Re: WHO’s malaria vaccine study represents a “serious breach of international ethical standards”
Dear Editor:
Excepting a response from WHO [1], the several contributing comments to Doshi's [2] criticism of the malaria vaccine (RTS,S/AS01) implementation assessment (MVIP) each [3-7] support Doshi's argument of a failure to meet ethical standards within the operational framework of that programme. Those contributors argue, principally, that the recipients of vaccine not being offered informed consent to participate in what they forcefully argue to be an experiment constituted a “serious breach” of ethics. This accusation is levelled not just at WHO, but a very large community of their research partners (representing many government, academic, and civil society organisations) that engaged with the MVIP. That included at least several highly regarded ethical oversight committees, in addition to the several regulatory agencies involved. According to Doshi and supporters [2-7], all of those players in the MVIP, collectively, seriously breached ethical standards in the conduct of that programme.
At the heart of this issue lies the process by which the vaccine was administered to participants of the MVIP and the subsequent collection of medical intelligence to be gathered and learned from it. Doshi and correspondents argue that the cluster-randomised distribution of the vaccine, taken together with deeply concerning safety signals from the earlier phase 3 clinical trial of the vaccine, represented a compelling need for informed consent by the vaccinated. Those responsible for the MVIP [1] point to a process whereby individuals were informed of the risks and benefits of vaccination and offered the opportunity to decline receiving it, calling that process “implied consent”. That terminology is arguably misleading – there is nothing implicit in parents presenting their children for vaccination; it is autonomous, dignified consent. Moreover, MVIP representatives [1] make the key point of the vaccine having been approved for practice by the regulatory agencies of the participating African nations. In other words, those authorities, by legal statute being responsible for the safety of their constituents, deemed the vaccine suitable for such offer to those constituents.
What Doshi and others take issue with is those parents not being taken through a formal process of informed consent via a protocol under responsible ethical oversight. That process offers a document describing vetted and thorough risks and benefits (along with key elements of voluntary consent) for witnessed signature affirming an informed willingness to participate. That appropriately lawyerly approach to the conduct of research involving human subjects protects us from intentional or unintentional abuse by exposure to unreasonable (extreme or unnecessary) risk of harm by medical experimentation. This is precisely the same responsibility borne by national regulatory agencies regarding the myriad devices and products applied to us in the practice of medicine. Where the responsibility of one ends and the other begins, depends as much on the intent to experiment as the product itself being experimental or registered for practice.
What constitutes relatively high risk experimentation and an obligation for direct ethical oversight is necessarily tied to that classification of a medical product. In experimenting with a product approved for practice, the high risk may not be considered to derive from indicated use of the product. By regulatory process, statute, and authority, that use does not carry intrinsically unacceptable risk. When one applies an approved product in a manner deviating from indicated use as a means of learning something about the product or the illness it relieves, we indeed incur the necessity of ethical oversight; especially if such deviation even slightly makes the medical product or state of illness a higher risk proposition. The MVIP did not do this, with or without an intent to experiment.
Doshi and correspondents point to an intent to experiment as the basis of required ethical oversight. Applied broadly and literally, as van der Graff does [7], phase 4 post-marketing surveillance undertaken by medical developers (often on the demand of responsible regulators) constitutes an experiment for which formal informed consent must be an ethical requirement. However, we routinely accept phase 4 studies of approved products without the informed consent of those on the receiving end of that practice. Those studies explicitly address uncertainty regarding the safety and efficacy of newly licensed products having relatively limited exposures in human populations. The MVIP did precisely that, but by implementing a cluster randomised distribution of vaccine. Doshi and correspondents [2-7] view that specifically as having crossed the line separating experiment from practice.
The “serious breach”, it seems, boils down to the inarguably deliberate intent to maximise the medical intelligence to be gained from MVIP rather than having placed vaccine recipients at unreasonable or unmeasured risk of harm. The experiment versus practice argument in this instance may be reasonably made, but no one should perceive what may be implicit in the “serious” verbiage used by Doshi [2], i.e., that vaccine recipients were placed at greater risk because the MVIP offered it to them in cluster-randomised fashion. The manner of distributing vaccine alone could not have done that. According to DuBois et al. [7] “serious ethical violations in medicine” include, “sexual abuse, criminal prescribing of opioids, and unnecessary surgeries, directly harm patients and undermine trust in the profession of medicine.” These exemplars attach physical meaning to what may be construed as “serious”. Even if flawed ethics occurred in the conduct of MVIP by perhaps overstepping the experiment vs. practice line, that should not be construed or misrepresented as a serious breach of ethical conduct. That terminology should be reserved for instances of real harm done lest we invite equity in harmless deviation from nuanced ethical standards with real harm in criminal deviation from the same.
The broad acceptance of phase 4 studies without informed consent hinges on the trust placed in the professionalism and expertise of the regulators approving products for practice as safe and effective, and the same in the practicing physician offering it to patients. Perhaps the most disturbing element of the criticisms of the MVIP is the conspicuous and nearly complete evacuation of trust in the regulatory authorities approving the vaccine and the healthcare professionals executing its initial implementation. The frank exaggeration of the gravity of perceived deviation from ethical standards in the MVIP, taken with the dismissal of trust in those responsible for it, unfairly and unreasonably impugns the professionalism of the WHO and its many partners in that enterprise.
If the current COVID-19 crisis teaches us nothing else, let it at least demonstrate the vital need of trust in the WHO – in all of its efficacy and imperfection – as a disinterested arbiter of what is good for humanity in health. That advice could perhaps be taken by WHO and its critics alike. Humanity requires an unconflicted and transparent WHO, without regard to whether conflict of interest is real or perceived. Either damages that institution in its intended, necessary, and enormously beneficial role for all of us. This ideal should not insulate the WHO from earned, measured, and reasoned criticism by the communities it genuinely strives to honourably serve.
References
1. Swaminathan S, O’Brien K, Alonso P. Rapid response. 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. 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. Thornton H. Rapid response to WHO’s malaria vaccine study represents a “serious breach of international ethical standards. 03 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
5. Weijer C. Rapid response. The WHO Malaria Vaccine Trial: a bioethicist responds. 05 March 2020; https://www.bmj.com/content/368/bmj.m734/rr-5
6. Benn CS. Rapid response. The Malaria Vaccine Implementation Program: the lack of informed consent is the only ethical challenge. 10 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
7. Van der Graaf R. Rapid response. Integrating public health programs and research and CIOMS guidelines. 25 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
8. DuBois JM, Anderson EE, Chibnall JT, Mozersky J, Walsh HA. Serious ethical violations in medicine: a statistical and ethical analysis of 280 cases in the United States from 2008-2016. Am J Bioethics 2019; https://doi.org/10.1080/15265161.2018.1544305
Competing interests:
The author has a long history of collaboration and consultation with the WHO Global Malaria Programme that does not include engagement of any sort with specific regard to the Malaria Vaccine Implementation Programme discussed here.
08 April 2020
J. Kevin Baird
Academic biomedical research scientist
University of Oxford, United Kingdom
Head of Unit, Eijkman-Oxford Clinical Research Unit, Eijkman Institute for Molecular Biology, Jakarta, Indonesia; and Professor of Malariology, the Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Rapid Response:
Re: WHO’s malaria vaccine study represents a “serious breach of international ethical standards”
Dear Editor:
Excepting a response from WHO [1], the several contributing comments to Doshi's [2] criticism of the malaria vaccine (RTS,S/AS01) implementation assessment (MVIP) each [3-7] support Doshi's argument of a failure to meet ethical standards within the operational framework of that programme. Those contributors argue, principally, that the recipients of vaccine not being offered informed consent to participate in what they forcefully argue to be an experiment constituted a “serious breach” of ethics. This accusation is levelled not just at WHO, but a very large community of their research partners (representing many government, academic, and civil society organisations) that engaged with the MVIP. That included at least several highly regarded ethical oversight committees, in addition to the several regulatory agencies involved. According to Doshi and supporters [2-7], all of those players in the MVIP, collectively, seriously breached ethical standards in the conduct of that programme.
At the heart of this issue lies the process by which the vaccine was administered to participants of the MVIP and the subsequent collection of medical intelligence to be gathered and learned from it. Doshi and correspondents argue that the cluster-randomised distribution of the vaccine, taken together with deeply concerning safety signals from the earlier phase 3 clinical trial of the vaccine, represented a compelling need for informed consent by the vaccinated. Those responsible for the MVIP [1] point to a process whereby individuals were informed of the risks and benefits of vaccination and offered the opportunity to decline receiving it, calling that process “implied consent”. That terminology is arguably misleading – there is nothing implicit in parents presenting their children for vaccination; it is autonomous, dignified consent. Moreover, MVIP representatives [1] make the key point of the vaccine having been approved for practice by the regulatory agencies of the participating African nations. In other words, those authorities, by legal statute being responsible for the safety of their constituents, deemed the vaccine suitable for such offer to those constituents.
What Doshi and others take issue with is those parents not being taken through a formal process of informed consent via a protocol under responsible ethical oversight. That process offers a document describing vetted and thorough risks and benefits (along with key elements of voluntary consent) for witnessed signature affirming an informed willingness to participate. That appropriately lawyerly approach to the conduct of research involving human subjects protects us from intentional or unintentional abuse by exposure to unreasonable (extreme or unnecessary) risk of harm by medical experimentation. This is precisely the same responsibility borne by national regulatory agencies regarding the myriad devices and products applied to us in the practice of medicine. Where the responsibility of one ends and the other begins, depends as much on the intent to experiment as the product itself being experimental or registered for practice.
What constitutes relatively high risk experimentation and an obligation for direct ethical oversight is necessarily tied to that classification of a medical product. In experimenting with a product approved for practice, the high risk may not be considered to derive from indicated use of the product. By regulatory process, statute, and authority, that use does not carry intrinsically unacceptable risk. When one applies an approved product in a manner deviating from indicated use as a means of learning something about the product or the illness it relieves, we indeed incur the necessity of ethical oversight; especially if such deviation even slightly makes the medical product or state of illness a higher risk proposition. The MVIP did not do this, with or without an intent to experiment.
Doshi and correspondents point to an intent to experiment as the basis of required ethical oversight. Applied broadly and literally, as van der Graff does [7], phase 4 post-marketing surveillance undertaken by medical developers (often on the demand of responsible regulators) constitutes an experiment for which formal informed consent must be an ethical requirement. However, we routinely accept phase 4 studies of approved products without the informed consent of those on the receiving end of that practice. Those studies explicitly address uncertainty regarding the safety and efficacy of newly licensed products having relatively limited exposures in human populations. The MVIP did precisely that, but by implementing a cluster randomised distribution of vaccine. Doshi and correspondents [2-7] view that specifically as having crossed the line separating experiment from practice.
The “serious breach”, it seems, boils down to the inarguably deliberate intent to maximise the medical intelligence to be gained from MVIP rather than having placed vaccine recipients at unreasonable or unmeasured risk of harm. The experiment versus practice argument in this instance may be reasonably made, but no one should perceive what may be implicit in the “serious” verbiage used by Doshi [2], i.e., that vaccine recipients were placed at greater risk because the MVIP offered it to them in cluster-randomised fashion. The manner of distributing vaccine alone could not have done that. According to DuBois et al. [7] “serious ethical violations in medicine” include, “sexual abuse, criminal prescribing of opioids, and unnecessary surgeries, directly harm patients and undermine trust in the profession of medicine.” These exemplars attach physical meaning to what may be construed as “serious”. Even if flawed ethics occurred in the conduct of MVIP by perhaps overstepping the experiment vs. practice line, that should not be construed or misrepresented as a serious breach of ethical conduct. That terminology should be reserved for instances of real harm done lest we invite equity in harmless deviation from nuanced ethical standards with real harm in criminal deviation from the same.
The broad acceptance of phase 4 studies without informed consent hinges on the trust placed in the professionalism and expertise of the regulators approving products for practice as safe and effective, and the same in the practicing physician offering it to patients. Perhaps the most disturbing element of the criticisms of the MVIP is the conspicuous and nearly complete evacuation of trust in the regulatory authorities approving the vaccine and the healthcare professionals executing its initial implementation. The frank exaggeration of the gravity of perceived deviation from ethical standards in the MVIP, taken with the dismissal of trust in those responsible for it, unfairly and unreasonably impugns the professionalism of the WHO and its many partners in that enterprise.
If the current COVID-19 crisis teaches us nothing else, let it at least demonstrate the vital need of trust in the WHO – in all of its efficacy and imperfection – as a disinterested arbiter of what is good for humanity in health. That advice could perhaps be taken by WHO and its critics alike. Humanity requires an unconflicted and transparent WHO, without regard to whether conflict of interest is real or perceived. Either damages that institution in its intended, necessary, and enormously beneficial role for all of us. This ideal should not insulate the WHO from earned, measured, and reasoned criticism by the communities it genuinely strives to honourably serve.
References
1. Swaminathan S, O’Brien K, Alonso P. Rapid response. 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. 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. Thornton H. Rapid response to WHO’s malaria vaccine study represents a “serious breach of international ethical standards. 03 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
5. Weijer C. Rapid response. The WHO Malaria Vaccine Trial: a bioethicist responds. 05 March 2020; https://www.bmj.com/content/368/bmj.m734/rr-5
6. Benn CS. Rapid response. The Malaria Vaccine Implementation Program: the lack of informed consent is the only ethical challenge. 10 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
7. Van der Graaf R. Rapid response. Integrating public health programs and research and CIOMS guidelines. 25 March BMJ 2020; https://www.bmj.com/content/368/bmj.m734/rapid-responses
8. DuBois JM, Anderson EE, Chibnall JT, Mozersky J, Walsh HA. Serious ethical violations in medicine: a statistical and ethical analysis of 280 cases in the United States from 2008-2016. Am J Bioethics 2019; https://doi.org/10.1080/15265161.2018.1544305
Competing interests: The author has a long history of collaboration and consultation with the WHO Global Malaria Programme that does not include engagement of any sort with specific regard to the Malaria Vaccine Implementation Programme discussed here.