By Beatrice Brown
A recent BMJ article has exposed ethical concerns with the informed consent process in the World Health Organization’s (WHO) large, randomized cluster trial of the world’s first licensed malaria vaccine, RTS,S, known as Mosquirix. The study is being conducted in Malawi, Ghana, and Kenya, and 720,000 children will receive the vaccine. The vaccine is currently limited to pilot implementation because of residual safety concerns from previous clinical trials, including: a tenfold rate of meningitis in those who received the vaccine versus those who did not, “increased cerebral malaria cases, and a doubling in the risk of death in girls.” Rather than engaging in the traditional informed consent process, the WHO is utilizing an implied consent process, leading several bioethicists, including Charles Weijer, Christine Stabell Benn, and Jonathan Kimmelman, to voice concern.
The WHO has defended their use of implied consent to BMJ on the grounds that “the study is a ‘pilot introduction’ and not a ‘research activity.'” A WHO spokesperson explained that in an implied consent process, “parents are informed of imminent vaccination through social mobilisation and communication, sometimes including letters directly addressed to parents. Subsequently, the physical presence of the child or adolescent, with or without an accompanying parent at the vaccination session, is considered to imply consent.” However, as Weijer rightly points out, this is not truly consent, as “We have no assurance that parents, in fact, received information about the study let alone that they understood it.” After the publication of the original article criticizing the WHO for going against international ethical standards for research involving human participants, the WHO released a response in BMJ and on their own website, contending that this implied consent process is “used for all vaccines provided through the Expanded Programme on Immunization” and that the study is in accordance with international ethical standards. Here, I further explore whether this implied consent process is ethically permissible in this specific trial by exploring the guidelines set out by two organizations.
The WHO’s Research Ethics Review Committee (ERC) follows the guidelines for research involving human participants set out by the Council for International Organizations of Medical Sciences (CIOMS). According to CIOMS’s International Ethical Guidelines for Biomedical Research Involving Human Subjects, “researchers must obtain informed consent from participants in a cluster randomized study unless a waiver or modification of consent is granted by a research ethics committee.” Three conditions must be met for this waiver to be granted: 1) “the research would not be feasible or practicable to carry out without the waiver or modification”; 2) “the research has important social value”; and 3) “the research poses no more than minimal risks to participants.” In the RTS,S study, it is clear that criterion (3) has not been met – the increased meningitis rate, increased incidences of cerebral malaria, and doubled female mortality rate are certainly greater than minimal risk. It is also unclear if criterion (1) has been met because although there may be a decrease in the number of the participants if the traditional informed consent process is utilized, it is difficult to ascertain whether the decrease in participation rate would undermine the feasibility or practicability of the study. Given that it is certain that criterion (3) is not met and unclear if criterion (2) is met, the study does not meet all three conditions required for an informed consent waiver, even though the research has important social value as set out by criterion (1) (the WHO reports an estimated 228 million malaria episodes and more than 400,000 premature deaths as a result of malaria per year). The WHO thus appears to violate CIOMS’s ethical guidelines by using an implied consent process rather than the traditional informed consent process.
Beyond CIOMS’s ethical guidelines for informed consent waivers, there is an additional consideration: the participants here are children, who cannot consent for themselves and instead rely on their proxies (parents or guardians) to consent on their behalf. As a result, CIOMS requires special considerations for children. According to CIOMS, “For research interventions or procedures that have the potential to benefit children or adolescents, the risks must be minimized and outweighed by the prospect of potential individual benefit.” For one, risks do not seem to be minimized here, but perhaps this guideline is not stringent enough to adequately protect children participants. According to the Common Rule (the regulatory statute for research involving human participants in the United States), research that involves greater than minimal risk but presents the prospect of direct benefit to the children involved, like the study considered here, is only considered to be ethical if: 1) “The risk is justified by the anticipated benefit to the subjects”; 2) “The relation of the anticipated benefit to the risk is at least as favorable to the subject as that presented by available alternative approaches”; and 3) “Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.” In the context of this study, it is unclear if the benefits justify the risks incurred by these children, nor were adequate provisions made for receiving consent from their guardians since implied consent was relied upon after materials were distributed. The Common Rule standards highlight the necessity of receiving adequate informed consent when children are involved, and merely distributing information to these parents, without the assurance that they have actually read and understand it, does not provide adequate protections for the well-being and lives of these children.
Despite the inherent social value of this pilot implementation study by the WHO, this social value should not be used to undermine appropriate ethical standards for research, particularly when children are the participants and there have been demonstrated, serious risks in prior clinical trials. Adequate informed consent must be taken seriously to both protect participants who are vulnerable and to uphold the integrity of the research enterprise – we cannot default to implied consent merely because it is more convenient. Not only does this study risk undermine “public trust in vaccines and health authorities,” as noted by Christine Stabell Benn, but it risks undermining the public’s trust in an organization as critical as the WHO and in the research enterprise more generally.