https://orcid.org/0000-0003-0221-243X
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ABSTRACT
It was in the 1990s, that the possibility of increased transmission of HIV with the use of injectable contraceptive Depo-Provera®, was first flagged in medical literature. This has posed a challenge for its use in countries, particularly in the African region, where the prevalence and transmission rate of HIV is high. In 2015, a randomised ‘clinical’ trial, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) was launched in four African countries to resolve the question whether the increased risk was causal. Contrary to expectations, the ECHO trial successfully recruited and randomised the specified number of girls/women participants. This paper argues that this was made possible by exercising undue influence, by using incentives, coercive language, and by concealing the real nature of the clinical trial during recruitment. The ECHO trial is unique in subjecting a group of healthy girls/women knowingly to a contraceptive drug with an intention not of finding out whether it is efficacious as a contraceptive, but to find out how risky or life-threatening its use could be. Thus, the ECHO trial has violated one of the central tenets of the Helsinki Declaration by privileging pursuit of knowledge over the interests of the girl/women trial participants from Africa.
Acknowledgements
This article forms part of a special issue on the theme of ‘African Voices in Global Health: Knowledge, Creativity and Accountability’, edited by Dr. Mandisa Mbali and Dr. Jessica Rucell. The author thanks Mandisa Mbali, Jessica Rucell and the anonymous reviewer for their thoughtful feedback on the earlier draft.
Disclosure statement
No potential conflict of interest was reported by the author.
Notes
1 This is partly donor driven. For instance, in 2016, countries in Africa received 79% of the USAID shipment of contraceptive (U.S. Agency for International Development, Citation2017) and, in 2017, more than 60% of UNFPA (United Nations Population Fund) contraceptive funding (UNFPA, Citation2017). Injectable contraceptives formed a sizeable amount of these procurements.
2 These included its potential carcinogenic, teratogenic and mutagenic effects (see Sathyamala, Citation2000). See Multinational Monitor (Citation1985), for details of the USFDA report by the then Commissioner Donald Kennedy rejecting the parent company Upjohn’s first application.
3 These two studies were prospective studies.
4 Mechanisms postulated for the increased HIV transmission are, increased HIV viral replications, effects on local genital tract physiology due to lowered estrogen levels and changes in immune response (Hickey, Marino, & Tachedjian, Citation2016). For a recent excellent review of the mechanisms for increased transmission see Hapgood, Kaushic, and Hel (Citation2018).
5 The ECHO consortium was formed by representatives of the US based FHI360, the University of Washington, the University of the Witwatersrand Reproductive Health and HIV Institute (Wits RHI) , and the BMGF. Apart from the BMGF, funding comes from the USAID, the Swedish International Development Cooperation Agency (SIDA), and the Medical Research Council of South Africa (Hofmeyr et al., Citation2018). In addition, UNFPA is also a funder of this trial (ECHO Consortium, Citation2017, p. 5), and it is part of the EDCTP2 programme supported by the European Union (Human Reproduction Programme, Citation2018).
6 Hofmeyr et al. (Citation2018) is the authoritative summary of study protocol of the ECHO trial on behalf of the ECHO consortium. It was first published on 29 December 2017 with the latest update, as of November 2018, on 16 July 2018. The paper was published in Gates Open Research after an open peer review by two referees.
7 ClinicalTrials.gov is a US database of privately and publicly funded clinical studies conducted around the world. The website makes it clear that ‘[l]isting a study on this site does not mean it has been evaluated by the U.S. Federal Government. The safety and scientific validity of a study listed on ClinicalTrials.gov is the responsibility of the study sponsor and investigators’ (ClinicalTrials.gov., n.d.a).
8 According to the ECHO trial protocol the trial was to be registered with the World Health Organization as part of their clinical trial database (ECHO Consortium, Citation2017, p. 42). However there is no reference to this in the paper by Hofmeyr et al. (Citation2018). Only on 2 November 2018, was it included in the ‘Current project brief’ issued by the WHO (Human Reproduction Programme, Citation2018).
9 In 1995, Upjohn, the parent company of Depo-Provera merged with Pharmacia and subsequently, in 2003, Pharmacia merged with Pfizer.
10 This paper will use the term ‘girls/women’ to reflect the age composition of the participants. In the ECHO trial protocol, participants aged less than 18 years are termed varyingly as ‘women’, ‘adolescents’, ‘young women’, and ‘minors’ (ECHO Consortium, Citation2017, p. 17, 19, and 44). Hofmeyr et al. (Citation2018, p. 4) refer to the participants aged 16–35 years as ‘women’. It is not clear how many of the centres recruited participants aged less than 18 years; all that is stated is ‘where permissible by national regulations and local IRB approval’ (ECHO Consortium, Citation2017, p. 18).
11 NET-EN (norethisterone enanthate) is a two monthly progestogen-only injectable hormonal contraceptive similar to Depo-Provera.
12 The secondary objectives of the ECHO study are to compare pregnancy rates, rates of adverse events leading to discontinuation and continuation rates among the three methods (Hofmeyr et al., Citation2018). The tertiary objectives are to evaluate whether age and HSV-2 (herpes simplex virus – type2) infection ‘modify the hormonal contraception and HIV acquisition relationship [and] to evaluate the effect of contraception on early HIV disease progression among seroconverters’ (Hofmeyr et al., Citation2018, p. 3). However, sample size calculations were based on estimating only the primary end point and therefore, may not have the necessary statistical power to evaluate the secondary and tertiary objectives.
13 See MRC Clinical Trials Unit (n.d) for a description of RCTs.
14 Ethical guidelines developed by the Council for International Organizations of Medical Sciences in collaboration with the WHO does not mention peer-driven recruitment and refers to finder’s fee only in relation to researchers (Council for International Organizations of Medical Sciences, Citation2016).
15 According to the study protocol, in centres recruiting girls (aged less than 18 years), ‘ … study staff will seek parental/guardian consent as well as assent from the minor participants’ (emphasis added) (ECHO Consortium, Citation2017, p. 44), making it somewhat ambiguous whether parental/guardian consent was mandatory or not.
16 The screening IC form template has 6 pages of information and the enrolment IC form template has 10 pages.
17 FHI360, the coordinator of the ECHO study has funded this manual and holds the copyright. However, there is a disclaimer, that ‘[t]he information contained in [the] publication does not necessarily reflect … FHI 360 policies’ (Rivera & Borasky, Citation2009, p. 5).
18 The two Informed Consent form templates, the supplementary document and paper by Hofmeyr et al. (Citation2018).
19 This framing is also vague as the ECHO trial is about the risks of the three study contraceptives only.
20 In the enrolment IC form template the wording is ‘choose your method by chance’ (FHI Citation360 Study #523201, Citation2017a, p. 4).
21 Note that the implant is mentioned by its brand name while the other two methods are not.
22 The ‘Investigator Brochure(s)’, mentioned in the ‘Investigator Signature Form’ of the trial protocol (ECHO Consortium, Citation2017, p. 5), do not exist.
23 For instance, both Vermund (Citation2015) and Pettifor (n.d.) who ‘open’ refereed the Hofmeyr et al. (Citation2018) paper and had declared no conflict of interest were former recipients of grants from the Gates Foundation.
24 Though, the result was not statistically significant, some of the observational studies showed a hazard ratio ranging from 1.27 to 1.34 (Polis et al., Citation2016).
25 Although Hofmeyr et al. (Citation2018) have cited the study by Butler et al. (Citation2013), the implications for countries in southern Africa has not been included. Were DMPA to be discontinued, the increase in maternal deaths by 18,000 is far less than 27,000 new HIV infections with just 20% increased risk.