IMPD Guidance

The following  detailed guidance concerning IMP Dossiers is an excerpt from 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” (Revision 3, March 2010).

The detailed guidance is based on Article 9(8) of the Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the approximation of laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

2.7. IMP dossier

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 related to the quality of any IMP (i.e. including reference product and placebo), manufacture and control of the IMP, and data from non-clinical studies and from its clinical use.

However, in many cases where the IMP has a marketing authorisation, an IMPD is not required. Reference is made to Section 2.7.1 (regarding compliance with Good Manufacturing Practice, GMP) and Section 2.7.3 (regarding data).

2.7.1. GMP compliance

As regards GMP compliance, in the following cases no documentation needs to be submitted:

— the IMP has a marketing authorisation in the EU or in an ICH country, is not modified, and is manufactured in the EU, or

— the IMP is not manufactured in the EU, but has a marketing authorisation in the EU, and is not modified.

If the IMP does not have a marketing authorisation in the EU or an ICH country and is not manufactured in the EU, the following documentation should be submitted:

— a copy of the importation authorisation as referred to in Article 13(1) of Directive 2001/20/EC, and

—  a certification by the qualified person (QP) in the EU that the manufacturing complies with GMP at least equivalent to the GMP in the EU. Regarding this certification, there are specific arrangements provided for in the Mutual Recognition Agreements between the EU and third countries (More information is available here.).

In all other cases, to document compliance with GMP as set out in Directive 2003/94/EC and the implementing detailed guideline for IMPs (Annex 13  to Volume 4  of EudraLex — The Rules Governing Medicinal Products in the European Union. ), the applicant should submit a copy of the manufacturing/importing authorisation as referred to in Article 13(1) of Directive 2001/20/EC stating the scope of the manufacturing/ importation authorisation.

2.7.2. Data related to the IMP  Introductory remarks

Regarding data, the IMPD can be replaced by other documentation which may be submitted alone or with a simplified IMPD. The details for this ‘simplified IMPD’ are set out in Section 2.7.3.

The IMPD should be prefaced with a detailed table of contents and a glossary of terms.

The  information  in  the  IMPD  should be concise. The IMPD should not be unnecessarily voluminous. It is preferable to present data in tabular form accompanied by brief narrative highlighting the main salient points.

Regarding various specific types of IMPs, guidance is also given by the Agency, and made available in Volume 3 of EudraLex — The Rules Governing Medicinal Products in the European Union. Quality  data

Quality data should be submitted in a logical structure, such as the headings of the current version of the Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (CHMP/QWP/185401/2004  final). This document also contains guidance for quality of placebos.

As regards biotechnological IMPs, reference is made to the Guideline on virus safety evaluation of biotechnological investigational medicinal products, as amended (Ref.  EMEA/CHMP/BWP/398498/2005).

In exceptional cases, where impurities are not justified by the specification or when unexpected impurities (not covered by specification) are detected, the certificate of analysis for test products should be attached. Applicants should assess the need to submit a TSE Certificate.  Non-clinical  pharmacology  andtoxicology  data

The applicant should also provide summaries of non-clinical pharmacology and toxicology data for any IMP used in the clinical trial. He should also provide a reference list of studies conducted and appropriate literature references. Full data from the studies and copies of the references should be made available on request. Wherever appropriate it is preferable to present data in tabular form accompanied by a brief narrative highlighting the main salient points. The summaries of the studies conducted should allow an assessment of the adequacy of the study and whether the study has been conducted according to an acceptable protocol.

Non-clinical pharmacology and toxicology data should be submitted in a logical structure, such as the headings of the current version of Module 4 of the Common Technical Document, or of the eCTD format.

Reference is made to the specific Community guidelines contained in Volume 3 of EudraLex, and especially the Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals, as amended (CPMP/ ICH/286/95).

This section should provide a critical analysis of the data, including justification for omissions of data, and an assessment of the safety of the product in the context of the proposed clinical trial rather than a mere factual summary of the studies conducted.

The protocols should meet  the  requirements of Good Laboratory Practice (GLP) guidelines where appropriate.

The applicant should provide a statement of the GLP status of all studies.

The test material used in the toxicity studies should be representative of that proposed for clinical trial use in terms of qualitative and quantitative impurity profiles.

The preparation of the test material should be subject to the controls necessary to ensure this and thus support the validity of the study.  Previous clinical trial and human experience data

Clinical  trial  and  human  experience  data  should  be submitted in a logical structure, such as the headings of the current version of Module 5 of the Common Technical Document, or of the eCTD format.

This section should provide summaries of all available data from previous clinical trials and human experience with the proposed IMPs.

All studies should have been conducted  in accordance with the principles of Good Clinical Practice (GCP). To this end, the applicant should submit the following:

— a statement of the GCP compliance of the clinical trials referred to,

— where a clinical trial referred to has been performed in third countries, a reference to the entry of this clinical trial in a public register, if available. Where a clinical trial is not published in a register, this should be explained and justified.

There are no specific requirements for data from clinical studies that must be provided before a clinical trial authorisation can be granted. Rather, this is to be assessed on a case-by-case basis. In this respect, guidance is provided in the guideline General considerations for clinical trials (CPMP/ICH/291/95).  Overall risk and benefit assess ent

This section should provide a brief integrated summary that critically analyses the non-clinical and clinical data in relation to the potential risks and benefits of the proposed trial unless this information is already provided in the protocol. In the latter case, the applicant should cross-refer to the relevant section in the protocol. The text should identify any studies that were terminated prematurely and discuss the reasons. Any evaluation of foreseeable risks and anticipated benefits for studies on minors or incapacitated adults should take account of the provisions set out in Articles 3 to 5 of Directive 2001/20/EC.

Where  appropriate,  the  sponsor  should  discuss  safety margins in terms of relative systemic exposure to the IMP, preferably based on area under the curve (AUC) data, or peak concentration (C max ) data, whichever is considered more relevant, rather than in terms of applied dose. The sponsor should also discuss the clinical relevance of any findings in the non-clinical and clinical studies along with any recommendations for further monitoring of effects and safety in the clinical trials.

2.7.3. Simplified IMPD by referring to other documentation

The applicant has the possibility to refer to other documentation which may be submitted alone or with a simplified IMPD to contain the information as set out in Table 1.  Possibility to refer to the IB

The applicant may either provide a stand-alone IMPD or cross-refer to the IB for the preclinical and clinical parts of the IMPD. In the latter case, the summaries of pre-clinical information and clinical information should include data, preferably in tables, providing sufficient detail to allow

assessors to reach a decision about the potential toxicity of the IMP and the safety of its use in the proposed trial.

If there is some special aspect of the preclinical data or clinical data that requires a detailed expert explanation or discussion beyond what would usually be included in the IB, the applicant should submit the preclinical and clinical information as part of the IMPD.  Possibility to refer to the SmPC or to the assessment of the IMPD in another clinical trials application

The applicant may submit the current version of the SmPC (or, as regards ICH countries, the documentation equivalent to the SmPC) as the IMPD if an IMP has a marketing authorisation in any Member State or in an ICH country. The exact requirements are detailed in Table 1.

Moreover, the IMPD may have been submitted previously by the same applicant or by another applicant and held by the national competent authority of the Member State concerned. In these cases applicants are allowed to cross- refer to the previous submission. If the submission was made by another applicant, a letter from that applicant should be submitted authorising the national competent authority to cross-refer to that data. The exact requirements are detailed in Table 1.

IMPD Guidance - Table 1

If the applicant is the MA holder and he has submitted an application to vary the SmPC, which has not yet been authorised, and which is relevant for the assessment of the IMPD in terms of patient safety, the nature of the variation and the reason for it should be explained.

If the IMP is defined in the protocol in terms of active substance or ATC code (see above, Section 2.5), the applicant may replace the IMPD by one representative SmPC for each active substance/active substance pertaining to that ATC group. Alternatively, he may provide a collated document containing information equivalent to that in the representative SmPCs for each active substance that could be used as an IMP in the clinical trial.

2.7.4. IMPD in cases of placebo

If the IMP is a placebo, the information requirements can be reduced in line with the requirements set out in Table 2.

IMPD Guidance - Table 2