Dossier structure

The content of the application is quite similar to EU requirements, although the structure and terminology is slightly different. The main headings are shown in Table 5.5. However, the FDA will now also accept IND application dossiers structured according to the CTD format (see Chapter 6 for the CTD format). 

Table 6.1 Relationship between CTD and previous EU dossier structure. ...

Figure 7.6 Outline of the dossier structure for a marketing application for a veterinary product.

An Investigational Medicinal Product Dossier (IMPD) is intended to be more comprehensive than an IB, in that it should contain summaries of available quality data in addition to the safety and efficacy information that constitutes the main part of the IB. In total, it should provide information on the chemistry, manufacture, control and stability ofthe medicinal product, together with the results of non-clinical and clinical studies. In order to avoid repetition, the IB can be cross-referenced for non-clinical and clinical results. Ideally, the IMPD should follow the same structure as that which will be used later for the marketing authorisation application. For products with existing marketing authorisations, the Summary of Product Characteristics may replace the IMPD to varying extents (see Chapter 6). 

For this, the manufacturer and the importer have to register the chemicals they are placing on the European market. The registration is mandatory for all chemicals that are sold in a volume of more than 1 Mg/a. With the registration the manufacturer and the importer have to provide a special registration dossier. This dossier should cover all necessary information to do the safety check. To be precise, the structure of the dossier has to follow well-defined requirements, which will not be explained in this article. More information is offered here [10, 11]. 

Directive 75/318/EEC required that the dossier be presented in four highly structured parts Parts I, II, III, and IV. Directive 83/570/EEC was the amending Directive, which introduced the requirements for a draft SPC to be produced by the applicant. Volume 2B of The Rules Governing Medicinal Products in the European Union gave a detailed breakdown of the structure of a European regulatory dossier. This format was accepted until the end of June 2003 when a new format known as the Common Technical Document (CTD) became mandatory (see later). 

An application for a marketing authorisation must be accompanied, among other items, by specified pharmaceutical, preclinical and clinical particulars and documents (the dossier ). Three important summary documents in the dossier are the SPC, a Package or Patient Information Leaflet (PIL), and the sales presentation of the product (label). The SPC has a formally prescribed structure (Box 17.1), and forms the basis for authorised chnical prescribing of the medicinal product concerned. 

Another important component of the protein dossier is structural information. Do high-resolution structures (either NMR or X-ray) exist that can be used for library generation and hypothesis testing/generation112,41-441 Are these structures with bound ligands In many medicinal chemists eyes, this is the most important of the criteria in fact, to many it is so important that hit follow-up will not be pursued until suitable structures are in hand. Several companies entire business model is based upon X-ray-based screening of fragment libraries. 

The Restrictions place conditions for the manufacture, placing on the market, or use of certain substances in the EU that are deemed to have unacceptable risks. Proposals for restrictions will be prepared by Member States or by the Agency on behalf of the Commission in the form of a structured Dossier. This Dossier is required to demonstrate that there is a risk to human health or the environment that needs to be addressed at Community level and to identify the most appropriate set of risk reduction measures. Deadlines for the procedure to prepare a Commission decision are set out in the Regulation. Interested parties will have an opportunity to comment and the Agency will provide opinions on any proposed restriction. 

The first part of a dossier contains basic information about the active substance and the applicant. Here are some examples name, structure, and route of synthesis of the substance must be described. The typical purity of the technical material and the identity isomers and impurities is determined by the analysis of five production batches to assess the reproducibility of the process and to help to identify fake products. In the next chapter the chemical and physical properties are described, determined according to official guidelines published by the OECD and other organizations. This applies to the active substance, all significant metabolites, and all formulated products. Some of the required studies are listed in Table 11.11. 

The Directives describe the specific structure of the registration dossier. Documentation in the English language is acceptable. Documentation in any other language besides Hebrew has to be translated and notarized. 

Application for marketing authorisation using either the centralised or the mutual recognition procedure has to be submitted in four highly structured parts - I, II, III and IV. Volume 2B of the Rules Governing Medicinal Products gives a detailed breakdown of the structure of each part of the dossier, including the three mandatory expert reports. 

The full revised text of the Notice to Applicants Volume 2B has been available since June 2001. The revised provisions, which take into account the ICH agreements, are ultimately intended to replace the previous structure of the European marketing authorisation dossier described in the 1998 edition of Volume 2B. However, in order to take into account the fact that the marketing authorisation holders may need some time to adapt their current procedures, it has been agreed that both the previous 1998 edition of Volume 2B and the new edition published in June 2001 will coexist for some time. Therefore, from 1 July 2001 the legal requirements governing the particulars and documents to accompany an application for marketing authorisation may be fulfilled by reference to either the 2001 edition or to the previous 1998 edition of Volume 2B (EudraLex Vol 2B). 

As a generalization, most large chemical companies review the information base on their chemicals on a periodic basis in order to establish research and testing priorities Absence of data, structure/activity similarity to chemicals with potent adverse effects, and potential for exposure are important considerations in setting priorities Usually, a dossier of available Information is prepared prior to establishing a testing program. 

Substance evaluation - carried out if a competent authority suspects that a substance poses a risk to human health or the environment (for example because of its structural similarity to a known dangerous substance). This involves examining the dossiers of all registrations for a substance to clarify the risks and may result in the authority requesting further information from those registering the substance. 

FDA approval of an MD also requires a dossier. The structure of the dossier differs in relation to the approval procedure selected 510(k) or PMA (See Section 6.2.2.4). Table 6.1 summarizes the documents required for biomedical approval in the EU and the US. 

With reference to Section 6.2.2.3, we now compare the structure of the dossier needed for approval of medicines and MDs. Of course, a direct comparison is not possible and the correlations estabhshed can therefore be challenged. We intend oidy to highlight some differences and similarities between the documents needed for medicines and MDs. 

The software architecture of the PIPC, developed in C, has a layered structure in order to benefit from the hierarchical approach of safety dossiers as advocated by the standard CENELEC EN 50129 [CEN 03]. 

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