International Conventions & Guidelines
COUNCIL OF EUROPE, STRASBOURG: Conventions on Biomedical research and on Biomedicine
! These Conventions are international legal instruments.
The Oviedo Convention : Convention on Human Rights and Biomedicine
The Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No 164) was opened for signature on 4 April 1997 in Oviedo (Spain) (ETS No.164).
Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, Strasbourg, 25/01/2005 - Treaty open for signature by the Signatories to Treaty ETS 164 (CETS No.195)
Additional Protocol to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine, on the Prohibition of Cloning Human Beings, Paris, 12/01/1998 - Treaty open for signature by the Signatories to Treaty ETS 164 (ETS No.168)
Additional Protocol to the Convention on Human Rights and Biomedicine concerning Transplantation of Organs and Tissues of Human Origin, Strasbourg, 24/01/2002 - Treaty open for signature by the Signatories to Treaty ETS 164, ETS No.186
Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing for Health Purposes, Strasbourg, 27/11/2008 - Treaty open for signature by the Signatories to Treaty ETS 164 (CETS No.203)
! Guidelines and Guidances are generally non-binding norms but they can have a direct effect if they are referred by legislative acts.
WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Good Clinical Practice
ICH- (E6) GCP Guideline: The Guideline for Good Clinical Practice E6 (R2) Integrated Addendum has reached Step 2 of the ICH process in June 2015. This Addendum is proposed to modernise ICH E6 to enable implementation of innovative approaches to clinical trial design, management, oversight, conduct, documentation, and reporting that will better ensure human subject protection and data quality.
EU Legal Framework & Guidelines
Regulations are legislative acts of the European Union which are directly binding in the member states
Directives are also legislative acts but without a direct effect. Directives require implementation into national law to be effective in the member states
Source: EU Portal : https://europa.eu/european-union/eu-law/legal-acts_en
Clinical Trials on Medicinal Products for Human Use
New EU legislation: not applicable yet
Regulation EU No 536/2014: Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance
Comment: The new Regulation will become effective once the new EU database has become available (no sooner than 2019).
- Current EU legislation:
Clinical Trials Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use ("the Clinical Trial Directive")
Directive 2001/83/EC the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (" the Community Code for medicinal products")
Commission Directive 2005/28/EC 8 April 2005 laying 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 – (" the GCP Directive").
Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use ("the GMP Directive")
- Further Information / Guidelines
Clinical Investigation of Medical Devices
New EU legislation : Not applicable yet
Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC ( spring 2020)
Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU ( spring 2022)
- Further Information / Guidelines
Better Medicines for Children
- EU Legislation
The Paediatric Regulation with its amendment is directly binding for all Member States and caused many changes in the regulatory environment for paediatric medicines. As there were many new tasks for the European Medicines Agency (EMA), a new section of the EMA website was created to provide new und updated information relating to the Agency’s work in the area: please see EMA - Medicines for children.
The overall aim of the Regulation is to improve the health of children in the European Union by:
- increasing the development of medicines for use in children
- ensuring that medicines used to treat children are subject to high-quality research and appropriately authorised for use in children
- improving the available information on the use of medicines in children
- avoiding unnecessary clinical trials in the paediatric population
- ensuring that the authorisation of medicines in the adult population is not delayed
A Paediatric Investigation Plan (PIP) (see Glossary) has to be filed at the Paediatric Board (see Glossary) of the EMA for all applications for marketing authorisation for new medicines, new indications, new dosages or new route of administration, but not for investigator-initiated grials. In some cases, a deferral can be obtained in order to avoid any delay in the development of new products for adults. In other cases, the requirement may be waived if the applicant can prove that there is no possible paediatric use of the product. The PIP is a research and development programme listing all studies planned to assess quality, safety and efficacy of the new medicinal product in all relevant subsets of the paediatric population. It must be admitted no later than upon completion of the pharmacokinetic studies in adults. After completion and submission of all relevant information to the regulatory authorities (either nationally or centrally at EMA), the medicinal product will be granted an extra 6 months extension of its Supplementary Protection Certificate (SPC, see glossary). The extension will also be granted if the PIP has been fulfilled but there is no paediatric indication (see: European Commission - PIP Guideline).
In cases where there is no SPC or where the SPC has expired, there is no financial incentive. For orphan medicinal products, there is an extra two years market exclusivity in addition to the ten years granted in case of orphan indication. In case of development of new paediatric formulations in off-patent products that are intended solely for use in children, these (so called paediatric use marketing authorisation = PUMA) will benefit from ten years market protection.
Scientific advice and help with the preparation of the PIP may be requested from EMA at any stage and is free of charge for all paediatric questions. FAQs can be found on the EMA - PIP site. For a list with EMA decisions on PIPs so far see EMA - Decisions on PIP.
The regulation also requires:
- the development of a European network for paediatric clinical trials (see: Implementing Paediatric Networks)
- the establishment of an inventory of therapeutic needs for the paediatric population (see Paediatric Needs)
- the provision of funding for clinical research on off-patent medicinal products based on a priority list (for further information and a priority list see Priority list of off-patent medicines)
- the establishment of a paediatric clinical trials database containing information on all trials conducted according to a PIP and including trials conducted solely outside the EU. This database will be publicly accessible and will be based on the EudraCT database (see also Guidance on the information concerning paediatric clinical trials - EudraCT).
- the creation of a new paediatric use symbol. Balancing benefits and risks, the Paediatric Board is at present not in a position of selecting a new symbol (see Recommendations regarding the symbol).
- Further Information / Guidelines
EMA (European Medicines Agency)- Medicines for Children
Comment: The website includes new und updated information relating to the Agency’s work in the area of paediatric medicines
EnprEMA: Informed Consent for Paediatric Clinical Trials in Europe 2015 (Pirkko Lepola, Allison Needham, Jo Mendum, Peter Sallabank, David Neubauer, Saskia de Wildt)
Comment: Summary table covering 28 European countries, published by the European Network of Peadiatric Research at the European Medicines Agency (EnprEMA)
Regulation EC No. 1901/2006 and the amending Regulation EC No. 1902/2006 are available in different languages on the EUR-Lex website (see EUR-lex - Regulation 1901/2006).
European Medicines Agency (EMA) - Better Medicines for children
7 Westferry Circus
London E14 4HB, UK
Phone: +44 20 74 18 84 00
Fax: +44 20 74 18 84 16
Note: this section contains all information from the TREAT-NMD Regulatory Affairs Database.
- EU Legislation
European Regulation (EC) No 141/2000 on Orphan Drugs (available in multiple languages on the EUR-lex website.)
Medicinal products which are intended to diagnose, prevent or treat a rare disease are called orphan drugs. Financial interest is normally low for the pharmaceutical industries to develop drugs diseases (those medicinal products are “orphans” among the pharmaceutical spectre). Regulation 141/2000 implements incentives for the pharmaceutical industry to stimulate research and development in this field of medicine. See: European Regulation (EC) No 141/2000 (Orphan Drugs), English version
Comment: According to Regulation 141/2000 drugs can be classified as orphan drugs if they affect less than 5 of 10,000 people in a serious or life-threatening disease or pose no market interests for the pharmaceutical industry and there is no adequate therapy available. Regulation 141/2000 implements incentives for the pharmaceutical industry to stimulate research and development in this field of medicine.
In order to obtain an designation as orphan drug (Orphan designation), sponsors can file an application at EMA. The Committee for Orphan Medicinal Products (COMP) at EMA is responsible for reviewing applications and also for advising the European Commission on the establishment and development of a policy on orphan medicinal products in the EU. Guidance and procedural information is available here: Orphan Designation - how to apply
For companies with a medicinal products in an orphan designation, there are the following benefits:
- listing in the European Community Register of medicinal products (more detailed information for each medicinal product can be found at Orphan medicinal products - opinions on orphan designation)
- marketing authorisation (10-year marketing exclusivity)
- free scientic advice during the product-development phase
- for protocol assistance
- free pre-authorisation inspections and reduced post-authorisation activities
- Further Information / Guidelines
Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA)
Comment: COMP is responsible for reviewing applications from persons or companies seeking 'orphan medicinal product designation' for products they intend to develop for the diagnosis, prevention or treatment of life-threatening or very serious conditions
OrphaNet is the reference portal for information on rare diseases and orphan drugs, for all audiences. Orphanet’s aim is to help improve the diagnosis, care and treatment of patients with rare diseases.
Comemnt: This portal for rare diseases and orphan drugs provids freely accessible services for health professionals and patients
EURORDIS Rare Diseases Europe: A non-governmental patient-driven alliance of patient organisations representing over 600 rare disease patient organisations in 63 countries covering over 4000 diseases
Comment: EURORDIS' mission is to build a strong pan-European community of patient organisations and people living with rare diseases, to be their voice at the European level.
Further information including services for health professionals and patients can be found at OrphaNet and Eurordis.
Note: this section contains all information from the TREAT-NMD Regulatory Affairs Database.
Compassionate Use vs Off-Label Use
'Compassionate use' is the technical term used to indicate a treatment option that allows the use of an unauthorised medicine outside a clinical study in individual patients under strictly controlled conditions. 'Compassionate use' differs from 'off-label' use. In 'off-label' use a licensed medicinal product is prescribed for an indication, or to a patient for which the product is not specifically licensed, whereas, in 'compassionate use' the medicinal product is not licensed and not used as a treatment for any disease.
- Compassionate Use Programmes in Europe
In Europe there are certain criteria to compassionate-use programmes (1). It only applies to patients who have a life-threatening disease with no satisfactory authorised therapies or who cannot enter a clinical trial (e.g. because they are outside the inclusion criteria). Furthermore, the medicinal product concerned must either be the subject of a marketing authorisation application, or under evaluation in a clinical trial. (1)
The compassionate use programme thus helps to make medicines that are still under development available to patients before they are approved. It should be mentioned that the clinical development of medicines serves to establish that newly developed medicines are effective and safe. Therefore, there is a risk that the medicines used in compassionate use programmes turn out not to be safe or effective. The risks of taking potentially unsafe and/or ineffective medicines have to be balanced with the risk of doing nothing for progressive diseases.
- How Compassionate Use Is Implemented in Different EU Countries
Compassionate use programmes are coordinated and implemented by the individual EU Member States, which decide independently how and when to open such programmes according to national rules and legislation. Doctors who wish to obtain a promising medicine for one of their seriously ill patients will need to contact the relevant national authority in their respective country and follow the procedure that has been set up. The national authority keeps a register of the patients treated with the medicine within the compassionate use programme, and systems are in place to record any side effects reported by the patients or their doctors.
Compassionate use programmes are governed by legislation in individual EU Member States, to make medicines available on a named-patient basis or to cohorts of patients. It will differ per country who is responsible (physician or license holder), what the programme is called, which authorities coordinate compassionate use, if and how adverse events and efficacy have to be reported and if and how compassionate use is reimbursed. (2)
Since many treatments for rare neuromuscular disorders are state of the art and complex drugs, they are generally quite expensive. For some countries reimbursement will be through national or local systems (e.g. ATU in France covers the costs of the medicines for French patients in compassionate use programmes), while for other countries, patients have to pay for the medicines themselves (which for rare diseases is often not possible due to the expensive nature of the medicines). It is also possible that the company provides the medicines to the patients free of charge through charity programmes.
Due to the different implementation, legislation and reimbursement of compassionate use in different EU countries, access to compassionate use programmes differs for patients based on where they live. Ideally, a pan-European system should be in place to allow equal access to all.
Access to medicines under development other than compassionate use or participation in a clinical trial.
Doctors can also obtain promising medicines for their patients by requesting a supply of a medicine from the manufacturer, to be used for a patient under their direct responsibility. This is often called treatment on a 'named-patient basis' and should not be confused with compassionate use programmes. In this case, the doctor responsible for the treatment will contact the manufacturer directly. While manufacturers do record what they supply, there is no central register of the group of patients that are being treated in this way.
Sometimes patients can enter 'expanded access programmes' (also called open label studies, or extension studies). A company that makes a promising medicine may choose to run one of these programmes to allow early access to their medicine and to widen its use to patients who can potentially benefit from it. For example, patients who have been treated with the medicine during a clinical trial and wish to continue treatment may be able to do so via an expanded access programme. These programmes are often authorised by national authorities in the same way as clinical trials, and patients are followed in the same way as patients in a clinical trial.
- Compassionate Use vs Clinical Trial Participation
Participation in placebo-controlled clinical trials may be another way to receive treatment with medicines that are in development before they are approved. A certain number of patients participating in a placebo-controlled trial will receive a placebo rather than the medicine that is being evaluated, so this is no guarantee to have access to drug during the trial. Nevertheless, sometimes the trial will have an expanded access programme to ensure access to the medicine after the patient has completed the clinical trial. Furthermore, without patients willing to participate in clinical trials it is impossible to develop treatments. Also here the disclaimer applies that treatments that are in clinical development may not be safe or effective.
Gene Transfer Medicinal Products
The Committee for Proprietary Medicinal Products of the EMA has published two detailed documents which are accepted throughout Europe:
CHMP/BWP/3088/99 - Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products
CHMP/BWP/2458/03 - Guideline on Development and Manufacture of Lentiviral Vectors
- EMA Guidelines
EMA - Guideline on clinical evaluation of new vaccines, London, 18 October 2006 (EMEA/CHMP/VWP/164653/05) (Currently under revision) "This Guideline covers the design of clinical development programs for new vaccines that are intended to provide pre- and post-exposure prophylaxis against infectious diseases.Some of the guidance provided is also relevant to the further development of licensed vaccines (i.e. generation of clinical data to support changes to the prescribing information in the post-authorisation period ".
EMA- Annex to the Guideline on clinical evaluation of new vaccines: SPC requirements guideline on clinical evaluation of new vaccines, London, 18 October 2006 (EMEA/CHMP/VWP/382702/2006)
This document " provides guidance on the format and content of sections 4 (Clinical particulars) and 5 (Pharmacological properties) of the SPCs"
- WHO Guidelines
WHO Guideline on clinical evaluation of vaccines: regulatory expectations (WHO Technical Report, Series No. 924, 2004)"This document provides guidance for national regulatory authorities and vaccine manufacturers on the clinical evaluation of vaccines"
WHO - ANNEX 9 - Guidelines on clinical evaluation of vaccines: regulatory expectations. Replacement of Annex 1 of WHO Technical Report Series, No. 924 (WHO Technical Report Series, No. 1004, 2017) "These revised WHO Guidelines have been prepared to reflect thescientific and regulatory experience that has been gained from vaccine clinical development programmes since the adoption of the 2001 version".
WHO - ANNEX 10 - Human challenge trials for vaccine development: regulatory considerations (WHO Technical Report Series, No. 1004, 2017)"The document only covers issues specifically relevant to the design and conduct of clinical trials that enroll healthy adult humans capable of truly informed consent, and that involve".
Other relevant EU legislation
The General Data Protection Regulation (GDPR)
Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data (available in multiple languages on EUR-lex websit) ( applicable from 25 May 2018 ).
Comment: EUR-lex provides free access to European Union Law. The EUR-Lex website contains European legislation in different languages and important background information concerning European Law.
Disclaimer: This is not an official Legal database. The information contained herein does in no way constitute legal advice.