European authorisation procedures
An application for a medicine in Europe runs through one of four procedures: the centralised procedure, which yields one authorisation for the whole Union, the mutual recognition and decentralised procedures, in which member states rely on one another's assessments, and a purely national procedure. The European procedures grew out of half a century of harmonisation, and they differ in their committees, timelines and scope. Alongside them stand the electronic forms an application is made on, an opinion procedure for medicines used outside the Union, and arrangements for sharing assessments with regulators beyond it.
The routes an application can take
Four authorisation procedures exist in Europe: centralised, decentralised, mutual recognition and national. The type of medicinal product, the intended therapeutic indication and several other legal regulations determine which of them a new marketing application is submitted through.
Whatever the legal basis of the submission, the procedures fall into two categories. The national authorisation procedures are the mutual recognition procedure, the decentralised procedure and a national submission. The other is the centralised procedure, whose main objective is to provide one marketing authorisation valid in all EU and European Free Trade Association countries, one invented name and one common product information, and centralised safety monitoring. The decentralised procedure can instead be used for approval in only those EU countries where the applicant seeks it.
The decentralised and mutual recognition procedures are national procedures in which member states work together and recognise each other's evaluations. The purely national procedure is rarely used, and only when an applicant seeks marketing authorisation in a single member state. For most medicines, the European procedures have replaced approvals based on purely national authorisations.
Most medicines containing a new active substance are approved through the centralised procedure. The mutual recognition and decentralised procedures are mainly used to extend existing marketing authorisations or for generic medicines.
Whatever the submission pathway, the regulatory procedure lasts 210 days, and a decentralised or mutual recognition procedure adds a national phase that lasts from four weeks to between one and a half and two years.
How harmonisation produced the routes
The European system has evolved over half a century from wholly separate national systems to one in which EU countries harness their regulatory and scientific expertise to harmonise and improve the evaluation of medicines across Europe.
Modern pharmaceutical regulation in Europe can be considered to have started in the 1960s. In the aftermath of the thalidomide tragedy, legislative control of pharmaceuticals increased, regulatory agencies were created all over Europe to approve medicines, and member states worked on European harmonisation, which led to the first pharmaceutical Directive, Council Directive 65/65/EEC, in 1965. The Directive required all medicines to have a marketing authorisation and aimed at harmonising standards for their approval within Europe. It also encouraged a single market for pharmaceuticals at a time when every country had its own approval procedure, which meant that companies had to submit a separate application in each country.
In 1975 two Council Directives were introduced. Council Directive 75/318/EEC concerned the testing of medicines that companies seeking a marketing authorisation had to carry out. Council Directive 75/319/EEC established a marketing authorisation procedure aimed at promoting the free movement of medicines, based on mutual recognition of national assessments, under which a company could seek authorisation in one member state on the basis of an existing authorisation in another. It also established the Committee on Proprietary Medicinal Products (CPMP), an advisory committee to the European Commission, to help member states adopt a common position on decisions to issue a marketing authorisation. The CPMP's opinions were not binding, and the system came under criticism as slow, bureaucratic and ineffective, with member states failing to recognise each other's assessments and seeking arbitration from the CPMP on nearly every occasion. This CPMP procedure was later simplified into the multi-state licensing procedure, which, though improved, was still considered by many to be ineffective and was little used by industry.
The single market project launched in 1985 included plans for creating the European Medicines Agency. In 1986 the concertation procedure was introduced, mandatory for biotechnology medicines, which required a Community-wide licensing opinion from the CPMP before a marketing authorisation for such a medicine could be granted in any member state. That opinion was again not binding, and member states could still approve or reject applications without reference to it.
A major step in harmonisation came in 1993 with Council Regulation (EEC) 2309/93, which established the European Agency for the Evaluation of Medicinal Products, now the European Medicines Agency, and turned the concertation procedure into the centralised procedure. The Regulation came into force in 1995 and re-established the CPMP as a new committee issuing the agency's opinions on marketing authorisations under the centralised procedure, opinions that now led to legally binding Commission decisions. The CPMP was later renamed the Committee for Medicinal Products for Human Use (CHMP). The centralised procedure and the European Medicines Agency have both been in operation since 1995. As the mandatory scope of the new centralised procedure was limited to biotechnology medicines, it replaced the existing national procedures for those medicines. Mutual recognition remained for other medicines and was introduced into European pharmaceutical law in 1993 by Council Directive 93/39/EEC.
By 1995 a harmonised European system had emerged, with a procedure based on mutual recognition of marketing authorisations by member states on one side and a procedure giving a Community-wide licensing opinion on the other. The mutual recognition procedure had two precursors: the CPMP procedure, which operated from 1976 to 1985, and the multi-state licensing procedure, which operated from 1985 and in 1995 became known as the mutual recognition procedure. The centralised procedure developed from the concertation procedure, which operated from 1986 until 1995. The early procedures were hampered by the lack of a binding CPMP opinion, but by 1995 this was no longer the case, and pharmaceutical regulation in Europe had become better harmonised and more effective.
Changes after 1995 strengthened the system further. Among them was the decentralised procedure, introduced in 2005 to avoid the potential for disputes that had been identified over time as a problem with the mutual recognition procedure, in which the member states where approval is sought were not involved early enough in the evaluation.
Although the different procedures may give an impression of complexity, they have simplified the authorisation process across member states, reducing the time new medicines take to obtain a marketing authorisation and improving patient access to them.
The centralised procedure
The centralised procedure requires a single application, which, if successful, results in a single marketing authorisation with the same product information available in all EU languages, valid in all EU countries as well as Iceland, Liechtenstein and Norway. The CHMP carries out the scientific assessment of the application. The review alternates periods of active evaluation with periods in which the clock is stopped to give the applicant time to resolve the issues identified, and lasts up to 210 active days in total before the CHMP issues its opinion. The opinion is forwarded to the European Commission, which then has 67 days to issue a legally binding decision on the marketing authorisation. The mean approval time for medicines the agency approved in 2012 was 14.8 months.
Once a marketing authorisation is granted, the applicant can start to market the medicine in any member state it chooses. In practice, before a medicine is marketed, it is subject to pricing negotiations and a review of its cost-effectiveness, which member states carry out at national level to determine reimbursement criteria.
The centralised procedure was at first mandatory only for biotechnology medicines, as the concertation procedure had been, and its mandatory scope was then gradually expanded. By 2005 the mandatory scope included orphan medicines, which are medicines for rare diseases, and human medicines that contain a new active substance not authorised in the Union before 20 November 2005 and are intended to treat AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions, or viral diseases. In 2009 the centralised procedure also became mandatory for advanced therapy medicines. It is optional for other medicines that contain a new active substance not authorised in the Union before 20 November 2005, and for products considered a significant therapeutic, scientific or technical innovation or for which an EU-wide authorisation is considered to be in the interests of public health.
Article 3 of Regulation (EC) No 726/2004 defines the scope of and eligibility for the centralised procedure as mandatory, optional or generic/hybrid. In outline, the mandatory scope includes biosimilars, advanced medicinal products such as gene therapy, somatic therapy or tissue-engineered products, medicinal products developed through biotechnological processes, and new active substances. Products in the generic/hybrid scope are in practice authorised through the decentralised procedure, but the centralised procedure is also open to a generic whose originator product was registered centrally, and certain applications for a paediatric-use marketing authorisation can also be eligible for it.
The first medicine authorised under the centralised procedure was the fertility treatment Gonal-F, in October 1995. By 2014 the agency received around 100 applications a year, of which around 10% were withdrawn without an opinion and around 5% received a negative opinion, and over 700 human medicines had been approved through the procedure since 1995. In the early years only innovative products were approved through the centralised procedure, but as data exclusivity for the first products approved began to expire, generics were also approved centrally. Applications for generics through the centralised procedure increased over the years, peaking in 2010 at around 50% of all applications.
The mutual recognition procedure
The mutual recognition procedure has been in place since 1995 and evolved from the multi-state licensing procedure. The applicant must first receive national approval in one member state, the reference member state, and then seek approval in other, concerned member states in a second step, on the basis of the assessment done in the reference member state.
The procedure differs significantly from the multi-state licensing procedure, notably in requiring that disagreements between member states be resolved at EU level. Disagreements are handled by the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), a body representing the member states, which is responsible for any question in two or more member states about the marketing authorisation of a medicine approved through the mutual recognition or the decentralised procedure. Where member states disagree on grounds of a potential serious risk to public health, the CMDh considers the matter in order to reach agreement within 60 days. If that is not possible, the procedure is referred to the CHMP, in a procedure called a referral, and the CHMP carries out a scientific assessment of the medicine on behalf of the EU, within a timeline of 60 days. In contrast to the earlier procedure, the CHMP's outcome is binding on the member states involved once the European Commission has adopted it.
Since the decentralised procedure was introduced, the mutual recognition procedure has been used to extend existing marketing authorisations to other countries.
The decentralised procedure
In the decentralised procedure, the applicant chooses one country as the reference member state when it applies for marketing authorisation. The reference member state prepares a draft assessment report and submits it to the other member states where approval is sought, for their simultaneous consideration and approval. Because those member states have access to the assessment at an early stage, issues and concerns can be dealt with quickly, without the delay that is sometimes known to occur in the mutual recognition procedure. Compared with the mutual recognition procedure, the decentralised procedure has the advantage that the marketing authorisation in all chosen member states is received simultaneously, which enables simultaneous marketing of the medicine and reduces the administrative and regulatory burden.
The decentralised procedure is mainly used for applications for generic medicines. As in the mutual recognition procedure, disagreements are handled by the CMDh, or by the CHMP where no agreement can be reached in the CMDh.
Electronic application forms
The electronic application forms are an online version of the paper application forms published and maintained on the European Commission's EudraLex website, and are designed to capture the same content as the paper forms. They offer users a more structured application process. The European Medicines Agency first made them available to companies in July 2012, following a successful pilot phase. Since that initial release the forms have been significantly improved following the feedback received.
From 1 July 2015, companies submitting applications through the centralised procedure were obliged to use the electronic application forms, which cover initial marketing authorisations, variations and renewals for human and veterinary medicines. From 1 January 2016 the electronic forms also became mandatory for the decentralised and mutual recognition procedures and for national submissions, and the application forms in Word format published by the European Commission were no longer available. The mandatory use of the forms was expected to reduce the administrative burden for both the regulatory authorities and industry, while improving data quality and consistency during data entry.
Opinions on medicines for use outside the EU
Under the procedure at Article 58, the European Medicines Agency can assess the quality, safety and efficacy of a medicine and give an opinion on its benefit-risk balance when it is used in low- and middle-income countries outside the EU. The procedure provides for a scientific opinion on treatments intended primarily for use in non-EU countries, given in close collaboration with the World Health Organization (WHO) and experts from those countries. Medicines submitted under it must meet the same standards as medicines intended for EU citizens. The CHMP's opinion helps to support regulators in countries where regulatory capacity may be limited, by providing an expert evaluation of the medicine when used in local practice, and national regulators can use the assessment to decide on the use of the medicine in their countries. In November 2018 the CHMP adopted a positive opinion on Fexinidazole Winthrop (fexinidazole), submitted under Article 58, the first oral-only medicine for human African trypanosomiasis due to Trypanosoma brucei gambiense. It was the tenth medicine the agency had recommended under Article 58.
Under the EU-Medicines for all programme, EU-M4all, the CHMP assesses medicines in collaboration with the WHO and the target countries, combining the agency's scientific review capabilities with the epidemiology and local disease expertise of the WHO and of experts and national regulators in the target countries. The CHMP's opinion under EU-M4all supports global regulatory capacity building and contributes to the protection and promotion of public health beyond the EU. It does so by assessing medicines for countries where regulatory capacity may be limited, and national regulators can rely on the CHMP's assessment to decide on the use of the medicine in their countries.
The agency supports parallel applications for an EU-M4all opinion and the centralised procedure, aiming to make innovative or generic medicines and vaccines that address unmet medical needs or are of major public health interest available in Europe and globally faster, while avoiding duplication of effort by regulators. The first such simultaneous review came in October 2022, when the CHMP adopted a positive opinion on Takeda's live attenuated tetravalent dengue vaccine, to prevent disease caused by dengue virus serotypes 1, 2, 3 and 4 in people from four years of age, reviewed for the EU market under the centralised procedure and for non-EU countries under EU-M4all.
In July 2025 the CHMP reviewed Yeytuo (lenacapavir) in the same way, simultaneously for the EU market under the centralised procedure and for non-EU countries under EU-M4all, in collaboration with the WHO and the target countries. The agency recommended granting Yeytuo a marketing authorisation in the EU for pre-exposure prophylaxis, in combination with safer sex practices, to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents at high risk of becoming infected. The CHMP evaluated it under an accelerated timetable because it was considered to be of major public health interest in the EU and the rest of the world.
Assessments shared with regulators outside the EU
The International Generic Drug Regulators Pilot (IGDRP) was launched in April 2012 to strengthen collaboration and convergence between regulatory agencies worldwide and to mitigate the challenges of global generic development and approval programmes. One of its work packages shares assessments of applications for generic medicines. It started in July 2014 with the EU decentralised procedure as its model, and in January 2015 it was extended to the centralised procedure, when the European Medicines Agency was ready to share its assessments of generic applications in real time with collaborating regulatory agencies outside the EU. The initiative aims to facilitate the timely authorisation and availability of safe, effective and high-quality generic medicines worldwide and to save global assessment resources, and the sharing of assessments is expected to allow generic products to be authorised in the concerned countries in a coordinated and resource-effective way.
The first phase of the pilot was to involve the EU, Australia, Canada, Chinese Taipei and Switzerland. Other IGDRP members that might take part at a later stage included Brazil, China, Japan, Korea, Mexico, New Zealand, Russia, Singapore and South Africa, and the European Directorate for the Quality of Medicines & Healthcare and the WHO participated in the IGDRP as observers. Ten applications for generic medicines were to be selected for the initial phase, with further products possibly considered after the first results were evaluated, and companies were invited to express their interest.
OPEN was established by the European Medicines Agency in December 2020, initially as a pilot, as a framework to increase international collaboration and share scientific expertise on the evaluation of COVID-19 vaccines and therapeutics. Every COVID-19 vaccine and therapeutic evaluated since the launch of the pilot was assessed under OPEN, and the participating non-EU experts attended and contributed to the evaluations of the CHMP and the agency's Emergency Task Force. OPEN allows regulators from Australia, Brazil, Canada, Japan, Switzerland and the WHO to conduct near-concurrent reviews of certain new medicines and to exchange their views and reports on the assessments. This can help accelerate and align regulatory decisions in several regions of the world, leading to fewer questions for industry and more alignment on product labelling, while each regulator keeps its independence in decision making. Through the collaboration with the WHO, OPEN can also accelerate regulatory decisions and the availability of medicines in low- and middle-income countries.
Following the success of the pilot, the agency's Management Board endorsed the expansion of OPEN in March 2022. In July 2023, on the basis of the positive findings and recommendations of the report on the pilot, its scope was extended to marketing authorisation applications for:
- medicines targeting antimicrobial resistance
- medicines supported through the agency's PRIority MEdicines (PRIME) scheme, not then including advanced therapy medicinal products
- medicines with the potential to address respiratory syncytial virus (RSV) infections or newly diagnosed myelodysplastic syndromes and other hereditary diseases
- medicines responding to health threats or public health emergencies
The first product assessed under the extended framework was an mRNA vaccine against RSV, assessed together with Swissmedic, and in July 2023 the selection of further products was under discussion with the OPEN partners. Assessment under OPEN requires the CHMP and at least one OPEN partner to agree to conduct parallel assessments, and the dossier content, claimed indication and timing of submissions to the agency and the partners should be aligned. Medicines assessed under OPEN are clearly labelled in the publicly available CHMP agendas and minutes and on the agency's website. The agency has bilateral agreements with every regulatory authority involved in OPEN, and its standard requirements for EU experts taking part in the assessment of medicines, such as confidentiality and the absence of conflicts of interest, also apply to OPEN experts.