Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (Text with EEA relevance) (c. 536)

ANNEX I U.K. APPLICATION DOSSIER FOR THE INITIAL APPLICATION

G. INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD) U.K.

36. The IMPD shall give information on the quality of any investigational medicinal product, the manufacture and control of the investigational medicinal product, and data from non-clinical studies and from its clinical use. U.K.

1.1. Data relating to the investigational medicinal product U.K.

Introduction U.K.

37. Regarding data, the IMPD may be replaced by other documentation which may be submitted alone or with a simplified IMPD. The details of this ‘simplified IMPD’ are set out in section 1.2 ‘Simplified IMPD by referring to other documentation’. U.K.

38. Each section of the IMPD shall be prefaced with a detailed table of contents and a glossary of terms. U.K.

39. The information in the IMPD shall be concise. The IMPD must not be unnecessarily voluminous. It is preferable to present data in tabular form accompanied by a brief narrative highlighting the main salient points. U.K.

Quality data U.K.

40. Quality data shall be submitted in a logical structure such as that of Module 3 of the ICH Common Technical Document format. U.K.

Non-clinical pharmacology and toxicology data U.K.

41. The IMPD shall also contain summaries of non-clinical pharmacology and toxicology data for any investigational medicinal product used in the clinical trial in accordance with international guidance. It shall contain a reference list of studies conducted and appropriate literature references. 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 shall allow an assessment of the adequacy of the study and whether the study has been conducted according to an acceptable protocol. U.K.

42. Non-clinical pharmacology and toxicology data shall be submitted in a logical structure, such as that of Module 4 of the ICH Common Technical Document format. U.K.

43. The IMPD shall 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. U.K.

44. The IMPD shall contain a statement of the good laboratory practice status or equivalent standards, as referred to in Article 25(3). U.K.

45. The test material used in toxicity studies shall be representative of that of the clinical trial use in terms of qualitative and quantitative impurity profiles. The preparation of the test material shall be subject to the controls necessary to ensure this and thus support the validity of the study. U.K.

Data from previous clinical trials and human experience U.K.

46. Data from previous clinical trials and human experience shall be submitted in a logical structure, such as that of Module 5 of the ICH Common Technical Document format. U.K.

47. This section shall provide summaries of all available data from previous clinical trials and human experience with the investigational medicinal products. U.K.

It shall also contain a statement of the compliance with good clinical practice of those previous clinical trials, as well as a reference to the public entry referred to in Article 25(6).

Overall risk and benefit assessment U.K.

48. This section shall provide a brief integrated summary that critically analyses the non-clinical and clinical data in relation to the potential risks and benefits of the investigational medicinal product in the proposed clinical trial unless this information is already provided in the protocol. In the latter case, it shall cross-refer to the relevant section in the protocol. The text shall 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 shall take account of the specific provisions set out in this Regulation. U.K.

49. Where appropriate, safety margins shall be discussed in terms of relative systemic exposure to the investigational medicinal product, 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 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 shall also be discussed. U.K.

1.2. Simplified IMPD by referring to other documentation U.K.

50. The applicant may refer to other documentation submitted alone or with a simplified IMPD. U.K.

Possibility of referring to the IB U.K.

51. The applicant may either provide a stand-alone IMPD or cross-refer to the IB for the reference safety information and the summaries of pre-clinical and clinical parts of the IMPD. In the latter case, the summaries of pre-clinical information and clinical information shall include data, preferably in tables, providing sufficient detail to allow assessors to reach a decision on the potential toxicity of the investigational medicinal product and the safety of its use in the proposed clinical trial. If there is some special aspect of the pre-clinical data or clinical data that requires a detailed expert explanation or discussion beyond what would usually be included in the IB, the pre-clinical and clinical information shall be submitted as part of the IMPD. U.K.

Possibility of referring to the SmPC U.K.

52. The applicant may submit the version of the SmPC valid at the time of application, as the IMPD if the investigational medicinal product is authorised. The exact requirements are detailed in Table 1. Where new data are provided, it should be clearly identified. U.K.

Table 1: Content of the simplified IMPD

(S: Data relating to the active substance; P: Data relating to the investigational medicinal product; A: Additional information on Facilities and Equipment, Adventitious Agents Safety Evaluation, Novel Excipients, and Solvents for Reconstitution and Diluents)
Types of previous assessment	Quality data	Non-clinical data	Clinical data
The investigational medicinal product is authorised or has a marketing authorisation in an ICH country and is used in the clinical trial:
— within the conditions of the SmPC	SmPC
— outside the conditions of the SmPC	SmPC	If appropriate	If appropriate
— after modification (for example blinding)	P+A	SmPC	SmPC
Another pharmaceutical form or strength of the investigational medicinal product is authorised or has a marketing authorisation in an ICH country and the investigational medicinal product is supplied by the marketing authorisation holder	SmPC+P+A	Yes	Yes
The investigational medicinal product is not authorised and has no marketing authorisation in an ICH country but the active substance is contained in an authorised medicinal product, and
— is supplied by the same manufacturer	SmPC+P+A	Yes	Yes
— is supplied by another manufacturer	SmPC+S+P+A	Yes	Yes
The investigational medicinal product was subject to a previous clinical trial application and authorised in the Member State concerned and has not been modified, and
— no new data are available since last amendment to the clinical trial application,	Reference to previous submission
— new data are available since last amendment to the clinical trial application,	New data	New data	New data
— is used under different conditions	If appropriate	If appropriate	If appropriate

53. If the investigational medicinal product is defined in the protocol in terms of active substance or ATC code (see above, paragraph 18), the applicant may replace the IMPD by one representative SmPC for each active substance/active substance pertaining to that ATC group. Alternatively, the applicant may provide a collated document containing information equivalent to that in the representative SmPCs for each active substance that could be used as an investigational medicinal product in the clinical trial. U.K.

1.3. IMPD in cases of placebo U.K.

54. If the investigational medicinal product is a placebo, the information requirements shall be limited to quality data. No additional documentation is required if the placebo has the same composition as the tested investigational medicinal product (with the exception of the active substance), is manufactured by the same manufacturer, and is not sterile. U.K.