Informed consent represents a fundamental ethical principal underlying valid clinical research. Any material risks should be part of any disclosure, for example, to parents involving children participants. Public policy from time to time can merit the use of “Emergency Exceptions” in times of crisis or emergency and implied consent when there no surrogate decision is available and the conditions merit action—e.g. In health crisis’ where the costs in terms of life of not undertaking a measure, such as a childhood vaccine, outweigh the perceived benefit of informed consent in such a situation. According to a provocative proclamation in Foreign Policy Journal the World Health Organization (WHO), GlaxoSmithKline (GSK) and supportive governments, with the noble goal of eradicating malaria, are making controversial compromises that could expose children in sub-Saharan Africa to greater risk than necessary. On the other hand, over 400,000 die from malaria each year and over 90% of these cases will be in Africa.
In the most recent Foreign Policy Journal, Jeremy R. Hammond recently published a critical view on a clinical trial supported by WHO and sponsored by GSK. The primary allegation: that the organizations are failing to secure informed consent from the parents of child participants (rather the use of implied consent is employed controversially) and that there appears to be a rush on the part of WHO to plan a mass roll out of the vaccine 24 months after a study—seemingly indifferent to evidence that there are material safety risks that merit longer study. According to data from previous studies, the GSK manufactured vaccine produces greater risk of clinical malaria after four years from point of vaccination, ten-times risk of meningitis and greater risk of cerebral malaria not to mention overall greater risk of death disproportionally higher for female children. On the other hand, WHO could point out that if nothing is done soon death tolls will only climb.
The Reality depends on the Point of View
The author alleges that not only are the sponsors and investigators of this trial not only exhibiting complete disregard securing parental informed consent, but that WHO will decide, based on this specific trial, whether it should recommend that use of the vaccine throughout the greatly impoverished sub-Saharan Africa just 24 months post study. Would that be enough time to assess the vaccine’s efficacy and safety given known risks? And what about childhood mortality? Could financial ties or dependencies to drug development ecosystem be the core underlying driver for what could be not the best deal for a great number of peoples in sub-Saharan Africa? The author of the Foreign Policy Journal article seems to think so. TrialSite News suspects that this true answer lies somewhere differently—namely the pragmatism associated with risk/benefit analyses and few true alternatives. And in a market-based society, there are always financial considerations. After all, developing drugs costs billions of dollars and firms must ensure they are viable so that they can subsidize important public health initiatives.
The dug is known as RTS,S/AS01E (Mosquirix) and first went through a major clinical trial in 2013. Published in the New England Journal of Medicine, the study, sponsored by the KEMRI-Wellcome Trust Collaborative Research Program and GSK and conducted in Kenya, revealed that the efficacy of the vaccine over the 4-year period was 16.8% and that it actually waned over time with increased malaria exposure per the Foreign Policy Journal article. WHO put forth a policy paper on the malaria vaccine in 2015 showcasing the benefits for a large and endangered population in sub-Saharan African population. WHO introduced risks in form of adverse events and assessed the overall safety in the context of risk/benefit framework as the estimated number of cases averted. The bottom line from the WHO perspective, the trial evidence that in all age groups involved there was “moderate but potentially important protection against clinical malaria that declined to a lower level of by 18 months after the third dose.” However, with a fourth dose, protection was partially restored with a fourth dose administered 1.5 year after the third dose but thereafter WHO acknowledges a “rapid decline in efficacy.” Overall, WHO is driven by pragmatic factors and forces to reduce mortality associated with malaria.
The following risk factors are identified in Hammond article:
· The vaccine’s effectiveness wanes after four years
· Clinical endpoint was malaria incidence and not mortality
· Vaccine efficacy of only 43.6% year one—falling to 0.4% by year four
· High levels of anti-sporozoite antibodies doesn’t necessarily equate to immunity
· Immunity conferred by the vaccine differs form that acquired naturally through infection
· Children receiving the vaccine had reduced exposure to later blood-stage parasites and hence risk of “delayed acquisition of natural immunity” (Possibly could explain negative efficacy by fourth year)?
· The potential sue of “implied” informed consent
These risks were also shared in a January 24, 2020 analysis published in the BMJ and authored by controversial Professor Peter Aaby of the Statens Serum Institut in Denmark as well as other Scandinavian based co-authors. This Scandinavian-based group cautions that 1) the studies of RTS,S malaria vaccine indeed identify safety concerns involving higher risks of meningitis, cerebral malaria and doubled female mortality; 2) the safety concerns now being assessed in 720.000 participating school children in Ghana, Kenya and Malawi; 3) based on the urgency associated with malaria controls, WHO will decide on vaccine extension only 24 months thereafter—using “prevention of ‘severe malaria’ as surrogate marker for overall mortality; 4) severe malaria not a good marker for either “all-cause mortality” or for that matter not for “malaria mortality”—malaria vaccine group may have higher case fatality from severe malaria; 5) a 24-month decision period may bias the study in favor of the vaccine—note that risks identified (e.g. female mortality) increased post booster dose at 20 months) and 6) recommend pilot studies use “overall mortality” as category to assess vaccine performance in combination with a lengthier follow up study period (e.g. 4-5 years) prior to mass rollout.
Author Hammond reminds the reader of the recent dengue vaccine crisis in the Philippines involving criminal indictments of government issues and a big drug company.
The Use Implied Informed Consent?
The crux of the author’s allegation of informed consent breaches stems from a 2014 WHO policy document articulating the “implied consent process” for vaccination in situations where parents would need to explicitly opt children out of a vaccination rather than explicitly opting them in. Hence, this practice enforces the automatic enrollment of school children into the vaccination program—e.g. parents offer implied consent by simply sending their children to school.
However, WHO does articulate that participating countries “are encouraged to adopt procedures that ensure that parents have been informed and agreed to the vaccination.” However, the author notes in the case of the GSK malaria vaccine the WHO advice was seemingly disregarded—that consent be obtained from parents for their children to be vaccinated. The author has considerable concerns about the general practice in the context of vaccine clinical trials. Moreover, as evidence that proper informed consent isn’t being followed, he refers to a BMJ article authored by Peter Doshi on February 26, 2020, concerning a study underway in Malawi, Ghana and Kenya intended to evaluate safety concerns of the GSK vaccine. The author refers that a WHO spokesperson mentioned to the BMJ that implied consent was sufficient for the 720,000 participating children in the study. Doshi notes, “Recipients of the malaria vaccine are not being informed that they are in a study. And the extent to which parents are being given information about the known safety concerns before vaccination is unclear.” If true, WHO positions this study as “pilot introduction” and not a “research activity” and, hence, participating children are part of a “country’s routine vaccination schedule and that consent is implied.” According to the WHO spokesperson, “An implied consent process is one in which parents are informed of imminent vaccination through social mobilization and communication, sometimes including letters directly 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.”
But a review of all studies reveal that sponsor GSK requires informed consent in all study protocols. The circumstances on the ground for the malaria vaccine safety study sound questionable when it comes to informed consent. There definitely should be a systemic and consistent communication to all parents about potential risks associated with the vaccine.
Healthy, critical debate is vital for scientific and health progress. A vigorous and judicious review of major vaccination campaigns is a matter of public health and safety and as much in the political and societal realm as that of the economy and healthcare system. The recent dengue vaccine crisis in the the Philippines evidences the importance of comprehensive and thorough planning as well as incorporating enough observations of data and risk, into major vaccine programs. In the African vaccine programs involving RTS,S/AS01E, there are undoubtedly important points that should be considered. WHO must make pragmatic decisions based on real-world constraints of time, resources, money, and drug product—all the while malaria takes its death toll in Africa. GSK well understands the importance of informed consent and includes such procedures in every study—moreover, the British drug-making giant will count on local agencies to structure, organize and enforce rational ethically-driven programs—the sponsor’s auditors will review and ensure that studies are being conducted safely, ethically and in line with laws and global standards. While there needs to be a thorough informed consent process, if implied consent is imperative, there should be systematic disclosure of risks to parents and/or family members. And at the same time, the critics’ perspectives should thoroughly understand, analyze and consider where, based on the true nature of the risks, further risk mitigation is in fact necessary.