THE INTRODUCTION OF MIFEPRISTONE INTO NEW ZEALAND
By Dr Margaret Sparrow DCNZM MBE
The story begins in France in the 1970s in the laboratories at Roussel Uclaf, where scientists were researching various aspects of steroid chemistry. The uterine progesterone receptor had been discovered in 1970. The research team were not looking specifically for an anti-progesterone but when in 1980, compound 486 showed a high affinity as a progesterone receptor blocker, it was marked for further investigation. It became best known by its research identifier, the RU standing for Roussel Uclaf. RU486 or mifepristone, is a 19-norsteroid, belonging to the same group of compounds as oral contraceptive progestogens.
The scientist who perceived the importance of RU486 and who was most responsible for its scientific development and promotion was Professor Etienne-Emille Baulieu. He was inspired by Gregory Pincus, the ‘father’ of the contraceptive pill, to participate in the search for better methods of fertility control. Baulieu was not a clinician and he arranged for the first clinical trial to be conducted in 1982 in the University Hospital, Geneva, Switzerland where 9 of the 11 volunteers with pregnancies from 6-8 weeks had their pregnancies terminated by RU486 alone. By 1983 trials were being conducted in a several countries. Until 1984 RU486 was used alone but the effectiveness was only 60 to 85 per cent.
In Sweden, Dr Mark Bygdeman first reported that RU486 was more successful when followed by a prostaglandin to stimulate uterine contractions and expel the fetus. Between 1985 and 1987 China became involved in clinical trials. The Chinese State Family Planning Commission was favourably impressed and decided that RU486 should be included in China’s fertility control programmes. When negotiations with Roussel Uclaf broke down, Chinese scientists used their own expertise to synthesise and manufacture the drug and since 1992 China has been self-reliant for supplies and now supplies the USA market.
Mifepristone is now accepted as a safe alternative to surgery in early pregnancies under 9 weeks gestation and is also used in later abortions. For early abortions an ectopic pregnancy should be excluded by ultrasound examination. One 200 mg tablet is given on Day 1 and about 3 per cent will expel the fetus without any further treatment. Most will require a prostaglandin and this is administered 36-48 hours later, either orally or vaginally, usually the latter. A final check is required on Day 10-14 to ensure that the fetus has been expelled. The method is successful in about 95 per cent of cases overall and the earlier the pregnancy the greater the efficacy. As with a natural miscarriage heavy bleeding may occur and about 1 in 400 women will require a transfusion. About 5 per cent will require surgery for an incomplete abortion or a continuing pregnancy. Women who choose the method see it as a more natural, less invasive procedure, even though there may be several days, or more, of bleeding and cramping. From a medical safety perspective both methods are acceptable. With medical abortions there is less infection, less trauma and no anaesthetic risks. With surgery, the procedure is over more quickly, there are fewer failed procedures and there is slightly less risk of haemorrhage. Because mifepristone is not safe for everyone the treatment is not a do-it-yourself method as some hoped and others feared. It should always be used under medical supervision. Recent cases of women importing the drug illegally and using it unsupervised have resulted in unsafe medical situations.
Mifepristone has now been approved for use in 21 countries for early termination of pregnancy up to 7 or 9 weeks gestation. In many countries, including New Zealand, it is also used for mid-trimester abortions or to induce labour after a fetal death in utero. Mifepristone reduces the dose of prostaglandin required, making it a more tolerable experience for the woman and shortens the time in hospital, making is less costly. Mifepristone is an effective postcoital contraceptive. Research has also been carried out on its use in other conditions including uterine fibroids, endometriosis, Cushing’s disease, meningioma, breast cancer and multiple sclerosis. It is not approved for use with other conditions in New Zealand.
Mifepristone was first approved for clinical use on 23 September 1988 in France. Both Roussel Uclaf and its German parent company Hoechst, were instantly embroiled in intense anti-abortion protests. On 26 October, after just one month of anonymous threats to wives and children of employees and warnings of commercial boycotts in the USA, France and West Germany, Roussel Uclaf, in an unprecedented move, cancelled its plans to distribute RU486. There had been intense pressure from Hoechst, where senior executives included staunch Catholics. In pre-unification West Germany abortion laws were restrictive and abortion was a highly controversial issue. Two days after the announcement that RU486 would no longer be distributed, the French Minister of Health, Mr Claude Evin ordered the company to resume distribution in the interests of public health, describing the drug as the ‘moral property of women’. The fact that the French government owned 36 per cent of Roussel’s stock gave the government considerable clout. Coincidentally at that time, the world’s leading reproductive health specialists were meeting at an International Federation of Gynaecology and Obstetrics (FIGO) congress in Rio de Janiero. RU486 was on the agenda and Baulieu and Dr André Ulmann from Roussel Uclaf were in attendance. Baulieu called for a public mobilisation to demand that RU486 be made available. The international response was swift and effective with over 1000 signatures gained on a petition from congress participants.
Since 1988 mifepristone has been widely used in France and in that time the abortion rate has not altered significantly. French law requires a week’s reflection time between the first consultation and the abortion. The time limit for terminating an early pregnancy is 7 weeks gestation. A setback occurred in April 1991 when a death occurred due to a myocardial infarction in a 32 year old woman, a heavy smoker, terminating her 13th pregnancy at 5 weeks gestation. The fatality occurred following an injection of sulprostone, a prostaglandin no longer used. Mifepristone is also used in France for mid-trimester abortions.
The flak directed at Hoechst and Roussel by anti-abortion groups in France was minor compared to the damage being threatened by anti-abortion crusaders in the USA. Together, Roussel and Hoechst owned several American subsidiaries. There were threatened boycotts of Hoechst’s other major products in the USA, such as agro-chemicals and drugs for diabetes and hypertension. Hoechst also feared that overseas customers might be reminded (by anti-abortionists) of a link to the Nazi death camps of World War II. Hoechst’s precursor, the Nazi chemical firm, IG Farben had produced the poison used in the gas chambers. To avoid a repeat of the French fiasco, Hoechst drew up tight conditions for supplying any country with RU486: (1) a watertight law for legal abortion, (2) strictly controlled distribution, (3) an invitation from the government and (4) a public that manifestly tolerates abortion. Only Britain (in 1991) and Sweden (in 1992) met these criteria.
In November 1990 Baulieu was invited to speak at the Abortion Providers Conference in Melbourne where he faced opposition from Dr Lynette Dumble, a medical scientist at the University of Melbourne. Subsequent to this, Dumble collaborated with two feminist writers Renate Klein, lecturer in Women’s Studies at Deakin University and Janice Raymond, ethicist from the Massachusetts Institute of Technology (MIT), to publish in 1991 a book which was to become influential among women’s groups. The authors argue that far from making abortion a woman-controlled affair, the repeated visits enable doctors to retain all their traditional control. Safety issues of both RU486 and prostaglandins are emphasised, including the possibility of fetal abnormalities should a pregnancy continue. They warn that the long term effects of both drugs are unknown.
Immediately following the Melbourne conference, Baulieu came to New Zealand at the invitation of the NZFPA and spoke at a seminar in Auckland. The meeting was picketed by anti-abortionists. In September 1992 NZFPA was invited by the WHO to participate in a multicentre study on the use of mifepristone as a postcoital contraceptive. This was a randomised double-blind study to compare three doses of mifepristone (600 mg, 50 mg and 10 mg) and surprisingly when the results were published the 10 mg dose was found to be as effective and had less effect on the menstrual cycle. Although the project was approved by health authorities in New Zealand, Roussel blocked our participation because they considered that New Zealand did not meet the strict guidelines imposed by Hoechst. Australia was more successful. Dr Edith Weisberg of Sydney and Professor David Healy of Melbourne were both principal investigators in this trial. Other countries that participated were Britain, China, Finland, Georgia, Hong Kong and USA. However, this and other trials in Australia did create controversy and in May 1996 anti-abortion Independent senator Brian Harradine moved an amendment to the Therapeutic Goods Act so that ministerial approval is now required for further clinical trials or distribution of abortifacients. Since 1996 that approval has not been forthcoming.
Britain had been involved in early research trials and in October 1989 a conference organised by the Birth Control Trust was held at the Royal College of Obstetricians and Gynaecologists (RCOG) in London. Professor David Baird of Edinburgh and Professor Allan Templeton of Aberdeen, both leaders in the field of medical abortion, spoke of their experience. Mifepristone was approved for use in the UK in 1991. In December 1997 Professor Baird was invited by the Royal New Zealand College of Obstetricians and Gynaecologists to speak at the main centres in New Zealand. In October 1999, the UK FPA and the Population Council (USA) held an international seminar in London to examine current practice worldwide with keynote speakers from France, Sweden, Austria and the UK.6 In March 2000, the RCOG launched their National Evidence-Based Guidelines which support the role of medical abortion complementing surgical services. These guidelines will be reviewed in 2003. For mid-trimester abortions mifepristone/prostaglandin regimens are recommended. In September 2001 UK and USA doctors met in London to discuss advances in abortion care, both medical and surgical.
The rate of uptake for early medical abortions in the UK varies widely. In Scotland women present earlier in their pregnancies and about 40 per cent of eligible women choose mifepristone, the same as in France and Sweden. In England and Wales, due to longer waiting times, fewer women present under 9 weeks gestation and in 1998 only 13.5 per cent of these opted for mifepristone, mainly due to the need for extra visits and a reluctance on the part of providers to change from efficient surgical services.
Feminist attitudes range from total support to entrenched opposition. One of the most extreme opponents is FINNRAGE, the Feminist International Network of Resistance to Reproductive and Genetic Engineering, to which Renate Klein belongs. In 1991 at a conference at the MIT, Dumble, Klein and Raymond denounced the drugs as unsafe for women. They published a book RU486: Misconceptions, myths and morals.
Later that year a major conference was held in Arlington, Virginia, sponsored by the American Society of Law and Medicine. The Department of Health sent a representative from New Zealand. Co-operating feminist organisations supporting choice for women, included the National Abortion Rights Action League (NARAL, USA), CARAL the equivalent Canadian organisation, Catholics for a Free Choice, the International Women’s Health Coalition, the Boston Women’s Health Book Collective and the Feminist Majority Foundation founded by Ellie Smeal who has among other activities led three delegations to Paris and Frankfurt with petitions from USA citizens, organised the ‘The Web of Influence’ campaign to influence public opinion and successfully pursued endorsements from major scientific and medical organisations.
In New Zealand the most active organisation with respect to women’s health issues is Women’s Health Action, and although spokesperson, Sandra Coney was initially opposed to the introduction of RU486 in 1990, a decade later, in October 2000, Women’s Health Action organised a meeting in Auckland to discuss the issues in an informative way. As with other women’s health groups they have concerns about presenting the information so that women can make a truly informed decision and concerns about the provision of services with regard to the safety and acceptability for women.
The story becomes very complex at this point and in the interests of space and clarity I will simplify. As early as 1983 Roussel Uclaf had provided RU486 for scientific testing in the USA. The recipient was the Population Council, an international nonprofit NGO established in 1952, based in New York, with a reputation for reproductive health research and development especially for the benefit of developing countries. In June 1989 the Bush administration with its anti-abortion agenda, banned the importation of RU486 for personal use. In a highly publicised case, this ruling was tested in July 1992 by a young woman, supported by abortion rights activist Lawrence Lader, who has campaigned over many years for abortion rights in general and RU486 in particular. In spite of a lower court ruling in her favour, the Supreme Court refused to reverse the ban. It stayed in place until the election of President Clinton.
Pharmaceutical mergers and takeovers are part of the complexity. In May 1994 Hoechst and Roussel Uclaf donated the American patent rights to the Population Council and advised that the name RU486 should no longer be used. Roussel retained all remaining rights to mifepristone, excluding USA and China. In 1995, Hoechst purchased American drug manufacturer Marion Merrell Dow to become Hoechst Marion Roussel (HMR). In 1999 HMR merged with another European pharmaceutical giant, Rhone Poulenc, to form Aventis.
Meanwhile, the Population Council employed a lawyer/entrepreneur by the name of Joseph Pike, to set up a series of companies to handle various aspects of the production, distribution and marketing of mifepristone. Pike and the Population Council first established a non-profit company called Advance in Health Technology (AHT) to promote the drug and provide public education and professional training. AHT also received the licence to manufacture mifepristone, which it in turn granted to two other for-profit companies set up by Pike, Danco Laboratories and Neogen Pharmaceuticals Inc. Danco was to be responsible for mifepristone as an abortifacient while Neogen was to arrange distribution of the drug for all other medical indications. Pike controlled both sub-licensees through another series of companies. Some confusion about the names of the various entities arose when Pike kept changing the names on bank accounts. Eventually Pike was exposed as a disbarred lawyer and convicted forgerer in October 1996, leading to a series of lawsuits between the Population Council, Pike and would-be investors. A settlement was made in February 1997, with the Population Council announcing a change in the project’s corporate structure.
AHT was replaced by Advances for Choice, to handle training and education functions. The identities of the manufacturer and other involved companies were to be kept secret. Danco was to be the marketer/seller of the finished product. The company that the Population Council had originally contracted in 1996 to manufacture the raw mifepristone, Hungarian pharmaceutical firm Gedeon Richter withdrew from their contract in February 1997. Danco sued Richter. Richter had another successful product Postinor, the new levonorgestrel postcoital contraceptive and the small Hungarian firm was taken over by the large German based firm, Schering.
Despite the unfortunate choice by the Population Council of a shady lawyer, despite various mergers and takeovers by pharmaceutical firms, despite threats by anti-abortionists to boycott products, despite not having a reliable source of the raw material, some things went right. The Clinton administration was supportive, Hoechst and Roussel were only too pleased to donate the patent rights to someone else, and the international medical fraternity was supportive e.g. in September 1994 the FIGO Committee for the Study of Ethical Aspects of Human Reproduction issued a strongly supportive policy statement. To cut a long story short, in September 2000, the FDA finally approved Mifeprex® as it is known in the USA. It is available only for early terminations up to 9 weeks gestation and providers must be trained in its use. They must make advance arrangements for the management of any complications including surgery for failed or incomplete abortions.
International events left New Zealand with no established pharmaceutical firm wishing to enter this minefield. In June 1995, abortion providers throughout New Zealand met for the first time in Wellington at a national conference where medical abortion was discussed. A keynote speaker was Earle Wilson, a recently retired New Zealand trained obstetrician and gynaecologist who had spent his career overseas, had worked with WHO and had been involved with the international research on RU486. Following this a working party of abortion providers in Wellington met to consider strategies for introducing medical abortion as a choice for New Zealand women. With little prospect of obtaining mifepristone our efforts were concentrated on the option of a methotrexate/misoprostol medical alternative and this went as far as an application to the local Ethics Committee, early in 1997. However on the advice of Earle Wilson we abandoned this plan for reasons of medical safety and concentrated our efforts on our first choice, mifepristone. At the 2nd abortion providers conference in Christchurch in June 1997 Professor David Healy spoke of his Melbourne experience with mifepristone.
There were three sources of mifepristone - France, USA or China. We spent most time investigating the first two. NZFPA had links with the Population Council and President, Margaret Catley-Carlson visited New Zealand on two occasions and we were able to meet with her and discuss obtaining the drug through the Population Council. She indicated that they were experiencing legal problems (an exquisite understatement) and advised that we should negotiate with the French. In August 1997 the commercial rights were transferred to Exelgyn, a small company founded by Dr Edouard Sakiz, ex chairman of Roussel Uclaf who had been involved with mifepristone since its discovery. Exelgyn initially were concerned about maintaining the supply of mifepristone to the established markets of France, UK and Sweden and were not seeking new ventures. After some time we approached them again and they agreed to negotiate but only if we nominated a reputable pharmaceutical firm to liaise with. There being none, five doctors, all experienced abortion providers formed a not-for-profit company which we named after Ishtar or Istar, an ancient Babylonian goddess of love, fertility and war.
Istar was incorporated in February 1999 and in May 2000 we signed an agreement with Exelgyn for the importation of Mifegyne® using the same packaging as that supplied to the UK. The following month we submitted an application to Medsafe, the medicines regulatory authority of the Ministry of Health. This mainly consisted of the 84 kg dossier provided by Exelgyn, photocopied and filed according to strict guidelines. Following the assessment by Medsafe, the application was referred to the Medicines Assessment Advisory Committee. The approval process is a lengthy and expensive one and it took 14 months to complete. Finally on 30 August 2001 Mifegyne® received ministerial approval with a notice published in the Gazette. It is approved for use as an abortifacient and will only be available through Istar, not through retail pharmacies. Because of the law it will only be administered in licensed institutions.
The Minister of Health, the Hon Annette King has been supportive throughout. A legal issue created initial uncertainty. Under the Contraception, Sterilisation and Abortion Act of 1977, Section 18 requires that all abortions must be performed in a licensed institution but there are differing legal interpretations. Some considered that the fetus must be expelled in a licensed institution while others considered that the woman could be discharged home even if the process has not been completed in the 6-8 hours following the administration of the prostaglandin. It was not a problem with later mid-trimester abortions, or induction of labour for fetal death in utero, as these cases are kept in hospital until the process is completed.
We were able to inform colleagues of progress at the 3rd abortion providers conference, held in Auckland in October 2000. Professional training has received priority attention and draft protocols have been forwarded to units interested in providing a medical service. Fortunately in some of the main centres there are staff with first hand experience of providing a medical service in the UK and their knowledge has been invaluable.
In April 2003 a High Court judjment resolved the legal problem. The two sets of pills must be taken in a licensed institution (clinic or hospital) but the woman is not required to stay there between the two doses or until the embryo or fetus is expelled.
It is possible that there are other antiprogestogens or other drugs which are more effective, safer and with less side effects, making it possible to offer a much less medicalised procedure, but if the history of mifepristone is an example of what can be expected, there will need to be considerable progress on the social, political, legal and commercial issues, before we see a genuine commitment to improving the methods of abortion for women.
[Article based on one published in Venereology 2001; 14: 143-147 and edited December 2004]
Reference:
Guideline Development Group RCOG. The care of women requesting induced abortion. Evidence-based Guideline click here