Legal Information

International Guidelines & Conventions

Ethical Guidelines

WMA Declaration of Helsinki
Comment: Update effective in 2016 

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.


European Regulatory Framework & Guidelines 

Terms

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

Guidelines and Guidances are generally non-binding norms but they can often provide helpful advice and sometimes they can have a direct effect if they are referred by legislative acts. 


Clinical Trials on Medicinal Products for Human Use

European 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")

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 (it will come into force no sooner than 28th May 2016). 

Further Information / Guidelines 

Guidelines for the application of Clinical Trials Directive: EudraLex - Volume 10 Clinical trials guidelines

European Commission: Section Clinical trials

EU Clinical trials register 

EMA- EudraVigilance Clinical Trial Module (EVCTM)

EMA Reflection paper on classification of advanced therapy medicinal products 

Clinical Investigation of Medical Devices

European Legislation

Council Directive 90/385/EEC on Active Implantable Medical Devices (AIMDD) (1990)

Council Directive 93/42/EEC on Medical Devices (MDD) (1993)

Council Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVDMD) (1998)

Directive 2007/47/EC (amending directives 90/385/EEC, 9342/EEC and 98/8/EC)

Further Information / Guidelines 

European Commission: Medical Devices - Guidance MEDDEVs 

National CA Clinical Investigations Contact point 


Better Medicines for Children 

Note: this section contains all information from the TREAT-NMD Regulatory Affairs Database.

Background

Paediatric Regulation (so called “Better medicines for children”) was adopted by the European Union in January 2007. The overall aim of the Regulation is to improve the health of children in the European Union by:

See:

European Regulation (EC) No 1901/2006 (Paediatric Regulation)
European Regulation (EC) No 1902/2006 (amending the Paediatric Regulation)

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.

Regulation EC No. 1901/2006 and the amending Regulation EC No. 1902/2006

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:

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).

Contact

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

Email: paediatrics@ema.europa.eu

 

Orphan Drugs

Note: this section contains all information from the TREAT-NMD Regulatory Affairs Database.

Regulation EC No. 141/2000 on orphan drugs 

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

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. 

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:  

The Regulation 141/2000 is available in different languages on the EUR-lex website.

Further information including services for health professionals and patients can be found at OrphaNet and Eurordis.  

European Legislation

European Regulation (EC) No 141/2000 on Orphan Drugs (available in multiple languages)
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.

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.


Biomedical Research in General 

Protection of Human Rights

The Oviedo Convention (Council of Europe).
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).
Comment: This Convention is the only international legally binding instrument on the protection of human rights in the biomedical field. It also deals specifically with biomedical research, genetics and transplantation of organ and tissues.
 

Compassionate Use 

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.

Sources:

(1) Article 83 of European Regulation 726/2004/EC

(2) EMA - Questions and answers on the compassionate use of medicines in the European Union

(3) Guideline on Compassionate Use of Medicinal Products, Pursuant to Article 83 of Regulation (EC) No 726/2004

(4) Trials Journal: Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries

 

Gene Transfer Medicinal Products

Miscellaneous

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


Useful Links

EUR-lex
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.

Council for International Organizations of Medical Science (CIOMS)

Wold Medical Association (WMA)

World Health Organisation (WHO) 

International Clinical Trials Registry Platform (ICTRP) of the World Health Organisation (WHO)



 

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