Method

METHOD

PEM is a non-interventional, observational cohort form of post-marketing surveillance. It is non-interventional because nothing happens to interfere with the doctor’s decision regarding which drug to prescribe for each individual patient. Thus, the method provides ‘real-world’ clinical data involving neither inclusion nor exclusion criteria: the patients studied are those who receive the drug in everyday medical practice. This ensures that the data are generalisable.

In the United Kingdom virtually all persons are registered with a general practitioner (GP) who provides primary health care and issues prescriptions (FP10s) for the medicines medically necessary. The patient takes the prescription to a pharmacist who dispenses the medication and then sends the FP10 to a central Prescription Pricing Division (PPD) which arranges the pharmacist’s reimbursement. The Drug Safety Research Unit (DSRU) is, by virtue of a long-standing and confidential arrangement, provided with electronic copies of all those prescriptions issued nationally for the drugs being monitored by PEM. These arrangements continue for a collection period which allows exposure data to be collected for 20 000– 30 000 patients. For each of these patients the DSRU prepares a computerised longitudinal record compris-ing, in date order, all of the prescriptions for the monitored drug. Thus, in PEM, the exposure data are national in scope throughout the collection period and unaffected by the kind of selection and exclusion crite-ria that characterise clinical trials. The exposure data are of drugs dispensed and provided to the patient but there is no method of measuring compliance or the use of non-prescription medication.

After an interval of 3–12 (usually 6) months from the first prescription for each individual patient the DSRU sends to the prescriber a ‘green form’ ques-tionnaire seeking information on any events that may have occurred since the drug was first prescribed. An event is defined as any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexplained deterioration (or improvement) in a concurrent illness, any suspected drug reaction, any alteration of clinical importance in laboratory values, or any other complaint which was considered of suffi-cient importance to enter in the patient’s notes.

Information which identifies the patient is deleted from the database when the green form is received from the doctor. The doctor enters any number or code used in the practice to identify the patient. This ensures that the clinical information received by the DSRU is anonymised. The practice code or number is used if follow-up information is sought from the doctor. In order to avoid placing an unreasonable demand on GPs no more than four green forms are sent to each doctor in any one month. The green form is illustrated in Figure 24.1, which shows the other information requested of the doctor.

The green form has been modified for certain studies with a small number of additional questions (with yes, no, don’t know answers). These questions focus on issues specific to the drug under study, for example the green form for the PEM study on the NSAID meloxicam included questions about previ-ous history of gastrointestinal conditions and intoler-ance to NSAIDs to identify possible confounding by indication.

General practitioners are not paid to fill in green forms. The arrangements allow good contact between the doctor and the DSRU and this facilitates the collection of any follow-up data that may be consid-ered necessary by the research physicians monitoring each study and working within the DSRU. One of the strengths of PEM is follow-up with the GP or the health service to obtain further information from the doctor for a large number of reports. A list of reports for which additional information is sought is included in Table 24.1.

Over the 78 studies listed in Table 24.2, an average of 58% of the green forms sent out have been returned by the GPs to the DSRU. The cohort sizes, with an average of 10 613 patients, as given in Table 24.2, are derived from the mean 52% of returned green forms which provide clinically useful data.

PEM collects event data and does not ask the doctor to determine if any particular event is due to an adverse drug reaction (ADR). If, however, the doctor does consider the event to be an ADR or he has completed a yellow card (a spontaneous ADR report) regarding the event, then he is asked to indicate this on the green form.

Further details of the methodology of PEM, includ-ing the methods of data coding, computerisation and analysis, have been provided in a number of publica tions (Inman, 1978b; Freemantle et al., 1997; Mann et al., 1997).

Each PEM study starts as soon as possible after the new drug has been marketed in England. Each study aims to collect exposure and outcome data on approx-imately 10 000 patients. Some studies have included almost double that number and attempts are now being made, when PEM is an ideal method for studying the early experience with an important new drug, to maximise the size of the cohort. The drugs included in the system are (as advocated by the Second Grahame-Smith Working Party of the Committee on Safety of Medicines) those intended for widespread, long-term use, special emphasis being given to drugs for which treatment is likely to be both initiated and continued by the GP (Secretary of State, 1986; BMA, 1996). In addition to drugs that are taken regularly, it has also been possible to study products that are not used daily, such as sildenafil for erectile dysfunction (Shakir et al., 2001).

In summary, the exposure data in PEM are derived from the prescriptions written by GPs attending the individual patients; the outcome data are derived from the green forms completed by those same GPs.

Within the DSRU each green form questionnaire is scanned into the system and the image is reviewed by a medical member of the DSRU staff so that impor-tant events can be investigated. In addition to impor-tant events (Table 24.1), pregnancies and deaths of uncertain cause are further investigated by the DSRU Research Fellows who can, with the permission of the GP, access the patient’s life-time medical records, death certificates, etc.

Interim reports are written to summarise the data on each study with every 2500 patients entered into the database. These reports include a listing, by month since the beginning of treatment, of all events reported. They are, if possible, discussed with the Product Licence holder so that reporting obligations to the regulatory bodies can be fulfilled. Wherever possible PEM is undertaken in a collaborative but always independent relationship with the drug orig-inator. The methodology of PEM is summarised in Figure 24.2.