Letter to ACOG Regarding Mifepristone (Mifeprex) Advocacy

May 23, 2002

Ralph Hale, M.D.
Executive Vice President
The American College of Obstetricians and Gynecologists
409 12th Street, S.W. Washington, D.C. 20090-6920

Dear Dr. Hale:

We write to object to your prior efforts, purportedly on behalf of the American College of Obstetricians and Gynecologists, to compromise the FDA’s proposed restrictions on the use of mifepristone in combination with misoprostol to terminate pregnancies. Your letter¹ to Dr. Jane Henney of the Food and Drug Administration (FDA), dated July 24, 2000, and the accompanying three-page ACOG “Analysis”², urged FDA to take steps that could endanger the lives of women. We are puzzled that ACOG would suggest that the FDA’s “requirements are not based upon scientific facts, do not follow current medical practice and impose inappropriate conditions on the practice of medicine,” and that ACOG would imply that these restrictions could negatively affect “the quality of healthcare.” We are particularly concerned by the following statement contained in the analysis accompanying the letter: “Requiring ultrasound to date a pregnancy or determine if there is an ectopic pregnancy is not required to administer the drug safely and correctly.”² Yet the U.S. clinical trials upon which the FDA Mifeprex approval was based employed transvaginal sonography on all prospective participants to assess gestational age and exclude ectopic pregnancy. If the safety data depended upon ultrasound confirmation of gestational age and location, should not the usage requirements do likewise? As you know, the combination of mifepristone and misoprostol cannot terminate an ectopic pregnancy, and the symptoms of an ectopic pregnancy, namely vaginal bleeding, cramping and pain, are mimicked by the Mifeprex procedure. Moreover, a delay in the diagnosis of an ectopic pregnancy can lead to death. The consequences of a failure to exclude patients with an ectopic pregnancy were starkly illustrated by the recent FDA report of the death of a patient from a ruptured ectopic pregnancy while undergoing the Mifeprex procedure. Further, the FDA has only approved the Mifeprex procedure for use at ≤ 49 days of gestation because the failure rate and frequency and severity of complications associated with the Mifeprex procedure increase with the increasing duration of a pregnancy. An error of one week in the estimation of gestational age can result in a nine-fold increase in “failures representing ongoing pregnancies.”³ The ACOG analysis states that without sonography “physicians and patients can quite accurately date a woman’s pregnancy.” This statement is at sharp variance with the published literature on ultrasound dating versus dating by clinical examination and menstrual history. Crenin and Spitz, for example, in their comparison of the accuracy of menstrual history dating versus sonographic dating of the women from the U.S. clinical trials of the Mifeprex procedure, found that “the gestational age according to the LMP was verified by transvaginal sonographic examination only 39% of the time when a gestational sac was present, and 51% to 63% of the time when an embryonic pole was present.”⁴ Does the ACOG leadership truly believe that the gestational dating errors inherent to clinical estimates without ultrasound confirmation can ever be in the best reproductive health interests of the pregnant women involved? In your letter, you state it is “imperative that the FDA’s work be based solely on evidence from the drug’s clinical trials, and be entirely free from any political influence.” Ironically, it is the American College of Obstetricians and Gynecologists that advocated a political position in contravention to the standards used in the clinical trials. At the very least, such a step should not have been taken without consulting the ACOG membership. We request the ACOG leadership to revisit this position and the recommendations to the FDA in light of both the recent death from an ectopic pregnancy in a patient being managed with Mifeprex, and the increased complications incurred when imprecise gestational dating accompanies Mifeprex use. Short of this, ACOG’s position and recommendations regarding the Mifeprex procedure would appear to be opposed to the stated mission of the College to safeguard the health of American women. We respectfully request a reply, particularly with reference to the questions in the second and fourth paragraphs above, and the request in the fifth paragraph above.

Sincerely,

Donna Harrison, MD, FACOG
Chairperson, AAPLOG Committee on Mifeprex Use
On behalf of the AAPLOG Executive Committee and Board of Directors

Notes

1Letter of July 24, 2000 from Dr. Ralph Hale of ACOG and E. Ratliffe Anderson of the AMA to Dr. Jane Henney of FDA. (Document obtained through the Freedom of Information Act) 2 ACOG Analysis of the Possible FDA Mifepristone Restrictions to the FDA, dated July 27, 2000. (Document obtained through the Freedom of Information Act) 3 Irving M. Spitz et al., “Early Pregnancy Termination with Mifepristone and Misoprostol in the United States,” New England Journal of Medicine 338 (1998): 1241-47, at 1247 (observing that for pregnancies of more than 49 days’ gestation, “the regimen is less effective and the incidence of adverse events is higher.”) 4 Crenin and Spitz, “Use of Various Ultrasonographic Criteria to Evaluate the Efficacy of Mifepristone and Misoprostol for Medical Abortion,” American Journal of Obstetrics and Gynecology 181 (1999): 1419-24.

Copies to: ACOG Officers, Committee and Section Chiefs, AAPLOG membership.