Phar 7041 Fundamentals of Pharmacoepidemiology

1. Fundamentals of
Pharmacoepidemiology
(PHAR 7041)
Department of Pharmaceutics
School of Pharmacy
College of Medicine and Health Sciences
University of Gondar
aberhaneth@gmail.com
Tel: +251912024213
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Berhanemeskel W.Gerima Atsbeha

2. Course Objectives
Enabling Objectives: To meet the course objective, at the end of the course, learners will:
 Describe the scope and applications of pharmacoepidemiology
 Discuss common study designs and methods used in pharmacoepidemiological studies
 Assess the relevance and limitations of various pharmacoepidemiological research designs
 Describe qualitative research concepts in pharmacoepidemiology
 Compute measures of association or risk
 Identify errors in pharmacoepidemiologic studies
 Explain sampling issues in pharmacoepidemiology
 Explain data sources and data collection techniques in pharmacoepidemiology
 Discuss drug utilization research
 Describe systems for the reporting of adverse effects and their use for pharmacoepidemiology.
 Discuss Pharmacovigilance
 Differentiate systematic review and meta-analysis
 Practice stages of systematic review and meta-analysis
 Assess heterogeneity in meta-analysis and handle it
 Assess reporting bias in systematic review and meta-analysis
 Apply pharmacoepidemiologic principles in practice
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3. Reference Materials
 Pharmacoepidemiology, 4th edition, Storm B. L. (Ed),
John Wiley and Sons Ltd, England, 2005.
 Textbook of Pharmacoepidemiology, Storm B. L.
And Kimmel S.E. (Eds), 2007, John Wiley, New Jersey.
 Pharmacoepidemiology – An Introduction, 3rd
edition, Hartzema A.G., Porta M., Tilson H.H., (Eds),
1998, Cincinnati OH, Harvey Witney Books Company.
 Remington’s: The Science and Practice of Pharmacy,
21st edition, University of The Sciences in
Philadelphia, 2005, USA.
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4. 1. Introduction (2 hrs)
1.1. What is Pharmacoepidemiology?
1.2. Potential Contributions of Pharmacoepidemiology
1.3. Reasons to Perform Pharmacoepidemiology Studies
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5. 5
Public
Health
Pharmacy
Pharmacoepidemiology
BRIDGE

6. 1.1. What is Pharmacoepidemiology?
Outline
1.1.1. Definition
1.1.2. Historical Background
1.1.3. Pharmacoepidemiology Scope and relationship
with other fields
1.1.4. Current drug approval process
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7. 1.1.1. Definitions of Pharmacoepidemiology
 Study of drugs as determinants of health and
disease in the general unselected population
 Science of measuring drug mediated health events
in well defined large number of populations
 Study of the utilization and effects of drugs in
large numbers of people
 Application of epidemiological methods to
pharmacological issues
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8. Definitions
 It links EXPOSURE and OUTCOME for any appropriate
sub-groups in any selected medicines in terms of
 Therapeutic gain
 Length of life
 Quality of life
 Adverse events
 Pharmacoepidemiology borrows from both
pharmacology and epidemiology
 A BRIDGE SCIENCE - spanning both
pharmacology and epidemiology
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9. 1.1.2. 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 in British Medical Journal (BMJ) in 1984.*
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*Lawson D. H. (1984). Pharmacoepidemiology: a new discipline. British medical journal
(Clinical research ed.), 289(6450), 940–941. https://doi.org/10.1136/bmj.289.6450.940

10. Drug Toxicity
 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
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11. What papers have shaped
Pharmacoepidemiology?
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14. 14

15. Controversies
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16. 1.1.3. Pharmacoepidemiology Scope and
Relationship with Other Fields
Pharmacoepidemiology Scope
Pharmacoepidemiology is the application of
epidemiological principles and methods to the
study of drug effects in human populations.
The goals are to
 characterize, control and predict the effects and
uses of pharmacological treatment regimens in a
defined population.
Pharmacoepidemiology is also concerned with the
economic impact and health benefits of
unintended drug effects.
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17. Pharmacoepidemiology
Clinical pharmacology
Epidemiology
Pharmacoepidemiology vs Other fields
Study of the effects of drugs in
humans
• Attempt to optimize the use of drugs
tried to individualize the therapy and
tailor to the needs of specific patient
• Individualization of therapy requires
determination of risk/benefit ratio
specific to the patient
• Useful in providing information
about the beneficial and harmful
effects of any drugs
• Permitting a better assessment of
the risk/benefit balance
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18. Pharmacoepidemiology
Pharmacology
Epidemiology
Therapeutics
Statistics
Study of the effects of drugs
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19. Health services
research
Health economics
Outcomes
research
Pharmaco-
Epidemiology
Epidemiology
Economics
Conceptualization
by Harry Guess
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20. 1.1.4. Current Drug Approval Process
The current drug approval process includes:
1. Preclinical phase- animal testing
2. Clinical Phase I- metabolism of the drug, safe dosage
range in humans, on Healthy subjects
3. Phase II- pharmacokinetics of the drug, common ADRs
on the possible efficacy of the drug, daily dosage and
regimen, on patient subjects
4. Phase III - evaluate a drug’s efficacy, more information
on toxicity, on patient subjects (500-3000)
5. Phase IV – POST MARKETING SURVEILLANCE
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21. 1.1.4. Current Drug Approval Process (2)
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Preclinical
animal
testing
Phase I
Phase II
Phase III
Phase IV
Pre-marketing Phase Post-marketing Phase
Drug
approval
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22. Limitations of Pre-marketing Trials
 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
 Study sample 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
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23.  About 20% of drugs get new “black box” warnings
after marketing
 About 4% of drugs are ultimately withdrawn for
safety reasons
Consequences of Limitations of
Pre-marketing Trials
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24. 1.2. Potential Contributions of
Pharmacoepidemiology
A. Information which supplements to the information available
from premarketing studies—better quantitation of the
incidence of known adverse and beneficial effects
I. Higher precision (eg. Prazosin)
II. In patients not studied prior to marketing, (e.g. the
elderly, children, pregnant women)
III. As modified by other drugs and other illnesses (eg.
Timolol)
IV. Relative to other drugs used for the same indication
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25. 1.2. Potential Contributions of
Pharmacoepidemiology
B. New types of information not available from premarketing
studies
1. Discovery of previously undetected adverse and beneficial
effects
(a) Uncommon effects
(b) Delayed effects
2. Patterns of drug utilization
3. The effects of drug overdoses
4. The economic implications of drug use
C. General contributions of pharmacoepidemiology
1. Reassurances about drug safety
2. Fulfillment of ethical and legal obligations
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26. 1.3. Reasons to Perform
Pharmacoepidemiology Studies?
 Common reasons to perform pharmacoepidemiology
studies are for
A. Regulatory decision about whether to approve a drug
for marketing or
B. Marketing purpose
C. Legal issue
D. Clinical decision about whether to prescribe a drug
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27. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
A. Regulatory
A1. Requirement: a plan for post marketing pharmacoepidemiology
study is required before the drug that will be approved for
marketing. This is designed to clarify residual questions about drug’s
efficacy and toxicity.
A2. To obtain earlier approval for marketing: if the drug
regulatory agency believed that serious problems could reliably and
rapidly detected after marketing, it could feel more comfortable
releasing the drug sooner.
A3. As a response to questions by regulatory agency: some
post marketing studies of drugs arise in response to case reports of
adverse reactions reported to the regulatory agency.
A4. To Assist Application for Approval for marketing
elsewhere
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28. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
B. Marketing
B1. To assist market penetration by documenting
the safety of the drug
B2. To increase name recognition: the fact that a
study is underway will often be known to
prescribers as well its results once it is publicly
presented and published increased name
recognition
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29. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
B3. To assist in repositioning the drug
 Different outcomes: one can explore different outcomes
resulting from the use of drugs for approved indication
 Different types of patients: one could also explore the use of
drugs for the approved indication in types of patients other
than those included in premarketing studies. Example:
children and elderly
 New indications: by exploring unintended beneficial effects,
or even drug efficacy, one could obtain clues to and
supporting information for new indications for drug use
 Less restrictive labeling: because of questions about efficacy
or about toxicity, drugs are sometimes approved for initial
marketing with restrictive labeling. Additional data may be
obtained from pharmacoepidemiology studies that help to
make the labeling less restrictive
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30. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
B4. To protect the drug from accusations about
adverse effects: when a question about drug
toxicity arises, it often needs an immediate
answer or else the drug may lose market share
or even be removed from market
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31. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
C. Legal
C1. Post marketing surveillance studies can
theoretically be useful as legal prophylaxis to defend
against product liability suits.
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32. 1.3. Reasons to Perform Pharmacoepidemiology Studies?
D. Clinical
D1. Hypothesis generating- need depend on
 Whether it is a new chemical entity
 The safety profile of the class
 The relative safety of the drug within its class
 The formulation
 The disease to be treated including its duration, its prevalence,
its severity, whether alternative therapies are available
D2. Hypothesis testing
 Problem hypothesized on the basis of drug structure
 Problem suspected on the basis of preclinical or premarketing
human data
 Problem suspected on the basis of spontaneous reports
 Need to better quantitate the frequency of adverse reactions
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