pharmaceutical regulaions; emergence & complexity
TRANSCRIPT
Saturday, May the 28, 2016
Pharmaceutical RegulationsEmergence & Complexity
Course on Health Reforms
Drug Regulatory Authority of Pakistan
Aga Khan University & Hospital
Obaid Ali, R. Ph., M. Phil., Ph. D.Civil Service Officer/ Deputy Director
Not the view of DRAP
Current judgment of speaker
No obligation on DRAP
Regulatory experience
It has nothing to do with any specific
commercial product or organization
It is just a knowledge sharing exercise
nothing more than that
DISCLAI
MER
Clinical trial
New Drug Approval
Generic Drug Approval
Manufacturing Standards
Advertisements & Promotions
Surveillance & Monitoring
Global language
Lets have a quick look on history and to clean the wind screen
Mal-practices in drug manufacturing
Regulations came into force
Tragedies occurred
Regulations continue to be stringent & complex
Historical Perspective
About Half a billion population died
4Lakh per year in Europe
Small pox Plague Meningitis Tuberculosis
Heart Attack Infections Psychiatry Diabetes
Hepatitis Ebola
Who Cares?
It is Pharmaceutical Industry … Science … Research ..
Pharmaceutical Companies
Regulatory Agencies
Very near to your and your beloved one’s lives
Drug Safety from Pre Market to Post Market"DO YOU KNOW IN 2008 ....., used to stop
bleeding during open heart surgery killed a lot of patients.
The lives of 22,000 patients in USA alone could have been saved if U.S. regulators had
been quicker to ban it. The same was extensively used in Pakistan too but no body
knows, it killed how many in our country
2008?
Over sulfated chondroitin sulfate (OSCS)
149 deaths
Test was passed
Signals not responded
Finally contamination
detected
Let’s think together
If it happened in Pakistan, were me & you able to catch?
What do you think can it be caught in testing?
Do you think we are capable to catch such level of contaminant or less?
No
YesDon’t know
100’s of
Deaths
2001-2005750m $ Mix up Too much or too
little API Contamination
A number of products, tablet, cream, control release etc.
Regulations
EnforcementCompliance
Guarantee
?
Clinical Trial
CLINICAL TRIALS
Phase 1: Efficacy studies on healthy volunteers
Phase 2: Clinical studies on a limited scale
Phase 3: Comparative studies on large number of patients
CLINICAL TRIALS/STUDIES (Cont’d)
New Drug Application (NDA): Regulatory review
Phase 4: Continued comparative studies Registration and market introduction
New Drug Approval
Safety Efficacy Quality
D R U G
Pre-clinical Studies
IND Application
Clinical studies (Phases 1-3)
NDA RA Review Approval
Post approval evaluation/
Phase4
Review of new drugs for approval, hold and ban
Extensive screening, examination, assessment, review and evaluation for
reasonable science based decision.
Continuous oversight and surveillance
Evaluates the research on the safety of the drug and
its effectivenessReviews the information to go on the drug label
Inspects the facilities where the drug will be
manufactured
The application will be classified as
“approvable” or “not approvable”
RA Role on NDA passed through IND
RA Role on NDA
If approvable, the RA requests additional information from the sponsor
The NDA is again reviewed
Following drug approval, sponsors of the drug will be required to continually assess the safety of the drug
CMC
Labeling
Testing
Animal & Clinical studies
Bioavailability
Generic Drug Approval
1. Labeling
2. Biopharmaceutical Evaluation
3. Chemistry, Manufacturing & Controls
4. Plant Inspection
Who will be responsible if any adverseevent or safety issue is identified?
Innovator or Generic?
If innovator discontinued drug due to any reason and new ADR appears
What will happen?
Manufacturing Standards
Pure
Consistent
Zero Mix Up
Drug Batches
1 2 3
Batch after Batch
Within Batch
Time after Time
Intent of GMP
• Identity, quality, and strength of pharmaceuticals.Provide assurance of
• Correct procedures are followed.Assure that
• Documentation, traceability.Provide
• Quality is “built in” to the approach.Overall Intent:To assure
What is cGMP & What it does?
DefinedRegulatory
Methodology to manufacture the
drugs
Protects Integrity &
Quality of manufactured product intended
for human use
GMP Elements
Premises Equipment Personnel Materials
Documentation Qualification & Validation Etc.
GMP Systems
Quality System
Production System
Lab Control System
Facilities & Equipment
SystemMaterials System
Packaging &
Labeling System
GMP System Indicators & Attributes
Complaints Recall Investigations & CAPA
Internal Audits Reviews
Change Management
Supplier Qualification
Risk Management Deviations
Master Maintenance
Plan
Master Validation
PlanMaster
Training Plan Calibration
Soft gelatin capsule Paracetamol tablet
Pyrimethamine tragedy Metronidazole label
?
Footsteps from our backyard
Dis
inte
grat
ion
failu
re
Dis
solu
tion
failu
re
Mat
eria
l mix
up
Labe
l Mix
up
1999 100 M2002 30 M2002 500 M2010 750 M
GMP
Advertisements & Promotion
• Off-label use promotion
P
USA • 0.43 billion USD fine
2004
• Fraud
M
• Kick-backs
USA • 0.95 billion USD fine
2008
• Off-label use promotion
P
• Kick-backs
USA • 2.3 billion USD fine
2009
• Off-label use promotion
L
USA • 1.4 billion USD fine
2009
• Off-label use promotion
AG
USA • 0.60 billion USD fine
2010
• Off-label use promotion
AZ
• Kick-backs
USA • 0.52 billion USD fine
2010
• Off-label use promotion
N
• Kick-backs
USA • 0.423 billion USD fine
2010
• Failure to disclose safety data
• Off-label use promotion
G
• Paying kick-back• Making false
misleading statements
USA • 3 billion USD fine• Criminal & civil
fine
2012
• Off-label use promotion
AT
USA • 1.9 billion USD fine
2012
• Off-label use promotion
J
• Kick-backs
USA • 2.2 billion USD fine
2013
Surveillance & Monitoring
Reports, Complaints, Surveillance & Vigilance
Adverse Drug Reaction Signal Detection
Errors Safety Alerts Communications
Hiding an alleged link b/w Pioglitazone & bladder cancer
Emails raising concern about the issue were deleted
9 billion USD penalty2014
Clinical Trial
2000 for HTN
Further trials for stroke & angina
EmployeesParticipatio
n
CoI not reported
Employees in data
analysis
Manipulation in
scientific reports
Data fabrication Reported
Retraction of several
papersPublicly
apologized
2014-2015Got temporary suspension of
business
Reputational hit Data tempering
False advertisingData hiding Ends up with sorry
Global Language
Science has one language & speaks with logic
Lets enjoy benefits of science
Doctor
Driver
Technician
Manufacturing facility
PharmacistAll require a license to work/practice
Harmonization saves Resources
Harmoniz/sation Works
ICH
Japan
EU
ICH
USA
Observers: WHO & Canada
Balance is required between
Fast Access
Sovereign interest
Western Medicine
Economical Interest
Innovation
Safety
Globalization
Alternative Medicine
Social Interest
Stewardship
Standardized Data Elements
Controlled Vocabularies
Common Format
Outcomes
Speak same language
Quality, accuracy & consistency
Improve timeliness
CTD/eCTDreduces
delays and costs
Outcomes
Global Regulatory Initiatives
Joint Inspections
Joint investigations
Mutual Recognition
Data sharing
Memorandum of Understanding
If you want to go fast, go aloneIf you want to go far, go together
Thanks