FREE CHAPTER from ‘A Guide to European Pharmaceutical Regulations for Human Medicines’ by Cliodhna McDonough



1.0 The Legal Basis of Medicines for Human Use

The European pharmaceutical sector is highly regulated in order to protect public health throughout the lifecycle of a medicine’s development, manufacturing and promotion. The first European Union (EU) legislation on human medicines was introduced to the community over 54 years ago. Over the past 24 years, the European Medicines Agency (EMA) remit has expanded, in line with new EU legislation. At the present time, in addition to its remit to evaluate human and veterinary medicines, the EMA is also responsible for products developed in the specialised areas of medicines for herbal medicines (since 2004), medicines for children (since 2006), orphan medicinal products (since 2000) and advanced-therapy medicines (since 2007) (Ref 19).

The EU legal system governing medicines is made up of numerous regulations, directives, opinions, recommendations and guidelines set by the European Commission to ensure the quality, safety and efficacy of all human medicinal products. Laws are implemented by member states through national competent regulatory authorities of the EU.

Article 1(2) of Directive 2001/83/EC (Ref 5) defines a medicinal product as;

(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or

(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

The legal basis for medicinal products is Article 168 of the Treaty on the Functioning of the European Union (TFEU), which states;

‘a high level of human health protection shall be ensured in the definition and implementation of all Union policies and activities’ (Ref 4)

The European Parliament and the Council contribute to this objective by adopting ‘measures setting high standards of quality and safety for medicinal products for medical use’.

The EU legal framework for human medicines sets standards to protect public health and ensure medicines are safe and effective. The rules for marketing authorisation and monitoring authorised products are primarily laid down in Directive 2001/83/EC and in Regulation (EC) No 726/2004.

The entire body of EU medicines legislation (EudraLex) is compiled in ‘The Rules Governing Medicinal Products in the European Union’. The legal basis for human medicines is collected in volume 1, while the remaining volumes contain a series of scientific guidelines supporting this legislative framework.

2.0 The Quality, Safety and Efficacy of a Medicine

The authorisation of a medicine builds on three key criteria namely to be of good quality, safety and efficacy (Ref 6). In relation to the first criteria, when applying for a marketing authorisation (MA), companies must provide regulatory documentation proving that the medicine is of suitable quality. This is assessed in accordance with criteria set out in EU legislation (Annex 1 of Directive 2001/83/) and guidelines (EudraLex Volume 3). The safety and efficacy of medicines is essential. For new medicines, companies are required to demonstrate safety and efficacy through the results of clinical trials. For established compounds, companies can refer either to data from already authorised medicines in the case of a “generic” MA or from existing published literature for “well-established use” medicines. The data on safety and efficacy will be carefully assessed by the competent authorities namely the European Medicines Authority (EMA) or National Competent Authorities such as the MHRA in the UK before a medicine receives a MA. The safety and efficacy of the medicine will continue to be closely monitored by regulatory authorities after the granting of a MA through pharmacovigilance activities (Ref 7).

2.1 The creation of policy in the European Union

Policymaking is the process of developing ideas or plans that are then put in place through legislation, creating a regulatory system. Many factors can drive new policy development including patient need and technological/scientific progress, meaning legislation is no longer fit for purpose and requires updating (Ref 8).

Policymaking in the European Union (EU) takes place across four EU institutions (Ref 9):

The European Commission;

The European Parliament;

The Council and;

The European Court of Justice

2.2 The European Commission

The European Commission is the executive body of the European Union responsible for managing the day-today business of the EU. This includes proposing legislation, implementing decisions and upholding the EU treaties. The Commission is made up of 33 Directorate Generals (DG) departments covering a wide remit of areas such as research and innovation, health, environment, communication, and budget. This is overseen by a College of 28 Commissioners, one from each Member State, each nominated by their respective national governments to serve five-year terms.

The Commission can adopt implementing measures as well as oversee the correct application of EU law on pharmaceuticals; propose new or amended legislation for the pharmaceutical sector and ensures appropriate collaboration with relevant international partners to promote the EU regulatory system globally. The Commission may grant or refuse, change or suspend marketing authorisations for medicines that have been submitted via the centralised procedure based on scientific assessments carried out by the EMA and oversee the implementation of safety measure for medicines across all member states (Ref 10).

2.3 The European Parliament

The European Parliament (EP) is the only directly elected EU body, made up presently approximately 751 Members (MEPs) elected to represent over 500 million citizens in the 28 member states. The EP decides jointly with the Council of the EU on laws that affect the daily lives of the European Union’s citizens. These include topics such as freedom of goods, medicinal product safety and consumer protection, the environment and most sectors of the economy.

The European Parliament has its own scientific advisory bodies, which are structured differently to those in the European Commission. The European Parliamentary Research Service (EPRS) provides analysis and scientific evidence on specific issues. (Ref 11).

2.4 The European Council

The EU’s broad priorities are set by the European Council, which brings together national and EU-level leaders. It is led by its president and comprises national Heads of State or Government and the President of the Commission. Given that the Council is made up of representatives from EU Member States, Ministers attending draw on their own national science advice mechanisms, rather than use a collective mechanism. As a co-legislator, the Council can choose to agree with the Parliament’s position, or suggest amendments.

2.5 The European Court of Justice

This European Court of Justice (ECJ) is the highest court in matters of EU law and it is based in Luxembourg. The Court interprets and ensures equal application of EU law across all Member States. It decides whether the institutions of the EU are acting legally, and it settles disputes between them in addition to also ensuring that the member states of the EU are complying with their legal obligations as set out in the EU treaties. The Court also permits member states to challenge EU legislation.

3.0 The History and progress of EU Regulation for Human

A robust regulatory system for medicines that is transparent and efficient is paramount in order to provide timely access to effective treatments for patients, protect patient safety, and foster research into new treatments.

The roots of the pharmaceutical industry lie back with the apothecaries and pharmacies that offered traditional remedies as far back as the middle ages. Traditionally, medicinal remedies involved the use of whole forms or extracts of flowers, barks, herbs or beneficial microbes and indeed many of these traditional remedies have formed the foundation for today’s pharmaceutical medicines.

The most notable emergence of the pharmaceutical industry began in the 19th century. During the 19th century, economic and industrial growth developed significantly, and scientists made rapid progress in identifying and preventing illnesses and in understanding how bacteria and viruses work. The concept of assessing the efficacy and effectiveness of medicines began to shift significantly towards one of evidence-based practice which, as we recognise today as “the integration of best research evidence with clinical expertise and patient values”. Originating as a pharmacy founded in Darmstadt in 1668, Merck pharmaceuticals is an example of one of the earliest pharmaceutical companies when in 1827 Heinrich Emanuel Merck began the transition towards an industrial and scientific concern, by manufacturing and selling alkaloids to patients (Ref 12).

3.1 Key advances in European Medicinal Product Regulation

Up until the 1960’s there was a limited level of regulatory control over the way in which therapeutic medicines were manufactured and marketed across Europe. By 1965, a key catalyst for advances in regulation across Europe was the thalidomide catastrophe that served as a call to governments to impose mandatory regulations on pharmaceutical manufacturers to prevent the availability of unsafe medicines to the public.

Thalidomide medicine was first introduced in 1957 by a German pharmaceutical company Chemie Grünenthal (Grünenthal) as a sedative tablet that could also control severe morning sickness in pregnant women. In the UK, Distillers Biochemicals Ltd. licensed thalidomide and began selling the medicine as Distaval in 1958. In addition, other companies also continued to license and sell the medicine worldwide under several different brand names.

Initially the medicine was sold and marketed as having no known serious side effects. However, in the absence of effective regulation governing in vitro clinical testing the company failed to predict any adverse effects of thalidomide when used by humans. By 1961, it was discovered that when taken in pregnancy, the medicine was associated with severe birth defects contributing to approximately 10,000 children being born with deformities worldwide the vast majority of which occurred in Europe and tragically contributing to a significant level of premature deaths of babies. (Ref 13).

The thalidomide case served as the “impetus” for over a half century of “progressive harmonization of requirements for the granting of marketing authorisations and post-marketing monitoring implemented across the entire European Union” resulting in stronger rules being introduced to improve the safety of medicines (Ref 14). The U.K responded to the thalidomide disaster by establishing a Committee on the Safety of Drugs in 1963 and a Yellow Card Scheme in 1964 for reporting suspected drugs reactions. The British Parliament legislated to ensure oversight of “safety, efficacy [and] quality of medicinal products” through the Medicines Act in 1968 to ensure that appropriate public health standards are met, maintained, and required medicines to be licensed before being allowed onto the UK market.

3.2 The Helsinki Declaration and Directive 65/65/EC

In 1964, the World Medical Association published the Helsinki Declaration, which established standards for clinical research and placed greater ethical strictures on clinical research, clearly cementing the difference between manufacturing of prescription medicines for human use. Following this declaration, the then European Economic Community (EEC) recognized the need to regulate medicines, and approved Directive 65/65/EEC of January 26, 1965, which formed the basis of European pharmaceutical legislation.

The aim of Directive 65/65/EC was to “safeguard public health” by implementing governing legislation to ensure trade in human medicines between EU member nations were subject to the regulatory approval of a “competent authority” within exporting and importing countries. Each Member State’s competent authority was instructed to deny the authorization of a drug that “is harmful in the normal conditions of use” or if “therapeutic efficacy is lacking or is insufficiently substantiated” (Ref 15) taking into account the medicines characteristics, uses and safety, based on evidence from clinical trials. Directive 65/65/EC continues to be the foundation of the regulatory framework for medicines today, namely the assessment of medicines based on quality, safety and efficacy. Since 1965, the European legal framework for the pre-marketing approval of medicines has been amended and enhanced by numerous pieces of legislation, which cover specific areas of pharmaceutical law.

In the 1970s, two landmark Council Directives were introduced, the first (Council Directive 75/318/EEC, 19752) relating to the harmonisation of analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products by companies seeking a marketing authorisation, and the second (Council Directive 75/319/EEC, 19753) establishing a procedure for marketing authorisation with the aim of promoting the free movement of medicines (Ref 16). The procedure was referred to as ‘mutual recognition’, which allowed a pharmaceutical company to market a product in all member states if only one member state approved the medicinal product application.

The introduction of the single market project in 1985, witnessed the adoption of a significant volume of Community directives with the objective of achieving a single, EU-wide market for pharmaceuticals. In 1987, a new procedure for the authorisation of medicines called the ‘concertation procedure’ was introduced. Under this procedure, the EU decided to centralize the review process for biotechnology and other high-technology products. However, the concertation procedure did not achieve the goal of free circulation of pharmaceuticals across all EU Member States because these procedures did not compel the member states to accept a majority opinion of the CPMP as its opinion was not legally binding, leading to member States issuing different decisions on medicine approvals.

3.3 Creation of the EMEA (EMA) and Marketing Authorisation

The European medicines regulatory system is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and the EMA.

Up until 1995, the European Commission did not require all member states to accept the medicine approval decisions made by the Commission or other Member States. In 1993, the EU enacted legislation that created a new medicine approval process. Council Regulation (EEC) No 2309/93 of 22 July 1993 was introduced laying down Community procedures for the authorization and supervision of medicinal products for human use. The new drug approval process established two new procedures for achieving EU-wide medicine approvals namely a centralized procedure and decentralized procedure.

At the same time that it established new approval marketing authorisation procedures, the Commission also created the European Medicines Evaluation Agency (EMEA) (now named the European Medicines Agency (EMA), which was inaugurated in 1995. The objective of the EMEA was to provide a faster and more efficient regulatory approval process that would benefit consumers as well as industry and harmonise the work of existing national medicine regulatory bodies.

Based in Amsterdam in the Netherlands, the EMA is a decentralised EU scientific agency (as opposed to a regulatory authority) comprising of over 50 National Competent Authorities (NCAs) of EU member states and evaluates centralised marketing authorisation applications which allows the marketing-authorisation holder to market the medicine and make it available to patients and healthcare professionals throughout the EU on the basis of a single marketing authorisation (Ref 17). The EMA’s Committee for Medicinal products for Human Use (CHMP) provides scientific opinions on the quality, safety, and efficacy of new medicines that manufacturers want to market in the European Union and monitors the safety of medicines across their life cycle through pharmacovigilance procedures. The European Commission uses the EMA opinions to decide whether to grant a product licence. Once granted by the European Commission, the centralised marketing authorisation is valid in all EU Member States as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.

3.4 National Competent Authorities (NCAs)

The majority of medicines available in the EU are authorised at national level primarily because they not within the scope of the centralised procedure. The national competent authorities (NCAs) are primarily responsible for the authorisation of medicines available in the EU that do not pass though the centralised procedure. National governments are responsible for establishing strong NCAs who are accountable to both the government and the public (Ref 18). In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood components for transfusion.

At national level, the pharmaceutical sector is one of the UK’s most productive industries, generating £41.8 billion turnover in 2018 (Ref 1) and contributed around one per cent of the UK’s output and 7.7 per cent of manufacturing GVA (Ref 2) and employed approximately 62,600 people across 543 companies, supported by 1,314 service and supply companies comprising a further 51,000 people (Ref 3). The European medicines regulatory system is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and the EMA.

In terms of Brexit as of the publication date of this book it is not known what kind of future relationship the UK will have with the EU on medicines after the exit day as negotiations are ongoing. Future possible outcomes for regulation of medicines in the UK following Brexit could range from an ongoing close cooperation and alignment with the EMA to an entirely separate standalone regulatory system in the UK (Ref 20).

4.0 The European Medicines Agency Scientific Committees

The primary aim of the EMA is to draw up scientific opinions for the evaluation of such medicines for the EU institutions and the Member States. This task is carried out by a large pool of approximately 4,500 European experts primarily sourced from the medicines regulatory authorities in the member states. These experts perform an important role in the EMA’s assessment teams, working parties and advisory groups, or participate as members nominated by the national competent authorities.

The seven scientific committees are:

  1. Committee for Medicinal Products for Human Use (CHMP)

A single evaluation of a marketing authorisation application for a medicine is carried out by the Committee for Medicinal Products for Human Use (CHMP). If the Committee concludes that the quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. This is forwarded to the European Commission to be transformed into a marketing authorisation valid for the whole of the EU.

  1. Committee for Medicinal Products for Veterinary Use (CVMP)

The Committee for Medicinal Products for Veterinary Use (CVMP) operates in similar fashion to the CHMP with regard to veterinary products.

  1. Committee for Orphan Medicinal Products (COMP)

This Committee administers the granting of orphan drug status. The COMP evaluates the application and makes a recommendation for the designation which is then granted by the European Commission

  1. Committee on Herbal Medicinal Products (HMPC)

The Committee on Herbal Medicinal Products (HMPC) assists with the integration of herbal medicinal products in the European market.

  1. Committee for Advanced Therapies (CAT)

The Committee for Advanced Therapies (CAT) assesses the quality, safety and efficacy of Advanced Therapeutic Medicinal Products (ATMP), and follows scientific developments in the field.

  1. Paediatric Committee (PDCO)

The Paediatric Committee (PDCO) deals with the implementation of the paediatric legislation in Europe.

  1. Pharmacovigilance Risk Assessment Committee (PRAC)

The Pharmacovigilance Risk Assessment Committee (PRAC) implements EU pharmacovigilance legislation.

5.0. The Future of Medicines in Europe?

Smarter and more complex areas of treatment medicine are rapidly emerging in areas such as cell and gene editing therapies, proteomics and metabolomics with the health benefits of such therapies indicating very positive signs as effective patient treatment methods.

Scientists and Healthcare Professionals are now looking more intensely at the root cause of an illness, rather than just treating symptoms. For example, Precision Medicine offers a deeper understanding of human physiology using genetic insights and advances in technology and is becoming an increasingly area of research development. Genomics-led Precision Medicine will allow for a more targeted, adaptable type of patient treatment, which used solely or as part of combination therapy can offer specific personalized, treatment plans for patients.

The progression of digital health allows for smarter, more effective and efficient clinical practice to be performed in many complex areas of medicine. Digital technology can develop an implementation plan that provides immediate controls, followed by right-paced implementation of new disease-process workflows to manage specific risks and costs inherent to the patient healthcare system. The emergence of real world scientific evidence and big data analytics will also be incorporated into regulatory processes to improve health outcomes of medicinal treatments.

Scientific innovation and regulatory innovation must work hand-in-hand. Regulation in the area of medicine may be perceived by some as a ‘tug on innovation’ with primary emphasis on the requirement to ‘prove a medicine is safe’ before awarding a marketing authorisation. However it is this fundamental and necessary requirement of having to firstly prove the safety of a medicine that leads to a significant level of reassurance and trust to be placed in the European regulatory structure by the its community.

No doubt, regulation will continue to evolve and be seen as the driver of medicine innovation by taking novel approaches to accelerate the adoption of innovations and incentivise therapies. The Adaptive Pathway concept highlights the EMA’s willingness to actively explore new approaches to medicine approval and applies primarily to treatments in areas of high medical need where it is difficult to collect data via traditional routes and where large clinical trials would unnecessarily expose patients who are unlikely to benefit from the medicine. Industry also has a responsibility to work with health systems to produce the innovative medicines patients require, which in turn requires the health community giving a clearer description of its needs whilst ensuring the regulation of medicine offers value and affordability for patients.



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