Protecting Providers and Access to Medication Abortion Part 1: Advising on Off-Label Drug Use
- April 21, 2023
- Natalie Birnbaum , Legal & Policy Consultant at Repro Solutions, P.C. and Of Counsel at Nelson Hardiman LLP
Last week, two judges with equal power issued opposing rulings in Texas and Washington that impact access to mifepristone. In Washington, a federal judge's decision protects mifepristone and confirms Food and Drug Administration (FDA) approval and status quo of its use in the 18 states (including Washington, D.C.) party to the case.
In Texas, a divided panel of the Fifth Circuit stayed the judge’s order in part pending its ultimate decision on appeal. The Supreme Court then placed its own stay on the Fifth Circuit’s decision to invalidate the FDA’s approval and the ability to mail the medication nationwide. The Supreme Court is expected to rule on the merits April 21.
As the courts opine and state governments respond, providers throughout the country are left to wade through confusing and contradictory laws to provide essential health care. These decisions impact providers' ability to use their medical judgment to provide abortion within the standard of care. Practically, providers must reconsider what medications they order, storage, dispensing, disposal, dosing regiments, who can provide them, and what new patient forms are needed. Off-label use of medication abortion is one way that providers can, and likely will, continue to offer care consistent with the evidence and current medical standards.
What is a medication abortion?
Over half of the abortions in the United States are medication abortions. Medication abortion is the most common, cost-effective, and least invasive method of early abortion in the country. The majority of medication abortion prescriptions include the ingestion of mifepristone and misoprostol. Mifepristone is an FDA-approved medication with a success rate of 99% when used correctly. In addition to a 20+ year track record of use in the U.S., the medication’s safety is well documented:
- documented in more than 100 peer-reviewed articles
- when taken effectively terminates a pregnancy 99.6% of the time
- holds only a 0.4% risk of major complications
- holds an associated mortality rate lower than 0.001%.
The World Health Organization (WHO) has even supported pre-prescribing abortion medication so people can have them on hand when needed, or "advanced provision." Since its approval in 2000, the FDA has modified the protocol and risk evaluation and mitigation strategies (REMS) on the drug multiple times to reflect updated safety and efficacy findings. Most recently, the FDA has allowed mifepristone to be sent through the mail, picked up at pharmacies, or obtained through a health care provider’s office.
Mifepristone is the standard of care for medication abortion. While it is the only drug specifically approved by the FDA for abortion, other medications are used for abortion care. A higher dose of misoprostol alone, methotrexate and misoprostol, or a letrozole and misoprostol regimen can safely and effectively terminate an early pregnancy. Following the recommended protocol for misoprostol-only, 93% of patients complete their abortions without additional intervention. Misoprostol is available in many places worldwide over the counter, without a prescription, and at low cost, making a “miso-only” regime the most common way to receive a medication abortion on a global scale. Misoprostol-only is not as common in the United States. This is likely because mifepristone is preferred because of its higher efficacy rates and fewer side effects. WHO recognizes the safety of efficacy of both misoprostol-only and a letrozole-plus misoprostol regime for medical abortion.
Understanding Off-Label Drug Use
Health care providers have a long and well-practiced history of prescribing medication abortion off-label. Off-label prescribing occurs frequently throughout the medical system and is a promising option for medication abortion in the face of legal restrictions that infringe upon professional judgment. According to the Agency for Healthcare Research and Quality, around 20% of all prescriptions in the United States are for off-label use.
The FDA recognizes that once a drug is approved, health care providers may prescribe it for an unapproved use based on what they judge as medically appropriate for their patient. Off-label use may include prescribing medication in a different dose, frequency, duration, or method of administration, or for a disease or medical condition it is not approved to treat.
Cancer drugs, for example, are commonly used off-label. Commonly, chemotherapy is approved to treat one type of cancer, but health care providers use it to treat a different type of cancer. Off-label medications are commonly used in psychiatry and cardiology as well. The most commonly used drug for treating ectopic pregnancy without surgery, methotrexate, is off-label for this purpose.
The Off-Label Prescription of Medication Abortion is Common, Safe, and Effective
Medication abortion has been, and will continue to be, prescribed off-label in four scenarios: (1) mifepristone protocols; (2) misoprostol-only protocols; (3) letrozole-misoprostol protocols; and (4) methotrexate-misoprostol. Misoprostol, methotrexate, and letrozole are not FDA-approved for abortion.
While the FDA approved mifepristone for medication abortion in 2000, the vast majority of providers used off-label dosing until 2016 when the FDA’s label caught up with evidence. Before 2016, the label required three times the necessary dose of oral mifepristone. It required the companion drug, misoprostol, to be given in the provider's office 48 hours later, in a dose and method of administration (oral) proven to be far less effective. In addition, the label limited use to 49 days after the patient's last menstrual period, while the evidence has shown effectiveness up through 77 days of pregnancy. As noted by Dr. Linda Prine, since 2000, “There was the clinical regime and there was the FDA-based regime.”
Before 2015 mifepristone’s medically unnecessary labeling restrictions required providers and patients to jump through excessive hoops to provide care. Physicians responded by prescribing mifepristone off-label to meet the needs of patients and match evidence-backed international standards. WHO recognizes safe and effective use in early and later pregnancy.
The Texas District Court and the Fifth Circuit both failed to correctly distinguish the difference between Mifepristone’s labeling requirements and the REMS. The 2016 REMS instructs providers to become specially certified and to follow a series of guidelines, which include dispensing to patients in person only. It is the drug manufacturer’s responsibility to ensure providers adhere to the REMS protocols and that mifepristone is not distributed to or dispensed through retail pharmacies.
Assessing Provider Risk in Off-Label Use of Medication Abortion
One possible outcome of the Texas case is that the FDA's mifepristone labeling requirements will regress to the 2000 label. Despite that off-label prescribing is an essential component of medical practice, abortion providers are concerned that hostile or restricted states may use creative and potentially extra-legal strategies to attack this medical practice. Abortion providers should consult teams with expertise in their state in order to assess their risk. The risk may be highest for providers working in states where medication abortion is legal, but the political and/or enforcement environment is hostile towards abortion, also known as “purple states.” Providers prescribing or administering off-label medication abortion in a state where abortion is legal, but the attorney general is vocally anti-abortion, must do a thorough risk calculation. States with expanded abortion access, however, are expected to exercise enforcement discretion, permitting providers to prescribe mifepristone off-label. Some considerations for a risk analysis include:
- Consumer Protection Claims: A hostile attorney general may rely on consumer protection regulations to target the off-label provision of medication abortion under state-based misbranding regulations. Consumer protections are designed to stop unfair and deceptive trade practices and misleading consumer information. A misbranded drug runs the risk of being interpreted as misleading if the provider fails to communicate to their patients that medication abortion is prescribed off-label.
In reality, providers may end up with stockrooms filled with safe, effective, and suddenly misbranded mifepristone. In this case, what is a provider supposed to do? After making a careful, state-based risk analysis, if a provider chooses to prescribe the mifepristone as previously labeled, one way to mitigate risk is by providing patients with written informed consent informing them of off-label use. Attorneys should assess each state's consumer protection laws, enforcement, regulations on drug labeling, and most importantly, the political climate when advising.
- State Regulations on Mifepristone: States may have specific regulations impacting the off-label use of mifepristone. Ohio, for example, has a 2011 law requiring providers to adhere to the medication abortion protocol approved by the FDA in 2000. This effectively prohibits the off-label use of mifepristone.
While these laws purportedly protect safety, they may ultimately result in worse medical outcomes as they drive care towards options that are less safe and effective. Notably, a study comparing patient outcomes before and after the law found that restricting medication abortion to the original FDA regimen resulted in women having three times the odds of requiring additional medical treatments to complete the abortions compared to women receiving the evidence-based off-label regimen pre-law.
- Medical Boards: Politicized state medical boards could also potentially use off-label use as a pretext for licensing penalties, even though these license actions are typically reserved for harmful practices that evidence shows lead to severe patient harm. However, given that the mifepristone/misoprostol medication abortion regime has been the standard of care for over two decades, and has hundreds of studies supporting its safety and efficacy, these actions seem less likely. Policy stances taken by organizations like the American Medical Association echo the sentiment that health care providers will continue to oppose government interference in the practice of medicine in the post-Dobbs world.
- Federal Enforcement Agencies: Enforcement action by the FDA limiting providers and manufacturers seems highly unlikely given the FDA’s continuous acknowledgment of medication abortion’s safe and effective use. There are a variety of ways that the FDA may enforce a regulation depending on the severity and nature of the violation. The four main actions are:
- Warning letters: FDA-issued warning letters require a response to correct the violation
- Seizure: the removal of an adultered or misbranded FDA-regulated product from the market
- An injunction by court order
- Criminal prosecution
It is more plausible that the FDA will issue an enforcement discretion notice clarifying that it will not regulate any judicially determined labeling requirements and REMS. The FDA issued a notice of enforcement discretion increasing access to mifepristone as recently as 2021 when it removed the in-person dispensing requirement, opening up the telehealth market for medication abortion.