Pharmaceutical Regulaions; Emergence & Complexity

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