The Application Dossier

1 Regional Administrative Information Summary of the Dossier Administrative Summary of Product Characteristics 1 1 a lb 

2 Overviews / Summaries of Quality Non-Clinical and Clinical Expert Reports I c 

3 Quality Chemical, Pharmaceutical and Biological Testing of Medicinal Products 11 

4 Non-Clinical Study Reports Toxicological and Pharmacological Tests 111 

The CTD format has been incorporated into the E U regulations and is set out in the revised version of Annex I to directive 2001/82/EC, which was published as Commission Directive 2003/63/EC. It is also supported by detailed guidance in the Rules Governing Medicinal Products in the European Union, Volume 2B - Presentation and content of the dossier - CTD2001 edition. The relationship between the CTD format and the previous four-section format that was used in the E U is shown in Table 6.1. 

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Preparation of Marketing Authorization Application Dossier The application dossier is divided into four parts ... 

As well as GCP site inspections, an examination is imdertaken of the raw or source data and records of Chemistry Manufacturing and Control (CMC), non-clinical and clinical reports that are the basis of the application. This is to ensure that the application dossier accurately reflects the source data. The procedure issued by PMDA details that list of raw data and records must be provided. The applicant is required to bring the data and records to PMDA on the specified days and when the examination finishes they should be retrieved. Therefore, the raw data and records stored at overseas sites are usually categorised as documents not to be submitted and not subject to reliability review by PMDA. Instead, the MHLW may investigate the data from non-Japanese studies at the site of storage since submission of a photocopy of the data is not permitted. 

From 1975 onward, however, the EU has requested experimental validation studies for a manufacturing process to be included in the application dossier where a nonstandard method is being used or where it is critical for the product (Council Directive 75/319/EEC [36] as amended by 91/356/EEC [37]). This requirement is amplified in the Notice to Applicants [38]. 

For some time, the opinion has been divided in the EU regarding the assessment of such validation steps. In many cases it was held to be the remit of the GMP inspectorate while member states would expect to see varying degrees of validation studies presented in support of application for marketing authorization. The guideline Development Pharmaceutics and Process Validation [39] defined more clearly what the agency wants to see in the application dossier. 

It clearly expects to see a process validation protocol included in the submission. Validation data should be generated for all products. It is accepted, however, that the amount of data presented in the application dossier will to a certain extent depend on the nature and complexity of the drug substance, drug product, and manufacturing process. 

Decentralized Procedure (DCP) The decentralized procedure was established as an application route in late 2005. This procedure is essentially a combination of the national and the mutual recognition procedures. The applicant chooses a reference member state to undertake the initial assessment. On completion of the RMS assessment, the concerned member states can put forward additional questions to those raised by the reference member state. If the questions are answered by the applicant to the satisfaction of the reference member state and concerned member states, the drug can be authorized. The benefit of the decentralized procedure is that all concerned member states are provided with the application dossier from the start of the procedure. 

The application dossier shall be submitted in 4 separate volumes (administrative, chemical and pharmaceutical, pharmacological and toxicological and clinical parts). Its presentation and content should be compiled in full conformity with the respective EU requirements. English, Russian or Bulgarian versions are accepted. The dossier shall contain the data listed in Regulation No. 17 (as shown in Appendix 2). 

One copy of the application dossier should be submitted to the Licensing Secretariat of the NDI (Koom 420, Telephone +359 2 944 13 89, Fax +359 2 943 44 87). Upon submission of the registration dossier an application form (Annex 1 of Regulation No. 17) shall be filled out in 3 copies. 

The entire procedure should be completed within 12 months of submission of the application dossier. In the case of a negative statement of the Specialized Commission the MOH shall issue a reasoned refusal. The appeal against the rejection shall be made in court in confirmity with the Law of the Administrative Procedures. 

B deals with the presentation and content of the application dossier. 

The requirements for the content of the application dossier are stated in Directive 75/318/EEC as amended, i.e., the documents and data in support of the application for marketing authorization pursuant to Article 4 of Council Directive 65/65/EEC must be organized in a file in four parts, containing ... 

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). 

The applicant must submit complete copies of dossier to the EMEA, and directly to each of the rapporteurs. The EMEA are allowed 14 days to validate the application to ensure that it is complete and in accordance with the regulations, after which the rapporteurs can commence the scientific evaluation. The review process involves considerable feedback between the rapporteurs, the CHMP and the applicant, central to which can be achieving agreement on the final text of the SPC, labels and leaflet. The rapporteurs are required to deliver preliminary assessment reports to the CHMP within 80 days of the start of the review process. The applicant is also copied on the report. Over the next 40 days issues raised in... 

If the opinion is unfavourable, the applicant has 15 days to notify the agency of its intention to request a re-examination of the decision, and a further 45 days to submit the grounds on which a review is requested. New rapporteurs are appointed to re-examine the dossier, and the C H M P is allowed 60 days to deliver its opinion in light of the re-examination. 

The decentralised procedure can be used in cases where the product has never been authorised in any of the Member States, and the applicant wishes to obtain a license in a number of states simultaneously. The applicant must submit applications with the complete dossier to the Competent Authorities of each of the Member States where authorisation is desired. A single Member State should be chosen as the reference state to undertake the scientific assessment ofthe complete dossier, while the other states are designated as concerned states. The review process has many parallels vhth the centralised procedure, in that similar time lines exist, the reference State plays the role ofthe rapporteur, and the concerned States replace the CHMP. Once all States have validated that the dossiers are complete, the reference State is allowed 70 days to review the dossier and prepare a preliminary assessment report, which is circulated to the concerned Member States and the applicant. Comments from the concerned Member States and applicant responses are collected so that by day 120 the reference State may issue a draft assessment report together vhth draft SPC, label and leaflet texts. The clock may be stopped until requested responses from the applicant are received. The application then enters the second step in the assessment process, during which all the concerned Member States consider the... 

The requirements for the contents of an application dossier are set out in Annex I of Directive 2001/82/EC. The dossier should be assembled in four parts, as outlined in Figure 7.6. The application form. Summary of Product Characteristics (SPC) and labelling, expert reports and quality sections are quite similar in content to human... 

A dossier that focuses on quality (manufacture, control, stability) and labelling of the product must be submitted in support of the application. 

Unlike the FDA, the EMEA itself does not directly undertake appraisals of drug dossiers submitted to support marketing authorization applications under the centralized procedure. Instead (as discussed in detail below), they forward the dossier to selected national EU regulatory bodies, who undertake the appraisal, and the EMEA makes a recommendation to approve (or not) the application based upon the national body s report. The overall role of the EMEA is thus to coordinate and manage the new system. The EMEA s annual budget is of the order of 120 million. The key objectives of the EMEA may be summarized as ... 

The application for a clinical trial authorisation (CTA) for the first administration of a NME to man comprises the same elements as all other CTAs but, of course, there will be no clinical data. The regulatory authority known as the competent authority (CA) of the EU member state requires receipt of confirmation of the EU clinical trials database (EUDRACT) number, a covering letter, a completed application form, the protocol with all current amendments, the IB and a full Investigational Medicinal Product Dossier (IMPD) (see below). If the study is to be conducted in more than one member state, a list of CAs should be included. If the opinion of the lEC is available, it should be provided. 

The basic requirements for the contents of the dossier of information accompan)dng the application for a marketing authorisation are the same whether it is submitted nationally or centrally and were laid out in detail in Directive 715/318/EEC and its subsequent amendments. These requirements were included as Annex 1 of the codified Directive 2001/83/EC. 

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). 

Part I was a summary of the information presented in the whole dossier and included the application forms and administrative particulars on fees, various declarations and the t)rpe of application as well as particulars of the marketing authorisation (lA), proposed SPC (IBl), proposals for packaging, labels and package or patient information leaflets (IB2), and any SPCs already approved in the Member State(s) for the particular product (IB3). Also included were separate Expert Reports on chemical and pharmaceutical (ICl), pharmacotoxicological (preclinical) (IC2), and chnical documentations (IC3), as... 

During the assessment process, there is a documented interactive dialogue between each assessor and the applicant to clarify points that are complex or ambiguous or to enable the applicant to provide additional raw data, statistical appendices and detailed protocols to facilitate the assessment process. However, none of the various parts of the dossier is self-standing or independent of others. There are areas within each, which are intricately linked to the others. In preparing a comprehensive and integrated regulatory assessment report, it is important that these areas of common interest are appropriately addressed. 

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