Investigator’s Brochure (IB)

CTR Appendix 1, section E, and Appendix A of Guideline for Good Clinical Practice (ICH E6(R3)) describe the requirements for an IB.

The IB shall be updated when new and relevant safety information becomes available, and shall be reviewed by the sponsor at least once per year (CTR article 55.2).

Reference Safety Information

Always indicate in the cover letter where the Reference Safety Information is located.

If the IB is not an SmPC (summary of product characteristics), it must contain a clearly identifiable section called the ‘Reference Safety Information’ (RSI). The RSI contains an overview of expected Serious Adverse Reactions (SARs). Only SARs included in the approved RSI do not need to be submitted to the EudraVigilance CT module.

For an IMP with a marketing authorization (MA) in the EU, which is used according to the MA, section 4.8 of the SmPC may be used as RSI.
If it is proposed to use an IMP outside the (EU) indication of MA within the trial, section 4.8 of the SmPC for the IMP(s) may only be used as the RSI, if scientifically justified by the sponsor in the clinical trial application cover letter. Otherwise the RSI must always be a clearly separated specific section within the IB.

See further questions 7.7-7.21 of the Q&A CTR. The Q&A also describes what to do in case there are no expected SARs and the conditions for addition of a new SAR to the RSI.

Good Laboratory Practice (GLP)

The IB describes the non-clinical safety studies conducted for the development of the medicinal product. Some of these non-clinical studies are designated as "pivotal" because they support the non-clinical safety conclusions of a research dossier. Which studies are considered pivotal is determined based on ICH guidelines. These pivotal non-clinical safety studies must be conducted in accordance with Good Laboratory Practice (GLP) (Article 25, paragraph 3, CTR).

The GLP principles have been published by the Organisation for Economic Co-operation and Development (OECD). The European Commission has adopted these GLP principles and incorporated them into Directive 2004/10/EC; see also the European Commission’s GLP website for more information. The CTR refers to these GLP principles.

In the Netherlands, the Health and Youth Care Inspectorate (IGJ) inspects test facilities for compliance with the GLP principles. This is carried out at the request of the test facility or a regulatory authority. For more information, please refer to the Good Laboratory Practice (GLP) page on the IGJ website.

To harmonize information on the GLP status of pivotal non-clinical safety studies in a research dossier and its assessment within the EU, a European Recommendation Paper has been published: Recommendation paper on principles of Good Laboratory Practices (GLP) for clinical trial applications under the EU Clinical Trials Regulation (Regulation (EU) No 536/2014). This paper describes what information should be submitted in CTIS on the GLP status of the non-clinical safety studies. See also question 1.19 of the Q&A CTR.

The cover letter should indicate whether the pivotal non-clinical safety studies have been conducted in accordance with the OECD GLP principles. Additionally, in an annex to the cover letter, a table must be included with information on the GLP compliance of the pivotal non-clinical safety studies. In line with the European recommendation paper, a template has been developed for this purpose and is available under 'Key documents list' of the Clinical Trials Coordination Group on the HMA website.

Question 1.20 of the Q&A CTR specifically describes which GLP requirements must be taken into account when submitting a research dossier for an ATMP. Due to the specific characteristics of ATMPs, it is not always possible to conduct non-clinical studies in accordance with GLP. The same applies to products covered by ICH guideline S6(R1). In such cases, the IB must provide a justification as to why the pivotal non-clinical safety studies could not be conducted under GLP conditions and to what extent this affects the reliability of the safety data obtained from those non-clinical studies.