Footnotes for "Citizen Petition to the U.S. Food and Drug Administration on RU 486" by Americans United for Life

  1. The comments submitted herein are limited to RU 486 as an abortifacient drug product. This petition does not, therefore, oppose or address in any manner the use of RU 486 in the treatment of diseases, such as breast cancer or meningiomas (brain tumors).
  2. See FDCA 505(d), 21 U.S.C. 355(d).
  3. 21 U.S.C. 355(b)(1)(A).
  4. See FDCA 505(d)(1) (emphasis added), 21 U.S.C. 355(d)(1).
  5. See FDCA 505(d)(4) (emphasis added), 21 U.S.C. 355(d)(4).
  6. The phrase "subsequent born children" is defined for the purpose of this document as children born as a result of a pregnancy continued after a failed RU 486 abortion as well as any additional children conceived and born after exposure to RU 486.
  7. 21 U.S.C. 355(d)(5).
  8. 21 U.S.C. 355(d).
  9. See Warner-Lambert Co. v. Heckler, 787 F.2d 147, 155 (1986).
  10. See United States v. Rutherford, 442 U.S. 544, 553 n.9 (1979); Warner-Lambert Co. v. Heckler, 787 F.2d at 155 (discussing United States v. Rutherford).
  11. See 21 C.F.R. 312.120, 314.106 (1994).
  12. See 21 C.F.R. 314.106 (1994).
  13. Dr. Meredeth Turshen has raised concerns about the accuracy of the complication and failure rates being reported by foreign studies funded by Roussel Uclaf (the French manufacturer of RU 486), in light of the results that have been obtained by some independent researchers, which have not been published. Dr. Turshen was a fellow at INSERM (the French equivalent of NIH) during 1989-90. See Comments by Dr. Turshen at "Contraceptive Technology: Promises and Politics" workshop at the annual meeting of the Am. Public Health Assoc. (Oct. 2, 1990); "Researcher suggests side effects of RU-486 may be underreported" Am. Medical News, Oct. 26, 1990, at 8; Boston Herald, July 31, 1992, at 25.
  14. An average value for the frequency of complete abortion with RU 486 alone is approx. 63%. WHO Task Force On Post-Ovulatory Methods For Fertility Regulation, Termination Of Early Human Pregnancy With RU 486 (Mifepristone) And The Prostaglandin Analogue Sulprostone: A Multi-Centre, Randomized Comparison Between Two Treatment Regimens, 4 Hum. Reprod. 718, 719 (1989) (hereafter "WHO Task Force, 1989"). See Table 1 for comprehensive statistics on complete abortion rates.
  15. Grimes, Mifepristone (RU 486) For Induced Abortion, 3 Women's Health Issues 171, 172 (1993) (hereafter "Grimes, 1993"); Grimes, et al., Early Abortion With A Single Dose Of The Antiprogestin RU-486, 158 Am. J. Obst. Gyn. 1307, 1308 (1988) (hereafter "Grimes, et al., 1988") (10% failure with 600 mg dose in women less than or equal to 49 days from last menstrual period ("LMP"); and Shoupe, et al., Pregnancy Termination With A High And A Medium Dosage Regimen Of RU 486, 33 Contraception 455 (1986) (hereafter "Shoupe, et al., 1986") (90% failure in high dose group -- 400 mg/day for 4 days (N=5) or 200 mg/day for 4 days (N=5) -- all women within 49 days of first day of LMP). For statistics on incomplete abortion rates, see Table 2.
  16. With RU 486 alone, from 8.3% to 46.3% of pregnancies continue. See Table 9 for reported statistics.
  17. Grimes, et al., found that the risk of failure from RU 486 alone for women in the largest body mass group studied was 2.9 times greater than that of women in the lowest body mass group studied. Grimes, et al., Predictors Of Failed Attempted Abortion With The Antiprogestin Mifepristone (RU 486), 162 Am. J. Obst. Gyn. 910, 913-14 (1990) (hereafter "Grimes, et al., 1990") (risk with a Quetelet's index [weight(kg)/height(m2)] greater than 23.81 was 2.9 times the risk with index less than 20.25); see also Grimes, 1993, at 172 (1993). See discussion infra Section 3.d.
  18. See Chan, et al., Blood Loss In Termination Of Early Pregnancy By Vacuum Aspiration And By Combination Of Mifepristone And Gemeprost, 47 Contraception 85 (1993) (hereafter "Chan, et al., 1993") (medical termination of pregnancy carries risk of incomplete abortion that requires surgical intervention).
  19. See Raymond, et al., RU 486: Misconceptions, Myths And Morals 38 (1991) (hereafter "Raymond, et al., 1991") ("Incomplete abortions . . . necessitate that the products of conception are removed by conventional abortion methods. Incomplete evacuation can be accompanied by severe bleeding. . . . This adverse effect of RU 486/PG abortion may lead to . . . pelvic inflammatory disease (PID) from infection, to infertility, and possibly uterine cancer.") For statistics on the incidence of infection with pharmaceutical abortion, see Table 3.
  20. See Pons, et al., Development After Exposure To Mifepristone In Early Pregnancy, 338 Lancet 763 (1991) (hereafter "Pons, et al., 1991") (although the researchers couldn't determine whether the abnormalities were related to RU 486, they concluded that "a deleterious effect of mifepristone cannot be ruled out."). See also infra Section 4.b.(1) and accompanying footnotes.
  21. Micrognathia is an abnormality characterized by smallness of the jaw, especially the underjaw. Stedman's Medical Dictionary 875 (5th ed. 1982). Hygroma is a cystic swelling, usually of the neck area, containing serous fluid. See Stedman's Medical Dictionary 668 (5th ed.); Dorland's Illustrated Medical Dictionary 789 (28th ed. 1994).
  22. Swahn, et al., Effect Of Oral Prostaglandin E2 On Uterine Contractility And Outcome Of Treatment In Women Receiving RU 486 (Mifepristone) For Termination Of Early Pregnancy, 4 Hum. Reprod. 21, 27 (1989) (hereafter "Swahn, et al., 1989"). See also, Zheng Shu-rong, RU 486 (Mifepristone): Clinical Trials In China, 149 Acta Obst. Gyn. Scand. Suppl. 19 (1989) (hereafter "Zheng Shu-rong, 1989") (4 patients (1.34%) suffered heavy bleeding, necessitating emergency curettage after receiving RU 486); The RU 486 Collaboration Group, Termination Of Early Pregnancy By RU 486 Alone Or In Combination With Prostaglandin, 25 Chinese J. Obst. & Gyn. 31 (1990) (clinically significant [177.4 ml] mean blood loss after complete abortion reported).
  23. Researchers have noted that the total amount of blood lost by women treated with RU 486 is not reduced with a RU 486/PG regimen. Swahn, et al., 1989, at 27 (1989); Rodger & Baird, Blood Loss Following Induction Of Early Abortion Using Mifepristone (RU 486) And A Prostaglandin Analogue (Gemeprost), 40 Contraception 439 (1989) (hereafter "Rodger & Baird, 1989"); Cameron, et al., Therapeutic Abortion In Early Pregnancy With Antiprogestogen RU 486 Alone Or In Combination With Prostaglandin Analogue (Gemeprost), 34 Contraception 459 (1986). But see, Zheng Shu-rong, 1989 (reporting a lower volume of blood loss with RU 486/PG regimen [52 ml (RU 486/PG) v. 117 ml (RU 486)] in women who aborted within 49 days amenorrhea).
  24. Thong & Baird, Induction Of Abortion With Mifepristone And Misoprostol In Early Pregnancy, 99 Br. J. Obst. Gyn. 1004, 1006 (1992) (hereafter "Thong & Baird, 1992"). See also Couzinet, et al., Termination Of Early Pregnancy By The Progesterone Antagonist RU 486 (Mifepristone), 315 N. Eng. J. Med. 1565, 1569 (1986); Sitruk-Ware, et al., The Use Of The Antiprogestin RU 486 (Mifepristone) As An Abortifacient In Early Pregnancy -- Clinical And Pathological Findings; Predictive Factors For Efficacy, 41 Contraception 221, 239-40 (1990); El-Refaey & Templeton, Early Induction Of Abortion By A Combination Of Oral Mifepristone And Misoprostol Administered By The Vaginal Route, 49 Contraception 111, 113-14 (1994) (hereafter "El-Refaey & Templeton, 1994"); Rodger & Baird, 1989, at 444; UK Multicentre Trial, The Efficacy And Tolerance Of Mifepristone And Prostaglandin In First Trimester Termination Of Pregnancy, 97 Br. J. Obst. Gyn. 480, 485 (1990) (hereafter "UK Multicentre Trial, 1990"); Chan, et al., 1993, at 85; Wu, et al., Clinical Trial On Termination Of Early Pregnancy With Ru 486 In Combination With Prostaglandin, 46 Contraception 203, 209 (1992) (hereafter "Wu, et al., 1992").
  25. For statistics on complete abortion rates using RU 486 alone, see Table 1 (average complete abortion rate [approx.] 63%); compare to complete abortion rates of 84.4% to 99% using RU 486/oral or vaginal misoprostol up to 63 days amenorrhea (Table 4). Complete abortion rates of 75.3% to 99% using RU 486 in combination with other prostaglandins up to 63 days amenorrhea are reported in Table 5.
  26. McKinley, et al., The Effect Of Dose Of Mifepristone And Gestation On The Efficacy Of Medical Abortion With Mifepristone And Misoprostol, 8 Hum. Reprod. 1502 (1993) (hereafter "McKinley, et al., 1993") (regimen of either 200 or 600 mg RU 486 followed by 600 ug misoprostol 48 hrs. later).
  27. Id.
  28. Id. at 1502. See also Ulmann, Warning On Low Dose Mifepristone Use, 6 PharmacoEconomics 90 (1994) ("Currently available information suggests that the efficacy of misoprostol following mifepristone is significantly lower in pregnancies above 49 days of amenorrhea. The efficacy rate drops to only 90% for pregnancies between 49 and 63 days of amenorrhea, a value that is medically unacceptable.").
  29. Aubeny & Baulieu, Contragestion With RU 486 And An Orally Active Prostaglandin, 312 C.R. Acad. Sci. Paris (III) 539 (1991) (31%); Thong & Baird, 1992 (21%); Peyron, et al., Early Termination Of Pregnancy With Mifepristone (RU 486) And The Orally Active Prostaglandin Misoprostol, 328 N. Eng. J. Med. 1509 (1993) (hereafter "Peyron, et al., 1993") (33.2% in study 1 and 25.4% in study 2); McKinley, et al., 1993 (36.4% and 26.4% in the two groups given 200 or 600 mg RU 486); Thong, et al., What Do Women Want During Medical Abortion?, 46 Contraception 435 (1992) (hereafter "Thong, et al., 1992") (29%).
  30. Thong, et al., 1992, at 440.
  31. See Thong & Baird, 1992, at 1006, reporting:
    The 3% incidence of ongoing pregnancies with this regimen is slightly higher than that reported using a combination of mifepristone with gemeprost or sulprostone (Sylvestre et al. 1990; UK Multicentre Trial, 1990). We have previously reported ongoing pregnancies in two out of 21 women (up to 56 days amenorrhea) who were given 200 mg mifepristone followed by 200 ug and 400 ug of misoprostol (Norman et al. 1991). Therefore, in a consecutive series of 121 women treated with mifepristone and misoprostol in our centre, the ongoing pregnancy rate was 4% (95% CL 0.6-8.6%). In a consecutive series of 470 pregnancies (<56 days) terminated with mifepristone (50-600 mg) and gemeprost (0.5 mg-l mg) in our institution, there has been only one ongoing pregnancy (0.2%). If the higher incidence of ongoing pregnancies is confirmed by a larger study . . . , the clinical usefulness of this combination of mifepristone and oral misoprostol for routine clinical use would be in doubt.
    Two other British researchers reported a 3% (5 patients) ongoing pregnancy rate in a series of 150 patients receiving oral misoprostol 800 ug after 200 mg RU 486. El-Refaey & Templeton, 1994, at 112.
  32. Peyron, et al., 1993.
  33. For data on RU 486/oral misoprostol abortion, see Table 6 (pain reported in from 79.1 to 85% patients; analgesia needed in from 12.5 to 57.1% patients). For data reported for RU 486 with other prostaglandins, see Table 7. See also WHO, Pregnancy Termination With Mifepristone And Gemeprost: A Multicenter Comparison Between Repeated Doses And A Single Dose Of Mifepristone, 56 Fertility & Sterility 32, 39 (1991) (hereafter "WHO, 1991") ("As anticipated, mifepristone-induced uterine contractions and vaginal bleeding were associated with lower abdominal pain, which became almost universal after gemeprost administration."); UK Multicentre Trial, 1990, at 484 (where 16% reported mild, moderate or severe pain the first 24 hours after mifepristone compared to 84% who reported pain 2 hours after gemeprost); Thong & Baird, 1992, at 1005 (11% reported abdominal pain before misoprostol administration and 85% 2 hours afterwards); McKinley, et al., 1993, at 1504 (53.6% reported abdominal pain before misoprostol administration and 79.1% 2 hours afterwards).
  34. Zheng Shu-rong, 1989, at 22 (reporting a higher incidence of abdominal pain resulting from uterine cramping and diarrhea in women given RU 486 plus a PG); Thong & Baird, 1992, at 1005-06 (reporting an expected increase in PG-related side effects 2 hrs. following administration of misoprostol, including vomiting, pain, faintness and diarrhea); McKinley, et al., 1993, at 1504 (reporting increases in vomiting, pain, diarrhea and fainting 2 hrs. after taking misoprostol); UK Multicentre Trial, 1990, at 484 (where 3% and 0.5% reported vomiting and diarrhea during the first 4 hours after mifepristone compared to 26% and 13% during the first 4 hours after gemeprost). See also Sachs, A., Abortion Pills on Trial, Time, Dec. 5, 1994, at 45-46.
  35. See Ulmann, et al., Medical Termination Of Early Pregnancy With Mifepristone (RU 486) Followed By A Prostaglandin Analogue, 71 Acta Obst. Gyn. Scand. 278 (1992) (hereafter "Ulmann, et al., 1992") (reporting 3 myocardial infarctions (1 fatal) and 3 cases of severe hypotension after sulprostone injection); Anonymous, A Death Associated With Mifepristone/Sulprostone, 337 Lancet 969 (1991) (discussing the same death reported in Ulmann, et al., 1992). See also Institute of Medicine, Clinical Applications Of Mifepristone (RU 486) And Other Antiprogestins 27 (1993) (hereafter "Institute of Medicine, 1993") (reporting one patient death during the first trial of RU 486 with oral misoprostol).
  36. WHO Task Force On Post-ovulatory Methods Of Fertility Regulation, Termination Of Pregnancy With Reduced Doses Of Mifepristone, 307 BMJ 532 (1993) (hereafter "WHO Task Force, 1993") (reported significant decrease in pulse rate during the first few hours after gemeprost (3-4 beats/min.); WHO, 1991 (reported significant (P<0.001) decrease in pulse rate during 4-hour period after gemeprost).
  37. Peyron, et al., 1993, at 1511.
  38. Id. (researchers attributed the hypotension to a vagal reaction secondary to painful uterine cramps).
  39. This list is based on expert review of the medical literature cited in Attachment 2.
  40. Wilcox, et al., Hysterectomy In The United States, 1988-1990, 83 Obst. & Gyn. 549 (1994) (fibroid tumor was reported as the primary diagnosis for 61% of African-American women and 29% of Caucasian women having hysterectomy); Kjerulff, et al., Hysterectomy And Race, 82 Obst. & Gyn. 757 (1993) (in study of more than 53,000 hysterectomies, African-American women were more than twice as likely to have a diagnosis of uterine fibroids as Caucasian women).
  41. Gohdes, et al., Diabetes In American Indians, 16 Suppl. 1 Diabetes Care 239 (1993); Gohdes, Diabetes In American Indians: A Growing Problem, 9 Diabetes Care 609 (1986); Freeman, et al., Diabetes In American Indians Of Washington, Oregon, And Idaho, 12 Diabetes Care 282 (1989); Knowler, et al., Diabetes Mellitus In The Pima Indians: Incidence, Risk Factors And Pathogenesis, 6 Diabetes/Metabolism Reviews 1 (1990); Knowler, et al., Diabetes Incidence And Prevalence In Pima Indians: A 19-Fold Greater Incidence Than In Rochester, Minnesota, 108 Am. J. Epidem. 497 (1978); Gardner, et al., Prevalence Of Diabetes In Mexican Americans--Relationship To Percent Of Gene Pool Derived From Native American Sources, 33 Diabetes 86 (1984); Carter, et al., Diabetes Mortality Among New Mexico's American Indian, Hispanic, And Non-Hispanic White Populations, 1958-1987, 16 Suppl. 1 Diabetes Care 306 (1993).
  42. Grimes, et al., 1990, at 913-14 (risk with a Quetelet's index [weight(kg)/height(m2)] greater than 23.81 was 2.9 times the risk with index less than 20.25); see also Grimes, 1993, at 172.
  43. See WHO Task Force, 1989, at 722, 724 (subjects where RU 486/sulprostone failed weighed 65.7 + or - 10.2 kg; those with complete abortion, 54.7 + or - 8.3 kg; and those with incomplete abortion, 54.5 + or - 10.6 kg). But see Thong & Baird, 1992 (complete abortion rate not influenced by body mass index; however, the study focused on the clinical efficacy of RU 486/misoprostol abortion in only 100 subjects, not on predictors of failed attempted abortion).
  44. WHO, 1991, at 35, 38 (women with vaginal bleeding prior to gemeprost administration had significantly greater weight (56.1 + or - 7.5 kg) and ponderal index (2.14 + or - 0.26) than those who started to bleed after gemeprost (53.7 + or - 7.4 kg; 2.06 + or - 0.23).
  45. See discussion infra Section 4.a.(5) and accompanying footnotes.
  46. One study found a higher rate of failure in patients over the age of 34. Thonneau, et al., Analysis Of 369 Abortions Conducted By Mifepristone (RU 486) Associated With Sulprostone In A French Family Planning Center, 61 Fertility & Sterility 627, 629-30 (1994) (hereafter "Thonneau, et al., 1994") ("The patient characteristics that correlated with failure were age over 34 years (6% <35 years versus 14% >34 years; P=0.05) . . . .") ("We are not aware of other studies indicating that age (>35 years) is a risk factor for failure. However, age over 35 has been considered to be a risk factor for morbidity. . . .").
  47. For data on RU 486/oral misoprostol abortion, see Thong & Baird, 1992 (4% of users: 1 woman needed emergency curettage for heavy bleeding due to incomplete abortion; 3 women were given intramuscular ergometrine for heavy bleeding at the time of expulsion of products); Peyron, et al., 1993 (0.4% of patients (2 women) in study 1 had hemorrhage requiring hemostatic curettage, with one patient needing a blood transfusion 9 days after misoprostol when hemoglobin fell from 13.0 g/dl to 6.1 g/dl); McKinley, et al., 1993 (5.5% had a drop in hemoglobin >2 g/dl, but no blood transfusions). For additional data on this complication with RU 486 and other prostaglandins, see Table 8.
  48. See Table 6 for pain data on RU 486/oral misoprostol abortion. For pain data on RU 486 with other prostaglandins, see Table 7.
  49. For infection data on RU 486 with prostaglandins other than misoprostol, see Table 3.
  50. For data on RU 486/oral misoprostol abortion, see Peyron, et al., 1993, at 1511 (6 women (1.2%) had a "substantial but transient decrease in blood pressure (more than 30 mm Hg for the systolic pressure and 15 mm Hg for the diastolic pressure) attributable to a vagal reaction secondary to painful uterine cramps."). For data on RU 486 with other prostaglandins, see Ulmann, et al., 1992 (reporting 3 myocardial infarctions (1 fatal) and 3 cases of severe hypotension after sulprostone injection).
  51. FDA should consider that complications with pharmaceutical abortion may result regardless of whether the abortion is complete. See Birth Control Trust, Mifepristone In Practice: Running An Early Medical Abortion Service, 38 (1994) (hereafter "Birth Control Trust, 1994") (an early complication rate of 14% among women who had a medical abortion (RU 486/gemeprost) even though 94% had a complete abortion); A World Health Organization ("WHO") study reported that 2.6% of the women with complete abortions (92.7%) required antibiotics to prevent or cure suspected genitourinary infection during a six week follow-up period. WHO, 1991, at 37. See also, WHO Task Force, 1989, at 722 (1.3% of subjects w/complete abortion (88.8% of subjects) given antibiotic therapy because of clinically suspected endometritis).
  52. The three largest studies only followed patients for approximately one week after PG administration. Ulmann, et al., 1992, at 279 ("approximately one week later. . . the final outcome of treatment was evaluated."); Aubeny, RU 486 Combined With PG Analogs In Voluntary Termination Of Pregnancy, 7 Adv. Contraception 339, 341 (1991) ("fourth visit took place on day 8-12 after expulsion."); Wu, et al., 1992, at 204 ("On the 8th day after medication, the woman returned to the clinic for evaluation of the result . . . . If complete abortion could not be confirmed, further follow-up on the 14th day was required."). The remaining studies typically follow patients until the onset of their next menstrual period (one, two and four or six weeks after the RU 486 abortion procedure). See, e.g., UK Multicentre Trial, 1990 and the WHO studies.
  53. See infra section 3.f. and accompanying footnotes for statistics on lack of patient compliance.
  54. Rodger, et al., Induction Of Early Abortion With Mifepristone (RU 486) And Two Different Doses Of Prostaglandin Pessary (Gemeprost), 39 Contraception 497, 501 (1989) (hereafter, "Rodger, et al., 1989") ("Careful follow-up is essential following treatment to exclude the presence of a continuing pregnancy."); Peyron, et al., warned that "[e]ctopic pregnancy is difficult to detect very early, and its possible occurrence makes a follow-up visit 8 to 15 days after the treatment mandatory . . . ." Peyron, et al., 1993, at 1512; Ulmann, et al., 1992, at 283 (RU 486/PG abortion is an "acceptable alternative to surgical procedures, provided that . . . the protocol recommended by the manufacturer is strictly followed."); Rodger & Baird, Induction Of Therapeutic Abortion In Early Pregnancy With Mifepristone In Combination With Prostaglandin Pessary, Lancet ii: 1415, 1417-1418 (1987) ("The occurrence of incomplete abortion after medical termination of pregnancy . . . makes careful follow-up a necessity.").
  55. UK Multicentre Trial, 1990. A study by Ulmann, et al., indicates a lower, but still significant incidence of noncompliance: (1) 0.3% of women given RU 486 were lost to follow-up prior to PG administration; and (2) 0.8% never received a PG even though they had not aborted. Thus, 1.1% of women who received RU 486 as part of an RU 486/PG protocol did not return and/or refused to take the prostaglandin analog. In addition, 2.6% of the women in the study were lost to follow-up after RU 486/PG administration. Ulmann, et al., 1992, at 280 (There were other protocol violations reported in this study: 11.6% took PG either before or after the protocol time (36-48 hr. after RU 486 intake); and 13.6% had pregnancies beyond the 7 week protocol cut-off (i.e., more than 49 days amenorrhea calculated from the first day of the last menstrual period). Id.
  56. See also Grimes, et al., 1990 (2.5% of patients were lost to follow-up after RU 486 administration; study did not include PG); Peyron, et al., 1993 (2.8% of the women in study 1 did not return for follow-up after RU 486/misoprostol administration; and 27.6% of the women in study 2 who had not aborted within 4 hours after 400 ug of misoprostol declined to take an additional 200 ug dose); Henshaw, et al., Comparison Of Medical Abortion With Surgical Vacuum Aspiration: Women's Preferences And Acceptability Of Treatment, 307 BMJ 714 (1993) (4% of patients in a study comparing medical to surgical abortion did not return for follow-up visit 16 days later); Hill, et al., The Efficacy Of Oral Mifepristone (RU 38,486) With A Prostaglandin E1 Analog Vaginal Pessary For The Termination Of Early Pregnancy: Complications And Patient Acceptability, 162 Am. J. Obst. Gyn. 414 (1990) (7%, 15%, and 13% of patients did not attend for follow-up at 7, 14, and 28 days after PG administration, respectively); Thonneau, et al., 1994, at 628-29 ("Sixteen patients (4.3%) did not return for follow-up on day 14, and no data about either efficacy or complications are available for these women."); WHO Task Force, 1993, at 534 ("Two women refused the gemeprost pessary . . . . Six other women received both mifepristone and gemeprost and attended the follow up visit one week later, but they defaulted from attending further follow up visits and attempts to contact them failed."); Indian Council of Medical Research Task Force On Hormonal Contraception, A Multicentre Clinical Trial With RU 486 Followed By 9-Methylene-PGE2 Vaginal Gel For Termination Of Early Pregnancy: A Dose-Finding Study, 49 Contraception 87, 91, 97 (1994) (4 patients (0.88%) did not come back for the PG gel: 3 for "personal reasons" and 1 was lost to follow-up); Maria & Stampf, Termination Of Early Pregnancy Using Mifepristone In Combination With Prostaglandin Analogs, 149 Acta Obst. Gyn. Scand. Suppl. 31 (1989) (4.9% (13 patients) were lost from study and did not receive the follow-up exam on day 10); Swahn & Bygdeman, Termination Of Early Pregnancy With RU 486 (Mifepristone) In Combination With A Prostaglandin Analogue (Sulprostone), 68 Acta Obst. Gyn. Scand. 293, 294 (1989) (hereafter "Swahn & Bygdeman, 1989") (0.85% (one woman) withdrew from study 24 hours after RU 486 administration -- prior to PG administration -- due to nausea); WHO Task Force, 1989, at 720 (0.4% (one woman) stopped RU 486 and did not receive the PG "for personal reasons unrelated to the treatment . . . ." And 0.4% (one) was lost to follow-up.); Broome, Using Mifepristone In A Family Planning Clinic, 20 Br. J. Family Planning 11 (1994) (11.2% failed to keep follow up appointment. "This rate has become much worse in the last few months. . . .").
  57. Ulmann, et al., 1992, at 280-81 (reporting that the success rate was significantly lower (88.6% instead of 95.3%) in the absence of PG administration and the incidence of ongoing pregnancy was higher (4.6% as opposed to 1.2% overall).
  58. Id. at 281. Ulmann reported 4.2% of patients who did not receive the PG required vacuum aspiration or D&C because of incomplete abortion (compared to 2.8% of total patients). Also, 2.6% of the group not receiving PG required a hemostatic surgical procedure (compared to 0.7% of total patients).
  59. The protocol followed in most published studies calls for administration of an anti-D immunoglobulin injection for Rh negative women at the time of PG administration. See Thong, et al., Changes In The Concentration Of Alpha-Fetoprotein And Placental Hormones Following Two Methods Of Medical Abortion In Early Pregnancy, 100 Br. J. Obst. & Gyn. 1111 (1993); Urquhart & Templeton, Reduced Risk Of Isoimmunisation In Medical Abortion, 335 Lancet 914 (1990).
  60. Id. at 280-81. Ulmann reported that the time lapse between RU 486 and PG intake had a significant effect on the complete abortion rate. This rate was highest (95.8%) at 36-48 hours, but dropped to 92.8% at less than 36 hours, and 93.9% at more than 48 hours.
  61. UK Multicentre Trial, 1990; Ulmann, et al., 1992, at 283. See also Wu, et al., 1992, at 209 ("It seems that the treatment regimen when followed carefully plays an important role on the effectiveness of the method.").
  62. "With RU-486, Will More Physicians Provide Abortions?," Amer. Med. News, Apr. 12, 1993, at 3.
  63. There is some published medical literature on RU 486 which medical experts assume is scientifically valid. However, this assumption may not be warranted and therefore FDA should not rely on the published literature without verification of the raw data supporting the publication.
  64. Vessey, et al., Oral Contraceptive Use And Abortion Before First Term Pregnancy In Relation To Breast Cancer Risk, 45 Br. J. Cancer 327 (1982) (this study is composed almost entirely of women who had a spontaneous abortion, with "only a handful" of patients who had undergone induced abortion.); Gandra, et al., Risk Factors For Breast Cancer: A Case-Control Study, 6 Acta Medica Portuguesa 129 (1993).
  65. Lindefors-Harris, et al., Risk Of Cancer Of The Breast After Legal Abortion During First Trimester: A Swedish Register Study, 299 Br. Med. J. 1430 (1989) (authors achieved a borderline significant negative association only by inexplicably excluding women aborted after age 30, and by comparing aborted women to the general population rather than to a bona fide control group. Since the general population had a 20% higher nulliparity rate than the study population of aborted women (49% versus 41%), the known protective effect of parity could account for the apparent protective effect of abortion.).
  66. Several studies are published in more than one report.
  67. See Dvoirin & Medvedev, Role of women's reproductive status in the development of breast cancer, Methods And Progress In Breast Cancer Epidemiology Research 53 Tallinn, Estonia (1978) (hereafter "Dvoirin & Medvedev, 1978"); La Vecchia, et al., Long-Term Impact Of Reproductive Factors On Breast Cancer, 53 Int. J. Cancer 215 (1993) (hereafter "La Vecchia, et al., 1993") (This study has appeared in at least four separate reports.); Ewertz & Duffy, Risk Of Breast Cancer In Relation To Reproductive Factors In Denmark, 58 Br. J. Cancer 99 (1988) (hereafter "Ewertz & Duffy, 1988"); Brinton, et al., Reproductive Factors In The Aetiology Of Breast Cancer, 47 Br. J. Cancer 757 (1983) (hereafter "Brinton, et al., 1983"); Rosenberg, et al., Breast Cancer In Relation To The Occurrence And Time Of Induced And Spontaneous Abortion, 127 Am. J. Epidem. 981 (1988) (hereafter "Rosenberg, et al., 1988"); Moseson, et al., The Influence Of Medical Conditions Associated With Hormones On The Risk Of Breast Cancer, 22 Int. J. Epidem. 1000 (1993) (hereafter "Moseson, et al., 1993"); Daling, et al., Risk Of Breast Cancer Among Young Women: Relationship To Induced Abortion, 86 J. Nat'l Cancer Inst. 1584 (1994) (hereafter "Daling, et al., 1994").
  68. Controls are generally younger than the cancer patients so relative risk estimates tend to be underestimated and confidence intervals are wider.
  69. This study reports relative risks of 1.2-1.3, despite the fact that the median patient age was 12 years greater than the median control age.
  70. See Adami, et al., Absence Of Association Between Reproductive Variables And The Risk Of Breast Cancer In Young Women In Sweden And Norway, 62 Br. J. Cancer 122 (1990) (hereafter "Adami, et al., 1990"); Nishiyama, The Epidemiology Of Breast Cancer In Tokushima Prefecture, 38 Shikoku Med. J. 333 (1982) (hereafter "Nishiyama, 1993"); Hirohata, et al., Occurrence Of Breast Cancer In Relation To Diet And Reproductive History: A Case-Control Study In Fukuoka, Japan, 69 Natl. Cancer Inst. Monogr. 187 (1985) (hereafter "Hirohata, et al., 1985"); Le, et al., "Oral Contraceptive Use And Breast Or Cervical Cancer: Preliminary Results Of A French Case-Control Study, Hormones And Sexual Factors In Human Cancer Aetiology 139 (Elsevier, Amsterdam 1984) (hereafter "Le, et al., 1984"); Andrieu, et al., Familial Risk Of Breast Cancer And Abortion, 18 Cancer Detection & Prevention 51 (1994) (hereafter "Andrieu, et al., 1994"); Pike, et al., Oral Contraceptive Use And Early Abortion As Risk Factors For Breast Cancer In Young Women, 43 Br. J. Cancer 72 (1981) (hereafter "Pike, et al., 1981"); Howe, et al., Early Abortion And Breast Cancer Risk Among Women Under Age 40, 18 Int. J. Epidem. 300 (1989) (hereafter "Howe, et al., 1989"); Laing, et al., Breast Cancer Risk Factors In African-American Women: The Howard University Tumor Registry Experience, 85 J. Nat'l Med. A. 931 (1993) (hereafter "Laing, et al., 1993").
  71. But see Parazzini, et al., Menstrual And Reproductive Factors And Breast Cancer In Women With Family History Of The Disease, 51 Int. J. Cancer 677 (1992) (a large case-control study in Milan, Italy). In Italy, over three-quarters of legal abortions occur among women who have already had one or more children. See Figa-Talamanca, et al., Epidemiology Of Legal Abortion In Italy, 15 Intl. J. Epidem. 343 (1986). This means that these women are at a lower risk of breast cancer anyway, because of the previous live birth.
  72. Lindefors-Harris, et al., Response Bias In A Case-Control Study: Analysis Utilizing Comparative Data Concerning Legal Abortions From Two Independent Swedish Studies, 134 Am. J. Epidem. 1003 (1991); Lindefors-Harris, et al., Risk Of Cancer Of The Breast After Legal Abortion During First Trimester: A Swedish Register Study, 299 Br. Med. J. 1430 (1989).
  73. For a general discussion of the biological changes in breast tissue during pregnancy, see Russo, et al., Differentiation Of The Mammary Gland And Susceptibility To Carcinogenesis, 2 Breast Cancer Res. Treat. 5 (1982) (hereafter "Russo, et al., 1982").
  74. Brooks S.C. & Pauley R.J., Breast Cancer Biology, Encyclopedia Of Human Biology (R. Dulbecco, ed. 1991). A full-term pregnancy protects against breast cancer by bringing breast cells into their specialized forms. These mature cells have almost no vulnerability to cancer. Abortion interrupts this process, leaving terminal end buds (immature cells) suspended in high risk transitional states.
  75. Russo, et al., 1982.
  76. Rosenberg, Induced Abortion And Breast Cancer: More Scientific Data Are Needed, 86 J. Nat'l Cancer Inst. 1569 (1994).
  77. Rosenberg, et al., 1988.
  78. Soini, Risk Factors Of Breast Cancer In Finland, 6 Intl. J. Epidem. 365 (1977); Hadjimichael, et al., Abortion Before First Livebirth And Risk Of Breast Cancer, 53 Br. J. Cancer 281 (1986).
  79. Lehrer, et al., An Estrogen Receptor Polymorphism And A History Of Spontaneous Abortion -- Correlation In Women With Estrogen Receptor Positive Breast Cancer But Not In Women With Estrogen Receptor Negative Breast Cancer Or In Women Without Cancer, 26 Breast Cancer Res. Treat. 175 (1993).
  80. Lentz, The Phylogeny Of Oncology, 2 Mol. Biother. 137 (1990).
  81. Gatanaga, et al., Identification Of TNF-LT Blocking Factor(s) In The Serum And Ultrafiltrates Of Human Cancer Patients, 9 Lymphokine Res. 225 (1990a); Gatanaga, et al., Purification And Characterization Of An Inhibitor (Soluble Tumor Necrosis Factor Receptor) For Tumor Necrosis Factor And Lymphotoxin Obtained From The Serum Ultrafiltrates Of Human Cancer Patients, 87 Proc. Nat'l Acad. Sci. 8781 (1990b).
  82. Lentz & Saltonstahl, Apheresis Of Low Molecular Weight Protein Fraction And The Onset Of Labor, 5 J. Clin. Apheresis 62 (1990) (hereafter "Lentz & Saltonstahl, 1990").
  83. Lentz, Continuous Whole Blood Ultrapheresis Procedure In Patients With Metastatic Cancer, 8 J. Biol. Response Modif. 511 (1989).
  84. Lentz & Saltonstahl, 1990.
  85. Clark & Chua, Breast Cancer And Pregnancy: The Ultimate Challenge, 1 Clin. Oncol. 11 (1989).
  86. Spitz & Bardin, Clinical Pharmacology Of RU 486 -- An Antiprogestin And Antiglucocorticoid, 48 Contraception 403 (1993) (hereafter "Spitz & Bardin, 1993"); Weiss, RU 486: The Progesterone Antagonist, 2 Arch. Fam. Med. 63 (1993).
  87. See, e.g., Healy, Clinical Status Of Antiprogesterone Steroids, 3 Clin. Reprod. & Fertility 277, 284 (1985) ("RU 486-induced blockade of the cortisol receptor may prevent the usual glucocorticoid stress response to anaesthesia and surgery in a patient who needs curettage after RU 486 treatment. This might make anaesthesia complex in such patients.").
  88. See Laue, et al., Effect Of Chronic Treatment With The Glucocorticoid Antagonist RU 486 In Man: Toxicity, Immunological, And Hormonal Aspects, 71 J. Clin. Endocrin. & Metab. 1474 (1990) (hereafter "Laue, et al., 1990") (in study designed to examine immune function, blockade of cortisol receptors with RU 486 in 11 healthy males was associated with marked compensatory elevations of plasma ACTH and cortisol; RU 486 (10 mg/kg/day) was administered twice a day for 7-14 days; however, one subject developed signs and symptoms consistent with adrenal insufficiency).
  89. Brogden, et al., Mifepristone: A Review Of Its Pharmacodynamic And Pharmacokinetic Properties, And Therapeutic Potential, 45 Drugs 384, 405 (1993) (hereafter "Brogden, et al. 1993"); Heikinheimo, Antiprogesterone Steroid RU 486: Pharmacokinetics And Receptor Binding In Humans, 69 Acta Obstet. Gynecol. Scand. 357 (1990).
  90. See Grimes, et al., 1990, at 913-14 (reporting that risk of failure of RU 486 as single-agent abortifacient was 2.9 times greater for obese women than for women in the lowest body mass group studied). See also infra Section 3.d. and accompanying footnotes.
  91. Spitz & Bardin, 1993, at 409; Heikinheimo, Antiprogesterone Steroid RU 486: Pharmacokinetics And Receptor Binding In Humans, 69 Acta Obstet. Gyn. Scand. 357 (1990).
  92. Lahteenmaki, et al., Pharmacokinetics And Metabolism Of RU 486, 27 J. Steroid Biochem. 859 (1987); see also, Heikinheimo, et al., Pharmacokinetics Of The Antiprogesterone RU 486: No Correlation To Clinical Performance Of RU 486, 123 Acta Endocrinologica 298 (1990).
  93. Avrech, Mifepristone (RU 486) Alone Or In Combination With A Prostaglandin Analogue For Termination Of Early Pregnancy: A Review, 56 Fertility & Sterility 385, 386 (1991).
  94. CDC, "Abortion Surveillance -- United States, 1990," 42 (SS-6) Morbidity & Mortality Weekly Report 29 (Dec. 17, 1993).
  95. See Birth Control Trust, 1994, at 43.
  96. WHO, 1991, at 35 (when both study groups [repeated doses and single dose RU 486] were combined, the difference between Chinese and non-Chinese subjects was significant [Chinese women: median -- 12 days bleeding; range -- 3 - 45 days, 95th percentile: 37.6 days, n=115; non-Chinese women: median: 10 days bleeding; range 2 - 54 days, 95th percentile: 23.8 days, n=224; P<0.01]). But see, WHO Task Force, 1993, at 534 (reporting no significant difference between Chinese women and non-Chinese subjects).
  97. Chan, et al., 1993 (2 women (2.08%) required emergency suction evacuation for heavy bleeding; because of heavy bleeding, researchers concluded that "strict supervision is mandatory" for RU 486/PG abortion).
  98. Id. at 93 (commenting on a study conducted by Rodger & Baird, see Rodger & Baird, 1989).
  99. Id. at 93 (citing Wong, et al., The Effect Of Oral Contraceptives On Coagulation And Fibrinolytic Parameters In The Chinese -- A Prospective Study, 48 Thromb. Haemostas. (Stuttgart) 263 (1982).
  100. Id.
  101. WHO, 1991, at 37; Spitz & Bardin, 1993, at 411. See also WHO Task Force, 1989, at 721; Swahn & Bygdeman, 1989, at 298; Shoupe, et al., 1986, at 457; Swahn, et al., 1989, at 24.
  102. Herting & Nissen, Overview Of Misoprostol Clinical Experience, 31 Dig. Diseases & Sci. 47S, 51S (Feb. 1986 Suppl.) (hereafter "Herting & Nissen, 1986").
  103. Namely, glucocorticoids reduce fluid movement from the blood to the tissues; decrease the permeability of blood vessels. This limits leukocyte migration to the site of tissue injury and reduces the body's ability to fight invading bacteria. Also research suggests that glucocorticoids affect transport of glucose, amino acids, and RNA in lymphocytes; and down regulate gene transcription within the lymphocyte. They also affect the intracellular ability of neutrophils to destroy ingested microorganisms and affect protein expression in lymphoid tissues and lymphoid function. Schulster, et al., Molecular Endocrinology Of The Steroid Hormones 282 (1976).
  104. Laue, et al., 1990; Van Voorhis, et al., The Effects Of RU 486 On Immune Function And Steroid-Induced Immunosuppression In Vitro, 69 J. Clin. Endocrin. & Metab. 1195 (1989) (hereafter "Van Voorhis, et al., 1989"); Bertagna, et al., Peripheral Antiglucocorticoid Action Of RU 486 In Man, 28 Clin. Endocrin. 537 (1988); Emilie, et al., Inhibition Of In Vitro Immunosuppressive Effects Of Glucocorticosteroids By A Competitive Antagonist RU-486, 8 Immunology Letters 183 (1984).
  105. Van Voorhis, et al., 1989.
  106. Redgrave, et al., An In Vitro Comparison Of The Immunosuppressive Potential Of Synthetic Prostaglandin Analogues, 23 Transplant. Proceed. 346 (1991) (an in vitro study which reported that a PGE1analog enhanced the immunosuppressant effects of cyclosporine); Moran, et al., Prevention Of Acute Graft Rejection By The Prostaglandin E1 Analogue Misoprostol In Renal-Transplant Recipients Treated With Cyclosporine And Prednisone, 322 N. Eng. J. Med. 1183, 1187 (1990) (hereafter "Moran, et al., 1990") (reporting that misoprostol acted in a synergistic manner with two known immunosuppressant drugs -- cyclosporine and prednisone (a glucocorticoid) in an in vivo study of kidney transplant recipients). By itself, misoprostol has not demonstrated any adverse effects on the immune system. See Waymack, et al., Effect Of Prostaglandin E On Immune Function In Normal Healthy Volunteers, 175 Surg. Gyn. & Obstet. 329 (1992); Herting & Nissen, 1986, at 51S; Moran, et al., 1990, at 1187.
  107. Moran, et al., 1990, at 1187
  108. Herve, et al., Evidence For Differences In The Binding Of Drugs To The Two Main Genetic Variants Of Human Alpha 1-Acid Glycoprotein, 36 Br. J. clin. Pharmac. 241 (1993); Bree, et al., Comparison Of Drug Binding Capacities Of Three AAG Glycan Variants Of Human Origin, 300 Prog. Clin. Biol. Res. 405 (1989).
  109. See Grimes, et al., 1988, at 1311.
  110. With RU 486 alone, from 8.3% to 46.3% of pregnancies have continued. See Table 9 for complete statistics. After RU 486/oral misoprostol administration, from 0.45% to 9.5% of pregnancies have continued (see Table 10 for statistics); and after medical abortion with RU 486 and other prostaglandins, from 0.4% to 6.2% of pregnancies have continued (see Table 11 for statistics).
  111. Hill, et al., Transplacental Passage Of Mifepristone And Its Influence On Maternal And Fetal Steroid Concentrations In The Second Trimester Of Pregnancy, 6 Hum. Reprod. 458 (1991) (hereafter "Hill, et al., 1991"); Hill, et al., The Placental Transfer Of Mifepristone (RU 486) During The Second Trimester And Its Influence Upon Maternal And Fetal Steroid Concentrations, 97 Br. J. Obst. Gyn. 406 (1990b) (hereafter "Hill, et al., 1990b"); Frydman, et al., Transplacental Passage Of Mifepristone, ii Lancet 1252 (1985).
  112. Raymond, et al., 1991, at 76-79.
  113. van der Schoot & Baumgarten, Effects Of Treatment Of Male And Female Rats In Infancy With Mifepristone On Reproductive Function In Adulthood, 90 J. Reprod. Fert. 255 (1990).
  114. Jost, Animal Reproduction -- New Data On The Hormonal Requirement Of The Pregnant Rabbit: Partial Pregnancies And Fetal Abnormalities Resulting From A Treatment With A Hormonal Antagonist Given At Sub-Abortive Dosage, 303 C.R. Acad. Sci. III 281 (1986); Silvestre, et al., Voluntary Interruption Of Pregnancy With Mifepristone (RU 486) And A Prostaglandin Analogue, 322 N. Eng. J. Med. 645 (1990) (hereafter "Silvestre, et al., 1990") (deformities were reportedly "attributed to uterine contractions secondary to decreased progesterone activity.").
  115. Wolf, et al., Tolerance Of Perinidatory Primate Embryos To RU 486 Exposure In Vitro And In Vivo, 41 Contraception 85 (1990) (hereafter "Wolf, et al., 1990"); see also, Raymond, et al., 1991, at 78.
  116. Wolf, et al., 1990, at 90.
  117. Id. Furthermore, one study in mice found that RU 486 retarded embryonic development in vivo and acted directly on the embryo, interfering with its development in vitro. Yang & Wu, RU 486 Interferes With Egg Transport And Retards The In Vivo And In Vitro Development Of Mouse Embryos, 41 Contraception 551 (1990).
  118. Institute of Medicine, 1993, at 28.
  119. See Pons, et al., 1991 (although the researchers couldn't determine whether the abnormalities were related to RU 486, they concluded that "a deleterious effect of mifepristone cannot be ruled out."). For explanation of micrognathia and hygroma see infra footnote 21.
  120. See Pons & Papiernik, Mifepristone Teratogenicity, 338 Lancet 1332 (1991). In addition, the published studies on human fetal exposure to RU 486 during the second trimester are inconclusive. Hill, et al., 1991 found no statistically significant changes in fetal concentrations of progesterone, oestradiol or cortisol, but a significant increase in fetal aldosterone occurred 4 and 24 hours after drug intake. However, researchers concluded that "[t]he importance of the increased fetal aldosterone levels is uncertain. In view of the small number of patients in each group this may have occurred by chance and similarly because of the study size, any effect of mifepristone on the other parameters studied cannot be totally excluded." Id. at 461. See also Hill, et al., 1990b.
  121. Silvestre, et al., 1990; Raymond, et al., 1991 at 89-90; Schonhofer, Brazil: Misuse Of Misoprostol As An Abortifacient May Induce Malformations, 337 Lancet 1534 (1991); Collins & Mahoney, Hydrocephalus And Abnormal Digits After Failed First-Trimester Prostaglandin Abortion Attempt, 102 J. Pediatrics 620 (1983).
  122. Fonseca, et al., Misoprostol And Congenital Malformations, 338 Lancet 56 (1991); Fonseca, et al., Misoprostol Plus Mifepristone, 338 Lancet 1594 (1991) (hereafter "Fonseca, et al., 1991").
  123. Mobius syndrome is characterized by congenital facial diplegia and a developmental bilateral facial paralysis associated with oculomotor or other neurological disorders. See Stedman's Medical Dictionary 1391 (5th ed. 1982).
  124. Gonzalez, et al., Limb Deficiency With Or Without Mobius Sequence In Seven Brazilian Children Associated With Misoprostol Use In The First Trimester Of Pregnancy, 47 Am. J. Med. Genetics 59 (1993) (hereafter "Gonzalez, et al., 1993").
  125. Many children exposed to misoprostol in utero appear normal. Schuler, et al., obtained information on 17 babies born to women who took misoprostol as an abortifacient during the first trimester and did not abort. No major malformations were found, although one child had a preauricular tag. Schuler, et al., Teratogenicity Of Misoprostol, 339 Lancet 437 (1992). "However, . . . we cannot evaluate the exposure risk since we do not know the drug effect in embryos (or fetuses) that are aborted." Gonzalez, et al., 1993, at 64.
  126. Fonseca, et al., 1991.
  127. Cekan, et al., Levels Of The Antiprogestin RU 486 And Its Metabolites In Human Blood And Follicular Fluid Following Oral Administration Of A Single Dose, 4 Hum. Reprod. 131 (1989) (researchers note that "the morphological appearance and cleavage rate of the oocytes fertilized in vitro were not affected by the treatment with RU 486"). However, the fertilized eggs were only developed to the four- to eight-cell stage. And "the developmental capacity of the oocytes after fertilization in vitro could not be fully determined, since the cleaving embryos were not replaced in a recipient uterus." See Raymond, et al., 1991, at 75 (citing Messinis & Templeton, The Effect Of The Antiprogestin Mifepristone (RU 486) On Maturation And In-Vitro Fertilization Of Human Oocytes, 95 Br. J. Obst. & Gyn. 592 (1988) (hereafter "Messinis & Templeton, 1988"). Interestingly, the women who received RU 486 had fewer eggs which fertilized in vitro as compared to the controls, although the difference was not statistically significant. Messinis & Templeton, 1988, at 593.
  128. Spitz & Bardin, 1993, at 417; Grimes, 1993, at 173.
  129. Wiedemann, et al., in a limited study, examined the role of glucocorticoids in sleep and demonstrated that RU 486 as a glucocorticoid receptor blocker disrupts sleep patterns. See Wiedemann, et al., Antiglucocorticoid Treatment Disrupts Endocrine Cycle And Nocturnal Sleep Pattern, 241 Eur. Arch. Psych. Clin. Neurosci. 372 (1992).
  130. Hill, et al., 1991 reported "a trend to higher . . . fetal cortisol concentrations 24 and 48 h after treatment, [however,] this increase failed to reach statistical significance. . . ." Id. at 460-61.
  131. See additional discussion infra Section 6.
  132. See Table 4.
  133. Rodger & Baird, 1989, at 445 ("It is likely that as pregnancy advances and the fetus and placenta increases in size, there is a larger vascular area from which bleeding can occur.").
  134. According to D. Danforth & J. Scott, there are several methods used to determine gestational age. Because of the unreliability of alternative methods, sonography is recommended as a standard abortion practice for assessing gestational age. Alternative methods include: (1) patient's menstrual history (least reliable method -- predictive only to within a margin of 3 weeks with 90% confidence, even if date of last menstrual period is known with certainty); (2) pelvic examination (inaccurate to plus/minus 2 weeks; with retroverted uterus (30% of women) inaccuracy reaches plus/minus 4 weeks); (3) maternal perception of fetal movement (only useful as "rough estimate"); and (4) measurement of fundal height (useful only to corroborate other clinical estimations of gestational age). Danforth & Scott, Obstetrics & Gynecology 263, 365-66 (5th ed. 1986); Hern, Abortion Practice 69-70, 109, 207 (1984) (sonography "appears to be considerably more accurate than are menstrual dates and even a careful examination by an experienced physician." Any doubt concerning length of gestation should be checked by real-time ultrasound examination.).
  135. Rodger, et al., 1989, at 501 ("It is important that an intrauterine pregnancy be established prior to treatment as mifepristone seems ineffective in the disruption of ectopic pregnancy."); Weiss, RU 486: The Progesterone Antagonist, 2 Arch. Fam. Med. 63, 66 (1993); Levin, et al., Mifepristone (RU 486) Failure In An Ovarian Heterotopic Pregnancy, 163 Am. J. Obst. Gyn. 543 (1990); Baulieu, Contragestion And Other Clinical Applications Of RU 486, An Antiprogesterone At The Receptor, 245 Science 1351 (1989).
  136. WHO Task Force, 1993 (1 patient in the study had undiagnosed tubal pregnancy which ruptured 2 weeks after an RU 486/PG abortion).
  137. Petitioners are unaware of any studies demonstrating safety and/or effectiveness of RU 486 in the pediatric population.
  138. UK Multicentre Trial, 1990, at 485 ("the procedure needs to be clinic based, and preferably hospital based, in view of the small but definitive risk of severe hemorrhage."); Roger, et al., 1989, at 501 ("Hospital admission . . . for four hours following prostaglandin administration is advisable."); Wu, et al., 1992, at 209 ("It should be emphasized that RU 486 in combination with PG be used only in clinics where emergency facilities are available."); Brogden, et al., 1993, at 404 ("Mifepristone should be administered in an environment where suitably experienced medical personnel and resuscitation equipment are immediately available."); Thonneau, et al., 1994, at 627 ("the risk of maternal morbidity associated with sulprostone and also the risk of fetal malformations in cases of continued pregnancy indicate that this method should only be used in specialist centers."). See also footnote 24 infra.
  139. See Testimony Before the Subcomm. on Regulation, Business Opportunities, and Technology of the House Comm. on Small Business, 103d Cong., 2d Sess. (May 16, 1994). Petitioners also urge FDA to compare the misuse of misoprostol as an abortifacient in Brazil where its distribution is not carefully regulated with the carefully controlled distribution of RU 486 in France. See Costa & Vessey, Misoprostol And Illegal Abortion In Rio de Janeiro, Brazil, 341 Lancet 1258 (1993); Coelho, et al., Misoprostol And Illegal Abortion In Fortaleza, Brazil, 341 Lancet 1261 (1993).