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European Association of Faculties of Pharmacy

2010 Annual Conference - Catania, June 24 - 26

The Experience with the Master Programme in Regulatory Affairs at the

University of Lisbon Faculty of Pharmacy

JosJoséé A. Guimarães MoraisA. Guimarães MoraisFaculdade de FarmFaculdade de Farmáácia, Universidade de Lisboacia, Universidade de Lisboa

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Master Programme in Regulatory Affairs

• Why?– Regulatory affairs is a growing field with a close connection with

Pharmaceutical Sciences

• What for?– There is a growing need for experts and workers in this crucial

area for Pharmaceutical Industry

• How?– By means of an Advanced Master Programme Master after

Master existing since 2001 at the Lisboa Faculty of Pharmacy

• Background– Need and history of drug regulation

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MAJOR TOXICOLOGICAL ACCIDENTSMAJOR TOXICOLOGICAL ACCIDENTS

• 30’s - sulfanilamide syrup- U.S.A.• ethyleneglycol as solubilizer - SAFETY

– Food, Drug and Cosmetics Act

• 60’s - thalidomide - Europe• fetal malformations - SAFETY

– Directive 65/65

• 60’s - hexaclorophene baby powder - France• strength error in the preparation – QUALITY

– Quality Control reinforcement and GMP• 70’s - digoxin - suprabioavailability – SAFETY

– phenitoin - infrabioavailability - EFFICACY– BA/BE evaluation

•• 5050’’s s -- penicilin/streptomycine injectable penicilin/streptomycine injectable -- Portugal Portugal •• Cholin derived neurotoxic amine used as an excipientCholin derived neurotoxic amine used as an excipient

– D.L. 41448 – QUALITY/SAFETY

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OTHER TOXICOLOGICAL ACCIDENTS OTHER TOXICOLOGICAL ACCIDENTS leading to withdrawal from the marketleading to withdrawal from the market

benoxaprofenbenoxaprofensuprofensuprofenglafenineglafeninetriazolamtriazolamnoscapinenoscapinelomefloxacinelomefloxacinedroxicam

19831983198719871989 1989 1991 1991 199019901994199419941994

• Phototoxicity• Renal Toxicity • Gastro-Intest.Toxic. • Psychiatric• Genotoxicity• Hepatotoxicity • Gastro-Intest.Toxic.

• Anti Inflammatory• Anti Inflammatory• Anti Inflammatory• Hypnotic• Anti-cough agent• Anti-bacterian• Anti Inflammatorydroxicam

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OTHER TOXICOLOGICAL ACCIDENTSOTHER TOXICOLOGICAL ACCIDENTS

gangliosides BSE 1989/94 Neurodegen. diseases CJD risk

felbamate 1995 Epilepsy Hepatotoxicity

anorectic agents 1996 Obesity Control Toxicodependency

oral contraceptives 3rd gen. 1996 Contraception Cardiovascular Acc.

sertindole 1998 Schysophreny QT Interval

tolcapone 1998 Parkinson Hepatotoxicity

mibefradil 1998 Hypertension Hepatotoxicity

trovafloxacine/alatrofloxacine 1999 Anti-bacterian Cardiovascular Acc.

COXIB’s 2003 Anti Inflammatory Cardiovascular Acc.

nimesulide 2007 Anti Inflammatory Hepatotoxicity

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Evaluable Properties of a medicinal product

• Efficacy– A set of therapeutic properties demonstrable

through clinical trials for a therapeutic indication; clinical safety

• Safety– Knowledge on the animal toxicity non-clinical

that can be extrapolated to humans• Quality

– A set of chemical, physical and galenical properties that ensure the maintenance of the benefit/risk ratio of medicinal products throughout their therapeutic life time

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SECOND APPLICANTSVARIATIONS

FULL M.A.APPLICATION

INNOVATORMANUFACTURER

EFFICACY

SAFETY

SPECIFICATIONS

EXCLUSIVITYAPPROVAL PATENT EXPIRATION

ESSENTIAL SIMILARITY ESSENTIAL SIMILARITYESSENTIAL SIMILARITY

FORMULATION QUALITY AND PERFORMANCETIME

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• Experience accumulated throughout the years imposes the need for a strong drug regulation system for the protection of public health

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Innovation and Cost in the Pharmaceutical Industry

• A simplified version of a very long and complex process: drug discovery and development

• How new drug products become available to patients

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Research paradigm in the Pharmaceutical Industry I

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Research paradigm in the Pharmaceutical Industry II

• Looking for lead compounds e.g. in-silico docking studies

• Synthesising chemical analogues – Combinatorial Chemistry

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Research paradigm in the Pharmaceutical Industry III

• High Throughput Screening of binding to receptors – 800 biological targets available

• Selected compounds submitted to further confirmatory in vitro tests

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Research paradigm in the Pharmaceutical Industry IV

Pre-clinical/non-clinical pharmacotoxicological safety studies

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Research paradigm in the Pharmaceutical Industry V

• Formulation and Pharmaceutical Technology

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Research Paradigm in the Pharmaceutical Industry VI

• Clinical trials• Phase I Clinical trials

– Toxicity/Pharmacokinetics in healthy volunteers• Phase II Clinical trials

– Dose finding; open label studies in patients• Phase III Clinical trials

– Large scale, multi-center, double blind, controlled studies

• Superiority trials 3 500 patients to prove a 5% difference• Non-inferiority trials• Equivalence trials

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Pharmaceutical Inovation and new Pharmaceutical Inovation and new Medicinal ProductsMedicinal Products

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The Funnel Effect in Drug DevelopmentN

o. m

olec

ules

sur

vivi

ng e

ach

proc

ess

6

3.62.4

1.2 1

> 1000

Screening Pre clinical ClinicalPhase I

ClinicalPhase II

ClinicalPhase III

Approval ofNCE

Number of Years needed and Cost of developing a New Medicinal Product

Number of Years needed to develop a New Medicinal Product

8.1

11.614.2 15.3

0

5

10

15

20

1960 1970 1980 1990 2000

Num

ber o

f Yea

rs

Cost of developing a New Medicinal Product

24.4 54

300

700800

1250

0

200

400

600

800

1000

1200

1400

1950 1960 1970 1980 1990 2000 2010M

illio

n of

Dol

lars

Sales, R&D investment and profits

Company Sales 103

US$

Market share %

R&D 103

US$

R&D% sales

Profit 103

US$

Margin %

1 Pfizer 40.3 9.7 7.41 18.4 12.9 45.72 GlaxoSmithKline 27.1 6.5 4.11 15.23 Merck Sharp Dome 21.6 5.2 2.68 12.4 9.65 44.64 AstraZeneca 17.3 4.2 3.07 17.75 Johnson & Johnson 17.1 4.1 2.69 15.7 5.79 33.76 Aventis 15.2 3.7 2.48 16.37 Bristol-Myers-Squibb 14.7 3.58 Novartis 13.6 3.3 2.31 17.0 3.89 28.7

10 Roche 11.5 2.8 11.5 19.3

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Bulgaria

Austria

France

Latvia

Poland

Belgium

Germany

Liechtenstein

Portugal

Cyprus

Greece

Lithuania

Slovak Republic

Czech Republic

Hungary

Luxemburg

Slovenia

Denmark

Iceland

Malta

Spain

Estonia

Ireland

The Netherlands

Sweden

Finland

Italy

Norway

United Kingdom

Romania

goal: consensus among MS regarding benefit/risk ratio

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Drug Regulation System in the EU

* Prescription, Non Prescription, Restrict Prescription

Directive 65/65Directive 65/65

75/318 – Norms &Tests 75/319 – Multi-State – CPMP75/318 – Norms &Tests 75/319 – Multi-State – CPMP

87/21 – Abridged applications87/22 – Biotecnology: Concertation 87/21 – Abridged applications87/22 – Biotecnology: Concertation

Extension Directives: 89/342 /343/381: Immunologicals; Radio labelled; Blood derivatives; Homeopatics Extension Directives: 89/342 /343/381: Immunologicals; Radio labelled; Blood derivatives; Homeopatics

89/105 – Transparency: pricing and reimbursement; 91/356 – Good Manufacturing Practice89/105 – Transparency: pricing and reimbursement; 91/356 – Good Manufacturing Practice

Rational Use Directives: 92/25/26/27/28: Wholesale Distribution; Dispensing Status*; Labelling; PublicityRational Use Directives: 92/25/26/27/28: Wholesale Distribution; Dispensing Status*; Labelling; Publicity

Directive 2001/83Directive 2001/83

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Legislation History• Regulations in force

– 2309/93 – Establishes the European Agency and Procedures

• Centralised for Biotecnology and Innovators• Decentralised/Mutual Recognition

– Directive 93/39

– 540/95 – Pharmacovigilance • Variations to Marketing Authorisations *

– 541/95 – in centralised procedures– 542/95 – in decentralised and national procedures

•Revoked and replaced by Regulations 1084/2003 and 1234/2008

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Legislation History

• New Directives– 2001/83 – Replaces Directives

• 65/65; 75/318; 75/319 + Extension and Rational Use Directives

– 2004/27 – amends Directive 2001/83• Parliament Directive

– Drug Regulation is a complex field closely related to the whole of Pharmaceutical Sciences, deserving a specialisation

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• Drug regulation in Europe encompasses the whole life cycle of a Medicinal Product, from research to utilisation

• In the last 30 years, the system developed in order to ensure quality/efficacy/safety of Medicinal Products available to the Public Health System

• A regulatory framework and guidelines dealing with assessment and control of Medicinal Products incorporate latest R&D achievements

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• To cover all aspects of drug regulation is a huge task challenging professionals within Industry and Health Authorities, thus the need for advanced education, prompting the existence of Master and PhD programmes in this area

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STUDY PLAN FOR DRUG REGULATORY AFFAIRS MASTER PROGRAMME

Trimester Curricular Units Lectures Discussion Hours/week ECTS

Introduction to Drug Regulation 30 0 3 5

Quality – Drug Substance 30 0 3 51stDrug Policy and Economics 30 0 3 5

Total 90 0 9 15

Quality – Drug Product 30 22 5.2 5

Veterinary Medicines 30 0 3 52nd Clinical Trials 30 22 5.2 5

Total 90 44 13.5 15

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STUDY PLAN FOR DRUG REGULATORY AFFAIRS MASTER PROGRAMME

Trimester Curricular Units Lectures Practical Hours/week

ECTS

Industrial Organisation and Patent System 15 0 1.5 4Health Products 15 0 1.5 4Seminars I* 15 0 1.5 2Pharmacoeconomics OP I** 15 22 3.7 5Farmacoepidemiology OP I** 15 22 3.7 5

3rd

Applied Bioestatstics OP I** 15 22 3.7 5Total 60 22 8.2 15

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STUDY PLAN FOR DRUG REGULATORY AFFAIRS MASTER PROGRAMME

Trimester Curricular Units Lectures Practical Hours/week

ECTS

Pharmacotoxicology 30 22 5.2 7Seminars II* 15 0 1.5 3Biotecnology Medicinal products OP II** 15 22 3.7 5Pharmacokinetics & Drug Development OP II** 15 22 3.7 5

4th

Pharmacovigilance OP II** 15 22 3.7 5Total 60 44 9.5 15

Grand Total 270 110 --- 60

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Drug Policy and Economics

Date/Time Hours Subject

08 Abr/18:00‐19:30 1,5 L INTRODUCTION

08Abr /20:00‐21:30 1,5 L Health Systems and their development

15 Abr /18:00‐19:30 1,5 L Health System in Portugal

15 Abr /20:00‐21:30 1,5 L Challenges and sustainability of Health Systems

22 Abr/18:00‐19:30 1,5 L Drugs in the Health System 

22 Abr /20:00‐21:30 1,5 L Drugs and the Health Market 

29 Abr /18:00‐19:30 1,5 L International Drug Policy and Regulation in Health

29 Abr /20:00‐21:30 1,5 L European Drug Policy

06 Mai/18:00‐19:30 1,5 L Development of the European System for Drug Evaluation and Supervision

06 Mai /20:00‐21:30 1,5 L Drug Policy of Political Parties and Government

20 Mai /18:00‐19:30 1,5 L Drug Financing System in Portugal and Other EU Member States

20 Mai /20:00‐21:30 1,5 L Challenges and Future Trends 

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General topics

Current challenges for Health Systems

Public Health reform

Contracts in Health Care

Drug price regulation: competitivenessDC and MR proceduresCentralised Procedure: an account 1995/05Future challenges in Drug Regulation

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Specific topics

Orphan DrugsNon-prescription drugsPaediatric DrugsNew Therapies in OncologyTissue EngineeringCurrent issues in Clinical InvestigationResearch in Medicinal Chemistry R&D opportunities in PortugalR&D in Pharmaceutical BiotechnologyNew tendencies in Biotechnology

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Thesis subjects

• Clinical Assessment of Medical Devices

• Non prescription Drugs – classification criteria and regulation

• Patient information – from Summary of Product Characteristics to Patient leaflets and clinical practice

• Orphan Drugs – regulation and applications

• Biosimilars – regulatory environment

• Counterfeit drug products – measures to be taken

• Paediatric medicines – regulatory framework

• Clinical trials – regulation in Europe

• Pharmacovigilance – the European system

• Quality management in Drug Regulation

• Off-label Use of Medicines

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Thesis subjects

• ADR reporting for cosmetics and other hygiene products

• Pricing and reimbursement policies in Europe

• Internationalisation of Portuguese enterprises

• Pre-clinical evaluation of Biotechnology products

• The generic market in Portugal

• Quality variations – regulation CE/1234/2008

• Medical devices – classification of border line products

• Maintenance of Marketing Authorisations for products with adverse safety profile

• Risk Management Plan for isotretinoine

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Master Programme in Regulatory Affairs

• Programme running since 2001 every 2 years with an average of 40 students

• Job opportunities– National Drug Agencies: INFARMED; AFSSAPS; MHRA– European Medicines Agency– Department of Regulatory Affairs – Industry

• Recognition by the Professional Body – Ordem dos Farmacêuticos– Specialisation in Drug Regulatory Affairs

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