In this issue...

• "RU-486" - It's Worse Than You Think

• Has the FDA Violated It's Own Regulations in Rushing M/M to Market?

• Caveat Emptor

• Strict Safeguards in Use of M/M Abroad are Evidence of Method's Dangers

• Half-Measures Earlier Proposed by the FDA

• Final Approval Ignores Safety Concerns

• Risks to U.S. Women Under Relaxed Controls

• Additional Dangers to Women Under Lax Standards Set by FDA

"RU 486"— It's Worse Than You Think

The most recent issue of Life Insight covered developments concerning mifepristone ("RU 486") prior to its final approval by the Food and Drug Administration (FDA) on September 28. As it turns out, the final guidelines are even worse than anticipated. Relaxing significantly the relatively modest safety standards reportedly proposed as recently as June 2000, they represent an almost total capitulation to the abortion lobby.

In discussing the troubling aspects of mifepristone/ misoprostol ("M/M") approval, one suffers an embarrass de richesses—possible procedural irregularities in the FDA actions, manufacturer concerns and the drugs' inherent dangers.

Has the FDA Violated Its Own Regulations in Rushing M/M to Market?

Lawyers looking into the mifepristone/misoprostol approval have raised a question whether the FDA has misused its regulatory authority. The approval letter states: "The application is approved under 21 CFR 314 Subpart H." This subpart, entitled "Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses," was promulgated in 1992, in response to criticism that the FDA was too slow in approving experimental drugs to combat HIV/AIDS. It allows patients with very severe or terminal illnesses to obtain experimental drugs and antibiotics even before their safety and efficacy are fully explored. Expedited processing and approval under Subpart H are limited as follows:

"This subpart applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy)" (21 CFR §314.500; emphasis added).

Every drug approved under Subpart H prior to July 2000 is conveniently listed on the FDA website at http://www.fda.gov/cder/rdmt/accapp.htm. About a third of the 28 listed drugs combat HIV, another 7 deal with specific types of cancer. One governs the use of thalidomide in treating leprosy. All apparently relate to the treatment of life-threatening illnesses.

The FDA's reliance on Subpart H to expedite approval of two extremely risky drugs for abortion seems a mockery of the regulatory purpose. Pregnancy is not an illness and certainly not one that is life-threatening in the first seven weeks (unless it is a tubal pregnancy in which case M/M abortions are absolutely contraindicated). Other "safe" methods of abortion are readily available. There is no medical urgency in approving the drug combination before completing customary studies; the only urgency is dictated by the approaching end of the current Administration which has fought so long and hard for approval.


Caveat Emptor

Searle, which manufactures misoprostol under the brand name Cytotec, has consistently opposed the use of Cytotec for labor induction and for abortion. An August 23, 2000 letter from Searle to all U.S. doctors and posted on the FDA's website (http://www. fda.gov/medwatch/safety/2000/cytote.htm), reiterates its opposition to these off-label uses and lists "serious adverse events" that have been reported: "maternal and fetal death; uterine hyperstimulation, rupture or perforation requiring uterine surgical repair, hysterectomy or salpingo-oophorectomy; amniotic fluid embolism; severe vaginal bleeding, retained placenta, shock, fetal bradycardia and pelvic pain."

An informal poll taken by the New York University School of Medicine found that "about half of the nation's teaching hospitals" have since pulled misoprostol from their shelves (National Public Radio News Reports, Oct. 12, 2000). In light of Searle's opposition to the off-label use of Cytotec in drug-induced abortion, it was difficult to understand how the FDA could go forward with final approval of the M/M regime. That question was soon resolved when an inquiry to Searle revealed that their patent on Cytotec expired in July 2000!

Searle can be expected to argue that it has taken all possible measures through these warnings to shield itself from legal liability for the improper and unapproved use of Cytotec in the M/M regime.

What of mifepristone's manufacturer? As predicted in a September 17 Wall Street Journal article (discussed in the last issue of Life Insight), Danco Laboratories plans to import mifepristone from China. The Hua Lian Pharmaceutical factory in Shanghai has been identified as the future source of mifepristone in a recent front-page Washington Post article (P. Pan, "Chinese to Make RU-486 for U.S.," Oct. 12, 2000).

The factory, along with two others, is said to supply mifepristone used in about half of China's annual 10 million abortions–many of which are performed coercively and against the mother's wishes, in enforcing China's one-child-per-family policy.

What guarantees can the FDA make concerning the purity and safety of pills produced halfway around the world?

Aware of the widespread human rights violations against women of reproductive age in China, violations which require the cooperation of employers, Sen. Jesse Helms sent letters to both Secretary of State Madeline Albright and Secretary of Health and Human Services Donna Shalala on September 18, right after the Wall Street Journal story broke. The National Right to Life Committee's Oct. 12 press release prints an excerpt from those letters, which, NRLC adds, have not been answered to date:

"Does the management of the facility enforce the birth-quota system, which involves the monitoring of all female employees' menstrual cycles for unauthorized pregnancies—and if so, what threats or penalties are applied to a female employee of the facility who becomes pregnant without a permit? (For example, is she threatened with the loss of her position unless she submits to an abortion?) Are abortion-inducing drugs already produced by the factory utilized as part of the nationwide birth-quota enforcement system, which has been well documented to rely heavily on many forms of coercion? Does the facility produce anti-coagulation drugs that are reportedly given to some condemned prisoners prior to their execution, in order to facilitate immediate harvesting of their organs, which are sometimes provided to Party officials or to foreign buyers?"

The American public is entitled to answers to these questions before M/M abortions are foisted on the medical community and unsuspecting women.


Strict Safeguards in Use of M/M Abroad are Evidence of Method's Dangers

The FDA based its 1996 finding that drug-induced abortion using mifepristone and misoprostol was "safe and effective" not on results of U.S. trials (which were then unavailable), but on results involving a subgroup of women (1,681 total) in French trials. M/M abortions in France are performed at government-operated hospitals and clinics, typically with or adjacent to emergency room facilities. Women are screened for numerous medical conditions that rule out use of the two drugs. Ultrasound is used to determine gestational age and to rule out tubal pregnancy.

After women are given prostaglandin (e.g., misoprostol), they are monitored on site for approximately four hours so that allergic reactions, cardiopulmonary "events," hemorrhaging and the like can be treated promptly before they become life-threatening.

A 1990 directive jointly signed by the French Republic's Director General of Health, Director of Hospitals and Director of Pharmacy and Medication, states that whenever prostaglandins are given "in association with RU 486" the "following technical conditions ... are indispensable and are to be followed: ... b) The doctor must ensure that diagnostic instruments and machines are close by, such as electrocardiogram equipment and particularly resuscitative cardiopulmonary equipment (including nitrous oxide and injectable calcium antagonists and a fibrillator). ... c) [C]linical observations and blood-pressure readings every half hour are indispensable for several hours following the administration of these drugs. d) Whenever there is chest pain, an electrocardiogram should be taken on the suspicion of rhythm troubles and in case of significant lowering of blood pressure" (April 12, 1990 letter from the French Republic, Department of Solidarity, Health and Social Protection, reprinted in Child & Family 21:102-103, 1990).
In Sweden, women are "supervised by the midwife for 4 to 6 hours at the outpatient clinic" (M. Bygdeman et al., "Medical Termination of Early Pregnancy: The Swedish Experience," Journal of the American Medical Women's Assn. ["JAMWA"], Supplement 2000, 55:3; 195, 196).

In China "the emphasis on close medical supervision is well accepted. ... It is stressed that misoprostol should be taken in the clinic and followed by several hours of observation" (S. Wu, "Medical Abortion in China," JAMWA, Supplement 2000 at 197, 199). The long observation is one reason staffs in some large hospitals in China are growing reluctant to prescribe the drug combination: "The number of medical abortions has decreased recently in some of the large hospitals. The staffs were too busy to handle the procedure (more counseling, more visits, and observation), and they also have to manage the referred cases with serious side effects and complications" (Id. at 199).


Half-Measures Earlier Proposed by the FDA

The private, less regulated health care system of the U.S. cannot offer women taking M/M the same level of safety achieved overseas unless the drugs are given, and women monitored, in settings like hospital out-patient facilities. It was widely reported in June 2000 that, nodding to safety concerns, the FDA proposed making mifepristone available only to licensed physicians trained in surgical abortion, trained and certified in ultrasonography and in the use of M/M under an FDA-approved curriculum. Prescribing doctors also would need to maintain admitting privileges at a hospital no more than one hour from their main office. (See July 24, 2000 Release, American College of Obstetricians and Gynecologists.)

Inexplicably, the FDA-proposed protocol did not mandate on-site observation after taking misoprostol, although this protocol is followed in France, China, Sweden, the United Kingdom and is the common practice virtually everywhere the drug combination is used.


Final Approval Ignores Safety Concerns

Between June and September 2000, something caused the FDA to relax even these modest precautions.
Now prescribing doctors need only sign an agreement with a distributor of mifepristone that he/she can do the following: assess pregnancy duration accurately; diagnose tubal pregnancy; provide surgical intervention OR have a referral arrangement with an abortion provider; assure patients access to medical facilities equipped to provide blood transfusions and resuscitation. Additionally, doctors must see patients at 14 days and report all on-going pregnancies, serious adverse events, hospitalizations and transfusions. (Mifeprex Prescriber's Agreement).


Risks to U.S. Women under Relaxed Controls

Bleeding: In U.S. trials conducted by Population Council ("PC"), 9% of women reported bleeding after 30 days and 1% were still bleeding after 60 days. "Excessive bleeding necessitated blood transfusions in four women and accounted for 25 of 27 hospitalizations (including [ER] visits), 56 of 59 surgical interventions, and 22 of 49 administrations of [IV] fluid" (I.M.Spitz, et al., "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," The New England Journal of Medicine, April 30, 1998, 338:18, 1241-47, hereinafter "NEJM"). In a Columbia University study, 20% of women bled or spotted for 5 to 6 weeks (A. Davis, et al., "Bleeding Patterns After Early Abortion with Mifepristone and Misoprostol or Manual Vacuum Aspiration," JAMWA, Supplement 2000, 141, 143).

Dr. Mark Louviere treated a Waterloo, Iowa woman who had participated in Population Council trials. Two weeks after her M/M abortion, she was taken to a hospital emergency room where Dr. Louviere found her "in obvious shock" having "lost between one-half to two-thirds of her blood volume. ... It was my clinical opinion that she would die soon. ... Without even doing the routine preparation we normally do for surgery, I realized that I had to take her immediately to surgery to save her life" (FDA Reproductive Health Drugs Advisory Committee, Hearing Transcript, July 19, 1996 at 224). The next day, he advised Planned Parenthood of Greater Iowa which in turn informed Population Council. Both organizations, however, reported "no complications," and "no adverse events ... during the course of this trial" (Id. at 19-20).

Two patients in Des Moines, Iowa trials told a TIME magazine journalist that their bleeding was "like turning a jug of water upside down" and "like a faucet was turned on. There was a steady stream of blood. I passed a golf ball size blood clot that scared me" (Sachs, "Abortion Pills on Trial," TIME, 12/5/94, p. 45).

Allergic reactions: The FDA warns that M/M abortion is contraindicated in women with known allergies to either drug. (Mifeprex Package Insert ["MPI"]). But how would one know of such an allergy in advance? Dr. Wu Shangchun, with the National Research Institute for Family Planning in Beijing reports: "The common complications of medical [drug-induced] abortion are profuse bleeding and allergy. ... Allergic reactions to mifepristone or misoprostol were not uncommon, manifesting in facial edema, skin rash and itching, numbness of feet and hands, and even a serious case of allergic shock. The potential for such reactions is one reason to keep clients for observation" (Wu, op. cit., at 198).

Infection: Four percent of women in PC's U.S. trials had fever, viral infection and vaginitis associated with the abortion. Ten cases of study-related endometritis (inflammation of uterine lining) also occurred. (NEJM, op cit., at 1244).

A recent review of M/M regimens around the world reports on a trial involving 2000 cases (P.W. Ashok, et al., "An Effective Regimen for Early Medical Abortion: A Report of 2000 Consecutive Cases," Human Reprod. 1998; 13:2962-2965): "The most common problems reported at follow-up were continued pain, vaginal bleeding, and offensive discharge. Antibiotics were prescribed for 5% of the 1322 women for presumed genital infection" (H. Von Hertzen, "Research on Regimens for Early Medical Abortion," JAMWA, Supplement 2000, 133, 136).

A World Health Organization study recommended giving antibiotics to women for six weeks following M/M abortions, finding an infection rate of 29.4% among women who had incomplete abortions. (World Health Organization, "Pregnancy Termination with Mifepristone and Gemeprost: A Multicenter Comparison Between Repeated Doses and a Single Dose of Mifepristone," Fertil. Steril., 56:1, 1990, 32-40).

Failure Rates: Mifepristone alone was effective for only 6% of women in PC's U.S. trials in the 48 hours preceding misoprostol administration. About half of the women studied expelled their embryo within four hours of taking misoprostol, and a total of 69% had completed abortions within 24 hours of taking misoprostol.

Many of the remaining 31% faced up to two weeks of pain, nausea and bleeding. Eight percent of women in the PC trials needed surgery, due to incomplete abortions (4.7%), ongoing pregnancies (1%), and medical reasons, usually excessive bleeding (1.6%); an additional 0.6% requested surgery. (NEJM, op. cit., at 1242).

Accuracy in determining gestational age is critical because failure rates increase dramatically after 49 days LMP—17% at 50-56 days and 23% at 57-63 days. (Id. at 1243). Untreated, incomplete abortion can result in infection, sterility and death.


Additional Dangers to Women under Lax Standards Set by FDA

Failure to diagnose an ectopic pregnancy can result in maternal death. (Wu, op cit., 198-199) "Some recent adverse events resulting from undiagnosed ectopic pregnancies have led providers to pay more attention to ultrasound examination. One study found that 84% of providers in Beijing used ultrasound routinely..." (Id. at 197). The FDA has dropped the reported requirement that prescribers be certified in the use of ultrasound.

Congressman Tom Coburn, M.D., a practicing ob-gyn, has proposed legislation that would, in effect, re-instate the safeguards previously considered by the FDA, but abandoned in the final approval. The American College of Obstetricians and Gynecologists ("ACOG"), a group whose leadership consistently supports abortion, objects to stricter precautions. On October 16, Dr. Coburn wrote ACOG's Executive Vice President to respond to that organization's opposition to his bill. Concerning the failure to require ultrasound use, Dr. Coburn writes:

"Given the risks associated with the administration of mifepristone later than seven weeks LMP or in the case of an ectopic pregnancy, it is critically important to the safety of the patient to make sure that the diagnosis is accurate. We have a wonderful diagnostic tool in ultrasound. It is reliable in answering both of these key questions. The only alternative is patient self-diagnosis–a perfectly acceptable diagnostic guide to traditional obstetrics, but potentially fatal in the administration of RU 486. Why in the world would ACOG object to requiring physicians prescribing mifepristone to be able to read an ultrasound? It would seem irresponsible on its face for any physician to prescribe a drug without an ultrasound diagnosis. Yet, thanks in part to your objection to this standard, the FDA now requires physicians to be able to diagnose these conditions in any manner, without specification. In practice, this means that patient self-diagnosis is an acceptable standard. If the patient errs by two weeks in recalling the date of her last period, or dismisses the pain that might suggest an ectopic pregnancy, that is just her tough luck; she should have been more observant. That is an utterly unacceptable standard of patient care. Failure to use ultrasound to get an accurate diagnosis is negligence. Advocacy of such negligence is nothing less than a willful disregard of patient safety" (Letter to Ralph W. Hale, M.D., Executive Vice President, ACOG, Oct. 16, 2000).

The nature of abortion practice in the United States is that nine out of ten abortions take place in free-standing abortion clinics or in doctors' offices (Alan Guttmacher Institute, Facts in Brief, 1997) with minimal government supervision.

There are no guarantees that doctors prescribing mifepristone and misoprostol to U.S. women will adequately screen for medical conditions that make use of these drugs dangerous, among which are: adrenal insufficiency; coagulation disorders; use of steroid medications; known allergies to the drugs; liver, respiratory, renal or cardiovascular disease; thrombo-embolism; hypertension; anemia; and insulin-dependent diabetes mellitus. (Source: MPI and NEJM, op. cit.)

Women in the U.S. often do not return to abortion clinics for the required follow-up appointment. Suzanne Poppema, a Seattle abortion provider, has said they are "lucky if 30-40% of patients" return. In PC's U.S. trials, despite stringent counseling standards, 5% of women failed to return for the day 14 checkup. Not only do women with incomplete abortions or hemorrhaging risk death, but those with ongoing pregnancies are also at risk. Eight malformations to children were reported in 71 cases of continuing pregnancy in France, Sweden and the United Kingdom between 1987 and 1998. (Von Hertzen, op. cit. at 136).

One hopes that Congress will act quickly to block the entry of mifepristone into the U.S. until these many serious concerns are addressed.