PEM is a method of pharmacovigilance that studies drug safety in real-world clinical practice. It involves collecting prescription data for new drugs and surveying prescribers about patient outcomes. Advantages include a large national scale and obtaining real-world safety data. Record linkage systems combine different healthcare records to efficiently study relationships between drug exposure and health outcomes. Claims databases contain prescription and medical claims information but may lack clinical details, while medical record databases provide more clinical data but only for illnesses that were medically attended to.

1. Pharmacoepidemologyandpharmacoeconomics
PrescriptionEvent Monitoring:
 PEM is a non-interventional, observational cohort form of pharmacovigilance.
 It is the method of studying the safety of new medications used by the general
practitioner.
 PEM was developed by Professor Bill Inman at the Drug Safety and Research Unit
(DSRU) at Southampton in 1981.
Evolution of PEM
 Pre-marketing clinical trials are effective in studying the efficacy of medicine but are
not able to define many aspects of drug safety because:
1. Small no of patients
2. Large no of patients receiving the drug for small durations
3. Doses and formulations of the drug may change during drug development
4. Exclusion of special population from the clinical trials
5. The contribution of spontaneous reporting system in detecting hazards such as
oculomucocutaneous syndrome with practolol led Inman to establish the system of
Prescription Event Monitoring (PEM) at DSRU.
6. In New Zealand, the medicines adverse reaction committee (MARC) is responsible
for conducting such studies for academic purposes and the programme is known as
Intensive medicine monitoring programme(IMMP).

2. Pharmacoepidemologyandpharmacoeconomics
 In UK, all the patients are registered with NHS-GP provides the primary
care and act as a gateway to specialist and hospital care
 File notes in general practice contains information about primary care, secondary and
tertiary care (life long record)
 GP issues prescription for medications he considers medically warranted
 Patient takes the prescription to the pharmacist, who dispenses the medication
and sends the prescription to the PPD (which is a part of NHS-BSA), for
reimbursement
 PPD provides DSRU with electronic copies of all the prescriptions issued
throughout UK, for the drugs being monitored
 Products that are selected for study by PEM
1. New drugs, expected to be used widely
2. Established products, used for new indication/ new population
 Collection of exposure data begins soon after the new product is launched

3. Pharmacoepidemologyandpharmacoeconomics
 These arrangements operate for a length of time necessary for the DSRU to collect
first 50,000 prescriptions, that identify 20,000-30,000 patients given the new drug
being monitored
 For each patient in the study, DSRU prepares a computerized longitudinal record in
the date order of drug use
 After 3-12 months from the date of first prescription for each patient, the DSRU
sends the prescriber a green form questionnaire
 This is done on an individual patient basis
 Doctor receives maximum of 4 green forms in a month
Green form for PEM study on Celecoxib
Request information on:
 Age
 Sex
 Indication for Rx
 Dose
 Start date
 Stop date
 Concurrent diseases
 Concomitant therapy
 All events that have occurred since Rx
 Cause of death

4. Pharmacoepidemologyandpharmacoeconomics
 Each green form is reviewed by a medical/ scientific officer monitoring the study,
to identify possible serious ADRs or events requiring action
 Events are coded and entered in database using a hierarchical dictionary arranged
by system-organ class with specific lower terms grouped under broader higher terms
PEM process:

5. Pharmacoepidemologyandpharmacoeconomics
Advantages
1. PEM is non-interventional
2. The method is national in scale and thus provides real world data
3. Exposure data is derived from dispensed prescriptions
4. Method can detect adverse reactions or syndromes that none of the reporting doctors
suspected to be due to the drug
5. Method allows close contact between the research staff and reporting doctors
6. ADR reporting is more complete by this method
7. Method is found to be successful in regularly producing data in 10,000 or more
patients given newly marketed drugs
8. Method identifies patient with ADRs who can be studied further
9. Allows comparison of safety profile of drugs belonging to the same therapeutic group
10. Evaluate signals generated by other systems or databases
Disadvantages:1.Not all green forms are returned
2.PEM depends upon reporting by doctors. Underreporting is possible
3.PEM is currently restricted to general practice
4.Its not known whether the patient took the dispensed medication
5.Detection of rare ADRs is not always possible

6. Pharmacoepidemologyandpharmacoeconomics
Applications of PEM
1. Searching for signal
2. Assessment of important AE
3. Medically important events
4. Reason for stopping the drug
5. Analysis of events during the study while on drugs
6. Ranking of ID and reason for withdrawal
7. Automated signal generation
8. Long latency adverse reactions
9. Comparison with external data
10. Outcomes of pregnancy
11. Studies to examine hypothesis generated by other methods
12. Studies of background effects and diseases
Example for PEM
 A study was carried out to assess the sedation properties of 4 anti-histaminic in the
market loratadine, cetrizine, fexofenadine and acrivastine
 Objectives: To investigate the frequency with which sedation was reported in post
marketing surveillance studies of four second generation antihistamines: loratadine,
cetrizine, fexofenadine, and acrivastine
 Design: Prescription event monitoring studies.
 Setting: Prescriptions were obtained for each cohort in the immediate post marketing
period.
 Subjects: Event data were obtained for a total of 43,363 patients.
 Main outcome measure: Reporting of sedation or drowsiness.
 Results: The odds ratios for the incidence of sedation were 0.63 (95% confidence
interval 0.36 to 1.11; P = 0.1) for fexofenadine; 2.79 (1.69 to 4.58; P < 0.0001) for
acrivastine, and 3.53 (2.07 to 5.42; P < 0.0001) for cetrizine compared with
loratadine. No increased risk of accident or injury was evident with any of the four
drugs.

7. Pharmacoepidemologyandpharmacoeconomics
Conclusions: Although the risk of sedation was low with all four drugs, fexofenadine
and loratadine may be more appropriate for people working in safety critical jobs.
This study not only showed the sedative effects of the anti-histaminic, and compared
them, it also gave an idea about the incidence of other ADRs associated with the 4
drugs.
Incidence density of ADRs in first month of treatment with 4 anti-histamine
Incidence density of events related to sedation in first month of treatment with 4
anti-histaminics

8. Pharmacoepidemologyandpharmacoeconomics
RecordLinkage Systems:
 Record linkage is the process of bringing together two or more records relating to the
same individual (person), family or entity (e.g. event, object, geography, business
etc).
 It is the process of assembling the outcomes of drug exposure into a single database
 Record linkage can be considered as part of the data cleaning process
 Provides rapid access to records of thousands of patients and thus reduces the time
required for exploring the relationship between drug exposure and outcomes
Diagrammatic representation of a linkage between two or more independent
entries

9. Pharmacoepidemologyandpharmacoeconomics
 An ideal database would include records from inpatient, outpatient, emergency care,
mental health care, laboratory and radiological tests, prescribed and over-the-counter
medications as well as alternative therapies
 All the parts should be easily linked by a unique patient identifier
 It should be updated regularly
Needfor record linkage
Objective of record linking
 The objective of the linking process is to determine whether two or more records refer
to the same person, object or event
Types of record linkage methods
Researchers and the community‘s demand for detailed statistical information
Reducing respondent burden and costs
Improving data quality and timeliness
In response to increasing business and health needs.
In reducing the complexity of data
International collaborative works

10. Pharmacoepidemologyandpharmacoeconomics
Deterministic record linkage
 A pair of records is said to be a link if the two records agree exactly on each
element within a collection of identifiers called the match key.
 For example, when comparing two records on last name, street name, year of
birth, and street number, the pair of records is deemed to be a link only if the
names agree on all characters, the years of birth are the same, and the street
numbers are identical.
Probabilistic Record Linkage
 Pairs of records are classified as links, possible links, or non-links.
 Here, we consider the probability of a match in the given observed data.
 In probability matching, a threshold of likelihood is set (which can be varied in
different circumstances) above which a pair of records is accepted as a match,
relating to the same person, and below which the match is rejected
General record linkage system
Types of
Record
Linkage
Strategi
es
Probabilisti
c
Determi
nistic

11. Pharmacoepidemologyandpharmacoeconomics
Claims databases
 Patient goes to pharmacy drug gets dispensed pharmacy bills the insurance
carrier for cost of that medication
 Should specify which drug was dispensed, amount dispensed, etc.
 Patient goes to hospital/physician for medical care bills the insurance carrier for
cost of the medical care
 Should justify the bill with diagnosis
 Common patient identification no link pharmacy and medical care claims
Medicalrecord databases
 Recent development with increased use of computerization in medical care
 Computers are used to record medical information
Advantages
 Provide large sample size, esp. for pharmacoepidemiological studies
 Inexpensive
 Data will be complete
 Population based
 Include information on outpatient drugs and diseases
 Avoid recall and interviewer bias
Disadvantages
 Uncertainty of diagnosis data

12. Pharmacoepidemologyandpharmacoeconomics
 May not contain information regarding smoking, alcohol, date of menopause,
etc.
 May not contain data of medications obtained without prescription or outside
insurance carriers prescription plan
 Instability of population due to job changes, changes in insurance plans, etc.
 Include illnesses severe enough to come to medical attention
Applications
1. Data Quality
2. Bias
3. Coverage
4. Tracing Tool
5. Benchmarking/Calibration
6. Building New Data Sources (e.g., Registries)
7. Creation of patient-oriented, rather than event-oriented statistics
8. Reducing costs and respondent burden