While the US Food and Drug Administration (FDA) sits on the fence over whether to approve preclinical or clinical trials using mitochondrial replacement techniques (MRT) to help prevent the transmission of certain diseases passed from mother to child, the Institute of Medicine (IOM) of the National Academies of Sciences, Engineering, and Medicine came out with a new report on Wednesday detailing how it believes FDA should allow such trials and regulate them.

Background

The report, commissioned by FDA, is the result of the work of a committee of academic experts from Harvard, Johns Hopkins University, California Institute of Technology, the National Institutes of Health and other top research institutes.

The committee was tasked with examining the issues of MRT and recommending whether and how FDA should move forward with initial clinical investigations that could potentially disrupt the passage of some types of inherited mitochondrial DNA (mtDNA) diseases.

Examples of mitochondrial diseases, sometimes caused by mutations in the mtDNA (and sometimes caused by mutations in genes of the nuclear DNA (nDNA)), include Leigh syndrome and Leber’s hereditary optic neuropathy.

So why did FDA commission a report on this sensitive subject? Because MRT preclinical research or clinical investigations would involve the creation, manipulation and possible destruction of embryos, which has long been controversial in the US. As the committee notes, even an FDA request that data from such research be submitted in support of an IND (investigational new drug) to start first-in-human clinical investigations could be controversial.

The recently passed omnibus spending plan even included language preventing FDA from reviewing applications related to genome-editing tools to modify the DNA of human embryos “until serious and unquantifiable safety and ethical issues can be resolved.”

FDA's Center for Biologics Evaluation and Research spokesman Paul Richards told Focus:"FDA appreciates the thoughtful work of the IOM in issuing its report on mitochondrial replacement techniques. We will be carefully reviewing the report and recommendations." 

Richards also noted how the omnibus "prevents the FDA from using funds to review applications in which a human embryo is intentionally created or modified to include a heritable genetic modification. As such, human subject research utilizing genetic modification of embryos for the prevention of transmission of mitochondrial disease cannot be performed in the United States in FY 2016."

So far, biologists at Oregon Health and Science University are some of the few who have sought FDA approval for a trial using a type of mitochondrial replacement therapy. As the authors note in that paper from 2013, it is “crucial” that FDA “initiates careful review of these new developments.”

Shoukhrat Mitalipov, a biologist at the Oregon University, told Nature on the committee report: “It’s good news, but the future seems very hazy compared to a few months ago,” noting the restrictions from the spending bill. 

In the UK, legislation regulating the clinical application of MRT was approved by the House of Commons and the House of Lords last year.

What’s at Stake

According to the committee, MRT, if effective, could help women have a genetically related child without incurring the risk of passing on an mtDNA disease, though FDA must first address a “unique combination of characteristics that raises a novel collection of ethical, social, and policy issues.”

Such issues involve creating embryos via the transference of healthy human eggs, that if transferred would result in offspring with genetic material from two women of different maternal lineage, which has never been approved by FDA or other US federal regulatory authorities; allowing for modifications in the mitochondrial genome that could be heritable if MRT were carried out to conceive female offspring, due to the matrilineal inheritance of mtDNA, and the effects of those modifications (whether beneficial or deleterious); some of the genetic modifications of which any resulting effects would not, at this time, be reversible; and some genetic modifications would affect every cell type of the resulting individual, meaning the changes wouldn’t be confined to a specific organ system.

“The committee concludes that the most germane ethical, social, and policy considerations associated with MRT could be avoided through limitations on the use of MRT or are blunted by meaningful differences between the heritable genetic modification of nDNA and that introduced by MRT,” the committee said.

Recommendations for FDA

Glenn Cohen, faculty director of the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School, wrote on the center’s blog Wednesday: “The big headline is they have recommended FDA largely move toward allowing [MRT] 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)."

The committee report outlines six recommendations for FDA, including:

1. Initial clinical investigations of MRT should only be considered by FDA if and when the following stipulations are met:
1. Initial safety is established and risks to all parties directly involved in the proposed clinical investigations are minimized.
2. Likelihood of efficacy is established by preclinical research using in vitro modeling, animal testing, and testing on human embryos as necessary.
3. Clinical investigations are limited to women who otherwise are at risk of transmitting a serious 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.
4. 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.
5. Intrauterine transfer for gestation is limited to male embryos. Cohen notes in a separate post about why this limitation is “clever and interesting,” particularly as it would “eliminate the risk of germ-line modifications being transmitted to future generations, which is the real boogy man in the picture and has been a major issue for CRISPR gene-editing,” though it would also mean the US is a step behind the UK, which does not have such a restriction.
6. Clinical investigations are limited to investigators and centers with demonstrated expertise in and skill with relevant techniques.
7. FDA has reviewed haplogroup/haplotype matching and if compelling, considered it as a means of mitigating the possible risk of mtDNAnuclear DNA (nDNA) incompatibilities.
2. “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.”
3. If the conditions in the first recommendation are met, 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:
1. 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.
2. 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.
3. 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.
4. 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.
4. Following successful initial investigations of mitochondrial replacement techniques (MRT) in males, FDA could consider extending research of MRT to include the transfer of female embryos if:
1. 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;
2. Preclinical research in animals had shown evidence of intergenerational safety and efficacy; and
3. 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 modifications
5. In addition to attention to best practices for consent in research, 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.
6. FDA’s overall plan for review and possible approval and subsequent marketing of mitochondrial replacement techniques (MRT) should incorporate:
1. 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 de-identified results in public databases.
2. 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.
3. Partnership: FDA should collaborate with other regulatory authorities within and outside the US.
4. 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.
5. 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.
6. 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.

And as the report notes, the prospect of FDA approving the use of MRT could have implications for off-label uses too, which the committee says: “FDA would need to use all of the tools at its disposal to control off-label uses of MRT beyond those indications and settings for which it had been tested and approved.”

IOM Report: Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations