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Use WPMLSERVE-Kenya Study
Title: Social, Ethical and Regulatory implications of conducting a malaria Vaccine Efficacy trial in a human infection study in Kenya.
Duration: 46 months
Background
Malaria remains an important public health problem in many LMICs, including Kenya – necessitating alternative prevention and control strategies. Malaria human infection studies (HIS) – trials that involve the deliberate infection of healthy volunteers with malaria parasites to assess the efficacy of potential vaccine and drug candidates and to understand the innate and acquired protection against malaria parasites – have become an important approach to fast-track the development of a malaria vaccine.
The KEMRI-Wellcome Trust Research Programme (KWTRP) has developed expertise in setting up and running research on malaria HIS, with two completed and two planned in the coming months. One of the planned studies is a Phase IIb malaria vaccine efficacy trial within a HIS funded by the EDCTP. While all scientific proposals at KWTRP are carefully reviewed by national and international science and ethics review bodies and are supported by a well-developed local community engagement platform, research to understand the social, ethical and regulatory issues for HIS from a grounded perspective is in early stages of development, especially in LMICs.
Given the particular opportunities provided by the KWTRP’s experience in running HIS, expertise in embedded social science research and the presence of a well-established community engagement platform, we plan to conduct a social science study within the HIS-based Phase IIb malaria vaccine trial.
Aims and purpose
We are funded by EDCTP to contribute to the development of locally responsive policies on the ethical conduct of malaria vaccine efficacy studies involving the use of a HIS in Kenya. Specifically, we first aim to explore the social, ethical and regulatory issues associated with an HIS-based malaria vaccine efficacy trial. Given the relative novelty of HIS, particularly from a wider public or community perspective, we then aim to feed the empirical findings into a series of in-depth deliberative engagement processes to explore the informed views and values of different community and research-HIS stakeholders around core emerging social and ethical issues. Drawing on the outputs of the deliberative processes and the wider international ethics literature, we will propose recommendations on the nature of responsive policies for the ethical conduct of malaria vaccine HIS.
Methodology
Overall, data will be collected from a range of HIS stakeholders, including HIS participants and their families, community members, HIS research team, ethics committees, regulatory authorities and policy makers through surveys, interviews, group discussions, participatory workshops, observations and document review. Data collection will primarily be undertaken at the sites for the main planned malaria HIS, namely: Ngerenya sub location in Kilifi county in Kenya. Some key informants will be based in Nairobi or other sites in Kenya (i.e. ethics review committees, regulatory authorities, and health policy stakeholders).
The detailed protocol of the study has been published in Wellcome Open Research and available at: https://wellcomeopenresearch.org/articles/9-193
Expected benefits
Findings from this study will contribute towards the development of recommendations around the nature of responsive policies for the ethical conduct of malaria HIS, including those involving malaria vaccine challenge models. These will be particularly useful for HIS researchers, ethics communities and regulatory authorities towards supporting the ethical conduct of HIS in Kenya.
Preliminary study findings
I. Objective I findings
To achieve objective 1, we undertook non-participant observation of key HIS activities & processes, and document review of relevant HIS literature and communications. Additionally, we conducted individual in-depth interviews, focus group discussions, and surveys with a wide range of HIS stakeholders. The HIS stakeholders that were engaged as part of the data collection were prospective HIS participants (at the time of screening into the malaria HIS), former & current HIS participants and their family members, opinion leaders and representatives, community members, fieldworkers and community engagement staff, research ethics committee (REC) and regulatory authority staff, health providers, HIS staff & policy makers. Through these data collection exercises, we expected to develop a synthesis of social, ethical and regulatory issues (SERIs) arising from conducting a malaria vaccine efficacy study in the context of a HIS. The key SERIs that emerged from the work include the following:
1. Benefits and burdens
Benefits
- Most participants spoke about medical screening as a benefit, considering they or their significant others were able to access screening tests for free which would not otherwise be the case at local health facilities.
- Financial compensation was viewed as both individual and family benefit as it provided a means to meet daily and immediate needs as well as investment in long-term projects. This view was expressed by study participants, significant others, and community members.
Burdens
a. In-residence
- Long periods of staying away from family.
- Limited movement within a stipulated area.
- Limited activities to engage in while in residence resulting in boredom.
b. Health Screening
- Some medical screening procedures were viewed as burdens, e.g. COVID testing and frequent blood draws.
2. Concerns – Social, ethical, regulatory
- Social concerns raised by participants included the implication of extended stay away from home e.g. Concerns about inappropriate behavior or relationships, being away from family too long, restricted visiting conditions, etc.
- Concerns of inappropriate behavior such as sneaking out of residence, rumors, and talks from neighbors resulting in domestic disputes and strains in relationships.
- For female participants, concerns around inappropriate advances from male participants.
- A few participants raised ethical concerns around result feedback, specifically around the confidentiality of the result feedback process. They felt privacy was reduced due to how people reacted and their mannerisms while /after receiving their screening results.
3. Motivations and Decision making
Motivations/considerations for participation
Key considerations included:
- Amount of financial compensation and what that amount could help them achieve.
- Altruism – to help future generations.
- Health screening- desire to know and understand one’s health status from the screening test done before study enrollment. Even those who did not have the opportunity or time expressed the desire to know their health status.
Decision making process
- Decision making process involved consulting and discussion with other people including family members (e.g. spouses, parents, siblings), friends, peers etc.
- A few participants also indicated they made individual decisions to participate without consulting anyone.
4. Participant experiences
- Participants shared both positive and challenging experiences with study procedures, in-patient stays, care while in residence, extended stays, and interaction with others as well as temptations to get into inappropriate relationships with other participants or students within the residential area.
- Concerns over limited movement and activities to engage in while in-residence resulting in boredom.
- Concerns about amenities and services within the in-residence facility. Eg. Food quality.
- Specific experiences unique to women include unwarranted or inappropriate advancements from male participants during in-patient stay.
- Result feedback specifically for those who didn’t qualify and were turned away was an unpleasant experience.
5. Community Engagement/ communication/ knowledge and understanding
- Community leaders mostly recommended different approaches they thought would be most effective in passing information during community engagement.
6. Acceptability and risk
- Across the different groups of stakeholders, the risks and harms were viewed as fear of unknown outcomes or sickness or death that may result from participating in studies that involved infecting people with a disease.
7. Financial compensation
- Financial compensation was viewed as a right that participants deserved to receive following their willingness to participate in the study.
- Recommendations to consider reviewing current rates upwards vis a vis rising cost of living e.g. cost of basic commodities like flour, cooking oil, etc.
- Weekly payments are most desirable however this can also be dependent on individual status and preferences e.g. married people would be able to cater to the family while away to avert unnecessary stress while single people may spend it on luxury as they may not have family responsibilities.
- For many women, continued participation was also on condition that they would remit funds back home otherwise spousal consent/permission to participate was withdrawn.
II. Objective 2
To achieve objective 2, we conducted a deliberative engagement process that comprised of large information giving workshops and small group discussions with different HIS stakeholders on selected SERIs that emerged from objective 1. Participants for this objective included Former HIS participants, community opinion leaders and representatives, fieldworkers and community engagement staff, REC and regulatory authority staff, health providers, HIS staff and policy makers. Our expected outcome was to develop a validated summary of recommendations/proposals for improving the design and implementation of HIS and experience of HIS participation. The deliberative consultation process explored four major topics: benefits of HIS participation, burdens of HIS participation, compensation for HIS participation, perceived risks and harms of HIS participation, and conditions necessary for the conduct of a HIS. The synthesis of the findings is presented below.
Individual/Family benefits
- Health screening/health checks – knowing one’s health status; levels of malaria immunity; saving money on tests.
- Close monitoring by clinical team.
- Free treatment during the study.
- Financial compensation – accomplishments resulting from the cash.
- Presumed immunity to malaria; reduction in malaria incidence and prevalence.
- Vaccine on trial – presumed to be protective.
- Residential stay – good amenities; good food; relaxation.
Societal benefits
- Effective vaccine will benefit future generations.
- Community’s pride in having taken part in successful studies.
- Former volunteers as a resource – encourage others to participate; dispelling existing rumours.
Institutional benefits
- Building trust in the research institute; good reputation.
- Less wariness about participation; demand to join studies in the community – evidence of successful participation/safe volunteers.
- Employment opportunities
- Improved relationship between staff and communities.
Recommendations on maximizing benefits
- Feedback of study results – regardless of whether positive/negative outcome.
- Making the vaccine available to community if successful.
- Health insurance; extending heath screening to the family & community
- Debate between HIS Volunteers only or HIS volunteers and their families.
- Extending medical care to family members might set a bad precedence; undue inducement; might start asking for more (fieldworkers)
- Appreciation and recognition of the volunteers – tokens of appreciation; vs. breach of confidentiality [This was not problematic among the volunteers].
- Improving dispensary/ community health facilities – a form of corporate social responsibility.
- Employment opportunities for young people; education scholarships/ vocational training.
2. Perceived burdens of HIS participation
- Close monitoring by clinical team – inconveniencing early morning calls; long queues; disruptive during lunch time.
- Repeated blood draws – volumes and pain from needle pricks.
- Distress associated with study procedures e.g., bleeding, mosquito bites.
- Health checks – fear of knowing status; ‘unaffordable’ diagnosis.
- Suffering the symptoms of malaria.
- Concerns about long-term effects of parasites/Vaccine [beyond follow up time].
- Restriction of movement –restrictive rules; restricted habits [mostly raised by men].
- Forgoing gainful activities to participate e.g., employment.
- COVID protocols – nasal swabbing.
- Psychological distress associated with being away from family/wives; worrying about their well-being; missing out.
- Burden of care giving (children) shifts to others [gender specific; mostly raised by women].
- Financial difficulties- providing for family before cash disbursement.
- Potential for compensation to bring disharmony within families.
- Delay in disbursement of compensation.
- Unintended breach of confidentiality/privacy – health screening failure; information spreading in the community; potential stigma.
- Challenges at the residence facility.
- Overall, burdens were considered bearable and comparable to challenges of everyday life; not excessive compared to benefits.
Recommendations on minimizing burdens
- Providing participants with cash at the beginning of the stay to help cater for family needs; ease the worrying [suggestion to have the amount deducted later].
- Having enough and well-trained staff in the clinical team; reduce queues.
- Allowing spousal [conjugal] visitation; avoid infidelity among partners
- counter argument to not grant this to promote equal treatment for all (married and singles)
If possible, limiting the number of blood draws
3. Compensation for study participation
- Agreement that the amounts for both overnight stay (KES 2000/-) and out-of-pocket (350/) are low; strong recommendation to increase the amounts.
- Few individuals expressed that the overnight amount was enough; no proposal to increase; prioritization of community benefits; ensure true volunteerism; avoid undue inducement
- Most prominent rationale for the recommended increase is the need to account for the increase in cost of living.
- Less agreement about the actual amounts; however, the proposed range remained modest.
- Overnight stay – increase to between KES 2500/- to 4000/- (Max 5,000/-)
- Out of pocket allowance – increase to KES 1000/- (Max. 1000/-)
- Shared understanding that amounts provided are not actual ‘wages’ but a relief for the burdens/inconveniences incurred.
- Determining fair compensation – Same rate for those participating in similar studies – should not be dependent on types or jobs or levels of earnings; unfairness.
- Volunteers express that compensation should also take account of their commitment to volunteer – therefore it should also be an appreciation and recognition of this sacrifice.
- Out-of-pocket allowances (KES 350/500) raised more concerns about leaving people worse off after participating in research
- Research participants forgo their daily gainful activities to participate in research activities – people earn more than KES 500/- for daily casual work.
- At a minimum benchmark to what casuals earn at construction sites or casual work in companies.
- Transport reimbursement policy/rates were deemed unfair to participants by fieldworkers – some received less than what was spent
- Less agreement whether a flat rate or payment based on what is spent.
Maximum and minimum levels of compensation
- ‘Too much’
- Fuel community rumours, discourage participation.
- People might be willing to participate in riskier studies e.g., HIV challenge.
- ‘Too little’
- raise concerns about exploitation.
- studies would recruit/disproportionately attract vulnerable participants.
- participants would bear too many burdens/inconveniences.
4. Perceived risks and harms of HIS participation
Perceived risks
- Risk of death; severe disability; severe disease.
- Risk of clinical procedures causing harm – needles and nasal swabs breaking in the body.
- Adverse reactions from the vaccine; malaria parasites.
- Side effects from contraceptives e.g., delayed childbirth.
- Failure of volunteers to report symptoms – risk condition getting worse.
- Risking job loss – having run off to come attend a research activity.
- Fear of health screening results – getting stressed; getting suicidal.
Perceived harms
- Pain and discomfort from bleeding procedures; multiple pricking; mosquito bites.
- Trauma and distress of going through study procedures.
- Psychological distress – missing people at home; children missing their parents; worrying over their well-being; distress if something goes wrong at home and cannot help out.
- Loss of property when away from home e.g., chicken stolen; food kiosk dishes broken etc.
- Social harms – misinformation, rumours about participants leading to broken marriages.
Risks/harms that volunteers should NOT be exposed to:
- Excessive volumes of blood should not be taken – risk of anaemia.
- Infection dosage should not be excessive – as to cause harm.
- Risks that result in terminal illnesses or lifelong disability.
- Diseases that cannot be contained e.g., COVID; or treated.
- No guaranteed treatment by researchers after infection with parasites.
- Risk of paralysis; possibility of death; convulsions.
- Exposure to infection or illness with no cure e.g., HIV, COVID, Cancer etc.
- Even if disease is treatable – duration of treatment matters e.g., TB
- Social harms – family disharmony as a result research participation.
Responsibility of minimizing risks/harms
Participants
- Reporting symptoms to clinical team – to avoid getting worse.
- Following the set rules – keeping time, being available when needed by clinical team, not leaving the residence facility.
Community
- Mobilize family members and others to join studies; passing out information about recruitment to others.
- Family members should check on those who are in the study.
Researchers/ research institute
- Be responsive to issues raised by the volunteers; solve the issues raised.
- Follow up volunteers to ensure they are available for clinical investigations.
- Ensure participants get what they require from the study.
5. Conditions perceived necessary for HIS conduct
- Ensure challenge agents and vaccines are safe to use.
- Maintaining high safety levels for volunteers; ensure the rights of participants are observed.
- Ensure voluntariness in research participation.
- Availability of qualified clinicians throughout – ensure safety of volunteers; availability in case of emergencies.
- Enough clinicians/doctors – reduce inconvenience of long waiting times and queuing.
- Good referral plan for emergencies.
- Multiple screening tests for infectious diseases during the study.
- Provide enough equipment to speed up clinical procedures e.g. thermometers.
- Insurance to cover events of injury for compensation if they occur.
- Having a competent technical and management team during the study.
- Researcher visibility during the study – ensure volunteers are well taken care of; check that clinical team is doing the right thing.
III. Objective 3
This objective will be achieved through a detailed analysis and writing up of the findings from objectives 1 and 2, drawing on the wider research ethics and HIS literature. Our expected outcomes for this objective are developing recommendations for ethical conduct of malaria vaccine HIS, organizing feedback sessions to share key study findings with community members, developing manuscripts & policy briefs, doing oral presentations of key findings at relevant conferences, and organizing a dissemination workshop to other key stakeholder groups.
From 2021 to date, key findings and learnings from the project has been presented at over eight local, national and international conferences: 10th and 11th EDCTP Forums (October 2021 & November 2023), International Alliance for Biological Standardization (IABS) 3rd and 4th Controlled Human Infection Model (CHIM) Meetings (February 2020 & May 2023), 2022-2024 Oxford Global Health and Bioethics conferences (June 2022, June 2023 & July 2024), 7th Bioethics Society of Kenya Annual Conference (March 2023), 2nd Kilifi County Scientific Symposium (November 2023), KWTRP workshop on ‘CHIS in the LMIC Ethics and Regulatory Ecosystem: Role, conduct, and utility of models’ (May 2024), and Brazilian symposium on CHIM 2024 (August 2024).
Additionally, I have participated in international initiatives aimed at developing ethics and regulatory guidelines around CHIMs and healthy volunteer studies. These include the Inserm-led VolREthics initiative that developed “The Global Ethics Charter for the Protection of Healthy Volunteers in Clinical Trials”, the World Health Organization’s Global Health Ethics & Governance Unit initiative on developing ethics guidance around CHIS. Our team contributed to the development of the “WHO guidance on the ethical conduct of controlled human infection studies” (published in January 2022). Our team members (Melissa Kapulu and Primus Chi) are also involved in another WHO ethics guidance focused on considerations for CHIS with priority pathogens of pandemic importance. Furthermore, two of our team members (Melissa Kapulu and Primus Chi) were selected into the Africa Vaccine Regulatory Forum (AVAREF) Experts Working Group for development of ethics and regulatory guidance for CHIM.
Our findings have also been shared institutionally with the main CHIM research team and the findings have shaped the way CHIMs are planned and conducted at our Programme. For example, the compensation for study participation that used to be disbursed as a lumpsum at the end of in-patient/residential stay is now disbursed on a weekly basis during residency due to participants preference. Also, the HIS study team now uses tubes to demonstrate the actual volume of blood that is drawn during each venipuncture while in residence as part of the informed consent process, among others. We have also shared our findings with the national ethics committee and medicine regulatory authorities in Kenya.
With respect to our feedback session, a back meeting has been held with community stakeholders and study participants to share key findings from the deliberative consultations.
Finally, analysis and writing of the study findings is ongoing and these will feed into additional open access publications and policy briefs.
Overall, our project has made substantial contributions to policy and practice around CHIM institutionally, nationally and internationally levels.
Funding
This project (TMA2019CDF-2751) is part of the EDCTP2 programme supported by the European Union.
Investigators
Dr. Primus Che Chi, Ms. Esther Awuor Owino, Dr. Melissa Kapulu, Prof. Vicki Marsh, and Dr. Dorcas Kamuya
