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The following key ethical questions should guide the initial and continuing review processes throughout the research cycle

Domain	Dimension	Questions to ask during initial review	Questions to ask during a continuing review
Social value	The overall value of the anticipated knowledge gain and change in health and wellbeing of groups of people or communities attributed to the intervention	How well are the objectives aligned to address an important knowledge gap (or scientific equipoise) for which antibacterial MDA is a potential solution? How appropriate are the selected interventions—both MDA and others in the study—for achieving real social value?	What new research findings and research ideas have emerged that affect social value? What circumstances would make it necessary to have design change, and/or additional research support to enhance social value?
Benefits (including ancillary benefits, i.e., benefits outside the scope of the study itself)	What is the magnitude, likelihood, and nature of the benefits (i.e., well-being) accruing from the intervention and from benefits outside the specific research target to individuals and the community and stakeholders?	What benefits (including ancillary ones) have been realized?
Additional interventions	What additional non-MDA interventions are or should be included to modify, complement or maximize social value?	What additional interventions have been implemented?
Assumptions regarding human and social responses to the MDA intervention	What study- and context-specific assumptions are being made that could affect the successful implementation of the MDA intervention?	Were the assumptions correct, and how do they need to change to facilitate MDA implementation?
Implementation of MDA (e.g., using existing health system or creating a parallel system)	What strategy will be used to deliver the MDA (e.g., via existing health or public health systems, or not) and how will this affect overall social value (including sustainability)?	What impact has the delivery strategy had on the health system?
Assessment of risks and burdens	Identifying risks and burdens arising from the antibacterial agent	What risks and burdens are anticipated to arise from the antibacterial drugs, including adverse events (AEs) and AMR? What mechanisms are proposed to monitor and measure AEs – including AMR and other drug-related risks—and burdens? How will both short- and long-term risks be monitored, for both enrolled individuals and the broader community?	What anticipated and unanticipated AEs were more or less frequent than expected? How complete was the reporting of AEs to the relevant Regulatory Authorities? What impact did the anticipated and unanticipated AEs have on the risk–benefit balance?
Risk and harms arising from adverse human and social responses to the intervention (pragmatic risks)	What is the magnitude, likelihood, and nature of the risks and harms anticipated to arise from human and social responses to the MDA and non-MDA interventions in the study?	How have the anticipated and unanticipated human and social responses affecting implementation been captured, and how should they be managed, moving forward?
Risk minimization	What proactive measures are proposed to minimize AEs, AMRs, and other drug-related risks and burdens? What measures are proposed to minimize risk and harms arising from human and social responses to MDA?	What measures for risk minimization were used?
Ethical issues concerning post-trial surveillance for AMR and other AEs	What ethical challenges will be addressed by the post-study surveillance plan for monitoring the emergence and spread of AMR and other MDA-related AEs (and for how long)?	What new relevant ethical challenges and solutions have been identified for continued monitoring and emergence of AMR and other MDA-related AEs?
Stakeholder engagement	Meaningful stakeholder engagement and community ownership of the study	How will the people and other entities likely affected by MDA research and its results be identified in order to engage them?	What were the challenges in defining stakeholders and engaging them? How were their interests and concerns addressed?
What are the study roles and responsibilities of the different stakeholders engaged?	What were the challenges and lessons learned in implementing the engagement plan?
Implementation plan	How realistic is the plan (goals, objectives; activities, adequate finances, and human resources?	How is engagement with stakeholders being evaluated (process, outcomes of engagement, development of mutual trust, respect, transparency)?
Minimization of undue influence or biases in engagement	How will undue influence or biases among engaged stakeholders be minimized and monitored? What controls are in the engagement plan and study design to mitigate ethical concerns that may arise from the potential influence of research partners from HICs?	Which ethical concerns surrounding HIC funding and researchers were formally or informally reported and how were they resolved? How well are the controls working and which improvements need to be put in place?
Post-MDA engagement	How will study communities and other stakeholders be engaged to prepare them for uptake of the MDA intervention in the post-study follow-up and scale-up?	How did study communities begin to prepare themselves for sustainability?
Are there plans for future financing of an MDA intervention program?	What agreements with policymakers and others are in place for a financing plan to support the scaleup of the MDA if the study findings are positive?
Study design-related ethical challenges	Pragmatic and other alternative trial designs are commonly used in MDA studies	Which are the most relevant ethical challenges arising from the particular study design?	To maintain high ethical quality, is the study design still ethically appropriate, or should protocol amendments be considered?
How are study participants defined in the study (e.g., as only those who take the MDA drug, or others)? How is minimal risk defined, and which potential risks and benefits will be disclosed to participants?	What were the challenges in the consent process? If the study was classified as minimal risk, does it still meet minimal risk criteria?
If a waiver of informed consent, its documentation, or other alterations to consent is included, is it justified?	What reasons were given by different types of refusals to participate in the whole or part of the study?
MDA trials are more akin to public health interventions; a straight-forward clinical trial ethics review is not ideal for review	How well are the nexus of public health, research, and clinical ethics challenges, including human rights, addressed? Does the IRB/REC have sufficient expertise to evaluate the study rigorously?	Have any new ethical challengers emerged that pose capacity challenges for the LMIC REC to review study progress satisfactorily? How can the capacity of HIC IRB be harnessed to strengthen LMIC REC capacity?
Choice of intervention in the comparator arm	What is the ethical justification for the intervention in the control arm (e.g., placebo)? What are the plans to ensure that contamination is minimized?	Does the justification of the control arm intervention still hold based on new scientific knowledge?