Marketing-authorisation applications

A European marketing-authorisation application depends on what is settled before and around the writing: the legal basis it is submitted under, the administrative particulars on the application form, a presentation that lets a reviewer find what the decision rests on, and the guidelines and standards the dossier meets.

What an application is

A medicinal product can be made commercially available only once it holds a marketing authorisation, which is obtained by applying to the responsible regulatory authority of the country where the product is to be sold. ¹ The application gives the product's life story, from the first stages of its formulation and development through its manufacture and quality control, and it concludes with the results of all the relevant pharmaceutical, preclinical and clinical trials performed. ¹ It addresses three aspects of the product: its quality, whether it is of consistent quality for human consumption; its safety, whether it is safe at the doses recommended; and its efficacy, whether it works for the condition it is indicated for. ²

The instructions for writing an application are in the Notice to Applicants, which in 2007 was published in three volumes: Volume 2A dealt with the procedures for obtaining an authorisation, Volume 2B with the presentation and format of the dossier, and Volume 2C with the regulatory guidelines to be followed. ² The application must be presented in the Common Technical Document (CTD) format. ²

The legal basis

Deciding the legal basis early is the most important step, because the legal basis determines the data any successful submission needs. ³ The content of the dossier is strongly interlinked with the legal basis selected, and the submission strategy is a key decision to take before development and submission activities proceed. ⁴

A line extension occurs when certain fundamental changes are made to a product, such as a change in strength (10 mg rather than 5 mg) or in pharmaceutical form (such as a modified-release tablet), and it should always take the same legal basis as the original product. ⁵

Regulatory authorities are not concerned with patents, and the applicant is responsible for not breaching patent law. ⁶ The data exclusivity period of the reference medicinal product should always be checked, so that no time is spent on an application for a product that cannot be placed on the market for a significant period. ⁶

The application form

Module 1 of the CTD is the administrative part of the application, and it contains the application form with its relevant appendices, additional national information, the labelling, the package leaflet and the summary of product characteristics. ⁷ The form sets out the main particulars of the application: the legal particulars, such as the legal basis of submission; the medical particulars, such as the therapeutic category and indications; and the pharmaceutical particulars, such as shelf life and pack sizes. ⁸ A copy can usually be obtained electronically from the website of the authority to which the application is submitted. ⁸ A separate form should be completed for each proposed marketing authorisation, that is, for each pharmaceutical form and strength of the product, and it should be completed in English unless the relevant national language is requested. ⁸

As of 2007, the main sections of the form asked for: ⁸

• the basic details of the product: its proposed name, active substance, strength and pharmaceutical form, the name and address of the proposed marketing authorisation holder, and the signature of the contact person on behalf of the applicant ⁹
• the strength, pharmaceutical form, route of administration, proposed packaging and pack sizes, with the pharmaceutical form, route of administration and container given in the standard terms the European Pharmacopoeia defines ¹⁰
• the legal status for supply: whether the product is to be supplied on prescription only or not, and whether its supply is restricted, for example to certain patients ¹¹
• the marketing authorisation holder's name, address, phone number and email address, and the contact person's details ¹²
• every site involved in any stage of the development, manufacture or testing of the product and its active substance, including distributors with reference to the relevant manufacturers' licences, each with its name, its own address rather than the headquarters address, its phone number and its email address ¹³
• the formulation, with the pharmacopoeial reference for each component, and the transmissible spongiform encephalopathy (TSE) declaration ¹⁴
• whether any scientific advice or recommendations were obtained from any EU member state for the application ¹⁵
• details of any studies performed or to be implemented to support the use of the product in children ¹⁶
• every application for the same product in other countries, whether it was authorised, is pending, or was refused, withdrawn, suspended or revoked, and whether different therapeutic indications were granted, with duplicate applications given by product name and marketing authorisation number ¹⁷

The regulatory authority should be informed when the contact person changes, because it contacts that person directly on any issue with the application. ⁹ The authorised manufacturer or importer responsible for batch release of the product should be based in the European Community. ¹³ Each country has its own additional data requirements, which the Notice to Applicants details. ¹⁸

Presenting and sending the dossier

A reviewer at the licensing authority approves or rejects the application on the information the application gives about the product, so that information should be presented clearly and leave no room for misinterpretation. ² Presentation is key to getting the information across simply and directly, so that the reviewer neither has to search through all the documentation for what they need to decide on the product's quality, safety and efficacy nor makes an unfavourable decision because they cannot find the correct information in the dossier. ¹⁹ The principles of style and plain English should be taken into consideration when writing an application. ¹⁹

A contents page should always be included, and each dossier labelled 'x of y', so that the reviewer knows how much documentation is being submitted. ²⁰

Where published literature is included, it is good practice to give a detailed description and justification of the search strategy used to find it, and a review of the literature is very helpful in supporting the application. ²¹ All the documentation should be included, whether favourable or unfavourable, with a justification for any document left out, so that the summary of the published literature is unbiased. ²¹ Each article should be given in full, with any necessary translations. ²¹

The application should be sent to the correct address and in the correct language. ²² As of 2007, the Notice to Applicants, Volume 2A, Chapter 7 'General Information', gave the addresses of the national authorities, the number of copies of dossiers and modules required, the languages to be used and further national requirements. ²²

Guidelines and standards the dossier meets

An applicant should always take into account the scientific guidelines on the quality, safety and efficacy of medicinal products for human use adopted by the Committee for Medicinal Products for Human Use and published by the European Medicines Agency. ² Medicinal products should comply with the tests of the specific and general monographs of the European Pharmacopoeia and of any relevant national pharmacopoeia, and all the European Pharmacopoeia's monographs, general monographs and general chapters apply to the quality part of the dossier. ² The manufacturing process should comply with the principles and guidelines of good manufacturing practice (GMP). ² Questions and Answers documents, a kind of frequently asked questions document, should be the first port of call where a situation is unclear. ¹⁸

Final checklist

The following checks are advised before an application is submitted: ²³

• Submit under the correct legal basis for the application.
• Present a legible and clearly written application.
• Follow the recommended Notice to Applicants, CTD format and guidelines.
• Check the relevant websites for the latest versions of, or additions to, the guidelines.
• Provide all the documentation the application needs.
• Justify any lack of relevant information in the application.
• Always check the documentation before submission.

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