Mitochondrial Replacement Techniques Ethical, Social, and Policy Considerations (2016) / Chapter Skim
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4 Regulation and Oversight of MRT in Humans
4 Regulation and Oversight of MRT in Humans
Pages 113-148
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From page 113... ...
This chapter reviews the trajectory of any potential preclinical and clinical investigations of MRT and the ethical, social, and policy considerations that would need to guide MRT investigations throughout the phases of research, the regulatory approval process, and postapproval. Addressed in turn are assessment of benefits and risks, submission of preclinical evidence prior to authorization of clinical investigations of MRT in humans, conditions for clinical investigations, principles and practices that should guide clinical investigations, extension of MRT research to female embryos, informed consent, and guiding principles for oversight.
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From page 114... ...
Another suggested benefit is the reduction in the number of children who would be born with serious mtDNA disease as a result of access to this reproductive technology. At present, women at known risk of passing on serious mtDNA diseases choose childlessness, adoption, or the use of donor oocytes or embryos (preimplantation genetic diagnosis [PGD]
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From page 115... ...
the potential future offspring of female children born as a result of MRT. Each of those parties could be exposed to risk directly or indirectly at some point in the preparation for and application and outcomes of MRT.
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From page 116... ...
In the case of MRT, attempts to minimize risk and burden for one of the above parties could interact with risk for another. However, the health and well-being, and minimizing risk of harm to any future children born as a result of MRT warrants priority in balancing benefits and risks in the design of clinical investigations.
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From page 117... ...
Before MRT was extended to female embryos, however, animal studies of second, and perhaps third, generations would need to be performed to collect data on the techniques' intergenerational safety and efficacy. CONDITIONS FOR CLINICAL INVESTIGATIONS Once safety had been established through preclinical research, MRT could be tested further through the transfer of embryos to intended mothers (or gestational carriers)
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From page 118... ...
In this sense, benefit would be maximized in initial clinical investigations by preventing the transmission of those mtDNA diseases known to be the most severe. In addition, to appropriately manage the balance of benefits and risks in MRT clinical investigations, individuals who provided oocytes would need to be pretested to ensure that they were not carriers of known pathogenic mtDNA mutations.
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From page 119... ...
Because of the scientific uncertainties associated with these novel techniques and because MRT in female embryos would have the effect of creating heritable genetic modification, an appropriately cautious approach to MRT research in the United States would need to include restricting initial first-in-human clinical investigations to male embryos. This restriction would be justifiable in two regards.
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From page 120... ...
. Although issues arising only in female offspring could not be resolved as long as MRT produced only male offspring, performing MRT initially only in males would allow preclinical research on intergenerational effects to continue while at the same time allowing families to use MRT to have male children with a significantly reduced risk of mtDNA disease.
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From page 121... ...
In addition, families who wished to have only female offspring or who were uncomfortable with sex selection would not be eligible for initial investigations. While there are real issues related to limiting initial investigations of MRT to male embryos, the committee believes the trade-offs involved are necessary and justifiable to effectively eliminate the risk of introducing deleterious heritable genetic modifications, and are consistent with eligibility criteria, design features, and research staging used for clinical investigations in other realms of medical innovation.
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From page 122... ...
. With regard to the design of potential MRT clinical investigations and in keeping with the principle of minimizing risk to children born as a result of MRT, should FDA's review of the preclinical data package reveal compelling evidence that mtDNA haplogroup matching between potential oocyte providers and intended mothers might mitigate the risk of mtDNA-nDNA incompatibilities resulting from MRT, such matching would be a reasonable inclusion criterion for initial investigations.
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From page 123... ...
• 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.
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From page 124... ...
In the case of MRT, it would be important to accumulate sufficient preclinical data on how the manipulation of gametes or embryos might affect the resulting embryos so as to reduce the risk of harm to children born as a result of MRT during clinical investigations. Preclinical research involving embryos of varying quality that would not be transferred would likely be necessary to produce the data necessary to protect future children.
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From page 125... ...
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.
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From page 126... ...
. The conditions for initial investigations laid out in Recommendation 1 -- including restriction to serious mtDNA disease, a healthy gestational mother, initial restriction to male embryos, and expertise of investigators -- represent an attempt to prioritize the minimization of risks to future children.
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From page 127... ...
The UK regulations allowing MRT as a clinical procedure went into effect at the end of 2015; FDA could utilize any data available from these procedures or MRT procedures performed in other countries.
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From page 128... ...
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 investi gations, 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.
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From page 129... ...
Significantly, transfer of female embryos would minimize the risk of passing on pathogenic mtDNA mutations that might otherwise be faced by all maternal members of a family's lineage over generations, effectively preventing mtDNA disease in future generations of families known to be at high risk. Giving families the ability to bear female children is also a value to be respected and one that could be served only by transferring female embryos.
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From page 130... ...
Preclinical Data on Intergenerational Effects Clinical investigations of MRT in males would generate data on safety and efficacy only in the first generation, that is, the children born as a result of MRT. Data on the effects of MRT in subsequent generations could only be generated by transferring female embryos, allowing time for these females to reach sexual maturity and choose to reproduce, and then assessing the health and well-being of these subsequent offspring.
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From page 131... ...
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 intergenera tional safety and efficacy; and • FDA's decisions were consistent with the outcomes of public and scientific deliberations to establish a shared framework concern ing the acceptability of and moral limits on heritable genetic modification. INFORMED CONSENT Informed and voluntary consent of those deemed research participants in MRT clinical investigations would be required pursuant to federal guidelines and applicable state laws and institutional practices.
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From page 132... ...
Nonetheless, the complexities and uncertainties associated with MRT suggest that the consent process holds significant potential to provide a thoughtfully designed structure for what is ultimately a highly valuable and critical component of research. The consent process would need to ensure that those participating in MRT research understood what their participation entailed and that it was voluntary.
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From page 133... ...
would be used for research purposes and stored indefinitely or destroyed. Incidental Findings Depending on the diagnostic techniques used to evaluate gamete providers and their gametes in the MRT research context, the consent process would need to include consideration of the possibility that the research would yield incidental findings with clear implications for participants' reproductive or other health care decisions (for example, if the gamete provider or his or her gametes were to undergo tests that revealed a particular genetic trait or mutation that would affect such decisions)
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From page 134... ...
. It would be important for MRT researchers and institutions, in consultation with local review committees or a central IRB, to consider current guidance and emerging best practices in determining appropriate compensation for gamete providers, taking into account the demands placed on a gamete provider by an MRT research protocol.
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From page 135... ...
Intended Mother and Intended Father (if applicable) Consent Components Applicable Specifically to the Intended Mother The consent process for an intended mother considering MRT in firstin-human investigations would likely be "a difficult and long-term process" (FDA Cellular Tissue and Gene Therapies Advisory Committee, 2014)
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From page 136... ...
In addition, an intended mother would need to be made aware of the potential that a child with significant disability could be born, and of the difficult decisions she might face regarding pregnancy termination if prenatal diagnostic testing revealed genetic or developmental anomalies or other adverse outcomes. Follow-up conversations as part of the informed consent process could help ensure that research participants had adequate information about the testing procedures (including information about each test's specificity, sensitivity, accuracy, risks, benefits, and limitations)
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From page 137... ...
It could be necessary to evaluate children to the point of sexual maturity to confirm that the reproductive system had not been adversely affected. Decades-long observation of children born as a result of MRT would be necessary to determine whether there were late-onset effects of MRT, and intergenerational follow-up would be necessary to track the health and well-being of subsequent generations if female embryos were transferred.
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From page 138... ...
The ethics review committee(s) charged with evaluating any initial MRT clinical investigation protocols, and the associated consent processes, would play an important role in ensuring that provisions for protecting the privacy of research participants were adequate and that the relevant parties were appropriately informed and prepared for any unintentional and inadvertent disclosures.
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From page 139... ...
It is ethically permissible, within limits, to try to persuade research participants, including children who have reached the age of consent, to continue to participate in research. In fact, in the committee's view, MRT research participants would have an ethical -- though not legal -- duty to remain involved in follow-up activities for their own benefit as well as that of other potential future users of MRT.
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From page 140... ...
Thus the potential effect of MRT on future generations needs to be a key consideration in broader policy discussions and research oversight related to MRT, becasue it cannot be addressed in the consent process for MRT clinical investigations. Conclusion: When intended parents provided consent to the MRT process, they would be, in essence, consenting on behalf of any future children.
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From page 141... ...
disease; − management of and potential restrictions on access to em the bryos 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; − importance of long-term follow-up and how it would be the part of the experience of any child born as a result of MRT; and − challenges of maintaining patient privacy given intense the media interest in MRT.
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From page 142... ...
Until 2014, for example, all gene-editing experiments were reviewed by the RAC, which holds public reviews and discussions when necessary. National-level bioethics commissions have been convened to address ethical, social, and policy considerations on such topics as cloning and stem cell research.
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From page 143... ...
This goal is especially important for MRT given the rarity of mtDNA diseases and the small number of patients that would be research participants. The UK regulations allowing MRT went into effect in October 2014; FDA could use any data available from these procedures, or from MRT procedures performed in other countries, to improve its assessment of benefits and risks.
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From page 144... ...
Long-term follow-up would need to continue, however, even if stopping criteria were employed to prevent further enrollment in or implementation of MRT clinical investigations. Circumscribed Use Given the novelty of MRT, its possible intergenerational effects, and the fact that the persons most affected -- future children -- would lack a role in making the decision to proceed, FDA would need to restrict approval to studies involving women with mtDNA disease with a compelling clinical need.
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From page 145... ...
overall plan for review and possible approval and subsequent market ing of mitochondrial replacement techniques (MRT) should incorpo rate the following elements: • Transparency: Regulatory authorities should maximize timely pub lic sharing of information concerning the MRT activities and deci sions within their jurisdiction.
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From page 146... ...
Public Workshop of the Committee on Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mito chondrial DNA Diseases, March 31, Washington, DC.
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From page 147... ...
Public Workshop of the Committee on Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases, March 31, Washington, DC. IOM and NRC (National Research Council)
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From page 148... ...
Presentation to the March 31-April 1 Public Workshop of the Committee on Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases, Washington, DC. http://iom.nationalacademies.org/Activities/Research/MitoEthics/2015 MAR-31.aspx (accessed August 26, 2015)
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