As readers know I’ve written on mitochondrial replacement therapy and its attendant ethical and regulatory issues. Today the National Academy of Medicine (formerly known as the IOM) released a terrific report today with its recommendations. I’ll have a second post with my reactions but here is a summary from the report of their recommendations. The big headline is they have recommended FDA largely move towards allowing it to go forward under a regulatory pathway with restrictions, the most important of which is the transfer only of male embryos (to avoid germ-line issues).
In the NAM’s own words:
Recommendation 1: Initial clinical investigations of mitochondrial replacement techniques (MRT) should be considered by the U.S. Food and Drug Administration (FDA) only if and when the following conditions can be met:
- Initial safety is established, and risks to all parties directly involved in the proposed clinical investigations are minimized. Because attempts to minimize risk and burden for one of the parties could interact with risk for another, minimizing risk to future children should be of highest priority.
- Likelihood of efficacy is established by preclinical research using in vitro modeling, animal testing, and testing on human embryos as necessary.
- Clinical investigations are limited to women who otherwise are at risk of transmitting a serious mitochondrial DNA (mtDNA) disease, where the mutation’s pathogenicity is undisputed and the clinical presentation of the disease is predicted to be severe, as characterized by early mortality or substantial impairment of basic function.
- If the intended mother at risk of transmitting mtDNA disease is also the woman who will carry the pregnancy, professional opinion informed by the available evidence determines that she would be able to complete a pregnancy without significant risk of serious adverse consequences to her health or the health of the fetus.
- Intrauterine transfer for gestation is limited to male embryos.
- Clinical investigations are limited to investigators and centers with demonstrated expertise in and skill with relevant techniques.
- FDA has reviewed haplogroup/haplotype matching and if compelling, considered it as a means of mitigating the possible risk of mtDNAnuclear DNA (nDNA) incompatibilities.
Recommendation 2: Ethical standards for the use of human embryos in research have been developed by the U.S. National Academies of Sciences, Engineering, and Medicine (the Academies), the U.S. National Institutes of Health (NIH), and the International Society for Stem Cell Research (ISSCR). These standards include the expectation of prospective independent review of research proposals. In light of concerns about the oocyte procurement and embryo manipulations necessary for mitochondrial replacement techniques (MRT) preclinical and clinical research, regulatory authorities should ensure the ethical provenance of preclinical or clinical data submitted to the U.S. Food and Drug Administration (FDA) in support of an Investigational New Drug (IND) application. To the extent possible, regulatory authorities should ensure that sponsors adhere to ethical standards comparable to those developed by the Academies, NIH, and ISSCR. In preclinical research, nonviable human embryos should be used when possible. When use of nonviable human embryos is not possible, viable human embryos should be used only when required in the interest of developing the science necessary to minimize risks to children born as a result of MRT, and even then only in the smallest numbers and at the earliest stages of development consistent with scientific criteria for validity.
Recommendation 3: If the conditions of Recommendation 1 are met, the U.S. Food and Drug Administration (FDA) should ensure that the design and conduct of initial and subsequent clinical investigations of mitochondrial replacement techniques (MRT) adhere to the following principles and practices:
- The health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority in the balancing of benefits and risks with respect to the design of investigations, eligibility of prospective mothers, numbers of participants, and pacing of investigations.
- Study designs of clinical investigation protocols of MRT should be standardized to the extent possible so as to minimize the number of variables and enable valid comparisons and pooling of outcomes
across groups. - Data from research or clinical practices outside FDA jurisdiction should be incorporated into FDA’s analysis to enhance the quality of the assessment of benefits and risks.
- Clinical investigations should collect long-term information regarding psychological and social effects on children born as a result of MRT, including their perceptions about their identity, ancestry, and kinship.
Recommendation 4: Following successful initial investigations of mitochondrial replacement techniques (MRT) in males, the U.S. Food and Drug Administration (FDA) could consider extending research of MRT to include the transfer of female embryos if:
- clear evidence of safety and efficacy from male cohorts, using identical MRT procedures, were available, regardless of how long it took to collect this evidence;
- preclinical research in animals had shown evidence of intergenerational safety and efficacy; and
- FDA’s decisions were consistent with the outcomes of public and scientific deliberations to establish a shared framework concerning the acceptability of and moral limits on heritable genetic modification.
Recommendation 5: In addition to attention to best practices for consent in research, the U.S. Food and Drug Administration (FDA), research institutions, investigators, and institutional review boards should pay special attention to communicating the novel aspects of mitochondrial replacement techniques (MRT) research to potential research participants.
- For individuals who provide gametes, consent processes should reflect
- the range of MRT procedures contemplated for preclinical and/or clinical investigations and the general ethical, social, and policy considerations surrounding MRT;
- the management of incidental findings, should they arise; appropriate compensation, with sensitivity to socioeconomic status;
- the prospect of future contact between individuals who provided their gametes and children born as a result of MRT; and
- the management of residual eggs and embryos.
- For intended parents, consent processes should reflect
- information on the MRT research protocol, with focus on the implications for the health and well-being of resulting children;
- alternative ways of becoming parents that can avoid maternal transmission of mitochondrial DNA (mtDNA) disease;
- the management of and potential restrictions on access to embryos created through MRT (e.g., if initial investigations are limited to male embryos);
- preimplantation and prenatal genetic diagnostic tests that would be incorporated into clinical investigation protocols;
- the importance of long-term follow-up and how it would be part of the experience of any child born as a result of MRT; and
- the challenges of maintaining patient privacy given intense media interest in MRT.
- For children born as a result of MRT, consent processes should reflect assent (and eventual consent) for monitoring and research procedures to be performed after birth, up to and including seeking informed consent from the children upon their reaching the legal age of consent.
Recommendation 6: The U.S. Food and Drug Administration’s (FDA’s) overall plan for review and possible approval and subsequent marketing of mitochondrial replacement techniques (MRT) should incorporate the following elements:
- Transparency: Regulatory authorities should maximize timely public sharing of information concerning the MRT activities and decisions within their jurisdiction. FDA should encourage sponsors to commit to depositing protocols and deidentified results in public databases.
- Public engagement: Regulatory authorities should incorporate ongoing exploration of the views of relevant stakeholders into the overall plan for review and possible marketing of MRT and should support opportunities for public meetings to gather these views.
- Partnership: FDA should collaborate with other regulatory authorities within and outside the United States to improve the quality of the data available for the assessment of benefits and risks.
- Maximizing data quality: FDA should require that sponsors have adequate resources, use appropriate designs, and plan studies that enable cross-referencing and pooling of data for assessments of benefits and risks.
- Circumscribed use: FDA should use the means at its disposal to limit the use of MRT to the indications, individuals, and settings for which it is approved, and should engage the public in a fresh ethical analysis of any decision to broaden the use of MRT.
- Long-term follow-up: FDA should require that sponsors design, fund, and commit to long-term monitoring of children born as a result of MRT, with a plan for periodic review of the long-term follow-up data.
