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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW
DRUG DEVELOPMENT
Prof. JanHasker G. Jonkman,
Ph.D., F.C.P., F.R.Q.A., R.Ph.,
Clinical Pharmacologist

University of Groningen (NL)

Professor Quality Management in Drug Research and Manufacturing

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

WORLDWIDE SALES OF MEDICINES:

BY REGION (2010)

Country

Sales
(billion US $)

% of worldwide
sales

North America

342

39.1

Europe
Asia (excluding Japan),
Africa and Australia
Japan
Latin America
TOTAL

250

28.6

129
99
53
875

14.8
11.3
6.2
100.0

(Source: PAREXEL R&D Sourcebook, 2011/2012)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

WORLDWIDE SALES OF TOP 10 MEDICINES:

BY THERAPEUTIC CLASS (2010)
Rank
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Therapeutic Class

Sales
(billion US $)

Cytostatics
Cholesterol &
Triglyceride reducers
Respiratory agents
Antidiabetics
Anti-ulcerants
Angiotensin-II inhibitors
Antipsychotics
Autoimmune agents
Antidepressants
HIV Antivirals

% of worldwide
sales

% of growth
(vs 2009)

56.0

6.4

+ 6.7

36.4
35.9
34.4
28.0
26.6
25.4
20.7
20.2
15.4

4.2
4.1
3.9
3.2
3.0
2.9
2.4
2.3
1.8

+ 2.0
+ 7.0
+ 12.2
- 6.5
+ 4.5
+ 9.0
+ 14.7
+ 3.4
+ 13.2

(Source: PAREXEL R&D Sourcebook, 2011/2012)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

WORLDWIDE SALES OF TOP 10 MEDICINES:

BY PRODUCT (2010) (1)
Rank
1.
2.
3.

4.
5.

Product
Lipitor
(atorvastatin; antilipidic agent)
Plavix
(clopidogrel; antithrombic agent)
Seretide
(salmeterol/fluticasone;
asthma/COPD)
Nexium
(esomeprazol; antiulcer)
Seroquel
(quetiapine; antipsychotic agent)

Sales
(billion US $)
12.7

Company
Pfizer

8.8

Sanofi-Aventis

8.5

GSK

8.4

Astra Zeneca

6.8

Astra Zeneca

(Source: IMS Health World Review, 2010)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

WORLDWIDE SALES OF TOP 10 MEDICINES:

BY PRODUCT (2010) (2)
Rank
6.
7.
8.
9.
10.

Product

Sales
(billion US $)

Crestor
(rosuvastatine; antilipidic agent)
Enbrel
(etanercept; antirheumatic agent)
Remicade
(infliximab; antirheumatic agent)
Humira
(adalimulab; antirheumatic agent)
Zyprexa
(olanzapine; antipsychotic agent)

Company

6.8

Astra Zeneca

7.3

Wyeth

6.0
6.0

Schering-Plough
(Merck&Co)
Abbott

5.7

Eli Lilly

(Source: IMS Health World Review, 2010)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

WORLDWIDE SALES OF MEDICINES:

BY COMPANY (2010)
Rank

Company

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Pfizer (US)
Sanofi-Aventis (F/Ger)
Merck & Co (US)
Novartis (Swi)
GlaxoSmithKline (UK)
Roche (Swi)
AstraZeneca (Swe/UK)
Johnson & Johnson (US)
Eli Lilly & Co (US)
Abbott (US)

Pharma sales
(billion US $)
58.2
40.3
39.8
39.1
36.1
35.6
33.3
22.4
21.1
19.9

(Source: Scrip 100, 2011)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

COSTS OF RESEARCH & DEVELOPMENT (2010)

World wide expenditure on R&D of new medicines
approximately $ 130.000.000.000 per year
Of which costs of clinical research: $ 75.000.000.000

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

TOTAL INDUSTRY R&D vs PHARMA R&D

Pharma R&D is approximately 10% of total Industry R&D

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

COSTS OF PHARMA R&D (2010)

Rank

Company

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Merck & Co
Pfizer
Roche
Novartis
GlaxoSmithKline
Sanofi-Aventis
AstraZeneca
Eli Lilly
Johnson & Johnson
Abbott

R&D spend
(US $ billion)
11.0
9.4
8.7
7.7
5.9
5.8
5.3
4.9
4.4
3.7

R&D as
%of sales
27.6
16.2
24.4
19.7
16.3
14.4
13.2
22.7
19.6
18.6

(Source: PAREXEL R&D Sourcebook, 2011/2012)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (2)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NUMBER OF NEW DRUG APPROVALS (1)

Number of New Molecular Entities (NMEs) or New
Chemical Entities (NCEs) approved for marketing:
approximately 20-60 per year

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NUMBER OF NEW DRUG APPROVALS (2)

New Molecular Entities
Approved in U.S.A.

36

27

26

25

24
22

21

18

17

2000

2001

2002

21

21

20

2003

2004

2005

2006

2007

2008

2009

2010

2011

(Source: U.S. FDA)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NUMBER OF NEW DRUG APPROVALS (3)

64

New Molecular Entities

Approved in the EU
51

50

42
39

39
34

32

24

24

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

22

21

2010

2011

(Source: EMEA)
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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NUMBER OF NEW DRUG APPROVALS (4)

But:
Also withdrawals: approx. 2-3 per year
e.g. Vioxx (rofecobix, COX-2 inhibitor; Merck & Co)
80 million people worldwide were using Vioxx:
sales were $ 2.5 billion in 2003
Widely promoted (but 21 studies by
Dr. Scott S. Reuben with fabricated positive results)
Severe side effects:
according to FDA; 88.000 139.000 heart attacks
(of which 30-40% fatal)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

DEVELOPMENT OF A NEW DRUG (2)

Synthesis of the molecule

Studies in animals

Studies in healthy volunteers

Studies in patients

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

SYNTHESIS (1)
(the development of a new therapeutic effective
molecule = drug / medicine)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

SYNTHESIS (2)
2005

2010

12%

18%

88%

Biotechnology

82%

Organic Chemistry
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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

SYNTHESIS (3)

1 out of 10,000 will reach the pharmacy

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: TIME OF DEVELOPMENT

Studies in animals

2 - 4 years

Studies in humans

4 - 5 years

Registration procedure :

2 - 3 years

TOTAL

8 - 12 years

average

10 years

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: DEVELOPMENT COSTS (1)

Approximately 800 million ($ 800.000.000) US dollars

per approved new drug
Costs are rapidly increasing

(Source: Tufts University, U.S.A., 2002)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: DEVELOPMENT COSTS (2)

802

U.S. year 2000 $ in millions

1970s approvals
1980s approvals
1990s approvals

467

335

318

214
104

84

138

54

Preclinical

Clinical

Total

(Source: Tufts University, U.S.A., 2002)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: DEVELOPMENT COSTS (3)

In 2010 US dollars the $802 million figure translates

to $1001 million

(Source: Tufts University, U.S.A., 2002)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: PATENT LIFE (1)

17 - 20 years
(depending on country)
Thereafter:
many generic versions of the drug

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NEW DRUG: PATENT LIFE (2)

Pay back period is approximately 10 years

10% of marketed new drugs are a commercial
success

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

NEW DRUG: PATENT LIFE (3)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

PHARMACOLOGY / TOXICOLOGY (2)

(the testing of efficacy and safety in animals)
Cells (tissues; in vitro)
Organs (in vitro)
Test animals (single + multiple dose)
- mice
- rats
- guinea pigs
- rabbits

- cats
- dogs
- pigs (!)
- monkeys

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (1)

(drug studies in humans)
Triad of activities:
CLINICAL RESEARCH CENTRE
(PHASE I & PHASE II)

BIOANALYTICAL
LABORATORY

BIOMETRICS
(STATISTICS)
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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (2)

(drug studies in humans)
Triad of activities:
CLINICAL RESEARCH CENTRE
(PHASE I & PHASE II)

BIOANALYTICAL
LABORATORY

BIOMETRICS
(STATISTICS)
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CLINICAL PHARMACOLOGY (3)

(drug studies in humans)
Phase I

(= clinical / human pharmacology)

Phase II

(= therapeutic exploration)

Phase III (= therapeutic confirmation)

Phase IV (= therapeutic use)

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (4)

Protocol

Participants

Phase I
Phase II
Phase III
Phase IV

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CLINICAL PHARMACOLOGY (5)

Key documents - Good Clinical Practices (1)

Declaration of Helsinki
World Medical Association
Since 1964

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (6)

Key documents - Good Clinical Practices (2)

Good Clinical Practices
United States Food and Drug Administration (FDA)
several laws since 1977

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CLINICAL PHARMACOLOGY (7)

Key documents - Good Clinical Practices (3)

Good Clinical Practices
European Union
Since 1991

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CLINICAL PHARMACOLOGY (8)

Key documents: Good Laboratory Practices (1)

United States Food and Drug Administration (FDA)
USA
Since 1978

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (9)

Key documents: Good Laboratory Practices (2)

Organization for Economic Co-operation and Development
(OECD)
Worldwide
Since 1981

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (10)

Key documents: Good Laboratory Practices (3)

Council Directive that adopts OECD
Good Laboratory Practices
European Union
Since 1986

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (11)

(drug studies in humans)
Triad of activities:
CLINICAL RESEARCH CENTRE
(PHASE I & PHASE II)

BIOANALYTICAL
LABORATORY

BIOMETRICS
(STATISTICS)
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LOOKING FOR A NEEDLE IN A HAYSTACK

INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

1% (pro cent)

10 g/kg

10 mg/g

1 (pro mille)

1 g/kg

1 mg/g

0,6 litre

1 milligram
= 10-3 g

6 litres

= 0.001 g

1 ppm (part per million)

1 mg/kg

1 g/g
1 microgram
= 10-6 g

6.000 litres
1 lump
of sugar (6 g)
dissolved in:

= 0.000 001 g

1 ppb (part per billion)

(billion = American for milliard)

1 g/kg

1 ng/g
1 nanogram
= 10-9 g

6 million litres

= 0.000 000 001 g

1 ppt (part per trillion)

(trillion = American for billion)

1 ng/kg

1 pg/g
1 picrogram
= 10-12 g

6 milliard litres

= 0.000 000 000 001 g

1 ppq (part per quadrillion)

(quadrillion = American for
1000 billion)
6 billion litres

1 pg/kg

1 fg/g
1 femtogram
= 10-15 g

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= 0.000 000 000 000 001 g

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

CLINICAL PHARMACOLOGY (12)

(drug studies in humans)
Triad of activities:
CLINICAL RESEARCH CENTRE
(PHASE I & PHASE II)

BIOANALYTICAL
LABORATORY

BIOMETRICS
(STATISTICS)
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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

PHASE I - STUDIES
(non-therapeutic studies; safety) (1)
Aim
to gather fundamental scientific information,
enabling the determination of the correct dosage
for use in larger clinical studies

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PHASE I - STUDIES
(non-therapeutic studies; safety) (2)

Required by authorities

Healthy young volunteers (a few dozen per study)

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PHASE I - STUDIES
(non-therapeutic studies; safety) (3)
Questions:
Adverse events (= side effects;

dosage)

Pharmacokinetics
how long does the drug stay in the body?
(
dosing frequency)
how is the drug metabolized in the body?
single and multiple dose (up to 4 weeks)

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PHASE I - STUDIES
(non-therapeutic studies; safety) (4)
Mass balance studies (14C)
Biopharmaceutics (optimal dosage form)
Result: dosing schedule (dose + frequency)

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PHASE I - STUDIES
(non-therapeutic studies; safety) (5)
Characteristics of Phase I studies:
work accurately
very detailed protocol ( 50 pages)
very detailed procedures (300 SOPs)

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PHASE I - STUDIES
(non-therapeutic studies; safety) (6)
Important aspects of Phase I studies:
fully equipped modern in-house clinical research centre
fully equipped modern bioanalytical laboratory
biometrics (data management, pharmacokinetics, statistics)

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INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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PHASE II - STUDIES
(therapeutic studies; efficacy; therapeutic exploration)
Patients in university hospitals ( 250)
Pharmacodynamics (measurements of effects)
single dose (Proof of Concept; Proof of Principle)
(multiple dose)

Result: immediate effect

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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PHASE III - STUDIES

(efficacy / safety; therapeutic confirmation)
Patients (peripheral hospitals; 2,500)
pharmacodynamics
(single dose + multiple dose: 6 to 12 months)
pharmacokinetics
(ibid)

Result: immediate and chronic effect

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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INTRODUCTION ON NEW DRUG DEVELOPMENT (INT-S.)

MARKETING AUTHORIZATION (1)

(registration)
European Union:

EMA
(European Medicines
Agency, London, UK)
(In the past: EMEA: European
Medicines Evaluation Agency)

USA:

FDA
(Food and Drug Administration)

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MARKETING AUTHORIZATION (2)

Definition:
Process of reviewing and assessing the dossier to
support a medicinal product in view of its marketing,
finalized by granting of the product license to sell it
(also called: registration, approval or licensing)

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MARKETING AUTHORIZATION (3)

Application is called:
USA: New Drug Application (NDA)
EU: Marketing Authorization Application (MAA)
or (in general): registration dossier

Format of dossier (agreed upon by ICH):

as Common Technical Document (CTD)
(or electronic CTD: eCTD)

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MARKETING AUTHORIZATION (4)

Module 1
1.0
2.1
2.2
2.4

2.5

2.3

Module 3
Quality

2.
6
Module 4
Nonclinical
Study Reports

(Source: L. Vromans)

2.7

1.0 Regional administrative

information (non CTD)
2.1 ToC of the CTD
2.2 Introduction
2.3 Quality overall summary
2.4 Nonclinical overview
2.5 Clinical overview
2.6 Nonclinical summary
(written & tabulated)
2.7 Clinical summary

Module 5
Clinical
Study Reports
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MARKETING AUTHORIZATION (5)

European Union (1)
Centralised Procedure (CP)
Mutual Recognition Procedure (MRP)
Decentralised Procedure (DCP)

(Source: L. Vromans)

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MARKETING AUTHORIZATION (6)

European Union (2)
Centralized Procedure (1)
Submission of dossier to European Medicines
Agency (EMA,London) for an EU-wide review
Compulsory for products in the field of
Biotechnology (including biosimilars)
AIDS
Neurodegenerative disorders
Cancer
Diabetes
Orphan drugs
Immune diseases and other immune dysfunctions
Viral diseases
Advanced therapy medicinal products
(cell/gene therapy; tissue engineered products)
(Source: L. Vromans)

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MARKETING AUTHORIZATION (7)

European Union (3)
Centralized Procedure (2)
Optional for other innovative products and for
generics if reference product used CP
Not allowed for other products

(Source: L. Vromans)

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MARKETING AUTHORIZATION (8)

European Union (4)
Centralized Procedure (3)
Review by the CHMP
(Committee for Medicinal Products for Human Use)
CHMP exists of 35 persons: one expert per EU Member
State + chairman + 5 additional members with specific
expertise
Final Marketing Authorisation issued by European
Commission
Marketing Authorisation valid in 30 countries:
27 EU countries + Norway, Iceland, Liechtenstein
Timeframe for procedure: 210 days
(plus two clock-stops)
(Source: L. Vromans)

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MARKETING AUTHORIZATION (9)

European Union (5)
Mutual Recognition Procedure
Assessment of file by one country:
Reference Member State (RMS); result is
one national approval
Choice for RMS by applicant
Start MRP: RMS Assessment report sent
to Concerned Member States (CMS)
CMS to recognise approval by RMS
(end of procedure)
National approvals in all CMS within 30 days
Choice of involved countries by applicant
(Source: L. Vromans)

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MARKETING AUTHORIZATION (10)

European Union (6)
Decentralised Procedure
Assessment by a group of National
Health Authorities
Choice of countries by applicant
Assessment report written by RMS,
sent to Concerned Member States (CMS)
for comments, before applicant is involved
RMS + CMS to agree on approval
(end of procedure)
National approvals in all CMS within 30 days
Popular route for generics
(Source: L. Vromans)

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MARKETING AUTHORIZATION (11)

USA (1)
New Drug Application (NDA)

(Source: L. Vromans)

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MARKETING AUTHORIZATION (12)

USA (2)
New Drug Application (1)
Application to obtain marketing approval
Dossier: CTD (= Common Technical Document)
format (not mandatory)
Large dossier since all Case Report Forms are included
Submission to the Food & Drug Administration (FDA)
Centre for Drug Evaluation & Research (CDER)
Centre for Biologics Evaluation & Research (CBER)
Centre for Devices & Radiological Health (CDRH)

(Source: L. Vromans)

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MARKETING AUTHORIZATION (13)

USA (3)
New Drug Application (2)
FDA review team:
Chemistry, Manufacturing and Controls reviewer
Pharmacology / Biopharmaceutics reviewer
Pharmacology / Toxicology reviewer
Biometrics / Statistical reviewer
Clinical / Medical reviewer
Bioresearch Monitoring reviewer
Continuous questions to applicant during technical review period
Pre-approval inspections are conducted
(Source: L. Vromans)

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MARKETING AUTHORIZATION (14)

Comparison EU vs USA (1)
EU

USA

Top-down approach in
evaluation
Expert evaluations
Raw data only analysed if
grounds for doubt are
found
Some interaction before
submission (increasing)
Limited company
interaction with experts
during procedure
Accelerated assessment
for high medical need
products
(Source: L. Vromans)

Bottom-up approach in
evaluation
ISS / ISE, integrated
summaries of safety &
efficacy
FDA always analyses raw
data
Many meetings before
submission
Advisory Committee
involvement
Accelerated development
and priority review for high
medical need products
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MARKETING AUTHORIZATION (15)

Comparison EU vs USA (2)
EU

USA

Withdrawal if a negative
opinion is expected
Labelling can not contain
detailed study results

Action letter evaluation

Detailed study results in
labelling (marketing!)

Approval in US does not automatically imply approval in EU,

and vice versa; co-operation between authorities is beginning
to take place (e.g. on paediatric development)

(Source: L. Vromans)

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MARKETING AUTHORIZATION (16)

Maintenance (1)
Marketing authorization is valid for 5 years

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MARKETING AUTHORIZATION (17)

Maintenance (2)
Marketing authorization need maintenance:
Variations
quality variations to improve production method
new indications, new formulations, new route of administration
results of pharmacovigilance, new safety information

Pharmacovigilance activities are required;

post-marketing surveillance
periodic Safety Update Reports
one renewal after five years (EU)
Risk management Plans (EU: RMP / US: REMS)

Registrations in other countries to extend

use of the product
(Source: L. Vromans)

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MARKET AUTHORIZATION (18)

The new drug (but also during the investigation

period) should be manufactured according to another
set of key documents:
Good Manufacturing Practices (GMP)
- 1975 : U.S.A.
- 1991 : EU

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MARKET AUTHORIZATION (19)

After receipt of market authorization continuous,

systematic documentation of side-effects:
pharmacovigilance (also called Phase V)

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MARKET AUTHORIZATION (20)

Pharmacovigilance (1)
purpose: to provide accurate, complete and timely
information about the benefit-risk profile of a medical
product throughout its life cycle

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Pharmacovigilance (2)
each pharmaceutical company need to maintain a system
that ensures:
- an active, systematic and continuous monitoring
of pharmacovigilance cases reviewed
- early detection of safety signals
- that appropriate actions are taken to minimize risks

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INTRODUCTION ON NEW DRUG DEVELOPMENT

TABLE OF CONTENTS

Worldwide Sales of Medicines

Costs of Research and Development
New Drug Approvals
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions

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PHASE IV - STUDIES
(efficacy/safety; therapeutic use)
Patients (ambulant GPs; 25,000)
Performed after marketing authorization was
obtained

Result: practical utility

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TABLE OF CONTENTS

Sales of Medicines in the Netherlands

Worldwide Sales of Medicines
Costs of Research and Development
New Drug Approvals
The Cost per Day of Delay
Development of a New Drug
Synthesis
New Drug
Pharmacology/Toxicology
Clinical Pharmacology
Phase I studies
Phase II studies
Phase III studies
Market Authorization
Phase IV studies
Conclusions
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CONCLUSIONS

New drugs: effective and safe

New drug development is expensive and time
consuming
($ 1 billion; 10 years)
Many laws and regulations (a.o. GCP; GLP) led to
better protection of study participants and study animals
more reliable study data (less scientific misconduct
and less fraud)
marketing authorization is extensive, time consuming
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