Bratislava University Workshop on GCP

Changing the Clinical Trials Directive – Needs and Opportunities for

Academic Research06.04.2011

Ingrid Klingmann, MD, PhD, FFPM, FBCPMEuropean Forum for Good Clinical Practice

Brussels, Belgium

The Current Situation in Europe

Numerous articles and case studies have postulated that Directive 2001/20/EC, the „Clinical Trials Directive“ (CTD) has failed to promote efficient clinical research in Europe and to better protect the study participants

However, there are more causes for the decreasing clinical research activity in Europe than the legal framework

The European Medical Research Council of the European Science Foundation has analysed in a series of workshops the current problems faced in IITs. They developed 26 high-level recommendations to improve patient-oriented research in Europe, presented in „Forward Look: Investigator-Driven Clinical Trials“ (2009)

European Science Foundation Report

ESF‘s EMRC identified 5 main issues:

Categories and design of patient-oriented research needed for promoting health research

Regulatory and legal issues, intellectual property rights and data sharing between stakeholders such as academia, industry and patient groups

Management of investigator-driven clinical trials

Education, training, careers and authorship

Funding and models of partnership

European Science Foundation Report

ESF‘s EMRC developed 26 recommendations. The top 5 were:

Better conditions for education, training and career for clinical researchers

Level of funding for clinical research in Europe

Risk-based approach to regulating clinical trials

Improved clinical trial authorisation process, ideally with a single CTA

Adequate scale for IITs: funding infrastructure for correctly powered trials

The ICREL Study

Focusing on the legislative environment as a potential source of hurdles for clinical research, DG Research funded within FP7 the „ICREL Study“ with the aim to generate objective information on the current situation

ICREL was performed in 2008 and provided evidence that important steps towards more sophisticated study review and harmonisation of clinical trial procedures in all EU Member States (MSs) have been made

BUT

so far the new legislation has made the preparation and performance of clinical trials more complicated and most probably hindered the performance of important research

Index of Total Number of CTAs

Index of the number of CTAs

0,00

20,00

40,00

60,00

80,00

100,00

120,00

140,00

160,00

1999 2001 2003 2005 2007 2009 Year

Inde

x

INDEX EU

INDEX non EU

Number of CTAs Submitted by Commercial Sponsors

Number of CTAs Submitted by Non-commercial Sponsors

0

100

200

300

400

500

600

700

1999 2001 2003 2005 2007 2009

Year

Nu

mb

er o

f C

TA

s

ABCDEFGHIJKLMNOPQRSTUVWXYZZZ

20%

36%

Number of Protocol Amendments Submitted to NCAs For Approval

Index of the number of amendments

0,0020,0040,0060,0080,00

100,00120,00140,00160,00180,00200,00

1999 2001 2003 2005 2007 2009 Year

Ind

ex

INDEX EU

INDEX non EU

Index of the Number of FTEs in Competent Authorities for Scientific Evaluation

Index of the number of FTE

0

20

40

60

80

100

120

1999 2001 2003 2005 2007 2009 Year

Inde

x INDEX EU

Increases in Work Forces for CT-Related Tasks in Pharmaceutical Companies

0

20

40

60

80

100

120

Cha

nge

in p

erce

nt

Unadjusted change (%)

Adjusted change (%)

Increases in Work Forces for CT-related Tasks in NCS

0

1

2

3

4

5

6

CTA to CA & EC Coordination andMonitoring

Pharmacovigilance Quality Assurance

FT

E

Average/ organisation 2003

Average/ organisation 2007

Changes

Mean Time To Obtain Authorisation

2000 2001 2002 2003 2004 2005 2006 2007MEAN / inst. EU (d) 64 63.83 70.14 60.38 50.43 49.63 47.34 48.66Sample size EU 6 6 7 8 8 9 11 15

Mean time to obtain authorisation per NCA

Time lines from CS protocol finalisation to inclusion of first patient and from (substantial) amendment release to first implementation in 2003 and 2007

Time Periods 2003 2007 Unadjusted change (%)

Adjusted change (%)

Days from protocol release to FPI 115 152 32.4 89.33

Days from (substantial) amendment release to first implementation

40 53 31.7 37.13

Number of Involved Countries, Centres and Participants in Commercial Trials

0

10

20

30

40

50

60

70

Ch

an

ge i

n p

erc

en

t

Unadjusted change(%)

Adjusted change(%)

Unadjusted change of multi-centre: overwhelming effect of B08 (+38 CTs)

Number of SAEs or SUSARs Reported to NCAs

Index of the number of SAEs

0

20

40

60

80

100

120

140

1999 2001 2003 2005 2007 2009 Year

Inde

x INDEX EU

Impact of Implementation of the EudraVigilance Database on the Safety of Participants per Stratum

Eud

ra v

igila

nce

DB

0,00

0,25

0,50

0,75

1,00

>100 Top 100 Top 15

Strata

no

yes

Room for Improvement!

So, what can be done

to improve

the future of clinical trials

in Europe?

Road Map Initiative for Clinical Research in Europe

Formed by academic organisations and institutions like ECRIN, EORTC, EFGCP, EBMT, ICREL, CLINT, LeukemiaNet

Organised multi-stakeholder one-day workshops to identify problems and discuss solutions on

Single CTA

Co-sponsorship

Risk-based approach

Harmonised ethical review

Safety reporting in clinical trials

Final workshop

Single CTA Workshop

Reducing the complexitiy of the study approval process:

ONE CTA application dossier, centrally placed, accessible to all CAs and ECs involved

Single CTA for multi-national trials

Single ethical approval with national input in multi-national trials

Clear definition of terms like „Investigational Medicinal Product“, „Non-interventional trial“, „Substantial Amendment“, etc.

Clear assignment of responsibilities in the process to NCAs and ECs

No additional review hurdles on national levels

Other Workshop Results

Facilitating sponsor definition and obligations:

Possibility of co-sponsorship based on a detailed contractual agreement between the parties

Identical application range of the legislation in all countries (e.g. Surgery trials? Medical devices? Radiotherapy?...)

Simplification of the administrative requirements according to a „risk-based approach to clinical trial regulation “

Other Workshop Results

Facilitating sponsor definition and obligations:

Coverage of the clinical trial liability insurance by government or healthcare system

Facilitating SUSAR-reporting through single entry into EudraVigilance and only periodic safety information to ethics committees and investigators

Harmonisation of safety reporting requirements between EMA and FDA

Harmonisation of inspection requirements between EMA and FDA

Other Workshop Results

Improving the infrastructure for clinical trials:

Adaptation of the funding level per study to the increased professionalism of the trial administration

Public funding of the creation of more dedicated, highly trained and efficiently managed clinical trial centres

25/25

Participants to the Survey & Countries Represented

Academia 77

Pharma Industry 29

CROs 28

Ethics Committees 8

Competent Authorities 4

Patient Organisations 11

Total 157

Personal responses 75

Institution responses 82

Country of origin

UK

Germany

Belgium

France

The Netherlands

Italy

Spain

Switzerland

Hungary

Others

26/25

Instead of parallel reviews and approvals by all NCAs involved there should be a “Single CTA” for multi-national clinical trials

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

27/25

For single-centre and national multi-centre CTs, the CTA should be submitted to the competent NCA

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

28/25

STANDARD OPERATING PROCEDURES

There should be a single application dossier, submitted at a central location (e.g. EudraCT) with access for the reviewing NCA(s).

No additional national documents would be requested

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

29/25

There should be a more harmonised Ethical Review Process in the EU

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

30/25

Improvement of Ethical Review

The quality of the ethical review should be improved and

harmonised through accreditation of ethics committees

There should be substantial funding for training of EC

members

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

31/25

Common Ethical Review Dossier

0

10

20

30

40

50

60

70

Industry Academia EC CA Patient

0

10

20

30

40

50

60

70

Industry Academia EC CA Patient

No opinion

Disagree

Agree

EC Common EC/NCA Dossier

32/25

SUSAR Reporting

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

0

10

20

30

40

50

60

70

80

Industry Academia EC CA Patient

No opinion

Disagree

Agree

Single entry in EVCTM -e-copy to CA

No expedited SUSAR reporting to EC and PI

33/25

The Risk-based Approach

0

10

20

30

40

50

60

70

80

Industry Academia EC CA P atient

0

10

20

30

40

50

60

70

80

Industry Academia EC CA P atient

No opinion

Disagree

Agree

Replacement of „one-fits-all“ by risk-based approach

Implementation of risk categories

Initiatives for Improvement

DG Enterprise launched a public consultation that closed in January 8, 2010. Key issues to be commented:

Multiple and divergent assessments of clinical trials

Inconsistent implementation of the CTD

Regulatory framework not always adapted to the practical requirements

Adaptation to pecularities in trial participants and trial design

Ensuring compliance with GCP in CTs performed in third countries

34

Initiatives for Improvement

DG SANCO released on 30.03.2010 a revision of the CTA guideline which will require legal changes in most Member States

Major revision with different structure

Including the new developments for paediatric and first-in-man trials

Possibility to submit additional information during an ongoing review procedure

CTA Submission electronically, only cover letter in paper

Information that specified EUDRACT entries will be made public

Initiative for Improvement

DG SANCO released on 30.03.2010 a revision of the CTA guideline which will require legal changes in most Member States

National Competent Authorities are requested to accept all documents in English with exception of PIS and EC

Definition of the content of the CTA dossier – not foreseeing national additional documentation requests anymore

Voluntary Harmonisation Procedure or any other CTA harmonising procedure is not mentioned

Initiatives for Improvement

DG SANCO released on 17 July 2010 a revision of the AE Guideline for consultation until 10.09.2010

SUSAR reporting by sponsor to EVCTM or Competent Authorities of all countries where the trial is performed

SUSAR reporting only to lead EC in which the SUSAR occurred

Annual Safety Report to other ECs and investigators

Definition of responsibilities for assessment of causality and expectedness between PI and sponsor

Initiatives for Improvement DG SANCO released on 09 February 2011 the public consultation

of a Reflection Paper on „Revision of the Clinical Trials Directive 2001/20/EC“

Proposal to have a single dossier submission to all Member States through a single portal, the EudraCT database

Proposal for different central CTA assessment procedures

Discussion of new scope of the CTD, especially concerning non-interventional study definition

Risk-adapted rules for the content of the application dossier and safety reporting

New definition of „IMP“

Proposal for insurance coverage by national healthcare systems

Initiatives for Improvement DG SANCO released on 09 February 2011 the public consultation

of a Reflection Paper on „Revision of the Clinical Trials Directive 2001/20/EC“

Proposal for sharing of sponsorship

Proposal for emergency clinical trials

Proposals for clinical trials in third countries

Conclusions There is much clearer and more common understanding of what is

going wrong at the moment

There is much common understanding between academic and commercial sponsors on how the situation should be improved

DG Research strongly supports the interests of the academic researchers

DG SANCO is in the process of achieving as much improvement as possible through guidelines and makes first attempts towards new legislation

The Heads of Agencies make strong efforts to improve the situation of CTAs within the current legal framework

However, new legislation will be required to force the Member States to apply strictly the same rules for clinical trial authorisation and safety reporting to enhance the performance of multi-national clinical trials in in the interest of patients‘ rapid access to n new treatments

Thank you

for

your attention