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Overview on medicinal products CTD dossier
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Medicinal products dossier https://www.regulatory-affairs.pl/en/medicinal- products.html
Documentation of human medicinal products • The basic requirements are specified in Directive 2001/83 (Annexes to the Directive), specific requirements are defind for particular issues in the guidelines for group of products • CTD format (Common Technical Document) is required • Details and requirements for each section vary depending on the nature of the product (e.g. synthetic products, herbal medicinal products, blood derrived products, biotechnology, antibiotics, etc.). 2
Documentation of human medicinal products • CTD documentation consists of sections called modules At the present moment we have 5 modules. The modules 2-5 has been agreed at the ICH (EU / US / JP). Module 1 is a specific module for the region THEIR 4
Documentation of human medicinal products 10
Electronic CTD dossiers • In order to speed up the assessmend and handling of CTD dossier as well as for better traceability of the variations in the documents the electronic version of the CTD format called eCTD is created. eCTD format consists of pdf files reflecting the different sections of the modules organized as in CTD in a precisely defined structure. In addition, relationships and attributes of files, dossiers and its history are listed in the XML files. As with the CTD specification module 2-5, for eCTD ICH module 1 is described in the context of the specification EU or other countries of particular region (GCC, CH, USA, CA). Every supplement the documentation (e.g. to answer agency questions) take the form of so-called next sequence consisting of a group of documents changed with the appropriate XML files describing the file changes. 11
Electronic CTD dossiers – NeeS format (Non-eCTD electronic submission). This is a simplified version of the eCTD in the form of pdf files in a strictly defined CTD structure with hyperlinking in pdf table of contents. There is no corresponding XML files for document tracking changes. – As of 2019 NeeS became obsolete in EU and eCTD is the only accepted format for human medicinal products. – For veterinary products VNeeS is introduced in EU. – Details and specifications of the EU eCTD format: http://esubmission.ema.europa.eu/eumodule1/index.htm 12
Categories of applications • There are two concepts: legal basis and legal status. • Legal basis is a category, which defines how safety and efficacy of the medicinal product is documented. • Legal status is a category of availability on the market (OTC / Rx) 13
Legal basis • The main categories of applications in EU – Full stand-alone application (Article 8 (3) Directive 2001/83 )- full clinical and preclinical dossier is required – Generic applications - simplified applications referring to other products with full clinical dossier (so called reference products). You have to prove the equivalence vs. reference products • Generic - the products that have the same strength, form, route of administration (oral form of immediate release are treated as equivalent, e.g., capsules, tablets) and the same indications as the reference product. Equivalence is proven by bioavailability (bioequivalence studies) or in special cases as a so-called biowaiver (exemption from bioequivalence studies- exclusively by the in vitro data, comparison of release profiles in the range of physiological pH (1,2-6,8 / 7.2)). Biowaiver is foreseen mainly for oral immediate release forms of the active substances of the classes I and III BCS, oral solutions, topical products in the form of solutions without the systemic action and parenteral solutions of identical / similar composition • Hybrid – generic like product which differs form the reference product in the field of the route of administration, indications, strenght or generics where due to the route of administration equivalence could not be demonstrated on the basis of the bioavailability studies and there is a need for testing therapeutic equivalence in conventional clinical equivalence / non-inferiority (inhalations). • Biosimilar - application for generic products of biological origin 14
Legal basis • The main categories of applications – Bibliographic applications (well established use WEU, article 10a of Directive 2001/83). This is a kind of full apllication (no reference product), the only difference is that all clinical and non-clinical topics are documented with studies published in literature. Formal requirement of presence of medicinal products for at least 10 years in the EU in the same indication, route of administration. – Fixed combination - the mixture of active substances used in medicinal products separately. The dossier not need to document efficacy and safety of single substances, but should be focused on the combination (e.g. interactions - pharmacokinetic, pharmacodynamic, the effect onthe safety, clinical benefit of combination etc.). The data for the combination should in principle be own data, but sometimes companies use this category to with bibliographic data for the combination to avoid documenting individual substances. It is also a full application dossier. 15
Legal basis • The main categories of applications – Informed consent - another company grants all the right for documentation (modules 2-5) to another entity. The condition is that the first product must already be registered in the particular country. The assessment is then shortened and is based on checking how this dossier corresponds to the current requirements. – Simplified applications for traditional herbal medicinal products (no evidence of efficacy with a proof of a minimum of 15 years in the EU), for homeopathy (without indications), pharmacopoeial products etc. – Mixed application - a WEU application, which presents its own trials for certain topics, for example additional indications, other age groups etc. Such applications officially are classified as a full application according to article 8(3). 16
