Applications for Marketing Authorisations

The amount of scientific information contained in a licensing application may be vast (often exceeding 1000 pages). The pharmaceutical company presents evidence to show that every aspect of production of the medicinal product has been controlled and validated and is of an acceptable quality. The application starts with a description of the discovery chemistry for the new drug. This may be a chemical synthesis or an extraction of an active natural product from a plant or microorganism. Spectroscopic (e.g. NMR, MS, IR) and chromatographic (e.g. HPLC, GC) data are presented to show that the correct compound has been synthesised, and that by-products are identified and their levels controlled. The new chemical entity is then subjected to stability testing under accelerated conditions of heat, humidity, etc. to calculate shelf-life and rates of decomposition. Each decomposition product is identified and any potential toxicity is controlled. 

The third section of an application usually contains clinical data. This may take the form of pharmacokinetic studies in both animals and human volunteers. Measurements such as plasma levels, area under the curve, protein binding, etc. are compared with data from other manufacturer s products and conclusions are reached about the safety, quality and efficacy of the new product. 

The final section of the application usually contains data on the patient information leaflet (PIL), labelling, instructions for use and packaging of the final product. These data are read carefully to ensure the patient receives clear and unambiguous information. 

Applications for licensing are considered by assessors at the MHRA. In arriving at a decision, the assessors may take independent advice on matters such as safety, quality and efficacy from medicine advisory bodies 

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Committee For Proprietary Medicinal Products, Xotes to Applicants for Marketing Authorisations on the Production and Quality Control of Monoclonal... 

AQ4a The use of ionising radiation in the manufacture of medicinal products (pages 23-30) 3AQ9a Excipients in the dossier for application for marketing authorisation of a medicinal product (pages 67-74)... 

Such is the emphasis on the scientific development of medicines for paediatric use that Section 4 of the application for marketing authorisation specifically requires the applicant to state whether or not there is a paediatric development programme. Following the Council Resolution of December 2000, in February 2002 the EC published a consultation paper on Better Medicines for Children - proposed regulatory actions in... 

On receipt of a valid application via the EMEA, the rapporteur and the co-rapporteur both prepare their separate detailed assessment reports, which are circulated to the EMEA and all other Member States by day 70 from the start of the procedure. The new Regulation requires that the duration of the analysis of the scientific data in the file concerning the application for marketing authorisation must be at least 80 days, except in cases where the rapporteur and co-rapporteur declare that they have completed their assessment before that time. 

The application format is to be harmonised with the EU Notice to Applicants (Expert Reports will also be requested). The particulars cind documents accompanying an application for marketing authorisation (MA) must be presented in four parts ... 

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). 

Excipients, including those added during the manufacture of the herbal preparations, should be described according to the Note for guidance on excipients in the dossier for application for marketing authorization of a medicinal product" (Eudralex 3AQ 9A) or the Note for guidance on excipients in the dossier for application for marketing authorisation of veterinary medicinal products" (EMEA/CVMP/004/98), as appropriate. Eor novel excipients, the dossier requirements for active substances apply (refer to Directive 2001/83/EC as amended for human medicinal products and Directive 2001/82/EC as amended for veterinary medicinal products). 

Committee for Proprietary Medicinal Products (CPMP) and European Medicines Evaluation Agency CEM EA) Guidance for industry notes on various aspects of product development and registration in Europe, e.g., Excipients in the dossier for application for marketing authorisation of a medicinal product (111/3196/91) Web sites http //www.eudra.org/ emea/cpmp and http //www.eudra. org/w3/emea.html... 

Volume 2A Notice to applicants—Medicinal products for human use—Procedures for marketing authorisation Volume 2B Notice to applicants—Medicinal products for human use—Presentation and content of the dossier Volume 2C Notice to applicants—Medicinal products for human use—Regulatory guidelines Commission of the European Communities, Luxembourg, 1998/1998/ 1999 (and amendments)... 

EMEA, CHMP. Guideline on therapeutic Areas Within the Mandatory Scope of the Centralised Procedure for Evaluation for Marketing Authorisation Application, October 2005. 

The completion of harmonisation of rules for plastic food contact materials and articles is within sight. The finalisation of the positive list for authorised additives is likely to happen in 2008. In 2007 the Commission will, besides the Community list of authorised additives, publish a list of additives authorised at national level for which a valid application for EU authorisation has been made to EES A. Only these substances may be used until evaluation is finalised by EES A and a decision on authorisahon is taken by the European Commission. Another project in the plastics sector is the extension of the rules to multimaterial multilayer structures where the plastic layer is in contact with the food. At this moment only plastic materials which consist entirely of plastic are covered by the plastics Directive. These materials, when they are made up from layers of plastic, constitute only about 15% of the mutilayer market. Other multilayer materials such as beverage cartons, which consist of a food contact layer of plastic and aluminium and/or paper, are not yet covered by specific legislation. Extension of the plastics mles to these materials will have to take into consideration requirements for the non-plastic layers and establish mles for migration testing of these materials. 

The Commission for Marketing Authorisations is consulted for all MA applications for medicines (Authorisation de Mise sur le Marche des Medicaments [AMM]) in Article R 5140 of the Code of Public Health as well as all requests for authorisation for temporary use (ATU). It encompasses a number of specialist working groups including pharmaceutics, toxico-pharmaco-clinical, antibiotic, medical interactions, AIDS, biotechnology, self-medication, and medical gases. 

Figure 34.3 provides a flowchart and timelines for the MRP (see also Vol. 2A of the Notice to applicants Procedures for Marketing Authorisation... 

Table 3.4 Standard terms for marketing authorisation applications, Notes for Guidance in 3593/91 EN final (updated February 1998)...

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001, on the approximation of the laws, regulations and administrative provisions of the member states, relates to the implementation of GCP in the conduct of clinical trials on medicinal products for human use. The commimity code relating to medicinal products for human use (2001/83/EC) was amended in 2003 (2003/63/EC), stipulating that clinical trials data used for marketing authorisation applications in the EU are required to be conducted in accordance with GCP. 

Evaluation of applications for drug marketing authorisations made either directly to the national authority or indirectly via the centralised procedure to the EMEA... 

Storage conditions will be used. Standard conditions to simulate normal storage are temperatures of 25 or 30 °C and relative humidity of 60 or 65%. A minimum of 12 months real-time data is required for a marketing authorisation application. Real-time data should be supported by accelerated and intermediate stress testing at higher temperature/relative humidity. Photostability should be verified using a single batch. 

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). 

Requests for permission to conduct clinical trials with pharmaceuticals in the US are termed Investigational New Drug Applications (INDs). The applications are actually a request for an exemption to supply a drug without a marketing authorisation. A cover sheet (Form 1571) must accompany the application. This cover sheet should also be used with each subsequent communication with the FDA, with each form consecutively numbered, starting at 000 for the initial submission. A copy of the form is shovm in Figure 5.6. 

A Form 1572 is used for investigators to summarise their educational qualifications and experience, and to make a required formal declaration as to their commitment to conduct the study according to the protocol, GCP and the regulations. The sponsor should also collect financial disclosure information from the investigators at this stage, although formal declarations on Form 3455 are not required until the submission of a marketing authorisation application. 

The procedures for obtaining a Community marketing authorisation are defined in EC Regulation No. 726/2004. The types of human-use medicinal products for which the procedure may be used are shown in Eigure 6.14. The applicant should notify the EMEA of their intention to submit an application at least 7 months... 

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