Pharmacoepidemiology

Prof. Shaikh Abusufiyan
Assistant Professor,
AIKTC-School of Pharmacy,
New Panvel-410206
Part-01:
Pharmacoepidemiology
Pharma Learning Forever

At the end of this e-learning session you are able to…
A. Explain pharmacoepidemiology?
B. Discuss different types or design of
epidemiological studies.
Copyright @shaikhabusufiyan2021

Definition and history
• Pharmacoepidemiology
the study of the use and the effects of drugs in
large numbers of people.
• Thalidomide tragedy:
• In the 1960s --> it was used to control
nausea in pregnancy
• reports of limb abnormalities
• need for pharmacovigilance

Types or design of epidemiological studies
• Randomized clinical trial (experimental study)
• Cohort study
• Case-control study
• Analyses of secular trends
• Case series
• Case reports

1. CASE REPORTS
• Case reports --> simply reports of single patients.
• It describes --> a single patient exposed to a drug
experiences adverse outcome.
Case: I
• a young woman --> on oral contraceptives suffered a pulmonary
embolism.

Use:
• It is useful for raising hypotheses about drug effects
tested with more rigorous study designs.
Limitation:
• Difficult to distinguished whether patient case report is
due to:
• The drug exposure
• or typical of those with the disease

• a case report cannot be directly used
to make a statement about causation.

• One exception to this would be:
• when the outcome is rare &
characteristic of the exposure
Case II:
• An cell vaginal adenocarcinoma -->
occurring in young women --> exposed in
utero to diethylstilbestrol.

Q&A
Q.1 Give definition of Pharmacoepidemiology?
Q.2 Enlist types or design of epidemiological studies.
Q.3 What are limitations of case report study?

• Another exception would be
• when the disease course is very predictable
• and the treatment causes --> a clearly
apparent change in this disease course.
Case III:
• ability of penicillin --> to cure streptococcal
endocarditis (a disease which is nearly fatal in
the absence of treatment).

• Case reports can be particularly useful to document
causation when:
1. the treatment causes a reversible change in disease course
patient returns to untreated state when the exposure is withdrawn
And can be treated again to improve patient disease

Case IV:
• A patient suffering from an overdose of methadone is comatose.
• If treated with naloxone, a narcotic antagonist, patient immediately awakens -->
very suggestive that the drug is efficacious as a narcotic antagonist.
• As the naloxone effect wears off the patient will become comatose again, and
then if he or she is given another dose of naloxone the patient will awaken again.

2. Case series
• Case series are collections of patients
who have a single exposure & often from a single
hospital
whose clinical outcomes are then evaluated and
described.

2. Case series
• Alternatively, case series can be collections of
patients with a single outcome
CASE I:
• 100 consecutive women under the age of 50
who suffer from a pulmonary embolism --->
30 of them had been taking oral
contraceptives.

• After drug marketing --> case series are useful for two
related purposes:
1. to quantify the incidence of an adverse reaction.
CASE II:
• ``Phase IV'' post-marketing surveillance study of
prazosin was conducted --> to quantitate the incidence
of first dose syncope from prazosin.

2. To ascertain that any particular adverse effect
does not occur in a population.

CASE III:
• The ``Phase IV'' post-marketing surveillance study of cimetidine was
conducted because:
• Metiamide was an H-2 blocker --> withdrawn after marketing
outside the US because it caused agranulocytosis.
• Since cimetidine is chemically related to metiamide --> there was a
concern that cimetidine might also cause agranulocytosis.

Reference:
• Pharmacoepidemiology. Edited by Brian L. Strom., Third
Edition. Wiley. Page no:3-24.

Disclaimer (Images)
• The images used in this presentation are found from different sources all over the
Internet, and are assumed to be in public domain and are displayed under the fair
use principle for education purpose.
Copyright @ Presentation
• The said presentation is copyright under Copyright @shaikhabusufiyan2021
• The presentation is for education purpose only, don’t use the same for any legal
perspective.

Q&A
Quiz-Attendance/Feedback:
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New Panvel-410206
Part-02:

A. Explain methods of case series studies of
pharmacoepidemiology?
B. Discuss analyses of secular trends design
of pharmacoepidemiological studies.

Method of case series study
• The manufacturer through its sales representatives
recruit physicians to participate in the study.
Each participating physician
enrolled the patients to whom the drug was prescribed.

Continue…
Advantages:
• One can ensure that the patients
are typical of those with the drug
exposure or with the disease

Continue…
Limitation:
• In the absence of a control group
One cannot ensure which features are
unique to the drug exposure, or
outcome.

3. ANALYSES OF SECULAR TRENDS
• Analyses of secular trends, also called ``ecological studies,’’
• It examine
trends in an exposure (Drug) --> that is a presumed to causes ADR
and trends in a disease --> that is a presumed to effect efficacy
and test whether the trends coincide.

• These trends can be examined over time
• one could analyze data from a single
region --> and examine how it changes
over time.

• Vital statistics are used for these studies.
• Eg. one might look at sales data --> for oral
contraceptives and compare them to death rates
from venous thromboembolism
• CASE I:
• Mortality rates from venous thromboembolism -->
were seen to increase in parallel with increasing
oral contraceptive sales in women of reproductive
age.

Q&A
Q.1 Who is responsible for recruitment of physicians in
case series study?
Q.2 What is limitation of case series study of
pharmacoepidemiology.
Q.3 What is synonyms of analysis of secular trend?

USE:
• Analyses of secular trends are useful --> for rapidly providing evidence
for or against an hypothesis.
Limitation:
• These studies lack data on individuals
• They only study groups
• Thus, among exposures whose trends coincide with that of the disease
--> unable to differentiate.

CASE II: Lung cancer mortality rate in US
• Lung cancer mortality rates in the US have been increasing in women
to the extend that lung cancer is now the leading cause of cancer
mortality in women.
This is consistent with the increasing rates of cigarette smoking observed
in women until the mid-1960s
supportive of the association between cigarette smoking and lung cancer.

CASE CONTROL STUDIES
• Case control studies are studies
which compare:
Cases with a disease to controls
without the disease.

CASE CONTROL STUDIES
• Eg. one could select cases of young women
with venous thromboembolism.
• and compare them to controls -->without
venous thromboembolism
• looking for differences in antecedent oral
contraceptive use.

USE:
• when one wants to study multiple
possible causes of a single
disease
• when one is studying a relatively
rare disease.

Challenges:
• Case control studies generally obtain their information on exposures
retrospectively i.e recreating events that happened in the past.
• Information is generally obtained by
• abstracting medical records or
• by administering questionnaires or interviews.

Continue:
• The proper selection of controls can be a challenging task,
appropriate control selection can lead to a selection bias
which may lead to incorrect conclusions.

• when case control studies are well done
subsequent cohort studies or randomized clinical trials
will generally confirm their results.

Q&A
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New Panvel-410206
Part-03:

A. Discuss Cohort studies of
B. Explain statistical methods of analyzing
case control and cohort studies.

COHORT STUDIES
• Cohort studies
identify subsets of a defined
population
follow them over time
observe differences in their outcome.

USE:
A. used to compare --> exposed patients to unexposed patients
B. they can also be used to compare --> one exposure to another.
CASE I:
• compare women of reproductive age who use oral contraceptives to
users of other contraceptive methods --> Observe the differences in
the frequency of venous thromboembolism.

• Result:
• the relationship between oral contraceptives and
thromboembolism was noted earlier using analyses
of secular trends and case control studies
confirmed after Cohort study.

Types
• 2 Types
1. Prospective:
Conducted simultaneous with
the events under study
2.Retrospective:
Conducted after the events by
recreating past events using
medical records, questionnaires,
or interviews.

The difference between cohort and case control studies:
• It is depends on the basis on which patients are recruited into the study.
Case control studies
Patients are recruited on
the basis of the
presence or absence of
a disease and their
antecedent exposures are
then studied.
Cohort studies
Patients are recruited
on the basis of the
presence or absence
of an exposure and
their subsequent
disease course is then
studied.

USE:
• Cohort studies are particularly useful:
• when one is studying multiple possible
outcomes from a single exposure
• useful --> in post marketing drug
surveillance studies --> which are looking at
any possible effect of a newly marketed
drug.

Limitations:
• It require extremely large sample sizes to
study relatively uncommon outcomes.
• In addition, prospective cohort studies
can require a prolonged time period to
study delayed drug effects.

Q&A
Q.1 What are two types of cohort studies?
Q.2 Give difference between cohort and case control study.
Q.3 What are limitations of cohort study?

ANALYSIS OF CASE CONTROL AND COHORT STUDIES
• Both case control and cohort studies
provide the same basic information
• The difference is --> how this information
is collected.

Relative risk:
The key statistic reported from these studies
is the relative risk.
• The relative risk is the ratio of
the incidence rate of an outcome in the
exposed group to incidence rate of the
outcome in the unexposed group.

Statistical Interpretation of Relative Risk
A.
Relative risk
greater than 1.0
exposed subjects
have a greater
risk of the
disease than
unexposed
subjects
B.
Relative risk
of 1.0
exposed subjects
and unexposed
subjects have the
same risk of
developing the
disease
C.
Relative risk
less than 1.0
exposed subjects
have a lower risk
of the disease
than unexposed
subjects

Problem with Case control study
• In a case control study
one cannot determine the size of either
the exposed population or the
unexposed population.
Therefore, relative risks cannot be
calculated directly from a case control
study.

Solution:
• While reporting the results of a case control study
one generally reports the odds ratio
which is an estimate of the relative risk when the
disease under study is relatively rare.

P VALUE
• Both relative risks and odds ratios
--> can be reported with p-values.
It allow to determine whether the
relative risk is statistically
significantly different from 1.0

• Preferably, relative risks and odds ratios can be
reported with confidence intervals.
an indication of the range of relative risks within which
the true relative risk for the entire theoretical
population is most likely to lie.
• A 95% confidence interval --> we can be 95%
confident that the true relative risk lies in this range.
CONFIDANCE INTERVAL

Excess risk
• The excess risk also called the risk difference
or attributable risk.
It is more important in considering the public
health impact of an association
it represents the increased rate of disease due
to the exposure.

CASE-I
• For example, oral contraceptives are strongly associated with the
development of myocardial infraction in young women.
The risk of myocardial
infarction in non-smoking
women in their 20s is so
low that even a fivefold
increase in that risk
i
v
would still not be of
public health
importance.
In contrast, women in
their 40s especially if
they are cigarette
smokers. i
v
higher risk
i
V
Oral contraceptives
should not be used
in these women.

Reference:
• Pharmacoepidemiology. Edited by Brian L. Strom., Third
Edition. Wiley. Page no:3-26.

Q&A
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New Panvel-410206
Part-04:

A. Discuss Randomized Clinical trial of
B. Explain different types of
pharmacoepidemiological studies and its
applications.

RANDOMIZED CLINICAL TRIALS
• Studies in which the --> investigator
controls the therapy given to each
participant.
randomly allocate patients

RANDOMIZED CLINICAL TRIALS
CASE I:
• For example, one could theoretically randomly allocate
sexually active women
to use either oral contraceptives or no contraceptive
To see whether they differ in their incidence of
subsequent venous thromboembolism.

• The major strength of this approach is random
assignment:
• the study groups are comparable in potential
confounding variables --> that are either
unknown or unmeasurable.
• For this reason, associations demonstrated in
randomized clinical trials --> are more likely to
be causal

Problems.
• It would be impossible --> to perform
ethically and logistically.
• In addition, randomized clinical trials are -->
expensive and artificial.

• Generally they have already been performed -->
prior to marketing.
• They are likely to be used in
pharmacoepidemiology studies mainly for -->
supplementary studies of drug efficacy.
• However, they remain the ``gold standard'' by
which the other designs must be judged.

Q&A
Q.1 What is randomized clinical trails?
Q.2 What are the problem associated with randomized
clinical trails?

CATEGORIES/ TYPES OF PHARMACOEPIDEMIOLOGICAL STUDIES
1. Observational studies
• Investigator measure the parameters but
does not intervene during the study
• Case report
• Case series
• Analysis of secular trend (Ecological studies)
• Case control
• Cohort studies

2. Interventional Studies: It Involve active attempt
• to change disease parameters (Ex. Exposure)
• Or Progress of disease (By treatment)
• Ex. Clinical Trial
• Field Trial
• Community Intervention studies

Field trials
• Trials conducted outside clinical settings
are called as field trials
• It generally involve participants who are
living
at home in their normal environment, rather
than being ‘captive’ in hospitals or outpatient
clinics.

• Most trials of preventive measures, such as:
• immunizations or health education, are
‘field’ trials.
• Important differences in field and clinical
trials include:
• inclusion and exclusion criteria that may be
less stringent in field trials than criteria
often imposed in clinical trials.

Community Intervention studies
• Community intervention trials are an
example of the broader class of studies
called group-randomized trials (GRTs)
investigators randomize identifiable groups
to conditions and observe members of those
groups to assess the effects of an
intervention.

Applications of Pharmacoepidemiology
1. Practitioners:
• Help Physicians, Pharmacist, Nurses and
other health practitioners to make proper
decision about the patient treatment.
• Help physician in evaluating and improving his
prescription.

Applications of Pharmacoepidemiology
2. Government agencies and Health
care plans:
• It help such agencies to decide
policies and public health care plan.

3. Academicians:
• Conduct pharmacoepidemiologic studies
to answer many questions related to the
utilization of the drug.
4. Patients:
• To learn about safety and effectiveness
of drug products --> patients relay on
pharmacoepidemiologic studies.
.

5. PE studies of
• New vaccines, devices
• Drug induced birth defect
• Risk management
• Medication errors
6. Study of Drug Utilization and drug
utilization review.

Q&A
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/forms.gle/Z7hAtQQw2PErBorAA

New Panvel-410206
Part-05:

A. Discuss Drug utilization studies.
B. Explain effect of Marketing, Patent and
market structure on utilization of drug.

Drug utilization studies
• Drug utilization studies aim to evaluate
factors related to the
• prescribing
• dispensing
• administering
• and taking of medication
• and its associated events (either
beneficial or adverse).

Scope of Drug utilization studies
• To evaluate the present state and future trends
of drug usage.
• To estimate:
• disease prevalence
• appropriateness of prescriptions
• drug expenditures
• and adherence to evidence-based
recommendations.

Aspect of drug utilization (Factor affecting drug utilization)
• Quality of drug utilization:
• Audit is conducted --> to compare actual use to
national and regional prescription.
• Quality indices consider includes:
• Choice of drug & Drug cost
• Drug dosage
• Drug interaction & ADR awareness
• Proportion of patients being aware/ unaware
of the cost and benefit of the treatment

• Pattern of use: Following aspects are
studied
• Extent and profiles of drug use
• Trends in drug use
• Cost over the time

Patient characteristics
• Patient characteristics or preferences that
influence the use of drugs are:
• age, educational levels
• perceptions about the disease
• generic drug information
• misconceptions
• and negative perceptions regarding some medicines

Disease pattern
• Drug utilization is also depend on
the disease pattern such as
• Acute or chronic disease
• Common or rare disease
• Disease in adult/ Geriatric/
Pediatric/ women’s etc.

Disease pattern: Case study of study conducted in geriatric
patient (Awanish P et al. 2010)
• Medication related risk factors and their
effect on health outcomes in geriatric
patients
remains unclear which can only be identified
by home visits.

Continue….
• Therefore in the present study -->
door to door survey was conducted in
an area of 2 sq. km in Dehradun
to determine drug utilization pattern
and prevalence of chronic diseases in
elderly

• The study shows that Cardiac disorders
(34%) were most prevalent among elderly
population.
• 40% patients were non-compliant -->
• due to poor economic status
• difficulty in swallowing of the prescribed
dosage forms
• and disturbing side effects.

• The study also shows
Self-medication (38%) was a prevalent phenomenon
among the elderly.
• 20% patients suffered from side effects of the
drug
were advised either to reduce their dosage regimen
or to visit their physician with a request for an
alternate medicine.

Q&A
Q.1 What drug utilization studies?
Q.2 Enlist factors related to disease pattern
which affect drug utilization.

Marketing, Patent and market structure
• Drug utilization is directly
proportional to the
marketing of the drugs and its
market structure.

Case study: (GautierDuflos et al, 2012)
• Microeconomic theory implies that
the demand for prescription drugs
should be inversely related to drug prices
and directly related to marketing
expenditure.

Continue…
• Changes in market structure due to
patent expiration or other factors is likely
to reduce both the average price of a drug
and marketing expenditure

Continue…
Method: Use longitudinal, molecule-level data on
virtually all prescription drugs sold during the period
2000–2004.
Objective: to analyse the impact of changes in market
structure (primarily resulting from patent expiration)
on U.S. drug prices, marketing, and utilization.

Continue…
Result:
• Price and marketing expenditure both
decline by about 50–60% in the years
immediately following generic entry
• but the number of prescriptions remains
essentially constant during those years.

Reimbursement
• Reimbursement is the amount the insurer pays for the drug,
whether it's a private insurer, Medicare or Medicaid.
• Typically, depending on the type of drug, the insurer pays either
• the physician directly
• the drug manufacturer
• or an intermediary, such as a pharmacy benefit manager

Case study on Drug Utilization and Reimbursement
• Prescription Drug Utilization and Reimbursement
Increased Following State Medicaid Expansion in
2014. (Mahendraratnam N et al., 2017).
• Study results suggest that Medicaid expansion
• offers vulnerable patients to increased access
to health care resources

References:
• Brian L. Strom and Stephen E. Kimmel. Textbook Of Pharmacoepidemiology. Wiley Publication. 2006.Page
No.3, 13-21.
• Awanish P, Poonam Tripathi, Rishabh DP. Prevalence of Diseases and Observation of Drug Utilization Pattern
in Elderly Patients: A Home Medication Review. Indian Journal of Pharmacy Practice, 2010; 3(1):58-63
• Gautier Duflos, Frank R.Lichtenberg. Does competition stimulate drug utilization? The impact of changes in
market structure on US drug prices, marketing and utilization. International Review of Law and Economics
Volume 32, Issue 1, March 2012, Pages 95-109.
• Mahendraratnam N1, Dusetzina SB2, Farley JF. Prescription Drug Utilization and Reimbursement Increased
Following State Medicaid Expansion in 2014. J Manag Care Spec Pharm. 2017 Mar;23(3):355-363.

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