Daniel Grossman

Sounding board: Sixteen years of overregulation: Time to unburden mifeprex: Mifeprex REMS study group

On March 29, 2016, the Food and Drug Administration (FDA) approved an updated label for Mifeprex (mifepristone 200-mg tablets, Danco Laboratories), the product that is commonly used in the United States in combination with misoprostol to induce a medical abortion. The changes made to the label were sweeping: they included a more effective dosing regimen containing less mifepristone and more misoprostol, expansion of the gestational limit for treatment from 49 to 70 days, omission of the recommendation for inperson follow-up, removal of language indicating that the prescriber must be a physician, and elimination of the requirement to report nonfatal adverse events. These revisions were supported by extensive data about mifepristone that have been accumulated since the FDA first approved the drug in 2000.1-7 Professional guidelines for medical abortion had already incorporated many of the new procedures,8-10 and thus the FDA’s action brought the drug label into line with current standard practice. The new label will undoubtedly have substantial benefits. Because the label now conforms with scientific evidence, it will reduce confusion among women, providers, and policymakers about the appropriate use of the drug. Moreover, it is expected to make abortion less expensive, more convenient, and more widely available in the handful of states where legislatures have enacted laws requiring adherence to the FDA-approved Mifeprex label.11 We suggest, however, that in merely updating the label, the FDA did not go far enough: the distribution of Mifeprex remains substantially and unnecessarily encumbered by a Risk Evaluation and Mitigation Strategy (REMS), which was left fundamentally unchanged. A REMS is a set of restrictions beyond the label that the FDA may impose under the authority of the federal Food, Drug, and Cosmetic Act (FDCA) when necessary to ensure that the benefits of a drug outweigh its risks.12,13 REMS programs are intended for drugs that are known or suspected to cause serious adverse effects that cannot be mitigated simply by the label instructions. The FDCA includes six factors that the FDA should consider when deciding whether to require a REMS, including the benefits and risks of the drug, the duration of treatment, the number of expected users, and the background risk of adverse events in the population (see Box). Each REMS is customized to address the specific risks of a given drug. The REMS for clozapine, which is indicated for the treatment of schizophrenia, is illustrative: because the drug can cause severe neutropenia, its REMS requires, among other measures, that pharmacists verify that each patient has had a recent neutrophil count before dispensing the drug.14 At this time, 7412 of the approximately 1750 prescription drug and therapeutic biologic active ingredients that have been approved by FDA and marketed in the United States15 have REMS programs. The core of the Mifeprex REMS is three provisions designated as “elements to assure safe use.”16 First, the drug may be dispensed to patients only in clinics, medical offices, and hospitals by or under the supervision of a certified prescriber; it may not be sold in retail pharmacies. Second, to prescribe the drug, a health care provider must become “certified” by completing and sending a form to the drug distributor attesting that he or she can assess pregnancy duration, diagnose ectopic pregnancy, and provide surgical intervention if needed, either personally or by referral. Third, each woman taking Mifeprex must be given an FDA-approved medication guide and sign an FDAapproved patient agreement that summarizes the use instructions specified in the label and the potential risks of the drug. Whereas drug labels are generally not binding for individual clinicians17 — misoprostol, for example, is approved for the prevention of gastric ulcers but is legally and widely used off-label for gynecologic purposes,

Uniqueness of Volume-Minimizing Submanifolds Calibrated by the First Pontryagin Form

One way to understand the geometry of the real Grassmann manifold Gk(R k+n) parameterizing oriented k-dimensional subspaces of Rk+n is to understand the volume-minimizing subvarieties in each homology class. Some of these subvarieties can be determined by using a calibration. In previous work, one of the authors calculated the set of 4-planes calibrated by the first Pontryagin form p1 on Gk(R k+n) for all k,n ≥ 4, and identified a family of mutually congruent round 4-spheres which are consequently homologically volume-minimizing. In the present work, we associate to the family of calibrated planes a Pfaffian system on the symmetry group SO(k + n,R), an analysis of which yields a uniqueness result; namely, that any connected submanifold of Gk(R k+n) calibrated by p1 is contained in one of these 4-spheres. A similar result holds for p1-calibrated submanifolds of the quotient Grassmannian G\k(R k+n) of non-oriented k-planes.