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Trials
Published in: Trials 1/2020

Open Access 01-04-2020 | Human Immunodeficiency Virus | Commentary

Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies

Authors: Augustine T. Choko, Gholamreza Roshandel, Donaldson F. Conserve, Elizabeth L. Corbett, Katherine Fielding, Karla Hemming, Reza Malekzadeh, Charles Weijer

Published in: Trials | Special Issue 1/2020

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Abstract

Background

Cluster randomized trials are common in health research in low- and middle-income countries raising issues that challenge interpretation of standard ethical guidelines. While the Ottawa Statement on the ethical design and conduct of cluster randomized trials provides guidance for researchers and research ethics committees, it does not explicitly focus on low- and middle-income settings.

Main body

In this paper, we use the lens of the Ottawa Statement to analyze two cluster randomized trials conducted in low- and middle-income settings in order to identify gaps or ethical issues requiring further analysis and guidance. The PolyIran trial was a parallel-arm, cluster trial examining the effectiveness of a polypill for prevention of cardiovascular disease in Golestan province, Iran. The PASTAL trial was an adaptive, multistage, parallel-arm, cluster trial evaluating the effect of incentives for human immunodeficiency virus self-testing and follow-up on male partners of pregnant women in Malawi. Through an in-depth case analysis of these two studies we highlight several issues in need of further exploration. First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious. Particularly in the case of implementation interventions, locally available care is required as the comparator to address questions of comparative effectiveness. However, locally available care might be lower than standards set out in national guidelines. Third, while the need for access to effective interventions post-trial is widely recognized, it is often not possible to guarantee this upfront. Clarity on what is required of researchers and sponsors is needed. Fourth, there is a pressing need for ethics education and capacity building regarding cluster randomized trials in these settings.

Conclusion

We identify four issues in cluster randomized trials conducted in low- and middle-income countries for which further ethical analysis and guidance is required.
Literature
1.
Donner A, Klar N. Design and analysis of cluster randomization trials in health research. London: Arnold; 2000.
2.
Taljaard M, McRae AD, Weijer C, Bennett C, Dixon S, Taleban J, Skea Z, Eccles MP, Brehaut JC, Donner A, Saginur R, Boruch RF, Grimshaw JM. Inadequate reporting of research ethics review and informed consent in cluster randomised trials: review of random sample of published trials. BMJ. 2011;342:d2496.PubMedPubMedCentralCrossRef
3.
Martin J, Taljaard M, Girling A, Hemming K. Systematic review finds major deficiencies in sample size methodology and reporting for stepped-wedge cluster randomised trials. BMJ Open. 2016;6(2):e010166.PubMedPubMedCentralCrossRef
4.
Weijer C, Grimshaw JM, Taljaard M, Binik A, Boruch R, Brehaut JC, Donner A, Eccles MP, Gallo A, McRae AD, Saginur R, Zwarenstein M. Ethical issues posed by cluster randomized trials in health research. Trials. 2011;12:100.PubMedPubMedCentralCrossRef
5.
6.
Edwards SJ, Braunholtz DA, Lilford RJ, Stevens AJ. Ethical issues in the design and conduct of cluster randomised controlled trials. BMJ. 1999;318(7195):1407–9.PubMedPubMedCentralCrossRef
7.
Hutton JL. Are distinctive ethical principles required for cluster randomized controlled trials? Stat Med. 2001;20(3):473–88.PubMedCrossRef
8.
Osrin D, Azad K, Fernandez A, Manandhar DS, Mwansambo CW, Tripathy P, Costello AM. Ethical challenges in cluster randomized controlled trials: experiences from public health interventions in Africa and Asia. Bull World Health Organ. 2009;87(10):772–9.PubMedPubMedCentralCrossRef
9.
Ledogar RJ, Hernández-Alvarez C, Morrison AC, Arosteguí J, Morales-Perez A, Nava-Aguilera E, Legorreta-Soberanis J, Caldwell D, Coloma J, Harris E, Andersson N. When communities are really in control: ethical issues surrounding community mobilisation for dengue prevention in Mexico and Nicaragua. BMC Public Health. 2017;17(Suppl 1):410.PubMedPubMedCentralCrossRef
10.
Kass NE, DeLuca AN, Coetzee L, Simwinga M, Churchyard GJ, Ayles H, Beyers N, Godfrey-Faussett P, Durovni B, Chaisson RE, Eldred LJ. Applying ethical principles to international community-based research: a case study from the Consortium to Respond Effectively to the AIDS-TB Epidemic (CREATE). IRB. 2014;36(3):1–8.PubMed
11.
Mtande TK, Weijer C, Hosseinipour MC, Taljaard M, Matoga M, Goldstein CE, Nyambalo B, Rosenberg NE. Ethical issues raised by cluster randomised trials conducted in low-resource settings: identifying gaps in the Ottawa Statement through an analysis of the PURE Malawi trial. J Med Ethics. 2019;45(6):388–93.PubMedCrossRef
12.
Puffer S, Torgerson D, Watson J. Evidence for risk of bias in cluster randomised trials: review of recent trials published in three general medical journals. BMJ. 2003;327(7418):785–9.PubMedPubMedCentralCrossRef
13.
Taljaard M, Weijer C, Grimshaw JM, Eccles MP, Ottawa Ethics of Cluster Randomised Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomised trials: précis for researchers and research ethics committees. BMJ. 2013;346:f2838.PubMedCrossRef
14.
15.
Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, Taljaard M, Ottawa Ethics of Cluster Randomized Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomized trials. PLoS Med. 2012;9(11):e1001346.PubMedPubMedCentralCrossRef
16.
Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224–60.PubMedPubMedCentralCrossRef
17.
18.
19.
Reddy KS. The preventive polypill—much promise, insufficient evidence. N Engl J Med. 2007;356(3):212.PubMedCrossRef
20.
Ostovaneh MR, Poustchi H, Hemming K, Marjani H, Pourshams A, Nateghi A, Majed M, Navabakhsh B, Khoshnia M, Jaafari E, Mohammadifard N, Malekzadeh F, Merat S, Sadeghi M, Naemi M, Etemadi A, Thomas GN, Sarrafzadegan N, Cheng KK, Marshall T, Malekzadeh R. Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial. Eur J Prev Cardiol. 2015;22(12):1609–17.PubMedCrossRef
21.
Malekzadeh F, Marshall T, Pourshams A, Gharravi M, Aslani A, Nateghi A, Rastegarpanah M, Khoshnia M, Semnani S, Salahi R, Thomas GN, Larijani B, Cheng KK, Malekzadeh R. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors. Int J Clin Pract. 2010;64(9):1220–7.PubMedCrossRef
22.
Pourshams A, Khademi H, Malekshah AF, Islami F, Nouraei M, Sadjadi AR, Jafari E, Rakhshani N, Salahi R, Semnani S, Kamangar F, Abnet CC, Ponder B, Day N, Dawsey SM, Boffetta P, Malekzadeh R. Cohort profile: the Golestan Cohort Study—a prospective study of oesophageal cancer in northern Iran. Int J Epidemiol. 2010;39(1):52–9.PubMedCrossRef
23.
24.
World Health Organization. Progress report 2016: prevent HIV, test and treat all. Geneva: WHO; 2016.CrossRef
25.
Johnson LF, Mossong J, Dorrington RE, Schomaker M, Hoffmann CJ, Keiser O, Fox MP, Wood R, Prozesky H, Giddy J, Garone DB, Cornell M, Egger M, Boulle A, International Epidemiologic Databases to Evaluate AIDS Southern Africa Collaboration. Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Med. 2013;10(4):e1001418.PubMedPubMedCentralCrossRef
26.
Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P, Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369(9562):657–66.PubMedCrossRef
27.
Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D, CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74.PubMedPubMedCentralCrossRef
28.
Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373(9657):48–57.PubMedCrossRef
29.
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV, iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–99.PubMedPubMedCentralCrossRef
30.
UNAIDS. 90–90-90: an ambitious treatment target to help end the AIDS epidemic. Geneva: UNAIDS; 2014.
31.
World Health Organization. Global update on the health sector response to HIV, 2014. Geneva: WHO; 2014.
32.
Kalichman SC, Simbayi LC. HIV testing attitudes, AIDS stigma, and voluntary HIV counselling and testing in a black township in Cape Town, South Africa. Sex Transm Infect. 2003;79(6):442–7.
33.
Wolff B, Nyanzi B, Katongole G, Ssesanga D, Ruberantwari A, Whitworth J. Evaluation of a home-based voluntary counselling and testing intervention in rural Uganda. Health Policy Plan. 2005;20(2):109–16.PubMedCrossRef
34.
Morin SF, Khumalo-Sakutukwa G, Charlebois ED, Routh J, Fritz K, Lane T, Vaki T, Fiamma A, Coates TJ. Removing barriers to knowing HIV status: same-day mobile HIV testing in Zimbabwe. J Acquir Immune Defic Syndr. 2006;41(2):218–24.PubMedCrossRef
35.
Wringe A, Roura M, Urassa M, Busza J, Athanas V, Zaba B. Doubts, denial and divine intervention: understanding delayed attendance and poor retention rates at a HIV treatment programme in rural Tanzania. AIDS Care. 2009;21(5):632–7.PubMedCrossRef
36.
Angotti N, Bula A, Gaydosh L, Kimchi EZ, Thornton RL, Yeatman SE. Increasing the acceptability of HIV counseling and testing with three C's: convenience, confidentiality and credibility. Soc Sci Med. 2009;68(12):2263–70.PubMedPubMedCentralCrossRef
37.
38.
Kranzer K, Simms V, Bandason T, Dauya E, McHugh G, Munyati S, Chonzi P, Dakshina S, Mujuru H, Weiss HA, Ferrand RA. Economic incentives for HIV testing by adolescents in Zimbabwe: a randomised controlled trial. Lancet HIV. 2018;5(2):e79–86.PubMedCrossRef
39.
Solomon SS, Srikrishnan AK, Vasudevan CK, Anand S, Kumar MS, Balakrishnan P, Mehta SH, Solomon S, Lucas GM. Voucher incentives improve linkage to and retention in care among HIV-infected drug users in Chennai, India. Clin Infect Dis. 2014;59(4):589–95.PubMedPubMedCentralCrossRef
40.
El-Sadr WM, Donnell D, Beauchamp G, Hall HI, Torian LV, Zingman B, Lum G, Kharfen M, Elion R, Leider J, Gordin FM, Elharrar V, Burns D, Zerbe A, Gamble T, Branson B, HPTN 065 Study Team. Financial incentives for linkage to care and viral suppression among hiv-positive patients: a randomized clinical trial (HPTN 065). JAMA Intern Med. 2017;177(8):1083–92.PubMedPubMedCentralCrossRef
41.
Maughan-Brown B, Smith P, Kuo C, Harrison A, Lurie MN, Bekker LG, Galárraga O. A conditional economic incentive fails to improve linkage to care and antiretroviral therapy initiation among HIV-positive adults in Cape Town, South Africa. AIDS Patient Care STDS. 2018;32(2):70–8.PubMedPubMedCentralCrossRef
42.
Choko AT, Desmond N, Webb EL, Chavula K, Napierala-Mavedzenge S, Gaydos CA, Makombe SD, Chunda T, Squire SB, French N, Mwapasa V, Corbett EL. The uptake and accuracy of oral kits for HIV self-testing in high HIV prevalence setting: a cross-sectional feasibility study in Blantyre, Malawi. PLoS Med. 2011;8(10):e1001102.PubMedPubMedCentralCrossRef
43.
Choko AT, MacPherson P, Webb EL, Willey BA, Feasy H, Sambakunsi R, Mdolo A, Makombe SD, Desmond N, Hayes R, Maheswaran H, Corbett EL. Uptake, accuracy, safety, and linkage into care over two years of promoting annual self-testing for HIV in Blantyre, Malawi: a community-based prospective study. PLoS Med. 2015;12(9):e1001873.PubMedPubMedCentralCrossRef
44.
Hayes JR, Moulton LH. Cluster randomised trials. Boca Raton, USA: Chapman and Hall/CRC; 2009.
45.
Shamu S, Abrahams N, Temmerman M, Musekiwa A, Zarowsky C. A systematic review of African studies on intimate partner violence against pregnant women: prevalence and risk factors. PLoS One. 2011;6(3):e17591.PubMedPubMedCentralCrossRef
46.
Nyondo AL, Choko AT, Chimwaza AF, Muula AS. Invitation cards during pregnancy enhance male partner involvement in prevention of mother to child transmission (PMTCT) of human immunodeficiency virus (HIV) in Blantyre, Malawi: a randomized controlled open label trial. PLoS One. 2015;10(3):e0119273.PubMedPubMedCentralCrossRef
47.
48.
Tindana PO, Kass N, Akweongo P. The informed consent process in a rural African setting: a case study of the Kassena-Nankana district of northern Ghana. IRB. 2006;28:1–6.PubMedCentral
49.
Molyneux CS, Wassenaar DR, Peshu N, Marsh K. 'Even if they ask you to stand by a tree all day, you will have to do it (laughter)…!': community voices on the notion and practice of informed consent for biomedical research in developing countries. Soc Sci Med. 2005;61(2):443–54.PubMedCrossRef
50.
51.
London AJ. The ambiguity and the exigency: clarifying 'standard of care' arguments in international research. J Med Philos. 2000;25(4):379–97.PubMedCrossRef
52.
Dal-Ré R, Ndebele P, Higgs E, Sewankambo N, Wendler D. Protections for clinical trials in low and middle income countries need strengthening not weakening. BMJ. 2014;349:g4254.PubMedPubMedCentralCrossRef
53.
Millum J, Grady C, Keusch G, Sina B. Introduction: the Fogarty International Research Ethics Education and Curriculum Development Program in historical context. J Empir Res Hum Res Ethics. 2013;8(5):3–16.PubMedPubMedCentralCrossRef
Metadata
Title
Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies
Authors
Augustine T. Choko
Gholamreza Roshandel
Donaldson F. Conserve
Elizabeth L. Corbett
Katherine Fielding
Karla Hemming
Reza Malekzadeh
Charles Weijer
Publication date
01-04-2020
Publisher
BioMed Central
Published in
Trials / Issue Special Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-020-04269-3