Pharmacoepidemiology is the study of the use and effects of drugs in large numbers of people. Some of the principles of pharmacoepidemiology are used to gain further insight into the efficacy, and especially the safety, of new drugs once they have passed from the limited exposure in controlled therapeutic pre-
31 For example, drug therapy for high blood pressure carries risks, but the risks of the disease vary enormously according to severity of disease: 'Depending on the initial absolute risk, the benefits of lowering blood pressure range from preventing one cardiovascular event a year for about every 20 people treated to preventing one event for about every 20 people treated. The level of risk at which treatment should be started is debatable' (Jackson R et al 1993 Management of raised blood pressure in New Zealand: a discussion document. British Medical Journal 307:107).
registration trials to the looser conditions of their use in the community. These (Phase 4) trials are not experimental (as is the randomised trial where entry and allocation of treatment are strictly controlled). They are observational in that the groups to be compared have been assembled from subjects who are, or who are not (the controls), taking the treatment in the ordinary way of medical care. Observational studies come into their own when sufficiently large randomised trials are logistically and financially impracticable. The following approaches are used.
Observational cohort32 studies. Patients receiving the drug are followed up to determine the outcomes (therapeutic or adverse). This is usually forward-looking (prospective) research. Prescription event monitoring (below) is an example, and there is an increasing tendency to recognise that most new drugs should be monitored in this way when prescribing becomes general. Major differences include selection of an appropriate control group, the need for large numbers of subjects and for prolonged surveillance. This sort of study is scientifically inferior to the experimental cohort study (randomised controlled trial) and is cumbersome for research on drugs. Happily, clever epidemiologists have devised a partial alternative, the case-control study.
Case-control studies. This reverses the direction of scientific logic from forward-looking, 'what happens next' (prospective) to a backward-looking, 'what has happened in the past' (retrospective)33 investigation. The investigator assembles a group of patients who have the condition it is desired to investigate, e.g. women who have had an episode of thromboembolism. A control group of women who have not had an episode of thromboembolism is then assembled, e.g. similar age, parity and smoking habits, from hospital admissions for other reasons, or primary care records. A complete drug history is taken from each group, i.e. the two groups are 'followed up' backwards to determine the proportion
32 Used here for a group of people having a common attribute, e.g. they have all taken the same drug.
33 For this reason Feinstein has named these trohoc (cohort spelled backwards) studies.
in each group that has taken the suspect agent, in this case the oral contraceptive pill.
To investigate the question of thromboembolism and the combined oestrogen-progestogen contraceptive pill by means of an observational cohort study required enormous numbers of subjects34 (the adverse effect is, happily, uncommon) followed over years. An investigation into cancer and the contraceptive pill by an observational cohort would require follow-up for 10-15 years. But a case-control study can be done quickly; it has the advantage that it begins with a much smaller number of cases (hundreds) of disease; though it has the disadvantage that it follows up subjects backwards and there is always suspicion of the intrusion of unknown and so unavoidable biases in selection of both patients and controls. Here again, independent repetition of the studies, if the results are the same, greatly enhances confidence in the outcome.
A major disadvantage of the case-control study is that it requires a definite hypothesis or suspicion of causality. A cohort study on the other hand does not; subjects can be followed 'to see what happens' (event recording). Case-control studies do not prove causation.35 They reveal associations and it is up to investigators and critical readers to decide what is the most plausible explanation.
SURVEILLANCE SYSTEMS: PHARMACOVIGILANCE
When a drug reaches the market, a good deal is known about its therapeutic activity but rather less about its safety when used in large numbers of patients with a variety of diseases, for which they are taking other drugs. The term pharmacovigilance refers to the process of identifying and responding to issues of drug safety through the detection in the
34 The Royal College of General Practitioners (UK) recruited 23 000 women takers of the pill and 23 000 controls in 1968 and issued a report in 1973. It found an approximate doubled incidence of venous thrombosis in combined-pill takers (the dose of oestrogen has been reduced since this study).
35 Experimental cohort studies (randomised controlled trials)
are on firmer ground with regard to causation. In the experimental cohort study there should be only one systematic difference between the groups (i.e. the treatment being studied). In case-control studies the groups may differ systematically in several ways.
community of drug effects, usually adverse. Over a number of years increasingly sophisticated systems have been developed to provide surveillance of drugs in the postmarketing phase. For understandable reasons, they are strongly supported by governments. The position has been put thus:
Four kinds of logic can be applied to drug safety monitoring:
• to attempt to follow a complete cohort of (new) drug users for as long as it is deemed necessary to have adequate information.
• to perform special studies in areas which may be predicted to give useful information
• to try to gain experience from regular reporting of suspected adverse drug reactions from health professionals during the regular clinical use of the drug
• to examine disease trends for drug-related causality.36
Drug safety surveillance relies heavily on the techniques of pharmacoepidemiology which include:
Voluntary reporting. Doctors, nurses and pharmacists are supplied with cards on which to record suspected adverse reaction to drugs. In the UK, this is called the 'Yellow Card' system and the Committee on Safety of Medicines collates the results and advises the government's Medicines Control Agency. It is recommended that for:
• newer drugs: all suspected reactions should be reported, i.e. any adverse or any unexpected event, however minor, which could conceivably be attributed to the drug
• established drugs: all serious suspected reactions should be reported, even if the effect is well recognised.
Inevitably the system depends on the intuitions and willingness of those called on to respond. Surveys suggest that not more than 10% of serious reactions are reported. Voluntary reporting is effective for identifying reactions that develop shortly after starting therapy, i.e. at providing early warnings of drug toxicity. Thus it is the first line in post-
36 Edwards I R 1998 A prespective on drug safety. In: Edwards IR (ed) Drug Safety. Adis International, Auckland, p xii.
marketing surveillance. Reporting is particularly low, however, for reactions with long latency, such as tardive dyskinesia from chronic neuroleptic use. As the system has no limit of quantitative sensitivity it may detect the rarest events, e.g. those with an incidence of 1:5000-1:10 000. Voluntary systems are, however, unreliable for estimating the incidence of adverse reactions as this requires both a high rate of reporting (the numerator) and a knowledge of the rate of drug usage (the denominator).
Prescription event monitoring. This is a form of observational cohort study. Prescriptions for a drug (say, 20 000) are collected (in the UK this is made practicable by the existence of a National Health Service in which prescriptions are sent to a single central authority for pricing and payment of the pharmacist). The prescriber is sent a questionnaire and asked to report all events that have occurred (not only suspected adverse reactions) without a judgement about causality. Thus 'a broken leg is an event. If more fractures were associated with this drug they could have been due to hypotension, CNS effects or metabolic disease'.37 By linking general practice and hospital records and death certificates, both prospective and retrospective studies can be done and unsuspected effects can be detected. Prescription event monitoring can be used routinely on newly licenced drugs, especially those likely to be widely prescribed in general practice, and it can also be implemented quickly in response to a suspicion raised, e.g. by spontaneous reports.
Medical record linkage allows computer correlation in a population of life and health events (birth, marriage, death, hospital admission) with history of drug use. It is being developed as far as resources permit. It includes prescription event monitoring (above). The largest UK medical record linkage is the General Practitioner Research Data Base at the Medicines Control Agency.
Population statistics, e.g. birth defect registers and cancer registers. These are insensitive unless a drug-induced event is highly remarkable or very frequent.
37 Inman W H W et al 1986 Prescription-event monitoring. In:
Inman WHW (ed) Monitoring for drug safety, 2nd edn. MTP, Lancaster, p 217.
If suspicions are aroused then case-control and observational cohort studies will be initiated.
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