Medial and Health Services Issues
Updating RU 486 Development Etienne-Emile Baulieu
RU 486' is a synthetic drug with antisteroid hormone properties, synthesized by the Roussel-Uclaf Company, Paris, France, which owns a world-wide patent for all uses. I have summarized the story of RU 486's discovery, testing and use in the Journal of the American Medical Association,zin Science? and in a book entitled The Abortion Pill,also published in French as Ginhation Pilule.4 Based on antiprogesterone action,r RU 486 was first approved in France for voluntary pregnancy interruption (VIP), within the framework of the abortion law, as a medical method to replace the instrumental technique in use when the law was passed in 1975. Registration of RU 486 was obtained in September 1988. More than IOO,OOO women have used the method, which currently, in France, involves four medical visits: a first visit for diagnosis of pregnancy and deciding for VIP; 2. after one week of reflection required by law in France, a second visit to take the RU 486 pill$ 3 . a third visit, made 48 hours later? to receive, as a complement, a small amount of prostaglandin in the form of a synthetic derivative;* and finally, 4. a fourth visit, as a control step to verify the completeness of the process. I.
This process, according to biological studies, animal experiments and clinical experience, is efficient9 and safe. In this article I would like to discuss: Prostaglandin; Distribution in different countries; and 3 . Some medical aspects.
I,
2.
Prostaglandin Administration of a small dose of prostaglandin makes RU 486 more efficient for obtaining complete abortionToessen-
tially because it can hasten and/or complete expulsion of the products of conception. In France the prostaglandin (PG) originally used was Sulprostone," which is injected intramuscularly. While efficient, this mode of treatment requires a medically competent staff who know how to perform the injection. After an injection, the product is very rapidly distributed through the entire body. This may explain the occasional cardiovascular problems for which this prostaglandin has been held responsible, whether administered after RU 486 in VIP or alone for other medical indications. Sulprostone has now been replaced by Misoprostol, orally taken, as the prostaglandin of choice for use with RU 486 in France due to the latter's safety, convenience, availability in many countries and low cost. There has been a near 97 percent success rate in pregnancies of less than 49 days amenorrhea for the first 600 cases of the current multicenter trial. This multicenter trial was requested by the French government after the first publication concerning 100 patientsTzindicated that the association of 600 mg RU 486 and 400 pg Misoprostol is a good combination. Recent work by David Baird and his colleagues confirms our results.I3 Some 70 percent of women complete expulsion 4 hours after the ingestion of z tablets of zoopg Misoprostol. In a recent study with Elisabeth Aubkny, we have tested the administration of a third tablet if there is no expulsion at 4 hours, and in approximately 400 cases, the global efficiency is greater than 99 percent (to be published). This method, with the optional third tablet, is designated RU 486-Misoprostol Z/Z+I. Whether it is possible to systematically give 3 tablets together or, very differently, to decrease RU 486 dosage and keep the same efficacy as with RU 486-600 mg Misoprostol ~ Z + I remains to be established,I4and in any case a larger number of trials is needed. Misoprostol is sold in France, the U.K., the U.S., Canada and more than 60 other countries for treatment of
Law, Medicine 6Health Care gastro-duodenal ulcers. The efficient dose of Misoprostol in recent French trials is less than the daily dose of the drug usually taken for weeks in the treatment of ulcers and is well tolerated. With Misoprostol, uterine cramps are much less severe than with Sulprostone and Gemeprost. Gemeprost, a PG-EI derivative like Misoprostol, has been given as a vaginal suppository in about 2,500 cases in France and the United Kingdom. The more progressive diffusion of the compound in the body may be responsible for the absence of cardiovascular problems. However, the relatively high dose used ( I mg) and the vaginal route may explain rather frequent painful uterine cramps. Neither Sulprostone nor Gemeprost is sold in the United States.
Distribution in different countries To date, RU 486 is registered and sold by Roussel-Uclaf in France and the United Kingdom. RU 486 is also registered (and synthetized) in China. Abortion trials using RU 486 conducted by the World Health Organization and also by Roussel-Uclaf (until the company's decision to stop on December 14, 1988) have taken place in several countries. Roussel-Uclaf did obtain approval of RU 486 use in conjunction with Gemeprost within up to 63 days of amenorrhea in the United Kingdom.'s At the end of 1991 Dr. Hilger, President of Hoechst, based in Frankfurt, Germany, told the press that when the legal problems concerning abortion and safe distribution of contraceptives are solved in Germany, there is no reason Roussel-Uclaf could not begin trials of RU 486 in that country. The new liberal abortion law enacted in 1992 to apply in unified Germany enhances the chances of clinical trials starting in the near future. The process for registration is progressing in Scandinavian countries, while the Ministry of Health in Spain has asked Roussel-Uclaf to begin trials. Canada, where abortion is decriminalized and regulated like any other medical procedure, is another country where distribution might be possible. In the United States trials of RU 486 could be performed by the many physicians who support its introduction and are ready to proceed immediately. Misoprostol is available and abortion is legal. A highly competent nonprofit organization such as the Population Councilrh would be ideal to organize these trials. The Population Council obtained an IND several years ago when it signed an agreement with Roussel-UclafI7 permitting its implementation. The trials could lead to registration and distribution by nonprofit organizations such as the Planned Parenthood Federation of America and others. To my knowledge, currently the biggest obstacle has been the opposition of the directorship of Hoechst-Celanese, the
USA-based subsidiary of Hoechst'* which itself is the majority shareholder of Roussel-Uclaf. Its reluctance is probably related to the difficult political climate in the United States. Hoechst-Celanese may consider becoming involved in such a controversial debate an unprofitable enterprise. However, in any case, its American branch,'g while it sells drugs in the USA, would not be engaged in the commercialization of RU 486 for at least one important reason: Hoechst-Celanese is not interested in the field of reproductive medicine and would not be the best distributor of RU 486. Therefore Roussel-Uclaf should find another distributor or, better, distribute it itself in a joint venture with a specialized company such as Gynopharma. I see possibilities for introducing RU 486 in developing countries where menstrual regulation (MR)is officially accepted. Bangladesh is a good example. On a recent visit there I could see that there were opportunities for implementation of a limited, well controlled trial of RU 486 600 mg + Misoprostol 2/2+1, perhaps under the guidance of the Human Reproductive Programme of the WorId Health Organization.
Medical considerations Use of RU 486 does not require anesthesia. It is not an invasive procedure and thus there is a minimum of infections, complications and mechanical sequelae. Medical supervision should be maintained, not because the RU 486 could be intrinsically dangerous, but because pregnancy itself is a risk. Whether a woman wants to have a child or would like to abort, to receive medical attention is a woman's right.'" Safety and relative simplicity of use make the RU 486 plus Misoprostol method of abortion adaptable to the needs of women in the developing world. However, education and money are major problems-problems common to the field of birth control worldwide. A medical examination must precede the decision of abortion and of the method to use. At this first visit, ectopic pregnancy (not aborted by RU 486) and other contraindications of a medical treatment are excluded, the length of gestation is determined, RU 486 is taken and the woman may be given her Misoprostol tablets to be ingested two days later. Another visit is essential to check that everything is back to normal and to provide contraceptive counseling and services. Naturally, in case of problems, the patient should be able to return before the programmed second visit, if necessary. In all countries, two rules are essential: 1.
2.
Medical supervision, just as for any pregnancyrelated event; and In case of failure, instrumental evacuation needs to be performed.21
Volume 20: 3 , Fall 1992 RU 486 is also a drug which may be useful for other medical indications: fetal or maternal accidents during pregnancy;‘” certain difficult deliveries;’3 women’s diseases such as endometriosis, fibroids, breast cancers and other t~mors.~4 It can also act as an anti-cortisone and may be used for the repair of wounds or burns and for some aspects of stress. It is not expected that most of these medical applications will be operational for several years. The entry of RU 486 into the United States for abortion use is important for several reasons, including: I.
2.
Until the abortion issue is resolved, testing of RU 486 for other medical purposes will be slower than it should be; In a pluralistic and democratic society, there is no reason to preclude a product of modern research from being available. The denial to women of the right to the benefits of scientific progress and its application constitutes sex discrimination.
The abortion issue is not the only problem that RU 486 may help to solve in the field of fertility control. Several studies on contraception with RU 486 are currently being performed or are concretely envisaged. The case study is set as follows: Monthly menses induction (with Misoprostol); Anti-implantation, post-ovulatory use;zx 3. Anti-ovulatory, including use in follicular phase of the cycle; and 4. Low dose administration over the whole cycle, with a specific anti-implantation effect.
References I. Generic name Mifepristone, trade name in France and the U.K. Mifegyne. 2 . “RU 486 as an Antiprogesterone Steroid: From Receptor to Contragestion and Beyond,” J.A.M.A., 262, (198y): 18081814; special article on the occasion of the Lasker Award for clinical research. 3. “Contragestion and Other Clinical Applications of RU 486, an Antiprogesterone at the Receptor,” Science, 245,
(198y): 1 3 5 1 - 1356. 4. Odile Jacob, Paris, 1990,translated and adapted for an
English-speaking readership: The Abortion Pill, New York (Simon & Schuster), 1991. 5 . Progesterone is a steroid hormone indispensable for the beginning and the continuation of pregnancy. 6. Three containing each zoo mg of RU 486 and taken together. 7 . Time of optimal antiprogesterone activity. 8. Prostaglandins are local hormones which are naturally involved in contractions of the uterus during delivery and abortion and physiologically help expulsion. y. y5 percent or more complete successes. 10.Dr. M . Bygdeman. I I. A PG-Ez derivative. 12. E. AubCny and E.E. Baulieu, “Activite contragestive de l’association au RU 486 d’une prostaglandine active par voie orale,” CR Acadm. Sci. Paris, 312, (1991):539-545. 13. J.E. Norman, K.J. Thong, D.T. Baird, “Uterine Contractility and Induction of Abortion in Early Pregnancy by Misoprostol and Mifepristone,” 338 The Lancet 1233-1236
I.
(1991).
2.
14.It was proposed to decrease RU 486 dosage when associated with Sulprostone or Gemeprost; however these prostaglandins were given at probably larger than adequate doses, and the data presented so far are irrelevant to the use of Misoprostol. IS. Registration on July Ist, 1991. 16. New York. 17. Signed in 1982, and remaining valid. 18. Frankfurt. 19.HRPI. 20. Rebecca Cook, International Protection of Women‘5 Reproductive Rights 24, New York University, 401-483 ( r y y z ) . 21. There is no predictable fetal abnormality, but there is no reason to take an additional risk. 2 2 . Registration just obtained in France. 2 3 . Objective: a baby in better health. 24. With Cushing syndromes, meningiomas. 2 5 . A Radestad, N. J. Christensen, L. Stromberg, “Induced Cervical Ripening with Mifepristone in First Trimester ; Bygdeman, M.L. Pregancy,” Contraception 3 8 ( 1 ~ 8 8 ) M. Swahn, E. Johannisson et a]., “The Effect of RU 486 Administered During the Proliferative and Secretory Phase of the Bleeding Pattern, Hormonal Parameters and the Endometrium,” Human Reprodzictzon 3 (1988):91 5-21. 26. See supra note 2 . 27.We should be free to have different opinions about this, just as we d o about the future of a human being after death.
Again, these studies demonstrate that RU 486 is not just an abortifacient. I have also discussed several times the concept of contragestion,z6which RU 486 can exemplify and which, between contraception and abortion as we have known it for centuries, may help women confronted with difficult situations. Medical abortion, using an antiprogestidprostaglandin regimen, may be better psychologically and physically for some women than surgical abortion. Prevention is usually better than curative intervention. Contraception is preferable to abortion and early abortion is preferable to late abortion. Contraception, however, may not always be possible or available, and most methods entail some degree of failure. RU 486 taken together with a prostaglandin as a contragestive agent will be a valuable back-up method in the coming decades.
Updating RU 486 Development Etienne-Emile Baulieu
RU 486' is a synthetic drug with antisteroid hormone properties, synthesized by the Roussel-Uclaf Company, Paris, France, which owns a world-wide patent for all uses. I have summarized the story of RU 486's discovery, testing and use in the Journal of the American Medical Association,zin Science? and in a book entitled The Abortion Pill,also published in French as Ginhation Pilule.4 Based on antiprogesterone action,r RU 486 was first approved in France for voluntary pregnancy interruption (VIP), within the framework of the abortion law, as a medical method to replace the instrumental technique in use when the law was passed in 1975. Registration of RU 486 was obtained in September 1988. More than IOO,OOO women have used the method, which currently, in France, involves four medical visits: a first visit for diagnosis of pregnancy and deciding for VIP; 2. after one week of reflection required by law in France, a second visit to take the RU 486 pill$ 3 . a third visit, made 48 hours later? to receive, as a complement, a small amount of prostaglandin in the form of a synthetic derivative;* and finally, 4. a fourth visit, as a control step to verify the completeness of the process. I.
This process, according to biological studies, animal experiments and clinical experience, is efficient9 and safe. In this article I would like to discuss: Prostaglandin; Distribution in different countries; and 3 . Some medical aspects.
I,
2.
Prostaglandin Administration of a small dose of prostaglandin makes RU 486 more efficient for obtaining complete abortionToessen-
tially because it can hasten and/or complete expulsion of the products of conception. In France the prostaglandin (PG) originally used was Sulprostone," which is injected intramuscularly. While efficient, this mode of treatment requires a medically competent staff who know how to perform the injection. After an injection, the product is very rapidly distributed through the entire body. This may explain the occasional cardiovascular problems for which this prostaglandin has been held responsible, whether administered after RU 486 in VIP or alone for other medical indications. Sulprostone has now been replaced by Misoprostol, orally taken, as the prostaglandin of choice for use with RU 486 in France due to the latter's safety, convenience, availability in many countries and low cost. There has been a near 97 percent success rate in pregnancies of less than 49 days amenorrhea for the first 600 cases of the current multicenter trial. This multicenter trial was requested by the French government after the first publication concerning 100 patientsTzindicated that the association of 600 mg RU 486 and 400 pg Misoprostol is a good combination. Recent work by David Baird and his colleagues confirms our results.I3 Some 70 percent of women complete expulsion 4 hours after the ingestion of z tablets of zoopg Misoprostol. In a recent study with Elisabeth Aubkny, we have tested the administration of a third tablet if there is no expulsion at 4 hours, and in approximately 400 cases, the global efficiency is greater than 99 percent (to be published). This method, with the optional third tablet, is designated RU 486-Misoprostol Z/Z+I. Whether it is possible to systematically give 3 tablets together or, very differently, to decrease RU 486 dosage and keep the same efficacy as with RU 486-600 mg Misoprostol ~ Z + I remains to be established,I4and in any case a larger number of trials is needed. Misoprostol is sold in France, the U.K., the U.S., Canada and more than 60 other countries for treatment of
Law, Medicine 6Health Care gastro-duodenal ulcers. The efficient dose of Misoprostol in recent French trials is less than the daily dose of the drug usually taken for weeks in the treatment of ulcers and is well tolerated. With Misoprostol, uterine cramps are much less severe than with Sulprostone and Gemeprost. Gemeprost, a PG-EI derivative like Misoprostol, has been given as a vaginal suppository in about 2,500 cases in France and the United Kingdom. The more progressive diffusion of the compound in the body may be responsible for the absence of cardiovascular problems. However, the relatively high dose used ( I mg) and the vaginal route may explain rather frequent painful uterine cramps. Neither Sulprostone nor Gemeprost is sold in the United States.
Distribution in different countries To date, RU 486 is registered and sold by Roussel-Uclaf in France and the United Kingdom. RU 486 is also registered (and synthetized) in China. Abortion trials using RU 486 conducted by the World Health Organization and also by Roussel-Uclaf (until the company's decision to stop on December 14, 1988) have taken place in several countries. Roussel-Uclaf did obtain approval of RU 486 use in conjunction with Gemeprost within up to 63 days of amenorrhea in the United Kingdom.'s At the end of 1991 Dr. Hilger, President of Hoechst, based in Frankfurt, Germany, told the press that when the legal problems concerning abortion and safe distribution of contraceptives are solved in Germany, there is no reason Roussel-Uclaf could not begin trials of RU 486 in that country. The new liberal abortion law enacted in 1992 to apply in unified Germany enhances the chances of clinical trials starting in the near future. The process for registration is progressing in Scandinavian countries, while the Ministry of Health in Spain has asked Roussel-Uclaf to begin trials. Canada, where abortion is decriminalized and regulated like any other medical procedure, is another country where distribution might be possible. In the United States trials of RU 486 could be performed by the many physicians who support its introduction and are ready to proceed immediately. Misoprostol is available and abortion is legal. A highly competent nonprofit organization such as the Population Councilrh would be ideal to organize these trials. The Population Council obtained an IND several years ago when it signed an agreement with Roussel-UclafI7 permitting its implementation. The trials could lead to registration and distribution by nonprofit organizations such as the Planned Parenthood Federation of America and others. To my knowledge, currently the biggest obstacle has been the opposition of the directorship of Hoechst-Celanese, the
USA-based subsidiary of Hoechst'* which itself is the majority shareholder of Roussel-Uclaf. Its reluctance is probably related to the difficult political climate in the United States. Hoechst-Celanese may consider becoming involved in such a controversial debate an unprofitable enterprise. However, in any case, its American branch,'g while it sells drugs in the USA, would not be engaged in the commercialization of RU 486 for at least one important reason: Hoechst-Celanese is not interested in the field of reproductive medicine and would not be the best distributor of RU 486. Therefore Roussel-Uclaf should find another distributor or, better, distribute it itself in a joint venture with a specialized company such as Gynopharma. I see possibilities for introducing RU 486 in developing countries where menstrual regulation (MR)is officially accepted. Bangladesh is a good example. On a recent visit there I could see that there were opportunities for implementation of a limited, well controlled trial of RU 486 600 mg + Misoprostol 2/2+1, perhaps under the guidance of the Human Reproductive Programme of the WorId Health Organization.
Medical considerations Use of RU 486 does not require anesthesia. It is not an invasive procedure and thus there is a minimum of infections, complications and mechanical sequelae. Medical supervision should be maintained, not because the RU 486 could be intrinsically dangerous, but because pregnancy itself is a risk. Whether a woman wants to have a child or would like to abort, to receive medical attention is a woman's right.'" Safety and relative simplicity of use make the RU 486 plus Misoprostol method of abortion adaptable to the needs of women in the developing world. However, education and money are major problems-problems common to the field of birth control worldwide. A medical examination must precede the decision of abortion and of the method to use. At this first visit, ectopic pregnancy (not aborted by RU 486) and other contraindications of a medical treatment are excluded, the length of gestation is determined, RU 486 is taken and the woman may be given her Misoprostol tablets to be ingested two days later. Another visit is essential to check that everything is back to normal and to provide contraceptive counseling and services. Naturally, in case of problems, the patient should be able to return before the programmed second visit, if necessary. In all countries, two rules are essential: 1.
2.
Medical supervision, just as for any pregnancyrelated event; and In case of failure, instrumental evacuation needs to be performed.21
Volume 20: 3 , Fall 1992 RU 486 is also a drug which may be useful for other medical indications: fetal or maternal accidents during pregnancy;‘” certain difficult deliveries;’3 women’s diseases such as endometriosis, fibroids, breast cancers and other t~mors.~4 It can also act as an anti-cortisone and may be used for the repair of wounds or burns and for some aspects of stress. It is not expected that most of these medical applications will be operational for several years. The entry of RU 486 into the United States for abortion use is important for several reasons, including: I.
2.
Until the abortion issue is resolved, testing of RU 486 for other medical purposes will be slower than it should be; In a pluralistic and democratic society, there is no reason to preclude a product of modern research from being available. The denial to women of the right to the benefits of scientific progress and its application constitutes sex discrimination.
The abortion issue is not the only problem that RU 486 may help to solve in the field of fertility control. Several studies on contraception with RU 486 are currently being performed or are concretely envisaged. The case study is set as follows: Monthly menses induction (with Misoprostol); Anti-implantation, post-ovulatory use;zx 3. Anti-ovulatory, including use in follicular phase of the cycle; and 4. Low dose administration over the whole cycle, with a specific anti-implantation effect.
References I. Generic name Mifepristone, trade name in France and the U.K. Mifegyne. 2 . “RU 486 as an Antiprogesterone Steroid: From Receptor to Contragestion and Beyond,” J.A.M.A., 262, (198y): 18081814; special article on the occasion of the Lasker Award for clinical research. 3. “Contragestion and Other Clinical Applications of RU 486, an Antiprogesterone at the Receptor,” Science, 245,
(198y): 1 3 5 1 - 1356. 4. Odile Jacob, Paris, 1990,translated and adapted for an
English-speaking readership: The Abortion Pill, New York (Simon & Schuster), 1991. 5 . Progesterone is a steroid hormone indispensable for the beginning and the continuation of pregnancy. 6. Three containing each zoo mg of RU 486 and taken together. 7 . Time of optimal antiprogesterone activity. 8. Prostaglandins are local hormones which are naturally involved in contractions of the uterus during delivery and abortion and physiologically help expulsion. y. y5 percent or more complete successes. 10.Dr. M . Bygdeman. I I. A PG-Ez derivative. 12. E. AubCny and E.E. Baulieu, “Activite contragestive de l’association au RU 486 d’une prostaglandine active par voie orale,” CR Acadm. Sci. Paris, 312, (1991):539-545. 13. J.E. Norman, K.J. Thong, D.T. Baird, “Uterine Contractility and Induction of Abortion in Early Pregnancy by Misoprostol and Mifepristone,” 338 The Lancet 1233-1236
I.
(1991).
2.
14.It was proposed to decrease RU 486 dosage when associated with Sulprostone or Gemeprost; however these prostaglandins were given at probably larger than adequate doses, and the data presented so far are irrelevant to the use of Misoprostol. IS. Registration on July Ist, 1991. 16. New York. 17. Signed in 1982, and remaining valid. 18. Frankfurt. 19.HRPI. 20. Rebecca Cook, International Protection of Women‘5 Reproductive Rights 24, New York University, 401-483 ( r y y z ) . 21. There is no predictable fetal abnormality, but there is no reason to take an additional risk. 2 2 . Registration just obtained in France. 2 3 . Objective: a baby in better health. 24. With Cushing syndromes, meningiomas. 2 5 . A Radestad, N. J. Christensen, L. Stromberg, “Induced Cervical Ripening with Mifepristone in First Trimester ; Bygdeman, M.L. Pregancy,” Contraception 3 8 ( 1 ~ 8 8 ) M. Swahn, E. Johannisson et a]., “The Effect of RU 486 Administered During the Proliferative and Secretory Phase of the Bleeding Pattern, Hormonal Parameters and the Endometrium,” Human Reprodzictzon 3 (1988):91 5-21. 26. See supra note 2 . 27.We should be free to have different opinions about this, just as we d o about the future of a human being after death.
Again, these studies demonstrate that RU 486 is not just an abortifacient. I have also discussed several times the concept of contragestion,z6which RU 486 can exemplify and which, between contraception and abortion as we have known it for centuries, may help women confronted with difficult situations. Medical abortion, using an antiprogestidprostaglandin regimen, may be better psychologically and physically for some women than surgical abortion. Prevention is usually better than curative intervention. Contraception is preferable to abortion and early abortion is preferable to late abortion. Contraception, however, may not always be possible or available, and most methods entail some degree of failure. RU 486 taken together with a prostaglandin as a contragestive agent will be a valuable back-up method in the coming decades.
