Quest for an ideal / by Peter E. Hall

Quest for an ideal S hould you ask any woman who has previously used contracep-tives to define the ideal contra- ceptive, the points she would raise would probably include the following. - It would have to be 100 per cent ef- fective but rapidly reversible, so as to allow an immediate return to fertility if she wants to have another child. - It would have no side effects, parti- cularly those changes in a woman's body chemistry which can lead to a risk of cardiovascular problems, or create changes in mood, or affect lac- tation when breastfeeding, or give rise to irregular episodes of vaginal bleeding or spotting which in some cultures might prevent a woman from praying or making food or making love. - It would have to be discrete, inde- pendent of coitus, and involve few visits to the health care clinic, except perhaps once a year when she could have an annual check-up. If you had asked the developers of new contraceptives 15 years ago whether they could make a contra- ceptive which fulfilled all these crite- ria, many would have said "yes- pro- bably by 1990, and definitely by the turn of the century." Today, most ex- perienced basic and clinical scientists might go so far as to say that it will never be achieved, but that they could devise contraceptives which fulfil some, even many, ofthese crite- ria and would at least allow a woman to choose a method closest to her requirements. Before we go any further - why are we talking only about women? What about contraceptives for men ? These same scientists will tell you: "We have tried, we are trying, we will con- tinue to try to make a contraceptive for men with which both men and women will be happy." It is easy to stop a man reproducing, injections could be made available next year - but the recipient would have little or no libido. Maybe we will have an acceptable male contraceptive by the year 2000 - maybe! W oRLD HEALTH, November 1987 by Peter E. Hall By the end of the 1990s, we will have vaccines for birth control which may answer many problems, but they are at an early stage of development and there is still much to learn about them. So at the moment, to respond to the many, many women around the world who consider that guaran- teed prevention of pregnancy is their most important criterion for a contra- ceptive, we are left only with the con- traceptive hormones which we know can achieve this. So what new hormonal contracep- Fitting an IUD forms part of the train- ing of family planning workers. Photo WHO/J. Mohr tives are likely to be available in the next few years? What do they have to offer compared with existing hor- monal contraceptives, and what is in- volved in their development? In the inset on page 15, we summarise the hormonal contraceptives that are li- kely to be available to family planning programmes during the next decade, with their main advantages and dis- advantages. So what is involved in their deve- lopment? If we talk to our contracep- tive development experts again, they will tell us that we shall need at least US$ 10 million (and probably S 20 million) and at least 10 to 15 years to get that new hormone (either as a pill or an injection, or incorporated into an implant or a vaginal ring) from the scientists' laboratory to the drugs cabinet of a family planning worker in a clinic in a developing country. It may well have taken a similar length of time and a similar amount of money to produce the hor- mone in the laboratory in the first place; the scientist almost certainly has been working on the principle that "many are screened - but few are chosen." Since all new drugs must be tested in animals and cell cultures before being applied to people, we must now go to the toxicologist who will tell us what testing is required by the Drug Regulatory Agencies of governments in the countries where the drug will eventually be used. The toxicologist will advise us on the conduct of the studies and how long they should be undertaken. After the first check of whether the compound has any toxic effect on ro- dents, the drug is tested in a small number of human volunteers. In these studies, called Phase I and Phase IIA studies, the action of the drug is assessed, the minimum amount of that drug required to achieve that action is found, and it is confirmed that the drug has no toxic effects on animals. Now we know the minimum effec- tive dose in the human, we can go back to the toxicologist with this information to design a longer term toxicity study in two different animal species. This may last from six months to as long as two years, de- pending on the characteristics of the compound or delivery system being investigated. These studies will tell us whether there is any toxic effect due to longer exposure of the drug. Other studies will be undertaken at this time to check on any possible adverse effects on reproductive function and on the potential of the compound to cause chromosomal changes. These studies, although re- 13 The ideal contraceptive may be a long way off, but already women can choose a method that is close to their require- ments. Right: More and more fathers are today recognising their responsibil- ity in matters of family planning. Photos WHO/UN/J. lsaac and WHO/E. Schwab quired in order to give a stronger feel- ing of security about the compound, are notoriously unreliable at predict- ing what might happen in the human. Now we go back to the human vo- lunteers, about 50 to 100 of them, and undertake a longer study of maybe up to one year in duration to check on how effective the dose we have deter- mined really is in preventing preg- nancy. The study may have to be re- peated with a higher dose to ensure that the drug is as effective as the wo- men want it to be. This stage oftest- ing is called Phase liB. At this point, two-year studies are begun in rats to check for the potential carcinogenic- ity of the compound. Again this study is designed to give security ; it does not mean that effects found in the rat will occur in the human - these can only be determined after long-term use in the human - but they should alert the toxicologist to any unusual findings which might make it essen- tial to abandon further development of the drug. This is something which could happen at any time of the test- ing programme, whether in animals or humans, and it is why the scientists responsible must be extremely ob- sessive and alert in monitoring all animal and human studies. 14 Large-scale Phase Ill studies can now be undertaken. These involve up to 1,000 subjects and last for at least one year. The new drug or delivery system should be studied in compari- son with an established method. Since there may be population diffe- rences with regard to efficacy and side-effects, the study must be under- taken in several representative popu- lations around the world. During the period in which the Phase Ill studies are under way, it may be necessary to undertake studies which look specifi- cally at certain problems such as the changes in body chemistry, which may indicate an increased risk of car- diovascular problems, or the actual amount of vaginal blood loss which occurs during treatment. On completion of Phase I-III trials and of the animal testing, the new method is ready for introduction into family planning programmes. This poses a number of new ques- tions. How acceptable is the method iri specific groups of women around the world? What measures should be adopted by family planning pro- grammes to ensure that the user is satisfied with the method and can use it properly? What must family planning programme managers do to ensure that facilities are available to deliver the method and appropriate information to those women that want it? How should the family plan- ning clinic staff be trained? Because of major cultural and socio-economic differences between users, some of these questions can only be add- ressed in each of the countries or regions of a country in which the method is being introduced. The animal testing mentioned above has been rationalised to at- tempt to get the most relevant infor- mation about problems of toxicity and other adverse reactions which could be caused by the drug. It has attempted to remove unnecessary toxicological tests, to reduce testing to the most relevant periods of time, to prevent the unnecessary use of certain species, such as beagle dogs, and to minimize the use of monkeys. Once again it is important to repeat that animal studies can only give a feeling of security about the drug. Only rarely are they predictive of what might happen in the human. The increased risk of cancer or of cardiovascular problems can only be truly determined when the drug is W oRLD HEALTH, November 1987 Quest for an ideal cardiovascular problems can only be truly determined when the drug is in wide-spread use. Epidemiological studies have been shown during the 1980s to be the most important way of assessing the real safety of a hormonal contraceptive. Thus once a drug or device finally becomes freely available in a family planning programme, long-term surveillance studies must be established to provide continuing monitoring of the drug. The centre spread (next two pages) summarises the stages of testing a ty- pical hormonal contraceptive. It as- sumes that no major problems are encountered. Therefore, in an ideal situation, it will take us at least a dec- ade from the time we took the bottle of white crystals from the scientist in the laboratory to the time the formu- What's in Store? Several new long-acting hor- monal contraceptives may be available to women before the year 2000, in the form of injec- tions, sub-dermal implants and vaginal rings. Norplant contraceptive im- plants have already been used by about 75,000 Indonesian women and are approved as contracep- tives in seven countries. Placed just under the skin on the inside of a woman's arm, the six capsules slowly release the progestogen, levonorgestrel. They are highly effective in preventing pregnancy for 5 years, after which time they must be replaced. They do, how- ever, need trained health care personnel for insertion and remo- val and give rise initially to some unpredictable menstrual bleeding and spotting. Once-a-month injectables contain an estrogen as well as a progestogen. This gives a major advantage over progestogen- only methods - that of regular menstrual bleeding episode.s; moreover they are virtually 1 00% effective. Some 1.5 million women in China and Latin .. America now use existing preparations, while two new ones will be available in 1988. They do require monthly visits to a clinic and are contra- indicated during lactation. The vaginal ring slowly releases hormone after insertion, making it the only long-acting method to be under the direct control of the woman. A 3-month levonorgestrel ring may be available in some W oRLD HEALTH, November 1987 countries by 1990. Its disadvan- tages are that it gives rise to some menstrual bleeding and spotting and that it is occasionally ex- pelled. A ring releasing progeste- rone is · being developed for breastfeeding women and should be available by 1992. Three-monthly injectables based on levonorgestrel will be available in the early 1990s. They will be simple and cheap and, although causing some distur- bance of menstrual bleeding, they are expected to be less disruptive than DMPA. Injectable microspheres are tiny particles consisting of the hor- mone in a polymer carrier which, ·· after being given by injection, dis- solve and release hormone at a given rate. The progestogen-only systems will give rise to some bleeding and spotting. The first microsphere contraceptive will deliver norethisterone over a pe- riod of 3 months and may be available in some countries in the early 1990s. Biodegradable implants are also placed under the skin, but they eventually dissolve and dis- appear. There are two types - (1) Capronor, a single capsule con- taining levonorgestrel, and (2) pel- lets of the hormone norethisterone combined with a small amount of cholesterol. Capronor is expected .. : to prevE?nt pregnancy for two years; the pellets, for at least one ... year. They may be available by the mid-1990s. lated drug reaches the hands of the health care worker in a family plan- ning clinic and is freely available. This short description of the eva- luation of a new drug does not take into account the many other issues which must be addressed while the method is being tested. These include, among other things, the production of the drug or device, the develop- ment of informational, educational and counselling materials, and the re- gistration of the drug or device in the countries where it will be used . Fewer and fewer pharmaceutical companies are undertaking research on new methods of fertility regula- tion, even those that are concentrat- ing on a new hormone they have made and which they control through patent rights. This can keep them profitable in the competitive pill mar- ket of the "western" industrialised nations and keep their shareholders happy. But it does not help them to make new methods available to fam- ily planning programmes in develop- ing countries at a price those pro- grammes can afford. Hence, in the late 1980s, a greater burden is placed on the public sector agencies - such as WHo's Special Programme of Research in Human Reproduction; the US-based agen- cies, such as the Population Council, Family Health International, PIACT and CONRAD; or the government programmes which support scientists in countries such as China, India or Mexico - to undertake this research and development work. And it is hap- pening; despite shortages of money and the time it takes to do the work, scientists and managers in the public sector in both developing and deve- loped countries are increasingly doing those things that have been tra- ditionally undertaken by industry. They are providing the public sector in developing countries with many of the contraceptive choices a woman wants, allowing her to decide for her- self the best contraceptive method once she has had all the advantages and disadvantages explained to her. Even though the pharmaceutical companies, the public sector agen- cies, governments and individual scientists will still be unable to provide the "ideal" contraceptive for the twentieth century, let us hope that their efforts will result in a closer approximation to those "ideal" methods for both men and women in the twenty-first century. • 15