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