Regulation and Procedures Governing Approval of Medicinal Products in the European Union and the UK
Similar to the U.S., the EU, and the UK comprehensively regulate, among other things, the development, manufacturing, placing on the market, advertising, distribution, import and export of medicinal products. Particularly, the placing on the market of a medicinal product for human use in the EU requires a marketing authorization (MA). Main Provisions governing medicinal products in the EU are Directive 2001/83/EC and Regulation (EC) No 726/2004 (each as amended). Regulation (EC) No 141/2000 and Regulation (EC) No. 847/2000 (each as amended) are also of particular relevance for orphan medicinal products. While directives need to be transposed into national law by member states of the EU (EU Member States) before they are applicable, regulations directly apply in the EU Member States once these have been enacted.
The process governing approval of MA applications (MAA) for the placing on the market of medicinal products in the EU and the UK generally follows the same lines as in the U.S. It entails satisfactory completion of pharmaceutical development, pre-clinical trials and adequate and well-controlled clinical trials to establish the safety and efficacy of the medicinal product for each proposed indication. The EU also requires the submission to relevant competent authorities for clinical trials authorization and to the European Medicines Agency (EMA) or to competent authorities in EU member states and granting of such MA by the EU Commission or relevant national authorities before the medicinal product can be marketed and sold in the EU or the relevant EU Member States. The below mentioned principles and rules generally apply within the EEA, i.e., the EU including Iceland, Liechtenstein and Norway.
Following the UK’s departure from the EU, a separate MA is required from the Medicines and Healthcare Products Regulatory Agency (the MHRA), the UK medicines regulator, in order to place medicinal products on the market in the Great Britain (England, Wales and Scotland), which has been extended to Northern Ireland following the Windsor Framework having taken effect (see below)). Under the recently introduced International Recognition Procedure (IRP), the MHRA may take into account decisions from the EMA (and certain other international regulators) when considering an application for an MA. In respect of Northern Ireland, the UK government and the EU have agreed to replace the Northern Ireland Protocol (pursuant to which the EU regulatory framework continued to apply to Northern Ireland) with the ‘Windsor Framework’. Under the Windsor Framework, the MHRA is responsible for approving all medicinal products destined for the entire UK market (including Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland. The medicines aspects of the Windsor Framework came into force on January 1, 2025.
Clinical Trial Approval
Both non-clinical and clinical data are generally required to support an MA for a medicinal product in the EU. Non-clinical investigations are performed to demonstrate the health or environmental safety of new biological substances. Non-clinical (pharmaco-toxicological) investigations must generally be conducted in compliance with the principles of good laboratory practice (GLP) as set forth in EU Directive 2004/10/EC (as amended).
Clinical trials are comprehensively regulated under the Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application on January 31, 2022, and (gradually) replaces the Clinical Trials Directive 2001/20/EC (CTD). By January 30, 2025, all still ongoing clinical trials under the CTD must be transitioned to the CTR. The CTR, aims to simplify and streamline the approval of clinical trials in the EU.
As before, many of the legal obligations are on the so-called sponsor, which is defined as the individual, company, institution, or organization that takes responsibility for the initiation, for the management and for setting up the financing of a clinical trial. The sponsor must obtain an authorization from the competent authority in the EU Member State(s) in which the clinical trial will be conducted as well as an approval from the competent national ethics committee in accordance with relevant national legislation in each of the relevant member states, before the commencement of such clinical trial.
The CTR also imposes requirements, among others, regarding the conduct of a clinical trial (which must be conducted in accordance with the protocol and good clinical practice to generate acceptable data for MA submission), safety reporting of adverse events and reactions, changes to clinical trials, protection and informed consent of clinical trial subjects. Clinical trials conducted outside the EEA must follow the principles set forth in EU legislation if their results are to be submitted in an application for an MA in the EU.
Before its exit from the EU, the UK implemented the CTD into national law through the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended). The entry into application of the CTR took place after the UK’s departure from the EU, so it does not apply to Great Britain. The MHRA ran a consultation on reforms to the UK clinical trials legislation, the outcome of which was published in March 2023. New draft legislation was laid for consideration before the UK Parliament in mid-December 2024. The draft regulations include a 12-month implementation period. The UK’s new clinical trials regime is therefore expected to come into force in early 2026 or thereafter.
Orphan Designation and Exclusivity
Regulation (EC) No. 141/2000 and Regulation (EC) No. 847/2000 (each as amended) provide that a product can be designated as an orphan medicinal product by the EU Commission if its sponsor can establish: (i) that the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition, (ii) either (a) the prevalence of the condition is not more than five in ten thousand persons in the EU when the application is made, or (b) without incentives it is unlikely that the marketing of the product in the EU would generate sufficient return to justify the necessary investment in its development and (iii) there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the EU or, if such method exists, the product has to be of a significant benefit compared to products available for the condition.
An orphan designation provides a number of benefits, including fee reductions and, regulatory assistance. If an MA is granted for an orphan medicinal product, this generally results in a ten-year period of market exclusivity for the approved orphan indication. It is, however, not possible to combine non-orphan and orphan indications within the same MA. Thus, for non-orphan indications treated with the same active pharmaceutical ingredient, a separate MA has to be sought. Alternatively, the orphan designation may be waived to allow for the addition of non-orphan indications to an existing MA. As a result, the approved medicinal product would no longer profit from the orphan designation’s benefits.
During an orphan medicinal product’s market exclusivity period, neither the EMA, the EU Commission nor the EU Member States can accept an application or grant an MA for a “similar medicinal product.” A “similar medicinal product”, i.e., a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication. The market exclusivity period for the authorized therapeutic indication may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation. For orphan medicinal products intended for pediatric use, the market exclusivity period may be prolonged by additional two years if they are authorized with a pediatric indication based on the results from studies conducted under an EMA-approved pediatric investigation plan or if they are authorized without a pediatric indication but the results of the studies conducted under the EMA-approved pediatric investigation plan are reflected in the summary of product characteristic and, if appropriate, in the package leaflet. Market exclusivity may also be revoked in very select cases, such as if (i) it is established that a similar medicinal product is safer, more effective or otherwise clinically superior; (ii) the MA holder (MAH) for the authorized orphan medicinal product consents to the second orphan application; or (iii) the MA holder for the authorized orphan medicinal product cannot supply sufficient quantities. Orphan designation must be requested before submitting an MAA and is reconfirmed during the MAA process. Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and MA approval process.
Since January 1, 2021, a separate process for orphan designation has applied in Great Britain. There is no pre-marketing authorization orphan designation (as there is in the EU) and the application for orphan designation is reviewed by the MHRA, at the time of an MAA for a UK or Great Britain marketing authorization. Until January 1, 2025, a UK-wide orphan MAA could only be considered in the absence of an active EU orphan designation. From January 1, 2025, MAs granted for products that fulfil UK orphan criteria are valid UK-wide (including in Northern Ireland), regardless of whether there is an EU orphan designation or EU authorization as an orphan medicinal product. The criteria are the same as in the EU and, following implementation of the Windsor Framework from January 1, 2025, apply to the whole of the UK. The criteria are that: the medicine must be intended for the treatment, prevention or diagnosis of life-threatening or chronically debilitating diseases; the prevalence of the condition must be no more than five in 10,000 persons in the UK or it must be unlikely that the medicine’s marketing would generate sufficient returns to justify the investment needed for its development; and there must be no satisfactory method of diagnosis, prevention or treatment of the condition concerned in the UK, or if such method exists the medicine must be of significant benefit to those affected by the condition.
Marketing Authorization
To obtain an MA for a medicinal product under the EU regulatory framework, an applicant must submit an MAA, either to the EMA using the centralized procedure or to competent authorities in the EU Member States using the other procedures (decentralized procedure, national procedure, or mutual recognition procedure). An MA may be granted only to an applicant established in the EU. Regulation (EC) No. 1901/2006 provides that prior to obtaining an MA in the EU, an applicant must demonstrate compliance with all measures included in an EMA-approved pediatric investigation plan, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver, or a deferral for one or more of the measures included in the pediatric investigation plan.
The centralized procedure provides for the grant of a single MA by the EU Commission that is valid for all EEA Member States. Pursuant to Regulation (EC) No. 726/2004 (as amended), the centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered products) and products with a new active substance indicated for the treatment of certain diseases, including products for the treatment of cancer and auto-immune diseases and other immune dysfunctions and neurodegenerative disorders. The centralized procedure is optional for certain other medicinal products.
Under the centralized procedure, the EMA’s Committee for Medicinal Products for Human Use (CHMP) is responsible for conducting the assessment of a product to define its risk/benefit profile. The CHMP recommendation is then sent to the EU Commission, which adopts a decision binding in all EEA Member States. Under the centralized procedure, the maximum timeframe for the evaluation of an MA application is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions asked by the CHMP, which can considerably extend the 210 days. Accelerated evaluation (150 days excluding clock stops) may be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and, in particular, from the viewpoint of therapeutic innovation.
MAs have an initial validity for five years, in principle, and they may be renewed after five years on the basis of a reevaluation of the risk benefit balance by the EMA, or by the competent authority of the EU Member State. Once renewed, the MA is valid for an unlimited period, unless the EU Commission or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period. Any MA that is not followed by the placement of the medicinal product on the EU market or on the market of the authorizing EU Member State(s) within three years after authorization, or if the drug is removed from the market for three consecutive years, ceases to be valid. In Great Britain, centrally authorized products converted from EU to UK marketing authorizations will have the same renewal date.
Following the departure of the UK from the EU, the UK is no longer covered by European centralized marketing authorizations issued by the EMA. As of January 1, 2025, the MHRA regulates medicines through UK-wide MAs and EU centralized MAs are not valid anywhere in the UK. Instead, medicines that were previously within scope of the EU centralized procedure are authorized by the MHRA under UK-wide MAs.
European Data and Market Exclusivity
In the EU, innovative medicinal products, approved on the basis of a complete independent data package, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity (for the more comprehensive protections applying to orphan medicinal products, please refer to Section 1.8.2 “Orphan Designation and Exclusivity” above). The data exclusivity, if granted, prevents generic or biosimilar applicants from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU, for a period of eight years from the date on which the reference product was first authorized in the EU. During the additional two-year period of market exclusivity, a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed in the EU until the expiration of the market exclusivity period. The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those 10 years, the MA holder obtains an MA for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are determined to bring a significant clinical benefit in comparison with currently approved therapies. There is no guarantee that a product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity. Even if a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company obtained an MA based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials. Similar arrangements apply in the UK.
Regulatory Requirements after Marketing Authorization
Following MA approval, the MA holder is required to comply with a range of requirements applicable to the manufacturing, marketing, promotion and sale of the medicinal product. These include compliance with the EU’s stringent pharmacovigilance or safety reporting rules under Directive 2001/83/EC and Regulation (EU) 726/2004 (each as amended) and the associated guideline on good pharmacovigilance practices (as amended), pursuant to which post-authorization studies and additional monitoring obligations can be imposed. In addition, the manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the principles of good manufacturing practice (GMP) set forth in Commission Directive 2017/1572 GMP and comparable requirements of other regulatory bodies in the EU, which mandate the methods, facilities and controls used in manufacturing, processing and packing of products to assure their safety and identity. Further, the wholesale distribution of authorized medicinal products requires a separate distribution license and must be conducted in strict compliance with good distribution practice standards. Finally, the marketing and promotion of authorized medicinal products is strictly regulated under Directive 2001/83/EC, (as amended) and as transposed into national laws.
Potential consequences for a failure to maintain regulatory compliance mainly depend on the relevant regulations in the EU Member States, but are, for example, in Germany, similar to those in the U.S. Please refer to section 1.7.1. “Post-Approval Regulations”.
Proposal for new EU Pharmaceutical Legislation
On April 26, 2023, the EU Commission has published a proposal for a new directive (COM/2023/192 final) and a new regulation (COM/2023/193 final), which would revise and replace the existing general pharmaceutical legislation, including e.g., Directive 2001/83/EC, as well as Regulations (EC) No. 726/2004, No. 141/2000, or No. 1901/2006 (EU Pharmaceutical Legislation). Proposed amendments include, among others, modifications to the orphan designation criteria as well as the introduction of a modulated framework for orphan market exclusivity. Regarding the latter, the regulation proposal envisages a shift to a staggered approach. Those orphan medicinal products that address a high unmet medical need shall still benefit from a market exclusivity period of ten years. Well-established use orphan medicinal products will have a five-year market exclusivity period. Nine years of market exclusivity shall apply for all other orphan medicinal products. In certain cases, exclusivity periods may be prolonged (e.g., obtaining of an MA for one or more new therapeutic indications).
Other key points of the proposed new EU Pharmaceutical Legislation include new measures to prevent and mitigate medicine shortages, to simplify the market entry of generics and biosimilars and the introduction of a new data protection regime for medicinal products. The proposal remains to be agreed and adopted by the European Parliament and European Council and may therefore be substantially revised before adoption, which is not anticipated before early 2026.
Brexit and the Regulatory Framework in the UK
On January 31, 2020, the UK officially ceased being a Member State of the EU (Brexit). For a period thereafter, immediate arrangements applied governing pharmaceutical legislation in the UK. However, as from January 1, 2025, following the implementation of the Windsor Framework, the MHRA is now the only authority approving medicines for the UK market. The Windsor Framework replaced the Northern Ireland Protocol, under which the EU regulatory framework continued to apply in Northern Ireland, and made the following key regulatory changes for medicines: (i) removed EU licensing processes in relation to Northern Ireland for novel medicines; (ii) removed any requirement for EU Falsified Medicines Directive packaging, labelling and serialization barcode for medicines in Northern Ireland; and (iii) required all medicines placed on the UK market to be labelled ‘UK Only’, indicating they are not for sale in the Republic of Ireland or other EU countries. More broadly, with the exception of the CTR, the UK and the EU’s regimes for the marketing, promotion and sale of medicinal products remain aligned, as the UK’s Human Medicines Regulations 2012 (as amended) implemented prior EU legislation on these topics before Brexit, and remain in force post-Brexit. However, these regulatory regimes may diverge increasingly in future, now that the UK’s regulatory system is formally independent from the EU.