New Clinical Test Approval Rules

The authorisation of clinical trials will in the future be managed via a centralised EU-wide portal operated by the European Commission. The process will become consistent across the EU rather than up to the individual Member States to determine. Additionally, the Commission will be given the power to conduct inspections, where these were previously the prerogative of the Member States.

These are among the main changes of a new legislative proposal recently presented by the European Commission, which aims to simplify, harmonise and speed up the process of obtaining authorisation for clinical trials. The Commission is proposing to replace the existing legislation, which is a Directive that gives Member States considerable flexibility in the application of broad principles, with a Regulation, in which all requirements are specified in detail and thus ensures consistency across the EU.

The initiative follows heavy criticism of the existing Directive by stakeholders, which had led to differing sets of national requirements, authorisation criteria and procedures, making the process complicated and time-consuming, and increasing costs and delays.

While the new legislation addresses many of the points of criticism (appointment of a Reporting Member State in case of multinational trials and co-sponsorship), it will remain the case that a trial to be carried out in several Member States will need to be first assessed and then authorised by the responsible national authority in each of those countries.

The legislation will govern the procedures (including forms, etc.) for obtaining authorisation to conduct a clinical trial (from application to trial reporting), and the legal aspects, but does not deal with medical aspects of the authorisation; these are left to the authorisation authorities, which will remain at a national level. It also does not address the manufacturing of medicinal products once they are successfully tested in a clinical trial.

Summary of the Proposal

Scope

The Regulation will apply to clinical trials conducted in the EU with the exception of non-interventional studies. Clinical trial is any investigation in relations to humans that aims to discover or verify the overall effects (clinical, pharmacological, pharmacodynamic, physiological etc.) of one or more Investigational Medicinal Products (IMP). IMP is a medicinal product being tested or used as a reference (including placebo) in a clinical trial.

Legal form

The new proposal has a legal form of Regulation that ensures a coherent set of rules across the EU. The current Directive left a considerable room to set details of implementation to Member States.

Authorisation procedure for a clinical trial

The proposal introduces a new authorisation procedure for clinical trials. Sponsor is an individual, company, institution or organisation responsible for the initiation and management of the clinical trial.

The main elements include:
• The obligation of a sponsor to submit the application dossier to Member States concerned via an EU portal linked to EU database managed by the Commission;
• Appointment of a Reporting Member State among the Member States concerned;
• Assessment of the application by the Reporting Member State and the Member States with regards to their own territory (communicate their considerations to the Reporting Member State), included in Part I and Part II of the Assessment Report respectively;
• Mutual communication between the sponsor, Reporting Member State and Member States concerned;
• Upon completion of the Assessment Report, each Member State needs to authorise a clinical trial. In certain cases, the conclusions of Member States concerned have to match the conclusions of the Reporting Member State.
• If necessary, sponsor may apply to another Member State concerned for a clinical trial. It can only do so after initial authorisation decision has been taken.
• Member States need to ensure that the people assessing the application have the necessary qualifications and experience, and remain impartial and independent of the sponsor.
• Assessment part of the process has been left to discretion of Member States to define organisational setup and internal competences as long as international guidelines are fulfilled. 
• All the necessary information, guidelines and forms for initial application are part of Annex I of the Regulation.

Authorisation procedure for a substantial modification of a clinical trial

Where a clinical trial is modified after it has been authorised, this modification is subject to assessment and authorisation. The main emphasis in the authorisation of a substantial modification is on the subject right and safety and reliability and robustness of the data generated in the clinical trial.

All the necessary information, guidelines and forms for substantial modification are part of Annex II of the Regulation.

Protection of subjects and informed consent

The overall conduct of a clinical trial is subject to strict rules on the subject right and safety, and as long as the benefits justify the foreseeable risks of the trial. The Regulation sets out requirements for an informed consent of subjects, incapacitated subjects, minors as well as trials in emergency situations.

Conduct of a clinical trial

The sponsor has to notify each Member State participating in the clinical trial of the start of the trial, end of recruitment of subjects, end of the trial as well as temporary halt or early termination the trial. Trial shall be conducted according to a Protocol.

Commission will publish guidelines on good clinical practice.

Sponsor is responsible for monitoring the conduct of a trial and is to report all information relevant to the trial. Sponsor also needs to provide suitable subjects and trial sites.

All the information reported during the conduct of the trial is to be properly recorded, processed, handled, stored and archived. Sponsor and investigator (person responsible for the trial itself) keep the master file with all the trial data.

Only authorised Auxiliary Medicinal Products (AMP) may be used in a clinical trial, except where no authorised AMP is available in the EU or when such a AMP cannot be reasonably expected to be used.

Safety reporting

The European Medicines Agency (EMA) will setup and maintain an electronic database (EU database) for the reporting.

Rules on safety reporting are aligned with international guidance principles and are being simplified as follows:
• The option to exclude reporting by the investigator to the sponsor of adverse events, if this is provided for in the protocol;
• Direct reporting of suspected unexpected serious adverse reactions by the sponsor to the EMA;
• The annual safety report is not submitted for authorised IMP that are used within their authorised indication

Technical aspects for safety reporting are included in the Annex III of this proposal.

Manufacturing and import of Investigational Medicinal Products (IMP) and Auxiliary Medicinal Products (AMP)

The manufacturers and importers of investigational medicinal products will need an authorisation, exempting the utilisation of these products by authorised personnel in hospitals, health centre or clinics, by pharmacists or other persons legally authorised in the processes of re-labelling, re-packaging or reconstitution prior to use or packaging as well as the manufacture and import of radiopharmaceuticals used as diagnostic investigational medicinal products.

The member states are required to oversee these processes to ensure subject safety and the reliability and robustness of the data generated in the clinical trial.

Labelling

The list of information that needs to be included on the outer package and on the immediate packaging of unauthorised IMPs and AMPs products is listed in Annex IV to the Regulation.

Co-sponsorship

Clinical trial may have one or more sponsors. The investigator and sponsor may be the same person. When a trial has several sponsors, all assume responsibilities under this Regulation. Unless they specify which sponsor is given the responsibility in a contractual agreement

The sponsor may be outside the EU, however in such a case a contact person within the EU has to be established. This person thus acts as a sponsor.

Compensation for damages

Sponsor and investigator are subjects to applicable liability laws in order to cover any damages suffered by the subject in a clinical trial, except low-intervention clinical trials.

Supervision by the Member States; EU nspections and controls

Member States appoint inspectors to supervise compliance with this Regulation. In case of a breach, a clinical trial may be terminated early, suspended or modified by a a Member State concerned.

The Commission is entitled to conduct inspections as necessary to verify:
• The correct supervision of compliance by the Member States;
• Whether the regulatory system for clinical trials outside the EU is complied with.

IT infrastructure

The Commission will setup a communication and information sharing contact point (EU portal). All the data related to a clinical trial will be stored in the EU database. All the information stored and shared is subject to data protection according to Directive 95/46/EC and Regulation (EC) No 45/2001.

Cooperation between Member States

Member states should cooperate via established contact points in order to facilitate authorisation for a clinical trial including a substantial modification of a clinical trial.

The Regulation establishes Clinical Trials and Advisory Group (CTAG) that comprises national contact points. It supports information sharing between the Member States and the Commission that is to support the Member States’ cooperation.

Fees

Member states may levy fees for the activities set out in the Regulation that are established in a transparent manner and on the basis of cost recovery principles. No multiple fees for an assessment of authorisation procedure of a clinical trial (valid for substantial modification of a clinical trial as well) should be required.

Implementing and delegated acts

Commission is empowered to adopt delegated acts to update the annexes I, II, III, IV. In addition The Commission shall adopt delegated acts in order to specify the detailed requirements of good manufacturing practice for ensuring the quality of IMP.

Relationship with other legislation

This Regulation does not amend the rules as set out in Council Directive 97/43/Euratom, Council Directive 96/29/Euratom, Directive 2001/18/EC of the European Parliament and of the Council, and Directive 2009/41/EC of the European Parliament and of the Council.

Next steps and entry into force

The proposed Regulation repeals the current Directive.

Both Directive and Regulation shall be applicable in parallel for three years after the date of application of this regulation.

Entry into force is foreseen in two years after its publication.