The WHO Malaria Vaccine Trial: a bioethicist responds
Dear Editor,
In its response [1] to Peter Doshi’s article on the malaria vaccine trial,[2] the WHO does not challenge the facts presented. They do, however, dispute the ethical conclusions drawn from these facts, asserting the malaria vaccine trial was “conducted in accordance with established and recognized national and international ethical standards.”[1] In the following, I examine the WHO’s claims about the ethical ramifications of the study.
The WHO consistently denies that the malaria vaccine trial as a whole is research, describing it instead as a “systematic evaluation of programmatic implementation” that is “good practice—not medical or scientific experimentation.”[1] Data collection is described as “independent of the vaccine implementation by the EPI programme.”[1] In fact, from the start the WHO designed this study as cluster randomized trial to address the effectiveness, safety and feasibility of the novel malaria vaccine. In their March 2017 presentation to the WHO’s Malaria Policy Advisory Committee, David Schellenberg and Mary Hamel described the study as using a “cluster randomized design.”[5] The use of a cluster randomized design indicates that it was always intended to be research. Further, since the malaria vaccine program and data collection are constituents of a randomized trial, they both constitute research and are subject to international ethical guidelines.
This puts the WHO’s claims about the use of randomization in a new light. Citing a scarcity of vaccine supply, the WHO contends that the rollout of malaria vaccine to districts in Ghana, Kenya and Malawi was randomized as a “fair way to allocate limited vaccine doses.”[1] In his response, Peter Doshi finds the claim “at odds with every other WHO document I have reviewed.”[3] He notes that the WHO’s website reports “GSK is donating up to 10 million doses of RTS,S [malaria vaccine] for use in the pilot programme”[4]—more than enough for the 360,000 children enrolled in the malaria vaccine trial annually. If vaccine supplies are indeed scarce and randomization was not for research purposes, why didn’t the WHO choose one of the more obvious paths of either vaccinating all children in one country, so that no child is denied access to a government program, or providing vaccine to districts across several countries with the highest rates of malaria in children? Indeed, it is plain that districts were randomized to receive the malaria vaccine program or not because the WHO and its host country partners were conducting research.
International ethical guidance specific to cluster randomized trials is found in the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials[6] and the CIOMS/WHO International Ethical Guidelines for Health-related Research Involving Humans (especially guideline 21).[7] The WHO malaria vaccine trial violates ethical requirements in both international ethics guidance documents.
The Ottawa Statement says that “[r]esearchers must submit a CRT [cluster randomized trial] involving human research participants for approval by a REC [research ethics committee] before commencing.”[6] “This includes CRTs conducted outside health care settings, such as…public health research.”[6] The CIOMS/WHO guidelines add that in “externally sponsored research, ethical review must take place in both the host and the sponsoring institution.”[7] In its response, the WHO makes clear that only “observational studies to evaluate the routine use of the vaccine” were submitted for research ethics committee review.[1] Randomized implementation of the malaria vaccine was approved by the Ministries of Health of Ghana, Kenya, and Malawi and not the research ethics committees.[1] Thus, host country research ethics committees were not given the opportunity to review questions of equipoise or consent for vaccination for the WHO malaria vaccine trial.
Why would the WHO not submit the full cluster randomized trial for research ethics committee review? It appears that the WHO is labouring under the misapprehension that government programs do not require research ethics committee review even when these are part of a cluster randomized trial. After all, governments have a democratic mandate to provide routine public health programs to citizens. But in randomizing districts to receive malaria vaccine or not, the government was not implementing the vaccine routinely; it was conducting research. As we explain elsewhere, the “government is collaborating with researchers to randomly allocate provinces [or] communities…to intervention or control…so the program may be evaluated.”[8] “Even if the government is the author of the program, researchers are the authors of the study design. And it is the design that triggers equipoise [and consent] issues…that must be assessed by the research ethics committee.”[8]
Further, both the Ottawa Statement and the CIOMS/WHO International Ethical Guidelines require consent for drug or vaccine interventions in cluster randomized trials.[6,7] Indeed, the CIOMS/WHO guidelines consider a hypothetical cluster trial of a school-based vaccination program and analyze the role of parental consent. They say, “parents will not be able to consent to their children’s school being randomized to a vaccination program or to being allocated to that cluster, but they could consent or refuse to consent to their child’s vaccination at school.”[7] This same reasoning applies to the WHO malaria vaccine trial. Parents cannot meaningfully consent to health districts being randomized to the vaccine program, but they can—indeed they must—consent to their child receiving the malaria vaccine.
In their response, the WHO tells us that “parents receive information about the vaccine from the ministry of health and can decide to present for, or to opt-out of, any or all vaccinations.” But there is no requirement that parents attend a community information session. Crucially, no parent is informed that their child is to be a research participant in a cluster randomized trial. Thus, the response from the WHO only provides further confirmation that the malaria vaccine trial represents a serious breach of international ethical standards.
References
[1] 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
[2] 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)
[6] Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, Taljaard M and the Ottawa Ethics of Cluster Randomized Trials Consensus Group. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLoS Medicine 2012; 9(11): e1001346.
[7] Council for International Organizations for Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). International Ethical Guidelines for Health-related Research Involving Humans. Geneva: CIOMS, 2016.
Rapid Response:
The WHO Malaria Vaccine Trial: a bioethicist responds
Dear Editor,
In its response [1] to Peter Doshi’s article on the malaria vaccine trial,[2] the WHO does not challenge the facts presented. They do, however, dispute the ethical conclusions drawn from these facts, asserting the malaria vaccine trial was “conducted in accordance with established and recognized national and international ethical standards.”[1] In the following, I examine the WHO’s claims about the ethical ramifications of the study.
The WHO consistently denies that the malaria vaccine trial as a whole is research, describing it instead as a “systematic evaluation of programmatic implementation” that is “good practice—not medical or scientific experimentation.”[1] Data collection is described as “independent of the vaccine implementation by the EPI programme.”[1] In fact, from the start the WHO designed this study as cluster randomized trial to address the effectiveness, safety and feasibility of the novel malaria vaccine. In their March 2017 presentation to the WHO’s Malaria Policy Advisory Committee, David Schellenberg and Mary Hamel described the study as using a “cluster randomized design.”[5] The use of a cluster randomized design indicates that it was always intended to be research. Further, since the malaria vaccine program and data collection are constituents of a randomized trial, they both constitute research and are subject to international ethical guidelines.
This puts the WHO’s claims about the use of randomization in a new light. Citing a scarcity of vaccine supply, the WHO contends that the rollout of malaria vaccine to districts in Ghana, Kenya and Malawi was randomized as a “fair way to allocate limited vaccine doses.”[1] In his response, Peter Doshi finds the claim “at odds with every other WHO document I have reviewed.”[3] He notes that the WHO’s website reports “GSK is donating up to 10 million doses of RTS,S [malaria vaccine] for use in the pilot programme”[4]—more than enough for the 360,000 children enrolled in the malaria vaccine trial annually. If vaccine supplies are indeed scarce and randomization was not for research purposes, why didn’t the WHO choose one of the more obvious paths of either vaccinating all children in one country, so that no child is denied access to a government program, or providing vaccine to districts across several countries with the highest rates of malaria in children? Indeed, it is plain that districts were randomized to receive the malaria vaccine program or not because the WHO and its host country partners were conducting research.
International ethical guidance specific to cluster randomized trials is found in the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials[6] and the CIOMS/WHO International Ethical Guidelines for Health-related Research Involving Humans (especially guideline 21).[7] The WHO malaria vaccine trial violates ethical requirements in both international ethics guidance documents.
The Ottawa Statement says that “[r]esearchers must submit a CRT [cluster randomized trial] involving human research participants for approval by a REC [research ethics committee] before commencing.”[6] “This includes CRTs conducted outside health care settings, such as…public health research.”[6] The CIOMS/WHO guidelines add that in “externally sponsored research, ethical review must take place in both the host and the sponsoring institution.”[7] In its response, the WHO makes clear that only “observational studies to evaluate the routine use of the vaccine” were submitted for research ethics committee review.[1] Randomized implementation of the malaria vaccine was approved by the Ministries of Health of Ghana, Kenya, and Malawi and not the research ethics committees.[1] Thus, host country research ethics committees were not given the opportunity to review questions of equipoise or consent for vaccination for the WHO malaria vaccine trial.
Why would the WHO not submit the full cluster randomized trial for research ethics committee review? It appears that the WHO is labouring under the misapprehension that government programs do not require research ethics committee review even when these are part of a cluster randomized trial. After all, governments have a democratic mandate to provide routine public health programs to citizens. But in randomizing districts to receive malaria vaccine or not, the government was not implementing the vaccine routinely; it was conducting research. As we explain elsewhere, the “government is collaborating with researchers to randomly allocate provinces [or] communities…to intervention or control…so the program may be evaluated.”[8] “Even if the government is the author of the program, researchers are the authors of the study design. And it is the design that triggers equipoise [and consent] issues…that must be assessed by the research ethics committee.”[8]
Further, both the Ottawa Statement and the CIOMS/WHO International Ethical Guidelines require consent for drug or vaccine interventions in cluster randomized trials.[6,7] Indeed, the CIOMS/WHO guidelines consider a hypothetical cluster trial of a school-based vaccination program and analyze the role of parental consent. They say, “parents will not be able to consent to their children’s school being randomized to a vaccination program or to being allocated to that cluster, but they could consent or refuse to consent to their child’s vaccination at school.”[7] This same reasoning applies to the WHO malaria vaccine trial. Parents cannot meaningfully consent to health districts being randomized to the vaccine program, but they can—indeed they must—consent to their child receiving the malaria vaccine.
In their response, the WHO tells us that “parents receive information about the vaccine from the ministry of health and can decide to present for, or to opt-out of, any or all vaccinations.” But there is no requirement that parents attend a community information session. Crucially, no parent is informed that their child is to be a research participant in a cluster randomized trial. Thus, the response from the WHO only provides further confirmation that the malaria vaccine trial represents a serious breach of international ethical standards.
References
[1] 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
[2] 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)
[3] Doshi P. Response from the author. March 4, 2020. https://www.bmj.com/content/368/bmj.m734/rr-4
[4] WHO. Q&A on the malaria vaccine implementation programme (MVIP). https://www.who.int/malaria/media/malaria-vaccine-implementation-qa/en/ (March 2020)
[5] Shellenberg D, Hamel M. Update to the Malaria Policy Advisory Committee.
March 22, 2017. https://www.who.int/malaria/mpac/mpac-mar2017-rtss-update-session2-prese...
[6] Weijer C, Grimshaw JM, Eccles MP, McRae AD, White A, Brehaut JC, Taljaard M and the Ottawa Ethics of Cluster Randomized Trials Consensus Group. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLoS Medicine 2012; 9(11): e1001346.
[7] Council for International Organizations for Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). International Ethical Guidelines for Health-related Research Involving Humans. Geneva: CIOMS, 2016.
[8] Weijer C, Taljaard M. Unnatural experiments. Journal of Medical Ethics Blog. November 28, 2019. https://blogs.bmj.com/medical-ethics/2019/11/28/unnatural-experiments/
Competing interests: I was quoted in the article that the WHO is criticizing. I receive consulting income from Eli Lilly & Company.