Pharmacoepidemiology:

Past, present and future

Dr.dr.Asep Sukohar,M.Kes
Pharmacology and Therapy
Medical Faculty of Lampung University
 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.
 Special Applications of
Pharmacoepidemiology
A. Studies of drug utilization
B. Evaluating and improving physician prescribing
C. Drug utilization review; special methodologic issues in
pharmacoepidemiologic studies of vaccine safety
D. Pharmacoepidemiologic studies of devices
E. Studies of druginduced birth defects
F. Pharmacoepidemiology and risk management
G. The use of pharmacoepidemiology to study medication
errors
H. Hospital pharmacoepidemiology
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.
Pharmacoepidemiology in practice
To quantify adverse events with medicines
in the population
Patterns of drug utilisation, including
adherence
Hypothesis generating
 Pharmacoepidemiology
Observational studies
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.
The potential for confounding is probably
larger in observational studies assessing
medications than in studies assessing
lifestyle factors.
 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.
 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.
Pharmacoeconomic Evaluation
 Pharmacoeconomics &
pharmacoepidemiology
Inter-related disciplines
Used by
Industry for marketing/price setting
HSE (Health Survey of England )- 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 (Ca
antagonis) for angina
Controversies
HSE-Primary Care Reimbursement
Services (PCRS)
The PCRS is part of the HSE, and is responsible for
making payments to healthcare professionals, e.g.
doctors, dentists and pharmacists, for the free or
reduced costs services they provide to the public.
It supports the delivery of primary healthcare by
providing reimbursement services in their own
community.
There are many schemes under the HSE-PCRS but
for drug prescribing the three main ones are: GMS
medical card scheme, Drug payment (DPS) and Long
Term Illness (LTI) schemes.
HSE-PCRS pharmacy claims
database
The number of GMS eligible persons by
December 2007 was 1.28 million people
( ~ 30% of population).
Not fully representative - socially
disadvantaged persons, children and the
elderly are over-represented.
Accounts for approximately 70% of all
prescribed medicines.
Limitations no diagnosis or outcome
data
 Examples
Quality prescribing indicators
Elderly population exposed to potentially
inappropriate medications; generic prescribing
European drug utilisation studies
Statins, PPIs, SSRIs, ACE/ARBs
Various disease areas including
adherence to tamoxifen in breast cancer
 Prevalence of potentially inappropriate
medication use in those 65+ years
The 1-year risk of receiving at least one PIM using the combination of Beers and
McLeod criteria was 20.6% using the national prescribing data (2004)
Criteria- PIM Proportion of all Proportion of Proportion of patients
patients (n=367,260) patients in the ERHA in ERHA nursing
(n=101,935) homes (n=2085)
Antidepressants 9515 (2.59%) 2340 (2.30%) 43 (2.06%)
amitriptyline,
doxepin, flouxetine
Sedatives 39059 (10.64%) 11963 (11.74%) 332 (15.92%)
Long-acting
benzodiazepines
Antibacterial 7028 (1.91%) 2277 (2.23%) 87 (4.17%)
Nitrofurantoin
Potential Drug-Drug
Interactions
Anticoagulants and 4943 (1.35%) 1588 (1.55%) 28 (1.34)
aspirin
Anticoagulants and 6370 (1.73%) 1767 (1.73%) 35 (1.68%)
NSAIDs
BMJ 2005
 On September 30, 2004, Merck and Co.
voluntary withdrew rofecoxib (Vioxx) due
to increased risk of CV events

B J Clin Pharm 2007

 Pharmacoepidemiology
Methodological developments
Studies based on large health care
utilization databases tend to use data
collected for reasons unrelated to the
research hypothesis thus lacking data on
all important confounders.
To address unmeasured confounding and
bias in database studies, several
approaches have been proposed.
Some examples of methodological
developments
STROBE and ISPE good practice guideline
for conduct of PE (Pharmaco epidemiology)
studies
ISPE :International Society for Pharmacoepidemiology
STROBE: Reporting of Observational Studies in Epidemiology
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

 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.
 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
and of increasing significance as drug licensing and
marketing take in the world.

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
 References
Kathleen bennett.
http://medicine.tcd.ie/pharmacology_therapeutics/research/research-
projects/pharmacoepidemiology.php
Strom BL and Kimmel SE. Text book of pharmacoepidemiology.
England: John Wiley & Sons Ltd;2006. h. 3-454
Strom BL . Pharmacoepidemiology. Third edition. England: John Wiley
& Sons Ltd;2006. h. 3-816