Unresolved Issues Surrounding RU-486
On September 28, 2000, the U.S. Food and Drug Administration approved marketing of RU486 (in combination with a second drug) as an abortion method. There are a number of unresolved issues relating to the safety of this two-drug method, and the process by which it was approved.
Invocation of the Subpart H Provision of the FDA's Approval Process
Unlike standard drug approvals, the FDA approved RU486 under a special provision of its drug approval regulations known as "Subpart H" (21 CFR 314.500-314.560). The U.S. Congress passed legislation creating the rules now reflected in the "Subpart H" provision in 1992 as part of an effort to streamline the approval process for AIDS drugs that were being delayed from reaching the market by what many considered excessively lengthy and overly cautious safety analyses.(1) Subpart H provided an accelerated review for drugs under consideration for the treatment of "serious or life-threatening illnesses" that offer "meaningful therapeutic benefit to patients over existing treatments."
Though the FDA has made repeated declarations of RU486's safety, it has not widely publicized its reclassification of "the termination of unwanted pregnancy" as a "serious condition" under Subpart H (2) allowing RU486 an accelerated approval, different standards of testing, higher levels of restrictions, and, if necessary, expedited withdrawal from the market for safety or other reasons.(3) Owing to this lack of publicity, few women appreciate the level of risk involved in taking RU486.
Dangers Associated With the Method
Despite the FDA's declaration of RU486's safety and efficacy, results from the clinical trials hint at serious public health consequences if use of RU486 becomes widespread.
Efficacy rates with RU486 were much lower in U.S. trials than they were in Europe. Where European studies have reported "success" rates of 95%-96% for women up to seven weeks pregnant (49 days l.m.p., i.e., after a woman's last menstrual period),(4) the American trial obtained a rate of only 92% for this same time frame.(5) If held constant, this would mean that the chemical method would fail about one out of every 12 women. "Success" rates for those eight or nine weeks pregnant were significantly lower (83% and 77%, respectively).(6) Though the FDA only approved the use of RU486 up to 49 days of pregnancy, reports appearing in the press and in medical journals already indicate that promoters of the pill plan to use it past the 49 day cut-off date.(7)
Side effects such as pain, nausea, vomiting, diarrhea have been severe enough to put women in the hospital.(8) The most serious concern, however, is bleeding, which can be excessive and extensive. Women taking RU486 usually bleed for at least a week or two, with 9% bleeding for 30 days or more.(9)
The amount of blood loss is significant, nearly four times the average blood loss from a standard surgical suction curettage abortion.(10) Two percent in the carefully controlled clinical trials hemorrhaged(11) and two percent required "surgical intervention" to stop the bleeding.(12) At least one out of every 100 women in the trials had to be hospitalized.(13)
The seriousness of these so called "adverse events" should not be minimized. One Iowa woman participating in the U.S. trials lost between one half and two-thirds of her total blood volume and probably would have died if she had not had emergency surgery (Des Moines Register, 9/21/95). The sponsor of the trial simply passed this off as normal, telling the press that this was "within the context of what happened before [in France]."(14)
Other public health concerns that remain are what to do about women who fail to return for their required second or third office visits, and what to do about children born to these women whose development may have been affected by the drug.(15) Over a hundred women in the U.S. trials did not return for their second or third visits, including some known to be pregnant at their last appointment.(16)
Complication rates and compliance problems are likely to be much worse in the open market than they were in the confines of a carefully controlled and monitored trial. Responding to pressure from the pill's promoters and sympathetic medical groups,(17) the FDA dropped or modified many of the protective measures that were in place during the clinical trials.(18)
According to numerous press accounts, FDA was considering much more rigorous safeguards just months before granting approval. In June of 2000, FDA was poised to put in place monitored distribution, requirements that doctors prescribing RU486 have surgical abortion experience or training, training in use of the drug, training in the reading of ultrasounds, admitting privileges to hospitals with emergency services within an hour's drive of their office, and follow up studies on the health of women taking the drug.(19)
Of these regulations, only those mandating monitored distribution and follow up studies appear to have been instituted in their original forms in the formal approval of September, 2000. Physicians now only have to sign a paper saying they have read and understood the prescribing instructions, indicate an ability to date pregnancy and diagnose ectopics, make arrangements for surgical backup, and assure patient "access" to relevant emergency services. (20)
Inappropriate FDA Pressure on Manufacturer of Cytotec
Acting on its own, RU486 is only able to induce an abortion 64% to 85% of the time, an efficacy rate most researchers consider insufficient.(21) In order to complete an RU486 abortion, doctors use a second drug, a prostaglandin, to stimulate uterine contractions which expel the tiny corpse.
The prostaglandin mandated by the FDA is misoprostol, sold by R.G. Searle under the name Cytotec. Searle developed Cytotec back in 1988 as a special anti-ulcer medication for those, such as those suffering from arthritis, who take a lot of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. Searle's FDA approved label, from the beginning, has stated that the drug is contraindicated for, or not to be used by, pregnant women because of its abortifacient capacity.(22)
In a 1993 letter to the Wall Street Journal, Searle said directly that it did not want its product used with RU486 for abortion, a position it has never, as far as is known, publicly altered.(23)
When the FDA approved RU486, however, in September of 2000, it specifically mandated the use of misoprostol as a necessary part of the chemical abortion procedure.(24) Searle never sought approval for this use, and its label (package insert) is inconsistent with this use.(25)
Information published in trade and medical journals indicates that the FDA is seeking to get Searle to change its label to endorse this use.(26) If the FDA is successful is pressuring Searle to make such a change, the FDA will force Searle to accept a use of their product which they find objectionable and which could expose them to potentially serious liability.
Concerns about Chinese Supplier
Despite unprecedented efforts by the FDA to keep the identity of the manufacturer of RU486 a secret, the press has discovered that a state-owned Chinese pharmaceutical company will be manufacturing the RU486 pills that will be sold in the United States.
Chinese firms have been identified as one of the leading sources of tainted drugs sold in the U.S., and the Hualian pharmaceutical firm now manufacturing RU486 has been among those cited for various violations in recent years. In 1998, a study by the California Department of Health Services found high levels of contaminants in an herbal medication made by Hualian's earlier incarnation, the Shanghai No. 12 Pharmacy Factory, known as composite tegafuri capsules, as well as high contamination levels in hundreds of similar products made at the same plant.(27)
Another drug (betamethasone) produced by Hualian was detained by FDA officials in Cincinnati in July of 2000 because of false or misleading labeling. This was during a time when the Chinese plant was undergoing an FDA re-inspection associated with the production of RU486, though inspectors there were not informed of the problem with the betamethasone intercepted in Cincinnati.(28)
Even so, FDA inspectors did encounter a number of irregularities in their inspection visits of 1999 and 2000. In October of 1999, the inspector found that the methods and specifications section of the Chemistry and Manufacturing Controls report filed by Hualian "didn't correspond to methods and specifications used by the firm."(29)
An interpreter explained to the FDA inspector that Hualian had simply "copied information from the Roussel NDA [the original French manufacturer's New Drug Application] in a number of sections rather than translate their own methods from Chinese to English." The inspector also said Hualian had inserted numerous references to the United States Pharmacopeia (USP - the legally recognized compendium of standards for drugs in the United States) in its Chemistry and Manufacturing Controls report after Hualian's consultant told them the FDA wanted all raw materials to meet this standard, even though the references they inserted "have nothing to do with the testing they perform." The FDA inspector gave up after four days of waiting for translations that correctly reflected Hualian's testing practices.(30)
These supposedly resolved, the FDA returned for another inspection in July of 2000. Even this inspection found several deficiencies, but, based on promises of corrective actions by Hualian, the FDA approved RU486.(31)
Even if FDA inspectors attempted to act in good faith, there are serious questions about the integrity of the manufacturing and testing processes at the Hualian factory. The factory has been identified as a source of tainted drugs shipped to the U.S. in the past and some question remains about Hualian's willingness to disclose deficiencies or possible problems.
Liability is also a question. The production of RU486 in communist China raises concerns not only about the safety or purity of the drug, but also about the ability of women or their families to collect damages if killed or injured by the drug.
Still unclear is whether the Chinese formula for RU486 is the same one tested and approved in the U.S.(32) If not, data from the U.S. trials of RU486 offer no reliable guide to the safety and efficacy of the Chinese product.
1. Christine Gorman, "Let's not be too hasty," TIME, September 19, 1994 (Vol. 144, No. 12); available at www.time.com/time/magazine/archive/1994/940919/940919.medicine.html .
2. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Memorandum, Approval of Mifepristone, September 28, 2000, p. 6.
3. Department of Health and Human Services, Food and Drug Administration, Final Rule, 21 CFR, parts 314 and 601, "New Drug, Antibiotic, and Biologic Product Regulations; Accelerated Approval," Federal Register, 57 FR 58942, December 11, 1992.
4. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Memorandum, Approval of Mifepristone, September 28, 2000, p. 1.
5. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247, at pp.1242-1243.
6. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247, at pp. 1242-1243.
7. Sarah Lueck, "Groups Offer Abortion-Drug Variations," Wall Street Journal, October 30. 2000, p. B2.
8. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247, at p.1244.
9. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247, at p. 1243.
10. Ob.Gyn. News (1989), No. 24, p. 1.
11. Testimony of C. Wayne Bardin, Population Council, Transcript of FDA Reproductive Health Drugs Advisory Committee meeting, "New Drug Application for the Use of Mifepristone for Interruption of Early Pregnancy," July 19, 1996, p. 65. FDA approved labeling for Mifeprex actually lists a figure of 5% for uterine hemorrhage in Table 3, "Type of Adverse Events Following Administration of Mifepristone and Misoprostol in the U.S. and French Trials."
12. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247, at p. 1243.
13. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247.
14. Tom Carney, "'Abortion pill' test goes awry for one patient," Des Moines Register, September 21, 1995, p. 1M. See also Dr. Mark Louviere, "Group lies when it said 'abortion pill' test resulted in no complications," Waterloo Courier, September 24, 1995, p. F3 and Testimony of Dr. Mark Louviere, Transcript of FDA Reproductive Health Drugs Advisory Committee meeting, "New Drug Application for the Use of Mifepristone for Interruption of Early Pregnancy," July 19, 1996, pp. 223ff.
15. See comments of Drs. Cassandra Henderson and Vivian Lewis, members of FDA Reproductive Health Drugs Advisory Committee, Transcript of July 19, 1996 meeting, pp. 266ff, 278ff, 295ff.
16. Irving M. Spitz, C. Wayne Bardin, Lauri Benton, Ann Robins, "Early Pregnancy Termination with Mifepristone and Misoprostol in the United States," New England Journal of Medicine, Vol. 338, No. 18 (April 30, 1998), pp. 1241-1247 at pp.1242 and 1246.
17. American College of Obstetricians and Gynecologists, American Medical Association, Letter to Jane Henney, M.D., Commissioner, Food and Drug Administration, July 24, 2000.
18. Nancy Gibbs, "The Abortion Pill," TIME, October 9, 2000, pp. 41-49, at 43.
19. Rita Rubin, "Abortion-pill backers fear a lack of access," USA Today, June 7, 2000; Sheryl Gay Stolberg, "F.D.A. Adds Hurdles in Approval of Abortion Pill," New York Times, June 8, 2000; Sarah Lueck, "FDA Restrictions May Deter Doctors From Prescribing the Abortion Pill," Wall Street Journal, June 8, 2000; Marc Kauffman, "Abortion Drug Proposal Criticized," Washington Post, June 7, 2000, p. A1; Lauran Neergard, "Abortion Pill May Have Restrictions," Los Angeles Times, June 7, 2000.
20. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Memorandum, Approval of Mifepristone, September 28, 2000, pp. 4-7.
21. Sophie Christin-Maitre, Phillippe Bouchard, and Irving Spitz, "Medical Termination of Pregnancy," New England Journal of Medicine, Vol. 342, No. 13 (March 30, 2000), p. 951. While Christin-Maitre, et al, specifically referred to the efficacy of mifepristone among women 49 days pregnant or les, Ulmann, Scientific American, p. 23, reported a range of 65% to 80%. Other studies using similar doses obtained "completion" rates of 65.2% (RU486 Colloboration Group, "Termination of early pregnancy by RU486 alone or in combination with prostaglandin," Chinese Journal of Obstetrics & Gynecology, Vol. 25 (1990), pp. 31-4, 62) and 63.5% (Zheng Shu-rong, "RU 486 (mifepristone): clinical trials in China," Acta Obst. Gyn. Scand, Vol 149 (1989), supplement, pp. 19-23.
22. Michael A. Friedman, M.D., "Manufacturer's Warning Regarding Unapproved Uses of Misoprostol," New England Journal of Medicine, Vol. 344, No. 1 (January 4, 2001), p. 61.
23. Charles L. Fry, Letter to the Editor, "Searle Against Use of Its Drug in Abortion," Wall Street Journal, March 19, 1993, p. A11.
24. FDA approved label, Mifeprex, September 28, 2000. Available at www.fda.gov/cder/drug/infopage/mifepristone.
25. "Cytotec,"Physicians' Desk Reference (Montvale, NJ: Medical Economics, 1996), pp. 2424-2426.
26. "Searle/FDA Cytotec Labeling Negotiations Continue Ahead Of Mifeprex Launch," F-D-C Reports "The Pink Sheet," October 9, 2000, p. 11.
27. Aaron Zitner, "RU-486 Firm Tied to Impurities," Los Angeles Times, October 20, 2000.
28. Letters from Rep. Tom Bliley, Chair, U.S. House of Representatives Commerce Commitee, to Jane Henney, M.D., Commissioner, Food and Drug Administration, October 18, 2000, and November 1, 2000.
29. Letter from Rep. Tom Bliley, Chair, U.S. House of Representatives Commerce Commitee, to Jane Henney, M.D., Commissioner, Food and Drug Administration, October 18, 2000, p.4.
30. Letter from Rep. Tom Bliley, Chair, U.S. House of Representatives Commerce Commitee, to Jane Henney, M.D., Commissioner, Food and Drug Administration, October 18, 2000, p. 4.
31. Letter from Rep. Tom Bliley, Chair, U.S. House of Representatives Commerce Committee, to Jane Henney, M.D., Commissioner, Food and Drug Administration, October 18, 2000, p. 5.
32. Regina Sitruk-Ware, a representative of Exelgyn, the current French supplier, told a 1998 Population Council sponsored conference that the Chinese synthesis for the abortion pill is different from the one developed by the French and said only that the pills are "very similar." See "Strategy for the introduction of Mifepristone," Population Council and The Wellcome Trust Conference, Towards Safe and Effective Use of Medical Abortion, Bermuda, January 10-13, 1998, Report of Meeting, p. 16.