04/19/23 1

MRT and Human Research Ethics

04/19/23 2

MRT Trials

Genetic modification of the early embryo or gametes used to create embryo

Primary intent is to alter genes in later-born child, but affects descendants, too

Complex subject monitoring

Vulnerable Populations

Phase I research

Impact on fetuses and children

Uncertain direct benefit

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MRT Trials

Embryo Control and Disposition

Lack of Regulatory Guidance on Certain MRT Research Issues

04/19/23 4

Risks to human subjects must be minimized

Any unavoidable risks justified by potential benefits to subjects, if any, and by value of knowledge study expected to produce

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Potential Harms and Benefits

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Risk Minimization & Justification What preclinical data needed? Would alternatives diminish

justification for MRT research? What is appropriate study

population? What monitoring needed?

Choice of Study Population Relative risk evaluation [e.g.,

phase I cancer trials] Uncertainty in determining which

cases are at highest risk of serious mitochondrial disorders

When there is reasonable chance child would be healthy or mildly affected, harder to justify research risks

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Multi-Generational Effects

Follow modified children throughout lives

Monitor offspring – what tests, etc.?

What is sufficient study length?

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Series of Participants

Prospective parents

Modified children

Modified adults

Offspring

04/19/23 10

Enrollment & Retention Questions

Would sufficient number of people enroll and remain in studies to produce data needed to determine safety and efficacy?