S3-2 MSF DoH Vatican

23/01/2024
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WMA
Declaration of Helsinki
Vatican City, January 2024
Melissa McRae
Senior Researcher Medical Ethics
Médecins Sans Frontières, Geneva
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Session 3: Experiences of conducting research in low-resource settings
(LRS) under the DoH
Raffaella Ravinetto
Chair of the MSF Ethics Review Board
Chair of the Institutional Review Board,
Institute of Tropical Medicine, Belgium
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Outline
o Brief overview of MSF, their role in research as a medical
humanitarian organisation and current research agendas.
o Case study: Ebola Viral Disease post-trial access, challenges
o MSF inputs and suggestions concerning the revision of DOH
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Map of MSF activities around the world
Source: https://www.msf.org/where-we-work
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MSF Charter
• We carry out our work with respect for
medical ethics, in particular the duty to
provide care without causing harm to
individuals, groups and communities
• We respect patients’ autonomy, patient
confidentiality and their right to informed
consent
• We treat patients with dignity, and respect
for their cultural and religious beliefs
• Confronted with lack of effective, safe,
feasible and/or context-tailored
interventions
• Attempting to make research
investment more equitable (i.e cancer,
new antibiotics)
• Medical research meant to serve the
needs of the beneficiaries
• Independent MSF Ethics Research
Committee
MSF in Research
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MSF’s Research Portfolio – 85 research initiatives in 2023
Typology of methodology
Source: MSF Ethics Research Board data
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MSF’s Research Portfolio
Topic Country
0 1 2 3 4 5 6 7 8 9 1 0
Vect or Bo rne Diseases
Mort al
it y, Nut rit ion +/- Violence
Measles
Repr oduct iv
e Health
Cho lera
Neglect ed Di
seases
Accesst o healthcar e
Occup ation Health & Safet y
Tuber culosi
s
Vaccination
HIV
An timicro bial Resistan ce
Non-Co mmun icable Diseases
Climat e change
Mal
n utr ition
Quality of car e
Ebola
Health surveillance sy
ste ms
HPV / cer vical cancer
Cer vical cancer
Mental healt h/lassa f ever
MS
F services handover
Palliative/end-o f-life car e
Popu lation A ssement too l
Sexual violence
Trau ma
0 1 2 3 4 5 6 7 8 9 1 0
DemocraticRepublicof Congo
Chad
Multisite
Niger
Nigeria
Bangl
adesh
South Su
dan
Malaw
i
Guinea
Hondur a
s
Gaza
, Palestine
Haiti
India
Kenya
Li
ber i
a
Mali
Yemen
Iraq
KyrugzRepublic
Le
banon
Moza
mbique
Guatemala
Eswatini
Ethiopia
Panama
Sie
r ra Leone
Suda
n
Ukraine
Source: MSF Ethics Research Board data
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Part II: MSF case study:
Ebola Viral Disease post-trial access
challenges
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Case Study: research for Ebola Viral Disease
Ø2014-2016: West African outbreak, 30 000 cases à Ebola could become ‘global’
– unprecedented public research funding and collaborative effort under WHO leadership
– a wide range of stakeholders …. including MSF, Ebola patients and their communities
ØA number of ethics challenges:
• Equipoise and placebo
• Community engagement
• Ownership of research data and samples
• Post-trial access
• Shortened R&D plan based on risk-assessment
• Resources allocation: routine care vs research
(in LRS with shortage of medical doctors)
• Informed consent modalities
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Setting the scene: Ebola Virus R & D timeline
• 1976: Zaire Ebola virus disease (EVD) discovered
• 2014: after many outbreaks in rural areas in LRSs, no treatment existed yet
• West African outbreak: accelerated research agenda, triggered by global biosecurity
concerns
• 2018-19: PALM trial in DRC à mAb114 and REGN-EB3 found effective
• 2022: WHO guideline treatment recommendations à post trial access for future patients
• 2023: no capacity to produce mAb-114 + REGN-EB3 stockpiled in US: “Should a major
outbreak happen tomorrow in Africa, there will be no readily available stocks (Torreele et al,
Lancet ID 2023)
• 2022-2022: over five outbreaks and only 34% of patients received either drug
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Analysis 1: costs, prices
• Overwhelming in-kind and financial contributions by public sector for the R&D of
mab114 & REGN-EB3. (i.e. US*, DRC governments) and NGOs (i.e. MSF)
• Limited private sector (i.e., developers) contributions by Ridgeback & Regeneron,
who hold exclusive licensing rights
• In the current innovation & intellectual property ecosystem, there is no ‘space’ for
alternative suppliers.
REGN-EB3
• Price (paid by USG): $6900/Treatment Course (TC)
• Estimated COGS: $750-$1875/TC
Mab114
• Price: unknown
• Estimated COGS: $250-$625/TC
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Analysis 2: stockpiling & access to monoclonal treatments
• Stockpiles in high income-countries, but not in endemic countries
– Monoclonal Ab stock under WHO supervision (1,000 TC), under review in 2024
• Unclear/no agreed mechanisms for rapid supply in case of outbreak overseas
• The current situation is inequitable and inadequate for outbreak response
• Ad-hoc donations with no clear governance/rules
• Access heavily dependent on goodwill of developers/ governments with stock
• For instance: small mab114 donation program in DRC, equated to very few TCs
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Analysis 3: post-trial access to the communities/countries
• R&D contributions of Ebola survivors, communities, NGOs, public funders,
researchers and governments in endemic countries is unrewarded
• High price of REGN-EB3
o Unaffordable for endemic countries, who are made dependent on donations
o A supply-demand loop issue: future manufacturing not ensured
• Slow regulatory pathways complicate access
• Lack of clear rules and ”will” to respect equitable and fair partnerships
• ? outbreak preparedness: access for future needs is highly compromised
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Case study reflections on post trial provisions (art. 22, 34)
22. The design and performance [….] In clinical trials, the protocol must also describe
appropriate arrangements for post-trial provisions
Comment: post-trial provisions should include the community and the country, in addition
to individual participants.
This can be achieved by protocols that address local health system capacity strengthening
and include adequate measures for translating research findings into local policies and
practices (consider commercial and intellectual property provisions, fair pricing etc).
Even if it goes beyond researchers’ power, they can advocate for this to happen.
Recommendation: add at the end “for study participants when applicable, and for the study
community and country”
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34. In advance of a clinical trial, sponsors, researchers and host country governments
should make provisions for post-trial access for all participants who still need an
intervention identified as beneficial in the trial. This information must also be disclosed to
participants during the informed consent process.
Comment: post-trial provisions should encompass all those in need, either now or in the
future, particularly in countries where innovative, high-priced health interventions are not
available/ affordable at an individual and/or collective level. Even if it goes beyond the
researcher’s power, individual researchers can advocate for this to happen.
Recommendation: complete art. 34 as “…. all participants who still need an intervention
identified as beneficial in the trial, as well as all those who are/will be in need in the future
in the general population”.
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Part III: MSF inputs and suggestions concerning
the revision of DOH specific articles
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Suggestions for the DoH from this case study (and other) MSF
research experience in LRS and vulnerable groups
• Be explicit that DoH applies to all health researchers (other health professionals) (art. 2)
• Benefit sharing and community engagement, including support to local health systems,
should be built in research from the start, and post-trial access include community and
country level (art. 22, 34)
• In global health research, you need to reconciliate ethical approaches (e.g. ethics
principle, ethics review) in both the study country and sponsor country (art. 10, 23)
• Extend the concept of ‘risk’ to both individuals and communities, and be explicit about
medical and non-medical risks (art. 9, 15, 17, 24)
• Vulnerability can be caused by inequalities, either pre-existing or introduced by research
conditionsà be cognizant of the duty to detect and protect those who are (made) socially
or economically vulnerable. This can create higher risks for coercion and therapeutic
misconception (art. 14, 19, 20, 27)
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Comment on the Preamble
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily
to physicians. The WMA encourages others who are involved in medical research
involving human subjects to adopt these principles.
Comment: This is particularly important in LRS with dearth of health care staff,
where tasks are often shifted to nurses, clinical officers etc.
Recommendation: we warmly support the underlined, and propose that the WMA
becomes binding for, at least, other health professions , or for ‘health researchers’
as a whole
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LRS Focus: Being inclusive of communities and local ethical norms (art. 10, 23)
10. Physicians must consider the ethical, legal and regulatory norms and standards for
research involving human subjects in their own countries as well as applicable international
norms and standards. No national or international ethical, legal or regulatory requirement
should reduce or eliminate any of the protections for research subjects set forth in this
Declaration.
Comment: In global (North-South) research, researchers and research institutions may work
elsewhere than in ‘their country’.
Recommendation: reformulate as “in their own countries and (if different) in the
country/ies where the research takes place, as well as applicable international norms and
standards. In case of conflict, the highest ethical standard for participants’ protection should
prevail”.
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23. The research protocol must be submitted for consideration, comment, guidance and
approval to the concerned research ethics committee before the study begins….[etc]
Comment: MSF research is submitted both to its own ERB and to the country ethics
committee, so as to ensure respect of local rules and regulations, and to prevent ethics
dumping. This ‘double ethical review’ often results in a rich complementarity of views.
Recommendation: specify that the ‘concerned’ ethics committees include both the
(main) one in the study country, plus the one in the country of the sponsor.
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LRS Focus: Respect for Research participants – Risks, Burdens & Benefits (art.
9, 15, 17, 24)
9. It is the duty of physicians who are involved in medical research to protect the life,
health, dignity, integrity, right to self-determination, privacy, and confidentiality of
personal information of research subjects.
Comment: It is equally important to protect the research participants and the research
communities, which may be vulnerable as such to exploitation, confidentiality
breaches, stigmatization etc.
Recommendation: add “and communities”
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15. Appropriate compensation and treatment for subjects who are harmed as a result of
participating in research must be ensured.
Comment: the classical approach of ad hoc (no-fault) research insurances may be
difficult to achieve in LRSs (e.g. lack of insurers, poor familiarity with the concept in).
Additionally, research participants in many LRSs pay out-of-pocket for essential and
life-saving treatments (not the case for MSF).
Recommendation 1: add “…. must be ensured, by using measures that are tailored to
and effective in each specific context”
Recommendation 2: include provisions for “ancillary care” when research participants
lack access to care for medical events unrelated to research participation
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17. All medical research involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and groups involved in
the research in comparison with foreseeable benefits to them and to other individuals
or groups affected by the condition under investigation. Measures to minimise the risks
must be implemented. The risks must be continuously monitored, assessed and
documented by the researcher.
Comment: in our experience, we often witness a bias of researchers toward physical
medical risks. However, non-medical risks (e.g. psychological, social, reputational, and
legal) can also be important, and even be more prevalent in LRSs and vulnerable
communities, both at individual and community level. The risk assessment must be
context and health system-specific.
Recommendation: add “…Measures to minimise all risks, medical and non-medical,
should be assessed and implemented for the specific context and research population.
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24. Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information.
Comment: privacy and confidentiality concerns need close attention in LRSs and
vulnerable communities. They should be protected not only at individual but also at
group level (e.g. in case of disease with a high potential for stigma, a full village, or a
full ethnic group may be blamed and stigmatised in case of data breach)
Recommendation: “the privacy of research subjects and the relevant community, and
the confidentiality of their personal and community information”.
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19. Some groups and individuals are particularly vulnerable and may have an increased
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
Comment: While some individuals may be intrinsically prone to exploitation (e.g. minors),
more often people and communities are made vulnerable by the circumstances: external
conditions that create or perpetuate poverty, exclusion, marginalisation, injustice.
Protection measures are the responsibility of researchers, to be carefully tailored to the
kind of vulnerabilities. This should be explicitly reminded.
Recommendation: reformulate as “are particularly vulnerable or are made vulnerable
under certain medical or socio-economical circumstances” and may have….
LRS Focus: Recognising and addressing vulnerability (art. 19, 20)
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20. Medical research with a vulnerable group is only justified if the research is
responsive to the health needs or priorities of this group and the research cannot be
carried out in a non-vulnerable group. In addition, this group should stand to benefit
from the knowledge, practices or interventions that result from the research.
Comment: This is critical for LRSs, and measures for benefit-sharing should be built in
the research protocol/plan, in concertation with the representatives of the local
communities and health systems. Even if it goes beyond researchers’ power, they can
push for this to happen.
Recommendation: add at the end “Measures for benefit sharing should include
consultation with local communities and health actors, and be prospectively built in
the research plan, not post hoc”.
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14. Physicians who combine medical research with medical care should involve their
patients in research only to the extent that this is justified by its potential preventive,
diagnostic or therapeutic value and if the physician has good reason to believe that
participation in the research study will not adversely affect the health of the patients
who serve as research subjects.
Comment: in so-called “humanitarian misconception”, prospective participants may
tend to perceive research participation as a part/ a condition of aid. Like therapeutic
misconception, it cannot be fully prevented, and researchers should be aware of it.
Recommendation: add “Researchers who combine medical research with medical care
or medical (humanitarian) aid”
LRS Focus: Higher risk of coercision and misconception (art. 14, 27)
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27. When seeking informed consent for participation in a research study the
physician must be particularly cautious if the potential subject is in a dependent
relationship with the physician or may consent under duress. In such situations
the informed consent must be sought by an appropriately qualified individual
who is completely independent of this relationship.
Comment: there are other reasons that can cause unwanted coercion, such as
“humanitarian misconception”, and lack of access to healthcare elsewhere.
Recommendation: add “if the potential subject is in a dependent relationship
with the researcher, may consent under duress or if a risk of other potential
reasons of coercion”
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In summary
Ø Prospective research participants & communities in LRS, as well as other
vulnerable individuals and groups in other settings, are at higher risk of
exploitation
Ø This requires respectful engagement, for adequate protection,
Ø Co-ownership rather than paternalism
Ø By upholding and enhancing ethics awareness among health researchers, the
DoH can prevent and correct structural injustices in (global) health research
Ø The DoH should be explicit that ethics principles equally apply in conditions of
emergency and non—emergency research.
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Thank you
Questions and comments please
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