FDA-Approved Labeling and Evidence-Based Alternative Uses

The professional labeling for mifepristone, like that for all other FDA-approved medications, outlines the clinical pharmacology, indications, and contraindications for the use of the drug. The professional labeling also describes the particular protocol the FDA approved. In addition to the professional labeling, the FDA approved a Medication Guide for use with mifepristone. The Medication Guide is a patient education booklet that sets forth in lay terms much of the information contained in the professional labeling. The key elements of these documents include the following:

• Mifepristone will be supplied only to licensed physicians. Mifepristone will not be available to the public through licensed pharmacies. 

• Mifepristone is approved for termination of intrauterine pregnancy through 49 days of pregnancy, dated from the first day of the woman's last menstrual period.

• The duration of the pregnancy may be determined from menstrual history and by clinical examination. Ultrasound should be used if the duration of the pregnancy is uncertain or if ectopic pregnancy is suspected.

• Providers must be able to provide surgical intervention in cases of incomplete abortion or severe bleeding, or have made plans to provide such care through others, and must be able to assure that patients have access to emergency medical care. 

• The patient takes three 200 mg. tablets of mifepristone in a single oral dose.

• The patient returns to the provider two days after ingesting mifepristone.

• At the second visit, the patient takes 400 mcg. of misoprostol orally unless a complete abortion is confirmed.

• The patient returns for a third visit approximately 14 days after the administration of mifepristone, to confirm that a complete termination of pregnancy has occurred.

The FDA's role is to decide what drugs can be marketed in the United States. The agency has no direct control over health care providers and therefore cannot limit them to prescribing a drug in a manner consistent with the FDA labeling. Indeed, courts have held that the FDA cannot regulate how doctors prescribe approved drugs and medical devices.1 Consonant with this limitation on its powers, the FDA has an official policy permitting evidence-based alternative use, or "off-label" use, in which a provider prescribes a medication in a way that differs from the FDA-approved label.2 Providers may prescribe medicine in a different dose, for a different patient population, or for a different purpose. According to the American Medical Association, up to 60% of prescription drugs in the United States are prescribed for "off-label" uses.3

Evidence-based use of a drug in and of itself has no bearing on whether a physician has committed malpractice.4 The only question relevant to malpractice is whether the physician acted within the standard of care in administering a drug for an "off-label" use.5 Generally, a physician acts within the standard of care if he or she prescribes a drug for a use that is considered safe and effective based on sound scientific evidence and medical opinion.6 Thus, a provider dispensing mifepristone in a manner inconsistent with the FDA-approved labeling will be liable for malpractice only if he or she acted outside the standard of care.7 

Evidence-based alternative uses of mifepristone and/or misoprostol might include prescription for use at different stages of pregnancy, at different doses, according to a different schedule, or in a different manner (e.g., for vaginal rather than oral administration of misoprostol) from that set forth in the FDA protocol. Mifepristone might also be prescribed for non-abortifacient purposes, for example, to prevent pregnancy after intercourse or to treat fibroid tumors.

FDA-Approved Distribution Plan for Mifepristone

Although the FDA has no direct control over medical providers, it can exert indirect control by regulating how a drug is distributed. In the case of mifepristone, the FDA conditioned its approval on the agreement of the licensee, Danco Laboratories, to follow a restricted distribution plan. 

This plan was imposed pursuant to a special regulation known as "Subpart H."8 Contrary to media reports and the accusations of some anti-choice advocates, the FDA did not accelerate the approval process for mifepristone under this regulation. In fact, the FDA approved mifepristone only after carefully reviewing three complete phases of clinical trials - the standard review process - and issued its approval more than four years after the sponsor submitted its application. According to the FDA itself, the agency employed Subpart H solely to impose unusual restrictions on the distribution of mifepristone.9

The distribution plan incorporates two agreements: the Prescriber's Agreement and the Patient Agreement. Providers must sign both agreements, and have patients sign the Patient Agreement, in order to receive a supply of mifepristone from Danco. The Prescriber's Agreement specifies that the consequence of disregard of its terms is potential loss of supply of the drug.

The Prescriber's Agreement does not incorporate the entire FDA protocol. Physicians signing the Agreement must confirm, however, that mifepristone will be provided by or under the supervision of a physician who is able to: (1) assess duration of pregnancy accurately; (2) diagnose ectopic pregnancies; (3) provide surgical intervention in cases of incomplete abortion or severe bleeding, or have made plans to provide such care through other qualified physicians; and (4) assure patient access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary.

Physicians must also ensure that (1) the patient receives the Medication Guide; (2) the patient and provider sign the Patient Agreement; (3) the patient returns for a follow-up visit after approximately 14 days to confirm that a complete termination of pregnancy has occurred and that there have been no complications; (4) Danco is notified of any pregnancy not terminated after conclusion of the 

treatment protocol; and (5) a report is made to Danco of any hospitalization, transfusion, or other "serious event."

The Patient Agreement incorporates other aspects of the FDA protocol. It asks the patient to confirm that (1) she has read the Medication Guide; (2) she believes she is no more than 49 days pregnant; (3) she will take mifepristone in her provider's office; (4) she will return to the provider's office two days after taking mifepristone to determine whether she is still pregnant and, if so, to take misoprostol in the provider's office; and (5) she will return to the provider's office about 14 days after taking the mifepristone to confirm that the pregnancy has ended.

The provider must also sign the Patient Agreement, affirming that: "The patient signed the Patient Agreement in my presence after I counseled her and answered all her questions. I have given her the Medication Guide for mifepristone." As part of post-marketing studies, the drug's sponsor will be reviewing a sample of patient charts, including an assessment of whether providers and their patients have signed the Patient Agreement.

Providers should be aware that the Patient Agreement is not sufficient to demonstrate a patient's informed consent to an abortion. The Agreement does not contain any discussion of the risks and benefits of alternatives to abortion, nor does it discuss the risks and benefits of various abortion methods. Providers must therefore use an additional informed consent form.

FDA Status of Misoprostol

Recently, significant media attention has been focused on the second drug in the mifepristone regimen, misoprostol. This attention is due in large measure to a letter the drug's United States manufacturer, Searle, wrote to OB/Gyns across the country on August 23, 2000, advising that misoprostol (sold under the brand name Cytotec) is FDA-approved only as an ulcer drug and should not be administered to pregnant women, for abortions or other purposes. The Searle letter has prompted concern among some abortion providers about the permissibility of using misoprostol for early medical abortions.

Although Searle has never filed an application for FDA approval of misoprostol as an abortion drug, the FDA approved a protocol for mifepristone that incorporates the use of misoprostol. The FDA's approval was based on its careful review of studies in which misoprostol was used. It is, indeed, impossible to comply with the FDA mifepristone protocol without using misoprostol. Accordingly, although misoprostol did not go through a separate process in order to receive official FDA approval for use in the mifepristone regimen, the FDA has endorsed its use for that purpose.

Moreover, even if the use of misoprostol in mifepristone abortions is still technically an "off-label" use, it is simply subject to the same malpractice standard - which looks to the standard of care - described above. While the Searle letter may well be introduced as evidence in any malpractice trial against a provider who prescribed misoprostol for a mifepristone abortion, that evidence can be directly rebutted by the FDA-approved protocol for mifepristone, which specifically calls for the use of misoprostol, thus establishing that its use in mifepristone abortions constitutes the standard of care. In addition, a physician may rely on clinical data establishing the safe use of misoprostol in combination with mifepristone to terminate pregnancy.

_____________________________________________

Endnotes

1. E.g., Sita v. Danek Med., Inc., 43 F. Supp. 2d 245, 262 n. 13 (E.D.N.Y. 1999) (citing 21 U.S.C. § 396).

2. Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices, 59 Fed. Reg. 59820, 59821 & n.4 (1994) (affirming longstanding FDA policy permitting "unapproved" uses of approved drugs, and citing Use of Approved Drugs for Unlabeled Indications, FDA Drug Bulletin 12:4-5 (1982)); Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration, 37 Fed. Reg. 16503 (1972); Nightingale, S.L., "Use of Drugs for Unlabeled Indications," 34(3) Am. Fam. Phys., 269 (Sept. 1986).

3. James M. Beck & Elizabeth D. Azari, FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53 Food & Drug L.J. 71, 80 & n.73 (1998).

4. See, e.g., Richardson v. Miller, No. M1997-00205-COA-R3-CV, 2000 Tenn. App. LEXIS 551, at *13 (Aug. 16, 2000) (describing "off-label" as a "medically neutral" term). 

5. See, e.g., Sita, 43 F. Supp. 2d at 262-63 (citing cases).

6. See AMA Policy H-120.988, Patient Access to Treatments Prescribed by Their Physicians (reaffirmed and modified by Res. 528, A-99). 

7. A large body of scientific evidence documents the safety and efficacy of alternative uses of mifepristone/misoprostol. Protocols and practice guidelines published by the American College of Obstetricians and Gynecologists, the National Abortion Federation, Planned Parenthood Federation of America, and the Royal College of Obstetricians and Gynecologists include evidence-based alternative regimens. 

8. 21 C.F.R. § 314.520.

9. September 28, 2000, Memorandum of the FDA Center for Drug Evaluation and Research to NDA 20-687 MIFEPREX (mifepristone) Population Council, at 6.