I am not going to go into the politics of Friday’s Supreme Court decision on abortion, and I need to start out by saying that I will reserve the right to delete comments to this post that are only politics-based flaming on the subject. But there is a drug regulation part of this story that could become increasingly important. This is of course the practice of “medication abortion”, which is most commonly done through taking mifepristone (also known as RU-486) and misoprostol. Mifepristone became available in the US in 2000, and has over the years become the route for about half the abortions in the country, on a steadily rising trend that will surely continue.
First the biology, then the regulatory affairs. Mifepristone is a competitive antagonist at the progesterone steroid receptor, a very potent one indeed (IC50 of about 25 picomolar) and it thus blocks progesterone’s effects. It’s an antagonist at some other steroid receptors as well (antiglucocorticoid and antiandrogen), but at potencies 100x to 1000x lower. Since we’re talking nuclear receptors here, the terms “agonist” and “antagonist” (which were imported from G-protein coupled receptors) don’t really fit all that well, though: mifepristone is an antagonist if it’s competing with progesterone, but by itself (no progesterone around) it might be better described as a partial agonist, which is a pretty roomy category with the steroid receptors and the nuclear hormone receptors in general. But in the case of pregnancy, there is most definitely progesterone around (it’s essential), and mifepristone shuts down its effects. That stops the maintenance of the uterine lining and starts its shedding process, detaching the embryo. After mifepristone treatment, misoprostol (a prostaglandin analog) dilates the cervix and induces muscle contractions, clearing the uterus. (Misoprostol itself can also induce an abortion, but it’s more effective in combination with mifepristone). This whole process is basically what happens naturally in case of a miscarriage, so this is in fact a voluntary, chemically induced miscarriage. The usual regiment is 200mg of mifepristone, followed by 800 micrograms of misoprostol 24 to 48 hours later, and this combination has a very high success rate.
As of 2016, this combination is approved for use 70 days (or fewer) since a woman’s last menstrual period. And now we get to the legal and regulatory aspects. FDA approval is of course a Federal decision – a drug (or a drug’s use) that is approved by the FDA is approved in all fifty states and US territories. Here we have an example of the Supremecy Clause, more specifically the doctrine of “pre-emption”, that Federal laws override state ones. If you really want to dive into that idea, it can be divided into “impossibility pre-emption”, where it would just be impossible to follow both a state and a Federal law that conflict with each other, and “obstacle pre-emption”, where a state law places undue obstacles to following the Federal one. But that is in constant tension with the Tenth Amendment, which says that the Federal government’s powers are not unlimited, that these are only the powers delegated to it by the Constitution, and that all other rights, etc. are reserved for the states themselves. There have been a number of battles over the years about where the line is drawn between these two. A particular battleground has been one of those enumerated powers of the Federal government known as the Commerce Clause. This is the power to regulate commerce “among the several states”, and for many years Federal authority had expanded in many areas under this heading. But in 1995, the Supreme Court in United States v Lopez held that Congress had managed to exceed its authority under the Commerce Clause (the first time in decades that any ruling like that had happened), and this came up again in United States v Morrison in 2000. You can come up with a lot of rationales for how some particular policy would affect interstate commerce, but you can’t go on doing that forever in all directions.
I am most definitely not going to dive into the complications of the Commerce Clause or pre-emption, but I did want to illustrate the basic principles and to show that these are very much fields for argument. Because that’s what we’re about to see. After Friday’s Supreme Court ruling in Dobbs, Attorney General Merrick Garland issued a statement that said (among other things) “we stand ready to work with other arms of the Federal government that seek to use their lawful authorities to protect and preserve access to reproductive care. In particular, the FDA has approved the use of the medication Mifepristone. States may not ban Mifepristone based on disagreement with the FDA’s expert judgment about its safety and efficacy.” Xavier Becerra of HHS had similar words. Here’s a Perspective piece earlier this year in the NEJM on pre-emption and mifepristone, which is a good look at the history of various state attempts to regulate it. Many of these are designed to avoid conflict with the safety-and-efficacy territory of FDA regulation, and instead come under the state-by-state regulation of medical practice – such as requiring an in-person doctor’s visit (rather than telehealth), addition of waiting periods, or even provisions that the drug has to be taken in the presence of a physician. But it has to be noted that some of these are part of the federal Risk Evaluation and Management Strategy (REMS) that applies to mifepristone anyway.
So there’s going to be plenty of sparring. This article from the New York Times is an early look at the landcape, and Steve Usdin has another at BioCentury. A key ruling is the 2014 attempt by the state of Massachusetts to ban the sale of Zohydro (a hydrocodone formulation), which was struck down in court because it could not stand up to FDA’s regulatory pre-emption. But this issue will be revisited with particular attention to the FDA’s ruling in April of 2021 that it would not enforce the mifepristone REMS requirement for in-person dispensing (which prohibited telehealth appointments and ordering through mail-order pharmacies). One side will argue that these have nothing to do with the agency’s purview of regulating safety and efficacy, while the other will counter that because the drug has been shown to be safe and efficacious that these modifications are appropriate and need to be stated to prevent unlawful attempts to narrow them. Personally, I have never liked “decline to enforce” as a regulatory principle. I think it’s a weak platform to stand on (are you trying to have things both ways?), and it just invites challenges that could be avoided by a more comprehensive change in the regulations. The FDA seems to be thinking this way as well – in December it announced that it was going to formally remove the in-person dispensing requirement from the REMS. You can expect lawsuits that will challenge this, probably from several states, and corresponding fights about whether the new rule should stay in effect while the court cases develop, etc.
Remember, the Dobbs ruling does not make abortion illegal. It reverses the Roe v Wade principle that it cannot be declared illegal, though, and thus returns the whole issue to a state-by-state battle. There’s a lot of confusion on this point, as well as a lot of confusion about “returning to the time before Roe v Wade”, since many people don’t realize that that time was one of loosening abortion restrictions in general (with wider access state-by-state than we’re going to see now, judging from the legislation already existing or underway in many states). Things have changed. But another one of those changes is the availibility of safe, effective abortion medication under federal regulatory law, and we’re about to see how that mixes with “let the states decide”.
