin B complex, vitamin C, folic acid and forms included a form for Concomitant Medications, ferrous sulphate. If necessary, trial participants are which listed all the medications a trial participant admitted to SMRU clinic in-patient departments. Case received for conditions other than vivax and falciparum. report form analysis indicates that two participants were At four of the five trial sites, we randomly sampled 50 admitted to Wang Pha Clinic and Mawker Thai Clinic anonymized case report forms (200 in total) to generate in-patient departments, respectively, with conditions Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 162 PRATT ET AL. deemed to be unrelated to study drugs: scrub typhus and there was no need to liaise with local health care pro- urinary tract infection. Of the eight trial participants viders prior to the start of the VHX trial in order to who were interviewed, only one had needed care for a identify trial participants’ ancillary care needs. The non-malarial health issue—an ulcer on his leg for which types of ancillary care to be offered were simple to iden- he was given treatment at each of his follow-up visits to tify, as the treatments available at trial sites (clinics) had Mae La Clinic for the VHX trial. already been established by senior SMRU doctors. The majority of ancillary care is provided by the The criteria used to select the range of ancillary care SMRU medics, nurses and home visitors responsible provided as part of the VHX trial were effectively those for the day-to-day running of the VHX trial. These that SMRU uses to determine what clinical care it offers staff are recruited from the border population and at its clinics. These selection criteria are largely consist- trained in clinical care and research. Some have a back- ent with the selection criteria endorsed by the health ground in health care before coming to SMRU, but capability paradigm. SMRU provides care for most others have less or no experience, as farming and acute illnesses experienced by the border population, wood-cutting are the main forms of employment in including but not limited to those health conditions the rural areas of Myanmar bordering Tak province that cause significant morbidity and mortality. In in Thailand. Staff training is administered through doing so, it offers ancillary care beyond that which lectures, practical sessions and on-the-job training global justice requires. SMRU does not offer treat- (e.g. daily patient rounds). At each trial site, three or ments for chronic illnesses such as cancer, Hepatitis C four staff members are in-charge of collecting trial data or diabetes. HIV treatment is only provided to TB pa- and are supervised by VHX trial investigators, who are tients, pregnant women and women following delivery also the doctors in-charge at SMRU clinics. At Mae Kon in order to prevent mother-to-child transmission. As Ken Clinic, for example, a nurse and home visitor are Investigator 01 explains responsible for running the VHX study. For simple diag- [i]t’s not because we don’t care. It’s because, first noses and treatments, they provide clinical care to trial of all, they are few compared to other needs and participants. For more complex cases, a senior nurse they are very difficult to treat in the long term and/or out-patient department medics diagnose and because of the commitment to see the patient on treat trial participants. Clinic staff consult with the site a regular basis. This population is relatively doctor in-charge when complex cases and/or potential mobile, so it’s difficult to start the treatment and you never know whether months later the adverse events arise. patient will be still there. We treat HIV but only Where SMRU is unable to treat trial participants’ ill- in pregnant women and after their delivery or in nesses, site doctors in-charge refer patients to other TB patients, not because we don’t care about HIV health care providers and arrange for their transport. while not in those two categories, but because we SMRU has relationships with the other health care pro- can’t afford. viders on the Thai–Myanmar border. These include the Thus, the criteria that determine which conditions Thai hospitals (Mae Sot Hospital, Phop Phra Hospital, SMRU treats include there being a high number of Marymount Hospital), the Myanmar hospital KoKo cases in the border population, having a low treatment (near Wang Pha Clinic), AMI Hospital (in Mae La cost and having a finite treatment period. Treatment for camp) and Cynthia Maung’s Mae Tao Clinic. Aside chronic conditions is not offered primarily because of from Mae Tao Clinic and AMI Hospital, the hospitals cost, the low prevalence of such conditions relative to generally charge fees for patients, which SMRU often infectious diseases and the mobility of the border pays. population. In keeping with the health capability paradigm, Selection of Ancillary Care in the VHX Trial SMRU’s other ancillary care selection criteria relate to What ancillary care is provided during the VHX trial is filling a health care gap and having the technical capacity to provide treatment for a condition. In the VHX trial, determined by the treatments available in the SMRU clinics that serve as trial sites. If trial participants SMRU provides ancillary care for a wide range of con- ditions because the Thai and Myanmar health systems become sick with non-malarial illnesses, they are given the care available at the particular clinic that they attend are largely inaccessible to the border population. SMRU offers care for conditions treated in Thai clinics and for the trial. Since a SMRU-run system was already in place to hospitals rather than care for only those conditions meet the health care needs of the border population, not addressed by the Thai health system. In doing so, Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 163 SMRU recognizes that, while the Thai hospitals are in participants and non-participants. We recognize this the vicinity, for refugees, illegal migrants and displaced issue and feel that it is important to consider how persons, they are physically and financially difficult to research groups might deal with it because it is highly access. Getting to Thai hospitals requires overcoming desirable to avoid creating inequality within host com- significant obstacles such as leaving Mae La camp, tra- munities. SMRU works to avoid generating this type of velling 15–20 (or more) kilometres beyond the border inequality and did not create it in the VHX trial, which is and/or passing through military checkpoints intended significant and worthy of discussion. to prevent Myanmar nationals from crossing into SMRU provides ancillary care to participants during Thailand. Such barriers are not frequently overcome. trials and to non-participants on a continual basis. It is Unlike SMRU clinics, Thai hospitals also charge patient able to do so because it runs the clinics that serve as its fees. It should be said, however, that whenever a non- research sites. The health care provided to non-partici- Thai patient, whether legally in Thailand or not, man- pants can be considered ancillary care because the clinics ages to present him/herself to a public hospital, s/he is would not have been set up had SMRU not wanted to do provided with care. If the patient is too poor to pay, this research in the area. The ancillary care provided to VHX care is free. Annually, the Thai public hospitals of trial participants is largely equivalent to the care other- Tak Province are millions of Thai baht short of their wise provided to SMRU clinic patients, which means budget due to the extra cost of providing care to the inequalities in access to health care are not generated non-Thai population. between participants and non-participants. According to Investigator 01, ‘there is no different level of quality Since the Thai and Myanmar health systems are largely inaccessible, SMRU migrant clinics, Wang Pha of health care because you are part of the study or you are not. It’s the same. It’s what we can provide to any- and Mawker Thai, offer health care for most infectious diseases free-of-charge. The situation in Mae La refugee body.’ Investigator 02 concurs, stating ‘we treat the same as the out-patient, so they will get the same kind of camp is slightly different, as SMRU and AMI Hospital share health care provision responsibilities. SMRU pro- medical care as the other patients who are not in the study.’ For Mae La, Mawker Thai and Wang Pha clinics, vides antenatal, newborn and paediatric specialized care and treats cases of malaria. AMI Hospital provides care this generally holds true because they have the capacity for the remainder of adult health problems free-of- to treat a wide variety of illnesses. charge. Mae Kon Ken Clinic is smaller than other Mae Kon Ken Clinic, however, is only slightly larger SMRU clinics and treats mainly fever-related illnesses. than a dispensary and treats mainly fever-related ill- All five SMRU clinics have a laboratory, out-patient de- nesses. As a result, the provision of ancillary care to partment and in-patient department where patients can trial participants does create inequalities in health care receive daily, free consultations and care. Mae La, Wang access. Investigator 04 affirms Pha and Mawker Thai clinics have antenatal care, deliv- my intention is to not to divide between the OPD ery and special care baby unit facilities. Finally, SMRU [out-patient department] and study but we provides ancillary care during the VHX trial for health cannot refuse or deny for their complaint in the conditions that Karen and Myanmar clinic staff have the study. Otherwise, they will looking for the drug skills and technical capacity to meet safely and that are outside and it can interfere with the study result. So that is why here is study cases get more health relatively inexpensive to treat. At Mawker Thai Clinic, care. They receive more health care than [OPD for example, this means that local staff generally do not patients], but not at the other clinics. Ideally, perform lumbar punctures because there is not a suffi- we have the equal health care system to the all cient volume of patients for them to maintain the skill patient. level necessary to do this procedure safely. During the VHX trial, patients at Mae Kon Ken Clinic receive less ancillary care than trial participants and, Ancillary Care Provision Creates Little in general, they have less access to care compared Inequality in Health Care Access with patients at other SMRU clinics. Investigator 04 The health capability paradigm identifies trial partici- suggests that creating some inequalities in access pants as the primary recipients of ancillary care obliga- to care is necessary in order to ensure the validity of tions. However, as the paradigm supports providing study results. ancillary care where there is an absence of others able Ultimately, the VHX trial’s provision of care for to meet a health need, there is potential that its delivery non-fever-related illnesses does introduce an inequality will create inequalities in access to care between trial in access to health care at one trial site. Even so, Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 164 PRATT ET AL. pre-existing inequalities in access to care between pa- paradigm’s requirements with respect to ancillary care tients at Mae Kon Ken Clinic and other SMRU clinics provision. are not exacerbated by the VHX trial. If anything, these Aside from delivery structures, financial support and inequalities are slightly reduced, with Mae Kon Ken trial human resources are necessary for the provision of an- participants being able to access more care than they cillary care in international clinical research. With re- otherwise would. spect to the former, the selection of research funder is key. For the VHX trial, the cost of ancillary care is largely supported by Wellcome Trust. The Trust allocated Facilitating and Obstructive Factors funds for patient care that cover most non-trial-related VHX trial investigators upheld their obligation to medical expenses, as most health problems experienced provide ancillary care to trial participants. This was by trial participants are inexpensive to treat. Investigator strongly facilitated by SMRU’s long history of combin- 05 notes ing research and health care services with the active the Trust are pretty understanding. Their man- involvement of the border population (its staff ). Since date is the research. I mean, they’re not there SMRU is already an established health care provider on to give aid. Lot more money in the world for aid the Thai–Myanmar border, trial investigators were able than there is for research, but they’re not narrow- to utilize existing structures that cater to the health minded about this. Some funders are more needs of the population from which trial participants narrow-minded, but I can’t give you specific ex- were drawn. They did not need to organize to bring amples because we tend to avoid those funders. additional medical equipment or medicines (unrelated Unlike research funders such as the US National to the treatment of vivax) into the field. All that was Institutes of Health, which is restricted by government needed to supply ancillary care to VHX trial participants regulations, Wellcome Trust permits the use of its re- was in place. search money to pay for ancillary care. However, there Combining a research unit and a medical NGO into a are limits to Wellcome Trust’s support, as the allocation single organization is unusual. However, it was done to for patient care is a set amount. In cases where uphold a moral obligation identified by SMRU chief Wellcome Trust’s budget is insufficient, SMRU takes investigators to provide care to the border population. its moral obligation to provide a service to the border This obligation was seen to arise when research is population quite seriously, performed in settings where the host population lacks access to a functional health system. As affirmed by [i]f [a trial participant] got run over by a bus, Investigator 05, in such cases, the two roles—doing trampled by an elephant, or had something research and providing health services—cannot be rather weird, I suspect we wouldn’t have had an dissociated, allocation for that. That’s the nature of these things. We’ll still look after these people obvi- [i]n the specific context, there are vulnerable ously. So it might be that some funds for unusual populations such as the migrants and workers problems might come from other pots within the and the refugees, and displaced persons, as SMRU budget. I mean we feel responsible, we they’re called along the border. They didn’t can’t just say, sorry we didn’t think you we’re have another source of health care, so we were going to have that, so we’re not going to look morally obliged to, you know, you couldn’t just after you. go in there and do research and ignore important past problems .. . So again it’s context specific, VHX trial investigators are able to fulfil the frame- but I think there is a moral obligation. work’s requirements due to the clinical care capacity of the Karen and Myanmar staff at SMRU clinics. These This sentiment underlies the structure of SMRU and staff are responsible for the day-to-day running of the reflects the vision of the two men—Nick White and VHX trial and have been trained as medics and nurses, Francois Nosten—who established the research unit in which enables them to diagnose and treat non-study- 1985 and continue to run it today. They did not think it related health conditions. Their clinical training is ad- was ethical to simply go in and do research when the ministered on a continual basis, with on-the-job train- Karen and Myanmar border population lacked access to ing received during daily in-patient department rounds the Thai and Myanmar health systems. Consequently, SMRU set up health structures for the border popula- with SMRU doctors and training sessions delivered for tion. These structures enable VHX trial investigators to different types of staff (e.g. midwives, medics, nurses efficiently and effectively fulfil the health capability and laboratory staff ). Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 165 Obstacles to the provision of ancillary care do exist in-charge and fear of doing the wrong thing. Comments but are not a noticeable impediment in the VHX trial. were made concerning the reluctance of clinic staff These obstacles relate to funding and building the to exercise initiative. Teaching abilities vary among clinical capacity of Karen and Myanmar clinic staff. expatriate doctors, who do not necessarily come to Sustaining SMRU’s service component has become SMRU with experience in training people with limited more difficult over the years, as the number of clinics, education who have grown-up in a rather oppressive staff and the population they serve have expanded. culture. Depending on the combination of doctor and staff, clinical capacity-building, particularly with Although the cost of building new clinics is cheap, staff salaries are not and comprise 70 percent of respect to making diagnoses and treatment recommen- dations independently, can either be quite successful or SMRU’s budget. According to one investigator, ‘it’s a constant battle to try and get enough money to provide a challenge. the service component because that’s a lot of staff and a lot of money for drugs and things.’ It is also becoming Fulfilment of Ancillary Care Obligations in the more difficult to pay for referrals that require expensive VHX Trial by External Stakeholders hospital care. Since SMRU is identified as a research organization rather than a medical NGO, it does not Wellcome Trust and VHX trial investigators largely fulfil have ready access to certain avenues of funding the health capability paradigm’s requirements for ancil- open to humanitarian organizations. At present, lary care (Table 2). The UK’s government has not en- SMRU health services are largely supported by grants acted policies that require international clinical trials to from the European Union, Global Fund and UK provide ancillary care, but its laws do permit the use of Department for International Development. research funding for non-study-related care, as the UK VHX trial investigators suggest that there are difficul- Medical Research Council does (Philpott et al., 2010). ties inherent in building the clinical capacity of Karen Oxford University (sponsor) does not appear to have a and Myanmar individuals recruited to work at SMRU significant role in SMRU health services, though it and from the border population. This is likely to be the result the Mahidol-Oxford Tropical Medicine Research Unit of many factors including lack of familiarity with the do play a role in administering the grants that support requisite medical knowledge among these staff, their these services. Nonetheless, it is difficult to envisage it perceptions of their relationship with expatriate doctors being necessary for Oxford University to take on a role Table 2. Ancillary care obligations supported by the health capability paradigm Obligation bearer Obligations of justice National Enact regulations that require international clinical research to provide ancillary care. governments Abolish policies and laws that impede international clinical research actors from meeting their ancillary care obligations. Funders Fund the provision of ancillary care identified as ethically essential by trial investigators (in grant applications). Abolish policies that restrict the use of research funding to provide ancillary care to trial participants. Sponsors  Support researchers to take the steps necessary to identify the ancillary care they have a duty to provide. Researchers  Identify the ancillary care needs that are ethically essential to address during a trial by, first, identifying illnesses with serious effects that are prevalent in host communities, second, determining if local health services or NGOs provide treatments for these conditions, third, determining whether trial personnel have the technical skills to treat the conditions and, fourth, identifying cost-effective and appropriate interventions for health conditions that meet criteria 1–3. Provide ancillary care for those conditions to participants during the trial. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 166 PRATT ET AL. malaria, but if they had a broken arm, they would supporting the identification of the border population’s not come to us. But because of the increasing size ancillary care needs. SMRU already has systems in place of the population and that there are no other to capture this information. They include: regular con- health structure in the area, except the Thai duct of epidemiological surveys, following prospective hospital, which is difficult for them to reach cohorts, clinic data collection systems and gathering in- and costly, then we now have many more larger formation from local clinic staff. spectrum of conditions and diseases and we try to cope with everything. Another investigator affirms: ‘Now we do the TB, Conclusions delivery, neonatal, and immunisations, all those This article has shown that a theory of justice—the things, so it’s like the SMRU is filling the gap in health capability paradigm—can provide guidance on this for the area.’ Nevertheless, this approach is not the provision of ancillary care in international clinical without its challenges, especially in relation to long- research that is capable of practical application. It has term sustainability of funding and building human been noted that international research ethics guidelines resource capacity. generally do not include requirements for the provision Ultimately, this case study takes the first step towards of ancillary care (Participants in the 2006 Georgetown developing guidance on how one might fulfil ancillary University Workshop on the Ancillary Care Obligations care obligations in international clinical research. Other of Medical Researchers Working in Developing successful strategies need to be identified, as LMIC Countries, 2008). Our theoretical analysis suggests that settings differ considerably. The context of the VHX obligations of justice demand the provision of ancillary trial is somewhat uncommon, as it involves refugee care. Our empirical findings confirm that fulfilment of and migrant populations that fall entirely outside of these obligations is feasible in LMIC settings where there state health systems. More frequently, international is strong commitment to doing so from chief investiga- clinical research is performed in settings where state tors and funders. There is no obvious reason why re- health systems exist but are under-resourced and offer quirements for providing ancillary care should not be limited care. VHX trial investigators think that SMRU’s made part of international guidelines such as the general approach would work in this sort of environ- Declaration of Helsinki (which is currently being ment, with the caveat that, rather than setting up clinics, revised). These requirements could retain some flexibil- researchers run studies through local clinics or partner ity (e.g. allow for permissible exceptions), as there may with the district health department to do health be instances where ancillary care is not provided directly research. However, other approaches may be employed but the research is still ethical. in such settings in practice and these approaches need Our case study research further describes a strategy to be described in order to generate more comprehen- that has led to fulfilment of the ancillary care obligations sive guidance on how ancillary care obligations might required by the health capability paradigm in a context be met. where trial participants could not access their state’s health system. Assuming a dual role as research unit and health care provider reflects an effective and prag- Acknowledgements matic response to states’ (Thailand and Myanmar) un- 12 The authors would like to thank Cindy Chu, Htun willingness to fully respect their obligations of justice. Htun Win and Minthura Wynn for their support in SMRU, under the leadership of its chief investigators, this work. They thank all study participants and the has undertaken significant and sustained health care staff at SMRU. They would also like to express gratitude capacity-building on the Thai–Myanmar border, creat- to the Australian Federal Government and Monash ing a health care system that supplements inaccessible University for the Australian Postgraduate Award schol- state health systems. Over the years, SMRU has grad- arship (2009–2012) that made this research possible. ually expanded the number of clinics it runs and the services they offer in order to meet the health needs of, initially, the Karen and Myanmar refugee population Funding and then the population of migrants and displaced per- sons living on the border. Investigator 01 states that This work was supported by an Australian Postgraduate Award scholarship (2009–2012) from the Australian [f]or many years, we were known as a fever clinic, so people would come if they thought they had Federal Government and Monash University. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 167 6. We recognize that some external research actors Conflict of Interest from high-income counties may have already Three of the co-authors of this paper are employed by internalized the norm of health equity. SMRU. However, their contribution to data collection, 7. Even though the United Nations’ refugee conven- data analysis, and the drafting of the paper did not result tion does not classify all Karen and Myanmar mi- in the exclusion of any negative findings. grants and displaced persons as being owed formal legal obligations by Thailand, we take the position that Thailand has a moral obligation to provide health care to not only refugees but also migrants Notes and displaced persons on the border. 1. The health capability paradigm is particularly suit- 8. We recognize that the political climate is shifting in able for the purpose of deriving such guidance Myanmar, following the elections in November because it has principles of justice that: (i) require 2011. However, so far, this has not resulted in sig- the conduct of health research and research capacity nificant changes on the Thai–Myanmar border. As a strengthening and (ii) can be relied upon to estab- result, Thailand maintains its secondary obligation lish specific obligations for external research actors to provide health care to the border population. from high-income countries to improve the health 9. Case report form analysis shows that only one VHX of individuals in LMICs. trial participant (of the 200 whose case report forms 2. The duty of rescue is an elementary moral principle. were examined) was referred for care during the It affirms that everyone has a duty to help study, first to AMI Hospital and then s/he was trans- people who are in need and whom no one else is ferred to Mae Sot Hospital for severe abdominal well-situated to help, provided that one can do so pain. As this was a severe adverse event, it is con- without serious sacrifice or risk (Merritt et al., sidered study-related care rather than ancillary care 2010). When researchers are the only agents who provision. can help, the duty is theirs. The duty of rescue 10. Registered migrant workers are entitled to some sets the baseline of what ancillary care is owed. health care from Thai hospitals if they purchase It describes researchers’ minimum obligation to health insurance, but this does not cover treatment provide ancillary care that accrues simply by their during research experiments. being in the right place at the right time with the 11. VHX trial participants receive ancillary care for non- needed resources. severe illnesses that are inexpensive and simple to 3. Entrustment refers to the fact that research partici- treat. Although the health capability paradigm does pants automatically entrust certain aspects of their not require treatment to be given for such illnesses, health into researchers’ care when they consent this does not mean that it disallows such actions. to join a study or clinical trial. Since a participant Clearly, there is flexibility to engage in such morally typically gives permission for a disease under study praiseworthy behaviour. to be monitored, the scope of entrustment typically 12. The strategy would also be applicable where states includes caring, as needed, for that disease, and are unable to fulfil their obligations, particularly in following up on any clinically relevant information areas where there is a complete lack of state health or diagnoses generated during the study. structures. 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Ancillary Care: From Theory to Practice in International Clinical Research

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Abstract

Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 PUBLIC HEALTH ETHICS VOLUME 6 NUMBER 2 2013 154–169 154 Ancillary Care: From Theory to Practice in International Clinical Research Bridget Pratt , Monash University Deborah Zion, Monash University Khin Maung Lwin, Shoklo Malaria Research Unit Phaik Yeong Cheah, Shoklo Malaria Research Unit; Mahidol-Oxford Tropical Medicine Research Unit; University of Oxford Francois Nosten, Shoklo Malaria Research Unit; Mahidol-Oxford Tropical Medicine Research Unit; University of Oxford Bebe Loff, Monash University Corresponding author: Bridget Pratt, Michael Kirby Centre for Public Health and Human Rights, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, 99 Commercial Road, Melbourne VIC 3004, Australia. Tel.: +61 3 9903 0314; Email: Bridget.Pratt@monash.edu How international research might contribute to justice in global health has not been substantively addressed by bioethics. This article describes how the provision of ancillary care can link international clinical research to the reduction of global health disparities. It identifies the ancillary care obligations supported by a theory of global justice, showing that Jennifer Ruger’s health capability paradigm requires the delivery of ancillary care to trial participants for a limited subset of conditions that cause severe morbidity and mortality. Empirical research on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial was then undertaken to demon- strate whether and how these obligations might be upheld in a resource-poor setting. Our findings show that fulfilment of the ancillary care obligations is feasible where there is commitment from chief investigators and funders and is strongly facilitated by SMRU’s dual role as a research unit and medical non-governmental organization. Peter Singer argued that ‘a new, proactive research Introduction ethics .. . must ultimately be concerned with reducing International health research partnerships were identi- inequities in global health and achieving justice in fied as a ‘powerful tool’ for advancing health in low- and health research and health care’ (Benatar and Singer, middle-income countries (LMICs) and promoting 2000: 826). Progress has been made towards this object- global health equity by the Commission on Health ive with the development of concepts (Benatar and Research for Development in 1990 (CHRD, 1990: Singer, 2010) such as: xvii). Since then, the premise has been reiterated in World Health Organization reports and at global min-  responsiveness to local health concerns in host com- isterial summits on health research (Ministerial Summit munities and/or countries (NBAC, 2001; CIOMS, on Health Research, 2004; WHO Task Force on Health 2002; Nuffield Council on Bioethics, 2002; London, Systems Research, 2005; Global Ministerial Forum on 2005; World Medical Association, 2008), Research for Health, 2008).  ancillary care (i.e. health care that is not required for The idea that international health research should either the scientific validity of a study or redressing contribute to global health equity led to the identifica- study-related harms) (Belsky and Richardson, 2004; tion of a new role for research ethics—linking research Merritt et al., 2010), to advancing health and building research capacity in  post-trial benefits such as medical treatments or LMIC host communities. In 2000, Solomon Benatar and practices developed by a study (NBAC, 2001; doi:10.1093/phe/pht015 Advance Access publication on 13 June 2013 ! The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 155 CIOMS, 2002; Nuffield Council on Bioethics, 2002; a whole (Belsky and Richardson, 2004; Richardson, Emanuel, 2008; Macklin, 2008; World Medical 2007; Dickert and Wendler, 2009). Efforts have subse- Association, 2008) and quently been made to define the content of the duties research capacity strengthening in host communities supported by each model, particularly for researchers. and/or countries (NBAC, 2001; CIOMS, 2002; A two-step framework has also been developed to UNAIDS/WHO, 2007; Meslin, 2008). assist with the identification of baseline ancillary care obligations derived from the duty of rescue (Merritt This article builds on earlier research that considers et al., 2010). This framework can supplement either how, using such concepts, international clinical research the partial-entrustment or whole-person model should contribute to the reduction of global health (Merritt, 2011). inequalities. That research applied the principles of a Ancillary care obligations described by the partial-en- theory of justice drawn from political philosophy to de- trustment and whole-person models are not intended to termine what is owed by external research actors from connect international clinical research with global high-income countries to improve the health of individ- health equity. There has been minimal investigation uals in LMICs. Jennifer Ruger’s health capability into what guidance theories of global justice can offer paradigm, a theory that extends the work of Amartya on ancillary care provision in international clinical Sen and Martha Nussbaum, was relied upon because it research. At most, duties to remedy global injustice has features that make it particularly suitable for deriv- have been used to ground broad ancillary care obliga- ing guidance on such matters (Pratt et al., 2012a). In tions for medical researchers (London, 2005). These ‘ex- brief, the health capability paradigm demands that pansive arguments’ have been criticized for failing to international clinical research target health conditions identify why researchers should bear a greater burden that are major contributors to host communities’ gap in for reducing global health inequities than other citizens health status from the optimal global level, be conducted of high-income countries. Richardson (2007: 1957) in partnership with local researchers and build their notes ‘general appeals to justice are difficult to translate capacity to conduct clinical research on diseases of into obligations incumbent on researchers in particular.’ local concern on their own (Pratt et al., 2012a; Pratt It has further been asserted that an obligation to address and Loff, 2012). For the purposes of this article, it all ancillary care needs encountered over the duration should be assumed that the research discussed meets of international clinical trials would ‘strain budgets these criteria. and monopolize the scarce time of trained personnel’ Building on that work, our article derives ancillary (Participants in the 2006 Georgetown University care obligations from the health capability paradigm Workshop on the Ancillary-Care Obligations of and discusses empirical research undertaken in order Medical Researchers Working in Developing to describe how these obligations can be upheld. Countries, 2008: e90). Developing robust guidance for ancillary care demands Hyder and Merritt (2009) state that debate is required a normative model with the following features: a prin- about the precise ethical justification of ancillary care. In cipled basis for determining that researchers have ancil- the philosophical analysis section of this article, we lary care obligations, specification of the content of these derive guidance on ancillary care from the health cap- obligations and definition of the obligations’ upper and ability paradigm and briefly compare it to what is lower limits (Merritt, 2011). Thus far, a normative required by existing normative models. This supple- model has not been developed that relies on a theory ments’ existing work by showing that a theory of justice of global justice to identify ancillary care obligations. is able to ground ancillary care obligations and allocate The two normative models that have been proposed— specific obligations of justice to external research actors the partial-entrustment model and the whole-person from high-income countries, including governments, model—argue for the existence of special ancillary research funders, sponsors, and investigators. These care duties for researchers (and sponsors) above general ancillary care obligations do not require delivery of duties of rescue. The partial-entrustment model holds unlimited health care to participants during trials. that special ancillary care duties derive from a morally Instead, the health capability paradigm supports an significant feature of the researcher–participant rela- obligation to provide ancillary care for a limited tionship—the entrustment of aspects of participants’ subset of health conditions causing severe morbidity health to researchers —whereas the whole-person and mortality in host communities. model considers such duties to be based on the moral Constructing a normative model, however, is not significance of the researcher–participant relationship as sufficient to ensure obligations are met in the research Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 156 PRATT ET AL. setting in most cases. A recent consensus paper noted, The health capability paradigm establishes a univer- ‘empirical research ... about current ancillary-care pra- sal obligation to efficiently reduce shortfall inequalities ctices, should be undertaken to inform the debate and in individuals’ central health capabilities, particularly in countries where the shortfall from the optimal level is the development of appropriate guidelines’ (Partici- pants in the 2006 Georgetown University Workshop large (Ruger, 2010). Central health capabilities refer to on the Ancillary-Care Obligations of Medical Research- individual ability and freedom to achieve certain health ers Working in Developing Countries, 2008: e90). To functionings (i.e. avoiding preventable morbidity and translate ethical requirements into practice, empirical mortality). Reducing shortfall inequalities in health investigation is needed to identify where ancillary care status for an individual or population refers to dimin- obligations are observed and to identify contextual fac- ishing the gap in their health status from the optimal tors that facilitate or obstruct adherence. The findings of level (the highest level of health achieved worldwide in empirical research can inform the development of prac- terms of life expectancy, disease prevalence and inci- tical guidance for research actors on how to uphold dence and other variables). The paradigm envisions a these obligations, which, in turn, will promote greater shared health governance model where individuals, fulfilment (Pratt et al., 2012b). health goods and services providers and health-related There has been some empirical research conducted institutions work together to reduce these shortfalls (Ruger, 2010). that describes the provision of ancillary care in interna- tional research (Heise et al., 2008; Taylor et al., 2011). Underlying this model of governance are shared moral values and ‘voluntary commitments’. Voluntary Of these studies, none has investigated the alignment of current practice with the guidance of a normative model, commitment is defined as the process through which the ethical norm of health equity is internalized at the col- let alone provided information on how adherence to the model might be achieved. In the empirical section of this lective and individual levels. Ruger (2009: 271) states ‘[o]nce individuals internalize these ethical commit- article, we describe the results of case study research that examined whether the ancillary care obligations sup- ments, they freely embrace them and obligate them- ported by the health capability paradigm were upheld selves to conform to them, sacrificing some of their in the Shoklo Malaria Research Unit’s (SMRU) ongoing resources and autonomy to be regulated and to distrib- vivax malaria treatment trial. This was a retrospective ute those resources to others.’ Voluntary commitments are the glue holding the system of shared health govern- application of a newly created ethical standard, as the vivax malaria treatment trial was not designed to adhere ance together, leading individuals and institutions to voluntarily make choices and take positive measures to the obligations we derived from the health capability paradigm. The data show that SMRU investigators not to ensure health disparities are reduced worldwide. Once the norm of health equity is internalized at the only met their ancillary care obligations but also pro- vided health care beyond that required by the justice collective level, most actors will not have to be coerced to carry out their duties of justice, though regulatory model described here. We identify the factors instru- mental to SMRU investigators fulfiling their ancillary mechanisms may be introduced to encourage duty ful- filment. Ruger describes how commitment to the public care obligations. We do not compare SMRU’s provision of care to other normative models, as our aim is to norm of health equity could be created by WHO and states (Ruger, 2009; Ruger and Yach, 2009). Her theory determine whether obligations linking ancillary care delivery to global justice can be met. recognizes that this norm internalization will occur gradually over time, as health equity is not necessarily embraced by populations worldwide today. Under the shared health governance model, actors Philosophical Analysis within the health sector (which includes health research) Understanding the Health Capability Paradigm work towards fulfiling the universal moral duty to Jennifer Ruger’s health capability paradigm is both a reduce shortfall inequalities in health capabilities by theory of health justice and a framework for a system upholding specific duties that are consistent with and of global health governance founded upon shared eth- arise from their role in society. Unlike the majority ical commitment to equity in health. As such, it operates of cosmopolitan theories of justice, Ruger’s paradigm concurrently at theoretical and practical levels. It seeks provides a principle for assigning particular duties to to establish new norms and to investigate how they protect and maintain the central health capabilities to might be applied using current global health architec- specific parties. Without such a second-stage principle, ture as the starting point. ‘it would be difficult, if not impossible, to allocate Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 157 responsibilities among the multitudes and levels of in- population’s gap from the optimal health status is stitutions and actors’ (Ruger, 2009: 272). A theory of large, in accordance with their function. External re- justice would offer little justification for why specific search actors from high-income countries then have an obligation to perform international research in a actors ought to act in particular ways. According to the functional requirements principle, duties are distrib- manner that reduces global health disparities (Pratt uted to institutions or actors because the functions that et al. 2012a). We have previously described what this they typically assume make them particularly capable of entails in terms of selecting research targets, capacity- performing the duties (Ruger, 2009). The principle rec- building and post-trial benefits (Pratt and Loff, 2012). ognizes that institutions and individuals have respective Here, we take the position that this obligation further roles in addressing health issues that make them the includes providing ancillary care during research. pragmatic choice to carry out certain duties of justice. Assisting with the delivery of health care where state Institutions and actors’ mandated roles and activities health systems (public and private) are not doing so equip them with the skills, resources and authority to effectively can improve the health of the worst-off in discharge the duties. LMICs. Research actors’ obligation to provide ancillary care further corresponds to their specific research role Individuals and institutions are allocated obligations of justice that are consistent with their functions prior to (i.e. funder, sponsor or researcher). To conduct clinical research, investigators engage in societies internalizing the norm of health equity (i.e. in the absence of voluntary commitments). As a result, repeated interactions with trial participants in a medical until individuals and institutions within states embrace setting. As clinical researchers, they are likely to have the the norm, incentive measures such as government regu- skills and resources to make a restricted contribution to lation and oversight will probably be required to ensure address health conditions experienced by participants that they fulfil their obligations (Ruger, 2011). that are not dealt with by the local health system. The provision of health care unrelated to studies may be viewed as extraneous to the researchers’ role. Grounding Ancillary Care Obligations for However, physician-investigators will be especially Research Actors capable of facilitating the delivery of a limited amount In accordance with the functional requirements prin- of care to study participants in LMICs that they would ciple, the primary responsibility for promoting health not otherwise receive. This includes care required to capabilities is allocated to states. National governments ensure a trial’s scientific validity and (ancillary) care are in the best position to reduce the shortfall between that is not. their population’s health status and the optimal level. National governments, research funders and sponsors States must establish public health, health care and from high-income countries similarly acquire ancil- health research systems in order to ensure that their lary care obligations that align with their functions populations are able to obtain the goods and services (Table 2). Governments are obligated to use their necessary to guarantee central health capabilities— legislative powers to create a supportive policy environ- namely, public health goods and services; health care ment for the provision of ancillary care. Research fun- goods and services for prevention, diagnosis, treatment ders are obligated to finance the provision of ancillary and rehabilitation; social support services; adequate nu- care during trials. Funders acquire this obligation not trition and sanitary and safe living and working condi- simply because they are able to provide money but be- tions (Ruger, 2010). cause they have a mandate to allocate their funds to Where states do not reduce shortfalls in their citizens’ research activities, including collateral benefits of re- health capabilities from the optimal level, global actors search, and access to the channels to do so efficiently. have an obligation to assist such states, though states Funding organizations are generally most able to spend retain primary responsibility (Ruger, 2009). (As it is their money in ways that are consistent with their mis- pertinent to our case study, we also take the position sions. For example, Wellcome Trust does not support that where government persecution leads members of a post-trial access to efficacious study interventions be- state’s population to seek refuge in another country, the cause doing so falls outside its remit as a research country of refuge acquires a secondary obligation to funder. However, it does support the provision of col- ensure those individuals’ basic capabilities such as lateral benefits during research programs, including an- health, though the state of origin retains the primary cillary care, insofar as doing so does not adversely affect responsibility.) Global actors must support and facilitate the local research environment (Wellcome Trust, 2009). state efforts to promote health, particularly where a Sponsoring institutions have a responsibility to support Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 158 PRATT ET AL. their researchers accurately identify the ancillary care ends of justice (Pratt et al., 2012a). As noted by Merritt needs that they are likely to encounter in particular (2011), if achieving justice in global health requires the overseas research settings prior to trials commencing. production of scientific results from clinical trials, par- ties’ ancillary care obligations cannot be so extensive In instances where there is no longstanding collabor- ation or clear demographic information on disease that they usurp the necessary amount of resources (i.e. burden, sponsors should assist researchers to liaise human, financial and physical) to complete a particular with health care providers in host districts or commu- trial (Merritt, 2011). nities to gather information on the health conditions The health capability paradigm prioritizes addressing experienced by the local population. those health conditions that are major contributors to At present, external research actors from high-income the health gap between host communities and the opti- countries have ancillary care obligations that are mal level. It further emphasizes efficiency (Ruger, 2010) grounded by their role in research. These obligations and establishes obligations for global actors to assist will eventually be strengthened through voluntary com- where state systems are unable or choose not to de- mitments (the process of norm internalization). Once liver health care. Obligations are allocated on the individuals and institutions freely internalize a norma- basis of actors’ roles and technical skills (Table 2). tive ethical commitment to health equity, they are obli- International clinical researchers would, therefore, be required to meet only those ancillary care needs that gated to act in ways that align with their commitment (Ruger, 2012). This reinforces/strengthens all function- they have the training and expertise to deal with. This related duties that are consistent with the norm, includ- may mean that the ancillary care offered in similar trials ing the duty to fund and perform research that contrib- run by different research groups will vary. The paradigm utes to the reduction of shortfall inequalities in health in additionally holds that cost-effectiveness and appropri- LMICs, which, in turn, demands (among other things) ateness be considered when determining what interven- the provision of ancillary care. Thus, in time, the ancil- tion(s) to provide for a particular health condition lary care obligations of research actors from high- (Ruger, 2010). income countries will be grounded in both their ‘volun- From this, it may be inferred that international clin- tary commitment’ to changed norms and their function. ical researchers are obligated to provide ancillary care As a minimum, ancillary care obligations are owed to during trials for health conditions that meet the follow- ing selection criteria: trial participants. In some trials, investigators may have substantial interaction with participants’ families. This they are major contributors to the health gap of host may extend the obligations to them, but, in most situ- ations, the claimants of care will be trial participants communities, local, state-run health care providers (public and pri- because they are directly part of the research enterprise. Under the health capability paradigm, actors are obli- vate) are unable or choose not to offer treatment for gated to offer care to those in need who they are espe- the condition(s) and cially able to help in light of their functions. External  research personnel have the necessary expertise to research actors are best positioned to provide care to treat the condition(s). participants, as follow-up visits for trials give opportu- nities for continual medical examination and treatment. Where resources for ancillary care are limited, which It is, nonetheless, morally praiseworthy to extend care to will likely be the case for most international clinical re- participants’ families and communities. search projects, they should be allocated to treatments for diseases that cause significant morbidity and mor- tality in host communities in order to promote the re- Specifying the Content and Extent of Ancillary duction of global health disparities. Such diseases can be Care Obligations reasonably expected to be encountered frequently. The health capability paradigm establishes ancillary care Where rare diseases with severe implications for health obligations for external research funders, sponsors and occur, if resources permit and the diseases meet the investigators to clinical trial participants in LMICs. other selection criteria for ancillary care, international However, this duty cannot be the provision of unlimited clinical researchers should address them as well. ancillary care. There is an upper limit on the amount of However, treating diseases that are not driving host ancillary care that investigators are expected to deliver in communities’ health gap is secondary. Ancillary care is trial contexts. The health capability paradigm considers not a replacement for full health services. The ancillary international clinical trials to be necessary to realize the care provided should also consist of interventions that Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 159 Table 1. Different models’ articulation of the content of ancillary care obligations Health capability Duty of rescue Partial-entrustment Whole-person model paradigm model component model Scope of candidate Health condition is a Health condition Health condition All health ancillary care major contributor is severe and/or is entrusted to conditions needs to the health gap of urgent. researchers encountered. host communities. through consent process. Criteria to deter- An absence of others An absence of others Participants’ Participants’ mine whether a able to meet that able to meet dependence on dependence on (strong) obliga- health need. that health researchers researchers tion exists to Cost-effectiveness and need. (whether they (whether they meet a candidate appropriateness of Ability to meet the lack other lack other ancillary care available need without sources of help). sources of help). need interventions. incurring Cost (money, Cost (money, Researchers possess the ‘inordinate’ personnel, study personnel, study expertise and tech- costs. power). power). nical capacity to Researchers possess Participants’ Participants’ meet the need the expertise vulnerability vulnerability safely. and technical (how badly off (how badly off capacity to meet they would be if they would be if the need safely. they did not re- they did not Researchers’ freedom ceive help). receive help). from competing Duration of Duration of obligations. researcher– researcher– participant participant relationship. relationship. Participants’ Participants’ uncompensated uncompensated risks and risks and benefits. benefits. Note: Where there is alignment between two or more models, text is highlighted in bold. are cost-effective and appropriate for the research popu- conditions are causing significant morbidity and mor- lation. The health capability paradigm further recog- tality). The partial-entrustment model, in contrast, re- nizes that other global actors have obligations to quires awareness of what health conditions are likely to deliver health care to LMIC communities. If local med- be diagnosed through study-related tests. ical non-governmental organizations (NGOs) are de- livering care for certain conditions, the functional requirements principle does not demand researchers Empirical Research do so as well. The Case Study The health capability paradigm’s guidance regarding the content of ancillary care obligations is fairly consist- A case study was undertaken to determine the extent to ent with the partial-entrustment and whole-person which the ancillary care obligations supported by the models, though differences do exist, particularly with health capability paradigm are capable of being upheld respect to the scope of candidate ancillary care needs in practice and to identify the factors that make doing so (Table 1). To advance global justice, identifying the feasible. It was intended to demonstrate what is possible, scope of ancillary care needs requires a broad assessment though not necessarily common practice in interna- of the health situation of host communities (i.e. what tional clinical research. We selected SMRU and its Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 160 PRATT ET AL. ongoing vivax malaria treatment (VHX) trial as our case study because SMRU has been consciously designing its clinical trials to meet the health needs of its host com- munity for the past 25 years (Cheah et al., 2010). There was a high likelihood that one of its trials would involve the provision of ancillary care and provide us with data on how it was achieved. We describe both SMRU and its VHX trial below. SMRU was established in 1985 as a field unit of the Mahidol-Oxford Tropical Medicine Research Unit. It is located on the Thai–Myanmar border in Mae Sot, Thailand and conducts its research with Karen and Myanmar refugees, migrants and displaced persons. Myanmar (Burma) has a long history of ethnic conflicts and political instability. The Karen, one of the largest ethnic groups in Myanmar and northern Thailand, has been engaged in armed rebellion against the Myanmar military forces since 1949. This resulted in population being displaced from eastern Myanmar to Thailand in 1984. Since 1995, there has also been a new influx of Myanmar refugees and migrants, including the Karen, coming to Thailand in search of work. Accordingly, we take the position that Thailand acquires a secondary obligation to enable these migrant workers and dis- placed persons to access its health system and to provide care to the Karen and Myanmar refugee population living in camps, with Myanmar retaining primary responsibility for ensuring the population’s health cap- Figure 1. Map of the location of the SMRU office in Mae Sot, Thailand and the SMRU clinics along the Thai–Myanmar abilities. However, neither Myanmar nor Thailand fully border. meets its obligations. Consequently, SMRU established clinics over a 15-year period to fill the health care gap for the border population. It functions as both a research conditions (Yin, 2008). Data on SMRU’s VHX trial unit and health care provider. were collected using a triangulation approach that The VHX trial seeks to describe the epidemiology and relied on a mix of qualitative research methods—in- compare the efficacy of three treatments for vivax mal- depth interviews, direct observation and document ana- aria—chloroquine/primaquine, chloroquine and arte- lysis. Nineteen in-depth interviews were conducted with sunate (web reference: http://clinicaltrials.gov/ct2/ four types of VHX trial stakeholders—investigators (five show/NCT01074905). Trial sites are five SMRU interviews), Tak Province Border Community Ethics clinics—Mae La, Wang Pha, Mawker Thai, Mun Ru Advisory Board (T-CAB) members (four interviews), Chai and Mae Kon Ken—located within 1 h’s drive of trial participants (eight interviews) and funder repre- Mae Sot, Thailand (Figure 1). Across these five sites, sentatives (Wellcome Trust science portfolio advisors) there were roughly 410 VHX trial participants at the (two interviews). Examples of interview questions are time of our research. Each was randomized into one provided in Pratt et al. (2012b). Interview data were of the three treatment groups and was completing the supplemented by direct observation at four of the five trial’s 1-year follow-up period. Funding for the trial is VHX trial sites over a 5-week period in March and April provided by Wellcome Trust. 2011 and by an examination of trial-related documents such as VHX trial participants’ case report forms (Pratt Research Methods et al., 2012b). At trial sites, we first observed for the Case study methodology was selected because it enables standard examinations and treatments given to VHX exploration of how or why a complex social phenomena trial participants. When this baseline was determined, works and can bring out important contextual we then observed for the provision of any additional Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 161 Box 1. Conditions for which ancillary care is provided during the VHX trial 1. Abscess 2. Amoebic dysentery 3. Anaemia 4. Bronchiolitis 5. Bronchitis 6. Chronic gastric ulcer 7. Common cold Figure 2. Most common conditions for which ancillary care 8. Conjunctivitis is provided during the VHX trial as of April 2011 (based on 9. Dengue analysis of 200 case report forms). 10. Diarrhoea 11. External otitis 12. Fever (non-malarial) a picture of what non-malarial conditions were treated 13. Fungal infection during the trial. 14. Gastroenteritis All interviews were transcribed verbatim and trans- 15. Headache lated from Burmese to English (where required). To 16. Herpes simplex, STIs ensure the accuracy of translation, two interviews that 17. Insomnia had been fully transcribed in Burmese were sent to a 18. Joint pain, arthritis co-investigator who is fluent in Burmese and English 19. Kidney stone to translate. We compared his translation of the inter- 20. Leptospirosis view transcript to that of our transcriber and found 21. Neuropathy no significant discrepancies. Data were then analysed 22. Non-severe pneumonia according to the principles of thematic analysis 23. Oral thrush described in Braun and Clarke (2006), with co-coding 24. Otitis media performed independently by two researchers. Once 25. Pain themes were identified that pertained to the provision 26. Pharyngitis of ancillary care, we assessed whether the collated data 27. Scabies extracts from each provided evidence that the VHX trial 28. Scrub typhus met the health capability paradigm’s requirements 29. Severe abdominal pain (Pratt et al., 2012b). The results of that analysis are 30. Skin infection discussed below. 31. Sty 32. Tonsillitis 33. Typhoid fever Ancillary Care Provided During the VHX Trial 34. Ulcer Case report form analysis demonstrates that, beyond 35. Urinary tract infection vivax and falciparum malaria, VHX trial participants 36. Viral illness are treated for a wide variety of conditions (listed in 37. Worms Box 1). The most common conditions to be treated are 38. Wounds viral illness, non-malarial fever, worms, common cold, anaemia, headaches and gastroenteritis (Figure 2). Viral illness, fever, colds and headaches are treated with para- cetomol. Cases of worms are treated with mebendazole; examinations and treatments that deviated from this gastroenteritis with aluminium hydroxide and anaemia norm to identify ancillary care delivery. Case report with vitamin B complex, vitamin C, folic acid and forms included a form for Concomitant Medications, ferrous sulphate. If necessary, trial participants are which listed all the medications a trial participant admitted to SMRU clinic in-patient departments. Case received for conditions other than vivax and falciparum. report form analysis indicates that two participants were At four of the five trial sites, we randomly sampled 50 admitted to Wang Pha Clinic and Mawker Thai Clinic anonymized case report forms (200 in total) to generate in-patient departments, respectively, with conditions Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 162 PRATT ET AL. deemed to be unrelated to study drugs: scrub typhus and there was no need to liaise with local health care pro- urinary tract infection. Of the eight trial participants viders prior to the start of the VHX trial in order to who were interviewed, only one had needed care for a identify trial participants’ ancillary care needs. The non-malarial health issue—an ulcer on his leg for which types of ancillary care to be offered were simple to iden- he was given treatment at each of his follow-up visits to tify, as the treatments available at trial sites (clinics) had Mae La Clinic for the VHX trial. already been established by senior SMRU doctors. The majority of ancillary care is provided by the The criteria used to select the range of ancillary care SMRU medics, nurses and home visitors responsible provided as part of the VHX trial were effectively those for the day-to-day running of the VHX trial. These that SMRU uses to determine what clinical care it offers staff are recruited from the border population and at its clinics. These selection criteria are largely consist- trained in clinical care and research. Some have a back- ent with the selection criteria endorsed by the health ground in health care before coming to SMRU, but capability paradigm. SMRU provides care for most others have less or no experience, as farming and acute illnesses experienced by the border population, wood-cutting are the main forms of employment in including but not limited to those health conditions the rural areas of Myanmar bordering Tak province that cause significant morbidity and mortality. In in Thailand. Staff training is administered through doing so, it offers ancillary care beyond that which lectures, practical sessions and on-the-job training global justice requires. SMRU does not offer treat- (e.g. daily patient rounds). At each trial site, three or ments for chronic illnesses such as cancer, Hepatitis C four staff members are in-charge of collecting trial data or diabetes. HIV treatment is only provided to TB pa- and are supervised by VHX trial investigators, who are tients, pregnant women and women following delivery also the doctors in-charge at SMRU clinics. At Mae Kon in order to prevent mother-to-child transmission. As Ken Clinic, for example, a nurse and home visitor are Investigator 01 explains responsible for running the VHX study. For simple diag- [i]t’s not because we don’t care. It’s because, first noses and treatments, they provide clinical care to trial of all, they are few compared to other needs and participants. For more complex cases, a senior nurse they are very difficult to treat in the long term and/or out-patient department medics diagnose and because of the commitment to see the patient on treat trial participants. Clinic staff consult with the site a regular basis. This population is relatively doctor in-charge when complex cases and/or potential mobile, so it’s difficult to start the treatment and you never know whether months later the adverse events arise. patient will be still there. We treat HIV but only Where SMRU is unable to treat trial participants’ ill- in pregnant women and after their delivery or in nesses, site doctors in-charge refer patients to other TB patients, not because we don’t care about HIV health care providers and arrange for their transport. while not in those two categories, but because we SMRU has relationships with the other health care pro- can’t afford. viders on the Thai–Myanmar border. These include the Thus, the criteria that determine which conditions Thai hospitals (Mae Sot Hospital, Phop Phra Hospital, SMRU treats include there being a high number of Marymount Hospital), the Myanmar hospital KoKo cases in the border population, having a low treatment (near Wang Pha Clinic), AMI Hospital (in Mae La cost and having a finite treatment period. Treatment for camp) and Cynthia Maung’s Mae Tao Clinic. Aside chronic conditions is not offered primarily because of from Mae Tao Clinic and AMI Hospital, the hospitals cost, the low prevalence of such conditions relative to generally charge fees for patients, which SMRU often infectious diseases and the mobility of the border pays. population. In keeping with the health capability paradigm, Selection of Ancillary Care in the VHX Trial SMRU’s other ancillary care selection criteria relate to What ancillary care is provided during the VHX trial is filling a health care gap and having the technical capacity to provide treatment for a condition. In the VHX trial, determined by the treatments available in the SMRU clinics that serve as trial sites. If trial participants SMRU provides ancillary care for a wide range of con- ditions because the Thai and Myanmar health systems become sick with non-malarial illnesses, they are given the care available at the particular clinic that they attend are largely inaccessible to the border population. SMRU offers care for conditions treated in Thai clinics and for the trial. Since a SMRU-run system was already in place to hospitals rather than care for only those conditions meet the health care needs of the border population, not addressed by the Thai health system. In doing so, Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 163 SMRU recognizes that, while the Thai hospitals are in participants and non-participants. We recognize this the vicinity, for refugees, illegal migrants and displaced issue and feel that it is important to consider how persons, they are physically and financially difficult to research groups might deal with it because it is highly access. Getting to Thai hospitals requires overcoming desirable to avoid creating inequality within host com- significant obstacles such as leaving Mae La camp, tra- munities. SMRU works to avoid generating this type of velling 15–20 (or more) kilometres beyond the border inequality and did not create it in the VHX trial, which is and/or passing through military checkpoints intended significant and worthy of discussion. to prevent Myanmar nationals from crossing into SMRU provides ancillary care to participants during Thailand. Such barriers are not frequently overcome. trials and to non-participants on a continual basis. It is Unlike SMRU clinics, Thai hospitals also charge patient able to do so because it runs the clinics that serve as its fees. It should be said, however, that whenever a non- research sites. The health care provided to non-partici- Thai patient, whether legally in Thailand or not, man- pants can be considered ancillary care because the clinics ages to present him/herself to a public hospital, s/he is would not have been set up had SMRU not wanted to do provided with care. If the patient is too poor to pay, this research in the area. The ancillary care provided to VHX care is free. Annually, the Thai public hospitals of trial participants is largely equivalent to the care other- Tak Province are millions of Thai baht short of their wise provided to SMRU clinic patients, which means budget due to the extra cost of providing care to the inequalities in access to health care are not generated non-Thai population. between participants and non-participants. According to Investigator 01, ‘there is no different level of quality Since the Thai and Myanmar health systems are largely inaccessible, SMRU migrant clinics, Wang Pha of health care because you are part of the study or you are not. It’s the same. It’s what we can provide to any- and Mawker Thai, offer health care for most infectious diseases free-of-charge. The situation in Mae La refugee body.’ Investigator 02 concurs, stating ‘we treat the same as the out-patient, so they will get the same kind of camp is slightly different, as SMRU and AMI Hospital share health care provision responsibilities. SMRU pro- medical care as the other patients who are not in the study.’ For Mae La, Mawker Thai and Wang Pha clinics, vides antenatal, newborn and paediatric specialized care and treats cases of malaria. AMI Hospital provides care this generally holds true because they have the capacity for the remainder of adult health problems free-of- to treat a wide variety of illnesses. charge. Mae Kon Ken Clinic is smaller than other Mae Kon Ken Clinic, however, is only slightly larger SMRU clinics and treats mainly fever-related illnesses. than a dispensary and treats mainly fever-related ill- All five SMRU clinics have a laboratory, out-patient de- nesses. As a result, the provision of ancillary care to partment and in-patient department where patients can trial participants does create inequalities in health care receive daily, free consultations and care. Mae La, Wang access. Investigator 04 affirms Pha and Mawker Thai clinics have antenatal care, deliv- my intention is to not to divide between the OPD ery and special care baby unit facilities. Finally, SMRU [out-patient department] and study but we provides ancillary care during the VHX trial for health cannot refuse or deny for their complaint in the conditions that Karen and Myanmar clinic staff have the study. Otherwise, they will looking for the drug skills and technical capacity to meet safely and that are outside and it can interfere with the study result. So that is why here is study cases get more health relatively inexpensive to treat. At Mawker Thai Clinic, care. They receive more health care than [OPD for example, this means that local staff generally do not patients], but not at the other clinics. Ideally, perform lumbar punctures because there is not a suffi- we have the equal health care system to the all cient volume of patients for them to maintain the skill patient. level necessary to do this procedure safely. During the VHX trial, patients at Mae Kon Ken Clinic receive less ancillary care than trial participants and, Ancillary Care Provision Creates Little in general, they have less access to care compared Inequality in Health Care Access with patients at other SMRU clinics. Investigator 04 The health capability paradigm identifies trial partici- suggests that creating some inequalities in access pants as the primary recipients of ancillary care obliga- to care is necessary in order to ensure the validity of tions. However, as the paradigm supports providing study results. ancillary care where there is an absence of others able Ultimately, the VHX trial’s provision of care for to meet a health need, there is potential that its delivery non-fever-related illnesses does introduce an inequality will create inequalities in access to care between trial in access to health care at one trial site. Even so, Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 164 PRATT ET AL. pre-existing inequalities in access to care between pa- paradigm’s requirements with respect to ancillary care tients at Mae Kon Ken Clinic and other SMRU clinics provision. are not exacerbated by the VHX trial. If anything, these Aside from delivery structures, financial support and inequalities are slightly reduced, with Mae Kon Ken trial human resources are necessary for the provision of an- participants being able to access more care than they cillary care in international clinical research. With re- otherwise would. spect to the former, the selection of research funder is key. For the VHX trial, the cost of ancillary care is largely supported by Wellcome Trust. The Trust allocated Facilitating and Obstructive Factors funds for patient care that cover most non-trial-related VHX trial investigators upheld their obligation to medical expenses, as most health problems experienced provide ancillary care to trial participants. This was by trial participants are inexpensive to treat. Investigator strongly facilitated by SMRU’s long history of combin- 05 notes ing research and health care services with the active the Trust are pretty understanding. Their man- involvement of the border population (its staff ). Since date is the research. I mean, they’re not there SMRU is already an established health care provider on to give aid. Lot more money in the world for aid the Thai–Myanmar border, trial investigators were able than there is for research, but they’re not narrow- to utilize existing structures that cater to the health minded about this. Some funders are more needs of the population from which trial participants narrow-minded, but I can’t give you specific ex- were drawn. They did not need to organize to bring amples because we tend to avoid those funders. additional medical equipment or medicines (unrelated Unlike research funders such as the US National to the treatment of vivax) into the field. All that was Institutes of Health, which is restricted by government needed to supply ancillary care to VHX trial participants regulations, Wellcome Trust permits the use of its re- was in place. search money to pay for ancillary care. However, there Combining a research unit and a medical NGO into a are limits to Wellcome Trust’s support, as the allocation single organization is unusual. However, it was done to for patient care is a set amount. In cases where uphold a moral obligation identified by SMRU chief Wellcome Trust’s budget is insufficient, SMRU takes investigators to provide care to the border population. its moral obligation to provide a service to the border This obligation was seen to arise when research is population quite seriously, performed in settings where the host population lacks access to a functional health system. As affirmed by [i]f [a trial participant] got run over by a bus, Investigator 05, in such cases, the two roles—doing trampled by an elephant, or had something research and providing health services—cannot be rather weird, I suspect we wouldn’t have had an dissociated, allocation for that. That’s the nature of these things. We’ll still look after these people obvi- [i]n the specific context, there are vulnerable ously. So it might be that some funds for unusual populations such as the migrants and workers problems might come from other pots within the and the refugees, and displaced persons, as SMRU budget. I mean we feel responsible, we they’re called along the border. They didn’t can’t just say, sorry we didn’t think you we’re have another source of health care, so we were going to have that, so we’re not going to look morally obliged to, you know, you couldn’t just after you. go in there and do research and ignore important past problems .. . So again it’s context specific, VHX trial investigators are able to fulfil the frame- but I think there is a moral obligation. work’s requirements due to the clinical care capacity of the Karen and Myanmar staff at SMRU clinics. These This sentiment underlies the structure of SMRU and staff are responsible for the day-to-day running of the reflects the vision of the two men—Nick White and VHX trial and have been trained as medics and nurses, Francois Nosten—who established the research unit in which enables them to diagnose and treat non-study- 1985 and continue to run it today. They did not think it related health conditions. Their clinical training is ad- was ethical to simply go in and do research when the ministered on a continual basis, with on-the-job train- Karen and Myanmar border population lacked access to ing received during daily in-patient department rounds the Thai and Myanmar health systems. Consequently, SMRU set up health structures for the border popula- with SMRU doctors and training sessions delivered for tion. These structures enable VHX trial investigators to different types of staff (e.g. midwives, medics, nurses efficiently and effectively fulfil the health capability and laboratory staff ). Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 165 Obstacles to the provision of ancillary care do exist in-charge and fear of doing the wrong thing. Comments but are not a noticeable impediment in the VHX trial. were made concerning the reluctance of clinic staff These obstacles relate to funding and building the to exercise initiative. Teaching abilities vary among clinical capacity of Karen and Myanmar clinic staff. expatriate doctors, who do not necessarily come to Sustaining SMRU’s service component has become SMRU with experience in training people with limited more difficult over the years, as the number of clinics, education who have grown-up in a rather oppressive staff and the population they serve have expanded. culture. Depending on the combination of doctor and staff, clinical capacity-building, particularly with Although the cost of building new clinics is cheap, staff salaries are not and comprise 70 percent of respect to making diagnoses and treatment recommen- dations independently, can either be quite successful or SMRU’s budget. According to one investigator, ‘it’s a constant battle to try and get enough money to provide a challenge. the service component because that’s a lot of staff and a lot of money for drugs and things.’ It is also becoming Fulfilment of Ancillary Care Obligations in the more difficult to pay for referrals that require expensive VHX Trial by External Stakeholders hospital care. Since SMRU is identified as a research organization rather than a medical NGO, it does not Wellcome Trust and VHX trial investigators largely fulfil have ready access to certain avenues of funding the health capability paradigm’s requirements for ancil- open to humanitarian organizations. At present, lary care (Table 2). The UK’s government has not en- SMRU health services are largely supported by grants acted policies that require international clinical trials to from the European Union, Global Fund and UK provide ancillary care, but its laws do permit the use of Department for International Development. research funding for non-study-related care, as the UK VHX trial investigators suggest that there are difficul- Medical Research Council does (Philpott et al., 2010). ties inherent in building the clinical capacity of Karen Oxford University (sponsor) does not appear to have a and Myanmar individuals recruited to work at SMRU significant role in SMRU health services, though it and from the border population. This is likely to be the result the Mahidol-Oxford Tropical Medicine Research Unit of many factors including lack of familiarity with the do play a role in administering the grants that support requisite medical knowledge among these staff, their these services. Nonetheless, it is difficult to envisage it perceptions of their relationship with expatriate doctors being necessary for Oxford University to take on a role Table 2. Ancillary care obligations supported by the health capability paradigm Obligation bearer Obligations of justice National Enact regulations that require international clinical research to provide ancillary care. governments Abolish policies and laws that impede international clinical research actors from meeting their ancillary care obligations. Funders Fund the provision of ancillary care identified as ethically essential by trial investigators (in grant applications). Abolish policies that restrict the use of research funding to provide ancillary care to trial participants. Sponsors  Support researchers to take the steps necessary to identify the ancillary care they have a duty to provide. Researchers  Identify the ancillary care needs that are ethically essential to address during a trial by, first, identifying illnesses with serious effects that are prevalent in host communities, second, determining if local health services or NGOs provide treatments for these conditions, third, determining whether trial personnel have the technical skills to treat the conditions and, fourth, identifying cost-effective and appropriate interventions for health conditions that meet criteria 1–3. Provide ancillary care for those conditions to participants during the trial. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 166 PRATT ET AL. malaria, but if they had a broken arm, they would supporting the identification of the border population’s not come to us. But because of the increasing size ancillary care needs. SMRU already has systems in place of the population and that there are no other to capture this information. They include: regular con- health structure in the area, except the Thai duct of epidemiological surveys, following prospective hospital, which is difficult for them to reach cohorts, clinic data collection systems and gathering in- and costly, then we now have many more larger formation from local clinic staff. spectrum of conditions and diseases and we try to cope with everything. Another investigator affirms: ‘Now we do the TB, Conclusions delivery, neonatal, and immunisations, all those This article has shown that a theory of justice—the things, so it’s like the SMRU is filling the gap in health capability paradigm—can provide guidance on this for the area.’ Nevertheless, this approach is not the provision of ancillary care in international clinical without its challenges, especially in relation to long- research that is capable of practical application. It has term sustainability of funding and building human been noted that international research ethics guidelines resource capacity. generally do not include requirements for the provision Ultimately, this case study takes the first step towards of ancillary care (Participants in the 2006 Georgetown developing guidance on how one might fulfil ancillary University Workshop on the Ancillary Care Obligations care obligations in international clinical research. Other of Medical Researchers Working in Developing successful strategies need to be identified, as LMIC Countries, 2008). Our theoretical analysis suggests that settings differ considerably. The context of the VHX obligations of justice demand the provision of ancillary trial is somewhat uncommon, as it involves refugee care. Our empirical findings confirm that fulfilment of and migrant populations that fall entirely outside of these obligations is feasible in LMIC settings where there state health systems. More frequently, international is strong commitment to doing so from chief investiga- clinical research is performed in settings where state tors and funders. There is no obvious reason why re- health systems exist but are under-resourced and offer quirements for providing ancillary care should not be limited care. VHX trial investigators think that SMRU’s made part of international guidelines such as the general approach would work in this sort of environ- Declaration of Helsinki (which is currently being ment, with the caveat that, rather than setting up clinics, revised). These requirements could retain some flexibil- researchers run studies through local clinics or partner ity (e.g. allow for permissible exceptions), as there may with the district health department to do health be instances where ancillary care is not provided directly research. However, other approaches may be employed but the research is still ethical. in such settings in practice and these approaches need Our case study research further describes a strategy to be described in order to generate more comprehen- that has led to fulfilment of the ancillary care obligations sive guidance on how ancillary care obligations might required by the health capability paradigm in a context be met. where trial participants could not access their state’s health system. Assuming a dual role as research unit and health care provider reflects an effective and prag- Acknowledgements matic response to states’ (Thailand and Myanmar) un- 12 The authors would like to thank Cindy Chu, Htun willingness to fully respect their obligations of justice. Htun Win and Minthura Wynn for their support in SMRU, under the leadership of its chief investigators, this work. They thank all study participants and the has undertaken significant and sustained health care staff at SMRU. They would also like to express gratitude capacity-building on the Thai–Myanmar border, creat- to the Australian Federal Government and Monash ing a health care system that supplements inaccessible University for the Australian Postgraduate Award schol- state health systems. Over the years, SMRU has grad- arship (2009–2012) that made this research possible. ually expanded the number of clinics it runs and the services they offer in order to meet the health needs of, initially, the Karen and Myanmar refugee population Funding and then the population of migrants and displaced per- sons living on the border. Investigator 01 states that This work was supported by an Australian Postgraduate Award scholarship (2009–2012) from the Australian [f]or many years, we were known as a fever clinic, so people would come if they thought they had Federal Government and Monash University. Downloaded from https://academic.oup.com/phe/article/6/2/154/1558577 by DeepDyve user on 12 July 2022 ANCILLARY CARE AND GLOBAL JUSTICE 167 6. We recognize that some external research actors Conflict of Interest from high-income counties may have already Three of the co-authors of this paper are employed by internalized the norm of health equity. SMRU. However, their contribution to data collection, 7. Even though the United Nations’ refugee conven- data analysis, and the drafting of the paper did not result tion does not classify all Karen and Myanmar mi- in the exclusion of any negative findings. grants and displaced persons as being owed formal legal obligations by Thailand, we take the position that Thailand has a moral obligation to provide health care to not only refugees but also migrants Notes and displaced persons on the border. 1. The health capability paradigm is particularly suit- 8. We recognize that the political climate is shifting in able for the purpose of deriving such guidance Myanmar, following the elections in November because it has principles of justice that: (i) require 2011. However, so far, this has not resulted in sig- the conduct of health research and research capacity nificant changes on the Thai–Myanmar border. As a strengthening and (ii) can be relied upon to estab- result, Thailand maintains its secondary obligation lish specific obligations for external research actors to provide health care to the border population. from high-income countries to improve the health 9. Case report form analysis shows that only one VHX of individuals in LMICs. trial participant (of the 200 whose case report forms 2. The duty of rescue is an elementary moral principle. were examined) was referred for care during the It affirms that everyone has a duty to help study, first to AMI Hospital and then s/he was trans- people who are in need and whom no one else is ferred to Mae Sot Hospital for severe abdominal well-situated to help, provided that one can do so pain. As this was a severe adverse event, it is con- without serious sacrifice or risk (Merritt et al., sidered study-related care rather than ancillary care 2010). When researchers are the only agents who provision. can help, the duty is theirs. The duty of rescue 10. Registered migrant workers are entitled to some sets the baseline of what ancillary care is owed. health care from Thai hospitals if they purchase It describes researchers’ minimum obligation to health insurance, but this does not cover treatment provide ancillary care that accrues simply by their during research experiments. being in the right place at the right time with the 11. VHX trial participants receive ancillary care for non- needed resources. severe illnesses that are inexpensive and simple to 3. Entrustment refers to the fact that research partici- treat. Although the health capability paradigm does pants automatically entrust certain aspects of their not require treatment to be given for such illnesses, health into researchers’ care when they consent this does not mean that it disallows such actions. to join a study or clinical trial. Since a participant Clearly, there is flexibility to engage in such morally typically gives permission for a disease under study praiseworthy behaviour. to be monitored, the scope of entrustment typically 12. The strategy would also be applicable where states includes caring, as needed, for that disease, and are unable to fulfil their obligations, particularly in following up on any clinically relevant information areas where there is a complete lack of state health or diagnoses generated during the study. structures. 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Public Health Ethics – Oxford University Press

Published: Jul 1, 2013

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