What should you know about EU and US drug approval? Part 1

Introduction

In both, the EU and the US, it is illegal to place a medicinal product on the market without approval^1,2. These regulations were not devised on the drawing board, but were introduced as consequence of serious pharmaceutical scandals. The Sulphanilamide disaster in 1937, in which a toxic solvent in a medicinal product claimed the lives of over 100 people in the US, led directly to the enactment of the Federal Food, Drug and Cosmetic Act (FD&C Act) in 1938^3,4.  The Thalidomide disaster in the late 1950s, which led to severe birth defects in newborns worldwide, tightened the requirements for drug approval in both the US and Europe and laid the foundations for today’s European pharmaceutical legislation^5-7. Both incidents have contributed to the requirement that pharmaceutical companies must now provide comprehensive evidence of the quality, efficacy and safety of their medicinal products as part of the regulatory approval process. The following section provides an overview of the different regulatory approval processes in the EU and the US.

Common Technical Document (CTD)

A key component of any marketing authorisation application is the dossier. Information on the non-clinical and clinical development of the product, as well as a detailed description of the manufacture of the medicinal product are included. The structure of the dossier follows the principles of the Common Technical Document (CTD), as described in the ICH M4 guideline⁸. The CTD is divided into five modules. Module 1 contains regional and administrative documents and is therefore country-specific. Modules 2 to 5 are internationally harmonised and comprise the scientific and technical documentation for a medicinal product. The dossier, which is based on ICH principles, is accepted in many regions of the world, including the EU and the USA.

Approval procedures in the EU

The legal basis for the approval of medicinal products in the EU is provided by Directive 2001/83/EC and Regulation (EC) No 726/2004, as amended^2,9. Within the EU, a distinction is made between four authorisation procedures: the exclusively national procedure, the decentralised procedure (DCP), the mutual recognition procedure (MRP) and the centralised procedure (CP). Whilst the national procedure is limited to a single country, the DCP and MRP enable approvals to be obtained in several member states of the European Economic Area (EEA). In addition to the 27 EU member states, the EEA also includes Iceland, Liechtenstein and Norway. The CP, on the other hand, leads to a single authorisation that is valid in all EEA states.

National Procedures
A particular feature of EU Directives is that they need be implemented into national law to come into force. In case of national procedures, this means that the requriements of Directive 2001/83/EC could be implemented differently in every single country.
However, Article 17 of Directive 2001/83/EC stipulates that member states must ensure that the procedure for evaluating a marketing authorisation application is completed within 210 calendar days. These 210 days are to be understood as a maximum duration, not as a fixed duration of the procedure. Once the evaluation has been completed, a decision is made as to whether the pharmaceutical company will be granted a marketing authorisation for the product in that member state.
National procedures are still possible today, but they are becoming an increasingly rare choice. The reason is simple: A marketing authorisation obtained in this way is valid in only one single member state. As many pharmaceutical companies wish to place their medicinal products on the markets in several EU/EEA countries simultaneously, further marketing authorisation instruments have been created to both facilitate market access and ensure the availability of new medicinal products within the European Community.

Mutual Recognition Procedure (MRP)
The basic principle of the MRP is simple: One member state has already done a scientific assessment, and the other member states recognise this assessment rather than repeating it. The legal basis is Directive 2001/83/EC; the procedure is described in detail in the ‘Notice to Applicants Volume 2A’, Chapter 2^2,10.
The MRP enables authorisation holders to use an existing national authorisation as a basis for applying in further EU/EEA member states. The authority that granted this initial authorisation becomes the ‘Reference Member State (RMS)'.
The member states in which additional marketing authorisations will apllied for, are referred to as ‘Concerned Member States (CMS)'. Once the MRP has been successfully completed, the national authorities of the CMS grant the marketing authorisations. The MRP may also be used on multiple occasions to obtain further authorisations in additional countries later in the medicinal product’s life cycle. These follow-up procedures are referred to in technical jargon as the Repeat-Use Procedure (RUP).

An MRP can be divided into the following phases:

Preparation or updating of an expert opinion by the RMS

Evaluation of the dossier by the CMS

Assessment of the dossier by the CMS

National phase, during which national marketing authorisations are granted by the CMS

Approximately 90 days prior to the submission of the CMS, the authorisation holder applies to the RMS for the preparation or updating of the report summarising the key aspects of the initial national authorisation. This report forms the scientific and technical basis for the subsequent mutual recognition.
The marketing authorisation holder then submits identical dossiers to the national authorities of the CMS. At the same time, the RMS shares the opinion with the applicant and the CMS. Following a evaluation phase, which checks the completeness of the documentation and takes an average of 14 days, the MRP begins. During the evaluation, the authorities may request corrections or missing documents, which should be submitted promptly so that the procedure can commence.
The CMS now have 90 days to comment on the approval documents, which consist of expert reports, the dossier and product information.
The applicant must respond to any queries from the CMS within this 90-days time slot. Unlike the DCP or the centralised procedure, there is no clock-stop in the MRP: The procedure continues to run, and the applicant must respond within the current deadline.
On day 90, the CMSs notify the RMS and the applicant of their final decision. If all CMSs reach an agreement, the RMS closes the procedure, and the CMSs have a further 30 days to grant national approval. This so-called national phase serves, amongst other things, to provide translations of the product information and to clarify further national requirements.

It may happen that no agreement can be reached by day 90. Such a situation should only arise if a CMS has identified a potentially serious risk to public health. In this case, the conciliation mechanisms set out in Directive 2001/83/EC applies. In the first instance, the Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) is in charge of the negotiations. If no agreement can be reached there either, the matter is referred to the EMA.

Decentralised procedure (DCP)
In addition to the MRP, the decentralised procedure (DCP) offers a second route to obtain multiple national marketing authorisations in different EU/EEA member states. The legal basis is the same as for the MRP, namely Directive 2001/83/EC; the procedure is also described in ‘Notice to Applicants Volume 2A’, Chapter 2,^2,10.
The key difference from the MRP is that no national approval is required for the DCP. The procedure is used to obtain national approvals de novo.

The DCP can be divided into the following phases:

• Evaluation of the marketing authorisation dossier by the RMS and CMS
• First assessment phase
• Clock-stop to respond to questions from the regulatory authorities
• Second assessment phase
• National phase

Once the approval documents have been submitted, they first undergo an evaluation phase. The completeness check usually takes 14 days. As with the MRP, the authorities may request missing documents or ask for corrections to be made. Once the evaluation is completed, the RMS initiates the procedure (Day 0) and thus the first assessment phase starts.

In the case of the DCP, the RMS takes the lead in the scientific and technical assessment of the application. Within 70 days of the evaluation phase, the RMS draws up a preliminary opinion and carries out an initial evaluation of the product information and the labelling of the medicinal product. The preliminary opinion is sent to the CMS and the applicant, together with further comments.
The CMS then have the opportunity to submit comments on the dossier to the RMS. All CMS comments must be received by the RMS by Day 100. The RMS forwards them to the applicant. If the comments cannot be answered promptly, the RMS suspends the procedure on Day 105 (clock stop) to give the applicant time to respond. The duration is agreed between the RMS and the applicant and is usually limited to three months. In rare cases, the clock-stop may be extended by further three months.
The applicant submits their responses to the RMS and the CMS by the end of the agreed clock-stop period. The RMS resumes the procedure on day 106 and has time until day 120 to submit a draft of the final opinion, together with the completed evaluation of the product information and labelling. This second assessment is again sent to the CMS and the applicant. If no further comments are received, the procedure may be concluded on Day 150 and proceed to Day 30 national phase.
If the CMS makes any further comments, these will be discussed between the RMS, the CMS and the applicant and must be resolved by day 210 of the procedure. If no agreement can be reached, the case will be referred to the CMDh for mediation; if no agreement is reached there either, the application may be referred to the EMA.

Once the procedure has been completed, the RMS sends the applicant the final outcome, the product information, the product labelling and the 'End-of-Procedure Letter'. The national phase then begins, during which national approvals are granted.

The remaining parts of the article will follow shortly as Part 2.

References/Useful links

1. Food and Drug Administration. Federal Food, Drug, and Cosmetic Act. https://www.fda.gov/regulatory-information/laws-enforced-fda/federal-food-drug-and-cosmetic-act-fdc-act.
2. European Parliament and Council of the European Union. Directive 2001/83/EC - 02001L0083. https://eur-lex.europa.eu/eli/dir/2001/83#src.E0001 (2025).
3. Wax, P. M. Elixirs, diluents, and the passage of the 1938 federal food, drug and cosmetic act. Annals of Internal Medicine vol. 122 Preprint at https://doi.org/10.7326/0003-4819-122-6-199503150-00009 (1995).
4. Ballentine, C. Sulfanilamide Disaster FDA Consumer Magazine June 1981 Issue. https://www.fda.gov/files/about%20fda/published/The-Sulfanilamide-Disaster.pdf.
5. Khan, M. A. A., Sara, T. & Babar, Z. U. D. Pharmacovigilance: the evolution of drug safety monitoring. Journal of Pharmaceutical Policy and Practice vol. 17 Preprint at https://doi.org/10.1080/20523211.2024.2417399 (2024).
6. U.S. Food and Drug Administration. Kefauver-Harris Amendments Revolutionized Drug Development. 1-2 Preprint at https://www.gvsu.edu/cms4/asset/F51281F0-00AF-E25A-5BF632E8D4A243C7/kefauver-harris_amendments.fda.thalidomide.pdf (2012).
7. Elisabeth A. Cawthon. Thalidomide Tragedy Prompts Passage of the Kefauver-Harris Amendment. https://www.ebsco.com/research-starters/history/thalidomide-tragedy-prompts-passage-kefauver-harris-amendment#significance (2023).
8. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH M4(R4) Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use. https://database.ich.org/sites/default/files/M4_R4__Guideline.pdf (2016).
9. European Parliament and Council of the European Union. Regulation (EC) No 726/2004. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02004R0726-20220128 (2004).
10. European Commission. Volume 2A Procedures for Marketing Authorisation CHAPTER 2 Mutual Recognition. https://health.ec.europa.eu/system/files/2016-11/vol2a_chap2_2007-02_en_0.pdf (2007).
11. EMA. European Medicines Agency Pre-Authorisation Procedural Advice for Users of the Centralised Procedure. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/european-medicines-agency-pre-authorisation-procedural-advice-users-centralised-procedure_en.pdf (2006).
12. European Commission. VOLUME 2A Procedures for Marketing Authorisation CHAPTER 6 DECISION MAKING PROCEDURE FOR THE ADOPTION OF COMMISSION DECISIONS. https://health.ec.europa.eu/document/download/a4774d9f-802d-4a71-af8b-e40b3590a84b_en?filename=vol2a_chap6_2005-11_en.pdf (2005).
13. FDA. Desk Reference Guide New Drug Application and Biologics License Application Reviews (NDA/BLA Review Process). https://www.fda.gov/media/78941/download.