Dossier for marketing authorization in the European Union

Extensive and complete documentation must be presented for marketing authorization of a medicinal product in the EU. Presented documentation should prove quality, safety and efficacy of the medicinal product. It is ensured that the applicant supplies the authorities with complete information. The legislation in Federation of Bosnia and Herzegovina has also taken more steps towards those European directions. The presentation and content of the dossier in the European Union has been redefined. The "old" EU format will be replaced with the Common Technical Document (EU CTD format) agreed in 2000, within the International Conference on Harmonization framework. These two formats are intended to coexist during the transition period until July 2003. The CTD is an internationally agreed upon format for the preparation of a well structured presentation for applications to be submitted to regulatory authorities in the three ICH regions of Europe, US and Japan.


Introduction
The centralized and mutual recognition procedures became applicable in the EU from 1995.In order to achieve the free movement of medicinal products within the Community, a Committee for the Proprietary Medicinal Products is set up.The Committee has a responsibility to examine any question relating to granting, variation, suspension or withdrawal of marketing authorization in EU.In order to obtain authorization to place a medicinal product on the market, an application shall be made by the competent authority of the Member State concerned, and followed by the particulars and documents (1): -Information about the applicant and, where applicable, about the manufacturer; -Name of the medicinal product; -Qualitative and quantitative particulars of all the constituents of the medicinal product; -Description of the manufacturing method; -Therapeutic indications, contraindications and adverse effects; -Posology, pharmaceutical form, method and route of administration and expected shelf life; -Reasons for any precautions and safety measures, with an indication of any potential risk presented by the medicinal product for the environment; -Description of the control methods employed by the manufacturer; -Results of the physical-chemical biological or

Correlation between old and new format of the application dossier
According to the Common Technical Document application dossier should be presented in five Modules: - The qualitatively different approach can be seen in Module 1, which is including the Environmental risk assessment and Demonstration of significant benefit for Orphan medicinal products in the Annexes.A space for Environmental risk assessment describes present attitude in valuing drugs, regarding their influence on the environment.The task of this evaluation is to discus possible risks to the environment from the point of view of products use and disposal, with proposition of measures for reducing this risk.In the EU format the Environmental risk assessment was divided and placed in Part II or III, depending on the presence of GMOs (genetically modified organisms) in the medicinal product.
There is another change in organization of the dossier in Module 2.Here should be presented the CTD Summaries, prepared by suitably qualified Experts.The classical "Expert Report" known from the EU format does not exist here.The term "Expert Report" is maintained for legal reasons, but the information is given in the form of Overviews and Summaries.
The Quality Overall Summary present information that provides an overview of Module 3, and discus key issues that support information from other Modules.The Nonclinical Overview is continuing with presentation of assessment of the non-clinical evaluation.The quality of batches of active substance used in this study should be discussed, so as the effects seen with related products.The Clinical Overview should be a critical analysis of the clinical data.It should include: description of the overall approach to the clinical development of the medicinal product, a brief overview of the clinical findings, an evaluation of benefits and risks of the medicinal product in its intended use, and description how the study results support critical parts of the prescribing information.
The content of the Module 3, 4 and 5 is parallel to the information from Part 2, 3 and 4 of the EU format.Mentioned parts include chemical, pharmaceutical and biological documentation, toxicological-pharmacological documentation and clinical documentation.
The scientific information from both versions of application dossier can be globally divided on: Quality, Nonclinical and Clinical information.The quality Part/Module is dealing with the quality of the manufacture series and the characteristics of the used test samples that can affect the results of evaluation process (table 2).The information on bioequivalence was more present in the pharmaceutical documentation of EU format and in EU CTD format is primary discussed inside of the clinical information and in Biopharmaceutical studies of Module 5. Non-clinical documentation should present the advantages of the new product pharmacological-toxicological profile, compared with the existing similar medicinal products, and define needed specific conditions and safety issues regarding the administration of the drug (4).The role of clinical documentation in the dossier is to provide information for analysis of one medicinal product with grading its effectiveness, safety and global therapeutic value (5).There has been an organizational change in the CTD format, regarding clinical information.The Tabular Overview of the Expert Report on the Clinical Documentation of Part I is now formed as Tabular listing of all clinical studies in Module 5 (table 3).

Correlation between the application dossier in the European Union and the Federation of Bosnia and Herzegovina
In the Federation of Bosnia and Herzegovina were discussed the differences between European and domestic rules for authorization, and some propositions that are in our country possibilities are adapted.In order to obtain marketing authorization, Applicant is considered to submit the following to the Regulatory authorities (2): -Application with basic information about Manufacturer and medicinal product; -Documentation on clinical, pharmacological-toxicological and laboratory evaluation; -Certificate of quality of the medicinal product according to the World Health Organization rules for quality of the products intended for international trade, that proves authorization of the product in the country of manufacture and that the manufacture process was by the rules of the Good manufacture practice; -List of the countries where the authorization is obtained, with the current prices; -Certificate of Manufacturers authorization for the name of the medicinal product; -Package Leaflet text; -The way of safe disposal of expired drug; -Manufacturers price of the medicinal product; -Samples of the medicinal product.

Conclusion
There are no substantial changes regarding the content of old and new EU format, but the way of presentation and organization of the files is redefined.The parts of the dossier that describes in details all characteristics of the medicinal product are more strictly defined in the EU CTD format, so the new way of presenting information has less space for improvisation.
If we compare the legislation of the content of the application dossier in the EU and Federation no substantial difference in the content of documentation is present.But application and presented information about the medicinal product are more defined and extensive in the dossier for European Union marketing authorization process.Generally, our legislation is trying to keep step with EU.One of the goals of our health management policy is to develop the legislation in this segment that will correspond to European standards.

Table 1
Correlation between old and new way of presentation of the application dossier in the EU (Part I -Module 1 and 2) and FBiH

Table 2
Correlation between old and new way of presentation of the application dossier in the EU (Part II -Module 3) and in the FBiH

Table 3
Correlation between old and new way of presentation of the application dossier in the EU (Part III and IV -Module 4 and 5) and in the FBi H