PHARMACOEPIDEMIOLOGY

Learning objectives
 What is Pharmacoepidemiology?

 Study designs available for PE studies

 Reasons to perform these studies

 Sources of PE data

 Molecular Pharmacoepidemiology

 Bioethical issues

 Pharmionics

 Special applications of PE

 Future
 What is Pharmacoepidemiology?

Definition:
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 an increasingly frequent

accusations about adverse drug reactions, often arising out of
spontaneous reporting system, followed by formal studies proving
or disproving those associations.
 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

(b) In patients not studied prior to marketing, e.g. the
elderly, children, pregnant women

(c) As modified by other drugs and other illnesses.

(d) Relative to other drugs used for the same indication
(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

 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
 •‘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
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.
 Reasons to perform PE studies:

(A) Regulatory

(1) Required
(2) To obtain earlier approval for marketing
(3) As a response to question by regulatory agency
(4) To assist application for approval for marketing elsewhere
(B) Marketing

(1) To assist market penetration by documenting the safety of the

drug
(2) To increase name recognition
(3) To assist in repositioning the drug
 Different outcomes, e.g., quality-of-life and economic
 Different types of patients, e.g., the elderly
 New indications
 Less restrictive labeling
(4) To protect the drug from accusations about adverse effects

(C) Legal
(1) In anticipation of future product liability litigation
(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
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.
 Sources of PE data

 Spontaneous AE reporting

 Global Drug surveillance

 Case- control surveillance

 Prescription event monitoring

 Automated databases

 Others
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.
•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)
•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

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?
Approach-
To confirm 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.
•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
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.

•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
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

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.
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.
 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

 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

Pregnancies
Selected Events Deaths
Questionnaire
sent to GP Cause of
Questionnaire death
for outcome
sent to GP
 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 Arise from increasing use of

health care system, & computerization in medical
submission of claims to care
insurance companies for
payment
•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

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
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
•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)
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
•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)
 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”
 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 .
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
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.
 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.
Common dosing errors made by ambulatory patients:

•Most common error- delayed dose (still taken within the scheduled
interval between doses)

•To omit 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
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.
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.
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.
•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.
 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
 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.
•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.
References

Strom BL & Kimmel SE. Textbook of

Pharmacoepidemiology.