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” .
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  and the International Ethical Guidelines for Health-related Research Involving Humans of the Council for International Organizations of Medical Sciences (CIOMS) . 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” . 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  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”  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 . 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 . 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” .
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 , 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 . 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 .”
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.
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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.
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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.