Clinical Trials Regulations, EU publishes draft guidance for comment on clinical trial registration, approval and notifications.

The European Commission has published draft guidance for comment on “Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial” Contributions should be sent by e-mail to entr-pharmaceuticals@ec.europa.eu on 8 September 2009 at the latest.

Scope

The scope of this guideline is the scope of Directive 2001/20/EC. Directive 2001/20/EC applies to all interventional clinical trials involving medicinal products as defined in Article 1(2) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (hereinafter “Directive 2001/83/EC”). This includes interventional clinical trials involving:

• Advanced Therapy Medical Products as defined in Article 2(1)(a) of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004
• Medicinal products derived from human blood or human plasma
• Immunological medicinal products as defined in Article 1(4) of Directive 2001/83/EC
• Herbal medicinal products as defined in Article 1(3) of Directive 2001/83/EC
• Radiopharmaceuticals as defined in Article 1(6) of Directive 2001/83/EC;
• Homeopathic medicinal products as defined in Article 1(5) of Directive 2001/83/EC
• Directive 2001/20/EC also applies to medicinal products for paediatric population.

The Guidance is too large to give a detailed review here but I will try and pull out the most interesting sections.

Requests for clinical trials authorisation

Covering Letter

The applicant should submit and sign a covering letter with the application. Its heading should contain the EudraCT number and the sponsor protocol number with a title of the trial. In the covering letter, the applicant should draw attention to peculiarities of the trial.

Before submitting an application to the national competent authority, the sponsor should obtain a unique EudraCT number from the EudraCT database by the procedure described in the Detailed guidance on the European clinical trials database.

Application Form

The application form is accessible via the internet by the procedure described in the Detailed guidance on the European clinical trials database. The  application form should uniquely identify the clinical trial and the organisations and key individuals responsible for the conduct of the trial.

Protocol

According to Article 2(h), 1st period, of Directive 2001/20/EC, the protocol is “a document that describes the objective(s), design, methodology, statistical
considerations and organisations of a trial.”

The content and format of the protocol should comply with Section 6 of the Community guideline on Good Clinical Practice (CPMP/ICH/135/95).

Investigators Brochure

According to Article 2(g) of Directive 2001/20/EC, the investigator’s brochure (“IB”) is “a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects.” A request for authorisation has to be accompanied with an IB.

The content, format and procedures for updating the IB has to comply with Article 8(1) of the Commission Directive 2005/28/EC laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products (hereinafter referred to as Directive 20005/28/EC) and with the Community guideline on Good Clinical Practice (CPMP/ICH/135/95).

Investigational Medicinal Product Dossier (IMPD)

Article 2(d) of Directive 2001/20/EC defines an IMP as follows: “[A] pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.”

The IMP Dossier (“IMPD”) gives information to justify the quality of any IMP (i.e. including reference product and placebo) to be used in the clinical trial. It should also provide data from non-clinical studies and the previous clinical use of the IMP or justify in the application why information is not provided.

The sponsor has the possibility to submit a simplified IMPD if the information can be made available by referring to other submissions.

Non-Investigational Medicinal Products used in the Trial

Medicinal products used in the context of a clinical trial and not falling within the definition of IMP are non-investigational medicinal products (“NIMPs”). The “borderline” between IMPs and NIMPs is described in the Guidance on Investigational Medicinal Products (IMPs) and other medicinal products used in Clinical Trials. It is strongly recommended that NIMPs with marketing authorisation in the Member State concerned are used for these purposes when possible. When this is not possible, the next choice should be NIMPs with marketing authorisation in another Member State. A SmPC for each NIMP with a marketing authorisation should be submitted with the clinical trials application dossier.

Notification of Amendments

Notification/submission for information40 is only obligatory if the amendment is substantial or otherwise significant. Directive 2001/20/EC does not require notification of non-substantial amendments.

Declaration of the End of a Clinical Trial

Article 10 (c) of Directive 2001/20/EC reads as follows: “Within 90 days of the end of a clinical trial the sponsor shall notify the competent authorities of the Member State or Member States concerned and the Ethics Committee that the clinical trial has ended. If the trial has to be terminated early, this period shall be reduced to 15 days and the reasons clearly explained.”

“End of the trial” is not defined in Directive 2001/20/EC. The definition of the end of the trial should be provided in the protocol and any change to this definition for whatever reason should be notified as a substantial amendment. In most cases it will be the date of the last visit of the last patient undergoing the trial. Any exceptions to this should be justified in the protocol.

Procedure for declaring the end of the trial

The sponsor should make an end of trial declaration using the form published in Volume 10 of Eudralex – the Rules Governing Medicinal Products in the European Union

Clinical Trial Summary Report

The clinical trial summary report is part of the end of trials notification. However, the clinical trial summary report can be submitted subsequently to the end of trials notification.

Follow up

If a new event occurs after the termination of the trial that is likely to change the risk/benefit analysis of the trial and could still have an impact on the trial participants, the sponsor should notify the national competent authority and Ethics Committee of the Member State concerned and provide a proposed course of action.

Details of the Table of Contents of the Common Technical Document (CTD, eCTD) are given in the appendix.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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