European Pharmacovigilance Legislation

EUROPEAN PHARMACOVIGILANCE LEGISLATION – MEMBER STATE IMPLEMENTATION

European Directives are not directly binding on Member States, but must be implemented nationally through domestic legislation. European Regulations have a direct effect on Member States, and no further procedural action is required for them to bind Member States.

UNITED KINGDOM

The European pharmacovigilance requirements have been implemented in the United Kingdom by the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994, as amended (the ‘1994 Regu-lations’) (see Appendix 6 at http://www.opsi.gov.uk). Schedule 3 of the 1994 Regulations creates certain criminal offences for non-compliance with European pharmacovigilance requirements. In addition, the Medicines for Human Use (clinical trials) Regulations 2004 (the ‘2004 Regulations’) (see Appendix 7 at http://www.opsi.gov.uk), which implemented Direc-tive 2001/20 relating to the implementation of good clinical practice in the conduct of clinical trials, imposes specific pharmacovigilance obligations on clinical trial investigators and sponsors in respect of reporting suspected unexpected serious adverse reac-tions arising in clinical trials. Regulation 49 of the 2004 Regulations makes it a criminal offence to fail to comply with those obligations.

The UK competent authority responsible for medicinal product pharmacovigilance is the Medicines and Healthcare products Regulatory Agency (‘MHRA’), an executive agency of the Department of Health.

The MHRA’s post-licensing division, together with the Commission on Human Medicines (‘CHM’),¹ runs the ‘Yellow Card’ scheme for the reporting of all suspected adverse drug reactions (the name of the scheme derives from the colour of the stan-dardised reporting forms, see Appendix 8 at http:// www.opsi.gov.uk). Voluntary reports are accepted by the MHRA/CHM from both health care profession-als and members of the public.² In addition, reports are received from marketing authorisation holders in accordance with their legal obligations.

For established products, the MHRA requests that health care professionals report only serious suspected adverse reactions. For newer products, for which relatively limited safety information will be avail-able, the MHRA/CHM encourages the reporting of all suspected adverse reactions. New products are identified with an inverted black triangle symbol ‘ ’ in the relevant professional publications and adver-tising material. In addition, the MHRA/CHM has a particular interest in adverse reactions in children and the elderly – delayed drug effects, congenital abnor-malities and herbal remedies.

In accordance with the requirements of the Data Protection Directive 95/46/EEC (as imple-mented in the United Kingdom by the Data Protec-tion Act 1998, as amended, see Appendix 9 at http://www.opsi.gov.uk) and with common law confi-dentiality requirements, personal details, such as the name and date of birth of a patient, are no longer requested for Yellow Cards completed by health care professionals. Instead, reporters include the patient’s age, sex and a reference number to enable identifi-cation of the particular report in any further corre-spondence. For Yellow Cards submitted by patients, personal details are requested so that the MHRA can get in contact with the person if more information is needed.

All reports are entered into the MHRA’s Adverse Drug Reactions On-Line Information Tracking (ADROIT) database. The MHRA evaluates the reports to assess the causal relationship between the drugs and reported reactions, and to identify possible risk factors contributing to the occurrence of the reactions. Marketing authorisation holders may subscribe to the MHRA’s ADROIT Electronically Generated Informa-tion Service (AEGIS), enabling electronic exchange of pharmacovigilance data.

On rare occasions, if the MHRA determines that the risks of a product outweigh its benefits, it may be necessary to withdraw the product from the market. Alternatively, and as is more usual, the MHRA may require that warnings be included in the product infor-mation or on the package label or that the indications for the use of the medicine be restricted.

The MHRA communicates with health care profes-sionals and patients to warn about adverse effects and to provide information. It sends doctors and phar-macists Current Problems in Pharmacovigilance, a bulletin providing alerts to problems identified with particular medicines. For urgent medicinal product hazard warnings, ‘Dear Health care Professional’ letters are sent to all doctors and pharmacists by post or electronic cascade. Fact sheets are also produced for both health care professionals and patients, and safety alerts are published on the MHRA’s website.

ITALY

The European pharmacovigilance requirements have been implemented in Italy by Legislative Decree n. 178 of 29 May 1991 and Legislative Decree n. 44 of 18 February 1997 which has been partially amended by legislative Decree n. 95 of 8 April 2003.

The Italian authority responsible for pharmacovigi-lance is the Department for the Evaluation of Medici-nal Products and Pharmacovigilance of the Agenzia Italiana del Farmaco (AIFA) (the ‘Italian Agency of Pharmaceuticals’).

The AIFA liaises with regional health authori-ties, with the national pharmacovigilance authori-ties of other Member States and with international institutions, such as the WHO. In accordance with European requirements, all pharmaceutical companies must appoint a ‘qualified person’ responsible for phar-macovigilance, on a continuous and permanent basis. Pharmaceutical companies must:

• maintain detailed records of all suspected adverse reactions that occurred in Italy, in the European Community or in any other third country;

• record and notify to the competent health authority and/or to the AIFA all suspected serious reactions that occurred in Italy and that were brought to their attention by health care professionals imme-diately and in any case within 15 days following the receipt of the information;

• ensure that all serious and unexpected adverse reactions that occurred in a third country and were brought to their attention by a health care profes-sional are reported to the AIFA immediately and in any case not later than 15 days following receipt of relevant information;

• report to the AIFA any suspected serious adverse reaction that occurred in the European Commu-nity, when the medical products were authorised according to the mutual recognition procedure and for which Italy acts as the Reference State.

Doctors and health care professionals shall submit all suspected adverse reactions of which they are informed immediately to the person responsible for pharmacovigilance in the health institution to which they belong, who in turn shall transmit electronically, immediately and in any case not later than 7 days from receipt of the information, the above information to both the holder of the marketing authorisation and to the AIFA. Health care professionals must notify any and all suspected adverse reactions (seri-ous, not serious, expected and unexpected) to vaccines and medicines that are under intensive control and included in lists published periodically by the AIFA.

Public health institutions and scientific institutions shall appoint a person responsible for pharmacovigi-lance, who must take care of the connection to and registration with the national electronic system for the management of pharmacovigilance issues. Private clinics satisfy their pharmacovigilance obligations through the individual responsible for pharmacovigi-lance at the public institution.

Adverse event reports are submitted online. Regis-tration on the national electronic system takes place through a very simple procedure laid down by the AIFA itself. The reporting form is in Appendix 10 (http://www.opsi.gov.uk).

The Decree n. 95/2005 abolishes the criminal sanc-tions that were provided for violations of the obliga-tion to notify medicinal adverse reactions by doctors, pharmacists and health care professionals and intro-duces higher administrative sanctions against phar-maceutical companies that do not comply with the law relating to the registration and notification of serious and adverse reactions. Moreover, the decree also provides for disciplinary sanctions against health care professionals at public health institutions.

In case of violation of the pharmacovigilance obli-gations set out above, the following sanctions may be applied:

·    a fine from E30 000 to E18 000 may be levied against the holder of the marketing authorisation. This amount is increased by an amount between 0.1% and 1% of the revenue generated by the sale of the product to which the information relates;

·     a fine from E20 000 to E120 000 levied against the person responsible for pharmacovigilance at the holder of the marketing authorisation; and the submission of the person responsible for phar-macovigilance at the public institutions to disci-plinary proceedings, according to law.

FRANCE

The European pharmacovigilance requirements have been implemented into French law by a Decree n. 95–278 of 13 March 1995. This decree was later amended by the Decrees n. 99–144 of 4 March 1999 and n. 2004–99 of 29 January 2004. The relevant provisions regarding pharmacovigilance are now codi-fied in Articles R.5121-150 et seq. of the French Public Health Code. In addition, on 28 April 2005, the Health Ministry published guidelines for good appli-cation of pharmacovigilance rules (‘Bonnes Pratiques de Pharmacovigilance’).

The competent authorities responsible for pharmacovigilance are the French Agency for the Sanitary Safety of Health Products (‘AFSS-APS’), the National Pharmacovigilance Commission (‘Commission Nationale de Pharmacovigilance’), the Technical Committee (‘Comité Technique’) and, at a regional scale, the regional pharmacovigilance centres (there are 31 centres).

The French Public Health Code provides for report-ing obligations on health care professionals. In particular, it requires medical doctors, dental surgeons and midwives to report any serious or unexpected adverse reactions in relation to a medicinal product, whether or not they have actually prescribed the product. Pharmacists are also obliged to report seri-ous or unexpected adverse reactions relating to the products they have dispensed. Reports are filed in a prescribed form at the nearest regional centre, which forwards the data to the AFSSAPS (see Appendix 11 at http://www.opsi.gov.uk). Voluntary reporting of adverse reactions which are not serious or unexpected may also be filed at the nearest regional centre. The Technical Committee is responsible for co-ordinating and evaluating the data provided by regional centres. Regional centres are obliged to forward information relating to serious adverse reactions to the AFSSAPS directly.

Reporting obligations are also imposed on compa-nies pursuant to the provisions of Article R.5121-178 of the French Public Health Code. In particular, pharmaceutical companies are required to appoint a qualified person responsible for pharmacovigilance (‘responsable de pharmacovigilance’), whose func-tion is to report every serious adverse reaction to the AFSSAPS.

Pursuant to the provisions of Article R.5121-171 of the French Public Health Code, any company which markets a medicinal product is required to record and report all suspected serious adverse reactions which are brought to its attention by a health care profes-sional or of which it can reasonably be expected to have knowledge. It must also report any serious and unexpected adverse reaction occurring in the territory of a third country which is brought to its attention.

GERMANY

The EU pharmacovigilance requirements have been implemented in the German Drug Act (Arzneimit-telgesetz, AMG). All individuals or businesses involved in the marketing of medicinal products, including manufacturers, wholesalers, physicians and pharmacists, are bound by an ongoing pharmacovigi-lance duty to ensure that no unsafe drugs enter the market (s. 5(1) AMG).

According to the legal definition, a drug is to be considered ‘unsafe’ if the current state of scien-tific knowledge suggests and gives rise to reasonable concerns that the adverse side effects of the properly applied drug outweigh its benefits (s. 5(2) AMG). This ban on the marketing of (purportedly) unsafe drugs applies irrespective of whether a marketing authorisa-tion for the product concerned has been granted but not yet revoked. Possible legal sanctions for viola-tions of this duty can be severe, with fines and terms of imprisonment of up to 3 years or 1 year in the case of simple negligence. In particularly severe cases, for example, if the conduct has endangered the health of a vast number of individuals this may lead to up to 10 years of imprisonment (s. 95 AMG).

The holder of a German national marketing authori-sation must report any serious adverse reactions within 15 days of learning of the effects to the competent German authority. This is generally the Federal Insti-tute for Medicinal Products and Medical Devices, ‘Bundesinstitut für Arzneimittel und Medizinprodukte’ (BfArM) unless either the Federal Agency for Sera and Vaccines, ‘Paul Ehrlich Institut’ (PEI), or the Federal Agency for Health Protection of Consumers and Veterinary Medicine is competent in the area of that product (s. 77 AMG).

The applicant must also make all related documen-tation available together with a scientific evaluation of the adverse reactions (s. 29(1) AMG). All adverse reactions, other than serious ones, must be recorded and reported at regular intervals. The reporting forms are in Appendix 12 (http://www.opsi.gov.uk).

Both BfArM and the district governments of the German states are vested with far-reaching powers to protect public health against hazards resulting from medicinal products by imposing certain restrictions on a medicinal product and/or withdrawing the pro-duct from the market. BfArM may restrict, suspend or revoke the marketing authorisation of the drug in question (s. 69 AMG), whereas the state authorities have competence for all other issues. As always in German public law, each acting authority must estab-lish that the measure taken is appropriate and reason-able under the particular circumstances of the case.

In cases where practical experience or scientific research leads to a new risk-benefit assessment of medicinal products on the market, BfArM may order a so-called Phased Plan Procedure (PPP, Stufenplan-verfahren; ss 62 and 63 AMG). The goal of the PPP is to arrive at an amicable solution for addressing and responding to health risks which come to light after the medicinal product concerned has been approved for circulation on the market.

If the available data and information support reason-able concerns that a certain drug is creating a health hazard, the competent authority must initiate the by calling meetings where all parties concerned (including the manufacturers) are represented and can put forward their arguments. If no consensus can be reached or if the majority recommendations are not voluntarily complied with, the authority may revert to its general supervisory powers and impose the above-mentioned measures, including informing the public of health hazards caused by certain medicinal products.

Each pharmaceutical company is legally obliged to appoint a PPP Officer (‘Stufenplanbeauftragter’, s. 63a AMG), whose duty is to comply with the reporting requirements of the AMG and to co-ordinate and implement pharmacovigilance activities within the company.