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Post Marketing Surveillance & Drug Safety
Day 6
Pharmaceutical & Biological
Regulatory Sciences
(PBRS 2015) 07th June 2015
Obaid Ali & Roohi B. Obaid
CT
ND Biological
Generic GMP
Opening Question
Is dying from a disease unavoidable?
Is dying from an adverse drug reaction unacceptable?
Yes, Sometimes
No, Not acceptable
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
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
Thalidomide Tragedy …. Paradigm Shift
Birth malformation, some survived with
Deafness
Blindness Disfigurement
Cleft palate Phocomelia
Thalidomide Tragedy …. Paradigm Shift
5000 survivors
Balance in Safety & Efficacy
Furazolidone
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
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
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
Efficacy & Quality
Furosemide
Injection
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?
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.
Quality: Capsules
Caps locking problem
Disintegration Dissolution
Uniformity of weight
Content uniformity
Quality: Injectables
Particles Metal flakes
Glass pieces
Microbial growth
Fibers Fungi
growth
pH problem
Quality: Syrups
Microbial Growth
Crystallization
Less volume
Quality: Suspensions
Caking Microbial
growth
Dissolution pH
disturbed
Quality: Creams/Ointments
Phase separation
Microbial growth
Moldy smell Leakage from
container
Quality: Cosmetic Issues
Label color
Shape of secondary packaging
Surveillance & Pharmaco-epidemiology
Use & off label use
Surveillance & Pharmaco-epidemiology
Therapeutic Effect & Adverse
Reactions
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
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
Pharmacovigilance is here
Post-market adverse event safety
evaluation
Serious AE-about 3 to 4,000
reports/day
Perform overall safety
reviews
Perform reviews of specific safety
issues FDA
Increase per year 160, 000
> 3.5 million per
year
Pharmacovigilance Aim
Early detection of unknown safety signals
Detection of elevated
safety issues
Risk factors Identification
Risk Assessment
Management & Mitigation
Strategy
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
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
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
Principles of Case Evaluation
Disease occurrence in expected time
Absence of symptoms prior to exposure
Positive de-challenge or re-challenge
Principles of Case Evaluation
Consistent with pharmacological effects
Consistent with known effects in the class
Event identified in clinical trials
Absence of alternative explanations
Surveillance & Pharmaco-epidemiology
Signals of Safety
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
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
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
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
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
Potential Regulatory Radar
Modification in Labeling
Alert to Doctors & Pharmacists
Mitigation strategy
Ban & withdrawal
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
Science speaks & is visible
Drug Risks Safe Use
Eval
uat
e
Bal
ance
Gravity of Regulation
• Passive spontaneous surveillance
• Adverse Event Reporting
• Spontaneous reports Assessment
Pharmacovigilance
• Understand case series
• Epidemiological studies
• Drug use analyses
Epidemiological analyses
• Trade name, packaging, & labeling Assessment
• Medication errors examination
Medication Error Prevention
• Proposed plans Evaluation
• Ongoing plans Monitoring Risk Management
Plans
Pharmacovigilance is soul of Regulation
Animal Experiments: Relevant?
Clinical Trials: Complete?
Pre marketing Safety Data
Pharmacovigilance is soul of Regulation
Post marketing …….
Unexpected AR
Interactions
Risk factors
Quality of life
Long-term efficacy
Cost assessment
Surveillance & Pharmaco-epidemiology
Use Pattern
Surveillance & Pharmaco-epidemiology
New Interactions
Surveillance & Pharmaco-epidemiology
Pharmaco-Economics
Surveillance & Pharmaco-epidemiology
Pharmaco-Metrics
Pharmaco-Metrics
Quantification
Drug
Disease Trial
Pharmaco-Metrics
Dru
g m
od
el
des
crib
e re
lati
on
ship
s
Response (PD)
Exposure (PK)
Des
ired
an
d u
nd
esir
ed e
ffec
ts/
ind
ivid
ual
p
atie
nt
char
acte
rist
ics
Pharmaco-Metrics
Disease
Biomarker
Clinical outcome
Disease
Time course
Placebo effect
Models describe
relationships
Pharmaco-Metrics
Supportive experiment
Clinical trial
Clinical experience in post marketing
Data informing the decisions are complex and diverse
Efficiency of drug development
Pharmaco-Metrics
Quantitative clinical
pharmacologist
Statistician
Engineers
Inte
grat
ed k
no
wle
dge
acr
oss
Drug Safety
Drug Safety
Risk Evaluation & Mitigation
Strategies
Drug Safety
Drug Information & Poison
Centres
Drug Safety
Periodic Safety Update Report
Drug Safety
Adverse Event Followed by
Immunization
Stay Safe , live attention & go healthy
Stay Safe , Live Attention & Go Healthy
Proton Pump Inhibitors
Fluoroquinolones
Stay Safe, Live Attention & Go Healthy
Domperidone
Ketoconazole
