An agency of the European Union

Regulatory pathways to new medicines EU 28: science, medicines, health – a regulatory system fit for the future 6 – 7 May 2013, Dubrovnik, Croatia Presented by: Tony Humphreys Head of Regulatory, Procedural and Scientific Committee Support Patient Health Protection

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 1

Post Nov 2005 Three European Systems

Centralised Procedure (via EMA)

Mutual Recognition procedure

Decentralised Procedure

2

Auto-immune disease and Other immune dysfunctions

Viral diseases

AIDS Cancer Neurodegenerative disorder

Diabetes

-Recombinant DNA technology

-Controlled gene expression

-Monoclonal AB ATMP

Orphan Med Prod NAS / “known” AS

Reg. 726/2004

Mandatory Scope of Centralised Procedure

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

New Active Substances

Significant Innovation

-Therapeutic

&/or Scientific

&/or Technical

Interest of Patients at

Community Level

Art. 3(2)(a) Art. 3(2)(b)

OR

Art. 3(2) of Regulation (EC) No 726/2004

Optional Scope of Centralised Procedure

3 Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 4

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 5

T-36/48 MO

T-36/12 MO

T-24/12 MO

T-12 MO T 0

Committees Co-ordination

Pre-submission phase

CHMP COMP CAT

PRAC PDCO

CHMP SAWP

CHMP PRAC CAT

Post Authorisation Evaluation

Launch

CHMP

Orphan Designation + Paed Req.

Scientific Adv. Protocol assist.

MAA Presub.

Regulatory Filing Strategy

MAA Evaluation Changes MA + PhV

COMP

PDCO PDCO SAGs WPs

CAT

6 Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

Assembling your Marketing Authorisation Application

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 7

All Marketing Authorisation applications must demonstrate

the same standard of

100% QSE

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 8

Applicants “choice” of legal basis

Innovator pharma

Art. 8(3) “Full” 100% non clinical /

clinical studies

Art. 8(3) “Mixed” > 0% - < 100% Non

clinical / clinical studies

100% balance bibliography

All Pharma

Art. 10 (c) Informed Consent

Art. 10 (a) Well Established Use 100% bibliographic

Art. 10 (b) Fixed Combination Dose

forms > 0% - < 100% Non

clinical / clinical studies

Generic / Biosimilar Pharma

Art. 10 (1) Classic “generic”

Bioequivalence +/- biowaiver

Art 10 (3) Complex “generic”

> 0% - < 100% Non clinical / clinical studies

Art. 10 (4) Biosimilars

“Comparability” QSE data package

Trends in EU marketing authorisation applications 1995-2012

0

10

20

30

40

50

60

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Orphan Other (biosimilar, generic, WHO, WEU etc) Non-orphan

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 9

10

Centralised Procedure Overview

D 80 Rap AR ------- Co-Rap

AR

D 115 Peer

Review Telecon

START

Assessment

Rap

Co-Rap

D -180

D 121 Response

Submission

D 120 Joint LoQ

Clock Stop (3 – 6 m) App R/cR

Assess Teams

D 121 Response

Submission

D 150 Joint

Response AR

D 180 LoOI

Clock Stop

(1-3 m)

D 181 Oral Expl

D 210 Opinion

Consensus Simple

Majority

CHMP

Comments

CHMP

Comments

SAG / WP consultation

Inspections GMP / GCP

Primary Evaluation

Secondary Evaluation Decision Making

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

11

Accelerated Assessment – Regulation 726 / 2004 Art. 33

In order to meet, in particular, the legitimate expectations of patients and to take account of the increasingly rapid progress of science and therapies, accelerated assessment procedures should be set up, reserved for medicinal products of major therapeutic interest, and procedures for obtaining temporary authorisations subject to certain annually reviewable conditions.

Soliris Isentress VPRIV Pumarix Zytiga Incivo

Victrelis Kalydeco

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

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Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 13

SAG / Working Party Constellation

CHMP

QWP*

SWP*

BWP*

Sci Adv

Patients & Consumers

Biosimilars

Biostatistics

Blood Prod

CNS

Rheumatology

Immunology

Infectious

Diseases Oncology Pharmacokinetics

Pharmacogenomics

Geriatrics

Cardiovascular

Vaccines

Gastroenterology

Respiratory

Urology

Radiopharmaceuticals

* 1 / MS representation

SAG diagnostics

SAG CVS

SAG Neurology

SAG Psychiatry

SAG HIV /

Antiviral

SAG Oncology

SAG CVS

SAG Diabetes

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 14

Scientific Advisory Groups: input

SAG CVS

S A G

Cardiovascular issues

Anti-infectives Diabetes /

Endocrinology Diagnostics HIV / Viral

Diseases Neurology Oncology Psychiatry Vaccines

To deliver independent recommendation to specific questions

Rapporteur / Co-Rapporteur: present the issue and provide additional information on the dossier Possible hearing from applicant

Provides answers to each question If no consensus: majority views recorded together with any divergent position in document “SAG answers and comments to the CHMP” Position is reflected in CHMP Assessment Report

Scientific Advisory Groups (SAGs) 2006 - 2013

15

Oncology; 39

Cardiovascular; 18

Diabetes / Encrinology; 16

Central Nervous system; 14

HIV / Viral diseases; 12

Anti-infectives; 10

Neurology; 8

Diagnostics; 6 Vaccines; 2 Psychiatry; 1

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

CHMP Voting Rules

16

32 members eligible to vote

(27 MS/NCAs + 5 co-opted)

Norway and Iceland recorded separately

Abstention!

Voting

Simple Majority: 17 to sustain a positive or negative opinion

Quorum =

No pre-determined MS position CHMP capacity scientific member, hence vote personal / individual

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

CHMP Outcomes 2012 - 2013

0

2

4

6

8

10

12

14

16

Jan Feb March April May June July Sept Oct Nov Dec Jan Feb March April

1

8

42

8 8

3 35

2 2

57 8

5

1

1

1

2

1

1

1

1

1 11

1

1

1

1

11

1

1

13

4

6

1

6

1

Neg Re ex

W/d

Neg Maj

Pos Maj

Neg Con

Pos Con

17 Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

Drug development and data criteria for different type of opinions / centralised MA

Full MA ?

Phase I Phase II Phase III Phase IV

Conventional development NOT possible (too rare):

Conventional development possible:

Surrogate endpoint confirmation of benefit

proved benefit

Exceptional circumstances

Full MA

Cond. approval Full MA

MA under EC

Phase I Phase II Phase III Phase IV

18

Conditional Approval

100

Adequate Data

Time

+ve CHMP opinion

“normal” MA

+ve CHMP opinion

Exceptional Circumstances

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Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 202020

Exceptional Circumstances 2006 – 2012

Metabolism

Elaprase

Vedrop

Orphacol

Glybera

Nervous System

Zenas

Vyndaqec

Anti-Infectives

Daronix

Focetria

Pandemrix

Celvapan

PIV – H5N1(X2)

Foclivia

Pumarix

Oncology

Evoltra

Atriance

Yondelis

Ceplene

Arcalyst

Ilaris

Blood

Atryn

Hormonal

Increlex

3

5

3

7

2 1 1

0

2

4

6

8

2006 2007 2008 2009 2010 2011 2012

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 20

21

Conditional Approval 2006 – 2012

Oncology

Sutent Orph

Vectibix

Tyverb

Arzerra

Votrient Orph

Votubia Orph

Caprelsa

Xalcori

Adcentris

Pixuvri

Anti-Infective

Prezista

Isentress

Intelence

Cayston

Arepanrix

Humenza

CNS / NDD

Diacomit Orph

Fampyra

Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013

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Real access to products?

Member States

Article 1 “The provisions of this Regulation shall not affect the powers of Member States’ authorities as regards setting the prices of medicinal products or their inclusion in the scope of the national health system or social security schemes on the basis of health, economic and social conditions.

In particular, Member States shall be free to choose from the particulars shown in the marketing authorisation those therapeutic indications and pack sizes which will be covered by their security bodies.”

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Regulatory pathways to new medicines, T. Humphreys, Dubrovnik, 6 - 7 May 2013 24

• First treatment pseudobulbar affect (uncontrolled emotional expression)

• CHMP opinion: +ve by consensus

• Eligibility: significant therapeutic innovation

• Legal basis: Art. 10(6)

• Transdermal formulation for patients with difficulty swallowing tablets

• CHMP Opinion: +ve by majority

• Eligibility: significant innovation / patient interest

• Legal basis: Art. 10(3)

• First combined tissue engineered medicine in EU

• CHMP Opinion: +ve by consensus based on draft CAT opinion

• Eligibility: ATMP

• Legal basis: Art. 8(3)

• Generic of Glivec = CML adults and paediatrics

• CHMP Opinion: +ve by consensus

• Eligibility: Art. 3(3) Generic CAP

• Legal basis: Art. 10(1)

Neudexta dextromethorphan

hydrobromide + quinidine sulphate

Sancuso Granisetron PONV

MACI Matrix induced antologous chondrocyte implantation

Imatinib Accord Imatinib

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