FDA scott gottlieb

How Scott Gottlieb is Wrong on the Gene Edited Baby Debacle

I am a huge fan of FDA Commissioner Scott Gottlieb.

He is by far my favorite Trump appointee — though the competition isn’t tough, to be honest— and he is doing great things at FDA on issues such as mobile health, software, and so on.

But in his comments on the news that gene edited embryos in China had led to live births, I think he has it wrong.

“The response from the scientific community has been far too slow and far too tepid, and the credibility of the community to self-police has already been damaged,” he said to Biocentury. “Governments will now have to react, and that reaction may have to take consideration of the fact that the scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line.” Read More

Investigating Conflicts of Interest in Patient-Centered Outcomes Research

By I. Glenn Cohen

The Patient Centered Outcomes Research Institute (PCORI) was established under the Affordable Care Act. Its goal is to fund and encourage Patient-Centered Outcomes Research (PCOR), understood as evaluating questions and outcomes that are meaningful not just to researchers, but to patients and caregivers as well.

One key way of achieving this is to involve patients as personnel in research projects as advisors, consultants, or team members involved in any aspect of research, from topic development through study design, implementation, interpretation, and dissemination.

But where do these patients come from? How representative are they of the patients who will ultimately participate in the study?

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Colorado Supreme Court Hears Important Case Re Constitutional Issues on Dispute About Frozen Preembyros – My Take on Oral Argument

By I. Glenn Cohen

On Tuesday, January 9th, the Colorado Supreme Court heard oral argument in In Re Marriage of Rooks. (Kudos to them for live streaming and archiving!)

This is the latest of a series of cases involving disputes between ex husbands and ex wives (or in some cases unmarried former partners) regarding the disposition of cryopreserved pre-embryos. These cases, that have been percolating in a large number of states for what has now been 25 years (!) and have come out in a myriad of ways on a myriad of theories as Eli Adashi and I recently detailed in the Hastings Center Report.

One thing many of these cases have in common, though, is that the Courts have avoided reaching the fundamental federal Constitutional question I wrote about now 10 years ago in the Stanford Law Review: Does the party opposing the implantation of embryos upon dissolution of the marriage have a right not to procreate recognized by the federal Constitution? I have argued that we need to realize we are talking about possible rights (plural) not to procreate and in particular separate out:

The right to be a gestational parent The right not to be a gestational parent
The right to be a genetic parent The right not to be a genetic parent
The right to be legal parent The right not to be a legal parent.

This case demonstrates well why such a distinction is important.

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Two Views About the Gene Editing ‘Breakthrough’ that Are Not Getting Enough Attention (IMHO)

As has now been well-covered in the news, Nature just published a paper from Mitalipov’s lab at the Oregon Health and Science University that used CRISPR/Cas 9 gene editing to correct the MYBPC3 mutation associated with hypertrophic cardiomyopathy — a heart muscle disease that affects 1 in 500 people. The more impressive element of the story is that by doing the alteration simultaneous with the sperm fertilizing the egg (not after fertilization) they were able to avoid the mosaicism that problematized early attempts in China — in mosaicism not all cells are repaired due to failure in the editing. The media coverage thus far, sadly but predictably, has focused on the soundbite of “designer babies” and “hope and hype” (indeed as my friend Hank Greely has suggested perhaps “overhype”.) These are worthy narratives to tell, to be sure, but here are two other narratives that I think are not getting the air time they deserve:

(1) The Importance of Genetic Ties: This use of CRISPR/Cas 9, as with most reproductive technologies, are attempts to allow those with disease-causing genes or other obstacles to reproduce genetically to do so. Investment and development of these technologies reifies the importance of genetic ties, as opposed to the kinds of ties associated with adoption, step-parenting, etc. It confuses a right to be a genetic parent, with a right to be a parent. We might have one right or both, but we should be clear they are different rights claims. Françoise Baylis has written eloquently about this issue in the context of In Vitro Gemetogenesis, and others (myself included) have mused on what claims the infertile have on society to have the state pay for these kinds of technologies instead of adopting. The National Academies report on gene editing suggested that clinical use of gene editing to eliminate disease be restricted to cases where there is an “absence of reasonable alternatives,” but does not take a position on when adoption is a reasonable alternative. Of course, in the U.S. at least, adoption is not easy and not available for everyone and there are a ton of interesting normative questions I have gestured at (including whether it matters for “reasonability” whether the child is of a certain age, race, or lacks developmental delay).

(2) The Importance of Embryo Sparing: A different alternative to gene editing in some cases is to fertilize large numbers of embryos and engage in preimplantation genetic diagnosis to eliminate those embryos that carry the disease-causing genes. There is a lot of obstacles to doing this: the fact that women may not retrieve enough eggs to do this, the cost (physical and financial) of repeated egg retrievals and PGD, the fact that this may not work for all genetic problems, etc. But one problem that vexes some is that this results in the destruction of large numbers of embryos (“discard” is sometimes used as the euphemism). Gene editing may be a solve for this problem. The Mitalipov group in their Nature paper have a line to this effect, “When only one parent carries a heterozygous mutation, 50% of the embryos should be mutation-free and available for transfer, while the remaining carrier embryos are discarded. Gene correction would rescue mutant embryos, increase the number of embryos available for transfer and ultimately improve pregnancy rate” (emphasis mine). This raises to me a very interesting question: some religious conservatives have tended to oppose both attempts to transform the human genome & embryo destruction (especially in the stem cell debate context). Could gene editing offer an olive branch to them as an alternative to the “greater evil” of routine PGD plus discard? Does it matter that to get to a place where we could achieve this we would have to actually destroy numerous embryos to perfect the research? (The Mitalipov embryos were not implanted, it seems under current U.S.  law that they could not be/) Is the right way to think about this consequentialist — destroy some embryos today to develop embryo sparing technologies to save many more tomorrow — or is this a case of complicity where the wrongfulness of the basic research taints what comes later?

John A. Robertson (1943 – 2017)

Renowned bioethics scholar, longtime University of Texas Law Professor, and frequent Bill of Health contributor John A. Robertson has recently passed away. We at the Petrie-Flom Center mourn his passing, and our Faculty Director I. Glenn Cohen writes a few words:

I saw John roughly a month ago at the Baby Markets Roundtable at UT Austin. He was, as he always was and as he still seems to me in my mind’s eye, full of electric intellectual energy, warmth, and whimsy. Every comment that I heard him make for over a decade at conferences began: “That’s so interesting…” and then he would proceed to subtly add something to whomever he responded to that was at once flattering of the idea and also five times better than what was said by original speaker. Certainly that’s how it felt when I was the person to whom he was responding.

Much will be said in coming weeks about his work—not only the centrality of Children of Choice to almost everything that has been written since on reproductive technology, but also the breadth of his work and the way in which almost every new technology soon had a wonderful take by him in print (IVF and uterus transplants most recently).

I’ll limit myself to two reflections. First, the way in which he put the field I write in (law and bioethics or law and the biosciences, depending on who you ask) on to the law school map, and with a few others (Rebecca Dresser, Alta CharoHank Greely, etc), gave it legitimacy as a real and important area of focus within law schools.

Second, and more personally, John was just about the best mentor to young scholars I have ever encountered. I met him first while I was a fellow at an ASLME event and I was blown away by the warmth and generosity of someone I considered a giant in the field (my idol if I’m honest) to a little pischer like me. Over the years I saw him do the same for countless others and I tried to do my best to palely imitate.

I can’t believe he is gone. The world seems a little darker.

Westworld and Bioethics

By I. Glenn Cohen

[WARNING: Spoilers below]

On Sunday, HBO’s Westworld finished its run. Though I thought some of the early episodes were arguably a bit of a failure as television (and my partner almost jumped off the bandwagon of making this one of “our shows”) IMHO the show finished very strong.

But whatever you thought of it as television, the show is wildly successful at raising a series of bioethics issues. There have been a bunch of other very good treatments of some of these issues in the last couple of decades – A.I., Ex Machina, Humans, Battlestar Galactica all come to mind – that touch on some of these issues. But, what I loved about Westworld is its lack of direct moralizing on these subjects, and how it leaves the viewer puzzling through them in a much more naturalistic way: I have been thrust in this unfamiliar world, and now I am trying to use my ethical compass to get my bearings.

Once upon a time I discussed Bioethics and the Martian, and my aim is to do the same here. I thought one way to share why I think the show is so successful as a text for bioethics exploration was to develop a “mock exam question” on the subject. This is really written more like an oral exam, with follow-up questions. The goal is not entirely fanciful since I do teach a course that uses films as texts to explore bioethics and the law.

Here goes: Read More

Initial Quick Thoughts on the Announcement of the Birth Through Mitochondrial Replacement in Mexico

The science media is abuzz about the birth of a child using mitochondrial replacement techniques in Mexico to Jordanian parents at the hands of NY Doctors. A few quick reactions (I am heading to this unrelated NAS/IOM Committee meeting tomorrow evening so may have some more thoughts when that settles down).

  • This is the first time this particular technique has been used to produce a live, but I am not sure from an ethical standpoint the arguments are all that different. That said, for those deeply interested in the more philosophical question of harm to children and the propriety of best interests argument in light of Parfit’s Non-Identity Problem (my take here and here) it may matter whether mitochondrial replacement is done through Pronuclear Transfer or Maternal Spindle Transfer as argued quite well here.
  • The fact that the doctors are from New York, the Patients are from Jordan, and the procedure took place in Mexico is not insignificant. This is a form of medical tourism, a topic I wrote a book on, most similar to cases of fertility and stem cell therapy tourism I cover in the latter half of the book. Absent making domestic prohibitions extraterritorial, something that I argue is permitted by international law and justified in some instances, there is very little that a home country can do about this. The going abroad is likely in part at least a function of some U.S. laws on the subject Eli Adashi and I wrote about for JAMA prohibiting FDA from considering approval of the technology.
  • As I wrote on this blog in February in relation to the IOM report “whatever the US policy in a world where medical tourism is possible and other countries adopt their own systems, so long as not everyone adopts the approach of the US some of these problems will manifest no matter what. So this is about harm reduction not harm avoidance.” This was a bit quicker than even I thought, but is not surprising. More generally if your concern about MRT is harm to offspring and transmission to future generations, people born elsewhere through the technology will inevitably enter the United States and/or marry, and procreate with U.S. citizens who themselves become U.S. citizens. To sound a bit X-Files about it “THEY WILL BE AMONG US!” This is a great example of the limits of unilateral regulation in a world of globalized health care.
  • Interesting that it was a male birth. This may be coincidence or in keeping with the IOM recommendation that only male embryos be transferred (to get rid of germ line transmission). Eli Adashi and I raised some ethical questions in Nature about whether that was an ethically problematic form of sex selection or not but in the reporting I have seen so far it has not been clear that they used only male embryos on purpose.
  • I wish we could stop calling it in the media “Three Parent IVF” or “Three Parent Reproduction.” That assumes the answer to what I think of as a subtle and interesting set of questions — is the mitochondrial donor a “parent” and what sense of the word do we mean.

More soon, I hope!

NIH Announces Plans for new Rules for Funding Chimera Research (Human-Animal Mixtures)

As reported by Science, today the NIH announced plans to lift a preemptive year long moratorium on funding chimera research – that which mixes human and animal cells, often at the embryonic stage.

Here is a snippet from the Science article about the new proposed NIH process:

According to two notices released today, NIH is proposing to replace the moratorium with a new agency review process for certain chimera experiments. One type involves adding human stem cells to nonhuman vertebrate embryos through the gastrulation stage, when an embryo develops three distinct layers of cells that then give rise to different tissues and organs. The other category is studies that introduce human cells into the brains of postgastrulation mammals (except rodent studies, which won’t need extra review).

These proposed studies will go to an internal NIH steering committee of scientists, ethicists, and animal welfare experts that will consider factors such as the type of human cells, where they may wind up in the animal, and how the cells might change the animal’s behavior or appearance. The committee’s conclusions will then help NIH’s institutes decide whether to fund projects that have passed scientific peer review.

The devil will, of course, be in the details. It will be interesting to see how much NIH takes a more categorical approach as opposed to more case-by-case rule making like in the Institutional Review Board or ESCRO setting. Read More

Whole Women’s Health, First Take: On the Major Victories and On Technocratic vs. Kulturkampf Approaches to Abortion Litigation at the Supreme Court

I have just made my way through all 107 pages of Whole Women’s Health v. Hellerstedt,  the Supreme Court’s decision this morning to invalidate Texas’ H.B. 2 admitting privileges and surgical center regulations as undue burdens on the abortion right. Full disclosure I filed an amicus brief arguing for this result.  The case was 5-3 with Justices Thomas, Alito, and Chief Justice Roberts in dissent.  I am sure I’ll have a lot more to say after I’ve read through the opinion 3 or 4 more times. Here’s what’s clear to me though even on a quick read.

First, this is a major victory for opponents of Targeted Regulation of Abortion Provider (TRAP) laws. Armed with this opinion they will have a much easier time in the lower courts challenging such laws. Among other things,  (1) the Court signals much less deference to legislatures than in Gonzales and prior cases (see p. 21 of Opinion); (2) the Court instructs that “The rule announced in Casey, however, requires that courts consider the burdens a law imposes on abortion access together with the benefits” conferred (p. 19) ; (3) the Court clarifies the “large fraction” language from Casey as to what is an undue burden in a way favorable to opponents of these regulations. Let me quote the majority here:

Casey used the language “large fraction” to refer to “a large fraction of cases in which [the provision at issue] is relevant,” a class narrower than “all women,” “pregnant women,” or even “the class of women seeking abortions identified by the State.” 505 U. S., at 894–895 (opinion of the Court) (emphasis added). Here, as in Casey, the rele- vant denominator is “those [women] for whom [the provi- sion] is an actual rather than an irrelevant restriction.” Id., at 895. (p.39)

Contrast that with Justice Alito’s long discussion in his dissent as to his understanding (with the pizzaz that shows why he is such a good writer) in a footnote:

The Court, by contrast, applies the “large fraction” standard without even acknowledging the open question. Ante, at 39. In a similar vein, it holds that the fraction’s “relevant denominator is ‘those [women] for whom [the provision] is an actual rather than an irrelevant re­ striction.’ ” Ibid. (quoting Casey, 505 U. S., at 895). I must confess that I do not understand this holding. The purpose of the large-fraction analysis, presumably, is to compare the number of women actually burdened with the number potentially burdened. Under the Court’s holding, we are supposed to use the same figure (women actually burdened) as both the numerator and the denominator. By my math, that fraction is always “1,” which is pretty large as fractions go.

Second, it is remarkable how differently these sets of opinions read from, let’s say, the gay marriage cases or even Gonzales v. Carhart. All the opinions, except perhaps Justice Ginsburg’s very short concurrence, are decidedly in the “technocratic” mode of writing as opposed to what we might call the “kulturkampf” mode that characterized much of Justice Scalia’s dissents on these kinds of issues. These opinion are written for lawyers not the public. I would have to do a proper count to be sure but it seems to me that something like 2/3 to 3/4 of the total pages of these set of opinions are devoted to issues that only lawyers will be able to engage in — res judicata/claim preclusion, severability, third-party standing, as-applied versus facial challenges, and the cogency of tiers of scrutiny.

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NPRM Symposium: Quick Take on New Analysis of the Comments on the NPRM to Amend the Common Rule (and the Challenge for Bioethics and the Public)

The Council on Governmental Relations (COGR), with support from the Association of Public and Land-grant Universities (APLU), undertook “to review and analyze the 2,186 public comments submitted in response to the 2015 Federal Policy for the Protection of Human Subjects” or “Common Rule” Notice of Proposed Rulemaking (NPRM).

I am going to discuss some highlights of their just released report, but this is far from exhaustive and you should read the whole report.

For the non-cognoscenti this is the most important revision to the rules for U.S. human subjects research since their inception. The report is largely unfavorable to several key proposed rule changes on my first read, but you should read it yourself to make up your own mind.

I’ll share some choice passages from the analysis

The results of our review (Table 2) find significant opposition to most major proposals, with mixed support for mandated use of a single IRB and extending the Common Rule and greater support for the concept of standard security safeguards. In addition, a number of responses suggested that the NPRM is overly complex, poorly written, and not supported by data; highlighted areas that could have a substantial impact on a final rule but were not included in the NPRM (e.g., proposed security safeguards, a consent template, a list of minimal risk studies and a decision tool); and suggested that some of the proposals would adversely affect human health with little perceived benefit.

Turning to Biospecimens, where we had a conference last year that will soon generate a book with MIT press:

The majority of responses, approximately 1,520, addressed one or more of the proposed changes detailed above involving non-identified biospecimens. Of these responses, 94 – 100% of patients and members of the research community, including researchers, universities, medical centers and industry, opposed the changes. Those commenting suggested that the proposed changes will significantly reduce the availability of biospecimens for research, will have a significant negative impact on medical advances, and will adversely affect human health. Per one patient, “I am asking for life saving policy not life ending policies.” From a biorepository, “Respecting autonomy at the expense of patient lives is a significant ethical concern.”

More surprising was their finding that “Among members of the general public, 55% opposed and 45% supported one or more of the major proposed changes related to biospecimens.” (They do a better breakdown of the various sub-constituencies in the report).

Turning to “broad consent” for biospecimen use:

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