icrin seminar on european commission s proposal for a new ... · 2001/20/ec directive •focus on...
TRANSCRIPT
![Page 1: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/1.jpg)
ICRIN seminar on European Commission’s proposal for a new
Regulation on clinical trials
March 12th, 2013, Mansion House, Dublin
European perspective
Jacques Demotes
www.ecrin.org
![Page 2: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/2.jpg)
Sponsor
Investigator
Patient
Competent
Authority Ethics
Committee
2001/20/EC Directive:
defining roles and responsibilities of
stakeholders in each country
![Page 3: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/3.jpg)
2001/20/EC Directive
• Focus on ‘interventional’ trials on medicinal products
• Definition of intervention (pharmacoepidemiology)
• Similar requirements whatever the sponsor, the risk and the marketing authorisation status
• Single sponsor in EU
• Insurance/indemnity
• No waiver of consent
![Page 4: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/4.jpg)
2001/20/EC Directive
• Single ethical opinion in each country
• Parallel CT authorisation process in involved countries, multiple dossiers (simplification through VHP)
• Symmetrical role for EC and CAs (SUSAR reporting)
• Requires transposition into national legislation – Harmonisation ?
– Simplification ?
• Poor alignment with non-EU systems
![Page 5: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/5.jpg)
Comparison of national requirements EC CA Sponsor Insurance AER
![Page 6: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/6.jpg)
Draft Regulation on clinical trials
proposed by the EU Commission
• Focus on ‘interventional’ trials on medicinal products
• Definition of intervention (pharmacoepidemiology)
• Provisions for “low intervention trials” based on the risk of diagnostic procedures and marketing authorisation status
• Co-sponsor
• Insurance/indemnity by public health systems (for “low intervention”)
![Page 7: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/7.jpg)
Draft Regulation on clinical
trials proposed by the EU
Commission
• Coordinated CT application through reporting MS (distinct from VHP), coordinating the authorisation Part 1: product and protocol
Part 2: national ethical review
• Sponsor selects reporting MS
• Each country is a “black box, should provide authorisation within specific timelines (part 1 & part 2)
• Limited possibility to opt-out (almost mutual recognition for Part 1)
![Page 8: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/8.jpg)
Draft Regulation on clinical trials
proposed by the EU Commission
• No reference to ethics committees and competent authority: “oversight bodies”
• Waiver of consent (for lower risk only)
• No transposition into national legislation (?)
• Need for systematic review ?
• Transparency ? Access to patient-level data ?
• Poor risk-based provisions and poor alignment with non-EU systems: see OECD Council Recommendation
![Page 9: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/9.jpg)
www.oecd.org/sti/gsf
Survey
WG on
harmonisation
WG on training and
infrastructure
WG on risk-based
approach
![Page 10: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/10.jpg)
OECD Council Recommendation on the
Governance of clinical trials
• EU Regulation on clinical trials
– Harmonisation: Regulation
– Simplification: single application portal
– Risk-based approach: “low intervention trials” • 2 risk categories based on IMP status (standard of
care), and on diagnostic intervention
• OECD Council Recommendation on the Governance of Clinical Trials – Global harmonisation
– 3 risk categories based on marketing authorisation
– Risk assessment for each individual trial http://webnet.oecd.org/OECDACTS/Instruments/ShowInstrumentView.aspx?Instrumen
tID=281&InstrumentPID=304&Lang=en&Book=False
![Page 11: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/11.jpg)
Principles for risk assessment:
stratified and trial-specific
approaches
•I - Risk to participant rights:
– I.1 patient information
– I.2 personal data protection
•II - Risk to participant integrity and safety:
– II.1 safety of the treatment intervention
• New product
• Modified use
• Usual care
– II.2 risk, burden and intrusion of non-treatment intervention
– II.3 vulnerability of patient population
•III – Risk to data quality, results and public health:
– III.1 data quality
– III.2 credibility of results
– III.3 impact on healthcare practice and public health
![Page 12: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/12.jpg)
New product (cat C)
Modified use (cat B)
registration
Clinical trial phases I II III IV
I>A A>I A>I
I>A I>A
C B
A Risk categories
I>A: trials mostly conducted by Industry
A>I: trials mostly conducted by Academia
A>I
Usual care (cat A)
1 - Stratified approach
Risk categories and clinical development of
medicinal products
![Page 13: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/13.jpg)
OECD risk categories for the
stratified approach
Medicinal product C - New
product
B – Modified use A – Usual care
Based on Marketing
Authorization (MA)
status,
with modulating
factors
(up/downgrade):
- Novelty
(new chemical
entity/class)
- Innovative nature
- MA in other
countries
Not authorized
(according to
national or
regional
regulation)
Authorized (according to
national or regional
regulation)
tested according to
treatment regimens
outside the marketing
authorisation (in terms of
population, condition,
administration, dosage)
(a) supported
(b) not supported by
published evidence
and/or guidance and/or
established medical
practice
Authorized
(according to
national or
regional
regulation)
tested in
accordance with
marketing
authorisation
![Page 14: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/14.jpg)
Simplified representation of the stratification and oversight
requirements for clinical trials on medicinal products in
various countries / regions Marketing authorisation status of the medicinal products
Non-authorised medicine
Authorised medicine, treatment regimen outside marketing
authorization
Authorised medicine tested within
marketing authorisation
not supported by established medical
practice
supported by established
medical practice
USA IND trials
supervision by FDA
approval by IRB
non IND studies
approval by IRB
Japan chiken trials
supervision by PMDA
approval by IRB
non-chiken studies
approval by IRB
Australia exemption scheme
approval by CA (TGA) approval by EC notification scheme
approval by EC
(EC decides if TGA should be involved, based on trial protocol)
2001/20/EC Directive
approval by CA
approval by EC
UK / 2001/20/EC Directive
approval by CA (MHRA)
approval by EC
approval by CA (MHRA) approval by EC
notification to CA (MHRA) approval by EC
Draft EU Regulation 2012
coordinated approval by
oversight bodies
low intervention trials
coordinated approval by oversight bodies
OECD Recommendation
approval by CA/regulatory
authority
approval by EC/IRB
approval by CA/regulatory authority
approval by EC/IRB
approval by EC/IRB
(notification to, or authorisation by CA is an
option)
IND: investigational new drug marketing EC: ethics committee
IRB: institutional review board
CA: competent authority
authorisation
![Page 15: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/15.jpg)
Impact of risk stratification on clinical
trial oversight and management
C - New
product
B – Modified use A – Usual care
Ethical review Approval
consent
Approval
consent
Approval
consent
Regulatory authority Approval Approval
(study specific provisions
for content of dossier)
No approval
(option: notification or
approval)
Adverse event
reporting
Periodic serious
adverse event
reporting
Expedited report of
unexpected serious
adverse reactions to
oversight bodies with
capacity to detect
signals
Periodic serious adverse
event reporting
Expedited report of
unexpected serious
adverse reactions to
oversight bodies with
capacity to detect
signals
Periodic serious adverse
event reporting
Expedited report of
unexpected serious
adverse reactions to
oversight bodies with
capacity to detect
signals
Indemnification /
insurance
Indemnification
mechanism by the public
health system (for
established use, Ba) for
IIT
Indemnification
mechanism by the public
health system for IIT
![Page 16: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/16.jpg)
Impact of risk stratification on clinical
trial oversight and management C – New
product
B – Modified use A – Usual care
Medicinal product Cost of medicinal product
covered by usual procedure
for IIT (for established use,
Ba).
Adaptation of labelling,
tracing, distribution,
accountability possible.
Repackaging and relabeling
without GMP-authorisation
Cost of medicinal product
covered by usual
procedure for IIT.
Adaptation of labelling,
tracing, distribution,
accountability possible.
Repackaging and
relabeling without GMP-
authorisation
Documentation Adaptation of Trial Master
File.
Investigator Brochure
replaced by Summary of
Product Characteristics.
Cross reference to
Investigational Medicinal
Product dossier.
Adaptation of Trial Master
File.
Investigator Brochure
replaced by Summary of
Product Characteristics.
No Investigational
Medicinal Product dossier
Quality
management
Trial-specific Trial-specific Trial-specific
![Page 17: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/17.jpg)
2 – Trial-specific approach
1. Risk assessment for each trial
Establishing common principles for risk assessment
2. Risk-adaptation/mitigation for each trial: optimising burden and
costs while ensuring high quality data, integrity and rights of patients
Establishing common principles for risk adaptation/mitigation
Multiple tools for risk assessment
Multiple strategies for risk adaptation/mitigation
But these tools should be available for international trials, ie.
adopted by all countries involved in a trial.
![Page 18: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/18.jpg)
A. Establishing common principles for
risk assessment – Risk assessment tools
– Training assessors
• I - Risk to participant rights:
– I.1 patient information, informed consent, process for obtaining consent
– I.2 personal data protection
• II - Risk to participant integrity and safety:
– II.1 known and unknown safety of the treatment intervention,
administration, dosage
– II.2 risk, burden and intrusion of non-treatment intervention and clinical
procedures specified by the protocol
– II.3 vulnerability of patient population and risk related to its environment
• III – Risk to data quality, results and public health:
– III.1 data quality: reliability of data collection, data management,
investigation sites, quality assurance, trial management and governance
– III.2 credibility of results: robustness of design and methods, complexity
of the trial, potential source of bias
– III.3 impact of trial results on healthcare practice and public health
![Page 19: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/19.jpg)
B. Establishing common principles for
risk adaptation/mitigation, driven by the
risk assessment
• Safety reporting: adapted to the individual protocol, the nature of
the intervention, and the medical condition of the patient
population. Possible to include specific provisions (in agreement
with regulatory body) for waiver of reporting of some
foreseeable adverse events. Requirement for a DSMB Data
Safety and Monitoring Board linked to the nature of trial.
• Medicinal product: traceability, labelling, blinding, compliance
adapted to the objective of the trial and the risk assessment.
• Indemnification / insurance: provisions and costs proportionate
to the risks to patient integrity and safety. Common principles for
risk assessment to determine nature and extent of risks to patient
integrity and safety.
![Page 20: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/20.jpg)
B. Establishing common principles for
risk adaptation/mitigation, driven by the
risk assessment • Documentation / regulatory bodies: possible to adapt the content
of the application dossier based on the trial protocol.
• Quality management: should adapt to the particularities of the
trial and to the nature and extent of risks. Risk assessment should
identify the key trial parameters. Quality management plans
should focus on mitigating key risks.
• Control procedures: Inspections, audits and monitoring should
be established in a manner that is proportionate to the risk
stratification and trial-specific assessment, and take into account
the provisions made to take these risks into account.
![Page 21: ICRIN seminar on European Commission s proposal for a new ... · 2001/20/EC Directive •Focus on ‘interventional’ trials on medicinal products •Definition of intervention (pharmacoepidemiology)](https://reader035.vdocument.in/reader035/viewer/2022081617/6047fa4e73d2f114ae1c9378/html5/thumbnails/21.jpg)
Thank you !