Note July 7, 2016: The EMA released a statement saying that “EMA would like to underline that its procedures and work streams are not affected by the outcome of the referendum (Great Britain's vote to exit from the European Union)." At present, the EMA has its headquarters with a staff of close to 900 people based in the UK.
INTRODUCTION
First, a little background. There are several agencies involved in approval of drugs or medical devices in Europe. This discussion will focus on approval and distribution of drugs or biologics; we will add information about medical devices later.
The European medicines regulatory system is a network of national regulatory agencies, the European Commission, and the European Medicines Agency (EMA) plus input from the International Committee on Harmonization (ICU).
National Medicine Agencies
Each country has their own medicines regulatory agency (MRA) like the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) or SwissMedic. Some countries like Germany have two agencies, one for drugs and one for vaccines and immunologics.
The European Medicines Agency (EMA)
The EMA is an organization responsible for the scientific evaluation and safety monitoring of medicines for use in the EU. The EMA was formed in 1995 with funding from the EU and the pharmaceutical industry to harmonize the work of the individual national regulatory groups. The EMA is governed by an independent Management Board that consists of 35 members appointed to “act in the public interest”. Board members do not represent any government, organization or sector. The EMA provides services to 31 counties, or as they call them, 31 “member states” and to the European Commission. These member states include 28 countries that are members of the EU: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom, plus 3 members of the European Economic Area (EEA), Iceland, Liechtenstein, and Norway. EMA's scientific committees provide independent scientific review of market applications of medicines for human and veterinary use and make recommendations for or against market authorization.
EudraCT
The EMA maintains EudraCT, the EU Clinical Trials Register that lists studies that have at least one European site. EudraCT also publishes summaries of study results.
EU Guidelines
Just as the FDA issues Guidance Documents, the EMA issues Guidelines that contain the latest scientific thinking on selected topics related to drug development. In many cases, the EMA has adopted the Guidelines of the International Committee on Harmonization.
Switzerland- the exception
Switzerland, the home of many large pharmaceutical companies, is not a member of the EU and is not part of the EMA. Switzerland has it’s own system for drug approvals. All drug applications must be reviewed by Swissmedic, the Swiss Agency for Therapeutic Products. Swissmedic can expedite product approval by relying on product reviews from countries that have “comparable control systems”, viz Australia, Canada, EEA member states, Japan, New Zealand, Singapore and the USA. Swiss approval is important because many non-European countries require approval in a product’s country of origin as a prerequisite for their own approval. The Switzerland and the EMA have a mutual recognition agreement for GMP inspections and batch certification for medicinal products manufactured in Switzerland or the European Community.
The European Commission
The European Commission is the executive body for the European Union (EU). It represents the interests of the European Union as a whole, not individual countries. The European Commission makes decisions on a variety of topics, not just drug or device approvals. If the EMA approves a drug application, the European Commission can authorize marketing in all the EU member states plus Iceland, Liechtenstein, and Norway.
International Council for Harmonisation (ICH)
In 1990, drug regulatory authorities and pharmaceutical associations from Europe, Japan, and the United States formed the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) to discuss scientific and technical aspects of drug registration. Membership now includes Health Canada and Swissmedic.
The ICH has issued Quality, Safety, Efficacy and Multidisciplinary Guidelines for drug development and other work products including the MedDRA medical dictionary, a format for electronic submissions called the Common Technical Document (CTD), and Electronic Standards for the Transfer of Regulatory Information (ESTRI). Regulatory authorities often adopt these Guidelines and systems as a substitute for designing their own formats.
Role of National Regulatory Agencies in Europe
The medicines regulatory authority (MRA) in each country is responsible for pharmacovigilance; for authorization of clinical trials; monitoring GCP compliance; and for inspection of manufacturing and distribution facilities. MRAs also review and authorize marketing of products intended for use only within their jurisdiction.
For pharmacovigilance, patients, physicians or other healthcare professional report suspected adverse events to their national medications authority. All events are entered into a centralized, web-based information database called EudraVigilance and thereby made available to all member nations. An EMA committee called the Pharmacovigilance Risk Assessment Committee, or PRAC makes oversees safety information about human drugs.
Manufacturers of any medicine authorized for European marketing, whether they are located in Europe or elsewhere, must be inspected by an EU competent authority,. European importers, manufacturers, or distributors of medicines are licensed by their national authority. Any active pharmaceutical ingredient imported into Europe must have documentation confirming that it was manufactured under GMPs at least equivalent to European standards. All batches of medicines marketed in Europe must be certified for quality and GMP compliance. If a batch of drug is manufactured outside Europe, it may have to be re-tested unless there is a mutual recognition agreement in place with the supplying country; once certified the batch can be transported to any EU country.
Market Authorization of New Drugs or Biologics
In Europe, there are several methods for “market authorization” of new drugs or biologics. Medications that are intended for use in only one country, and which do not require centralized review, can authorized by the national competent authority (NCA). For drugs that will be marketed in more than one country, there are three procedures; a centralized procedure, a decentralized procedure, and a mutual-recognition procedure. Medical devices are handled in a different manner which we will discuss at a later date.
Centralized Procedure
Innovative or high technology medicines including biologics, orphan medical products, and human products with a new active substance (not authorised before 20 May 2004) which are intended for treatment of AIDS, cancer, diabetes, neurodegenerative disorders, autoimmune or other immunologic disorders, or viral diseases must be reviewed by the centralized procedure. Centralized authorization is also required for veterinary products that promote growth of animals or increase the yield from animals. Centralized review may be requested for other products containing new active substances or products which constitute a significant therapeutic, scientific or technical innovation.
Under the centralized procedure, a company submits a single market authorization application to the EMA. The EMA appoints a “rapporteur” and sometimes a “co-rapporteur,” plus an assessment team to coordinate the EMA's assessment of the medicinal product and prepare draft reports. The EMA’s Committee for Medicinal Products for Human Use (CHMP) or the Committee for Medicinal Products for Veterinary Use (CVMP) completes a scientific assessment of the data submitted and makes a recommendation for or against approval. If the Committee votes for approval, the European Commission can grant marketing authorization which is valid throughout the entire EU plus Iceland, Liechtenstein, and Norway. Decisions about pricing and reimbursement for the authorized product take place in each individual country. The EMA publishes an assessment report (EPAR) for each human or veterinary medicine that is approved or refused authorization.
In the decentralized procedure, a company can apply for simultaneous authorization of a new product in more than one European country if it has not yet been authorized in any EU country and if the centralized procedure is not required.
In the mutual-recognition procedure, companies can ask that a product that has been authorized in one EU member country be recognized in other countries.
The Resource Section provides a list of Medications Regulatory Agencies in each of the European states, links to further information about the EMA, EudraCT, and the ICH.
INTRODUCTION
First, a little background. There are several agencies involved in approval of drugs or medical devices in Europe. This discussion will focus on approval and distribution of drugs or biologics; we will add information about medical devices later.
The European medicines regulatory system is a network of national regulatory agencies, the European Commission, and the European Medicines Agency (EMA) plus input from the International Committee on Harmonization (ICU).
National Medicine Agencies
Each country has their own medicines regulatory agency (MRA) like the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) or SwissMedic. Some countries like Germany have two agencies, one for drugs and one for vaccines and immunologics.
The European Medicines Agency (EMA)
The EMA is an organization responsible for the scientific evaluation and safety monitoring of medicines for use in the EU. The EMA was formed in 1995 with funding from the EU and the pharmaceutical industry to harmonize the work of the individual national regulatory groups. The EMA is governed by an independent Management Board that consists of 35 members appointed to “act in the public interest”. Board members do not represent any government, organization or sector. The EMA provides services to 31 counties, or as they call them, 31 “member states” and to the European Commission. These member states include 28 countries that are members of the EU: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom, plus 3 members of the European Economic Area (EEA), Iceland, Liechtenstein, and Norway. EMA's scientific committees provide independent scientific review of market applications of medicines for human and veterinary use and make recommendations for or against market authorization.
EudraCT
The EMA maintains EudraCT, the EU Clinical Trials Register that lists studies that have at least one European site. EudraCT also publishes summaries of study results.
EU Guidelines
Just as the FDA issues Guidance Documents, the EMA issues Guidelines that contain the latest scientific thinking on selected topics related to drug development. In many cases, the EMA has adopted the Guidelines of the International Committee on Harmonization.
Switzerland- the exception
Switzerland, the home of many large pharmaceutical companies, is not a member of the EU and is not part of the EMA. Switzerland has it’s own system for drug approvals. All drug applications must be reviewed by Swissmedic, the Swiss Agency for Therapeutic Products. Swissmedic can expedite product approval by relying on product reviews from countries that have “comparable control systems”, viz Australia, Canada, EEA member states, Japan, New Zealand, Singapore and the USA. Swiss approval is important because many non-European countries require approval in a product’s country of origin as a prerequisite for their own approval. The Switzerland and the EMA have a mutual recognition agreement for GMP inspections and batch certification for medicinal products manufactured in Switzerland or the European Community.
The European Commission
The European Commission is the executive body for the European Union (EU). It represents the interests of the European Union as a whole, not individual countries. The European Commission makes decisions on a variety of topics, not just drug or device approvals. If the EMA approves a drug application, the European Commission can authorize marketing in all the EU member states plus Iceland, Liechtenstein, and Norway.
International Council for Harmonisation (ICH)
In 1990, drug regulatory authorities and pharmaceutical associations from Europe, Japan, and the United States formed the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) to discuss scientific and technical aspects of drug registration. Membership now includes Health Canada and Swissmedic.
The ICH has issued Quality, Safety, Efficacy and Multidisciplinary Guidelines for drug development and other work products including the MedDRA medical dictionary, a format for electronic submissions called the Common Technical Document (CTD), and Electronic Standards for the Transfer of Regulatory Information (ESTRI). Regulatory authorities often adopt these Guidelines and systems as a substitute for designing their own formats.
Role of National Regulatory Agencies in Europe
The medicines regulatory authority (MRA) in each country is responsible for pharmacovigilance; for authorization of clinical trials; monitoring GCP compliance; and for inspection of manufacturing and distribution facilities. MRAs also review and authorize marketing of products intended for use only within their jurisdiction.
For pharmacovigilance, patients, physicians or other healthcare professional report suspected adverse events to their national medications authority. All events are entered into a centralized, web-based information database called EudraVigilance and thereby made available to all member nations. An EMA committee called the Pharmacovigilance Risk Assessment Committee, or PRAC makes oversees safety information about human drugs.
Manufacturers of any medicine authorized for European marketing, whether they are located in Europe or elsewhere, must be inspected by an EU competent authority,. European importers, manufacturers, or distributors of medicines are licensed by their national authority. Any active pharmaceutical ingredient imported into Europe must have documentation confirming that it was manufactured under GMPs at least equivalent to European standards. All batches of medicines marketed in Europe must be certified for quality and GMP compliance. If a batch of drug is manufactured outside Europe, it may have to be re-tested unless there is a mutual recognition agreement in place with the supplying country; once certified the batch can be transported to any EU country.
Market Authorization of New Drugs or Biologics
In Europe, there are several methods for “market authorization” of new drugs or biologics. Medications that are intended for use in only one country, and which do not require centralized review, can authorized by the national competent authority (NCA). For drugs that will be marketed in more than one country, there are three procedures; a centralized procedure, a decentralized procedure, and a mutual-recognition procedure. Medical devices are handled in a different manner which we will discuss at a later date.
Centralized Procedure
Innovative or high technology medicines including biologics, orphan medical products, and human products with a new active substance (not authorised before 20 May 2004) which are intended for treatment of AIDS, cancer, diabetes, neurodegenerative disorders, autoimmune or other immunologic disorders, or viral diseases must be reviewed by the centralized procedure. Centralized authorization is also required for veterinary products that promote growth of animals or increase the yield from animals. Centralized review may be requested for other products containing new active substances or products which constitute a significant therapeutic, scientific or technical innovation.
Under the centralized procedure, a company submits a single market authorization application to the EMA. The EMA appoints a “rapporteur” and sometimes a “co-rapporteur,” plus an assessment team to coordinate the EMA's assessment of the medicinal product and prepare draft reports. The EMA’s Committee for Medicinal Products for Human Use (CHMP) or the Committee for Medicinal Products for Veterinary Use (CVMP) completes a scientific assessment of the data submitted and makes a recommendation for or against approval. If the Committee votes for approval, the European Commission can grant marketing authorization which is valid throughout the entire EU plus Iceland, Liechtenstein, and Norway. Decisions about pricing and reimbursement for the authorized product take place in each individual country. The EMA publishes an assessment report (EPAR) for each human or veterinary medicine that is approved or refused authorization.
In the decentralized procedure, a company can apply for simultaneous authorization of a new product in more than one European country if it has not yet been authorized in any EU country and if the centralized procedure is not required.
In the mutual-recognition procedure, companies can ask that a product that has been authorized in one EU member country be recognized in other countries.
The Resource Section provides a list of Medications Regulatory Agencies in each of the European states, links to further information about the EMA, EudraCT, and the ICH.