pharmacoepidemiology is the study of use and effect of drugs in large number of population. pharmacoepidemiology enhances or supplements the information from the preclinical studies.

1. PHARMACOEPIDEMIOLOGY
Jyothsna Ravilla
M.Pharmacy Ist year, Pharmacology
RAGHAVENDRA INSTITUTE OF
PHARMACEUTICAL EDUCATION AND
RESEARCH (RIPER)- AUTONOMOUS

2. CONTENTS:
› Definition
› why do we need pharmacoepidemiology (PE)
› Origin and Evolution of PE
› Aims of PE
› Methods to perform PE studies.
› Application fields of PE
› Summary

3. Definition:
› Pharmacoepidemiology (PE) is the
study of use and effect of drugs in
large number of population.
› PE is the application of principles
of epidemiology to drug effects
and drug use.
› The term pharmacoepidemiology
contains two components
“Pharmaco” and “epidemiology”
› Pharmaco means drug and
epidemiology means study of
distribution and determinants of
disease in a population.

4. › Epidemiology has two major areas- one is the study of infectious disease in
large population called epidemics and the second is the study of chronic
disease.
› PE involves gathering & analysis of information in order to identify possible
causation & related factors that can be applied in clinical practice to group
of people &also individual undergoing treatment.
› So it examines the relationship b/w drug exposure & health outcome in a
defined population.

5. Why do we need pharmacoepidemiology?
› Information which enhance or supplements the information from
preclinical studies.
1.Better estimation of the incidence or the occurrence of the known adverse
and beneficial effects.
a) Higher precision (e.g. Prazosin)
b) In patients not studied prior to marketing, e.g. the elderly, children,
pregnant women
c) As modified by other drugs and other illnesses (e.g. Timolol)
d) Relative to other drugs used for the same indication
› New types of information not available from premarketing studies.
1. Discovery of previously undetected adverse and beneficial effects like
uncommon effects and delayed effects.
2. Patterns of drug utilization.
3. The economic implications of drug use.

6. Origin and Evolution of PE:
› In 1906 US govt passed pure food and drug act in response to excessive
adulteration & misbranding of food and drugs.
› In 1937 ,over 100 of people died from renal failure as a result of the elixir
sulfanilamide dissolved in diethylene glycol.
› In 1938 D&C act was passed ,because of this manufactures required an approval
from FDA before marketing a drug.
› In 1950 chloramphenicol induced aplastic anaemia was discovered.
› In 1961 , the case reports of maternal use of thalidomide with malformation in
offspring results in awareness of the potential for drugs to cause ADR.
› In 1968 UK established a committee on safety of medicine.
› WHO established a bureau to collect and analyze information from this and similar
national drug monitoring organizations.
› In early 1960, the related field of drug utilization was developed along with the
study of ADRs
› With all these development 1960’s considered to be the beginning of field
of pharmacoepidemiology.

7. › ‘Pharmacoepidemiology’ first appeared in medical literature (BMJ) in 1984.
› ISPE was formed to obtain more data on risk & benefits of drugs in
population and to discuss, develop & disseminateinformation about
pharmacoepidemiologic methods.
DRUG TOXICITY examples:
› Thalidomide
› Chloramphenicol and Grey Baby Syndrome
› Gynecological cancer in offspring of women receiving Diethyl Stilboestrol
› Oculomucocutaneous syndrome with practolol
› Liver disease from Benoxaprofen
› Valvular heart disease from Dexfenfluramine
› Cardiac arrhythmias with terfenadine
› Multiple drug interactions with mibefradil

9. Aim of PE:
› The pharmacoepidemiologic studies concentrate on the period after the
drug enters the market known as post marketing surveillance (PMS)
› These studies are concerned with two main aspects:
1. the study of adverse effects of drugs
2. the appropriate use of medicines
3. Reassurances about drug safety
4. Fulfillment of ethical and legal obligations.

10. Methods to Perform PE studies:
› Ecological/ cross sectional studies
› Case control studies
› Cohort study
› Surveillance systems: Pharmacovigilance
– voluntary reporting
– prescription event monitoring
– medical record linkage
– population statistics

11. Ecological/ Cross sectional studies:
› The results of this type of study design can be compared with other areas
to investigate if there is a difference in the rate of daily purchases of drugs,
which further inform area public health officials of the geography of the
outbreak. Studies using aggregated data are called ecological studies.
› Example:
1. Data on cough and cold preparations bought over-the-counter (OTC) in a
town’s two pharmacies.
2. Total number of packages sold by the pharmacies each day is recorded, but
no data are collected on the individual purchases by patients/customers.
3. Analysis of aggregated data of daily purchases can inform decision-makers on
what types of products are sold or required and may inform public health if
there is a possible outbreak of upper respiratory infection in the area.
4. The data do not necessarily relate it to a particular outcome of interest but
can provide information on the use of medications in a particular population.

12. Limitations:
Confounding arises because there is a lack of individual patient information
Here let us take the confounding factor as smoking, the individual though has cough but the
confounding factor elevates risk of the respiratory depression or illness, in the cross sectional
data the confounding factors are not studied or analysed as we lack individual patient
information.
› Here we measure the aggregate data, This is a simple calculation of the number of people
that are affected by the total population that are at risk. For example, using the above
situation, there were 130 purchases of OTC cough and cold products in 1 day from both
pharmacies. The town has a total population of 5145 people. Therefore, the rate of OTC
cough and cold purchases is 130/5145= 0.025 or 25 purchases per 1000 people

13. Cohort study:
1. Patients receiving a drug are followed up to determine the outcomes
(therapeutic or adverse).
2. This is usually forward-looking (prospective) research. A cohort study
does not require a suspicion of causality; subjects can be followed ‘to see
what happens’(event recording).
3. Prescription event monitoring is an example, and there is an increasing
tendency to recognize that most new drugs should be monitored in this
way when prescribing becomes general.
4. This may take a long time, so cohort studies may take years or generations
until an outcome is identified.
For example, the WHO MONICA Project is a large cohort of 10 million people aged
35-64 from 26 countries of Europe, North America, and Western Pacific. Subjects
were followed forward in time to a fatal or nonfatal cardiovascular event or stroke.
Physical examinations and surveys were performed at regular intervals under a
standardized protocol. This study has provided information on risk factors
contributing to MI and medications used to control blood pressure and their effects
on the mortality rate of acute MI.

14. › A major advantage of cohort studies is that the entire population is at risk
because the study population started the study outcome free. Therefore, an
accurate incidence of the outcome can be calculated for the exposed (Ie) and
unexposed (Io) populations. The incidence is used in the measure of
association termed the relative risk (RR), that is association between a risk
factor and future outcome.
› Incidence of disease is defined as the number of newly diagnosed cases of the disease in a
population divided by the total population at risk of the disease.

16. Case Control study:
1. This reverses the direction of scientific logic from a forward-looking, ‘what
happens next’ (prospective) to a backward-looking, ‘what has happened in
the past’ (retrospective) investigation.
2. The case–control study requires a definite hypothesis or suspicion of
causality, such as an adverse reaction to a drug, The investigator
assembles a group of patients who have the condition.
3. A control group of people who have not had the reaction is then
assembled (matched, e.g. for sex, age, smoking habits) from hospital
admissions for other reasons, primary care records or electoral rolls.
4. A complete drug history is taken from each group, i.e. the two groups are
‘followed up’ backwards to determine the proportion in each group that
has taken the suspect agent.
5. Case–control studies do not prove causation(relationship between
cause and effect) They reveal associations or connection and it is up
to investigators and critical readers to decide the most reasonable
explanation

17. Advantages:
Requires a much smaller number of cases (hundreds) of disease and can thus
be done quickly and cheaply.
Disadvantage:
It follows up subjects backwards and there is always suspicion of the intrusion or interruption
of unknown and so unavoidable biases in the selection of both patients and controls.
› Independent repetition of the studies are performed if the results are the same, greatly
enhances confidence in the outcome.

18. The measure of association for a case control study is the OR. The calculation of the OR is
relatively easy if some simple rules are established and the researcher sets up their results
appropriately to identify the exposure and outcome.
Interpreting the OR can be remembered by using the result to answer cell “A.” For example,
there is an increased/decreased risk of the outcome if exposed to the medication.

19. 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 community of drug effects,
usually adverse.
› For understandable reasons, they are strongly supported by governments.
Voluntary reporting:
Doctors, nurses, pharmacists and patients may report suspected adverse reaction to
drugs. In the UK, this is called the ‘Yellow Card’ system.
It is recommended that for:
• Newer drugs: all suspected reactions should be reported, i.e. any adverse or
any unexpected event, however minor, that could conceivably be attributed
to the drug
• Established drugs: all serious suspected reactions should be reported, even
if the effect is well recognized.

20. › Voluntary reporting is effective for identifying reactions that develop shortly after
starting therapy, i.e. at providing early warnings of drug toxicity, particularly rare
adverse reactions. Thus, it is the first line in post-marketing surveillance.
› Reporting is low for reactions with long latency, such as tardive dyskinesia from
chronic neuroleptic use.
› As the system has no limit of quantitative or measuring sensitivity, it may detect the
rarest events, e.g. those with an incidence of 1:5000 to 1:10 000.
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) with no judgement regarding
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’. By
linking general practice and hospital records and death certificates, both prospective
and retrospective studies can be done and unsuspected effects detected.

21. › Prescription event monitoring can be used routinely on newly licensed
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.

22. 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 Practice
Research Database (GPRD) at the Medicines and Healthcare products
Regulatory 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. If suspicions are
aroused then case–control and observational cohort studies will be initiated.

24. Applications:
› Prescription and drug consumption studies
› Study of drug effectiveness
› Risks associated to drugs

25. Summary
› The challenge is to identify patterns of use of medical drugs that
compromise their beneficial effects on public health.
› The prerequisite for a medical drug to be marketed is that the information
obtained from clinical trials, i.e. in experimental conditions of use, allows
considering that the benefit it will provide to public health outweighs the
burden of its unavoidable adverse effects.
› Once a medical drug gets marketed, it is no longer used in this experimental,
controlled, setting but in real-life “natural” conditions, in which some
specific patterns of uses or some uses in specific populations can convey
increased risks for public health.
› These uses and associated risks can alter drastically the benefit-risk balance
of the drug and its impact on population health.

26. › The objective of the team is to identify such situations; the key aspects
of the researches conducted in this purpose are the following:
– the more a drug is used, the most important its impact on public health (positive or
negative)
– this impact, in terms of risk, can be increased when the populations
using the drug present with specific frailties, as in the case of cancer
for instance in situations of massive use, even mild to moderate
effects on health induced by drugs can convey a tremendous impact
on public health.
– such mild to moderate changes (beneficial or detrimental) are the
most difficult to identify and quantify in an real-life setting.
– Conducting such researches consequently implies, aside to the
performing of studies applied to specific fields of health, to
continuously develop and assess new methods for the study of drugs
in real-life setting.