PHARMACO-EPIDEMIOLOGY

“The study of the use and effects of medications

in large numbers of people”

“The application of epidemiologic knowledge,

methods, and reasoning to the study of the effects
(beneficial and adverse) and use of drugs in human
populations.”
What is pharmacoepidemiology?

• Defined as the study of the utilization and effects of

drugs in large numbers of people.
• Pharmacoepidemiology borrows from both
pharmacology and epidemiology, a bridge science
spanning both pharmacology and epidemiology.
• Pharmacoepidemiology can also be defined as the
application of epidemiological methods to
pharmacological issues.
‘A desire to take
medicine is, perhaps,
the great feature
which distinguishes
man from other
animals’
William Osler,1891
PHARMACO-EPIDEMIOLOGY
“The study of the use and effects of medications in large numbers of
people”

“The study of drugs as determinants of health and disease in the

general unselected population.”

“The application of epidemiologic knowledge, methods, and reasoning

to the study of the effects (beneficial and adverse) and use of drugs in
human populations.”
 Historical background
• US law, Pure Food and Drug Act, passed in 1906, followed
by FD and cosmetic Act in 1938.
•
• Preclinical toxicity testing and clinical data about drug
safety required before drug marketed.

• ‘Thalidomide disaster’ in 1961 led to establishment of

committee of safety of medicines in 1968 in UK and
changes elsewhere.
• ‘Pharmacoepidemiology’ first appeared in medical
literature (BMJ) in 1984.
What papers have shaped
Pharmacoepidemiology?
Pharmacoepidemiology in practice

• To quantify adverse events with medicines in the

population
• Patterns of drug utilisation, including adherence
• Hypothesis generating
Pharmacoeconomics
• Pharmacoeconomics is that branch of health
economics that focuses upon the costs and benefits of
drug therapy.
• Definition: The comparative analysis of alternative
courses of action in terms of BOTH their costs and
consequences.
Pharmacovigilance
• There are also some areas that are altogether unique
to pharmacoepidemiology, e.g. pharmacovigilance.
• Pharmacovigilance is a type of continual monitoring
for unwanted effects and other safety-related aspects
of drugs that are already on the market.
• Pharmacovigilance refers almost exclusively to the
spontaneous reporting systems which allow health
care professionals and others to report adverse drug
reactions to a central agency.
• It relies heavily on reporting of safety events by health
professionals.
Pharmacogenomics
• The rapidly advancing field of pharmacogenomics, have
created important new opportunities in cancer research
and control.
• Pharmacogenomics involves identifying an individual's
response to a drug based on his or her genetic, genomic,
and/or proteomic profile.
• The concept that each patient's cancer or risk of cancer
has a unique genetic and/or molecular profile – this may
provide new ways to personalize an individual's therapy
for increased clinical benefit.
 Clinical pharmacology

Pharmacoepidemiology

Epidemiology
Pharmacology Therapeutics

Pharmacoepidemiology

Epidemiology Statistics
 Health services
research Economics
Epidemiology
Health
Outcomes economics
research
iology
Clinical epidem

Pharmaco-
Epidemiology

Conceptualization by Harry Guess

pharmacoepidemiology
Method and application
 Pre-marketing

Post-marketing

Pre-de-marketing
Animal studies

Phase 1

Phase 2 Human subjects

Phase 3

Drug approval
•Not always required
Phase 4 •Human subjects
Limitations of Pre-marketing Trials-1
• Carefully selected subjects may not reflect real-
life patients in whom drug will be used

• Study subjects may receive better care than real-

life patients

• Short duration of treatment

Limitations of pre-marketing trials-2
• Study size
• Studies with 3000 patients cannot reliably
detect adverse events with an incidence of
< 1 per 1000, even if severe
• Studies with 500 patients cannot reliably
detect adverse events with an incidence of
< 1 per 166, even if severe
Consequences of Limitations of Pre-marketing
Trials

• About 20% of drugs get new “black

box” warnings after marketing
• About 4% of drugs are ultimately
withdrawn for safety reasons
 E p id e m io lo g ic s tu d y d e s ig n s
D e s c r ip tiv e A n a ly tic
C a s e re p o rt N o n -e x p e r im e n ta l E x p e r im e n ta l
C a s e s e r ie s C o h o rt RCT
E c o lo g ic C a s e -c o n tr o l
 Hypothesis generating

Hypothesis strengthening

Hypothesis testing
Case Reports & Case Series
Cerivastatin (Baycol), an effective and inexpensive
lipid lowering drug, was introduced in 1997. It
was removed from the market in 2001 because of
reports of fatal cases muscle breakdown
(rhabdomyolysis).
Pharmacoepidemiology – Observational
studies

• The potential for confounding is probably larger in

observational studies assessing medications than in
studies assessing lifestyle factors.
• Without treatment allocation by chance, bias due to
different baseline risks for disease in users and non-
users of drugs cannot be ruled out completely -
confounding by indication.
Ecologic studies
Obtain group-level exposure
information and disease
prevalence at the same
point in time.
Pharmacoeconomics &
pharmacoepidemiology
• Inter-related disciplines
• Used by
• Industry for marketing/price setting
• HSE - reimbursement decisions
• Public health - e.g. vaccination programmes
• Can help identify whether particular sub-groups of
patients will benefit most from a new drug and in which
it is most cost-effective.
 Drug Toxicity

Thalidomide
Chloramphenicol and Grey Baby Syndrome
Gynaecological 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
Controversies
 The Pill Scare

In October 1995, the Committee of Safety of Medicines

(CSM) issued a warning on the increased risk of
thromboembolism associated with the third-generation
oral contraceptive steroids.
This ‘Pill Scare’ led to some users stopping the oral
contraceptive steroids mid-cycle and a rise
subsequently in abortions and pregnancies was noted.
The Irish Medicines Board did not advise discontinuation
of third -generation oral contraceptives , but advised
further study and analysis of the previous studies to
evaluate the impact of biases and confounders.
No regulatory action was taken.
 Percentage uptake of oral contraceptives by
generation between January 1995 and November
1st
1996.
2nd
60 3rd
50 Norgestimate
Percentage

40

30

20

10

96
95

95

96

6
5

6
95

6
95

96
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-9

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-9

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Month
Some examples of methodological
developments

STROBE and ISPE good practice guideline

for conduct of PE studies
Propensity scores
Optimal selection of controls
Time dependency in cohort studies
Immortal time bias
Validation Studies
Case-crossover design
Future research
• Linkage studies
• Electronic record linkage now established between NCRI and
HSE-PCRS for GMS patients (probabilistic matching of breast,
colorectal cancers and continuing for all cancer sites).
• Every GMS eligible patient on NCRI will have prescribing data
available from 2000 onwards.
• Will enable future studies
• Outcomes from prescribing (protective or otherwise)
• Drug utilisation before and after diagnosis of cancer
• Pharmacoeconomics of cancer treatments
• Hypothesis generating, etc.
Current proposals
• Adherence to oral hormonal therapies and outcomes
in breast cancer.
• Building on existing work but linked to breast cancer
outcomes.
• Breast cancer and digoxin
• There is recent laboratory work linking cardiac glycosides to
hypoxia inducible factor (HIF-1) inhibition which has been
show to inhibit tumour growth and cancer metastasis.
• Considering this effect it may be worthwhile to examine the
effect of digoxin (cardiac glycoside) on disease progression
and mortality in women who already have a diagnosis of
breast cancer.
 Future scientific development
• Application of new epidemiological methods to this area

• Quality of life studies linked to prescribing

• Individualising drug therapy

Example
• Co-prescription rates of
tamoxifen and CYP2D6 inhibitors
• Co-prescription rate of tamoxifen and CYP2D6 inhibitors is 13.2%
• Literature suggests link to reduced breast cancer outcome
• Avoidance of moderate and potent CYP2D6 inhibitors advised where possible
 Conclusion
• Pharmacoepidemiology is relatively new science in
Ireland, but of increasing significance as drug licensing and
marketing take on a European dimension.

• From a public health perspective, it is important to assess

the impact that vaccines and drugs have on the overall
patterns of disease in the population.

• Finally, society is now more sensitive to the costs of

medical care and in particular drug use.
Pharmacoeconomics can help predict the economic
implications of drug use prior to their marketing.
 The young physician starts life with 20 drugs for each
disease, and the old physician ends life with one drug
for 20 diseases.

William Osler

Acknowledgements
HSE-PCRS for supply of data for research purposes.
Dr Ian Barron, Dr Lesley Tilson
Typically, pharmacists collect and report adverse drug reactions on a regular basis to pharmacy and

therapeutics committees (P&T committees) in their individual institution.

These reports are most commonly used to monitor the safety of drugs within institutions, but

pharmacists are usually also responsible for forwarding serious adverse drug reactions to the Food

and Drug Administration (FDA).

Just as the FDA acts after receiving several serious adverse drug reactions associated with a particular

drug, the P&T committees of individual institutions react to serious adverse drug reactions within the

institution by creating medication guidelines and restrictions.

Drug Utilization Studies
• The World Health Organization (WHO) defines drug utilization as "the
marketing, distribution, prescription, and use of drugs in a society, with
special emphasis on the resulting medical, social, and economic
consequences.''

• Pharmacists conduct drug utilization studies, or DUEs, as part of their

routine activities.

• Like adverse drug reaction monitoring, the Joint Commission for the
Accreditation of Health Care Organizations (JCAHO) requires health
care institutions to conduct drug utilization studies.
• DUEs are most commonly conducted to monitor prescribing patterns.

• Medications monitored via DUE are chosen according to:

• cost
• frequency of use
• risk of toxicity.

• Drugs newly approved by the FDA that have shown serious adverse effects in
phase III trials are typically chosen to be monitored via DUEs.
• Example:
• when alteplase (TPA ®) was first approved by the FDA, many practitioners
were concerned about the bleeding side effects that had occurred in
phase III trials.
• Consequently, pharmacists chose to conduct DUEs to monitor the use of
alteplase.
• Information was collected on both prescribers and patients.
• Data collected on patients included:
• demographic information
• past medical history
• Indication
• Dose
• duration of therapy
• specific documentation of unintended bleeding effects.
• The goal of the DUEs was to monitor the use of alteplase to ensure that
the drug was being used as indicated in the proper patients and to
measure the extent of bleeding associated with alteplase.
• Subjects exposed to a particular drug are followed for a period to determine the
incidence of an adverse reaction.

• These DUEs can easily be expanded to a prospective cohort model.

Pharmacoepidemiological Research as an Extension of Daily
Clinical Practice
• Pharmacists in clinical settings monitor the uses and effects of drugs on a daily
basis.

• Clinical pharmacists collect information about individual patients; however,

pharmacists can also choose to view patients as populations, rather than
individuals, for the purpose of epidemiological research.

• If information collected about patients is systematic and routine, then the routine
monitoring of individual patients can easily be applied to a cohort study design.

• The data collected can then be analyzed to generate new hypotheses or to identify
trends of drug use.
• For example, a pharmacist conducting rounds in a critical care
unit will collect information about individual patients with regard
to demographics, past medical history, current medical problems,
laboratory data, physical findings, and so forth.

• The pharmacist will monitor each individual patient in an effort to

optimize pharmaceutical care.

• The data collection may or may not be consistent from patient to

patient.

• In this scenario, the information is typically used solely for the

purpose of caring for the patient.
• The pharmacist could instead choose to develop data-collection
forms to be used on all patients.

• If data collection is systematic and consistent, then the data can

be analyzed to determine the effects of drugs within populations
of patients, rather than thinking of patients only as individuals.

• New hypotheses can be generated from the data collection and

analysis; these hypotheses can then be tested using more
sophisticated observational or interventional studies.
Pharmacoeconomic Evaluation