Integrating public health programs and research and the CIOMS guidelines
Integrating public health programs and research and the CIOMS guidelines
Rieke van der Graaf, Ruth Macklin, Annette Rid, Anant Bhan, Eugenijus Gefenas, Dirceu Greco, David Haerry, Samia Hurst, Alex John London, Rodolfo Saracci, Dominique Sprumont, Johannes JM van Delden
Recently several commentators have argued that the WHO Malaria Vaccine Implementation Program (MVIP) involves “a serious breach of international ethical standards” [1,3,4]. WHO representatives have responded that they consider the MVIP a routine public health implementation program and “strongly disagree” with the claim that the MVIP “is at odds with international ethical standards” [5].
Charles Weijer has argued [1,3,4] that the MVIP violates both The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials [6] and the International Ethical Guidelines for Health-related Research Involving Humans of the Council for International Organizations of Medical Sciences (CIOMS) [7]. The CIOMS guidelines were produced in close collaboration with WHO and WHO states that its Research Ethics Review Committee (ERC) is “guided in its work by the CIOMS guidelines” [8]. In what follows, we respond from the perspective of the CIOMS guidelines [8,9].
Whether or not MVIP as an intervention is regarded as “good practice” and non-experimental [5] is irrelevant to the question of whether a particular activity within that program constitutes research. If the activity is “designed to … develop or contribute to generalizable knowledge” [10] and to reduce uncertainty about the given intervention, it counts as research. The use of cluster randomization to assess the endpoint of safety and registration of the program on clinicaltrials.gov clearly establishes that the MVIP was designed, at least in part, to generate valuable information rather than solely to advance the goals of public health [1]. The MVIP program therefore must also be seen as research.
The protocol is not publicly available, but based on the currently available information we agree with the concerns about the informed consent and ethical review process [1,4]. In addition, we emphasize that to justify a waiver of informed consent, the intervention must be regarded as minimal risk (guideline 10). Yet the outstanding concerns about higher risks of meningitis, risks of cerebral malaria and doubled female mortality [11-14] suggest the risks of receiving the vaccine were greater than minimal at the start of the MVIP. Another concern is whether the MVIP meets the social value requirement (guideline 1). High-quality research to reduce lingering uncertainties certainly has social value since malaria poses a major burden of disease globally. However, compared to a conventional randomized controlled trial a cluster randomized trial involves more people and creates weaker evidence, which is not preferable in a situation of serious doubts about safety [15]. In addition, the MVIP is designed in ways that make it, for example, possible to “overlook if the RTS,S[/A01] vaccine truly increases female mortality” [16].
When research and public health interventions are combined because important uncertainties about the safety and efficacy of products remain, it seems prudent to apply ethical norms for research involving humans, such as the CIOMS guidelines [7], rather than the generally less demanding norms that currently govern routine care programs. This is especially important in the context of implementation programs that pilot vaccines, given well-known concerns about vaccine hesitancy [17]. An illustrative past example is a pilot vaccination implementation/post licensure demonstration project in India, which was ethically controversial and led to the derailment of national roll-out plans for the HPV vaccine [18].”
We recommend treating the MVIP as research. The full protocol should be assessed by the relevant ethics committees, new and already enrolled parents should be informed about the uncertainties under investigation and given a real opportunity to consent or refuse (continued) participation, communities should be engaged, and aspects of MVIP that require alteration in light of ethical review should be altered, if possible.
References
1. Doshi P. WHO’s malaria vaccine study represents a “serious breach of international ethical standards” BMJ 2020;368:m734 https://doi.org/10.1136/bmj.m734 (Published 26 February 2020)
2. WHO. Q&A on the malaria vaccine implementation programme (MVIP). https://www.who.int/malaria/media/malaria-vaccine-implementation-qa/en/ (March 2020).
3. Dohsi P. Rapid response to WHO’s malaria vaccine study represents a “serious breach of international ethical standards”. BMJ 2020;368:m734 https://www.bmj.com/content/368/bmj.m734/rr-4 .
4. Weijer C. The WHO Malaria Vaccine Trial: a bioethicist responds. 05 March 2020 https://www.bmj.com/content/368/bmj.m734/rr-5
5. Swaminathan S, O’Brien K, Alonso P. The WHO Malaria Vaccine Implementation Program: clarifying misconceptions. March 2, 2020. https://www.bmj.com/content/368/bmj.m734/rr-1.
6. Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, et al. (2012) The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLoS Med 9(11): e1001346. https://doi.org/10.1371/journal.pmed.1001346.
7. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Health-related Research Involving Humans. Geneva, CIOMS 2016.
8. World Health Organization. Global health ethics. Research Ethics Review committee. Available from: https://www.who.int/ethics/review-committee/en/.
9. Rieke van der Graaf, Ruth Macklin, Annette Rid, Anant Bhan, Eugenijus Gefenas, Dirceu Greco, David Haerry, Samia Hurst, Alex John London, Rodolfo Saracci, Dominique Sprumont, Johannes JM van Delden. Integrating public health programs and research after the Malaria Vaccine Implementation Program (MVIP): recommendations for next steps, in press.
10. Office of the Secretary Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report, 1979. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-...
11. Aaby P, et al. WHO’s rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months? BMJ 2020;368:l6920 https://www.bmj.com/content/368/bmj.l6920.long
12. World Health Organization. Malaria vaccine: WHO position paper, January 2016-recommendations. Vaccine 2018;36:3576-7.
13. Strategic Advisory Group of Experts. Highlights from the Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization 2-4 April 2019. Available from: https://www.who.int/immunization/sage/meetings/2019/april/SAGE_April_201...
14. European Medicines Agency. Mosquirix Procedural steps taken and scientific information after the authorization 2017. https://www.ema.europa.eu/en/documents/medicine-outside-eu/mosquirix-pro....
15. Halloran ME, Longini IM, Struchiner CJ. Design and Analysis of Vaccine Studies: Introduction. Springer; 2009. https://doi.org/10.1007/978-0-387-68636-3.
16. Benn CS. The WHO Malaria Vaccine Implementation Program: the lack of informed consent is not the only ethical challenge 10 March 2020, https://www.bmj.com/content/368/bmj.m734/rapid-responses
17. Larson HJ, Jarrett C, Eckersberger E, Smith DM, Paterson P. Understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007-2012. Vaccine. 2014 Apr 17;32(19):2150-9.
18. Ganapati Mudur. Human papillomavirus vaccine project stirs controversy in India BMJ 2010;340:c1775.
Competing interests:
The views expressed in this paper are those of the authors and do not necessarily reflect the opinion or policies of CIOMS, the National Institutes of Health or the U.S. Department of Health and Human Services or any other institute they might be affiliated with.
Funding: This work was supported in part by the Clinical Center Department of Bioethics, which is in the Intramural Program of the National Institutes of Health.
RG is a member of the independent Bioethics Advisory Committee to Sanofi.
25 March 2020
Rieke Van der Graaf
Associate professor
Ruth Macklin, Distinguished University Professor Emerita, Albert Einstein College of Medicine, Bronx, NY, USA; Annette Rid, Department of Bioethics, The Clinical Center, U.S. National Institutes of Health, USA; Anant Bhan, Yenepoya (deemed to be University), India; Eugenijus Gefenas, Centre for Health Ethics, Law and History, Institute of Health Sciences, Medical Faculty of Vilnius University; Dirceu Greco, Professor Emeritus, Infectious Diseases and Bioethics, Federal University of Minas Gerais, Brazil; David Haerry, European AIDS Treatment Group, Brussels, Member of the Working Group that authored the 2016 CIOMS International Ethical Guidelines for Health-related Research Involving Humans; Samia Hurst, Institute for Ethics, History, and the Humanities, Faculty of Medicine, University of Geneva, Switzerland; Alex John London, Carnegie Mellon University, Center for Ethics and Policy, Pittsburgh, PA, USA; Rodolfo Saracci, Former President, International Epidemiological Association, Lyon, France; Dominique Sprumont, Deputy Director, Institute of Health Law, University of Neuchâtel, Switzerland, Chairman, Research Ethics Committee of the Canton of Vaud, Lausanne, Switzerland; Johannes JM van Delden University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Netherlands. RG was the scientific secretary of the Working Group that authored the 2016 CIOMS International Ethical Guidelines for Health-related Research Involving Humans; RM,AR,AB,EG,DG,DH,AJL and RS were members, JD was chair of this WG; he was also Former President of CIOMS and is currently a member of the CIOMS Executive Committee. SH and DS are also members of the CIOMS Executive Committee
University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care
Rapid Response:
Integrating public health programs and research and the CIOMS guidelines
Integrating public health programs and research and the CIOMS guidelines
Rieke van der Graaf, Ruth Macklin, Annette Rid, Anant Bhan, Eugenijus Gefenas, Dirceu Greco, David Haerry, Samia Hurst, Alex John London, Rodolfo Saracci, Dominique Sprumont, Johannes JM van Delden
Recently several commentators have argued that the WHO Malaria Vaccine Implementation Program (MVIP) involves “a serious breach of international ethical standards” [1,3,4]. WHO representatives have responded that they consider the MVIP a routine public health implementation program and “strongly disagree” with the claim that the MVIP “is at odds with international ethical standards” [5].
Charles Weijer has argued [1,3,4] that the MVIP violates both The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials [6] and the International Ethical Guidelines for Health-related Research Involving Humans of the Council for International Organizations of Medical Sciences (CIOMS) [7]. The CIOMS guidelines were produced in close collaboration with WHO and WHO states that its Research Ethics Review Committee (ERC) is “guided in its work by the CIOMS guidelines” [8]. In what follows, we respond from the perspective of the CIOMS guidelines [8,9].
Whether or not MVIP as an intervention is regarded as “good practice” and non-experimental [5] is irrelevant to the question of whether a particular activity within that program constitutes research. If the activity is “designed to … develop or contribute to generalizable knowledge” [10] and to reduce uncertainty about the given intervention, it counts as research. The use of cluster randomization to assess the endpoint of safety and registration of the program on clinicaltrials.gov clearly establishes that the MVIP was designed, at least in part, to generate valuable information rather than solely to advance the goals of public health [1]. The MVIP program therefore must also be seen as research.
The protocol is not publicly available, but based on the currently available information we agree with the concerns about the informed consent and ethical review process [1,4]. In addition, we emphasize that to justify a waiver of informed consent, the intervention must be regarded as minimal risk (guideline 10). Yet the outstanding concerns about higher risks of meningitis, risks of cerebral malaria and doubled female mortality [11-14] suggest the risks of receiving the vaccine were greater than minimal at the start of the MVIP. Another concern is whether the MVIP meets the social value requirement (guideline 1). High-quality research to reduce lingering uncertainties certainly has social value since malaria poses a major burden of disease globally. However, compared to a conventional randomized controlled trial a cluster randomized trial involves more people and creates weaker evidence, which is not preferable in a situation of serious doubts about safety [15]. In addition, the MVIP is designed in ways that make it, for example, possible to “overlook if the RTS,S[/A01] vaccine truly increases female mortality” [16].
When research and public health interventions are combined because important uncertainties about the safety and efficacy of products remain, it seems prudent to apply ethical norms for research involving humans, such as the CIOMS guidelines [7], rather than the generally less demanding norms that currently govern routine care programs. This is especially important in the context of implementation programs that pilot vaccines, given well-known concerns about vaccine hesitancy [17]. An illustrative past example is a pilot vaccination implementation/post licensure demonstration project in India, which was ethically controversial and led to the derailment of national roll-out plans for the HPV vaccine [18].”
We recommend treating the MVIP as research. The full protocol should be assessed by the relevant ethics committees, new and already enrolled parents should be informed about the uncertainties under investigation and given a real opportunity to consent or refuse (continued) participation, communities should be engaged, and aspects of MVIP that require alteration in light of ethical review should be altered, if possible.
References
1. Doshi P. WHO’s malaria vaccine study represents a “serious breach of international ethical standards” BMJ 2020;368:m734 https://doi.org/10.1136/bmj.m734 (Published 26 February 2020)
2. WHO. Q&A on the malaria vaccine implementation programme (MVIP). https://www.who.int/malaria/media/malaria-vaccine-implementation-qa/en/ (March 2020).
3. Dohsi P. Rapid response to WHO’s malaria vaccine study represents a “serious breach of international ethical standards”. BMJ 2020;368:m734 https://www.bmj.com/content/368/bmj.m734/rr-4 .
4. Weijer C. The WHO Malaria Vaccine Trial: a bioethicist responds. 05 March 2020 https://www.bmj.com/content/368/bmj.m734/rr-5
5. Swaminathan S, O’Brien K, Alonso P. The WHO Malaria Vaccine Implementation Program: clarifying misconceptions. March 2, 2020. https://www.bmj.com/content/368/bmj.m734/rr-1.
6. Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, et al. (2012) The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLoS Med 9(11): e1001346. https://doi.org/10.1371/journal.pmed.1001346.
7. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Health-related Research Involving Humans. Geneva, CIOMS 2016.
8. World Health Organization. Global health ethics. Research Ethics Review committee. Available from: https://www.who.int/ethics/review-committee/en/.
9. Rieke van der Graaf, Ruth Macklin, Annette Rid, Anant Bhan, Eugenijus Gefenas, Dirceu Greco, David Haerry, Samia Hurst, Alex John London, Rodolfo Saracci, Dominique Sprumont, Johannes JM van Delden. Integrating public health programs and research after the Malaria Vaccine Implementation Program (MVIP): recommendations for next steps, in press.
10. Office of the Secretary Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report, 1979. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-...
11. Aaby P, et al. WHO’s rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months? BMJ 2020;368:l6920 https://www.bmj.com/content/368/bmj.l6920.long
12. World Health Organization. Malaria vaccine: WHO position paper, January 2016-recommendations. Vaccine 2018;36:3576-7.
13. Strategic Advisory Group of Experts. Highlights from the Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization 2-4 April 2019. Available from: https://www.who.int/immunization/sage/meetings/2019/april/SAGE_April_201...
14. European Medicines Agency. Mosquirix Procedural steps taken and scientific information after the authorization 2017. https://www.ema.europa.eu/en/documents/medicine-outside-eu/mosquirix-pro....
15. Halloran ME, Longini IM, Struchiner CJ. Design and Analysis of Vaccine Studies: Introduction. Springer; 2009. https://doi.org/10.1007/978-0-387-68636-3.
16. Benn CS. The WHO Malaria Vaccine Implementation Program: the lack of informed consent is not the only ethical challenge 10 March 2020, https://www.bmj.com/content/368/bmj.m734/rapid-responses
17. Larson HJ, Jarrett C, Eckersberger E, Smith DM, Paterson P. Understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature, 2007-2012. Vaccine. 2014 Apr 17;32(19):2150-9.
18. Ganapati Mudur. Human papillomavirus vaccine project stirs controversy in India BMJ 2010;340:c1775.
Competing interests: The views expressed in this paper are those of the authors and do not necessarily reflect the opinion or policies of CIOMS, the National Institutes of Health or the U.S. Department of Health and Human Services or any other institute they might be affiliated with. Funding: This work was supported in part by the Clinical Center Department of Bioethics, which is in the Intramural Program of the National Institutes of Health. RG is a member of the independent Bioethics Advisory Committee to Sanofi.