The document discusses post-marketing drug safety and surveillance. It begins by discussing the thalidomide tragedy in the 1950s and 1960s that led to increased regulation. It then discusses several more recent drug safety issues in the 21st century. The bulk of the document focuses on the importance of pharmacovigilance and post-marketing surveillance in monitoring drug safety, identifying new risks, and ensuring drug quality after approval. It describes the goals, principles, and methods of post-marketing surveillance and emphasizes its critical role in balancing drug efficacy and safety.
2. Post Marketing Surveillance & Drug Safety
Day 6
Pharmaceutical & Biological
Regulatory Sciences
(PBRS 2015) 07th June 2015
Obaid Ali & Roohi B. Obaid
6. Thalidomide Tragedy …. Paradigm Shift
1954, Synthesis in
West Germany by
Grunenthal
Available to
patient in 1957 in
West Germany
Available in 46
countries till
early 1960s
Withdrawal in
Dec 1961
Available in
Canada till 1962
Called as “wonder
drug” for safe and
sound sleep
7. Thalidomide Tragedy …. Paradigm Shift
Effective against
symptoms
associated with
morning sickness
Thalidomide
crossed the
placental wall
Peripheral neuritis
Killer and disabler
of thousands of
babies
8. Thalidomide Tragedy …. Paradigm Shift
Birth malformation,
some survived with
Deafness
BlindnessDisfigurement
Cleft palate Phocomelia
23. Efficacy & Quality
Bupripion
HCl tab
• Study on
low dose
and waiver
on high
dose
Failure
• Desired
kinetics
was not
achieved
Teva
• FDA asked
to stop
distribution
in sep 2012
24. Efficacy & Quality
In 2006, Generic version
Mfg by Impax/Teva were
approved
Based on evidence
demonstrating BE with low
strength
Bupripion SR Tab 1996
& XL Tab 2003
Bupripion (Wellbutrin) IR
Tab of SKB 1985
Re-switched on brand
Increased side effects,
Decreased therapeutic effect
Experienced undesirable
effects
85 post marketing reports
from Jan-Jun 2007
B
U
P
R
I
P
I
O
N
25. Efficacy & Quality
Withdrawal of Teva drug
in Mar 2013 against Sep
2012 FDA advice
Conducted study
FDA re-examined BE
data
Temporal relationship
under question
Its life, please care
General rule will not
work always
A new challenge
Also generic of Actavis
withdraw their version
B
U
P
R
I
P
I
O
N
30. Efficacy & Quality
Metoprolol
Succinate Tabs
ER Recall due to
dissolution
Tropol XL
(Sandoz)
approved in 1992
Therapeutic
failure reported in
2007
Formulation had
not been properly
validated (FDA
2008)
2009 Ethex (KV
Pharmaceuticals)
2014 Wockhardt
& Ranbaxy
Recalled due to
dissolution
What do you
think?
What should we
learn?
31.
32. Quality: Tablets
Mix up
Child resistant
caps
Less quantity
Wrong label Discoloration Chipping
Broken edges
Empty pockets
in blister
Sticking
Cracking of
tablet
Material release
from within the
tablet etc.
45. Pharmacovigilance is here
The science and activities relating to the
detection, evaluation, understanding and
prevention of adverse drug reactions or any
other drug-related problems
47. Look at the magnitude from documented
References
Adverse Drug Reactions
are among the top ten
causes of mortality
The percentage of
hospital admissions due
to drug related events in
some countries is about
or more than 10%.
Drug related morbidity
and mortality expenses
exceeded US$ 177.4
billion in the USA in
2000
50%
can be
avoided/
managed
49. Pharmacovigilance Aim
Early detection of
unknown safety signals
Detection of
elevated
safety issues
Risk factors
Identification
Risk
Assessment
Management
& Mitigation
Strategy
50. Pharmacovigilance Practice
Applies to post-marketing
activities
Involves all activities relating to
monitoring of product safety
• Collection
• Detection
• Assessment of adverse effects or risks
of products
51. Elements of AE Report
Temporal relationship to drug
Therapy details (dose,
dates/duration of use)
Baseline patient status (age, co-
morbid conditions, concomitant
medications, risk factors)
Details of adverse event (AE)
Lab results at baseline
and during event
Clinical course of AE
including outcomes
Method of diagnosis of
AE
Dechallenge and
rechallenge information
52. Assessment of previously unrecognized
(unlabeled) serious adverse events
Hands-on daily assessment
direct reports, monitors all
safety issues including known
adverse events
Extensive monitoring in initial
years of New Molecular Entities
but continued
53. Principles of Case Evaluation
Disease occurrence in
expected time
Absence of symptoms prior to
exposure
Positive de-challenge or re-
challenge
54. Principles of Case Evaluation
Consistent with
pharmacological effects
Consistent with known effects
in the class
Event identified in clinical trials
Absence of alternative
explanations
56. Safety Signals
New unlabeled
adverse events
An observed
increase in a
labeled event in its
severity or
specificity
New drug or food
interactions
Newly identified
at-risk population
Catch
57. Identifying Safety Signals
Depends on Good Reporting
Practice to acquire quality case
information to perform case-
level review or case-series
• Acquire complete information during
initial contacts and subsequent follow
up
• Entail a focused line of questioning
58. Evaluating Potential Signals
Safety issue of interest identified
AE literatures search for related cases
Case definition established; cases
assessed
Additional cases: Literature, WHO,
foreign regulators
59. Data Mining
Provides additional support to the case report
evaluation and other safety information
Comparison of observed frequency of reports for
specific drug/event combination to expected
frequency of reports for that AE in entire database
60. Epidemiological Analysis
Review and analysis of Phase IV studies
Additional study in longitudinal databases
Cooperative Agreements
Reporting Rates
cases/estimated
usage
Comparison with
background rates
Comparison to
drugs within the
same class
Comparison to
drugs for similar
indication
Interpretation
difficult to make
62. Aim of Regulation
PMR: Assessment of safety and
effectiveness of new medical
technology
PS&C: Inspection of manufacturing
facilities and products to assure
safety, quality & compliance with
regulations
C&PS: Post-marketing surveillance
to ensure the safety of consumers
& patients who use regulated
products
66. Pharmacovigilance is soul of Regulation
Animal
Experiments:
Relevant?
Clinical Trials:
Complete?
Pre marketing Safety Data
67. Pharmacovigilance is soul of Regulation
Post marketing …….
Unexpected AR
Interactions
Risk factors
Quality of life
Long-term
efficacy
Cost
assessment