Hypothesis-Generating Methods

HYPOTHESIS-GENERATING METHODS

Spontaneous ADR Reporting

Doctors (in some countries, other healthcare professionals and patients as well) are provided with forms upon which they can notify a central authority of any suspected ADRs that they detect. In the United King-dom, the ‘yellow card’ has been used for this purpose since 1964. Similar forms are provided in the FP10 prescriptions pads, the British National Formulary and other sources. In the United States, the MedWatch form is used and is made broadly available to health professionals to encourage reporting.

The great strength of spontaneous reporting is that it operates for all drugs throughout the whole of their lifetime; it is the only affordable method of detecting really rare ADRs. The data may represent merely the suspicions of the reporter, but they provide the opinion of a doctor or health professional attending a real-life patient. The main weaknesses are that there is gross under-reporting, and the data provide a ‘numerator’ (the number of reports of each suspected reaction) only. Nevertheless, the scheme is invaluable, and it is essential that health professionals should be provided with the means of reporting their suspicions.

Spontaneous reporting has led to the identifica-tion and verification of many unexpected and seri-ous ADRs. These findings have resulted in many marketed drugs being withdrawn or additional infor-mation being provided to guide safer use of the product.

A variety of formal epidemiological studies can be undertaken to generate or test hypotheses.

Prescription Event Monitoring

This monitoring, abbreviated as PEM, as conducted in the United Kingdom and New Zealand, represents a ‘hybrid’ method, combining aspects of public health surveillance and spontaneous reporting with aspects of formal epidemiological studies. In the United King-dom, this important technique takes advantage of many features of the British National Health Service (NHS). Within the NHS, prescriptions written by general practitioners are sent, once they have been dispensed, to a central Prescription Pricing Author-ity (PPA). The PPA provides confidential copies of certain prescriptions for newly introduced drugs that are being monitored to the Drug Safety Research Unit (DSRU) at Southampton. Six or twelve months after the first prescription for an individual drug in an indi-vidual patient, the DSRU sends a ‘green form’ ques-tionnaire to the general practitioner who wrote the original prescription. Changing requirements regard-ing confidentiality and the effect that these have had on PEM are discussed in the appropriate chapter of this volume.

Thus, the prescriptions provide the ‘exposure data’ showing which patients have been exposed to the drug being monitored, and the green forms provide the ‘outcome data’ showing any events noted during the period of monitoring. Pregnancies, deaths or events of special interest can be followed up by contact between the DSRU and the prescribing doctor who holds, within the NHS, the lifetime medical record of all of his or her registered patients.

The great strengths of this method are that it provides a numerator (the number of reports) and a denom-inator (the number of patients exposed), both being collected over a precisely known period of observa-tion. Furthermore, nothing happens to interfere with the doctor’s decision regarding which drug to prescribe for each individual patient, and this avoids selection biases, which can make data interpretation difficult. The main weakness of PEM is that only 50%–70% of the green forms are returned, and the experience of the patients whose forms are not returned may differ from those returned. In addition, because PEM limits follow-up to 6 or 12 months, it cannot identify events of long latency. Thus, it is of great importance that doctors should continue to support the scheme by returning those green forms that they receive.

So far, some 90 drugs have been studied by PEM, and the average number of patients included in each study (the cohort size) has been over 10 000. This is a substantial achievement and a tribute to the general practitioners who have participated. PEM in the United Kingdom and a similar programme in New Zealand are unique in providing a monitored-release programme that can detect or help refute new signals in the early life of a medicine.

Considerable interest centres around those patients who produce major ADRs that are too rare to be detected in cohorts of around 10 000 patients. How many of these patients have inborn errors of metabolism or other rarities that reflect features of the patient rather than the drug? We do not have adequate facilities to investigate the genetic and metabolic features of those patients who produce these very rare type B adverse reactions.

Other Hypothesis-Generating Methods

Other systematic methods are used in signal gener-ation. In some cases, data being collected for general public health surveillance, such as cause of death files, cancer registries and birth defect registries are used to identify patterns of events that might be associated with medication use. Other programmes, such as case–control surveillance of birth defects, conducted by the Slone Epidemiology Center, screen for potential associations between birth defects and prescription and over-the-counter medi-cations. Analytic methods that allow screening of enormous amounts of data for patterns that might deviate from expected – data mining techniques – are being applied to spontaneous reporting databases, databases on potential drug abuse and diversion and large population-based health records.