Regulatory pathways in the European Union

Abstract

In principle, there are three defined procedures to obtain approval for a medicinal product in the European Union. As discussed in this overview of the procedures, the decision on which regulatory pathway to use will depend on the nature of the active substance, the target indication(s), the history of product and/or the marketing strategy.

In general, the approval of medicines is harmonized in the European Union (EU). Besides a few national specifics, the approval is based on the principles laid out in the Directives and Regulations of the European Parliament and Commission. It is possible to get national approval in one of the member states; however, as soon as a company seeks approval in two or more member states they must use the EU procedures.

In principle, there are three procedures for submitting a Marketing Authorization Application (MAA) in the EU: (1) the mutual recognition procedure (MRP); (2) the decentralized (DCP) and (3) the centralized procedure (CP). The submission strategy for a given product will depend on the nature of the product, the target indication(s), the history of the product, and the marketing plan.

The centralized procedure leads to approval of the product in all 27 EU member states and in Norway, Iceland and Liechtenstein. Submission of one MAA thus leads to one assessment process and one authorization that allows access to the market of the entire EU. The process of the centralized procedure is triggered when the applicant sends the letter announcing the intent to submit a MAA (letter of intent), which is usually done at least seven months prior to the targeted submission date. Dedicated submission dates for each month of the year are provided by the European Medicines Agency (EMA) on its website. The letter of intent also initiates the assignment of the Rapporteur and Co-Rapporteur, who are the two appointed members of the Committee for Human Medicinal Products (CHMP) representing two EU member states. The Rapporteur and Co-Rapporteur will assess the MAA and provide the CHMP with the result of their analysis, which will be the basis of the conclusions of the CHMP, i.e., questions for the applicant or positive opinion with subsequent decision on final approval by the commission.

When using the MRP or DCP, the applicant must select which and how many EU member states in which to seek approval. In the case of an MRP, the applicant must initially receive national approval in one EU member state. This will be the so-called reference member state (RMS) for the MRP. Then, the applicant seeks approval for the product in other EU member states, the so-called concerned member states (CMS) in a second step: the mutual recognition process.

For the DCP, the applicant will approach all chosen member states at the same time. To do so, the applicant will identify the RMS that will assess the submitted MAA and provide the other selected member states with the conclusions und results of the assessment. In principle, the applicant can choose any EU member state as RMS; however, in almost all member states the applicants need to send a request for a time slot when they will be allowed to submit the application. Depending on the agency selected as RMS, the interval between submission of the request to the actual submission date can be two years or longer. Therefore, planning for the DCP well in advance is highly recommended.

In practice, the applicants are not completely free to decide which procedure is the most relevant. There are certain products, indications and conditions for which the centralized procedure is mandatory and not all products are eligible for this procedure. The centralized procedure is mandatory for three types of products as laid down in the Regulation 726/2004: (1) Medicinal products developed by means of one of the following biotechnological processes (e.g., recombinant DNA technology, controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, hybridoma and monoclonal antibody methods); (2) New active substances for which the therapeutic indication is the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorder, diabetes, auto-immune diseases and other immune dysfunctions, viral diseases and (3) Medicinal products that are designated as orphan medicinal products pursuant to Regulation (EC) No 141/2000. Products such as advanced therapy medicinal products (ATMPs) and biosimilars fall under the mandatory scope.

Besides the products falling under the mandatory scope, the centralized procedure is also open for other innovative products. Examples are new active substances or other medicinal products that constitute a significant therapeutic, scientific or technical innovation, or the granting of a Community authorization for the medicinal product is in the interest of patients at Community level. The decision as to whether the product is eligible or not is made by the EMA upon the submission of the corresponding request (letter of eligibility) by the applicant.

Since the centralized procedure focuses on innovative products, generics were not initially submitted. However, now that data exclusivity has ended for more and more products initially approved under the centralized procedure, the proportion of generics approved has increased recently.

In conclusion, in case that an applicant wants to launch a medicinal product in more than one EU member state there are three submission procedures. For biotechnology products including monoclonal antibodies, as well as ATMPs like gene and cell therapies and certain indications, there is no other way but the centralized procedure. Applicants of products with new active substance that do not fall under the mandatory scope have access to all three options and the decision on the procedure will be made based on health care standards, reimbursement considerations, timelines, size of the company and target markets.