Intended for healthcare professionals

Education And Debate

Synthesising licensing data to assess drug safety

BMJ 2004; 328 doi: (Published 26 February 2004) Cite this as: BMJ 2004;328:518
  1. Klim McPherson, visiting professor in public health epidemiology (,
  2. Elina Hemminki, research professor2
  1. 1Nuffield Department of Obstetrics and Gynaecology, Research Institute, Churchill Hospital, Oxford OX3 7LJ
  2. 2National Research and Development Centre for Welfare and Health, Health and Social Services, PO Box 220, 00531, Helsinki, Finland
  1. Correspondence to: K McPherson

    Small randomised trials conducted for licensing purposes should record data on adverse results and be made public

    The safety of drugs is important. For full information we need to assess not only the immediate effects but also unexpected longer term effects on serious disease like coronary heart disease or cancer, especially for drugs that will be widely used. Reliably assessing the safety of drugs, however, is fraught with problems such as rare events, long follow up, strong vested interests, and biased reporting. The example of hormone replacement therapy and risk of cardiovascular disease shows some of the problems and presents useful lessons.

    Lessons from hormone replacement therapy

    Observational studies and trials on intermediate cardiovascular variables indicated that oestrogen and progesterone supplements might protect menopausal women from cardiovascular disease as well as menopausal symptoms. The evidence was convincing. For example, the nurses' study of 120 000 women followed for 30 years estimated the adjusted relative risk for coronary heart disease at 0.47 (95% confidence interval 0.32 0.69) for women currently taking hormone replacement therapy compared with never users.1 This was a common finding in observational studies and understandably led to the strong belief that hormone replacement therapy would be protective. Since the drugs also benefited lipid profiles,2 the argument seemed invincible.

    If the results were correct, the risk:benefit ratio of hormone replacement therapy was unambiguously positive.3 Hormone replacement therapy would be beneficial even for asymptomatic women, notwithstanding possible detrimental effects such as an increased risk of breast cancer. These data affected marketing and prescribing; prevention of coronary heart disease became an added indication among symptomatic women, although the licensed indications were for menopausal symptoms and the prevention of osteoporosis.

    Embedded Image

    Hormone replacement patch: better use should have been made of existing evidence on the risks of HRT

    Credit: AJ PHOTO/SPL

    The enthusiasm, however, was …

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