ICRIN seminar on European Commission’s proposal for a new

Regulation on clinical trials

March 12th, 2013, Mansion House, Dublin

European perspective

Jacques Demotes

jacques.demotes@inserm.fr

www.ecrin.org

Sponsor

Investigator

Patient

Competent

Authority Ethics

Committee

2001/20/EC Directive:

defining roles and responsibilities of

stakeholders in each country

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

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

Comparison of national requirements EC CA Sponsor Insurance AER

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”)

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)

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

www.oecd.org/sti/gsf

Survey

WG on

harmonisation

WG on training and

infrastructure

WG on risk-based

approach

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

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

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

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

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

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

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

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.

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

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.

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.

Thank you !