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1. AN
INTRODUCTION TO
PHARMACOEPIDEMIOLOGY
Khadga Raj Aran
M.Pharm

2. What is
Pharmacoepidemiology?
Study designs available for PE
studies
Pharmionics
Special applications of PE
Future
Reasons to perform these
studies
Sources of PE data
Molecular
Pharmacoepidemiology
Bioethical issues

3. What is Pharmacoepidemiology?
Defn:
Pharmacoepidemiology is the study of the use of and the
effects of drugs in large numbers of people.
New applied field bridging between clinical pharmacology and
epidemiology.
The history of pharmacoepidemiology is a h/o increasingly
frequent accusations about adverse drug reactions, often arising
out of spontaneous reporting system, followed by formal studies
proving or disproving those associations.

4. Potential contributions of pharmacoepidemiology
(A)Information which supplements the information
available from premarketing studies—better
quantitation of the incidence of known adverse and
beneficial effects
(a) Higher precision (eg. 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 (eg. Timolol)
(d) Relative to other drugs used for the same indication

5. (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

6. (C) General contributions of pharmacoepidemiology
(1) Reassurances about drug safety
(2) Fulfillment of ethical and legal obligations

7. Study designs available for PE studies
In hierarchical order of progressively harder to perform but more
convincing
Randomized clinical trials
Prospective cohort studies
Retrospec tive cohort studies
Case-control studies
Analysis of secular trends
Case series
Case reports

8. •‘Criteria for causal nature of an association’ is how one can
decide, how likely an association demonstrated in a particular study
is, in fact, a causal association
• First put forth by Sir Austin Bradford Hill in 1965
1. Coherence with existing information (biological plausibility)
2. Consistency of association
3. Time sequence
4. Specificity of association
5. Strength of association
a) Quantitative strength
b) Dose-response relationship
c) Study design

9. In general,
•Case reports and case series- useful to suggest an association
•Analysis of secular trends and case-control studies- useful to
explore these associations
•If study question warrants investment and can tolerate the delay
until results become available, then cohort studies and RCTs -
can be used to assess these associations more definitively.

10. Reasons to perform PE studies:
(A) Regulatory
(1) Required
(2) Toobtain earlier approval for marketing
(3) As a response to question by regulatory agency
(4) Toassist application for approval for marketing elsewhere

11. (B) Marketing
(1)Toassist market penetration by documenting the safety of the
drug
(2) Toincrease name recognition
(3) Toassist in repositioning the drug
(a) Different outcomes, e.g., quality-of-life and economic
(b) Different types of patients, e.g., the elderly
(c) New indications
(d) Less restrictive labeling
(4) Toprotect the drug from accusations about adverse effects
(C) Legal
(1) In anticipation of future product liability litigation

12. (D) Clinical
(1) Hypothesis testing
(a) Problem hypothesized on the basis of drug structure
(b)Problem suspected on the basis of preclinical or premarketing
human data
(c) Problem suspected on the basis of spontaneous reports
(d) Need to better quantitate the frequency of adverse reactions
(2) Hypothesis generating—need depends on:
(a) whether it is a new chemical entity
(b) the safety profile of the class
(c) the relative safety of the drug within its class
(d) the formulation
(e) the disease to be treated, including
(i) its duration
(ii) its prevalence
(iii) its severity
(iv) whether alternative therapies are available

13. Thus, the decision to conduct a PE study can be viewed as similar
to the regulatory decision about whether to approve a drug for
marketing or the clinical decision about whether to prescribe a
drug.
In both cases, decision making involves weighing the costs and
risks of a therapy against its benefits.

14. Sources of PE data
 Spontaneous AE reporting
 Global Drug surveillance
 Case- control surveillance
 Prescription event monitoring
 Automated databases
 Others

15. Spontaneous reporting of adverse events
•Spontaneous reporting systems are the most common method
used in pharmacovigilance to generate signals on new or rare
adverse events not discovered during clinical trials
•Very useful in HYPOTHESIS GENERATION, with need to explore
possible explanations for the adverse event in question
•A spontaneous report is a clinical observation that originates
outside of a formal study.

16. •In order to ensure that safe and effective pharmaceuticals are
available, FDA relies on:
Voluntary reporting by health care professionals or consumers
Mandatory reporting of AEs by manufacturers as required by law
and regulation.
•Individual spontaneous reports of ADRs, medication errors, &
product quality problems, sent to FDA directly or
indirectly, combined with data from formal clinical studies and
from medical and scientific literature, comprise the primary data
source upon which postmarketing surveillance depends.
•FDA also employs data mining techniques to identify ‘signals’
(previously unrecognized or unidentified serious AE)

17. •After confirmation of a ‘signal’, FDA can initiate various regulatory
actions like:
Labeling change such as a ‘boxed warning’
Restricted use or distribution of the drug
Name or packaging changes
A “Dear Health Care Professional” letter
Withdrawal of a medical product from the market

18. Example: Signal identified via spontaneous reporting confirmed
by a formal Pharmacoepidemiology study.
Background-
Phenylpropanolamine (PPA)- ingredient used in OTC and
prescription cough and cold medications as a decongestant, and in
OTC weight loss products.
In 1984, FDA received reports of Hemorrhagic stroke (bleeding
into brain or into tissue surrounding brain) in association with PPA.
In addition, there were published reports in literature.
Question-
Is the use of PPA-containing products associated with
hemorrhagic stroke?

19. Approach-
Toconfirm this signal, an ad-hoc case-control study was
conducted
Results-
The study demonstrated a statistically significant increased risk of
hemorrhagic stroke among both appetite suppressant users and
first-time users of PPA as cough/cold remedy
Outcome-
FDA Advisory Committee meeting discussed the case-control
study and recommended that PPA be considered not safe for OTC
use
FDA then took steps to remove PPA from all drug products and
requested all drug companies to discontinue or reformulate PPA-
containing products.

20. •Thus, a formal epidemiological study is usually needed to confirm
a signal identified through spontaneous reports.
In spite of its limitations (underreporting , incomplete reports, etc)
spontaneous reports of AEs provide an important cornerstone for
pharmacovigilance in the US.
Yellow Card Scheme:- The UK national spontaneous ADR reporting
scheme

21. Global Drug Surveillance
•Global reporting of concerns about suspected adverse drug
reactions is a vital alerting tool
•The WHO Collaborating Centre for International Drug Monitoring
in Uppsala (now known as the Uppsala Monitoring Centre, UMC)
•Today, 73 countries – Full official members
12 countries – associate members
•National centres should report at a min monthly frequency.

22. •Recently, there has been an international effort to :
harmonize the terms used to describe the adverse events and
to set criteria and definitions for at least the major serious
types of reactions
to harmonize the way data are stored and communicated
internationally
•Main agencies involved in this are WHO, CIOMS, ICH and the EU.
•The Medical Dictionary for Regulatory Activities (MedDRA) is
being used more and more worldwide.
•Also, ICH E2B format, which is a guideline for the transmission
format for information to be included on an ADR case report is
being used

23. Case-control Surveillance
•Like prescription drugs, non-prescription drugs can also have
serious adverse effects and unintended benefits.
•Drugs previously available on prescription being approved for
OTC sales
•In CCS, multiple case-control studies are conducted simultaneously
in order to monitor the effects of prescription and OTC medications
and dietary supplements (e.g. herbals) on risk of various illnesses.
•CCS relies on self-reports of medication and dietary supplement use
•Asks about 43 indications or medication categories

24. Strengths:
1. CCS has the capacity to monitor :
Prescription drugs
Potentially important confounders
Over-the-counter drugs
Dietary supplements
2.Can have high statistical power because of large number of
cases accrued
3.As CCS obtains data on many exposures and many outcomes, it
has capacity to discover unsuspected associations.
•Example : Inverse association between aspirin and risk of
colorectal cancer was documented in CCS
Publication provoked many subsequent studies which confirmed
the association.

25. 4.Assessment of effects after long intervals or duration of use Eg:
Adverse effect of estrogen supplements on risk of endometrial
cancer persisted for 15-19 yrs after cessation of use.
5.Allows for assessment of whether genetic polymorphisms
modify the effect of a medication or supplement on the risk of the
illness.(buccal cell samples)
•Limitations-
Potential for selection bias and recall bias.

26. Prescription Event Monitoring
•PEM is a pharmacoepidemiological study in which a cohort of
users of a medicine is defined from prescriptions and followed-up
for a defined period (often 6-12months) so as to identify all adverse
events occurring in the early post-treatment period.
•The limited contribution of spontaneous ADR reporting system in
detecting hazards such as oculomucocutaneous syndrome with
practolol, led Inman to establish the system of PEM at the Drug
Safety Research Unit (DSRU) at Southampton in 1981
•It is one form of pharmacovigilance and is complementary to
spontaneous reporting of suspected ADRs
•Method of both hypothesis generation and testing

27. DSRU notifies PPD of new drug to be studied
Patient takes prescription to pharmacist
Pharmacist dispenses drug and forwards prescription to PPA for reimbursement
purposes
PPA sends prescription data to DSRU in strict confidence
DSRU sends questionnaire (Green Form) to GP
GP returns questionnaire to DSRU; scanned; reviewed
Data from questionnaire entered on DSRU database
Follow-up
Selected Events
Questionnaire
sent to GP
Pregnancies
Questionnaire
sent to GP
for outcome
Deaths
Cause
of
death

30. Automated databases
•There is a growing use of computerized databases containing
medical care data, called “automated databases” which are
potential data sources for pharmacoepidemiology studies.
CLAIMS DATABASES MEDICAL RECORD DATABASES
Arise from person’s use of
health care system, &
submission of claims to
insurance companies for
payment
Arise from increasing use of
computerization in medical care

31. •Advantages :
1. Provide a very large sample size , so uncommon outcomes can
be detected
2. Provides denominator needed to calculate incidence rate
3. Relatively inexpensive to use because studies using these
databases do not need to incur the cost of data collection
4. No opportunity for recall or interviewer bias
5. When time is limited
6. When budget is limited

32. Other sources of data:
•Drug utilization data
•Disease incidence data
•Ad hoc case-control studies
•Registry data
•Pharmacy based postmarketing surveillance studies
•Ad hoc cohort studies

33. Why do individuals or groups of individuals respond differently to a
specific drug therapy, both in terms of beneficial and adverse
effects?
MOLECULAR PHARMACOEPIDEMIOLOGY
Defn:
It is the study of the manner in which molecular biomarkers
alter the clinical effects of medications in populations
 Genes can affect a drug response via:
-alteration of drug pharmacokinetics
-Pharmacodynamic effects on drug targets
-Gene-drug interactions in the causal pathway of disease

34. •Pharmacogenetics- study of how genetic variability is responsible
for differences in patients’ responses to drug exposure. (candidate
gene approach)
•Pharmacogenomics- Studies of genetic variability on drug
exposure + encompasses approaches simultaneously considering
data about thousands of genotypes in drug discovery and
development, as well as responses in gene expression to existing
medication (genome-wide approach)
•Molecular PE- focuses on effects of genetics on clinical outcomes
from medication use
•Pgenetic & Pgenomic studies are designed to examine
intermediate endpoints between drugs and outcomes (like drug
levels, PD properties or surrogate markers of drug effects)

35. Molecular PE answers questions related to:
•Population prevalence of SNPs and other genetic variants
•Evaluating how these SNPs alter disease outcomes
•Assessing impact of gene-drug and gene-gene interactions on
disease risk
•Evaluating usefulness and impact of genetic tests in populations
exposed, or to be exposed, to drugs

36. •The ability of genes and other biomarkers to improve patient care
and outcomes needs to be tested in properly controlled
studies, including RCTs
•Cost-effectiveness of such approaches must be justifiable given
the additional costs of genetic testing in clinical care
•Ethical, legal and social implications of genetic testing must be
considered and addressed
•Another concern, that medicines will be developed only for the
most common, commercially attractive genotypes, leading to
ORPHAN GENOTYPES.
•Idiosyncratic side effects in susceptible patients based on
genotyping---- eg. Carriers of HLA B5701 in use of
abacavir…..(orphan drugs)

37. Bioethical issues
•Violation of privacy and confidentiality is the chief risk in
pharmacoepidemiology studies
•Research ethics guidelines have stressed the procedural
requirement of a subject’s “informed consent”

38. Pharmacoeconomics: Economic evaluation of
Pharmaceuticals
•Ongoing concern about cost of medical care
•Cost of drugs is not limited to their purchase price
•Includes the cost of preparation, administration, monitoring for
and treating side effects,etc…
•In addition to differences in efficacy and safety, differences in
efficiency (or effectiveness of the agent in actual clinical practice
compared to its cost) distinguish drugs from one another.

39. •Several national governments now require presentation of
pharmacoeconomic data at the time of product registration for
pharmaceuticals to qualify for reimbursement through the
national health insurance systems
•Economic data from Phase III studies are used to support initial
pricing of new therapies and are used in professional educational
activities by pharmaceutical firms
•Post marketing economic studies are used to compare new
therapies with existing ones and also to confirm the initial Phase
III economic assessments of the product.
•3 types of economic analysis- cost-benefit
- cost-effectiveness (mc used in
medical care)
- cost-identification

40. Use of QOL measurement in PE research
•In addition to objective measures of judging the impact of
interventions like, ↓mortality, ↓rate of hospitalization, or
alteration in physiological and biochemical outcomes, “Patient-
reported outcomes” are also important tools of measurements
•HRQOL has become an established outcome measure in clinical
research
•Encompasses - ability to function normally
- to be free of pain
- free of physical, psychological and social limitations
or dysfunction
- free from iatrogenic problems associated with
treatment

41. •2 types of instruments- 1) generic
2) disease-specific
•In the form of questionnaires administered to the patients to
evaluate changes in health status over time with the treatment in
consideration
•Most common primary objective of QOL assessment in trials is ‘ to
see the effects of therapy indicated by changes in score of the
instrument over time’

42. Pharmionics
Defn:
The topic of ‘what patients actually do with prescribed
drugs’ has become a field of research known as pharmionics.
Importance:
i. Prescription drugs are cornerstone of medical care
ii. It is a basic axiom of pharmacology that ‘all therapeutic drug
actions are dose and time dependent’
Pharmionics integrates clinical epidemiology and clinical
pharmacology for better understanding of the effects of what
pts do with prescriptions , thus improving the outcomes of t/t
with medications .

43. Dosing errors made by ambulatory patients:
•They may opt not to accept the recommended treatment, and so
never procure the medicine from pharmacist. Or in some
cases, they may procure it but may take none or only a few doses.
•Patient may commence taking the medicine but, execute the
prescribed dose regimen poorly
•They may discontinue taking the medicine altogether at anytime
The high incidence of early discontinuation gave rise to the term
“persistence” which is defined for each patient as the time
between the first-taken and the last-taken doses

44. Key terms used in pharmionics:
•Adherence – encompasses all three major types of errors:
non-acceptance
poor execution
early discontinuation
Methodologic problems in monitoring patient adherence to
therapy:
•Early methods included clinical judgement, counting of untaken
pills or capsules, questionnaires, interviews, diaries and
measurement of drug concentration in plasma.
•White-coat compliance- major bias in interpretation of plasma
drug concentrations as an indicator of quality of patient’s execution
of prescribed dosing regimen.

45. Currently available solutions
ELECTRONIC MEDICATION EVENT MONITORING (eMEM)
•Essence of eMEM is to imbed into the drug package microcircuitry
that is connected to one or more micro-switches which detect when
the maneuvers occur that are needed to remove a dose of drug from
the package
•These maneuvers which vary from one type of package to another,
are referred to as “medication events”.
•Microcircuitry enters the time of occurrence of each medication
event and stores the information in its memory for later transfer to
the computer which analyses the data.

46. Common dosing errors made by ambulatory patients:
•Most common error- delayed dose (still taken within the scheduled
interval between doses)
•Toomit a single dose
•Miss two sequential doses, miss 3 sequential doses, so on…
•A prominent feature with patients’ dosing histories is –
-the higher occurrence of dose omissions with evening doses
than with morning doses
-higher omissions on weekends than on weekdays
-gradual ↑ in frequency of dose omissions as duration of t/t
increases.
-white coat compliance

47. There is a simple pragmatic reason for wanting to know what
impact these deviations from the recommended dosing regimen
have on the effectiveness and safety of the drug in question
Case example: “How much adherence is enough?”
Background- Doxycycline hyclate 100mg , orally BD for 7 days, is
generally accepted std of care for chlamydial infections of male
urethra or lower genital tract of females.
Question- How much does adherence alter responsiveness to
doxycycline
Approach- Study carried out by Public Health Dept of State of
Alabama(USA) to examine the impact of poor compliance with
prescribed dosing regimen of doxycycline on outcome of chlamydial
treatment.

48. Prescribed doxycycline was supplied to trial participants in
electronically monitored drug packages
Results-
•Pts who took as few as 25% of prescribed doses appeared to have
had successful outcomes of t/t in no significantly lesser percentage
than those who took all of the prescribed doses
•Outcomes of t/t appeared to be independent of adherence!
•This is prima facie evidence that prescribed dose could be
substantially reduced
Strength-
•Pts performed the “natural experiment” of underdosing and
demonstrated that as little as 25% of prescribed dose appeared to be
effective in treating chlamydial infection in both males and females.

49. Limitation-
•Being a natural experiment, it should be viewed as a ‘red flag’
rather than as definitive proof about how the dosing regimen could
be revised
Summary-
•“Natural experiment” can indicate the possibility of reducing
recommended doses
•It is preferable from the consumers’ perspective, to make such a
discovery early rather than late in a pharmaceutical product’s
commercial lifetime
•Pharmaceutical product developers can use such natural
experiment early in drug development, before recommended
dosing regimen and pricing has been set. This can avoid the adverse
economic consequences of postmarketing , post pricing reduction in
actually used doses.

50. •Cessation and resumption of drug actions, as patients go into and
emerge from drug holidays, are potential sources of adverse events
•Early discontinuation of medications-
-Halts the drug action, and thus the beneficial effects that the drug
may have induced up to the point of discontinuation
-Halts manufacturer’s revenue from sale of the product to patient
-Wastes whatever costs were incurred in tests and other maneuvers
to prepare the patient to start taking the drug in question.

51. Special applications of pharmacoepidemiology
•Studies of Drug Utilization
•Evaluating and improving physician prescribing
•Drug Utilization Review
•Special methodologic issues in PE studies of Vaccine Study
•PE studies of Devices
•Studies of Drug-induced birth defects
•PE and Risk management
•Use of PE to study Medication Errors
•Hospital PE

52. Future of Pharmacoepidemiology
•PE can contribute to information about drug safety and
effectiveness that is not available from pre-marketing studies
•The discipline of PE has been growing and will continue to grow
within academia, industry and government
•Methodologic advances in risk management and molecular PE
•Content areas like drug utilization review, hospital
PE, pharmacoeconomics, medication adherence, patient safety and
surrogate markers will grow as interest and need for these foci
increase

53. •Both computerized databases and de novo studies will serve as
important complements to each other
•Challenges faced by PE include :-
-
-
limited funding opportunities
regulatory restrictions
privacy concerns surrounding
human research
- limited training opportunities
- inadequate personnel
resources
•All sectors like academia, industry and government must address
the challenges facing PE and support its continued development so
as to maximize benefit and minimize risks inherent in all
medications and medical devices.

55. References
Strom BL & Kimmel SE. Textbook of
Pharmacoepidemiology.