FOOD AND DRUG 

ADMINISTRATION

Information on 

Mifeprex Labeling 

Changes and 

Ongoing Monitoring 

Efforts

Report to Congressional Requesters

March 2018

GAO-18-292

United States Government Accountability Office
United States Government Accountability Office

Highlights of GAO-18-292, a report to 

congressional requesters

March 2018

FOOD AND DRUG ADMINISTRATION

Information on Mifeprex Labeling Changes and 

Ongoing Monitoring Efforts

What GAO Found

The Food and Drug Administration (FDA) followed its standard review process 

when it approved the application and revised labeling reflecting certain changes, 

including the indication and dosing regimen, for the drug Mifeprex, which is used 

for the medical termination of early pregnancy. It based its approval on reviews 

of peer-reviewed published studies, articles, and other information submitted by 

Mifeprex’s sponsor. These studies focused on topics related to the proposed 

labeling changes, including revision of the dosing regimen, increased gestational 

age, method of follow-up care, and type of health care provider authorized to 

prescribe Mifeprex. FDA also received three letters from advocacy groups 

requesting that FDA revise the Mifeprex labeling in a manner that would reflect 

clinical practice. In addition, FDA reviewed the Risk Evaluation and Mitigation 

Strategy (REMS)—a set of restrictions beyond the label that FDA may impose—

associated with Mifeprex, and determined it continued to be necessary. FDA also 

reviewed adverse events—which the agency refers to as any untoward medical 

event associated with the use of a drug in humans, whether or not the event is 

considered to be drug related—associated with Mifeprex. It determined that the 

rates of certain adverse events remained stable and acceptably low. In addition, 

FDA reviewed information regarding potential risks of specific conditions 

associated with the use of Mifeprex and revised the labeling accordingly. FDA 

determined that the information it reviewed supported the changes to the 

Mifeprex labeling.

FDA has conducted a variety of monitoring activities and these have not 

identified significant concerns with the safety and use of Mifeprex, in accordance 

with its approved REMS.

• FDA has conducted three inspections of Mifeprex’s sponsor since 2008 

regarding adverse event reporting associated with Mifeprex—in 2010, 

2014, and 2016—and identified minor deficiencies, such as the use of an 

outdated reporting form.

• FDA conducted a REMS compliance inspection in 2014 and did not 

identify any deficiencies.

• FDA identified approximately 4,200 instances of adverse events 

associated with Mifeprex from September 28, 2000, through June 30, 

2017, among the approximately 3.2 million women who have used the 

drug. FDA identified 20 deaths in this period—a rate much lower than for 

women who proceeded to live birth. FDA learned of 2 additional deaths

associated with Mifeprex since June 30, 2017.

GAO found that the views of stakeholder organizations were mixed regarding 

FDA’s monitoring of Mifeprex. Positive comments included that the agency has a 

comprehensive monitoring program and a robust adverse event reporting 

system. Criticisms included that adverse events may be underreported and that 

FDA may only be aware of a fraction of them. Similarly, stakeholder 

organizations shared mixed views on the drug’s safety. Positive comments 

included that the mortality rate associated with Mifeprex is extremely low. Safety 

concerns included that the revised labeling no longer requires patients to have a 

second visit with a health care provider, and that certain safety issues may be 

exacerbated by the increased gestational age limit approved by FDA.

View GAO-18-292. For more information, 

contact Marcia Crosse at (202) 512-7114 or 

crossem@gao.gov.

Why GAO Did This Study

FDA initially approved Mifeprex in 2000

and restricted the drug’s distribution to 

assure its safe use. In 2011, the 

agency approved a REMS for the drug. 

In March 2016, FDA approved an 

application for changes to the 

indication and dosing regimen for 

Mifeprex, which were reflected in 

revised labeling. Other changes 

included omitting the requirement that 

the prescriber be a physician. At that 

time, FDA also made modifications to

the REMS. Some have questioned the 

safety implications of these changes 

for women using the drug.

GAO was asked to review FDA’s 

relabeling of Mifeprex. GAO describes

(1) the information FDA used to make 

its decisions regarding the relabeling of 

Mifeprex; and (2) what FDA’s 

monitoring of Mifeprex has revealed, 

and stakeholders’ views of FDA’s 

monitoring and the safety of the drug.

GAO reviewed documents related to 

Mifeprex's relabeling, including FDA 

policies and regulations. GAO 

analyzed adverse event reports related 

to Mifeprex and reviewed FDA 

inspection reports of Mifeprex's 

sponsor. GAO also examined studies 

and data related to the safety and use 

of Mifeprex, and obtained information 

from FDA officials; Mifeprex's sponsor; 

and 13 stakeholder organizations, 

including medical associations and 

advocacy groups selected on the basis 

of their medical or scientific expertise, 

relevant publications, or familiarity with 

the drug’s safety.

The Department of Health and Human 

Services provided technical comments 

on a draft of this report, which we 

incorporated as appropriate.
Page i GAO-18-292 Revised Mifeprex Labeling

Letter 1

Background 4

FDA Reviewed Published Studies that Supported the Efficacy of 

the Proposed Mifeprex Labeling Changes, and Evaluated 

Safety Information and Adverse Event Data 11

FDA’s Monitoring Activities Have Not Identified Significant Safety 

Concerns with Mifeprex; Stakeholders’ Views on FDA’s 

Monitoring and the Drug’s Safety Were Mixed 19

Agency Comments 27

Appendix I GAO Contact and Staff Acknowledgments 29

Tables

Table 1: Key Components of the Original Mifeprex Regimen and 

Prescriber Requirements, Approved in 2000, and the 

Revised Mifeprex Regimen and Prescriber Requirements, 

Approved in 2016 7

Table 2: Adverse Events Associated with Mifeprex Reported to 

FDA from September 28, 2000, through June 30, 2017 22

Contents
Page ii GAO-18-292 Revised Mifeprex Labeling

Abbreviations

FDA Food and Drug Administration

FAERS Food and Drug Administration Adverse Event Reporting 

System

HHS Department of Health and Human Services

REMS Risk Evaluation and Mitigation Strategy

This is a work of the U.S. government and is not subject to copyright protection in the 

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Page 1 GAO-18-292 Revised Mifeprex Labeling

441 G St. N.W.

Washington, DC 20548

March 28, 2018

Congressional Requesters

The prescription drug Mifeprex, in combination with the prescription drug 

misoprostol, is used for the medical termination of early pregnancy. The 

Food and Drug Administration (FDA), an agency within the Department of 

Health and Human Services (HHS), initially granted marketing approval of 

Mifeprex in September 2000. As a condition of the drug’s approval, FDA 

imposed restrictions on the distribution of Mifeprex under its general 

authority to help assure the safety and effectiveness of new drugs.1 More 

than 3 million women in the United States are estimated to have used this 

drug.

We have previously reported on FDA’s approval of Mifeprex and its 

oversight of the drug’s safety, including the restrictions the agency placed 

on the drug’s distribution.2 Since that time, in 2011, FDA approved a Risk 

Evaluation and Mitigation Strategy (REMS) for Mifeprex, with the goal of 

informing patients about the benefits and risks of Mifeprex, and to 

minimize the risk of serious complications associated with the drug.3 In 

May 2015, Mifeprex’s sponsor proposed several changes to the 

administration of the drug.4 It submitted a supplemental new drug 

application to FDA to obtain approval to revise the drug’s labeling.5

 1

See 21 C.F.R. § 314.520 (2000).

2

GAO, Food and Drug Administration: Approval and Oversight of the Drug Mifeprex, 

GAO-08-751, (Washington, D.C.: Aug. 7, 2008).

3

A REMS is a set of restrictions specifically authorized by statute that FDA may impose to 

ensure that a drug’s benefits outweigh its risks. See 21 U.S.C. § 355-1.

4

A drug sponsor is the person or entity who assumes responsibility for the marketing of a 

new drug, including responsibility for complying with applicable provisions of laws, such as 

the Federal Food, Drug, and Cosmetic Act and related regulations. Danco Laboratories, 

L.L.C., the sponsor of Mifeprex, is responsible for the marketing and manufacturing of 

Mifeprex, and submitted the supplemental application to FDA. 

5

Supplemental new drug applications are submitted to make certain changes to already 

approved new drug applications, including adding or modifying an indication or claim, or 

revising the dose or dosing regimen. FDA review and approval of most types of

supplemental new drug applications is required before the drug may be marketed with 

these changes. FDA characterized the supplemental application submitted for Mifeprex as 

an efficacy supplement that, among other things, revised its dosing regimen. See 21 

C.F.R. § 314.3 (2017). Throughout this report, references to the Mifeprex application 

pertain to this supplemental new drug application, submitted as an efficacy supplement. 

Letter
Page 2 GAO-18-292 Revised Mifeprex Labeling

Among other things, the sponsor proposed changing the dosing regimen, 

increasing the gestational age limit up to which Mifeprex can be taken, 

and eliminating the requirement that the dose of misoprostol be 

administered in a medical facility. FDA approved the labeling change in 

March 2016 and determined that the REMS continued to be necessary, 

with some modifications.

You and others have questioned whether the revised Mifeprex labeling 

has safety implications for the women who use the drug. For example, 

some stakeholder organizations, such as medical associations and 

research organizations, have raised concerns regarding FDA’s 

postmarketing monitoring of Mifeprex and the drug’s safety.6 You asked 

us to report on FDA’s relabeling of Mifeprex and its monitoring activities. 

This report describes

1. the information FDA used to make its decisions regarding the 

relabeling of Mifeprex; and

2. what FDA’s monitoring of Mifeprex has revealed, and stakeholders’ 

views of FDA’s monitoring and the safety of the drug.

To describe the information FDA used to make its decisions regarding the 

relabeling of Mifeprex, we obtained information regarding the agency’s 

review and subsequent approval of the revised Mifeprex labeling. 

Specifically, we reviewed documents in FDA’s approval package for the 

Mifeprex supplemental new drug application. The approval package

included FDA’s assessments of the published literature submitted by 

Mifeprex’s sponsor to support the safety and efficacy of the proposed 

changes.

7 Additionally, we reviewed other documents in the approval 

package, including communications between FDA and Mifeprex’s 

sponsor during the application process, and the revised Mifeprex labeling 

and REMS. In addition, we studied FDA’s assessments of adverse events 

associated with Mifeprex.8 Finally, we examined federal regulations and 

FDA’s policies and guidance documents, and interviewed FDA officials.

 6

The term postmarketing refers to activities occurring after a drug has been approved for 

marketing. 

7

FDA has posted documents pertaining to its review and approval on the agency’s website 

(see 

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020TOC.cfm). 

8

FDA uses the term adverse event to refer to any untoward medical event associated with 

the use of a drug in humans, whether or not the event is considered to be drug related.
Page 3 GAO-18-292 Revised Mifeprex Labeling

To describe how FDA monitors the safety and use of Mifeprex, we 

analyzed FDA’s postmarketing adverse event summary reports 

associated with the use of Mifeprex from September 28, 2000, (when the 

drug was approved) through June 30, 2017, and obtained information 

from FDA officials regarding the agency’s monitoring activities.9 We also 

reviewed quarterly adverse event summary reports submitted to FDA by 

Mifeprex’s sponsor for fiscal year 2017. To further describe FDA’s 

monitoring, we reviewed documentation from inspections the agency 

conducted to determine the sponsor’s compliance with relevant 

regulations and the Federal Food, Drug, and Cosmetic Act. Specifically, 

we reviewed FDA’s reports from inspections of Mifeprex’s sponsor for 

compliance with adverse event reporting requirements and the Mifeprex 

REMS that were performed since our 2008 report was issued.10 We 

obtained information from FDA on the number and results of inspections 

that FDA has conducted since 2008 for compliance with current good 

manufacturing practices.11 We also reviewed studies and data related to 

the safety and use of Mifeprex from FDA, stakeholders, and other entities. 

We discussed FDA’s data collection processes and any limitations with 

agency officials and determined that the data we used were sufficiently 

reliable for the purposes of this report. We also obtained information from 

Mifeprex’s sponsor on its perspectives of FDA’s monitoring. Finally, to 

describe stakeholders’ views of FDA’s monitoring and the safety of the 

drug, we obtained information from 13 organizations, including medical 

associations and advocacy groups with a variety of perspectives for their

 9

FDA officials said that the adverse events associated with Mifeprex in its summary 

reports do not necessarily reflect a conclusion by the company or FDA that the drug 

caused or contributed to an adverse event. See 21 C.F.R. § 314.80(l) (2017).

10See GAO-08-751.

11Current good manufacturing practices provide a framework for a manufacturer to follow 

to produce safe, pure, and high-quality drugs. See 21 C.F.R. pts. 210-21 (2017).
Page 4 GAO-18-292 Revised Mifeprex Labeling

views on FDA’s monitoring of Mifeprex, including any safety-related 

concerns they may have about the drug.12

We conducted this performance audit from April 2017 to March 2018 in 

accordance with generally accepted government auditing standards. 

Those standards require that we plan and perform the audit to obtain 

sufficient, appropriate evidence to provide a reasonable basis for our 

findings and conclusions based on our audit objectives. We believe that 

the evidence obtained provides a reasonable basis for our findings and 

conclusions based on our audit objectives.

The treatment regimen of taking Mifeprex, in combination with 

misoprostol, works by both interrupting the hormones that the body needs 

to maintain a pregnancy and inducing the uterine cramping necessary to 

cause a medical abortion.13 Mifepristone, the active ingredient in 

Mifeprex, was first approved in France and China in 1988, and is now 

approved in approximately 60 other countries, including the United 

States.

FDA must approve an application for a new drug before it can be 

marketed in the United States. FDA reviews scientific and clinical data 

contained in these applications as part of its process in considering them 

for approval to be marketed. FDA initially approved Mifeprex for use in the 

 12We obtained information from the following 13 organizations: the American Association 

of Pro-Life Obstetricians and Gynecologists; American College of Pediatricians; American 

Congress of Obstetricians and Gynecologists; Association of Reproductive Health 

Professionals; Bixby Center for Global Reproductive Health, University of California San 

Francisco; Charlotte Lozier Institute; Family Research Council; Guttmacher Institute; 

Gynuity Health Projects and the lead author of the Mifeprex REMS Study Group; Institute 

for Safe Medication Practices; National Right to Life Committee; Office of Population 

Research, Princeton University; and Planned Parenthood Federation of America. We 

selected these organizations on the basis of their medical or scientific expertise, their 

publication of relevant articles and web-based materials, or their familiarity with the safety 

and use of Mifeprex.

13Mifeprex is the trade name for one of the two mifepristone products approved and 

marketed in the United States (the trade name for the other product is Korlym, which has 

a different, unrelated indication). Mifepristone is the underlying drug substance and is also 

sometimes called RU-486, a reference to the name the drug had during laboratory testing. 

Medical abortion terminates a pregnancy using medications, rather than through a surgical 

procedure.

Background

FDA’s Review of New 

Drug Applications and 

Supplemental Applications
Page 5 GAO-18-292 Revised Mifeprex Labeling

United States on September 28, 2000.14 FDA approved the drug subject 

to restrictions that it considered necessary to ensure safe usage.

In addition to reviewing applications to market new drugs, FDA reviews 

supplemental new drug applications that drug sponsors submit to propose 

changes to an approved drug, such as adding or modifying an indication, 

revising the dose or dosing regimen, providing for a new route of 

administration, or changing the marketing status from prescription to overthe-counter use. As with original new drug applications, the agency 

assembles an internal team of reviewers—including medical officers, 

chemists, statisticians, pharmacologists, and other experts—to evaluate 

the information submitted in a supplemental application. During the 

review process, FDA may communicate with sponsors about issues that 

arise that may affect the approvability of the supplemental application. In 

response, sponsors can submit additional information to FDA in the form 

of amendments to the pending supplemental application. The review 

team compiles the results of its analyses and recommends to FDA 

management whether the supplemental application should be approved. 

Once the review is completed, the agency issues an action letter to the 

sponsor. FDA may approve the supplemental application (approval letter) 

or, if it determines it will not approve the supplemental application in its 

present form, it describes the specific deficiencies it identified in the 

supplemental application (complete response letter).

The review process for a drug application, including a supplemental 

application, may span several cycles before the agency approves the 

application.

15 For those applications that receive a complete response 

letter during a review cycle, the next FDA review cycle begins once the 

sponsor resubmits its application, providing responses to the deficiencies 

FDA identified in its previous review. These resubmissions often contain 

additional studies, analyses, data, or clarifying information to address 

FDA’s concerns. The agency’s review team examines the additional 

information provided by the sponsor, conducts any additional analyses 

 14In general, the mifepristone treatment regimens approved in other countries were similar 

to the regimen approved in the United States, although in some cases the specific drug 

used in combination with mifepristone was different than misoprostol.

15The first review cycle begins when FDA receives an application from a sponsor and 

ends when FDA issues an action letter. If FDA does not approve the application during the 

first review cycle, a new review cycle begins if the sponsor resubmits the application to 

provide responses to the deficiencies identified by FDA in the previous review cycle. See 

21 CFR § 314.110(b)(1) (2017).
Page 6 GAO-18-292 Revised Mifeprex Labeling

that are required, studies the results of any additional inspections that 

have been conducted, and again recommends either an approval or 

complete response action. As with the first review cycle, the process ends 

once FDA management reviews the recommendations of the review team 

and makes its decision on the action to take on the application.

Prior to submitting its supplemental application, Mifeprex’s sponsor met 

with FDA officials on January 29, 2015, to discuss the proposed labeling 

and Mifeprex REMS changes. At this meeting, both parties agreed that 

the sponsor should submit a supplemental new drug application covered 

by section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act.16 On 

May 29, 2015, Mifeprex’s sponsor submitted a supplemental application 

to FDA to revise the dosing regimen, amend the Mifeprex labeling, and 

modify the Mifeprex REMS. FDA’s review for this supplemental 

application was classified as a standard review—as opposed to a priority 

review—with the performance goal of completing the application review 

and issuing an action letter to Mifeprex’s sponsor within 10 months.17

FDA approved the supplemental application on March 29, 2016, after one 

review cycle, meeting the agency’s performance goal for the timely review 

of supplemental applications.18 Table 1 shows key components of the 

original Mifeprex regimen and the revised regimen.

 16This pertains to new drug applications that rely, at least in part, on investigations that 

“were not conducted by or for the applicant and for which the applicant has not obtained a 

right of reference or use from the person by or for whom the investigations were 

conducted . . . .” See 21 U.S.C. § 355(b)(2). For example, such an application may rely on 

the finding of safety or effectiveness for an approved product or on published literature in 

addition to studies conducted by the sponsor.

17FDA generally grants priority review to applications for drugs that treat serious 

conditions and that, if approved, would provide significant improvements in safety or 

effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to 

available therapies. FDA has a performance goal for completing priority reviews of 

supplemental applications in 6 months. FDA assigns a standard review designation to 

applications for drugs that do not meet the priority review designation criteria. FDA’s goal 

is to generally complete review of these applications in 10 months.

18Food and Drug Administration, Mifeprex label, March 2016, accessed January 25, 2018, 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020687s020lbl.pdf. 

Mifeprex’s Supplemental 

Application
Page 7 GAO-18-292 Revised Mifeprex Labeling

Table 1: Key Components of the Original Mifeprex Regimen and Prescriber Requirements, Approved in 2000, and the Revised 

Mifeprex Regimen and Prescriber Requirements, Approved in 2016 

Regimen component Original regimen Revised regimen

Dosage 600 mg Mifeprex (mifepristone);

400 mcg misoprostol

200 mg Mifeprex (mifepristone);

800 mcg misoprostol

Dosing regimen Day 1: 600 mg Mifeprex in a single 

oral dose.

Day 3: 400 mcg misoprostol in a single 

oral dose if termination of pregnancy is not 

complete.

Day 1: 200 mg Mifeprex in a single oral dose.

Day 2 or 3: 800 mcg misoprostol by buccal route (i.e., in 

the cheek pouch), 24 to 48 hours after taking Mifeprex.

Maximum gestational age 

(since first day of last 

menstrual period)

49 days 70 days

Prescriber requirements To become certified, a licensed physician 

must sign and return the Prescriber 

Agreement Form to Mifeprex’s sponsor.

a

To become certified, a healthcare provider who 

prescribes must sign and return the Prescriber 

Agreement Form to Mifeprex’s sponsor.

a

Office visits and follow-up 

visits with prescriber, and 

location of dosing 

administration

Required three office visits by the patient:

(1) 600 mg of Mifeprex administered to the 

patient by the physician or under the 

supervision of the physician in a clinic, 

medical office, or hospital.

(2) Patient returns on day three for 

examination with physician; if termination 

of pregnancy is not complete, physician 

administers 400 mcg of misoprostol for 

patient to take orally.

(3) Patient returns to physician for followup visit approximately 14 days after 

administration of Mifeprex to confirm 

complete termination of the pregnancy 

occurred.

Requires one office visit by the patient:

(1) 200 mg of Mifeprex administered to the patient by 

the healthcare provider who prescribes, or under the 

supervision of a healthcare provider who prescribes, in 

a clinic, medical office, or hospital.

(2) Patient takes 800 mcg of misoprostol by buccal 

route 24 to 48 hours after Mifeprex administration; the 

healthcare provider who prescribes discusses with the 

patient an appropriate location for her to be when she 

takes the misoprostol.

(3) Patient should follow up with healthcare provider 

who prescribes approximately 7 to 14 days after 

Mifeprex administration to confirm complete termination 

of pregnancy has occurred and to evaluate the degree 

of bleeding.

Repeat misoprostol dose, 

if necessary

N/A If the pregnancy has ended, but complete expulsion did 

not occur after the initial dose of misoprostol, the patient 

may be prescribed an additional 800 mcg of misoprostol 

to take buccally; women who choose to take a repeat 

dose of misoprostol should have a follow-up visit with 

their healthcare provider who prescribes in 

approximately 7 days to assess for complete expulsion.

Source: GAO analysis of information from the Food and Drug Administration. | GAO-18-292

a

By signing the Prescriber Agreement Form, the prescriber certifies that he or she agrees with all 

specified requirements, including that the sponsor’s Medication Guide will be supplied to all patients.
Page 8 GAO-18-292 Revised Mifeprex Labeling

FDA initially approved a REMS for Mifeprex in June 2011.19 When FDA 

approved the revised Mifeprex labeling in March 2016, the agency 

determined the REMS continued to be necessary, with some 

modifications.20 Modifications from the original REMS to the revised

REMS included

• changing the requirement that Mifeprex be provided “by or under the 

supervision of a physician” meeting specified qualifications to “by or 

under the supervision of a healthcare provider who prescribes” and 

meets such qualifications;

• changing the requirement for prescribers to agree to report to 

Mifeprex’s sponsor any serious adverse event associated with 

Mifeprex, including hospitalizations and blood transfusions, to 

requiring prescribers to agree to report deaths associated with 

Mifeprex to the sponsor;21

• requiring Mifeprex’s sponsor to report to FDA any death associated 

with Mifeprex, whether or not the death was considered drug-related, 

no later than 15 calendar days from the initial receipt of the 

information);22 and

• removing the Medication Guide (which contained specific patient 

information, such as how to take Mifeprex and potential side effects) 

as an element of the REMS, although the Medication Guide remains 

part of the approved Mifeprex labeling, and the revised REMS 

requires the healthcare provider to provide a copy of the Medication 

Guide to the patient.23

 19As part of a REMS, FDA can require “elements to assure safe use,” 21 U.S.C. § 355-

1(f)(1). This may include restrictions similar to those required to assure safe use under 

which Mifeprex was originally approved. 21 C.F.R. § 314.520 (2000).

20Food and Drug Administration, Mifeprex Risk Evaluation and Mitigation Strategy, March 

2016, accessed January 25, 2018, 

https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2016-03-29_REMS_full.

pdf.

21This requirement does not affect the sponsor’s other reporting requirements under 

federal regulations.

22This requirement does not affect the sponsor’s other reporting requirements under 

federal regulations.

23See 21 C.F.R. 208.24 (2017).

Mifeprex REMS
Page 9 GAO-18-292 Revised Mifeprex Labeling

As part of the REMS, Mifeprex’s sponsor is required to submit REMS 

assessments to FDA. The first REMS assessment was due one year from 

the date of initial approval of the REMS. Subsequent assessments are 

due every three years thereafter.24 The REMS assessments include data 

on the cumulative number of health care providers enrolled in the 

Mifeprex REMS program; the number of providers ordering Mifeprex 

during the assessment reporting period; and the number of women 

exposed to Mifeprex, both cumulative and during the reporting period. In 

addition, they include copies of reports for certain adverse events, 

including hospitalizations due to complications, blood transfusions, 

serious infections, and deaths, as well as the cumulative numbers of 

these adverse events since the approval of Mifeprex and the number 

during the reporting period.

Federal regulations require sponsors of approved drugs to report 

periodically to FDA on safety information and specific types of adverse 

events that occur in association with their use.25 Sponsors must provide in 

periodic reports—quarterly for the first three years after approval and 

annually thereafter—a narrative summary and analysis of adverse event 

information to FDA. For adverse events that are considered both serious 

and unexpected, sponsors are required to submit a Postmarketing 15-day 

Alert Report to FDA within 15 calendar days of initial receipt of the 

information.26

In some instances, FDA may request sponsors to study matters that it 

has determined worthy of further examination. Such requests are known 

as postmarketing study commitments and include studies or clinical trials 

that FDA has requested—and sponsors have agreed to conduct—to 

 24Mifeprex’s sponsor submitted its first REMS assessment to FDA in June 2012, and the 

second one in June 2015.

25See 21 C.F. R. § 314.80 (2017).

26Serious adverse events are those that result in any of the following outcomes: death, a 

life-threatening adverse event, inpatient hospitalization or prolongation of an existing 

hospitalization, a significant or persistent disability or incapacity, or a congenital anomaly 

or birth defect. Unexpected adverse events are those that are not included in the current 

labeling for a drug. Adverse events associated with a drug do not necessarily imply the 

drug caused the event.

FDA’s Postmarketing 

Oversight Activities
Page 10 GAO-18-292 Revised Mifeprex Labeling

address such issues.27 FDA requires sponsors to report on the status of 

these studies in an annual report that also includes other information such 

as updates on the distribution of the drug, labeling changes, clinical 

literature published on the drug, and the drug’s marketing.28 FDA 

designates unfulfilled study commitments as submitted, pending, ongoing, 

delayed, released, or terminated.

FDA conducts postmarketing adverse drug experience inspections of 

sponsors to assess compliance with adverse event reporting 

requirements. FDA also conducts inspections of sponsors’ compliance 

with the REMS, as applicable.29 In addition, FDA inspects manufacturers 

for compliance with current good manufacturing practices. FDA classifies 

the results of each type of inspection in one of three ways:

• A classification of “official action indicated” means that objectionable 

conditions were found that may warrant regulatory action by the 

agency.

• A classification of “voluntary action indicated” means that 

objectionable conditions that do not meet the threshold for regulatory 

action were identified, and any corrective actions are left to the 

establishment to take voluntarily.

• A classification of “no action indicated” means that no objectionable 

conditions or practices were found during the inspection, or that the 

significance of the documented objectionable conditions found does 

not justify further FDA action.

To monitor and analyze adverse events associated with an approved 

drug, FDA compiles data from sponsors’ reports on adverse events, as 

well as data from voluntary reports submitted to the MedWatch program, 

all of which are entered into FDA’s Adverse Event Reporting System 

 27See Pub. L. No. 105-115, § 130, 111 Stat. 2296, 2331-2 (codified at 21 U.S.C. § 356b). 

Sponsors may also be required to conduct additional postmarketing studies or clinical 

trials (i.e., in connection with accelerated approval of drugs for serious conditions or 

approval based on animal efficacy data, or where determined necessary to identify or 

assess a serious risk related to use of a drug). See 21 U.S.C. §§ 355(o) (serious risk), 

356(c)(2)(A) (accelerated approval); 21 C.F.R. § 314.610(b)(1) (2017) (animal efficacy 

data).

28See 21 C.F. R. § 314.81(b)(2) (2017).

29In 2008, we reported that FDA conducted three postmarketing adverse drug experience 

inspections of Mifeprex’s sponsor in 2002, 2004, and 2006. The REMS for Mifeprex was 

not in place at that time. See GAO-08-751.
Page 11 GAO-18-292 Revised Mifeprex Labeling

(FAERS).30 FDA also established the Sentinel System, which may be 

used to monitor drugs using electronic health care data. This system 

complements FDA’s existing monitoring capabilities, such as FAERS, by 

providing administrative and claims data that can be queried to monitor 

the use of FDA-regulated medical products and potential outcomes of 

treatment. The Sentinel System currently includes reimbursement data 

related to diagnoses, procedures, and drugs dispensed to over 223 

million patients derived from 17 different data partnerships, including 

national health insurers and managed care organizations. While 

reimbursed health care encounters, procedures, and medications are 

included in the Sentinel System, those that are not reimbursable—such 

as visits to free health care clinics, drug samples given in physicians’ 

offices, use of low-cost generic medications that do not incur an 

insurance copayment, or over-the-counter medications—generally are not 

captured.

In considering the supplemental application to revise the Mifeprex 

labeling, FDA reviewed 62 studies and articles that were submitted by the 

drug’s sponsor related to different aspects of the efficacy and safety of 

the proposed changes. Over the course of FDA’s application review, the 

agency also requested and received more detailed information from the 

authors of select publications through communication with Mifeprex’s 

sponsor. Additionally, FDA evaluated adverse event data associated with 

Mifeprex.

 30MedWatch is a voluntary reporting system through which health professionals and 

consumers can report adverse reactions, product problems, and errors in use related to 

drugs and other products approved by FDA.

FDA Reviewed 

Published Studies 

that Supported the 

Efficacy of the 

Proposed Mifeprex 

Labeling Changes, 

and Evaluated Safety 

Information and 

Adverse Event Data
Page 12 GAO-18-292 Revised Mifeprex Labeling

To determine the efficacy of the proposed changes to the Mifeprex

labeling, FDA reviewed numerous published studies submitted by 

Mifeprex’s sponsor, which included both U.S. and international studies.31

Some of these studies assessed the efficacy of one component of the 

proposed Mifeprex labeling changes, such as the dosing regimen. Other 

studies assessed more than one component, such as home 

administration of misoprostol and the gestational age limit for Mifeprex. 

FDA also requested and received more detailed information from the 

authors of select publications through communication with Mifeprex’s 

sponsor. In their review of the application, FDA reviewers identified what 

they considered major proposed changes. Some of the published studies 

submitted by Mifeprex’s sponsor that FDA reviewed to support each of 

these proposed changes included the following:

• Changes to the proposed dose and dosing regimen. FDA 

reviewed 30 studies that evaluated changes to the dose and dosing 

regimen. For example, 22 of these studies, collectively, evaluated 

over 35,000 women who took the proposed dosing regimen—200 

milligrams of Mifeprex orally and 800 micrograms of misoprostol 

buccally (i.e., in the cheek pouch) 24 to 48 hours after Mifeprex 

administration. The efficacy rates, defined as complete termination of 

the pregnancy without need for surgical intervention for any reason, 

ranged from 91 percent to 98 percent. One of these publications 

summarized the results of 20 studies, all but one of which used the 

proposed Mifeprex regimen in gestations through 70 days.32 The 

overall efficacy rates in these 20 studies ranged from 97 percent to 98 

percent for those studies that provided this information.

• Extending the gestational age to 70 days. FDA reviewed 19 studies 

that evaluated increasing the gestational age limit for taking Mifeprex. 

In addition to the publication discussed above that summarized the 

 31FDA accepts the use of peer-reviewed literature as primary or supportive data for an 

application under the framework of a 505(b)(2) application. See U.S.C. 21 § 355(b)(2). As 

part of its submission to FDA, Mifeprex’s sponsor noted that it did not provide financial 

support or sponsor any of the studies submitted in its supplemental application. FDA’s 

webpage pertaining to its review and approval of the Mifeprex supplemental application 

includes review documents (e.g., Cross Discipline Team Leader Review and Medical 

Review(s) documents) that contain lists and tables of references citing the publications 

FDA reviewed in the supplemental application (see 

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020TOC.cfm). 

32M.J. Chen and M.D. Creinin, “Mifepristone with Buccal Misoprostol for Medical Abortion: 

A Systematic Review,” Obstetrics & Gynecology, vol. 126, no.1 (2015): 12-21.

FDA Reviewed Numerous 

Studies in Considering the 

Efficacy of the Proposed 

Changes to the Mifeprex 

Labeling
Page 13 GAO-18-292 Revised Mifeprex Labeling

results of 20 studies, 4 of the studies that FDA reviewed evaluated the 

proposed dosing regimen through 70 days gestation.33 Three of these 

studies evaluated the efficacy rates for gestational ages of 64 to 70 

days, which ranged from 91 percent to 96 percent. The fourth study 

evaluated the efficacy rates through 70 days gestation when the drug 

was administered by physician providers (98 percent) and by nurse 

providers (98 percent). An additional publication submitted by the 

sponsor was a systematic review of studies that covered various 

dosing regimens, including the proposed regimen from 64 to 70 days 

gestation, which had a 93 percent efficacy rate.34 Two other studies 

evaluated the efficacy rates from 64 to 70 days gestation, but used 

different dosing regimens than the proposed regimen, with efficacy 

rates of 92 percent for one study and 95 percent for the other study.35

The remaining 11 studies evaluated efficacy rates for gestation 

greater than the then-approved 49 days gestation, but less than 64 

days, with efficacy rates ranging from 87 percent to 100 percent.

• Home administration of misoprostol. FDA reviewed 15 studies that 

evaluated home administration of misoprostol, although FDA reported 

that none of these studies evaluated treatment outcomes with the use 

of misoprostol at home compared to a clinic setting. However, one 

study was a large literature review of 87 studies that included over 

 33The four studies were: (1) B. Winikoff, I.G. Dzuba, E. Chong, et al., “Extending 

Outpatient Medical Abortion Services through 70 Days of Gestational Age,” Obstetrics & 

Gynecology, vol. 120 (2012): 1070-1076; (2) A.A. Boersma, B. Meyboom-de Jong, and G. 

Kleiverda, “Mifepristone Followed by Home Administration of Buccal Misoprostol for 

Medical Abortion up to 70 days of Amenorrhoea in a General Practice in Curacao,” The 

European Journal of Contraception & Reproductive Health Care, vol. 16 (2011): 61-66; (3) 

P. Sanhueza Smith, M. Pena, I.G. Dzuba, et al., “Safety, Efficacy and Acceptability of 

Outpatient Mifepristone-Misoprostol Medical Abortion through 70 days Since Last 

Menstrual Period in Public Sector Facilities in Mexico City,” Reproductive Health Matters,

vol. 22 (2015): 75-82; and (4) C.D. Olavarrieta, B. Ganatra, A. Sorhaindo, T.S. Karver, A. 

Seuc, A. Villalobos, S.G. Garcia, M. Pérez, M. Bousieguez, and P. Sanhueza, “Nurse 

Versus Physician-Provision of Early Medical Abortion in Mexico: A Randomized Controlled 

Non-Inferiority Trial,” Bulletin of the World Health Organization, vol. 93 (2015): 249-258.

34D. Abbas, E. Chong, and E.G. Raymond, “Outpatient Medical Abortion is Safe and 

Effective through 70 Days Gestation,” Contraception, vol. 92 (2015):197-199.

35The two studies were: (1) H. Bracken, R. Dabash, G. Tsertsvadze, et al., “A Two-Pill 

Sublingual Misoprostol Outpatient Regimen following Mifepristone for Medical Abortion 

through 70 Days’ LMP: A Prospective Comparative Open-Label Trial,” Contraception, vol. 

89(3) (2014): 181-186; and (2) E.V. Gouk, et al., “Medical Termination of Pregnancy at 63-

83 Days Gestation,” BJOG: An International Journal of Obstetrics and Gynaecology, vol. 

106 (1999): 535-539. FDA noted that these two studies were relevant because the dosage 

levels and routes of administration were expected to have similar or lower effectiveness 

than the proposed dosing regimen.
Page 14 GAO-18-292 Revised Mifeprex Labeling

45,000 women evaluated using a variety of mifepristone treatment 

regimens with different misoprostol doses, routes of administration, 

and dosing intervals in gestations through 63 days.36 Half of the 

studies in this review did not require women to take misoprostol in a 

clinic. The results showed that the rates of treatment failure and 

ongoing pregnancy were very similar regardless of whether 

misoprostol was taken in a clinic or at another location. A further 

analysis of factors leading to increased failure found no evidence that 

home use of misoprostol increased rates of treatment failure or 

serious complications.

• Use of a repeat misoprostol dose. FDA reviewed 10 studies to 

support the use of a repeat dose of misoprostol. This repeat dose 

would be taken in instances when complete expulsion did not occur 

after the initial misoprostol dose and Mifeprex dose. For example, one 

study evaluated 68 women who did not have complete expulsion after 

taking Mifeprex and were given a second vaginal dose of misoprostol, 

with an efficacy rate of 62 percent.37 In another study that evaluated 

the proposed regimen through 70 days gestation, 5 of 330 women 

took a second dose of misoprostol, because of the absence of 

bleeding after the first dose of misoprostol. The study found that one 

of the five women who took the second dose did not achieve the 

desired result.38 In one other study that evaluated women using the 

proposed regimen through 63 days gestation, 16 of 863 women 

received a second dose of misoprostol, with an efficacy rate of 100 

percent.39 The other 7 studies had efficacy rates for an additional 

dose of misoprostol ranging from 67 percent to 100 percent.40

 36E.G. Raymond and D.A. Grimes, “The Comparative Safety of Legal Induced Abortion 

and Childbirth in the United States,” Obstetrics & Gynecology, vol. 119 (2012): 215-219.

37M.F. Reeves, A. Kudva, and M. Creinin, “Medical Abortion Outcomes after a Second 

Dose of Misoprostol for Persistent Gestational Sac,” Contraception, vol. 78 (2008): 332-

335.

38Boersma, Meyboom-de Jong, and Kleiverda, “Mifepristone Followed by Home 

Administration of Buccal Misoprostol,” 61-66.

39K.S. Louie, T. Tsereteli, E. Chong, F. Ailyeva, G. Rzayeva, and B. Winikoff, 

“Acceptability and Feasibility of Mifepristone Medical Abortion in the Early First Trimester 

in Azerbaijan,” The European Journal of Contraception & Reproductive Health Care, vol. 

19, no. 6 (2014): 457-464.

40Mifeprex’s sponsor noted to FDA that approximately 1 percent to 5 percent of women 

will need a second dose of misoprostol following the initial Mifeprex dosing regimen.
Page 15 GAO-18-292 Revised Mifeprex Labeling

• Follow-up care requirements. FDA reviewed 11 studies that 

evaluated different methods for follow-up care after Mifeprex 

administration. One of these studies, which FDA considered a key 

publication on this topic, was a review of studies that assessed the 

impact of the timing of follow-up care.41 This study found no 

differences in the failure rates between women who received followup care within one week of taking mifepristone compared to those 

who received follow-up care a week or more after taking mifepristone. 

The other 10 studies included a variety of study designs and dosing 

regimens through 63 days gestation, and FDA determined that the 

various methods of follow up, including home pregnancy testing and 

phone contact with the patient to inquire about symptoms, were 

acceptable alternatives to an in-clinic follow up.

• Change in provider qualifications. FDA reviewed four studies that 

addressed the efficacy of medical abortion performed by nonphysician 

health care providers; three of which used the proposed dosing 

regimen and one evaluated vaginal administration of misoprostol.42 In 

these studies, almost 1,500 women had gestations through 70 days or 

more, and over 700 of these women had nonphysician care. In 

addition, almost 2,300 women had gestations up to 63 days, and over 

1,000 of these women had nonphysician care. The efficacy rates were 

greater than or equal to 96 percent across all of the studies, 

regardless of gestational age or provider type.

FDA also received three letters from representatives of advocacy 

organizations and professional associations—some of which were signed 

by more than one entity—requesting that FDA revise the Mifeprex 

labeling in a manner that would reflect then-current clinical practice, 

 41E.G. Raymond, et al., “First-Trimester Medical Abortion with Mifepristone 200 mg and 

Misoprostol: A Systematic Review,” Contraception, vol. 87 (2013): 26-37.

42The three studies that used the proposed regimen were (1) H. Kopp Kallner, R. 

Gomperts, E. Salomonsson, M. Johansson, L. Marions, and K. Gemzell-Danielsson, “The 

Efficacy, Safety and Acceptability of Medical Termination of Pregnancy Provided by 

Standard Care by Doctors or by Nurse-Midwives: A Randomized Controlled Equivalence 

Trial,” BJOG: An International Journal of Obstetrics and Gynaecology, vol. 122 (2015): 

510-517; (2) Olavarrieta, Ganatra, Sorhaindo, Karver, Seuc, Villalobos, Garcia, Pérez, 

Bousieguez, and Sanhueza, “Nurse Versus Physician-Provision of Early Medical 

Abortion,” 249-258; and (3) M. Puri, A. Tamang, P. Shrestha, D. Joshi, “The Role of 

Auxiliary Nurse-Midwives and Community Health Volunteers in Expanding Access to 

Medical Abortion in Rural Nepal,” Reproductive Health Matters, vol. 44 Supplement 

(2015): 94-103. The study that addressed vaginal misoprostol was: I.K. Warriner, D. 

Wang, N.T.M. Huong, K. Thapa, A. Tamang, I. Shah, et al., “Can Midlevel Health-Care 

Providers Administer Early Medical Abortion as Safely and Effectively as Doctors? A 

Randomized Controlled Equivalence Trial in Nepal,” Lancet, vol. 377 (2011): 1155-1161.
Page 16 GAO-18-292 Revised Mifeprex Labeling

including the new dosing regimen and extending the gestational age limit 

through 70 days.43 Among others, the signers of these letters included the 

American Congress of Obstetricians and Gynecologists, American Public 

Health Association, Gynuity Health Projects, Ibis Reproductive Health, 

and National Abortion Federation. FDA officials told us that the peerreviewed studies the agency received from external entities (i.e., entities 

other than Mifeprex’s sponsor) were also submitted by Mifeprex’s sponsor 

in the supplemental application, which FDA reviewed.44 In addition, FDA 

officials told us that they received letters from organizations that were 

based on other than scientific perspectives, and FDA officials noted that 

they only considered scientific information in their review of the Mifeprex 

supplemental application.

FDA also reviewed published studies submitted by the drug’s sponsor to 

assess the safety profile of the proposed dosing regimen, including both 

U.S. and international studies. Of the seven U.S. studies submitted with 

the Mifeprex supplemental application that examined safety issues, one 

specifically addressed deaths associated with Mifeprex.45 This study 

noted that there were no deaths among 578 patients who received the 

proposed Mifeprex dosing regimen through 63 days gestation. According 

to FDA, because only one of these studies addressed deaths associated 

with Mifeprex, this may reflect the fact that it is a rare outcome and, 

therefore, the absence of reported deaths might not be noted by the 

authors of a study. In addition, FDA reviewed an observational study from 

Australia that was also submitted as part of the application. It identified 

one death from sepsis—a life-threatening complication of an infection—

 43According to FDA, once the agency approves a drug, health care providers generally 

may prescribe the drug for an unapproved use when they judge that it is medically 

appropriate for their patient, a practice known as off-label use. FDA also indicated that the 

proposed changes approved in the Mifeprex supplemental application were consistent 

with current medical practice.

44According to FDA officials, the agency received one study from an external entity that 

was superseded by a more current publication on the same topic by one of the same 

authors. In this instance, FDA officials reviewed the more current publication provided by 

Mifeprex’s sponsor.

45D. Grossman, K. Grindlay, T. Buchacker, K. Lane, and K. Blanchard, “Effectiveness and

Acceptability of Medical Abortion Provided through Telemedicine,” Obstetrics & 

Gynecology, vol. 118 (2011): 296-303.

FDA Evaluated Safety 

Information and Adverse 

Event Data as Part of Its 

Assessment of the 

Proposed Changes to the 

Mifeprex Labeling
Page 17 GAO-18-292 Revised Mifeprex Labeling

among 13,345 pregnancy terminations using the proposed dosing 

regimen through 63 days gestation.46

In addition to reviewing published studies submitted by Mifeprex’s 

sponsor, FDA reviewed adverse event reports from the drug’s approval 

on September 28, 2000, through November 17, 2015. During this time, 

there were 17 reported deaths in the United States associated with 

Mifeprex, and 8 of those were associated with sepsis. Seven of the 8 

sepsis cases were associated with vaginal use of misoprostol, which was, 

but no longer is, a common practice, according to FDA. The agency found 

that the adverse event data that it reviewed demonstrated that the rates 

of hospitalizations, severe infections, blood loss requiring transfusion, and 

complications related to ectopic pregnancy remained stable and 

acceptably low.

FDA also reviewed common adverse events, such as nausea, vomiting, 

diarrhea, and fever/chills, reported in U.S. and international studies 

submitted by Mifeprex’s sponsor, and found the reporting of the 

frequencies of these events was higher in the U.S. studies. However, 

FDA determined that these differences likely reflected lower reporting of 

adverse events in international studies. These common adverse events 

are included in the Mifeprex labeling. The labeling also cites bleeding and 

cramping, which are expected effects of the drug regimen, according to 

FDA. Overall, FDA found the rate of deaths and nonfatal serious adverse 

events associated with Mifeprex to be acceptably low, and data for the 

proposed regimen did not suggest a safety profile that deviated from that 

of the originally approved Mifeprex regimen, which was approved as part 

of an application with restrictions to assure safe use. In addition, no 

association between adverse outcomes and increasing gestational age 

was identified.

In January 2016, FDA completed a review of adverse event data 

associated with Mifeprex in its FAERS database, as well as the published 

medical literature, on a potential safety concern regarding anaphylaxis 

and angioedema associated with mifepristone.47 FDA’s review of FAERS 

data found one case of anaphylaxis and six cases of angioedema with 

 46P. Goldstone, J. Michelson, and E. Williamson, “Early Medical Abortion Using Low-Dose 

Mifepristone Followed by Buccal Misoprostol: A Large Australian Observational Study,” 

Medical Journal of Australia, vol. 197 (2012): 282-286.

47Anaphylaxis is a severe, potentially life-threatening allergic reaction. Angioedema is a 

form of severe swelling beneath the skin’s surface.
Page 18 GAO-18-292 Revised Mifeprex Labeling

mifepristone administration, with six of the seven cases seen in women 

using mifepristone for pregnancy termination, as opposed to using 

mifepristone for Cushing’s syndrome.48 The sole case of anaphylaxis 

could not be directly attributed to mifepristone because an oral antibiotic 

(doxycycline) was concomitantly administered, according to FDA. FDA 

did not find any additional cases of anaphylaxis or angioedema with 

mifepristone administration in its review of the literature. FDA noted that 

anaphylaxis was included in the current labeling for misoprostol. Because 

the approved Mifeprex regimen includes misoprostol, FDA determined 

that the Mifeprex labeling should also be updated to include anaphylaxis, 

despite the lack of anaphylaxis cases with mifepristone alone. The 

addition of angioedema was supported by the FAERS data documented 

in FDA’s review. As a result, anaphylaxis and angioedema were added to 

the areas of the Mifeprex labeling that address allergic reactions.

The potential risk of uterine rupture was also considered in FDA’s review 

of the Mifeprex supplemental application. FDA reviewers conducted a 

literature search on this topic, and identified five reports of uterine rupture 

in studies published from 2000 through 2014; three of which occurred 

with the combined mifepristone/misoprostol dosing regimen. FDA also 

completed a review of FAERS from January 1, 1965, through October 15, 

2015, for reports of uterine rupture.49 Of the 80 reports found in FAERS, 

77 cited use of misoprostol alone, and 3 cited use of both mifepristone 

and misoprostol. Two reports of uterine rupture in the first trimester were 

identified in the FAERS review, both using misoprostol alone. One report 

entailed an unspecified dose and route of misoprostol at 5 weeks 

gestation. The other report involved vaginal administration of 800 

micrograms of misoprostol at 8 weeks gestation for cervical preparation 

prior to a surgical abortion in a woman with a prior uterine scar. 

Information regarding this safety concern was added to the Mifeprex 

labeling when the supplemental application was approved on March 29, 

2016. The agency concluded, however, that no restriction of use was 

needed, because this was an extremely rare adverse event.

FDA concluded that the evidence it reviewed and evaluated, including the 

revisions to the REMS, demonstrated acceptable safety for the proposed 

 48Cushing’s syndrome is a hormonal disorder affecting both men and women caused by 

prolonged exposure of the body’s tissues to high levels of the hormone cortisol. 

Mifepristone is also approved for this indication, under the brand name Korlym.

49According to FDA, January 1, 1965, is the date that the FAERS predecessor system 

was initiated.
Page 19 GAO-18-292 Revised Mifeprex Labeling

changes to the Mifeprex regimen, and that the dosing regimen had a 

similar safety profile as the original regimen approved in 2000. The 

agency further concluded that adverse events of interest—such as 

deaths, serious infection, transfusions, ectopic pregnancies, and uterine 

rupture—remained rare, and were not necessarily attributable to Mifeprex 

use.

50

FDA’s monitoring of Mifeprex—primarily through inspections, and review 

and analysis of adverse event data—has not identified any significant 

concerns with the safety and use of Mifeprex. The views of the 

stakeholder organizations that we contacted regarding FDA’s monitoring 

of the safety of Mifeprex and the safety of the drug itself were mixed.

Since our prior report was issued in 2008, FDA conducted three 

postmarketing adverse drug experience inspections of Mifeprex’s 

sponsor—in 2010, 2014, and 2016.51 It identified minor deficiencies, but 

no significant safety concerns. These inspections each contained 

between two and four inspection observations—that is, the investigator 

observed conditions that, in his or her judgment, constituted violations of 

applicable federal requirements. In each of these inspections, FDA’s final 

classification was “voluntary action indicated,” meaning that objectionable 

conditions or practices were found, but they did not meet the threshold of 

regulatory significance. According to agency officials, FDA’s practice for 

 50Similarly, a recently issued study by the National Academies of Sciences, Engineering, 

and Medicine reported that complications—such as hemorrhage, hospitalization, 

persistent pain, infection, or prolonged heavy bleeding—are rare after a medical abortion. 

This study cited some of the same studies FDA relied on and noted that complications 

occur in no more than a fraction of a percent of patients. National Academies of Sciences, 

Engineering, and Medicine, The Safety and Quality of Abortion Care in the United States 

(Washington, D.C.: prepublication copy).

51See GAO-08-751.

FDA’s Monitoring 

Activities Have Not 

Identified Significant 

Safety Concerns with 

Mifeprex; 

Stakeholders’ Views 

on FDA’s Monitoring 

and the Drug’s Safety 

Were Mixed

FDA’s Monitoring Has Not 

Identified Any Significant 

Concerns Regarding the 

Safety and Use of 

Mifeprex as Marketed with 

the Approved REMS
Page 20 GAO-18-292 Revised Mifeprex Labeling

inspections resulting in this classification is to review the corrective 

actions taken by the establishment related to the objectionable conditions 

or practices during the course of the next regularly scheduled inspection. 

FDA officials told us that they have not yet scheduled the next 

postmarketing adverse drug experience inspection.

According to FDA, violations associated with postmarketing adverse drug 

experience inspections classified as voluntary action indicated are 

typically technical in nature. Examples of some of the observations from 

inspections of Mifeprex’s sponsor include the following:

• In 2010, the sponsor was found to have used an older version of the 

form used for mandatory reporting of adverse events (FDA Form 

3500A), rather than the more recent version.

• In 2014, two serious adverse events were not reported to FDA within 

the required 15-day period, and instead were included in the 

sponsor’s subsequent quarterly adverse event report to FDA.

• In 2016, the sponsor’s quarterly adverse event reports did not include 

the required analysis of the Postmarketing 15-day Alert Reports that 

occurred over the period.

In addition to postmarketing adverse drug experience inspections, 

Mifeprex’s sponsor was subject to a REMS compliance inspection, which 

the agency conducted in 2014. According to FDA officials, the agency did 

not identify any compliance issues and determined that the final 

classification was no action indicated.

FDA also conducted three inspections since 2008 of the facility where 

Mifeprex is manufactured to ensure compliance with current good 

manufacturing practices. FDA did not find any deficiencies during two of 

these inspections; however, in the other inspection, FDA’s findings 

resulted in a final classification of voluntary action indicated. According to 

the inspection report, FDA officials found an improperly performed test on 

a raw material used in another product produced at the same facility, not 

related to Mifeprex. A subsequent inspection determined that corrective 

action was taken by the manufacturer.

In addition to inspection data, FDA conducted ongoing monitoring of 

adverse event data. These data are collected through required reporting, 

including periodic reports on adverse events provided by the sponsor and 

reports by the prescriber to the sponsor, which, depending on the event, 

may be required under the REMS. In addition, voluntary reports may be 

made by the public. FDA compiled this information into periodic 
Page 21 GAO-18-292 Revised Mifeprex Labeling

postmarketing adverse event summary reports, the interval of which 

ranged from 2 to 18 months. These reports show that between 

September 28, 2000, and June 30, 2017, there were approximately 4,200 

reports of adverse events associated with Mifeprex, including 

approximately 1,000 hospitalizations and 20 deaths.52 These deaths 

represented a reporting rate of 0.0006 percent for the approximately 3.2 

million women who have used Mifeprex since 2000. For context, a study 

of mortality among women who did not have an abortion and proceeded 

to a live birth estimated a mortality rate of 0.009 percent. Nonfatal 

adverse events, including blood loss requiring transfusion and infections, 

were more common among women who took Mifeprex, but still relatively 

low compared to the number of users. (See table 2.)

 52Mifeprex’s sponsor reported two additional deaths to FDA that had not yet been included 

in FDA’s periodic adverse event report—one reported in September 2017 and one 

reported in December 2017. FDA gathers and reports data on adverse events associated 

with Mifeprex, which are not necessarily caused by Mifeprex. For example, an unrelated 

health condition observed near the time that a woman took Mifeprex may be included in 

FDA’s adverse event summary data.
Page 22 GAO-18-292 Revised Mifeprex Labeling

Table 2: Adverse Events Associated with Mifeprex Reported to FDA from September 28, 2000, through June 30, 2017 

September 28, 2000 to October 

31, 2012a November 1, 2012 to June 30, 2017a

Adverse event category Number of cases Number of cases

Any adverse eventb 2,740 1,439

Specific types of adverse eventsc

Deathsd 14 6

Hospitalization 768 273

Blood loss with transfusion 416 182

Infections 308 103

Ectopic pregnancies 66 31

Severe infections 57 12

Source: GAO analysis of Food and Drug Administration (FDA) data. | GAO-18-292

Notes: (1) Approximately 3.2 million women have taken Mifeprex since its initial approval in 2000. (2) 

An adverse event associated with Mifeprex does not necessarily indicate that Mifeprex caused the 

event.

a

FDA implemented the FDA Adverse Event Reporting System (FAERS) in 2012, and migrated all the 

data from the previous reporting system to FAERS. Adverse event summary reports beginning on 

November 1, 2012, are based on FAERS data. Differences may exist when comparing case counts in 

FAERS with FDA’s previous reporting system. Therefore, FDA does not recommend calculating a 

cumulative number for the data in table 2, with the exception of the case counts for deaths and 

ectopic pregnancies. These data were harmonized by FDA and may be added.

b

Any adverse event includes all the categorized adverse events listed below it (i.e., deaths, 

hospitalization, blood loss with transfusion, infections and severe infections, and ectopic 

pregnancies), as well as other noncategorized events.

c

Of the six types of categorized adverse events, only deaths are solely recorded as such—that is, 

they are not reflected in the tally for other categorized adverse events. The remaining categories are 

overlapping, meaning that a single case could be counted within multiple categories. Also, the 

hospitalization category includes both categorized and noncategorized adverse events. According to 

FDA, the most common adverse events among those that are not categorized (accounting for 

approximately 94 percent) are vaginal bleeding not requiring transfusion, retained products of 

conception, ongoing pregnancy, cramping, dizziness, and nausea. Among noncategorized adverse 

events resulting in hospitalization, the most common is dilation and curettage (accounting for 

approximately 81 percent).

d

In addition to the 20 deaths included in FDA’s periodic adverse event reports, the sponsor reported 

two additional deaths to FDA—one reported in September 2017 and one reported in December 

2017—which the agency said will be included in its next periodic adverse event report.

Although postmarketing study commitments or requirements are another 

method for obtaining additional information about drug safety and use, in 

the case of Mifeprex the planned studies were deemed by FDA to be 

infeasible. As we previously reported, FDA originally approved Mifeprex 

subject to the sponsor’s commitment to conduct two postmarketing 

studies.53 For the first study, the sponsor agreed to assess whether 

 53See GAO-08-751. 
Page 23 GAO-18-292 Revised Mifeprex Labeling

clinical outcomes were similar for patients under the care of providers 

who possessed the surgical intervention skills to perform a surgical 

abortion compared with patients of providers who did not have such skills 

and referred patients for surgical abortions. FDA said the sponsor 

reported that the number of physicians who prescribed Mifeprex and did 

not possess the surgical intervention skills to perform a surgical abortion 

was so small that such a study was not feasible. FDA agreed and 

released them from that commitment in September 2008. For the second 

study, the sponsor was required to examine, through a surveillance and 

reporting system, the outcomes of pregnancies where the drug regimen 

failed to result in their termination. According to FDA officials, Mifeprex’s 

sponsor reported to FDA that over nearly 2 years of monitoring (January 

2006 through November 2007) there were one or two instances per year 

of the drug not resulting in termination. The sponsor told FDA that this 

was, in part, because patients had to consent to being monitored, 

resulting in a very small number of participants. Given these low 

numbers, FDA agreed that this study was also not feasible.

We also found that FDA’s Sentinel System, which was developed to 

enhance the agency’s ability to monitor postmarketing safety, is not a 

viable option for monitoring the use of Mifeprex. Although it contains 

millions of records, the Sentinel System is based on administrative and 

claims data, and only reimbursed health care encounters, procedures, 

and medications are captured in the system. Because of the REMS 

restrictions placed on the drug’s distribution, Mifeprex is not dispensed in 

pharmacies. Instead, it is only available under certain conditions and from 

certain clinics, medical offices, and hospitals. Therefore, according to 

FDA officials, the Sentinel System does not include a sufficient number of 

Mifeprex dispensings to generate valid results. Nonetheless, we asked 

FDA to query the Sentinel System for mifepristone (the active 

pharmaceutical ingredient for Mifeprex) beginning in 2000, when the drug 

was first approved. The results of this query showed that, until 2012, 

mifepristone registered a small number of drug dispensings. Specifically, 

between 2000 and 2011, only 12 individuals were identified as potentially 

exposed to mifepristone. However, from 2012 through 2016, 243

individuals were identified, including both men and women. FDA officials 

explained that another drug—Korlym, which treats Cushing’s syndrome 

and contains the same active pharmaceutical ingredient as Mifeprex—
Page 24 GAO-18-292 Revised Mifeprex Labeling

became available in 2012.54 Even with additional dispensings beginning 

in 2012, FDA officials said there were still insufficient data captured to 

enable a robust safety assessment.

The views of the stakeholder organizations that provided us with 

information on FDA’s monitoring of the safety and use of Mifeprex, and 

the safety of the drug itself, were mixed. Stakeholders provided positive 

comments regarding FDA’s monitoring of Mifeprex and also made 

suggestions to improve what they considered to be weaknesses. Positive 

comments included that

• FDA had a very comprehensive monitoring program that mandated 

the reporting of serious adverse events associated with Mifeprex up 

through 2016. In light of the low rates of nonfatal adverse events and 

the good safety profile of Mifeprex, FDA no longer requires providers 

to report nonfatal adverse events.

• FDA is properly monitoring the safety and use of Mifeprex through a 

robust adverse event reporting system, and FDA is doing its due 

diligence, based on the agency’s mission, to identify any safety issues 

with the drug.

• FDA’s requirement that Mifeprex be subject to a REMS has made it 

more likely that adverse events would be reported. Specifically, 

additional contacts with health care providers, as is required by the 

Mifeprex REMS in the form of prescriber certification and patient 

education, generally lead to higher adverse event reporting rates than 

drugs without such requirements.

Stakeholders that either commented that FDA’s monitoring efforts could 

be improved or that expressed concern about the agency’s ability to know 

the extent of potential safety issues said, for example, that

• FDA may only be aware of a fraction of adverse events associated 

with Mifeprex. There are anecdotal examples of adverse events, such 

as severe bleeding, that may not be reported as such or that may be 

interpreted by emergency health care providers as a natural 

 54The analysis that was conducted in the Sentinel System only recognizes the active 

pharmaceutical ingredient and does not distinguish between the drugs dispensed, 

according to FDA officials. The data show both men and women receiving mifepristone 

since 2012. Korlym’s dose of mifepristone is significantly higher than that of Mifeprex and, 

unlike Mifeprex, the drug is taken by patients on an ongoing basis.

Stakeholder Organizations 

Had Mixed Views on 

FDA’s Monitoring of 

Mifeprex and of Mifeprex’s 

Safety
Page 25 GAO-18-292 Revised Mifeprex Labeling

miscarriage. Underreporting may get worse under the revised 

Mifeprex label, which eliminates the follow-up visit and does not 

require prescribers to report nonfatal adverse events.

• FDA may not have reliable data on the number of women who have 

used Mifeprex, which would affect the denominator for tracking 

adverse events. With an unclear denominator, FDA may not have an 

accurate measure of adverse event rates associated with Mifeprex.

Regarding the safety of Mifeprex, stakeholders we contacted provided a 

mix of favorable comments about the drug, as well as certain safety 

concerns. Positive comments included the following

• The mortality rate associated with Mifeprex is extremely low—about 

one fourteenth the mortality rate associated with live birth.

• Nonfatal serious adverse events following Mifeprex use, such as 

hospital admission, blood transfusion, or serious infection, are also 

rare, occurring at rates ranging from 0.01 percent to 0.7 percent, and 

are almost always treatable without permanent effects. Side effects, 

such as bleeding, cramping, fever, and chills, are typically minor and 

transient.

• In the years since mifepristone’s approval, multiple clinical trials, 

dozens of studies, and extensive experience across the globe have 

confirmed FDA’s finding that mifepristone is a safe and reliable 

method of abortion. Thus, any significant concern about the safety of 

Mifeprex would be unwarranted.

Stakeholders also expressed some concerns about Mifeprex’s safety. For 

example, they reported that

• Mifeprex may be linked to hemorrhaging and serious infections. A 

study was cited that showed adverse events were more likely to be 

associated with a medical abortion rather than a surgical abortion.55

Two other studies were cited that examined the effect mifepristone 

may have on the body’s ability to control hemorrhaging and prevent 

 55M. Niinimäki, et al., “Immediate Complications after Medical Compared with Surgical 

Termination of Pregnancy,” Obstetrics & Gynecology, vol. 114, no. 4 (October 2009): 795-

804. This study of over 42,000 women in Finland who had abortions from 2000 to 2006 

found that, overall, medical abortion had roughly four times the rate of adverse events 

than surgical abortion, and hemorrhaging was experienced by 16 percent of medical 

abortion patients compared with 2 percent of surgical abortion patients.
Page 26 GAO-18-292 Revised Mifeprex Labeling

serious infections.56 For example, one of the studies found that 

serious bacterial infection and sepsis may occur without the usual 

signs of infection with the use of mifepristone for medical abortion.

• Safety issues may be exacerbated by the Mifeprex labeling changes. 

For example, a study was cited that found that the rates of pregnancy 

termination with Mifeprex dropped from 92 percent up to the 7th week 

of gestation to 77 percent at the 9th week.57

• Women in the later weeks of pregnancy who live far from a health 

care provider may be at increased risk of serious hemorrhaging under 

the revised labeling, which does not require a second visit with a 

health care provider.

In addition, another comment we heard was that the agency was being 

too restrictive by continuing to require a REMS for the drug. Specifically, 

we were told that Mifeprex should not continue to be restricted to being 

dispensed at a clinic, medical office, or hospital—as it is under the 

Mifeprex REMS—because ample research shows Mifeprex to be safe 

and adverse events to be rare. Stakeholders also noted that women in 

rural areas may have less access to the drug, and Mifeprex’s sponsor 

commented that the distribution restrictions likely result in the drug being 

less accessible than it otherwise would be.58

In response to the concerns regarding Mifeprex that we heard from 

stakeholder organizations, FDA officials said that the agency approved 

the supplemental application for Mifeprex under the same approval 

standards that it applies to all new drug applications and supplemental 

applications, and found that the data and information submitted in the 

supplemental application demonstrated that Mifeprex is safe and effective 

 56R.P. Miech, “Pathopharmacology of Excessive Hemorrhage in Mifepristone Abortions,” 

Annals of Pharmacotherapy, vol. 41, no. 12 (December 2007): 2002-2007. See also, R.P. 

Miech, “Pathophysiology of Mifepristone-induced Septic Shock due to Clostridium 

sordellii,” Annals of Pharmacotherapy, vol. 39, no. 9 (September 2005): 1483-1488.

57I. M. Spitz, C. W. Bardin, L. Benton, and A. Robbins, “Early Pregnancy Termination with 

Mifepristone and Misoprostol in the United States,” New England Journal of Medicine, vol. 

338, no. 18 (Apr. 30, 1998): 1241-1247.

58In October 2017, a doctor and several professional health associations filed a lawsuit in 

the U.S. District Court for the District of Hawaii to challenge the distribution restrictions 

imposed by FDA under the Mifeprex REMS. Chelius, et al. v. Wright, No. 17-cv- 00493 (D. 

Hawaii, filed Oct. 3, 2017). Plaintiffs argued that REMS requirements may be imposed 

only when necessary to ensure that a drug’s benefits outweigh its risks, and that 

restrictions requiring Mifeprex to be distributed through clinics or hospitals do not meet the 

criteria.
Page 27 GAO-18-292 Revised Mifeprex Labeling

for its intended use. FDA officials noted that Mifeprex also has a REMS in 

place to ensure safety. They also stressed that, as with all FDA-approved 

drugs, Mifeprex is subject to adverse event reporting requirements and 

continued postmarketing safety monitoring by the agency.

We provided a draft of this report for comment to HHS. HHS provided 

technical comments, which we incorporated as appropriate.

We are sending copies of this report to the Secretary of Health and 

Human Services, appropriate congressional committees, and other 

interested parties. In addition, the report will be available at no charge on 

the GAO Web site at http://www.gao.gov.

If you or your staff have any questions about this report, please contact 

me at (202) 512-7114 or crossem@gao.gov. Contact points for our

Offices of Congressional Relations and Public Affairs are on the last page 

of this report. GAO staff who made major contributions to this report are 

listed in appendix I.

Marcia Crosse

Director, Health Care

Agency Comments
Page 28 GAO-18-292 Revised Mifeprex Labeling

List of Requesters

The Honorable Robert Aderholt

Chairman

Subcommittee on Agriculture, Rural Development, 

Food and Drug Administration, and Related Agencies

Committee on Appropriations

House of Representatives

The Honorable Tom Cole

House of Representatives

The Honorable Chuck Fleischmann

House of Representatives

The Honorable Jeff Fortenberry

House of Representatives

The Honorable Tom Graves

House of Representatives

The Honorable Andy Harris

House of Representatives

The Honorable Steven Palazzo

House of Representatives

The Honorable Kevin Yoder

House of Representatives
Page 29 GAO-18-292 Revised Mifeprex Labeling

Marcia Crosse (202) 512-7114 or crossem@gao.gov

In addition to the contact above, Geri Redican-Bigott (Assistant Director), 

Lisa A. Lusk (Analyst-in-Charge), George Bogart, Drew Long, and Perry 

Parsons made key contributions to this report. Kaitlin Farquharson also 

made contributions to this report.

Appendix I: GAO Contact and Staff 

Acknowledgments

GAO Contact

Staff 

Acknowledgments

(102036)
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