format elderly/pediatrics/women - who...

7.4: Cross cutting issues: Women

Priority Medicines for Europe and the World"A Public Health Approach to Innovation"

Background Paper

Pharmaceuticals and Women

By M.J.C. Willemen; F.F.T. Ververs, Pharm D; and Prof. H.G.M. Leufkens

7 October 2004

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Table of ContentsSummary................................................................................................................3Introduction...........................................................................................................5Size and nature of disease burden........................................................................6

Reproduction control......................................................................................................6Subfertility......................................................................................................................7Pregnancy and lactation, including birth defects...........................................................8Post-reproduction hormones..........................................................................................9

What are the current or likely future factors that impact disease burden?........10Reproduction control....................................................................................................10Subfertility....................................................................................................................11Pregnancy and lactation, including birth defects.........................................................11Post-reproduction hormones........................................................................................12

What is the control strategy?...............................................................................12General.........................................................................................................................13

Improving participation in clinical trials...............................................................13Specific.........................................................................................................................13

Reproduction control............................................................................................13Subfertility............................................................................................................13Pregnancy and lactation, including birth defects.................................................14Post-reproduction hormones.................................................................................15

Why does the disease burden persist?.................................................................15General problems.........................................................................................................15

Lack of knowledge................................................................................................15Specific problems.........................................................................................................16

Reproduction control............................................................................................16Subfertility............................................................................................................16Pregnancy and lactation, including birth defects.................................................17Post-reproduction hormones.................................................................................17

What can be learnt from past/current research into pharmaceutical interventions for these conditions?.................................................................18What is the current "pipeline" of products that are to be used for this particular condition?........................................................................................19

General.........................................................................................................................19Research in women...............................................................................................19

Specific issues..............................................................................................................19Hormone therapies...............................................................................................19Pregnancy and lactation, including birth defects.................................................19

What are the opportunities for research into new pharmaceutical interventions including delivery methods?................................................................................20What are the gaps between current research and potential research issues which could make a difference, are affordable and could be carried out in a) 5 years or b) in the longer term? For which of these gaps are there opportunities for pharmaceutical research?..........................................................................20Conclusion...........................................................................................................21References...........................................................................................................22

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SummaryThe thalidomide-crisis in the early 1960s made the world aware of the difficulties of drug use in women.1 Since then, women’s health is at the top of virtually every health care policy agenda. Paradoxically, there are still various gaps in knowledge and research related to female drug treatment.

Four issues (reproduction control, female subfertility, pregnancy and lactation (including birth defects and teratogenicity) and post-reproduction hormones) are discussed in this paper. Reproduction controlSince the introduction in the 1960s, the use of pharmaceutical contraceptives has increased enormously. Due to different reasons, the use varies widely between different countries.2 Although, the discussions about the safety are still ongoing. In the beginning, high doses of estrogens were of major concern. In the 1980s, the differential risks of progestogens, as part of low dose OCs have been the subject of an ongoing series of controversies, scientific inquiry and societal debate.3

Opportunities for research concerning contraceptives lay in the field of looking for new targets for intervention,4 new classes of chemical compounds (compounds which have estrogenic effects such as synthetic steroids like tibolone),5 and new drug delivery systems (e.g. the vaginal ring, injections).6, 7 As compliance is a major factor for effective contraception, the development of long acting or controlled release formulations should be encouraged. Current societal developments ask for more emphasis on equal responsibility and burden between women and men, including strengthening the search for pills for men. Female subfertilityFemale subfertility can be caused by different disorders. With the increasing age of women having children, the rates of female infertility increase due to a decrease in the oocyte/follicle pool. Also ovulation disorders (25%), tubal disorders (20%) and endometriosis (5-10%) cause infertility. Although the knowledge of subfertility has increased in the previous years, in about 30% of the cases the cause of the subfertility is unknown.8, 9

In vitro fertilisation (IVF) is for many couples the last opportunity to have children. The success rate of IVF is only about 25% per cycle and the technique is associated with side effects, increased risks for complications, and multiple births.10 Multiple births are associated with an increased morbidity and mortality (e.g. prematurity, low birth-weight, neurological handicaps). The hormones used by IVF are another concern. The effects of these hormones are not completely clear yet. The long term effects (e.g. puberal development, future fertility of the child) are still unknown. To obtain sufficient information of the effects of the hormones on both the mother and the child, long-term follow up is needed. 11, 12

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Pregnancy and lactation, including birth defectsResearch in pregnant and lactating women is very controversial, especially since the thalidomide disaster in the early 1960s.1 Although many women need to use medication during their pregnancy or lactation, there is a lack of knowledge of the safety of many drugs.

The wide variation in prevalence of teratogenic effects imply the need for large data banks which include information on different issues (e.g. drug exposure, illness of the mother before/during pregnancy, epidemiology of congenital abnormalities) from large numbers of women and their children, during a long period of time, are needed. 13

To prevent neural tube defects, the preconceptional use of folic acid is strongly recommended. Unless various public awareness campaigns, less than 50% of the women uses folic acid before conception.14 Accordingly, the enrichment of food with adequate amounts of folic acid might be considered.

Because of the risks, pharmaceutical industry is far from eager to financially support studies which involve pregnant women and tend to advise negatively in using their drug during lactation. Recently, both FDA and EMEA developed guidelines to improve the post-marketing research in pregnant women.15, 16 It is expected that these guidelines will work out good, but only the future will tell us. Hormone replacement therapy (HRT)Postmenopausal hormone replacement therapy is indicated to relieve symptoms of menopause.17 The use of HRT varies widely between populations. HRT is on the one hand associated with prevention of chronic diseases18 (osteoporosis,17

some forms of cancer19), but on the other hand, the use of HRT may increase risks of several cancers and cardiovascular diseases.20, 21

Since the introduction of HRT for postmenopausal disorders, there is a discussion about the risk-benefits balance. Aside from several proved adverse effects, there is still a large number of women using HRT worldwide.18, 19 In December 2003, EMEA published a public statement about HRT.22 Considering the recent publications, they recommend that HRT as a therapy for the treatment of the direct symptoms of menopause is the first choice (using a minimal dose for a short duration). To prevent/treat osteoporosis, HRT is not the first choice; in women without direct symptoms of the menopause HRT is not recommended at all.GeneralBoth FDA and EMEA have developed several guidelines to improve research in women, but there is still a lack of knowledge of specific female issues. Close cooperation between pharmaceutical industry, regulatory agencies and academic centers is warranted to improve the knowledge and to carry out clinical research in women in an ethical way.

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IntroductionFemales are among the heaviest users of medicines. Virtually all drug prescribing and utilization data reflect the intriguing contrast between women and men with respect to the volume, the nature and the quality of the use of medicines. The Dutch Foundation for Pharmaceutical Statistics (SFK) found that women fill on average 10.8 prescriptions per year, while in men this figure is only 6.8 prescriptions per year.23 A study in the Spanish population showed that 50.6% of the participating women had used some kind of medication in the two previous weeks. In men, this was only 39.6%.24 We can continue to report on such consistent gender differences and available research data point to a complex, and often erratic, interplay between social and economic factors, health care seeking behavior, diagnostic procedures, and 'real' physiological and pharmacological differences between the women and men.25, 26

Although the numbers related to drug use in women are impressive, there are concerns about unresolved aspects related to the availability of suitable medications, rational use and a variety of safety aspects concerning reproduc-tive technologies, exposures in pregnancy, and unique female morbidities (e.g. breast cancer, postmenopausal conditions). The recent debate as to whether pregnant women with HIV should be treated with antiviral therapy, is a clear example of uncertainty around a unique female condition where not only the mother is involved, but also the health of the unborn baby.27

One may argue that this is always the case with relatively new therapies like HIV antivirals, but the issue also arises in the context of medicines we have known for decades (i.e. tricyclic antidepressants).28 Very relevant are recent reports on gender differences in the undertreatment of diseases where appropriate therapy is indicated and available.29, 30

Obviously there is a paradox. While women's health is at the top of virtually every health care policy agenda, there are still various gaps in knowledge and research related to female drug treatment that can been identified. These include [1] females are frequently excluded from clinical trials and other types of medical research because of complexity issues related to reproduction and hormone cycles;31 [2] most typical female drug therapies are long-term (e.g. oral contraceptives, hormone replacement therapies, psychotropics, etc.) and are in need of sound risk management systems for long duration drug exposures; [3] since the thalidomide disaster, medication safety in pregnancy is a well known concern, but this area is still under-funded and poorly developed, i.e. in terms of availability of appropriate (multinational) data on birth defects and susceptible exposures, methodology and classification systems.32

In this chapter, we aim to identify and analyze important aspects related to drug use by females. We have chosen to group the various issues under the heading of 'reproduction'. 'Reproduction' covers various aspects, including:

- Reproduction control (pharmacological contraceptives)- Female subfertility- Pregnancy and lactation, including birth defects and teratogenicity- Post-reproduction hormones (e.g. hormone replacement therapy)

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Size and nature of disease burden The size and nature of disease burden of the four 'reproduction' issues captured above differ widely. For clarity matters, we will discuss all four separately. Some of the issues have different issues which all contribute to the burden; therefore, some of them are broader than others.

Table 1: Summary of the burden of specific female reproduction conditions

Reproduction control by

pharmacological

contraceptives

Female subfertility

Pregnancy and lactation

Post-reproduction hormone

replacement therapy (HRT)

Ongoing safety debate

Lack of basic knowledge

Absence of a uniform classification system concerning safety (drug use in pregnancy and lactation)

Direct symptoms: high disease burden

Access to available technologies

High societal burden

Lack of knowledge and data about drug-safety in pregnancy / lactation

Effect on chronic conditions like osteoporosis

Social-ethical controversies

Delay in childbearing age/medicalisation of social problem

Chronic conditions and diseases (HIV/Aids, mental disorders, diabetes mellitus)

HRT associated with risks on cancers and cardiovascular diseases

Off-label use menstrual disorders

Lack of known targets for pharmaceutical therapeutic intervention

Short-term drug use (pain, infections) in pregnancy and during lactation

Long-term use

Reproduction controlContraceptive development has always been affected by cyclic changes in what science can add with new and better methods, the controversial climate, perception of risks by consumers, and various forms of political pressure. Controversies around the intrauterine device (IUDs) and the mini pill (Norplant) in the late 1980s and early 1990 have resulted in significant drawbacks in the development of new contraceptives.33 Contraception is an issue that frequently provokes intense societal discourses and controversies. Contraceptive needs of many women still remain unmet due to political, economical, and religious factors.4 The use of oral contraceptives (OC) varies widely between populations in the world. A multinational study showed that the prevalence of OC use in women (25-44 years old) ranges between 1 and 58%. The application of OCs as a contraceptive method is more prevalent in Western-Europe and in Australasian populations, whereas the use of this method of reproduction technology is relatively low in Central and Eastern Europe and North America.2 The UN Report World Contraceptive Use 2003 showed that the overall use of the contraceptive pill in North America is 15.5%, whereas in Western Europe about half of females in their reproduction ages are using the 'pill'. In Oceania and Africa, these figures are about 17.6% and 7.3%, repectively.34

Few studies about the duration of OC use exist, although this factor has been shown to be an important determinant of drug-related risk.35 A study from 1990 showed that about 40% of the women who had ever used OC, had used it for three years or less; 45% of the 'ever-users' had used OC for five or more years

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7.4: Cross cutting issues: Womenwhereas 20% of the women had used OC for more than 10 years.36 Another study showed that about 25% of the women used OC for less than 1 year, 37% used OC for 1-4 years, 24% for 5-9 years and 14% used OC for more than 10 years.37 The time of use for oral contraceptives varies widely, but a considerable number of women are using oral contraceptives for a longer period of time (>10 years). Moreover, timing of OC use has been changing over the last decades. The pill was mainly used in the early years (1960 and 1970s) after a family was founded and completed, while in more recent decades, the pill is used frequently by young females before family building plans are decided.

In terms of 'disease burden', the most obvious topic related to OC use is the ongoing safety debate. Besides this, there is an efficiency problem if the drug is not taken on a strictly daily base. Since the advent of this method of reproduction control in the early 1960s, health risks have been at the top of virtually every agenda in the pharmaceutical marketplace. In the beginning, high doses of estrogens were of major concern. In the 1980s, the differential risks of progestogens, as part of low dose OCs have been the subject of an ongoing series of controversies, scientific inquiry and societal debate.3

OCs are not only used as a contraceptive method. A very common off-label indication of OC is the treatment of menstrual disorders.38 Primary dysmenorrhoea (painful menstruation, not due to gynaecological pathophysio-logy)39 is the most prevalent menstrual disorder, reported by 40-90% of the women in the reproductive age range.40, 41 Although dysmenorrhoea accounts for a high disease burden there are no specific drugs developed for the illness. NSAIDs are the treatment of first choice, and OCs are second-line therapy.38, 41

Menorrhagia (heavy cyclical menstrual bleeding occurring over several consecutive cycles) is also a common menstrual disorder. It is estimated that about 30% of the women complain of menorrhagia.42 Menorrhagia is mainly treated with NSAIDs or with oral contraceptives (progestogens or combinations of estrogen/progestogen).42 SubfertilityIn general, there are only a few studies about female subfertility; much more attention is paid to male subfertility. Available data show that in women between 19-26 years old the percentage of subfertility is about 8%, increasing up to 13-14% in women aged 27-34 years old and 18% in women aged between 35 and 39 years old.43 There are several disorders that may lead to subfertility. More than 25% of the female subfertility is caused by ovulation disorders (ranging from amenorrhoea to irregular cycles).8 Another 20% of subfertility in women is probably related to tubal diseases, whereas 5-10% is caused by endometriosis.8, 9

It is estimated that the mechanism leading to subfertility is unknown in about 30% of the cases (including men and women).8, 9,Environmental occupational exposure to chemical substances like smoking is also associated with decreased female fertility, as is the increasing age of women having children.44

Since the 1970s, many western countries have shown a major shift in the age of childbearing. The age of getting married is an important factor to consider, since in most societies marriage is still an important 'driver' of pregnancies. People are older when they are getting married, the mean age for men increased from 25.4 to 27.2 years, and in women from 21.5 to 23.2 years (worldwide). In developed countries, the increases are even greater: for men the average age increased from 25.2 to 28.8 and for women from 22.0 to 26.1 years.45, 46 The increasing age of women bearing children coincides with a

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7.4: Cross cutting issues: Womendecline in both the quality and the quantity of the oocyte/follicle pool. Therefore, the ability to become pregnant declines with increasing age, while the risk of birth defects increases.43, 46

As well as the higher age of people getting married, other factors (social and economic) contribute to a delay in childbearing contributing to an increasing incidence of subfertility.46 It is estimated that subfertility is having a great impact on the quality of life, marital adjustment and sexual function.47 Also, in current society, it is against the norm to be childless. This often results in a social stigma about subfertility.48

Pregnancy and lactation, including birth defectsSince the thalidomide crisis in the early 1960s, there is an ongoing concern about drug use in pregnancy. In several studies, it is estimated that about 62-80% of pregnant women take at least one drug during pregnancy. These drugs include both medications on prescription and over-the-counter medicines (including vitamins and iron supplements).49, 50, 51

A most critical period in pregnancy is the first weeks after conception, a period in which the foetal organs are developing. While a woman might not be aware of the fact that she is pregnant, the foetus might be exposed to drugs. About 60% of the women reduce drug use the moment they know they are pregnant,51, 52 but the period between conception and awareness remains an uncertain period in every pregnancy.

Despite the common belief that the use of medications should be avoided (as much as possible) in pregnancy and during lactation, there are several conditions in which it is virtually impossible to prevent drug use.53 There might be chronic conditions which are already present before pregnancy (e.g. epilepsy, mental disorders, HIV/AIDS) and in need of treatment during pregnancy and lactation.54 There are also conditions which start during pregnancy (e.g. nausea, diabetes mellitus, hypertension, early contractions) and which also need to be treated.55, 56 The third category includes the short-term, acute treatments (e.g. infections, pain).57, 58 Still, most of these drug exposures exist without certainties about the risks to the foetus.53

There are also controversies and uncertainties around the risks of drug use during lactation. In general, available evidence indicates that the benefits of breastfeeding (which are both medical and societal) exceed the disadvantages.59

Breastfeeding is seen as an important contributing factor to a newborn's health.59 Recent survey data shows that there is a constant weighing of the risks and benefits of breastfeeding given drug use, and that many women either discontinue lactation when starting drug therapy or visa versa.60

The occurrence of teratogenic defects is probably much higher than estimated when quantifying birth defects in actually born babies. It is expected that embryo or pregnancy loss, fetal loss or spontaneous abortion (even before a pregnancy is noticed) occur much more often than observed. This might be seen as a mechanism of nature to eliminate unfit genotypes, thereby preventing the birth of children with major defects.46 The rate of birth defects is also increasing with the age at which a woman bears children. Well known examples of age-related birth defects are Down syndrome and other chromosomal abnormalities.61 Much less is known about the subtle effects of drugs on mental (or neuro-) development and fertility of the offspring. Although an increasing number of women in the western world take antidepressants and tranquillizers

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7.4: Cross cutting issues: Womenduring pregnancy, there still is no evidence for safety concerning neurodevelopment.62

Post-reproduction hormones A study in 32 populations in 20 different countries showed that the prevalence of HRT-use varies widely in women aged between 45-64 years old. The prevalence ranged between 0 and 42%. The distribution of HRT between the age groups showed more similarity: highest use was seen in the women aged 45-49 years, followed by women aged 50-54 and 55-59 years old.2 A German study found that the prevalence of HRT-use between 45-64 years old women is 23% in 1994-1995.63 A study among Norwegian women shows a prevalence of 32%, who are current users of local or systemic HRT.64 This study also showed that the mean duration had increased from 1.4 years to 3.3 years (local treatment) and from 2.2 up to 4.6 years for systemic treatment.64 The use of HRT is higher in Western and Northern Europe, North America and Australia in comparison with Eastern and Southern Europe and China.2

As women get older, their ovarian follicles are depleted, which is followed by menopause.65 Due to the depletion of the follicles, physiological levels of estrogens decrease.66 This hypo-oestrogen status may result in several problems (e.g. vasomotor flushes, sweats).17 Although the occurrence of such problems may vary among populations, numerous postmenopausal women feel discomfort and significant limitations in their quality of life. Postmenopausal hormone replacement therapy is indicated to relieve symptoms of menopause.17 On the one hand, long term HRT-use has been found to be associated with prevention of chronic diseases18 (osteoporosis,17 some forms of cancer19), on the other hand, the use of HRT may increase risks of several cancers and cardiovascular diseases.20, 21

- Endometrial cancer: The risk of endometrial cancer seems to be higher when using only estrogens, whereas the use of estrogens/progestagens combination seems to have protective effects.17, 18

- Breast cancer: Since HRT was first introduced, there have been persistent concerns about breast cancer risk. The Million Women Study published in 2003 has created a critical momentum with respect to the HRT safety controversy. About one million women were followed between 1996 and 2001 and information about HRT-use and cancer incidence was generated. The study showed that the incidence of (fatal) breast cancer increases in women who were current users of HRT, whereas the effect was greater for estrogen-progestogen combinations than for other types of HRT.67 Other studies have shown the same relationship between HRT-use and cancer risk.17, 20, 68

- Colon cancer: The use of HRT seems to have a protective effect on the risk of colon cancer, although there is an ongoing controversy about the size and the direction of the association.68, 69

What are the current or likely future factors that impact disease burden?

Reproduction controlNot specifically related to women health, but to demographic developments in general, are the worldwide consequences of the increasing use of contraceptive methods. Fertility rates are decreasing rapidly (see Figure 1),70 and the part of the population which is 65 and older, is also growing rapidly. Therefore, the

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7.4: Cross cutting issues: Womenstructure of the population is changing, which means that the working part of the society is getting smaller, thereby increasing the economic burden on fewer people.71

Figure 1: Fertility rate(Data from World Population Prospects, The 2002 revision database, UN Population division)70

Fertility rate

0

1

2

3

4

5

6

7

1980-1985 1990-1995 2000-2005 2010-2015 2020-2025 2030-2035 2040-2045

Year

Fert

ility

rate World

More developed countriesLess developed countriesLeast developed countries

Even with the extensive possibilities of birth control, it is estimated that nearly one third of all pregnancies are unintended.72-75 It is important to reduce the numbers of unintended pregnancies, thereby reducing the future social, econo-mic and medical burdens.76 Unintended pregnancies are associated with post-ponement of educational or career goals which may lead to a decreased quality of life and financial limitations.77 Several causes are associated with unintended pregnancies. Failure of contraceptive methods is an important factor. Patient-adherence to available birth control technologies remains an important determi-nant of unintended pregnancies.4, 77 In the developing world, there is a special need for controlled family planning. The fertility rate in developing countries is still higher than in other parts of the world and the population is growing every year (see Figure 1). In many of these countries, there is an unmet need for better contraceptive methods, but because of several factors (religious, politics, practical)78 access to these technologies remain cumbersome.76, 79

With respect to control the burden of menstrual disorders, many social and cultural factors contribute. For many women, menstrual disorders have great impact on their quality of live. Next to the uncomfortable monthly experience of extensive blood loss or pain, menstrual disorders could also impact a woman's social, occupational or sex life.80, 81, 82 There are also concerns related to menstrual disorders, masking possible serious underlying diseases (e.g. cancer).42 The impact on the health systems and the economic burden of menstrual disorders is considerably high. By an accurate and safe treatment of the menstrual disorders, both the individual and the economic burden may decline.SubfertilityAs said before, the increasing age at which women decide to have their children has contributed significantly to lower fertility rates.43 This trend of decreasing fertility will continue and will have large impact on society, both in medical, social and economic terms.47

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7.4: Cross cutting issues: WomenThe societal costs of subfertility are high, not only the medical costs for diagnosis and treatment of subfertility,48 but also the costs associated with the increase of the incidence of multiple births due to assisted reproduction techniques.83 Current procedures to cope with subfertility are cumbersome, and require a large range of tests involving both partners; intensive counseling and follow-up surveillance. The burden for both the individual couple and society are high.8

The treatment of female subfertility often starts with drug therapies, depending on the cause of the subfertility.8 In vitro fertilisation (IVF) is for many couples the last opportunity to have children. The success rate of IVF is about 25% per cycle and the technique is associated with side effects, increased risks for complications, and multiple births.10 A Swedish study showed that the incidence of multiple births by in vitro fertilisation is 27%, whereas the incidence in the control group is only 1%.84 Multiple births are associated with an increased morbidity and mortality (e.g. prematurity, low birth-weight, neurological handicaps).83, 85 Therefore, the higher incidence of multiple births causes higher maternal and neonatal costs, especially for the prematurity, low-birth weights and neurological handicaps.83, 85

While the treatment of subfertility with IVF still shows a number of significant limitations, we may anticipate that the demand for IVF will increase, even in countries where IVF is nowadays hardly used.8 The increasing application of current IVF technologies will coincide with considerable impacts on health care systems. If the number of embryos transferred does not decline, the number of multiple births will increase. The impact of the multiple births on both individual, medical and economic burden is considerable.85 Pregnancy and lactation, including birth defectsWith the increasing prevalence of severe conditions in young women in the reproductive age range (e.g. HIV/AIDS, mental disorders, several cancers), the need for medication which is proven to be safe in pregnancy and during lactation is increasing.54 Nowadays, hardly any medication is tested in humans in pregnancy or during lactation, which leads to unproven, off-label drug use in pregnancy or during lactation.86 Use of medication in pregnancy is often based on educated guesses of the physicians who consider the risk-benefit relation for both the mother and the unborn child. Because of the wide variation in prevalence and time-onset of teratogenic effects, elucidation of drug induced birth defects is complex.87, 88

Prenatal testingThe improvement in prenatal screening tests and their extended use lead to much earlier knowledge of birth defects in the unborn child. In many countries, prenatal screening, and possible subsequent abortions in case of serious fetal abnormalities, are offered to a significant part of pregnant women.89,89, 90 The increasing opportunities to detect fetal abnormalities early in pregnancy may lead to less birth defects. It is important to realize that decision-making around prenatal screening, genetic counseling etc., is associated with various ethical and social considerations.89 Whether or not future parents decide to terminate a pregnancy, this is a very difficult decision, often surrounded by intense social, religious and ethical dilemmas.

The economic burden of birth defects is considerable. They are associated with high medical costs and in the case of serious fetal abnormalities, the care of the upgrowing child has a great impact on the health system and is also associated with high costs.91, 92

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Post-reproduction hormonesThe symptoms associated with menopause (e.g. hot flushes, vaginal dryness) cause discomfort for women, and may interfere with a woman's social or sexual life.18, 66 Next to the direct symptoms of menopause, there are also several severe chronic conditions such as osteoporosis and dementia associated with the decrease in estrogens in the menopause.18 The growing and ageing population comes with an increase in the number of menopausal women and it is expected that the burden of postmenopausal disorders will increase.70

The postmenopausal symptoms which are directly associated with the decline in estrogens can be treated with HRT. Therefore, the burden of these symptoms it expected to be limited.66 However, as stated before, next to these 'direct' symptoms, there are also some severe, long-term outcomes of the decline in estrogens are seen.65 These conditions are associated with high individual burden, because of the impact on morbidity and mortality. Next to the individual burden, these conditions have considerable impact on health systems, and are associated with higher costs (direct costs of the necessary treatment and indirect costs of the loss of productivity).65, 93

- Osteoporosis is characterized by an increased fragility of bone mass, which can more easily lead to fractures.65, 66 The effect of HRT on the reduction of risk on fractures is established in a few small randomized trials, but most evidence comes from observational studies.18, 19, 66 Osteoporosis is a major cause of disability in the elderly, associated with high impact on health systems and high costs. By preventing and reducing the decrease in bone fragility in postmenopausal women, considerable costs can be saved and the impact on the health systems can be reduced.94 - Cardiovascular diseases are the leading cause of death among postmenopausal women in Europe and North-America.18 In the past, the use of HRT has been associated with a preventive effect on the development of coronary heart diseases.95-97 During the last years, there were several studies published, which have shown that HRT does not confer cardiac protection.21, 98, 99 With the increase of postmenopausal women, there will also be an increase in the prevalence of cardiovascular diseases. This will have impact on the health systems and brings considerable costs along.18

What is the control strategy?As described above, a wide range of problems is associated with female reproduction and related drug use. Several of these problems are related to one of the specific reproductive issues. Therefore, specific control strategies might be required. Next to these control strategies, one major control strategy, which is suitable for all reproductive issues, will be discussed.General

Improving participation in clinical trialsA large part of the problems associated with female reproduction is caused by a lack of basic knowledge (e.g. about the effects of hormones, changing physiology in pregnancy or during lactation, causes of subfertility). In the past decades, women's health is often neglected and more attention was paid to men's health.100 Women were excluded from clinical trials for a long time. This was partly due to ethical considerations, but industries also argued that research in women comes along with major practical difficulties.101, 102 Since women are improving their societal, economic and educational position, the

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7.4: Cross cutting issues: Womendemand to include more women in clinical trials has increased.100 In the last decade, the policy of the regulatory agencies towards the inclusion of women into clinical trials has changed.103 Both FDA and EMEA developed guidelines which stimulate the participation of women in clinical trials.103, 104 Specific

Reproduction controlPharmaceutical contraceptive methods are nowadays widely used.34 Despite the improved access in the past decades, the World Fertility Report of the UN shows that there are large differences between countries. For example, oral contraceptives were used in 58.6% of German women (1992), whereas in Cameroon only 2.0% were using the pill (1998).34 Therefore, on national and international level attention must be paid to improving the access to contraceptives in both the developed and developing world.79, 105 To do so, it is necessary to make the national governments recognize the importance of birth control. By improving the birth control, not only the individual burden will decline,76 but also the burden on a national level will decrease.

Moreover, there remains a consistent need for improvements in available methods. For certain, current oral contraceptives are very reliable and relatively safe, but there is still room for improvements on the level of drug targets, drug delivery and a better safety profile. As compliance is a major factor for effective contraception, the development of long acting or controlled release formulations should be encouraged. Current societal developments ask for more emphasis on equal responsibility and burden between women and men, including strengthening the search for pills for men. SubfertilityTo treat female subfertility, IVF is used if other therapies are not effective.8 As stated before, IVF is associated with multiple births. In the past, it was widely accepted to transfer 3 or more embryos. The resulting increase in multiple births, coming along with an increase in morbidity and mortality, is one of the unfavorable effects.10, 85 Nowadays, this opinion is changing. The success rates with transferring 2 embryos does not significantly decrease in comparison with the transfer of three or more, whereas the change of multiple births does increase significantly.106 The policy of the embryo-transfer has been changing, and the number of embryos transferred has to be kept to a minimum.107

Another difficulty with IVF are the hormones which are used during the treatment. An important part of the IVF treatment is the use of gonadotropin-releasing hormone (GnRH) agonists or antagonists. The effects of these hormones are not completely clear yet. In short term, no alarming effects are seen, but the long term effects (e.g. puberal development, future fertility of the child) are unknown. To obtain sufficient information on the effects of the hormones of both the mother and the child, long-term follow up is needed. 11, 12

Pregnancy and lactation, including birth defectsThe exclusion of pregnant and lactating women from clinical research has resulted in a gap in knowledge on the effects of drugs, the physiology of pregnancy and pathophysiology of specific conditions in pregnancy (e.g. hypertension or diabetes mellitus),102 or the effects of drug use in lactation.59

This kind of information can hardly be obtained from animal research; research in humans remains necessary. In this kind of research the welfare of the mother and the unborn child must receive the highest attention. Of course, post-

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7.4: Cross cutting issues: Womenmarketing research is not necessary in all drugs, but only in drugs which are going to be used in conditions in women which may become pregnant.32

One widely used method to report possible teratogenic effects is by case reports. Case reports are of high value, because they provide important warning symptoms.32, 108 But individual case reports have some serious disadvantages: there is no control group, there might be barriers to report and the documentation of cases might not be accurate or comprehensive.32

Nowadays, the need for post-marketing (phase IV) studies which can identify possible teratogenic effects in humans and which can improve the knowledge of drug effects in pregnancy is increasing. FDA and EMEA have developed guidelines to stimulate post-marketing research in pregnant women.15, 16 The prevalence of teratogenic side effects differs widely. In the thalidomide-case, it took only four years to detect the causal relationship between drug use and teratogenic effects. But for warfarin, which is associated with a much more subtle pattern of malformations, it took more than 20 years to identify teratogenic effects.109 Because of this wide variation in prevalence, a large number of women need to be included and as much information as possible should be collected. To study rare teratogenic effects, large data banks which include information on different issues (e.g. drug exposure, illness of the mother before/during pregnancy, epidemiology of congenital abnormalities) from large numbers of women and their children, during a long period of time, are needed. 13

Prevention of birth defectsThe use of preconceptional folic acid is proven to be effective in reducing the risk of neural tube defects.110 It is strongly advised to use folic acid before conception, because the neural tube closure occurs between days 22 and 28 after conception, a period when many women are not aware of their pregnancy. Unless various public awareness campaigns, less than 50% of the women uses folic acid before conception.14 By stimulating the use of preconceptional folic acid, the risk of neural tube defects can be reduced significantly. Although national governments have set up campaigns to promote the preconceptional folic acid, the effects are minimal. Accordingly, the enrichment of food with adequate amounts of folic acid might be considered. In several countries, including the U.S.A. and Chile, folic acid is added. A recent study in Chile showed a decrease in neural tube defects of about 40%.111 In the U.S.A., a reduction of 19% in neural tube defects is seen.112 Post-reproduction hormonesIn the past, all women were treated in the same way. Since the relation between HRT-use and its several adverse effects (e.g. cancers, cardiovascular diseases) has been proven in several studies,20, 69, 99 the discussion about HRT is still ongoing. In December 2003, EMEA published a public statement about HRT.22

Considering the recent publications, they recommend that HRT as a therapy for the treatment of the direct symptoms of menopause is the first choice (using a minimal dose for a short duration). To prevent/treat osteoporosis, HRT is not the first choice; in women without direct symptoms of the menopause HRT is not recommended at all.

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Why does the disease burden persist?

General problems

Lack of knowledgeIn the past, women's health was not considered as important as men's health. This was mainly due to the basic inequality of women in society.100 The access and quality of health care for women was often poor. Since the emancipation of women in many countries since the 1960's, the socio-economic position of women has improved greatly. Nowadays, in many societies, men and women are equal, and this comes along with improving health care for women.100

Despite awareness of the importance of ethical considerations in medical research, in 1961 the thalidomide disaster made the world aware of the risks and difficulties involved in medical research in women.1 Thalidomide entered the market in the late 1950's. It was prescribed to pregnant women to combat the symptoms of morning sickness. In the early 60's, the first case reports of newborn children with limb malformations were published. It was found that thalidomide used in the first trimester of pregnancy could cause limb malformations in children.1 This disaster resulted in the exclusion of women from clinical trials, in order to prevent such disasters in the future.113 This policy is comprehensible with regard to the events in that period, but it resulted also in unwanted effects.

The exclusion of women from clinical research caused a lack of knowledge of the specific issues related to women's health. It was seen that drug effects in women may differ from the effects in men (e.g. paracetamol, propanolol).31, 114 In addition, many medications used by women are prescribed for a long time, for example oral contraceptives and psychotropics. There is still little known about the effects of these therapies in long term use (>10 years). Another important issue is the changing of pharmacokinetics and dynamics during pregnancy.115

Therefore, it may be necessary to prescribe adapted doses or doses regimes in pregnancy, in order to obtain effective therapy or prevent harm to the unborn child. In this area, there is still a lack of research, mainly due to ethical considerations.102

In the last decade, the policy towards women and clinical research has been changing.116 Policy makers started to realize that the differences between men and women were not negligible. To achieve a complete picture of the efficacy and safety of a new drug, it is necessary to include the full spectrum of the population in a study.116

Specific problems

Reproduction controlIn the 1960's, the first oral contraceptives were introduced. In the beginning, the only approved indication was the treatment of gynaecologic disorders. Despite this, everyone knew that the drug could be used as contraception, but because of the expected resistance of different parties (religion, women themselves, men), the industry hesitated to apply for approval for the contraceptive indication,117 unless the number of women which started using 'the pill' was growing rapidly.117

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The first OC contained relatively high doses of hormones, and this has always been a source for concern about adverse effects. Cardiovascular effects (thrombothic events, high blood pressure) have been another major concern. In the following decades, the doses of hormones have declined. The discussion about the risk of thrombosis is still ongoing, especially by the introduction of new oral contraceptives.117 In general, the safety of OC is proven, and even non-contraceptive benefits of the use of OC are studied.117

SubfertilitySince the 1960's, the economic and societal status of women has improved, and contraceptive methods became available. These factors made controlled family planning possible, and women were able to plan when and how many children they wanted. The age of which women decided to bear children, increased. By the increasing age of women getting children, the rates of subfertility increase.43 As described above, this is due to the ageing of the female reproductive system, thereby decreasing both the quantity and quality of the oocyte/follicle pool.46

Ageing is also associated with an increase in meiotic non-disjunction, leading to early pregnancy loss.46

Next to problems associated with increasing age, a considerable part (estimated 30%) of subfertility is due to unknown causes.118 The treatment of this subfertility is much more difficult and mainly all available treatments are tried. In the last decades, the burden of subfertility has increased. Nowadays, being childless is running against the norm and therefore subfertility is associated with a high burden.47, 48

IVF is used if the other treatments have not been successful,118 but it has some important disadvantages.

In the first part of an IVF-treatment the patient has to use different hormones (e.g. gonadotropin-releasing hormone (GnRH) agonists or antagonists). The use of these hormones raised questions about the safety of these medications for both the mother and the child. The available information is still limited and no information is yet available about the effects on pubertal development and further fertility of the children.119

Continued assessment of the long-term effects on both the mother and the child is recommended.11, 12

Multiple births are also a disadvantage of IVF-treatment. As discussed before, the incidence of multiple births by IVF is considerable higher in comparison with the incidence by unassisted births.84 These multiple births are associated with increased morbidity and mortality.83, 85

Pregnancy and lactation, including birth defectsThe general concern of clinical research in pregnant women is the possibility of harming the mother and the unborn child by the unknown effects of new drugs.101 The thalidomide disaster in the early 1960's showed that the effects could be very serious. As a result, pregnant women are excluded from clinical trials for a long time. If a participating woman becomes pregnant during a clinical trial, she is excluded.32, 104

Only animal studies (usually conducted in mice, rats and rabbits) are 7.4-16


been carried out to study the possible effects of new drugs on development and reproduction.86

There is not a uniform research method for estimating risks-benefits of drug-use in pregnancy and lactation. Several different classification systems are used. Well-known are the Swedish system (implemented in 1978), and the system introduced by the U.S.A. Food and Drug Administration (FDA) in 1979.120 Both systems use the categories A to D to qualify the risks of drugs. The FDA system also uses an X category. The definitions for the different categories differ widely, which makes it difficult to compare the outcomes.121-123

Post-reproduction hormonesIn 1946, the first study about a possible relation between HRT and an increased risk on endometrial cancer, was published.124 Several decades later, in 1995, a study about a positive relation between HRT and breast cancer was published.125 This study received a lot of attention from health professionals and the public. Although the results of this study were critical, HRT was still prescribed, but the study highly stimulated the discussion about the safety of HRT.126 In 1998, the discussion about the cardiac protection of HRT started following a study in JAMA, which showed that there is no cardiac protection of HRT seen in the population of the trial.98 The most recent and largest crisis is caused by the premature termination of the Women's Health Initiative (WHI) (the largest, randomized clinical trial on the health effects on several parameters) in July 2002, because of the finding of an increased overall risk associated with the use of HRT.127 Since the introduction of HRT for postmenopausal disorders, there is a discussion about the risk-benefits balance. Aside from several proved adverse effects, there is still a large number of women using HRT worldwide.18, 19

What can be learnt from past/current research into pharmaceutical interventions for these conditions?

Stimulating research in womenThe thalidomide disaster showed that women are a vulnerable group. This resulted in a policy of excluding women from clinical trials.113

Despite the exclusion of women from clinical trials for many years, the opinion is currently changing. Policy makers have become more aware of the importance of studying new drugs in representative samples of the population, including women, but also elderly and children.116

As described in the chapter 7.3 "Pharmaceuticals and Children", the participation of children in clinical trials is also negligible. These reasons include practical problems e.g. different pharmacokinetic, and -dynamic properties.128 In children, also ethical considerations play an important role in the decision of the exclusion of clinical research.129 In order to stimulate the pharmaceutical industries to perform research in children, in the U.S.A. the Best Pharmaceuticals For Children Act (BPCA) (2002) passed. In addition to the obligations this law contains, there is also a

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prolonged market exclusivity of 6 months for industries who get a license for paediatric use.128

To stimulate research in women, the case of research in children can be used as an example. Development of a guidance or law like the BPCA will likely stimulate pharmaceutical industry to do more research in women, in a practical and ethical acceptable way.Post-marketing research in pregnant womenIn women there is a special need for large case control studies to study possible teratogenic drug effects.13 Databases which contain information about large numbers of women are needed. By using this study-design, even rare birth defects can be studied An good example of this is EUROCAT. EUROCAT is established in 1979 and collects a wide range of data in 41 regions in Europe, thereby covering about 25% of the European birth population.130

In the last years, EMEA and FDA recognized the importance of monitoring drug effects in pregnant women. They both developed guide-lines, which recommend pregnancy exposure registries to gain knowledge about drug effects in pregnancy in a safe and effective way.15,

16 Although these guidelines do not include obligations, it is a good step forward to improve the knowledge of drug effects in pregnancy.

What is the current "pipeline" of products that are to be used for this particular condition?

General

Research in women Both FDA and EMEA have started to commit pharmaceutical companies to involve reasonable numbers of women in clinical trials.104, 131 Research in pregnant and lactating women is still not required, but the need for post-marketing prospective and observational research is increasing.32 Specific issues

Hormone therapiesIn the past years, there is a trend in lowering the doses of hormones used for the treatment of various female conditions. The assumption is made that lower doses will have the same beneficial effect with less adverse effects. In the following years, this assumption will need further research and proof.117, 132 Much attention also is paid to the development of compounds which have estrogenic effects (e.g. synthetic steroids like tibolone). These compounds are expected not to have the side effects, whereas the beneficial effects are the same.5 Also, other routes of administration are under development. By using other administration routes, it might be possible to lower the dose and thereby reduce the adverse effects and improve the compliance.133, 134

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Pregnancy and lactation, including birth defectsThere is a need for developing new drugs for specific conditions in women together with a need for improving research in women. Especially for the most vulnerable groups of women; the pregnant and lactating women, there is a need for well structured, extensive post-marketing research in the special conditions which occur in pregnancy and during lactation.32 Several guidelines for drug use during pregnancy have been developed, including one by the FDA in 2002,15 whereas the EMEA recently published a Note for Guidance which is expected to be approved at the end of 2004.16 These new guidelines of EMEA and FDA are a very positive development in this area, but we cannot look into the future to see how these guidelines will work out.

Besides development of safe drugs for pregnant women and post-marketing research in the effects of existing drugs on the unborn child, research to improve the knowledge of doses and administration regimens in pregnancy and during lactation. It is seen that the pharmacokinetics in pregnancy (e.g. absorption, distribution, metabolism) change and therefore specific doses are required.115, 135

What are the opportunities for research into new pharmaceutical interventions including delivery methods? Reproduction and female hormones differ women from men. These features also make women a more vulnerable group in comparison to men. As stated before, women use more medication in comparison to men. It is necessary to have accurate knowledge but there is still a lack of knowledge about the specific female issues. Extensive research of the underlying principles of the female issues is required.25, 115 Opportunities for research concerning contraceptives lay in the field of looking for new targets for intervention,4 new classes of chemical compounds and new drug delivery systems.6, 7 Little is known about the long term effects of the use of hormones (e.g. contraceptives, post reproduction, IVF), the causes of subfertility or pharmacodynamics changes in pregnancy and lactation.

The development of safe medications for use in pregnancy and lactation is of significant interest. Combining an accurate treatment for the mother and protection of the unborn child is necessary. Purely observational pharmacodynamic and pharmacokinetic research can be performed in pregnant women who are exposed to drugs during pregnancy. The results of these studies can be used in estimating optimal dosing schedules and evaluate safety issues for pregnant women. If all data about (drug) exposures during pregnancy and lactation are collected in data bases, this may produce a large pool of knowledge which can be used for making therapeutic strategies. There are also opportunities in performing meta-analyses on all the studies that include a small number of women. Beside studies that investigate the risk-benefit of all kinds of drugs used during pregnancy, one can also investigate the possibility of developing drugs that are safe for the fetus or ideally do not cross the placenta.

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What are the gaps between current research and potential research issues which could make a difference, are affordable and could be carried out in a) 5 years or b) in the longer term? For which of these gaps are there opportunities for pharmaceutical research?

Research in womenThe main area which can be supported by government, is basic research in the field of reproductive issues. There is still a lack of knowledge of the basic principles of the female reproduction and all surrounding issues.100

If there is accurate understanding of these principles of reproduction, it will be easier to understand the pathophysiology of conditions, which occur specifically among women. Traditionally, this field is covered by academic centers, but increasingly we see translational collaboration with industry and other private institutions.

As discussed in this paper, the exclusion of the (pregnant) women in clinical trials leads to a lack of knowledge on the use of drugs in women. Although several studies showed differences in drug effects between men and women, there is little information about issues like doses and administration regimes.31 This may lead to inaccurate treatment of (pregnant) women, resulting in increasing morbidity and higher costs. An accurate treatment might be possible if the information is available. By improving the participation of (pregnant) women in research, these problems might be solved.101

Because of the risks, pharmaceutical industry is far from eager to financially support studies which involve pregnant women and tend to advise negatively in using their drug during lactation. Recently, both FDA and EMEA developed guidelines to improve the post-marketing research in pregnant women.15, 16 It is expected that these guidelines will work out good, but only the future will tell us.

To improve the participation of (pregnant) women in (long-term) research, close cooperation between pharmaceutical industry, regulatory agencies and academic centers is warranted.32 Together, it is possible to carry out clinical research in an ethical way, and also practical problems can be solved more easily. DosingAfter marketing of a new drug, often changes in doses are seen.136 It might be necessary to change doses used by women, in comparison with men. Several studies have shown that there might be differences in drug effects between men and women.31, 114 Also, in pregnancy, different drug doses may be required due to the change in phamracokinetics,115, 137

ConclusionResearch in women has been a neglected area since the thalidomide-disaster in the 1960s.92 In the last decade, more and more attention is

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paid to women's health and the specific issues we have captured in this section under the heading of 'reproduction'.78

Nowadays, the participation of women in clinical trials is being improved. Despite this, there is still a lack of knowledge of the specific female issues; little is known about the effects of hormones, causes of subfertility or the pharmacokinetic changes in pregnancy or during lactation. There is an urgent need to improve the basic and translational research in this field. The improvement of basic knowledge is an area in which support of national governments or international institutions, like the European Union, can make a difference.

Next to improving the basic research, more attention must be paid to the effects of long-term use of hormone therapies and to the effects of drugs used during pregnancy and lactation. Large databases and controlled prospective research should be set up to monitor the drug effects during pregnancy, but also during the child's life (development, both physical and mental).4

References

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format elderly/pediatrics/women - who...

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