Guidelines set by The National Committee for Medical Research Ethics in Norway, 2001-09-01
It has become increasingly clear that the two genders are different in respect of many biological variables. This means that the manifestations and the progress of diseases may differ according to gender. Correspondingly, any therapeutic measures will have to take account of such differences. Consequently, both genders must be included in medical research to enable results to be assessed specifically for men and for women.
Previously, women have often been excluded as medical research subjects, partly because female cyclicity may confuse results and partly due to the risk of damaging the foetus should the subject be or become pregnant during the trial. The Thalidomide tragedy of the fifties and sixties, in which many thousands of children were born with severe malformations, led the American authorities (FDA) to introduce guidelines excluding fertile women from clinical trials on new drugs. Precautions of this kind meant that any knowledge educed about the efficacy of drugs in this period was largely based on men.
The problem of the lack of knowledge about the efficacy of drugs on fertile and pregnant women was gradually recognised, as was the lack of gender-specific analyses in the development of biological and medical knowledge.
In consequence, in 1994 the National Institutes of Health (NIH) in the USA published its "Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research".
These guidelines recommend that women be included in all biomedical and behavioural research supported by the NIH. Similarly, a Swedish report on equal care "Jämställd vård" (SOU 1996:3) recommends consideration of gender distribution in all applications to Swedish research councils. It is also recommended that the ethical committees ensure that the researcher has taken account of gender distribution in the study population.
NEM, the National Committee for Medical Research Ethics in Norway, was asked by the Ministry of Health and Social Affairs to follow up the official report NOU 1999:13 on women’s health in Norway. This report points out that insufficient attention is paid to gender as a variable in medical research. With this in view NEM has drawn up guidelines for the inclusion of both genders in medical research, with particular emphasis on the inclusion of women of fertile age and pregnant women, and the need for gender-specific analyses.
I Inclusion of both genders
1. Both genders must be included in all medical research, including the testing of drugs, clinical epidemiological research, clinical trials, case-control studies, cohort studies, health service research, studies of current therapy practice and the testing of medical equipment.
2. There are many indications of the existence of gender sensitive variables in biology, identity, symbols and structure. Research that does not take account of this is incomplete, and therefore not good enough to elicit new knowledge. All projects must therefore give consideration to the inclusion of both genders. Protocols shall consider and evaluate possible gender-sensitive differences. To obtain results of equal relevance to both genders, it is not enough just to include both men and women. It is necessary to include gender-sensitive variables and, where possible, carry out analyses of gender differences. Studies must be designed to allow for gender-specific analysis.
3. The requirement for the inclusion of both genders in all research does not necessarily apply to each individual research project. Where one gender is excluded from the study, the decision must be justified on both ethical and scientific grounds. It may, for example, be deemed justifiable in research that is not relevant to both genders (such as the testing of drugs for prostate cancer).
II Inclusion of women of fertile age
1. Fertile age is not acceptable as the only reason for exclusion from clinical trials. Women must be informed when inclusion in the trial is contingent on their taking precautions to avoid pregnancy.
2. The protocols of trials that include women who may become pregnant shall specify the procedures to be followed if a woman becomes pregnant during the trial.
If a woman who has been included in a clinical study involving risk of foetal damage becomes pregnant, the testing of the drug shall be discontinued and information provided on the possible risk of foetal damage.
III Inclusion of pregnant women
1. Pregnant women shall always be included in studies relating to pregnancy and should be included in other types of medical research that are relevant to the situation of pregnant women.
2. The interests of the pregnant woman and her foetus shall always take priority over research considerations. Studies must be discontinued immediately where the interests of the woman or the foetus dictate the appropriateness of following other procedures than those indicated by the study protocol.
3. In the case of drugs for use by women of fertile age, separate studies should be carried out on pregnant women, at least on severe conditions requiring treatment during pregnancy, ensuring that the knowledge necessary for such treatment is obtained. Diabetes, asthma, epilepsy, mental illnesses are examples of such severe conditions.
4. The following conditions apply to the inclusion of pregnant women:
a) Studies of pregnant women shall offer potential therapeutic benefit to women or foetuses.
b) If molecular structure, animal experiment studies or similar indicate that a drug might be teratogenic, pregnant women shall as a rule not be included in trials. Inclusion may, however, be considered despite preclinical/pharmacological/clinical indications of possible teratogenicity if the benefit is deemed to be greater than the risk for the woman and/or the foetus.
c) When pregnant women are included in a study, the project leader has a duty to take all steps possible to exclude the risk of foetal damage. This duty means that the project leader must have knowledge of relevant documentation from research and clinical practice and of potential foetal damage associated with use of the method or treatment in question. Adequate preclinical and/or clinical documentation on non-pregnant women and adequate clinical experience of other patient groups are prerequisites for conducting studies on pregnant women.
The Norwegian Medicines Agency shall determine whether the documentation and clinical experience are adequate for each individual study.
d) Any drug studied should have marketing authorisation in Norway and/or an EEA member state before the inclusion of pregnant women.
e) All intervention studies are subject to a follow-up requirement. The woman shall be followed up during pregnancy and the child shall be followed up after birth.
f) The decision to participate in the study may only be taken by the woman herself.
IV Administration of the guidelines
1. All medical research projects involving humans shall be submitted for evaluation to the regional committees for medical research ethics.
2. The regional committees for medical research ethics administer the guidelines for the inclusion of women in medical research. This entails responsibility for ensuring that the guidelines are known, respected and complied with.
3. When submitting a project for evaluation by a regional ethics committee, the project leader shall include an account of the gender perspective, including knowledge of any gender-sensitive variables and differences, and also of any ongoing studies addressing such issues. The gender perspective shall also be addressed in the project description. The project leader must furthermore evaluate and describe the consequences of pregnancy in the subjects and the follow-up that is planned.
4. The research ethics committees are responsible for keeping abreast of developments in respect of the inclusion of both genders in medical research and for revising these guidelines as required.