How European Regulation will impact Clinical Trials · 2. Clinical Trials Legislation Dagmar Chase...

Algiers, 2 April 2017 Hotel Sofitel

Workshop: Access To Innovation and Clinical Research

Dr. Stefano Marini, MD EUCROF Vice-President European Contract Research Organization Federation

How European Regulation will

impact Clinical Trials

EUCROF 2017

• EUCROF is a non-profit organisation founded on 2005

• Members are legal entities registered in at least one

European Country:

• Associations of CROs, or

• Private companies working in Clinical Research Services

European CROs Federation

National Association Country N. CROs

1. ACRO-CZ Czech Republic 18

2. ACRON The Netherlands 40

3. AECIC Spain 31

4. AFCROS France 48

5. AICRO Italy 20

6. ASCRO Sweden 7

7. BeCRO Belgium 29

8. BVMA Germany 39

9. CCRA United Kingdom 36

10. HACRO Greece 10

11.SAKDER Turkey 26

12. SACROP Slovakia 22

Local CROs 1. Portugal

2. United Kingdom

3. Denmark

4. Switzerland

5. Ukraine

6. Spain

7. Austria

8. Serbia

TOTAL: 326 Companies, 18 Countries , over 20.000 employees 2 02-04-2017 –Stefano Marini

EUCROF Geographic Representativeness Mar - 2017

3

EUCROF Members, Associate & Partners Relationship in development

EUCROF Mission

EUCROF is a legal non-profit entity representing the interests of

CROs in Europe towards

• regulatory bodies

• pharmaceutical, biotech, medical device industry

• healthcare related industry within the field of clinical research

• patients associations

EUCROF’s goal is to promote Clinical Research by improving the

knowledge, competence and skills of CROs in Europe

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Working Groups

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1. Paediatric Working Group Martine Dehlinger-Kremer

2. Clinical Trials Legislation Dagmar Chase

3. Education and Training Antoinette van Dijk

4. Late Phase Giovanni Fiori

5. Early Phase Keith Berelowitz

6. Medical Devices Judith Köhnen

7. Communication Christophe Golenvaux

8. New Technologies Yoani Matsakis

9. Pharmacovigilance Nicolas Tsiakkas

10. Outsourcing Management Philippe Van der Hofstadt

Number of Clinical Trials in EU

6

Clinical trials on the EU Database «Eudract supporting documentation»

YEAR N. CTs in EU

2007 5.028

2008 4.618

2009 4.609

2010 4.153

2011 4.127

2012 3.943

2013 3.383

2014 3.249

2015 3.918

Meaningful Study

7

Clinical Trials Migration

Method: The authors measure CT migration during the last 14 years per geographic area, analysing: • 15 Clinical Trial Registries (WHO approved) • 205.455 Clinical Trials Results: Trials move from high income countries to low- medium income, mostly in Asia, with all subsequent implications: Clinical, of public health, ethical, regulatory and economical.

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Clinical Trials Migration

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Clinical Trials North Africa

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Source: www.clinicaltrials.gov Algeria: 24 trials recruiting

http://www.clinicaltrials.gov/

Indice di attrattività per sperimentazioni cliniche

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Changing Environment

Studies

Sponsor

Technology

Regulatory

• Rare diseases, second and third line Tx • Globalisation, emerging markets • New therapeutic areas

• Purchasing power • Effective oversight models • Geographical market focus

• Data capturing, wearables • Risk based monitoring, remote site management • Real world Big-data

• New directives, Voluntary Harmonisation Procedure (VHP) • RBM requirements • Transparency regulations

Background – Technology Evolution W

HY

2000-2010 2010-2020 1990-2000 1980-1990

WH

ERE

Dedicated On Prem Hosted / Portals

Apps

WH

O

Specialists Key

Contributors All

Employees Everyone

Need Speed Convenience Productivity

Computerized Systems Used in Clinical Investigations 21CFRpart11

Annex 11 General Principles of Software Validation; Final Guidance for Industry and FDA Staff

CGMP Applicability To Hardware and Software

Electronic Source Data in Clinical Investigations

Virtualization

16 of 20 4 July -2013 –Stefano Marini

Addendum to ICH E6 Guideline

• Since first adoption of ICH E6 GCP in 1996, clinical trials have evolved substantially: increases in globalization, study complexity, and technological capabilities

• Approach to GCP needs modernization to keep pace with the scale and complexity of clinical trials and to ensure appropriate use of technology

European Commission Intent in 2012

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And they have delivered this ……

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Objectives of the CTR

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• Reduce un-necessary costs

• Make UE a more attractive place for clinical research

• Harmonize approval processes: the 2001/20 determined national peculiarities

• Introduction of a coordinated evaluation for multinational trials Authorization will not be centralized, but only the application Member Stats maintain their autonomy in authorizations

• Electronic application through the Portal

Simplifications for Sponsors, for EU/EEA Member State:

• 1 Uniform procedure in EU: whether single or multi- country clinical trials (CT)

• 1 Communication hub: Electronically by Portal

• 1 Clinical trial number

• 1 Contact per CT part I: Reporting Member State (RMS)

• 1 Set of documents per initial CT and follow up

• 1 Common assessment (part I) by all concerned MS together

• 1 Decision per MS (Part I + II)

• 1 Fee per MS

• 1 Safety reporting: SUSAR and Annual Safety Report to PV database

Regulation (EU) No. 536/2014 - Matter of ONE

Main characteristics

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• Ethics Committees will act according to national laws, but within a a strict timeline

• Extension of the principle of silent consent to the entire process

• Simplified and unified reporting procedures • Increased transparency on CTs and their results

• Trials conducted in non-EU countries are reported in

the EU application, provided that they have been conducted according to requirements at least equivalent to those of EU

Definitions

23

Delicate aspects 1/3

24


25


26

• All listed conditions need to be fulfilled

• Here too, all listed conditions need to be fulfilled

Innovative aspects: emergency 1/2

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Innovative aspects: emergency 2/2

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Archiving issue

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Content of the Annexes

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Annex I - Application dossier for the initial application Annex II - Application dossier for substantial modification Annex III - Safety reporting Annex IV - Content of the summary of the results of the clinical trial Annex V - Content of the summary of the results of the clinical trial for laypersons Annex VI - Labelling of investigational medicinal products and auxiliary medicinal products Annex VII – Correlation table

EU portal and database – High Level System Overview

Business Processes

User Interfaces

CT System

Create Application

Evaluate Application

Supervise CT

Manage Reports

Submit CSR Disseminate CT Info

Issue Notification

Submit Results

Manage Users

Manage Publication

Access CT Info

CT Portal/ EU DB

Sponsors

Secure Access

Open

Access

NCAs and Ethics Committees EC EMA MA Applicant Public

BI Reports UI Authority Workspace

Sponsors/MA applicant Workspace

Public Website

MS Interface

Sponsor’s Interface

Business Intelligence

Sponsor System

Authority System

MS Workflow Engine

CT Public Register

CT DB Public DB

Master Data Management (RMS/OMS)

Data Warehouse

(DWH)

User Registration & Security

(IAM)

Document Management

(DMS)

EMA

WHO

Sponsors

EV Human

MSs

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EU portal and database – System Interfaces

Business Processes

User Interfaces

CT System

CT Portal/EU DB

CT DB Public DB

Please note that this image is a mock-up

Access User Management Screen

Che cosa sta succedendo

• Stati Membri EU adottano Clinical Trial Regulation n. 536/2014;

34 of 20

UAT 1,2 & 3 – high level scope for sponsors

Business process* Use case Level of implementation

1.1 Initiate application

1001 Create new initial application

1002 Cancel clinical trial application

1.2 Populate application

1005 Populate country dependent CTA information

1006 – Upload document(s)

1007 Populate additional sponsor information

1008 – Complete trial details

1009 Complete product details

1011 Submit clinical trial application

1023 Search and select organisation

2.1 Validation application

1022 – Prepare and submit response to Request for information (RFI)

Multiple 1016 Manage trials and applications

1017 – Register organisation

1013 – Withdraw Application

* Only sponsor related business processes shown in table

17-11-2016 –Stefano Marini

System screenshots (1/4)


System screenshots (2/4)


What should be done?

38

• Prepare the application for authorization

• Nominate the Reporting Member State

• Define the Concerned Member States

• Insert/upload the application in the Portal

Coord.

10

Wiiling

to be

RMS

MSC

send

consi-

dera-

tions

Outcome

of valida-

tions or

request for

additional

informa-

tion

38 45 57 69 25

Final

assessment

report or

request for

information

MSC

send

conside-

rations

Final

assess-

ment

report

7 20

Initial

Spon-

sor to

comm-

ent

Final

out-

come

valid

ation

RMS notification to

Sponsor

0 3 6

Cons.

76

Draft

assess-

ment

report

Sponsor

addresses

request for

information

MSC

send

conside

rations

3 3 4 10 5 12 7

Cons.

12

Coord.

12 5

MS concerned

Reporting MS

Sponsor

Legend:

Day

Initial Application Validation

Evaluation

Deci-

sion

Deci-

sion

5

26 0

26

MSs will already have 11 days in the case

day 12 falls in a public holiday and

weekend

39

Timelines

EU portal and database - key milestones

1 2 3

Audit

~ Aug – Nov 2017

System goes live & Regulation Applies

~Oct 2018

European Commission Notice

~ Mar 2018


The online learning will be delivered using the following channels:

Short demo videos (5 – 10 minutes) which are tailored to a specific task or sub-

task which can be completed on the system, categorised by user group and split

according to the business process to which they relate

User manual which will provide detailed instructions on all aspects of the system for

all users.

Dedicated training webinars which will be targeted at specific stakeholder groups,

will be based around a specific set of processes and act as a question and answer forum

Quick guides which are a tailored and slimed down version of manuals which walk a

user through a specific action or process

In-system information training provided within the EU portal and database itself via

built in help sections. These will provide the user with instant access to the relevant

sections of the user manual for the task they are completing within the system

EU portal and database - online training approach


Category 1 Clinical Trials

“Pharmaceutical development clinical trials”


“Therapeutic exploratory and confirmatory clinical trials”


“Therapeutic use clinical trials”

Phase I trials in healthy volunteers or patients to study pharmacokinetics/ pharmacodynamics

“Phase 0” trials

Bioequivalence and bioavailability trials,

Etc.

Safety and efficacy trials in patients or target population carried out for treatment, diagnosis or prevention

Includes Phase II and III trials for new product, new indications, formulations, etc.

Includes trials by academic researchers or by commercial sponsors

Trials carried out for treatment, diagnosis or prevention in the target population, using:

MPs with MA used within terms of MA

IMPs with MA when use is evidence based and supported by published scientific evidence on safety and efficacy

Includes both Phase IV and low-intervention clinical trials

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EU-CTR “Appendix on Disclosure Rules”

Disclosing Clinical Trials – A balanced Approach Results of trials are proposed to be made public depending on clinical trial categories


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EU-CTR “Appendix on Disclosure Rules” Disclosing Clinical Trials – A balanced Approach

Option to defer summary reporting up to 30 months.

Registry: Details of phase I trials may be deferred and published with the summary results)

CTA dossier parts (IMPD specific sections, protocol, IB can be deferred.

Clarification on what data will be made

public at what time is provided in the

addendum and appendices of this

specification

Results of trials are proposed to be made public depending on clinical trial categories

12 months after the end of the trial, both summary results and layperson summary.

30 days after the decision on marketing authorization or its withdrawal by the applicant – the clinical study report of trials authorized under this Regulation and included in a EU marketing authorization.

Standard Disclosure Timelines Early Phase Disclosure Timelines


OPPORTUNITYISNOWHERE

What do you read?

A small reading exercise….

OPPORTUNITY IS NOWHERE!

OR

OPPORTUNITY IS NOW HERE!

Programming the mind…..

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