On August 13th the Food and Drug Administration (FDA) approved the drug “ella” (ulipristal acetate) for prescription use as emergency contraception (EC). The agency recommended it for “occasional” use up to five days following either unprotected intercourse or contraceptive failure, causing the Drudge Report to name it the “week-after pill.” The innocently named ella has the potential to do far more than merely prevent ovulation or even prevent embryonic implantation: there is good reason to believe it can also act as an “abortion drug” in the vein of RU-486, interfering with and indeed ending implanted pregnancies. As such, the approval of ella rightly ought to have involved more than antiseptic scientific data, institutional reviews, and clinical trials: ella’s approval and use raises fundamental questions of life, death, and ethics that our regulatory system is ill-equipped to answer.
Given the probable usefulness of ella as an abortion pill, the FDA’s approval of the drug for EC prescription is only the beginning of the controversy surrounding ulipristal. A newly approved abortion drug for EC purposes will warrant future regulatory battles over the drug’s labeling, disputes over abortion funding, and, ultimately, demonstrate the inadequacy of our current pharmaceutical regulatory regime in controlling the “off-label” use of drugs. (“Off-label” use of drugs, of course, refers to the use of drugs for purposes outside of their FDA marketing approval. The possibilities for the “off-label” use of ella are obvious.)
News reports on the approval of ella note that it is an improvement over the previous form of emergency contraception “Plan B” (levonorgestrel), which purports to work only seventy-two hours after unprotected sex or contraceptive failure. Levonorgestrel has been used in hormonal contraceptives for decades, and Plan B simply uses a large dose of it to prevent pregnancy by preventing a woman’s ovulation. (Plan B’s label, however, also notes that it can wok by obstructing fertilization of the ovum or by preventing the fertilized embryo from implanting in the womb.) The ulipristal in ella works in a similar manner according to its label: “When taken immediately before ovulation is to occur, ella postpones follicular rupture. The likely primary mechanism of action of ulipristal acetate for emergency contraception is therefore inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy.” While the operation of the drugs as EC might be similar, ella can boast that it is approved for use up to two days longer than Plan B.
In all likelihood, however, ulipristal does more than simply prevent ovulation or implantation like levonorgestrel. As the American Association of Pro-Life Obstetricians and Gynecologists (AAPLOG) pointed out in their submission to the FDA prior to ella’s approval, ulipristal acts as a “selective progesterone receptor modulator” (SPRM). An SPRM acts to block receptors of the hormone progesterone throughout the body. AAPLOG described three ways this could possibly kill the developing child:
1. Ulipristal blocks progesterone at the level of the endometrial glands, and destroys the receptivity of the endometrium so that the embryo cannot implant;
2. Ulipristal destroys the capacity of the corpus luteum granulose cells to produce progesterone; production of progesterone at the corpus luteum level supports the implanted embryo throughout the first 10 weeks of pregnancy; absent this corpus luteal progesterone production, the placenta which feeds the embryo will die; this mechanism of action is identical to the action of [abortion drug] RU-486 on the corpus luteum;
3. Ulipristal directly blocks progesterone receptors in the endometrial stromal tissue, identical to the mechanism of action of mifepristone (RU-486) which kills the implanted embryo by directly destroying the maternal component of the placenta.
AAPLOG notes that the second and third abortifacient mechanisms, similar to those of mifepristone, distinguish ulipristal from levonorgestrel, which does not interfere with an implanted embryo. So while ella has been approved for marketing as contraception in the same vein as Plan B, it has the capacity to operate like the (more tightly regulated and more controversial) abortion pill RU-486.
AAPLOG, in its submission to the FDA, suggested that ella should have a “black box” warning on its label about its abortifacient properties, not unlike the drug Cytotec (misoprostol)—a drug approved for the treatment of certain ulcers that also moonlights as the abortion drug of choice in places where RU-486 is not available. As it stands, the ella label does note that “use of ella is contraindicated during an existing or suspected pregnancy.” This notice to users, however, is practically meaningless in the world of drug regulation, as the approved use of a drug by the FDA has more to do with marketing than with use.
FDA approval is a notoriously costly and laborious process, and when a drug company submits a “new drug application,” the drug undergoes no fewer than three phases of clinical testing for a specific population (e.g. “adults”), with specific administration criteria (e.g. “by prescription”) for a specific condition (e.g. the treatment of NSAID-induced gastric ulcers). When the FDA approves a drug, it can be marketed by the drug company under the conditions set forth—so the manufacturer can market misoprostol to adults to take the drug by prescription to treat NSAID ulcers. This marketing takes the form of marketing to “learned intermediaries” (physicians) who then recommend and prescribe the drug to patients, or, more recently “direct to consumer” (DTC) marketing, alerting consumers directly what their options are so they inquire with their physicians about the possibility of taking a drug. (The myriad commercials ending with, “Ask your physician if [drug X] is right for you,” following a comically long list of horrible side effects are examples of DTC marketing.) The FDA approval process bears directly on how drug companies can market drugs, not on how physicians can prescribe them.
It is an established fact of law that the FDA does not regulate the practice of medicine. As such, physicians are free to prescribe drugs as the practice of medicine dictates, not as the FDA has approved them. This “off-label” prescription of drugs is so commonplace that in some specialties a physician’s failure to prescribe a drug in an “unapproved” manner can open her up to malpractice liability. In many ways, this makes sense: in fields such as oncology, time is of the essence in treatment, so the cutting edge of the specialty might rely on accumulated knowledge and academic studies in lieu of plodding regulatory approval in Washington; in pediatrics, most drugs are approved already for adult populations, but getting them approved with a supplemental new drug application for children would be prohibitively costly (leaving aside the ethical problems with conducting clinical trials on children). Thus the current FDA regulatory framework does not constrain “unapproved” uses of drugs.
In the case of ella, this means that its labeled contraindication for pregnant women is wholly irrelevant to how it can be prescribed. While the label professes agnosticism as to how ulipristal might interact with an implanted pregnancy, the science of SPRMs like mifepristone is well established. A physician who is aware of ulipristal’s embryocidal properties has nothing to prevent him from prescribing ella to a patient in the early stages of pregnancy, regardless of what the FDA label indicates. Indeed, the main constraint on a physician doing so would be the fear of malpractice liability in the case of an adverse event.
In a sense, ella’s manufacturers do not need the FDA to approve ulipristal for anything more than EC. If they were to get it approved as an abortion drug, that would simply allow them to market it as such, and the political and commercial realities of contemporary America make DTC (or even learned intermediary) marketing of an abortion drug a dubious goal for a corporation. With or without FDA approval, the sorts of physicians who prescribe abortion drugs will be able to prescribe ulipristal to terminate a pregnancy.
Herein lies an immediate problem: If ella is labeled for use as emergency contraception, but can be prescribed to effect an abortion, what is to prevent Federal monies from subsidizing it as contraception, only to have it used as an abortifacient? Congressman Chris Smith has concluded that coverage of the drug is probably mandated under the recent healthcare reform act, and has called on President Obama to issue an Executive Order clarifying that federal agencies and affected insurance plans are not to fund the drug. Given the already blurry line between contraceptive family planning and abortion, executive clarification is certainly in order.
Another development that is probably pending is a dispute over ella’s administration criteria. As it stands, it is only available by prescription, in stark contrast to the other available EC, Plan B. When the FDA allowed Plan B to be distributed to adult women without a prescription for over the counter distribution for women 18 and older it was hailed by Planned Parenthood’s Cecile Richards as “great news for women and great news for women's health.” It is highly unlikely that the reproductive health left will be content with the administration discrepancy between the two drugs, and similarly unlikely that Watson will pass up the opportunity to increase the drug’s market share as EC by removing the necessity of having a doctor write the prescription (regardless of its capacity to function as an abortion pill). In the coming months and years we should expect a supplemental new drug application from Watson asking for a dual administration label like Plan B, thus allowing adult women to buy ella without prescription. This would put the FDA in the position of approving an OTC abortion pill.
According to Kirsten Moore of the Reproductive Health Technologies Project, ella’s approval “was consistent with standard FDA procedure and based on scientific evidence, not politics.” Those standard FDA procedures, however, are not well equipped to respond to the unique problems posed by the emergency contraception ulipristal: namely its potential for off-label use as an abortion pill. Even if the FDA were to rightly adopt stricter labeling guidelines warning of abortifacient potential, like those employed with misoprostol, that would only serve to inform consumers, and not have any bearing on physicians who prescribe the drug to perform an abortion. Such warnings will also have little effect on women who purchase the drug on their own, should ella become over-the-counter like its predecessor Plan B, with the intent of procuring an abortion.
The possibilities of public funding for ella, its switch to over-the-counter availability, and its usefulness as an abortion drug implicate more than just “scientific evidence,” and necessarily involve politics. Drugs like ulipristal further blur the line between contraception and abortion, and lawmakers like Congressman Smith are right to demand that those lines remain bright when it comes to appropriations, regardless of the confusion caused by FDA labeling. More generally, the relatively quiet approval of an abortion drug as contraception should cause us all to step back and consider whether our current regulatory framework is in the best interests not only of Big Pharma, physicians, and patients, but also those of the body politic.
Michael Fragoso, formerly a policy analyst at the Family Research Council, is a law student at the University of Notre Dame.