Discussion

DISCUSSION

PEM is best regarded as a hypothesis-generating method of pharmacovigilance. However, provided appropriate care is taken, the kind of hypotheses it provides can be further explored, or tested, by vali-dation of selected cases, the study of age- and sex-adjusted relative risks, comparing products in the same therapeutic class, comparing reported events with national statistics, and conducting nested case– control studies. Hypothesis-testing methods, such as randomised controlled clinical trials, can only be satis-factorily undertaken when a hypothesis is already available.

The disadvantages and limitation of PEM, like those of most of the available techniques of pharmacovigi-lance, are however real. They include the following:

•   An average of only 58% of the green forms sent out are returned and an average of only 52% contain clinically useful data. This is significantly higher than the reporting rate in the yellow card and similar schemes (Martin et al., 1998; Wilton et al., 1998) but could conceal biases as it cannot be established in each PEM study whether the patients whose doctors return the green forms are in any way different from those whose doctors fail to complete and return the questionnaire. We already know (MacKay, 1998) that the responding and non-responding GPs differ very little in the distribution of ages in which they became principals or in their geographical distribution. Recently, second green forms were sent to doctors who did not return the first green form, the data will be analysed to see whether there are differences in the safety profile between these patients and those reported initially.

•   PEM does not yet extend into hospital monitor-ing, although pilot studies have been conducted. Thus, for drugs started in hospital it is important to follow-up reports of interest in order to identify the first prescriptions because a ‘survivor bias’ can operate for patients who both started and stopped a drug under hospital care and may never receive a GP prescription and may, therefore, be undetected by PEM. None of the current methods of pharma-covigilance is ideal in respect of this problem – hence the importance of extending PEM into hospi-tal practice.

•   PEM data include confounders, for example the highest value for IDt with the anti-epileptic drugs lamotrigine and vigabatrin for convulsions. Medi-cal evaluation and relating the various findings in PEM to each other is an essential part of the analysis. However, even without analysis, lists of reported events are useful to prescribing doctors for they show which events are reported in every-day clinical practice and the relative frequency with which these events will be seen. They are perhaps more useful than the unquantified long lists of possible side effects given in the standard prescrib-ing information.

•   It is a further limitation that statistical comparisons between drugs need to be undertaken with great care. Each PEM study begins as soon as the drug is launched and the ‘trade-off’ is between capturing the real-world and generalisable data from PEM and randomisation in clinical trials, which have many logistical and even ethical difficulties as well as limited external validity caused by exclusion criteria and other restrictions.

•   While one of the strengths of PEM is that it collects dispensed rather than prescribed data, compliance is not examined routinely in PEM stud-ies. However, it is possible, if necessary, to monitor repeated dispensing for the same patient as an indi-cator of compliance.

In essence, PEM can be as good but can be no better than the clinical case notes of the GPs or their precision in completing event forms for their patients.

The advantages of PEM are:

•   It is non-interventional and thereby minimises the selection biases that occur when the study design interferes with the doctor’s choice of drug for the individual patient.

•   It is national in scale and the cohort comprises all patients given the drug immediately after its launch into general practice. In Europe it is the only database that can identify cohorts of more than 10 000 patients for newly introduced medicines soon after launch.

•   The system prompts all prescribers who auto-matically receive a green form for each patient prescribed the drug being monitored. It is proba-bly this prompting function that is responsible for the success of the method: it does not rely on the doctor taking the initiative to report happen-ings. These features ensure that the studies are population-based and that they disclose the real-life clinical experience with the drug: there are no exclusions and all patients prescribed the drug are recruited even if they are very old, very young, or receiving several drugs concurrently for multiple illnesses.

•   Because the data are concerned with events, the system could detect side effects which none of the doctors has suspected to be due to the drug. The information provided by event reporting does not require the doctor to decide whether or not an individual event in a single patient is drug-related. It thereby avoids a very difficult clinical decision for, as most reactions resemble fairly common clin-ical events, avoiding the doctor having to decide on causation may well encourage reporting.

•   The system allows direct contact between the doctors working in the DSRU and GPs so that follow-up surveillance of individual cases or deaths and all pregnancies is facilitated PEM can explore the possibility of long-latency adverse reactions and cohorts can be tagged on the NHS Central Register so that very long-term or lifetime follow-up can be undertaken.

•   Additional advantages accrue from the increasing size of the PEM database which has been built up since 1984. The database now contains informa-tion on 78 completed PEM studies and one million patients. This has started to provide opportunities for comparing products and patient groups in the database. As time passes and more studies are completed the value of the database as a research tool increases progressively.

Future plans include hospital monitoring, establish-ing registries of iatrogenic diseases, monitoring by community pharmacists, monitoring the safety of herbal products, and the establishment of an investi-gational unit in which the mechanisms of some of the uncommon ADRs identified by PEM can be explored by pharmacological and pharmacogenetic techniques.