History n evolution of the branch. brief description follows.

1. Pharmacoepidemiology
Dr. Haripriya Uppala
Post Graduate
Pharmacology
S.V.M.C

2. Source
• ISPE – International Society of
PharmacoEpidemiology webite -
http://www.pharmacoepi.org
• Drug Benefits and Risks: International
Textbook of Clinical Pharmacology-By
Christoffel Jos van Boxtel, Budiono Santoso, I.
Ralph Edwards
• Internet – various websites.

3. Pharmacoepidemiology
Clinical
Pharmacology
Epidemiology

4. “The study of the use and
effects of medications in large
numbers of people”
Strom

5. “The application of epidemiologic
knowledge, methods, and reasoning
to the study of the effects (beneficial
and adverse) and use of drugs in
human populations.”
Porta & Hartzema

6. “The study of drugs as
determinants of health and
disease in the general
unselected population.”
Spitzer

7. History and evolution

8. 1906

9. The initial drug-oriented law in
U.S.
“Pure Food and Drug Act“
(Wiley act)
Pillar of progressive era
Illegal to manufacture
adulterated or misbranded
foods or drugs
No evidence/proof regarding
safety/efficacy required.
CHANGE IS A GOOD THNING
- Theodore Roosevelt

10. 1937

11. Taste of Raspberries, Taste of Death
The 1937 Elixir Sulfanilamide Incident
• 1932: 1st sulfa drug
• Elixir of Sulfanilamide – chemist Watkin’s
creation, a liquidated sulfanilamide for children.
• 10% sulfanilamide, 72% diethylene glycol (DEG),
16% water, “elixir flavor”, raspberry extract,
saccharin solution, amaranth, and caramel.
• 107 deaths, 208 survivors.
• Cause of death – Renal failure.

12. 1938: Food, Drug & Cosmetic (FD&C)
Act
• Requires new drug pre-marketing safety studies –
Origin of what is now the pharmacoepidemiology
• Prohibits false therapeutic claims
• Authorizes factory inspections
• Allows FDA to request court injunctions (previously:
only seizures & prosecutions)
• Extends control to cosmetics and devices
• Requires safe tolerances for unavoidable poisonous
substances

13. 1961

15. Thalidomide tragedy
• introduced in the 1960s
• marketed as Contergan®
• used to control nausea in pregnancy
• reports of limb abnormalities

16.  Dr. William McBride of Australia
reported increased frequency of
birth defects (seal limbs) with
thalidomide usage, that left
10,000 babies disabled for life.
• Kefauver-Harris Amendments
• “Proof of Efficacy” required
• Adverse events reporting to
FDA required
• “Informed consent” for clinical
studies
• Drug ads must disclose side
effects
• 2-year inspection mandate

17. The Vioxx® controversy
First reports of MI in VIGOR
2007
Confirmed by cohort study
Published in the Lancet
400K Medicaid patients
Î in risk of MI
Need for post-marketing
drug studies

18. • Recent data indicate that 100000 Americans
die each year from Adverse Drug Reactions,
and 1.5 million US hospitalizations each year
result from Adverse Drug Reactions; yet, 20-
70% of Adverse Drug Reactions may be
preventable. The harm that drugs can cause
has led to the development of the field of
pharmacoepidemiology.

19. In INDIA ???????
No sufficient data till date

20. Pharmacoepidemiology
• All drugs have adverse effects.
• Pharmacoepidemiology will never succeed in
preventing them.
• It can only detect them, hopefully early, and
thereby educate health care providers and
public, which will lead to better medication
use.

21. • The net results of increased activity in
Pharmacoepidemiology will be better for industry
and Academia but most importantly, for public’s
health.
• Pharmacoepidemiology can minimize its adverse
public health impact by detecting it early.
• At the same time, it can improve the use of drugs
that have genuine role, protecting against the loss
of useful drugs.

22. • Pharmacology is the study of the effect of drugs; and
clinical pharmacology is the study of effect of drugs in
humans.
• Part of the task of clinical pharmacology is to provide a
risk benefit assessment for the effect of drugs in
patients.
• Doing the studies needed to provide an estimate of the
probability of beneficial effects in populations, or the
probability of adverse effects in populations and other
parameters relating to drug use may benefit from using
epidemiological methodology.

23. • Epidemiology = Epi(on the) demos(people)
logos(study)
• Epidemiology can be defined as the study of
the distribution and determinants of diseases
in populations.
• Epidemiological studies can be divided into
two main types:

25. Observational VS Experimental studies
• Observational studies , Allow nature to take its
cause; the investigator measures but does not
intervene.
• Descriptive study: focuses on the description
of the occurrence of a disease in a population.
• Analytical study analyses relationships
between health status and other variables.

26. • Experimental or interventional studies: involve
an active attempt to change a disease
determinant(e.g an exposure or a behaviour)
or the progress of a disaese (through
treatment)
• The studies are based on a group which has
had the experience compared with control
group which has not had the experience.

27. Purpose of descriptive epidemiology
• To generate hypothesis
• To permit evaluation of trends in health &
disease and comparisons among countries
and subgroups within countries.
• To provide a basis for planning, provision and
evaluation of health services
• To identify problems to be studied by
analytical methods and to suggest areas that
may be fruitful for investigation.

28. Case reports
• Documents unusual medical occurrences
• Can represent the first clues to the
formulation of hypothesis
• Generally report a new or unique findings
• Previous undescribed disease.

29. • Eg; Zappacosta presented a case report of a
patient treated with minoxidil that was
discovered to stimulate the hair growth.
• Subsequently a topical formulation of
minoxidil was developed to take advantage of
that effect

30. Case series
• Collection of individual case reports which
may occur within a fairly short time
• Experience of a group of patients with similar
diagnosis.

31. • Eg: Krishnamoorthy and king reported on the
adverse effects associated with the use of
olanzapine in 5 children with severe
behavioural problems.
• Adverse events includes: wt. gain(3/5
children)sedation(2/5 children) and akathisia
(2/5 children).

32. Case series
Advantages
Useful for hypothesis generation
Informative for very rare disease with few
established risk factors
Usually of short duration.
Disadvantages
Cannot study cause and effect relationships
Cannot assess disease frequency

33. Cerivastatin (Baycol), an
effective and inexpensive
lipid lowering drug, was
introduced in 1997. It was
removed from the market
in 2001 because of reports
of fatal cases muscle
breakdown
(rhabdomyolysis).

34. Ecological Study
• Obtain group-level exposure
information and disease
prevalence at the same point of
time.

35. Ecologic Studies:
Breast Cancer Incidence
by National Fat Intake
0
50
100
150
200
250
500 700 900 1100 1300 1500 1700
Fat intake (kcal/d)
Incidenceper100,000p-y

36. Cross-sectional study
• It is also called epidemiologic study or prevalence
study.
• It analyses (describes)data collected on a group of
subjects at one point in time rather than over a period
of time. i.e. they survey exposure and disease at a
single point in time.
• Both exposure and outcome variables are been
evaluated at the same point in time(without any inbuilt
directionality).
• Most sophisticated descriptive study.
• It answers the question “WHAT IS HAPPENING RIGHT
NOW?”

37. • Eg: cross-sectional studies was published by
Dua and colleagues, who examined
inappropriate sale of antibiotic use in
pharmacies in Nagpur.
Such studies can identify problem areas and
suggest where remedial action should be
directed

38. Cross-sectional studies
Advantages
• Best for determining the
status
(prevalence)
• Quick
• Relatively inexpensive
Disadvantages
• Only a snapshot at a time
leading to a misinformation
• Response rate may be low
,with result not
representative of the
population

39. Correlational study designs
• A study comparing incidence/prevalence of
one event against another on a global scale
• Measures that represent characteristics of
entire populations are used to describe the
disease in relation to some factor of interest
(such as age, calendar time, food
consumption, drug use and utilization of
health services)

40. Correlational study designs
Advantages
• Compares events among
nations.
Disadvantages
• Doesn’t compare
individuals, so it might lead
to overgeneralization.

41. Analytical studies
Two basic designs:
• Case – control or retrospective study
• Cohort or prospective
• NOTE
• There must be a comparison group
• No control No conclusion(NCNC)

42. Case control or case history study

43. Advantages of case control
studies
• Relatively easy to carry out.
• Rapid and inexpensive.
• Requires comparatively few
subjects.
• Can assist one in studying
different etiological factors.
• Does not need an ethical
clearance.
• No risk to the subject .
Disadvantages of case control
studies
• Introduces bias
• To select an appropriate
control could be difficult
• It may be difficult to
distinguish between the
cause of a disease and an
associated factor

44. Cohort study
• A cohort is a group of people who have
something in common and remain part of a
group over an extended time
• A group of people exposed to a suspected
etiological agent are compared with a matched
control who have not been similarly exposed.
Subject selected on the basis of exposure [a
etiological factor; cigarette smoking]
• Follow-up over a period to compare the outcome
• aka Longitudinal study or Prospective study

45. Cohort Study design

46. Advantages
• No bias
• Risk can be calculated bcos the
incidence can be calculated
• Effective for studying rare
exposures
• Allows the study of the natural
history of the disease
• Assists in determining the
temporal relationship between
the etiological factor & the
disease
Disadvantages
• Takes a long time
• Expensive
• Large no of subjects are
needed
• There could be changes in
the standard methods or
diagnostic criteria

47. Experimental studies
• Studies in which 1 group is deliberately
subjected to an experience compared with a
control group with no similar experience
• The gold standard in medicine because it
proves causality
• Can be controlled or uncontrolled

48. Experimental / intervention studies
Uncontrolled experimental
studies
• Intervention is not
compared with a control
• The aim is to confirm that
the Intervention made a
difference
Uncontrolled experimental
studies
• In this study, a drug or
procedure is compared to:
1. Another drug
2. Procedure
3. Placebo
4. Previously accepted tx
• The aim is to prove the
difference due to tx

49. Uncontrolled experimental studies
• Control could be:
• Blind trial-single or double
A. METHODOLOGY
1. Concurrent or parallel: randomized or non-
randomized(quasi)
2. Sequential control: self controlled or cross over
3. External control

50. Study population
1. Clinical trials
2. Field trials
3. Community trials

51. Experimental studies
Advantages
• Best study type
• Greatest proove of causality
• Gold standard for other
design
• Least bias
• Proves best tx or procedure
efficacy
Disadvantages
• Greatest expense
• Long duration
• Unproven facts adopted by
community can hinder
study acceptance

52. Drug utilization study
• Aims to evaluate factors related to the
prescribing, dispensing, administering and taking
of medication, and its associated events (either
beneficial or adverse).
• Since the early 1960’s the interest in Drug
Utilization Studies has been increasing, first with
market-only purposes, then for evaluating the
quality of medical prescription and comparing
patterns of use of specific drugs.

53. • The increasing importance of drug utilization studies as
a valuable investigation resource in
pharmacoepidemiology has been bridging it with other
health related areas, such as public health,
pharmacovigilance, pharmacoeconomics, eco-
pharmacovigilance or pharmacogenetics.
• Drug utilization research is thus an essential part of
pharmacoepidemiology as it describes the extent,
nature and determinants of drug exposure. In common
use, the distinction between these two terms has
become less sharp, and they are sometimes used
interchangeably.

54. Insights into the following aspects of drug
use and drug prescribing
• Pattern of use:
• extent and profiles of drug use
• trends in drug use and costs over time.
• Quality of use:
Audits comparing actual use to national and regional prescription
guidelines or local drug formularies.
Quality indices of drug use may include the
• choice of drug
• drug cost
• drug dosage
• drug interaction awareness
• ADR awareness
• proportion of patients being aware of/unaware of the cost/benefit
of the treatment, etc.

56. 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

57. Impact of pharmacoepidemiology
• population based drug related studies
• rare drug adverse events
• drug efficacy
• drug interactions
• patterns of use

58. Studying drug interactions in
pharmacoepidemiology
– drug interaction studies
usually small human studies
in vitro studies
soft end-points
– usually look at soft outcomes
– clinical significance of interaction-unknown
Eg., cimetidine vs. P-450 inhibition
not all interactions clinically significant

59. Drug interactions in
pharmacoepidemiology
• case-control study by Juurlink (JAMA;2003)
• looked at interaction between
1. cotrimoxazole+glyburide----hypoglycemia
2. clarithryomcin+digoxin ---- digoxin toxicity
3. K+sparing diuretics+Ace-inhibitors-- hyperkalemia
• used the ODB data using 1.5 million older adults
• 7 years time span
• matched for age, sex, medication, renal disease,
comorb

60. Bias in pharmacoepidemiology
• Bias -- Systematic error in research
• Types of bias
1. Recall bias -- difficulty recalling drug
2. Selection bias -- one group different than another
3. Channeling bias --- drug prescribed to sicker patients
4. Misclassification bias ---- Either disease or drug misclassified

61. Pharmacovigilance
• A type of continual monitoring for unwanted
effects and other safety-related aspects of drugs
that are already on the market. In practice
• Spontaneous reporting systems which allow
health care professionals and others to report
adverse drug reactions to a central agency.
• The central agency can then combine reports
from many sources to produce a more
informative safety profile for the drug product
than could be done based on one or a few
reports from one or a few health care
professionals.

62. Clinical Pharmacology
Epidemiology
&Biostatistics
Pharmacovigilance
Drug utilisation
studies
Pharmacoeconomics
&
Pharmacogenomics

63. The gem cannot be polished
without friction, nor medicines
perfected without trials.
– Chinese proverb.