Litany of Unknowns Surface at FDA Meeting on Germline Mitochondrial Techniques

Posted by Jessica Cussins March 6, 2014
Biopolitical Times

An FDA committee held a historic public meeting last week to discuss the scientific, technologic, and clinical issues related to experimental procedures that would alter the human germline. The February 25-26 meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee was webcast live, and will be available in archived form in a couple of weeks.

What was most striking about the meeting was that the committee members, many of whom are scientists themselves, are so wary of the techniques at this time. Questions about efficacy and safety – in fact a litany of concerns about every aspect of these techniques – largely dominated the discussions. And although the FDA’s pre-meeting briefing document explicitly put social and ethical issues outside the scope of the discussion, a myriad of these problems also edged their way in.

I highly recommend watching the webcasts – particularly the afternoon session of the first day, which included public comments, discussion by committee members, and a summary of the deliberations by chair Evan Snyder. But if you don’t have time for that, please read on for an overview of what transpired.

The beginning of the first day was devoted to scientific presentations, most by researchers who are developing mitochondrial manipulation techniques: Gerald Shadel of Yale University, Salvatore DiMauro of Columbia University, Marc-André Sirard of Université Laval, Keith Latham of Michigan State University, Shoukhrat Mitalipov of Oregon Health and Science University (OHSU), Dieter Egli of Columbia University and the New York Stem Cell Foundation Research Institute, and Mary Herbert of Newcastle University.

The work described by Mitalipov at OHSU and by Herbert at Newcastle University has enjoyed the lion’s share of media attention. Their labs have been conducting animal and in vitro research on spindle transfer and pronuclear transfer, two of the mitochondrial manipulation techniques proposed as ways to enable women affected by mitochondrial disease to have unaffected and genetically related children. Both research teams are eager to move to human clinical trials in their respective countries.

After the research presentations, time was scheduled for public comments from people who had contacted the FDA in advance. Seven people were each given four minutes to speak; among them were Marcy Darnovsky, Executive Director of the Center for Genetics and Society; Jaydee Hanson, Director of the International Center for Technology Assessment; Stuart Newman, Professor of Cell Biology and Anatomy at New York Medical College; Enola Aird, Founder and Director of Mothers for a Human Future; and Sheldon Krimsky, Professor of Urban & Environmental Policy & Planning and Public Health and Family Medicine at the Tufts School of Medicine. (Links on their names go to samples of their writings on this issue.)

Not one member of the public spoke in favor of the techniques. The points raised by the speakers included these:

  • If the FDA were to approve these techniques, it could be the first time any jurisdiction in the world had authorized intentional genetic modification of children and their descendants, and the agency would be making this decision with little or no input from the public or elected officials.
  • The FDA is the wrong agency to have jurisdiction over such techniques.
  • These techniques could be a gateway technology for human cloning and germline engineering.
  • Any child resulting from this procedure would develop from a fertilized egg in which the non-mitochondrial maternal genes derive from a second woman, the intended mother, a situation with potentially harmful biological incompatibilities and deleterious trans-generational impacts.
  • Approval of clinical trials would represent an unprecedented level of human experimentation for which there can never be truly informed consent.
  • These techniques would pose risks to young women recruited to donate their eggs. 
  • Preferable alternatives for having healthy children are available to the small number of women who would be candidates for these techniques.
  • These techniques may not be specific enough to prevent further attempts at inheritable genetic engineering.
  • There has already been “mission creep” in proposals for applications of these techniques: the discussion has moved from considering them solely for the prevention of serious disease to also considering them for some cases of infertility.

The committee’s discussion followed. While different members seemed to lean in different directions about whether the techniques should move to clinical trials – some seemed in favor, some against, some undecided – the discussion was notable and informative because of the range and seriousness of the safety concerns raised by a large majority of them. (A roster of committee members gives their titles and affiliations.) Linda Dahlgren pointed out that data for clinical trials are not sufficient, and that the studies carried out so far have limited relevance as a proof of concept. Douglas Diekema said that, as head of an IRB, he would need to see larger sample sizes and long-term follow-up in the animal studies before he would be able to give approval. Sharon Reeder spoke as a woman who has mitochondrial disease about the huge physical toll giving birth took on her body, landing her in a wheelchair. She noted that it’s extremely challenging for children to live with chronically ill parents, and that she hopes more research will be done on treatments for people who already have mitochondrial diseases.

Larry Couture pointed out that we can’t predict the impact of these kinds of modifications down the line and that grading blastocysts is a not a good enough measure of health. He also refuted the argument that babies born to mixed-race couples could tell us anything about the health of babies resulting from these experiments, since they have inherited genes from two, and not three, people. Steven Goldman noted that in vitro trials will need to be very specific about which mutations in which tissues they are supposed to be treating, adding that the variability of mitochondrial diseases may make rigorous interpretation of clinical trials impossible. Tabassum Ahsan pointed out that better metrics would be needed for quality control of donor oocytes, and that it will be very difficult to define success in any trial. Timothy Cripe asserted that the bar for any pre-clinical trials will have to be high, given that this isn’t a treatment for sick people.

David Keefe’s remarks were particularly compelling. Apologizing for quoting Donald Rumsfeld’s notorious comments about “weapons of mass destruction” in Iraq, Keefe said, “There are things we know. There are things we don’t know. And there are things we don’t know we don’t know.” As a reminder, he cited the outcomes of DES and thalidomide, and argued that we must tread lightly. He asserted that using the techniques in question to treat infertility “should be taken off the table” and added that even using them to prevent the births of children with mitochondrial disease is a “very very slippery slope.” He pointed out that the US doesn’t regulate the fertility industry like the UK does, and that sick patients will put their trust in their doctors, who have a responsibility not to give them false hope.

Katharine Wenstrom reiterated that these patients are particularly vulnerable and that pregnancy for women with mitochondrial diseases can be extremely dangerous. She added that the inability to know whether the techniques had caused new problems for a child would be a huge burden for parents. John Gearhart expressed frustration over the term “mitochondrial manipulation or replacement” since technically it is nuclear replacement, or egg/embryo manipulation. Renee Reijo Pera commented that without first trying to develop techniques to see whether affected women might produce healthy eggs, we’re “over-engineering.” She noted the de facto “pact” against genetic manipulation of human embryos, and later told USA Today, "I just don't think that this is an avenue that we should pursue in humans."

In his summary remarks, committee chair Evan Snyder concluded that the discussion’s common theme had been the shared concern for the well-being of children born as a result of mitochondrial manipulation techniques. The sense of the committee, he said, was that there is not enough data either in animals or in vitro to move on to humans, and that these concerns involved both the preclinical data and the basic science. He asked: Are there better alternatives? What’s the unmet clinical need? And is this worth the risk? Acknowledging that some committee members found the data “very intriguing,” he went on to note that many felt that no one research model would be perfect. He added that long-term follow up in animal studies, of larger sample sizes, will be crucial; and that some studies may need to be mutation specific.

What will the FDA do next? The agency has not actually revealed whether it has received any formal proposals to approve clinical trials. And though it is not required to follow the guidance of its advisory committees, it often does. After the meeting, FDA press officer Jennifer Rodriguez told Reuters, “We have heard the concerns expressed at the advisory committee meeting, and will take the information back to consider whether we need to facilitate a public discussion and, if so, how best to do this.”

Chair Evan Snyder told reporters that he does not think the committee or the FDA will address the topic again within the year, though it will likely come up again after more animal research has been completed.

Previously on Biopolitical Times: