Exclusion from clinical trials harming women's health
Women are still largely under-represented in clinical trials in Europe, and there is a growing body of evidence showing that this is having a detrimental effect upon their healthcare. For a long time, clinical studies of diseases and conditions affecting both men and women were carried out almost entirely on men. One reason for this is that it was assumed that differences in the health of men and women were largely restricted to their reproductive systems. The other main reason for excluding women from clinical trials was the entirely laudable desire to protect unborn children. However, in the late 1980s and early 1990s, researchers began to realise that in fact there were many differences between men and women which caused a wide range of diseases to run differently in the sexes, or the body to respond to drugs in a different way. Some of these differences can be attributed to the social differences between men and women; as they often do different jobs and perform different tasks, they are exposed to different disease risk factors. Other differences are biological, resulting from genetic, hormonal and metabolic differences. One example of a disease which behaves differently in men and women is Lyme disease, which is transmitted by ticks and if not treated quickly can have severe consequences on the central nervous system. A doctor in Sweden noticed that women over 40 were being diagnosed with the disease later than men. One of the most important signs of the disease is a red ring on the skin, but after the menopause, women did not show this classical symptom, displaying instead a red spot. Immunological tests revealed that the reaction to infection with Lyme disease is related to hormones. Medicines can also behave differently in men and women. The drug digoxin was designed to help heart failure patients by helping their hearts pump better. The trials were carried out on a group which was 80% male, and the results showed that although the drug did not prolong life, patients taking the drug had fewer hospitalisations. On the basis of this, guidelines in both Europe and the US recommended that the drug be given to improve quality of life. Some years later, researchers carried out a post-hoc analysis which looked at the results separately for men and women. They found that while men taking digoxin did better than those on a placebo, women taking digoxin died earlier than those taking a placebo. However, because they made up such a small proportion of the initial study group, this effect had not been picked up. This difference could be due to the fact that while men tend to develop heart disease after a heart attack, heart disease in women is more often brought on by diabetes or hypertension, and these conditions may affect the heart in different ways. These examples show how women's health is being seriously compromised by their ongoing exclusion from clinical trials. Dr Clara Moerman of the University of Amsterdam believes the issue is one of justice. 'Everyone in society has the right to receive good quality healthcare,' she says emphatically. 'You have to have knowledge to do this and you have to do research which takes this into account.' She also points out that including both sexes in research is good scientific practice. 'If you exclude women, this means you don't generate knowledge on them,' she notes. 'If there are differences, these should be interesting for researchers.' And while it is perfectly legitimate to want to protect the unborn child, Dr Moerman points that not all women of childbearing age are planning to get pregnant, and furthermore those running trials can ask female participants to use birth control for the duration of the study. 'This is a barrier which can usually be overcome!' she says. In the US, legislation has been in place since 1993 which requires clinical studies funded by the National Institutes of Health to include men and women as well as people from ethnic minorities in their study populations. A year ago the rules were broadened to include all NIH-funded health research. Effectively these rules enshrine the right of every citizen to participate in research and share in the benefits and risks it brings. In the EU, the Commission works to promote gender balance in research on the one hand, but questions of ethics often refer back to the Helsinki Declaration, which focuses on protecting people taking part in research. 'What is missing is the issue of justice and fairness to all people in society,' said Dr Joke Haafkens, also of the University of Amsterdam. Dr Moerman and Dr Haafkens recently led an EU-funded study investigating whether Research Ethics Committees (RECs) in five EU Member States paid attention to gender equality when evaluating trial protocols. They found that none of the committees studied had formal requirements to include experts on sex and gender issues on their panels. 'An evaluation of equitable inclusion of women and men in studies is required neither in regulations nor in tools supporting ethical assessment procedures,' they write. 'This is also true for gender-specific analysis of risks and benefits associated with study participation.' However, it is not enough to just include women in research. As the digoxin example shows, scientists also need to present their results in such a way that differences between men and women can be analysed. In a recent paper, Spanish researchers Maria Teresa Ruiz Cantero and Maria Angeles Pardo point out that trials of the osteoarthritis drug Vioxx included more women than men. However, 80% of the trials did not describe the efficacy of the drug by sex, and only one study reported side effects by sex. 'In this respect, it is noteworthy that 78% of the side effects reported to Vioxx in Spain occurred in women,' they write. This is also a problem in America; a recent study found that three quarters of clinical cardiovascular trials published in the top journals in the field failed to provide a sex-based analysis of their results, although trials funded by the NIH were more likely to provide this information than other trials. 'Heart disease is the number one threat to a woman's health and we need to be able to tell women whether the diagnostic tests we order are accurate and how treatments will effect them, but today we don't have enough data specific to women,' says Sharonne Hayes of Mayo Clinic's Women Heart Clinic. Solving this problem requires action from many stakeholders, including the EU. 'In our opinion, the EU Directive on clinical research should also include provisions to enhance gender equality in ethical review of clinical research - both by encouraging equitable representation of men and women in RECs and by demanding that protocol evaluation should be more sensitive to gender-specific health needs and other possible sex and gender-specific differences,' Moerman and Haafkens write in their paper. They also recommend that DG Research initiate a debate among stakeholders 'against the background of the need for equitable inclusion and equitable distribution of benefits and risks associated with study participation.' Meanwhile the Spanish paper calls for greater input from the European Medicines Agency (EMEA), which, it states, has not developed gender specific guidelines or strategies. 'The EMEA should provide a regulatory clout to ensure safety and effectiveness for the women who use the drugs,' they write. Action is also need from journals. 'A change by the NIH and other sources of funding to encourage sex-specific research is just the beginning,' says Dr Mary Norine Walsh of The Care Group in Indianapolis, one of the authors of the American heart study. 'More sustained change will occur when those planning large clinical trials include enrolment of enough women to allow for pre-specified end-point analysis, and when journal editors and reviewers uniformly require such analysis.' Doctors also need to be sensitised to these issues, and this should start in medical school. According to Dr Haafkens, Dutch medical schools have recently started to place more emphasis on these issues in their courses. Patients also have a role to play. 'When a physician recommends a certain treatment or test to a woman, she should ask, 'Were women included in the research?',' says Dr Hayes. 'When I tell a patient, 'You need this medication or test or procedure,' I should be able to say, 'This has been tested in women.' In many cases now, I cannot say that. But I think those questions from women can drive our behaviour and push us to make sure future research is more applicable to them.'