A walk through EU medicines legislation

Last updated: 20 August 2024

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This post is an attempt to walk through European Union (EU) medicines legislation starting from the 1960s. It has been difficult to strike a balance between not including too much detail and including insufficient detail. This has meant that the post has grown longer and longer. Even then, it barely scratches the surface of the large body of EU legislation. Hopefully, this post might spark an interest you to delve further into the details and nuances of the various pieces of legislation. The reference list includes some reports which are well worth reading in order to provide context and develop a better understanding of the legislation.

It is not possible to talk about EU legislation without mentioning some of the important EU institutions.

Institutions of the European Union (EU)

• European Parliament – It is one of the EU’s two law-making bodies. One of its main roles is legislative i.e. passing EU laws together with the Council of the EU, based on European Commission proposals.
• Council of the European Union– This is the second of the EU’s two law-making bodies. It represents the governments of the member states. It negotiates and adopts EU laws together with the European Parliament, based on proposals from the European Commission
• European Commission (EC) – The Commission represents the general interests of the European Union. It has several responsibilities which include: proposing legislation designed to implement the objectives outlined in EU treaties and acting as the guardian of the treaties; monitoring compliance with EU law and referring suspected cases of non-compliance to the Courts.
• Court of Justice of the European union (CJEU) – Ensures that EU law is interpreted and applied the same in every EU country and that the EU countries and institutions abide by EU law.

Further information on the EU institutions and bodies is available here.

The role of the European Commission (EC) in the regulation of medicines in the EU

The European Commission (EC) plays an important role in the regulation of medicines in the EU¹.

• On the basis of scientific assessments carried out by European Medicines Agency (EMA), it grants or refuses, changes or suspends marketing authorisations for medicines that have been submitted via the EU wide licensing procedure known as the centralised procedure.
• It can also take EU-wide action when a safety issue has been identified for a nationally authorised product and when harmonised regulatory measures in all Member states (MSs) are considered necessary following assessment by the EMA’s Pharmacovigilance Risk assessment Committee (PRAC).
• The Commission can also take action concerning other aspects of medicine regulation e.g.
  • Right of initiative — it can propose new or amended legislation for the pharmaceutical sector
  • Implementation — it can adopt implementing measures as well as oversee the correct application of EU law on pharmaceuticals.

Types of EU law

The European Union is based on the rule of law. This means that every action taken by the EU is founded on treaties that have been approved democratically by its members. EU laws help to achieve the objectives of the EU treaties and put EU policies into practice. There are two main types of EU law:

• primary
• secondary

Primary law

Treaties are the starting point for EU law and are known in the EU as primary law.

The treaties

Treaties form the legal basis for all other EU legislation.

A treaty is a binding agreement between EU member countries. It sets out EU objectives, rules for EU institutions, how decisions are made and the relationship between the EU and its member countries. Under the treaties, EU institutions can adopt legislation, which the member countries then implement.

Information is provided below on a small number of the treaties.

1958

Treaties of Rome

The Treaties of Rome (also known as the founding treaties) came into force on 1 January 1958. The purpose of one of the Treaties of Rome was to set up the European Economic Community (now known as the European Union). This treaty and further founding treaties contain a number of articles which form the basis of European legislation. As regards medicinal product law, Article 100 was the most important as it regulated the creation of harmonising directives in order to realise the internal market.

1993

Maastricht Treaty

The Maastricht Treaty which came into force on 1 November 1993 established the European Union (EU) as it is now known.

1999

Treaty of Amsterdam

Following the Treaty of Amsterdam which entered into force on 1 May 1999, Article 100 was replaced with Article 95 as the basis for harmonising legislation. The main purpose of this treaty was reform the EU institutions in preparation for the arrival of future member countries.

Secondary law

The body of law that comes from the principles and objectives of the treaties is known as secondary law. It includes the following:

• regulations
• directives
• decisions
• recommendations
• opinions
• delegated acts
• implementing acts

As this post refers often to Regulations and Directives, they are defined below. A definition of guidelines is also provided.

Regulations

Regulations are legal acts that apply automatically and uniformly to all EU countries as soon as they enter into force, without needing to be transposed into national law. They are binding in their entirety on all EU countries.

Directives

Directives require EU countries to achieve a certain result, but leave them free to choose how to do so. EU countries must adopt measures to incorporate them into national law (transpose) in order to achieve the objectives set by the Directive. National authorities must communicate these measures to the European Commission.

Transposition into national law must take place by the deadline set when the directive is adopted (generally within 2 years). When a country does not transpose a directive, the Commission may initiate infringement proceedings.

Further information is available here.

Guidelines

European rules which are established but are not legally binding are called guidelines. Guidelines are rules of ‘soft law’ and often fulfill an interpretative role. Applicants or or MA holders can in certain circumstances justify deviation from guidelines².

The EU, The EEA and the EFTA

With the exit of the UK, currently, there are 27 countries in the European Union (EU). The European Economic Area (EEA) includes all of the EU countries plus Iceland, Liechtenstein and Norway. It allows the three countries to be part of the EU’s single market.

Four countries are part of the European Free trade Association (EFTA). They are Iceland, Norway, Liechtenstein and Switzerland.

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EU medicines legislation

Although many European countries have long had laws regulating the use of various medicines, modern pharmaceutical regulation in Europe can be considered to have started in the 1960s³.

The Thalidomide tragedy exemplified the need for evidence based authorisation of medicinal products. It served as the catalyst for harmonised European pharmaceutical Legislation.

The current requirements and procedures for marketing authorisation, as well as the rules for monitoring authorised products, are primarily laid down in Directive 2001/83/EC and in Regulation (EC) No 726/2004. They also include harmonised provisions for the manufacture, wholesale or advertising of medicinal products for human use.

The current system for regulating medicines in Europe is unique in the world. It is based on a closely-coordinated regulatory network of national competent authorities in the Member States of the European Economic Area (EEA) working together with the European Medicines Agency (EMA) and the European Commission.

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The Rules Governing Medicinal Products in the European Union

All EU legislation in the area of medicinal products for human use is listed in Volume 1 of “The Rules Governing Medicinal Products in the European Union”.

To facilitate the interpretation of the legislation and its uniform application across the EU, numerous guidelines of regulatory and scientific nature have been adopted that are also published in Volumes 2 – 10 of “The rules governing medicinal products in the European Union”

A detailed explanation of the marketing authorisation procedures and other regulatory guidance on medicinal products for human use is contained in Volume 2 commonly known as the Notice to Applicants.

1961-1962

The Thalidomide Tragedy

Thalidomide, a glutamic acid derivative (α[N=Phthalimido] glutarimide), was first described in 1953 by the Swiss pharmaceutical firm Ciba. The company discontinued its research on the drug when no pharmacologic effects were apparent. Despite Ciba’s decision, Chemie Grünentha GmbH, a German pharmaceutical company, synthesised the drug in 1954 and undertook its development. It was originally intended to be used as a sedative or tranquiliser, but was soon used for treating a wide range of other conditions, including colds, flu, nausea and morning sickness in pregnant women.

It first entered the German market in 1957 as an over-the-counter remedy, based on the maker’s safety claims. By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin.

In December 1961, the Australian obstetrician William McBride warned in a letter to the Lancet that he had observed “multiple severe abnormalities” in babies delivered from women who had taken the drug thalidomide during pregnancy. The drug interfered with the babies’ normal development, causing many of them to be born with phocomelia. McBride’s concerns about thalidomide were subsequently confirmed by researchers in Europe, and by early 1962 the drug was banned in most countries around the world.

The story of thalidomide does not end there. The drug has since been reintroduced in some countries for the management of Erythrema Nodosum Leprosum (ENL) reactions in leprosy. Because of its known teratogenic effects, the World Health Organisation does not recommend its use in leprosy. More recently, the drug has been used in some countries (e.g. Canada and the UK) for the treatment of mutliple myeloma.

1965

Directive 65/65/EEC (repealed by Directive 2001/83/EC) – Required all medicines to have a marketing authorisation and also aimed at harmonising standards for the approval of medicines within Europe

Following the thalidomide tragedy, this was the very first piece of pharmaceutical legislation introduced in January 1965. The Directive required all medicines to have a marketing authorisation and also aimed at harmonising standards for the approval of medicines within Europe. Additionally, it encouraged the creation of a single market for pharmaceuticals in the EU at a time when every country had its own separate approval procedures meaning that companies had to submit separate applications for approval of a medicine in each country³.

The criteria for grant of a marketing authorisation were (and continue to be)¹:

• proven therapeutic effect (efficacy)
• safety in normal use
• pharmaceutical quality

The Directive applied to proprietary (or branded) medicinal products only. Its scope did not extend to any of the following products²:

• pharmaceutical preparations i.e. medicinal products which were marketed under the name of the drug substance (dealt with under Directive 83/570/EEC, now repealed)
• Immunological medicinal products e.g. vaccines (dealt with under Directive 89/342/EEC ,repealed by Directive 2001/83/EC)
• radiopharmaceuticals (dealt with under Directive 89/343/EEC, repealed by Directive 2001/83/EC)
• medicinal products made from human blood or plasma (dealt with under Directive 89/381/EEC, repealed by Directive 2001/83/EC)

1975

In 1975, two Directives were introduced. They were:

Directive 75/318/EEC (repealed by Directive 2001/83/EC)

Adopted in May 1975, it established detailed requirements for scientific dossiers submitted in support of marketing authorisation applications⁴.

Directive 75/319/EEC (repealed by Directive 2001/83/EC) – Established a ‘multi-state’ procedure and created the CPMP

Adopted at the same time as the above Directive, Directive 75/319/EEC established a “multi-state” approval procedure (an early form of mutual recognition, without provision for mandatory EC decisions) and created the Committee for Proprietary Medicinal Products (CPMP) to oversee the procedure. The committee was later renamed to its current name, the Committee on Medicinal Products for Human Use (CHMP)⁴.

The procedure was called originally the ‘CPMP procedure’ (operational from 1976 to 1985) and was later simplified and became the ‘multi-state licensing procedure’ (operational from 1986 until 1995). Although improved, it was still considered by many to be ineffective and was little used by industry³. It was replaced in 1995 by the mutual-recognition procedure.

1983

Directives 83/570/EEC (no longer in force)

This Directive which entered into force in October 1983 expanded the scope of Directives to cover pharmaceutical preparations. The term ‘proprietary medicinal products’ was replaced with the term ‘medicinal products’ which included both branded medicinal products and pharmaceutical preparations. Changes were then made to the legislation relating to the specific dossier requirements for generic medicinal products, leading in particular to data exclusivity for innovative medicinal products (under Directive 87/21/EC)².

The following changes were also introduced:

• A Summary of Product Characteristics was mentioned for the first time (Article 4 point 9). Member States agreed on a uniform way to summarise key characteristics of an authorised product. Headings were provided for the Summary of Product Characteristics under which the information should be provided
• The concept of post-authorisations changes was introduced
• Introduction of the validity of a granted marketing authorisation for five years, to be renewable for five year periods upon application by the holder

1986

Directive 87/21/EC (no longer in force)

This Directive came into force in December 1986 and amended Directive 65/65 to provide for acceptance of abridged applications, subject to data protection periods and other limitations, and revised the provisions relating to literature-based applications. The basic data protection period was six years, but member states were given the option of establishing a ten-year period or recognising no data protection after the patent expired. Biotechnology and other high-technology medicines approved under a “concertation” procedure established by Council Directive 87/22/EEC were entitled to a uniform ten-year period of data protection⁴.

Directive 87/22/EEC (no longer in force) – Introduced the concertation procedure (which was later modified and became the centralised procedure)

It introduced a new procedure for the authorisation of medicines called the ‘concertation procedure’. This procedure was mandatory for biotechnology medicines, requiring a community-wide licensing opinion by the CPMP for these medicines before marketing authorisations could be granted in any Member State. However, this opinion was not binding on Member States and they could still approve or reject applications without reference to the opinion³. Biotechnology and other high-technology medicines approved under the ‘concertation procedure’ were entitled to a uniform ten-year period of data protection⁴.

1993

Directive 93/39/EEC (no longer in force) – Established the mutual recognition procedure

It was adopted in June 1993 and established a mutual recognition procedure, backed up by binding EC decision-making power, to replace the old multi-state system (introduced under Directive 75/319/EEC). The procedure took effect on January 1, 1995, and became mandatory for marketing authorisation applications for the same product submitted to more than one member state after 1 January 1998⁴.

The mutual-recognition procedure is where companies that have a medicine authorised in one EU Member States can apply for this authorisation to be recognised in other EU countries. This process allows Member States to rely on each other’s scientific assessments¹.

The mutual-recognition procedure has significant differences from the former multi-state licensing procedure, notably the requirement that disagreements between Member States must now be resolved at EU level. Disagreements are handled by the Co-ordination Group for Mutual
Recognition and Decentralised Procedures – Human (CMDh), a body representing Member States, whichis responsible for any questions in two or more Member States relating to the marketing authorisation of a medicinal product approved through the mutual recognition (or the decentralised procedure introduced in 2005)³.

Regulation EEC No 2309/93 (replaced with Regulation (EC) No 726/2004) – Established the European Agency for the Evaluation of Medicinal Products (now known as the European Medicines Agency) and the Centralised procedure

With this regulation came a major step step in harmonisation. It established the European Agency for the Evaluation of Medicinal Products (now known as the European Medicines Agency). In addition, the concertation procedure was modified and became the centralised procedure. The Regulation, which came into force in 1995, also re-established the CPMP as a ‘new’ CPMP to issue the Agency’s opinions on the granting of marketing authorisations in accordance with the centralised procedure, which now led to legally binding Commission decisions. The CPMP was later renamed the Committee for Medicinal Products for Human Use (CHMP)³.

As the mandatory scope of the new centralised procedure was limited to biotechnology medicinal products; it replaced existing national procedures for these medicines³.

The advantage of the centralised procedure is that it requires a single application which, if successful, results in a single marketing authorisation with the same product information available in all EU languages and valid in all EU countries, as well as Iceland, Liechtenstein, and Norway. The scientific assessment of the marketing authorisation application is carried out by the CHMP. The scientific review process consists of alternating periods of active evaluation and periods during which the clock is stopped in order to give the applicant time to resolve any issues identified during the evaluation. In total, the duration of the process is up to 210 ‘active’ days before an opinion is issued by the CHMP. Once an opinion has been given, it is forwarded to the European Commission which then has 67 days to issue a legally binding decision on the marketing authorisation³.

Initially, the centralised procedure was mandatory only for biotechnology medicines, as was the case with the previous concertation procedure. Over time, however, the mandatory scope of the centralised procedure has been gradually expanded and by 2005, it included orphan medicines (medicines for rare diseases) as well as human medicines that contain a new active substance (not previously authorised in the Union before 20 November 2005) and that are intended for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions, and viral diseases. in 2009, the centralised procedure also became mandatory for advanced therapy medicines³.

The centralised procedure is also optional for other medicines that contain a new active substance not authorised in the Union before 20 November 2005, and for products which are considered to be a significant therapeutic, scientific, or technical innovation, or for which an EU-wide authorisation is considered to be in the interests of public health³.

1994

Good Manufacturing Practice (GMP)

Directive 2003/94 of 8 October 2003 lays down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.

Good manufacturing practice (GMP) describes the minimum standard that a medicines manufacturer must meet in their production processes.

Any manufacturer of medicines intended for the EU market, no matter where in the world it is located, must comply with GMP.

GMP requires that medicines:

• are of consistent high quality;
• are appropriate for their intended use;
• meet the requirements of the marketing authorisation or clinical trial authorisation.

1995

The European Agency for the Evaluation of Medicines (EMEA)

The European Agency for the Evaluation of Medicinal Products (EMEA) (now known as the European Medicines Agency (EMA)) was launched on 26 January 1995.

Working with the Member States and the European Commission as partners in the European Medicines Regulatory Network, the Agency has a range of primary activities which include⁵:

• Applying efficient and transparent evaluation procedures to help bring new medicines to the market by means of a single, EU-wide marketing authorisation granted by the European Commission.
• Provide independent, science-based recommendations on the quality, safety and efficacy of medicines, and on more general issues relevant to public health that involve medicines.
• Develop best practice for medicines evaluation and supervision in Europe, and contributes alongside the Member States and the European Commission to the harmonisation of regulatory standards at the international level.

2000

Orphan medicinal products – To increase the number of products for rare diseases, the Orphan Regulation was adopted.

About 30 million European Union citizens are affected by one of the over 6000 rare diseases currently recognised. The EU considers diseases to be rare when they affect no more than 5 per 10,000 people in the EU. 80% of these diseases are of genetic origin, and they are often chronic and life-threatening; almost 90% can begin in childhood⁶.

For these patients, and for more than 100 million European children, treatment was either limited or non-existent before the introduction of EU legislation on rare diseases and on medicines for children (in 2000 and 2006 respectively). That situation represented a huge unmet medical need and a significant public health challenge. There were often no medicines at all available for doctors treating patients with rare diseases. Children were regularly prescribed medicines indicated for adults, which had not been tested or adapted specifically for use in young patients. This ‘off-label’ use of adult medicines comes with the risk of inefficacy and/or adverse reactions in children, who cannot simply be regarded as ‘small adults’ from the developmental and physiological points of view⁶.

When these policy challenges were identified, the EU already had a well-established legislative framework for medicinal products that had developed considerably since its inception in 1965. Its main aim was, and still is, to ensure that all medicines in the Union are authorised by demonstrating their safety, quality and efficacy before they reach patients⁶.

However, this framework was general in nature. It contained no incentives for development in particular areas of medical need. Decisions on product development were generally left to the market and were subject to commercial decisions driven by considerations of return on investment. Public research funding was often the only means available to support neglected fields⁶.

Both the areas of rare diseases and medicines for children were economically unattractive. This was because the market size was generally small and the research and development of products, including the conduct of clinical trials, was more complex⁶.

From the 1990s onwards, this led to a policy discussion about how best to correct this market failure and ensure the development of more medicines to treat patients suffering from rare diseases and/or appropriate for use in children⁶.

On 22 January 2000, Regulation (EC) No 141/2000 (the Orphan Regulation) came into force.

The specific objectives of the Orphan Regulation are to ensure⁶:

• research and development and the placing on the market of designated orphan medicinal products (availability)
• that patients suffering from rare conditions have the same quality of treatment as any other patient (accessibility).

An orphan designation is a status assigned to a medicine intended for use against a rare condition. The medicine must fulfil certain criteria for designation as an orphan medicine so that it can benefit from incentives such as protection from competition once on the market. 

Products fall under the scope of the Orphan Regulation if they either⁶:

• fulfill the ‘prevalence criterion’ of no more than 5 in 10,000 people affected by the disease in the EEA
• or the ‘insufficient return upon investment criterion’ meaning that, without incentives, it is unlikely that the marketing of the medicinal product in the EU would generate sufficient return to justify the necessary investment.

Additionally, the condition in question has to be life-threatening or chronically debilitating. No satisfactory treatment should exist in the EU, or, if it exists, the product in question should provide a significant benefit to patients affected by that condition in comparison with the existing treatment⁶.

• The regulation lays down the EU procedure for the designation of orphan medicines
• It established the Committee for Orphan Medicinal Products (COMP). COMP is the European Medicines Agency’s (EMA) committee responsible for recommending orphan designation of medicines for rare diseases.
• It defines incentives for the development and placing onto the market of designated orphan medicines. The incentives are:
  • Protocol assistance
  • Access to the centralised procedure
  • Ten years of market exclusivitiy
  • Additional incentives for micro, small and medium-sized enterprises (SMEs)
  • Fee reductions
  • Grants

On 28 April 2000, Regulation (EC) No 847/2000 came into force. On this date, sponsors could begin to submit applications for orphan designation, to the European Medicines Agency. The regulation lays down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’.

2001

Directive 2001/20/EC – Clinical Trials Directive

Clinical trials in the EU are currently governed by this Directive on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

• The Directive came into force on 1 May 2001
• It established a legal framework for the conduct of clinical trials in the EU.
• It was Introduced to simplify and harmonise the administrative provisions governing clinical trials in Europe.

This Directive will be repealed by the Clinical Trials Regulation (EU) No 536/2014 ) when it becomes applicable.

Directive 2001/83/EC on the Community code relating to medicinal products for human use

In the interest of clarity and rationalisation, this Directive codified and consolidated in a single text, the texts of Community legislation on medicinal products for human use. It entered into force on 18 December 2001.

2003

Introduction of the Common Technical Document (CTD)

Directive 2003/63/EC – Introduced the Common Technical Document (CTD) format through which a homogeneous organisation and presentation of a marketing authorisation application dossier for human medicinal products could be achieved. It also standardised the marketing authorisation dossier requirements (harmonised format) to be applicable to any type of medicinal product for human use, regardless of the procedure for the granting of the marketing authorisation.

2004

Directive 2004/27/EC amending Directive 2001/83/EC on the Community code relating to medicinal products for human use introduced the decentralised procedure and the concept of biosimilars⁷.

Regulation (EC) No 726/2004, lays down Community procedures for the authorisation and supervision of medicinal products for human use and establishing a European Medicines Agency, as amended. It replaces Regulation EEC No 2309/93.

2005

Good Clinical Practice (GCP)

Directive 2005/28/EC lays down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products.

Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected and that clinical-trial data are credible.

The Decentralised Procedure

After 1995, additional changes were made to the European approval system to further strengthen it. This included the introduction of a new procedure in 2005 called the decentralised procedure (under Directive 2004/27/EC) which sought to avoid the potential for disputes which was identified over time as a problem with the mutual recognition procedure as Member States in which approval is sought were not involved early enough in the evaluation³.

Using the decentralised procedure, companies can apply for the simultaneous authorisation of a medicine in more than one EU Member State if it has not yet been authorised in any EU country and does not fall within the scope of the centralised procedure¹.

2006

Paediatric medicines regulation

The Paediatric Regulation is comprised of:

• Regulation (EC) 1901/2006 of December 2006 upon which The legal framework for paediatric medicines is based.
• Regulation (EC) No 1902/2006, is an amending regulation in which changes to the original text were introduced relating to decision procedures for the European Commission.

The Paediatric Regulation came into force in the European Union (EU) on 26 January 2007. Its objective is to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years. It is designed to tackle the lack of appropriate medicines for children in Europe and has following specific objectives⁶:

• Enable high-quality clinical research in children
• Ensure, over time, that most medicines used by children are specifically authorised for such use with age-appropriate forms and formulations and are made available
• Increase the availability of high-quality information about medicines for use in children.

It aims to achieve this without subjecting children to unnecessary trials or delaying the authorisation of medicines for use in adults.

To achieve these objectives, the Regulation has established a system of obligations compensated by rewards. Companies are obliged to screen every new product they develop for its potential use in children, thereby gradually increasing the number of products with paediatric indications and paediatric information. The possibility of obtaining certain rewards compensates for the burden thus created⁶.

The paediatric-use marketing authorisation (PUMA) is a dedicated marketing authorisation covering the indication(s) and appropriate formulation(s) for medicines developed exclusively for use in the paediatric population. It was introduced by the Paediatric Regulation for medicines that are:

• already authorised
• no longer covered by a supplementary protection certificate (SPC) or a patent that qualifies as a SPC
• to be exclusively developed for use in children.

The development of a PUMA must follow a paediatric investigation plan (PIP), to be agreed by the Paediatric Committee (PDCO).

Incentives for the applicant

• Automatic access to the centralised procedure if the applicant chooses this route, even if the application falls outside of the mandatory scope of this procedure.
• 8 plus 2 years of data and market protection
• Authorisation under the same name and branding as the authorised medicine containing the same active substance, if the marketing authorisation holder is the same
• Partial fee exemption under the centralised procedure for marketing authorisation and post-authorisation activities for a year.

Paediatric committee

The Regulation dramatically changed the regulatory environment for paediatric medicines in Europe. Its main impact was the establishment of the Paediatric Committee (PDCO),

The PDCO:

• is responsible for coordinating the Agency’s work on medicines for children.
• Its main role is to determine the studies that companies must carry out on children as part of PIPs.
• replaced the Agency’s previous Paediatric Working Group.

In 2020, the European Commission published a joint evaluation⁶ of the regulation on the Paediatric regulation and the Orphan regulation. Some of its findings are follows:

• The evaluation found that new paediatric products such as orphan drugs are not being developed in the therapeutic areas where needs are greatest.
• The Regulation has no effective instrument for channelling R&D into specific therapeutic areas.
• Development has been boosted mainly in areas where adult development was already planned. It thus looks as if the Regulation works best in areas where the needs of adult and paediatric patients overlap.
• Major therapeutic advances have mostly failed to materialise for diseases that are rare and/or unique to children, and which often receive equal amounts of support under the orphan legislation.
• The existing design of the obligations laid down in the legislation may not be up to the task of capturing all adult developments that could potentially benefit children e.g. medicines are increasingly studied on the basis of their mechanism of action.
• The mechanism of action of a product developed to treat an ‘adult-only’ disease could also be helpful in treating a different disease in children. However, the Regulation exempts products for adult-only diseases from the obligation of designing a PIP.
• Innovative clinical trial design may face difficulties with fitting in with the way PIPs are currently designed and agreed.

2007

Advance Therapy Medicinal Products (ATMPs)

Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment of disease and injury.

A legal framework for advanced-therapy medicines was established by Regulation (EC) No 1394/2007, amending Regulation (EC) No 726/2004 and Directive 2001/83/EC.

The ATMP Regulation applies since 30 December 2008. However, a transitional period was foreseen for ATMPs that were already in the EU market when the Regulation was adopted. Specifically, gene therapy and somatic cell therapy were required to comply with the Regulation by 30 December 2011, while tissue engineered products were required to comply with the new requirements by 30 December 2012⁸.

ATMPs can be classified into three main types:

• gene therapy medicines: these contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting ‘recombinant’ genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases.
• somatic-cell therapy medicines: these contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases.
• tissue-engineered medicines: these contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue.

In addition, some ATMPs may contain one or more medical devices as an integral part of the medicine, which are referred to as combined ATMPs. An example of this is cells embedded in a biodegradable matrix or scaffold.

The Committee for Advanced Therapies (CAT)

The evaluation of advanced therapy medicinal products often requires very specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors such as biotechnology and medical devices. For this reason, within the EMA, a Committee for Advanced Therapies was created, which is responsible for preparing a draft opinion on the quality, safety and efficacy of each advanced therapy medicinal product for final approval by the Agency’s Committee for Medicinal Products for Human Use (CHMP).

In 2015, the European Commission published a report⁸ which allowed it to take stock of the situation of ATMPs in the EU and analyse the impact of the Regulation on advanced therapies.

On the basis of the experience accumulated since the entry into force of the ATMP Regulation, some possibilities to help the translation of research into ATMPs available to patients across the EU while maintaining a high level of public health protection can be identified, including⁷:

• clarification of the scope of the ATMP Regulation by fine-tuning the current definitions of ATMPs and by reflecting on the appropriate regulatory framework for new innovative products that many not be captured by existing provisions
• considering measures to avoid disparities in the classification of ATMPs in the EU
• clarification of the conditions for the application of the hospital exemption, as well as the role of data obtained from the use of ATMPs in hopitals in the context of marketing authorisation procedures
• revising the requirements for the authorisation of ATMPs with a view to ensure that applicable requirements are proportionate and well-adapted to the specific characteristics thereof, having specific consideration to autologous products
• streamlining the marketing authorisation procedures⁸.

2008

Post-authorisation variations

Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use became applicable in January 2010.

This regulation provides the legal framework for handling of post-authorisation variations to the terms of marketing authorisation for human medicines. It was amended by Regulation (EU) No 712/2012.

After over 10 years of experience of the Variations Regulation Commission Regulation (EC) No 1234/2008), according a 2020 report from Medicines for Europe⁹, disproportionate resources are allocated to the variations process in view of the overall benefit for patients and the entire regulatory system. The current regulatory framework for maintaining products on the market needs to continue evolving to better reflect the scientific progress and operational efficiency. The Medicines for Europe report lays out a compelling case for how this could be achieved.

2009

The EMEA becomes the EMA (European Medicines Agency)

As per Regulation (EC) No 726/2004, the name of the European Agency for Medicinal Products (EMEA) was simplified to the European Medicines Agency (EMA) in December 2009.

The European Medicines Agency (EMA) is a decentralised EU agency located in The Netherlands. It was founded in 1995 as the European Medicines Evaluation Agency (EMEA) and has been operating since 2004 on the basis of Regulation (EC) No 726/2004.

The European Medicines Agency is the European Union (EU) body responsible for coordinating the existing scientific resources put at its disposal by Member States for the evaluation, supervision and pharmacovigilance of medicinal products. The Agency provides the Member States and the institutions of the EU the best-possible scientific advice on any question relating to the evaluation of the quality, safety and efficacy of medicinal products for human or veterinary use referred to it in accordance with the provisions of EU legislation relating to medicinal products⁵.

2010

Pharmacovigilance legislation

The pharmacovigilance legislation, which came into effect in July 2012, was the biggest change to the regulation of human medicines in the European Union (EU) since 1995. It had significant implications for applicants and holders of EU marketing authorisations, as well as for patients, healthcare professionals and regulators.

The development of the pharmacovigilance legislation was based on the observation that adverse drug reactions (ADRs), caused close to 200.000 deaths per year in the EU.

Because of this, in 2005 the European Commission began a review of the European system of safety monitoring, including sponsoring an independent study as well as extensive public consultation through 2006 and 2007.

This process resulted in the adoption of Directive 2010/84/EU and Regulation Regulation (EU) No 1235/2010 by the European Parliament and Council of Ministers in December 2010, bringing about significant changes in the safety monitoring of medicines across the EU:

The legislation amended existing pharmacovigilance laws contained in Directive 2001/83/EC and Regulation (EC) No. 726/2004. This legislation was accompanied by the implementing regulation No 520/2012 being published by the European Commission in June 2012 that provides details on the operational aspects for the legislation:

The Guideline on Good pharmacovigilance practices (GVP)

• Good pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU).
• GVP apply to:
  • marketing-authorisation holders,
  • the European Medicines Agency (EMA) and
  • medicines regulatory authorities in EU Member States.
• They cover medicines authorised centrally via the Agency as well as medicines authorised at national level.

The guideline on GVP was a key deliverable of the 2010 pharmacovigilance legislation.

• Each chapter and revisions are developed by a team consisting of experts from the EMA and from EU Member States.
• It is divided into chapters that fall into two categories:
  • modules covering major pharmacovigilance processes;
  • product – or population-specific considerations.

GVP modules I to XVI cover major pharmacovigilance  processes and the development of this set of guidance is concluded. The module numbers XI, XII, XIII and XIV stay void, as their planned topics have been addressed by other guidance documents on the EMA website.

Pharmacovigilance Risk Assessment Committee (PRAC)

The Pharmacovigilance Risk Assessment Committee (PRAC) is the EMA’s (EMA) committee responsible for assessing and monitoring the safety of human medicines. It was formally established in line with the pharmacovigilance legislation which came into effect in 2012 to help strengthen the safety monitoring of medicines across Europe.

The PRAC is responsible for assessing all aspects of risk management of human medicines, including:

• the detection, assessment, minimisation and communication of the risk of adverse reactions, while taking the therapeutic effect of the medicine into account;
• design and evaluation of post-authorisation safety studies;
• pharmacovigilance audit.

You can find more information on the PRAC here.

2011

Falsified medicines

Directive 2011/62/EU on falsified medicines

Falsified medicines are often disguised as authentic medicines but may contain ingredients of poor or toxic quality, or in the wrong dosage. As they have not been properly checked for quality, safety and efficacy, as required by strict EU authorisation, they can pose a real risk to health. As falsified medicines become more sophisticated, the risk of them reaching patients in the EU increases. They represent a serious threat to global health and call for a comprehensive strategy both at European and international level.

Following adoption by the European Council and the European Parliament, the Falsified Medicines Directive 2011/62/EU was published on 1 July 2011, and applies since 2 January 2013. It amended Directive 2001/83/EC. This Directive introduces harmonised European measures to fight medicine falsifications and ensure that medicines are safe and that trade in medicines is rigorously controlled. Measures include:

• Obligatory safety features – a unique identifier and an anti-tampering device – on the outer packaging of medicines
• A common, EU-wide logo to identify legal online pharmacies
• Tougher rules on import of active pharmaceutical ingredients
• Strengthened record-keeping requirements for wholesale distributors.

2014

Clinical Trials Regulation

The Clinical Trials  Regulation (EU) No 536/2014 (CTR) was adopted and entered into force on 16 June 2014.

2022

The Regulation on Health Technology assessment

On 11 January 2022, the Regulation (EU) 2021/2282 on Health Technology Assessment entered into force on and it will become applicable from 12 January 2025.

You can read more about Health Technology Assessment and the regulation in this blog post.

The Clinical Trials Regulation (CTR)

On 31 January 2022, the CTR became applicable harmonising the submission, assessment and supervision processes for clinical trials in the European Union (EU). The backbone of the changes brought about by the CTR is the new Clinical Trials Information System (CTIS). CTIS is a single entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial data which includes a public searchable database for healthcare professionals, patients and the general public. The European Medicines Agency (EMA) is responsible for setting up and maintain CTIS, in collaboration with the Member States and the European Commission.

The goal of the CTR is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information. The Regulation will require:

• consistent rules for conducting clinical trials throughout the EU;
• information on the authorisation, conduct and results of each clinical trial carried out in the EU to be publicly available.
• This will increase the efficiency of all trials in Europe with the greatest benefit for those conducted in multiple Member States.
• It aims to foster innovation and research, while helping avoid unnecessary duplication of clinical trials or repetition of unsuccessful trials.

The key benefits of the Regulation include:

• harmonised electronic submission and assessment process for clinical trials conducted in multiple Member States;
• improved collaboration, information-sharing and decision-making between and within Member States;
• increased transparency of information on clinical trials
• highest standards of safety for all participants in EU clinical trials

Upon the CTR becoming applicable, the existing EU Clinical Trial Directive (EC) No 2001/83 and national legislation that was put in place to implement the Directive were repealed. The CTR will also apply to trials authorised under the previous legislation if they are still ongoing three years after the Regulation has come into operation. You can read more about the CTR in this blog post.

2023

Clinical trials and CTIS

From 31 January 2023, all initial clinical trial applications in the European Union (EU) must be submitted via the Clinical Trials Information System (CTIS). CTIS is now the single-entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial data. This follows a one-year transition, during which sponsors could choose whether to apply for a new clinical trial in the EU/EEA in line with the Clinical Trials Directive or under the new Clinical Trials Regulation (CTR), which entered into application on 31 January 2022.

The CTR foresees a three-year transition period, from 2022 to 2025. The first milestone has been reached today; in the next two years, by 31 January 2025, all ongoing trials that were approved under the Clinical Trials Directive will be governed by the new Regulation and will have to be transitioned to CTIS.

European Commission proposes pharmaceuticals reform for more accessible, affordable and innovative medicines

On 26 April 2023, the Commission published a proposal to revise the EU’s pharmaceutical legislation – the largest reform in over 20 years – to make it more agile, flexible, and adapted to the needs of citizens and businesses across the EU. You can read more about this in this post and also in this post which looks at specific aspects of the revision of the EU pharmaceutical legislation.

2024

Parliament adopts its position on EU pharmaceutical reform

On 11 April 2024, MEPs adopted their proposals to revamp EU pharmaceutical legislation, to foster innovation and enhance the security of supply, accessibility and affordability of medicines.

The legislative package, covering medicinal products for human use, consists of a new directive (adopted with 495 votes in favour, 57 against and 45 abstentions) and regulation (adopted with 488 votes in favour, 67 against and 34 abstentions)

You can read more about this here or in this blog post.

Source: European Parliament

Commission delegated regulation on Variations

On 17 June 2024, the amendments to the Variation Regulation i.e. Commission Delegated Regulation (EU) 2024/1701 of 11 March 2024 amending Regulation (EC) No 1234/2008 as regards the examination of variations to the terms of marketing authorisations for medicinal products for human use on new measures for the better lifecycle management of medicine authorisations was published.

This Regulation entered into force on 7 July 2024 following that of its publication in the Official Journal of the European Union. It shall apply from 1 January 2025.
This Regulation shall be binding in its entirety and directly applicable in all Member States.

Further information is available in this blog post.

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References:

1. The European regulatory system for medicines, A consistent approach to medicines regulation across the European Union published 26 August 2014 and last updated on 19 December 2017.
2. An Introduction to EU Pharmaceutical law by John Lisman and Carla Schoonderbeek (Brookwood Medical Publications 2005).
3. The approval process of medicines in Europe by Inga Abed, European Medicines Agency, London, UK (The European Medical Writers Association 2014 Vol 23 Issue 2, pages 117 -121)
4. Data and Marketing Exclusivity for Pharmaceuticals in the European Community by Richard F. Kingham and Grant H. Castle, Food and Drug Law Journal , 2000, Vol. 55, No. 2 (2000), pp. 209-223 (Food and Drug Law Institute)
5. European Medicines Agency, Overview of the Agency’s role, activities and priorities for 2015
6. Joint evaluation of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products
7. Biosimilars in the EU, Information guide for healthcare professionals. Prepared jointly by the European Medicines Agency and the European Commission. Last updated on 2 October 2019
8. Report from the Commission to the European Parliament and the Council in accordance with Article 25 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004, 28 March 2014
9. Why is now the right time to modernise the EU variations system? (Medicines for Europe)
10. EU pharma law reforms face delay 31 August 2022 (Pinsent Masons)