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    Commission européenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel - Belgium. Telephone: (32-2) 299 11 11. E-mail: EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL Public health and Risk assessment Pharmaceuticals   Brussels, 18/03/2011 SANCO/C/8/SF/cg/a.5.001(2011)332855 T HE RULES GOVERNING MEDICINAL PRODUCTS IN THE E UROPEAN U NION  VOLUME   10   -   G UIDANCE DOCUMENTS APPLYING TO CLINICAL TRIALS  G UIDANCE ON I NVESTIGATIONAL M EDICINAL P RODUCTS (IMP S )  AND ' NON INVESTIGATIONAL MEDICINAL PRODUCTS '   (NIMP S ) ( REV .   1,   M ARCH 2011) Document history: Date of discussion of draft by the ad-hoc group for the development of implementing guidelines for the “Clinical Trials Directive” 2001/20/EC: 25 February 2011 Date of publication by the Commission: 18 March 2011 Date of coming into operation: Supersedes: Guidance on investigational medicinal products (IMPs) and other medicinal products used in clinical trials (2007) Description of changes: - An additional Annex 2 sets out dossier requirements - Minor clarifications and update of references - Cross-reference for rules on safety reporting (section 3.4.) Keywords: Clinical trials, Directive 2001/20/EC, NIMPs  Important notice:  The views expressed in this questions and answers document are not legally binding. Ultimately, only the European Court of Justice can give an authoritative interpretation of Union law.  2 1.   I NTRODUCTION   To facilitate the conduct of clinical trials in the Member States of the European Union 1 , especially multi-centre clinical trials carried out in more than one member State it is necessary to have a common understanding of the definition of an investigational medicinal product ('IMP'). This document intends to clarify and provide additional guidance on the definition of IMP and to provide specific guidance about the use of non-investigational medicinal products (NIMPs), in accordance with the applicable EU legislation. This document complements the “Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)' 2  ('detailed guidance CT-1') and the “Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use”. 3   2.   M EDICINAL PRODUCTS INTENDED FOR RESEARCH AND CLINICAL TRIALS AND I NVESTIGATIONAL M EDICINAL P RODUCTS (IMP) The Community Code relating to medicinal products for human use excludes, in Article 3(3) of Directive 2001/83/EC, medicinal products intended for research and development trials from its scope of application. Directive 2001/20/EC defines in Article 2 (d) an IMP as  “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 authorization 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 .” It follows that medicinal products with a marketing authorisation are IMPs when they are to be used as the test substance, reference substance or comparator in a clinical trial, provided the requirement(s) in the definition are met. 3.   N ON - INVESTIGATIONAL M EDICINAL PRODUCTS (NIMP S ) 3.1.   What is an NIMP?  NIMPs are medicinal products that fall within Article 3(3) of Directive 2001/83/EC, while not falling within the definition of IMP as defined in Article 2(d) of Directive 2001/20/EC. 1 For the purposes of this document, references to the EU, EU Member States or Member States should  be understood to include the EEA or EEA contracting States, unless indicated otherwise.   2  OJ C82, 30.3.2010, p. 1. 3  EudraLex, Volume 10.  3 For instance, some clinical trial protocols require the use of medicinal  products such as concomitant or rescue/escape medication for preventive, diagnostic or therapeutic reasons and/or to ensure that adequate medical care is provided for the subject. They may also be used in accordance with the  protocol to induce a physiological response. A list of types of NIMPs, with examples, is contained in Annex 1. Medicinal products that do not have a marketing authorisation, but prepared in accordance with a magistral formula, i.e. prepared in a pharmacy in accordance with a medical prescription for an individual patient, and medicinal products prepared in a pharmacy in accordance with the  prescriptions of a pharmacopoeia 4  and intended to be supplied directly to the  patients served by the pharmacy in question, i.e. officinal formula, as referred to in Article 3(1) and (2) of Directive 2001/83/EC may also be an NIMP. 3.2.   Requirements for Non Investigational Medicinal Products The manufacturing of NIMPs  per se  does not fall within ã   The rules for manufacturing of medicinal products, as set out in Title IV of Directive 2001/83/EC 5 ; or ã   The rules for manufacturing of IMPs, as set out in Article 13 of Directive 2001/20/EC, Article 9 of Commission Directive 2005/28/EC, and Commission Directive 2003/94/EC. 6  However, the safeguarding of the clinical trial subject, in accordance with Article 3 and the objectives of the Directive has to ensured inter alia by guaranteeing the quality and safety of the products and substances used in the trial. Therefore, section 2.8 of the detailed guidance CT-1 provides for the principal rules for the choice of NIMP. When NIMPs do not have a marketing authorization in the EU, appropriate GMP requirements foreseen for the safety of the patients should still be applied and the sponsor should ensure that NIMPs are of appropriate quality for the  purposes of the trial, taking into account, among other things, the source of the raw materials and any repackaging. To meet the requirements of Articles 3(2) and as referred to in Article 6(3) of Directive 2001/20/EC relating to protection of the trial subject, the same level of quality and safety should be ensured for the NIMPs as for the IMPs used in the trials. 4  For reference to acceptable pharmacopoeial monographs see section 1.5 General Considerations — “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials” CHMP/QWP/18540/2004 final which is part of Eudralex Volume 10 of Rules Governing Medicinal Products in the European Union. 5  Cf. Article 3(3) of Directive 2001/83/EC. 6  An NIMP is not an IMP as defined in Article 2(d) of Directive 2001/20/EC.  4 This requirement will be fulfilled by applying for these NIMPs the same requirements as provided for the IMPs, in particular, the standards as provided for in Title IV of Directive 2001/83/EC and the requirements established under Articles 13(3) and 15 of Directive 2001/20/EC should be applied. The sponsor is responsible for implementing a system to ensure that the trial is conducted and data are generated in accordance with the principles of Good Clinical Practice. To comply with these principles, a trial has to be conducted according to the protocol and all clinical trial information should be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified. In this context, traceability of medicinal products which allows adequate reconstruction of NIMP movements and administration should be ensured taking into account the purpose of the trial and trial subjects’ safety. It has at least to include a procedure to record which patients received which NIMPs during the trial with an evaluation of the compliance, where necessary.  NIMPs may be supplied by the sponsor or by the investigator site. 3.3.   Documentation requirements in the application dossier As a general rule, the documentation requirements in the application dossier for IMPs 7  also apply to NIMPs. However, there are possibilities for simplified documentation requirements ('simplified dossier') depending on the extent of knowledge of the NIMP. Annex 2 sets out those simplified documentation requirements. Regarding language requirements for the documentation in the dossier, reference is made to the detailed guidance CT-1. 8  Within each document, the amount of data might differ. A risk-based approach will be applied in determining the type and amount of data required for each specific case. Existing voluntary cooperation mechanisms between national competent authorities should be used to ensure harmonised application of a risk-based approach on each specific case. 3.4.   Adverse reactions related to NIMPs Regarding safety reporting related to NIMPs, reference is made to the detailed guidance on safety reporting published in Chapter II of EudraLex, Volume 10. 7  Cf. section 2.7. of the detailed guidance CT-1. 8  Section 2.1.6.
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