European Pharmacovigilance for Centrally

EUROPEAN PHARMACOVIGILANCE FOR CENTRALLY AUTHORISED MEDICINAL PRODUCTS – REGULATION (EC) NO. 726/2004

Articles 57(1)(c)–(f) of Regulation (EC) No. 726/2004 make the Agency and particularly its committees responsible for the co-ordination of the supervision of medicinal products which have been authorised within the Community and for providing advice on the measures necessary to ensure the safe and effec-tive use of these products. Title II Chapter 3 of Regulation (EC) No. 726/2004 deals specifically with pharmacovigilance relating to medicinal products for human use.

THE AGENCY

Article 22 requires the Agency to co-operate with the national pharmacovigilance systems, in order to receive all relevant information about suspected adverse reactions to authorised medicinal products. If necessary, the Agency’s CHMP will provide opinions on the measures necessary to ensure the safe and effec-tive use of particular medicinal products, which may include amendments to the marketing authorisation granted.

EudraVigilance is a central computer database created by the Agency in December 2001, and it contains reports of suspected serious adverse reactions to medicinal products that have been authorised by the Community. These reports are received from the vari-ous competent authorities and from the pharmaceuti-cal companies. This satisfies the Agency’s obligation under Article 57(1)(d) to ensure the dissemination of information on adverse reactions to medicinal prod-ucts authorised in the Community by means of a database permanently accessible to all Member States. In the future, health care professionals, marketing authorisation holder and the public will all have appro-priate levels of access to these databases. This is because the Agency believes that those groups could benefit from receiving feedback based on information in EudraVigilance and that this could help improve treatment and prevent side effects.

As of 1 May 2004, EudraVigilance can also be used for reporting side effects from clinical trials.

The Agency is also responsible for collabora-tion with the World Health Organisation (WHO) on matters of international pharmacovigilance, and must take any steps necessary to submit appropriate and adequate information promptly to the WHO regard-ing the measures taken in the EU which may have a bearing on public health protection in third countries (Article 27).

THE COMMISSION

The Commission’s obligations under Article 26 in relation to the publication of guidance are discussed above.

MARKETING AUTHORISATION HOLDERS

Article 22 requires marketing authorisation holders to ensure that all relevant information about suspected adverse reactions to centrally authorised products is brought to the attention of the Agency and also importantly states that patients should be encouraged to communicate any adverse reaction to health care professionals.

Article 24 requires holders of centralised market-ing authorisations to ensure that all suspected serious adverse reactions to one of their products occurring within the Community that are brought to their atten-tion by a health care professional, are recorded and reported to the Member States where the incidents have taken place within 15 days of receipt of the infor-mation. Marketing authorisation holders must also ensure that all suspected serious unexpected adverse reactions and any suspected transmissions through medicinal products of any infectious agents occurring in the territory of a third country are reported to the Agency and all the Member States within 15 days of receipt of the information.

As with holders of marketing authorisations granted under national or mutual recognition procedures, hold-ers of marketing authorisations for centrally autho-rised products are required to maintain detailed records of all suspected adverse reactions occurring within or outside the EU reported to them by health care professionals.

Subject to the specific terms of a marketing authori-sation, all suspected adverse reactions must be submit-ted to the competent authorities in the form of a PSUR (including a scientific evaluation of the risk/benefit balance):

·    immediately upon request or at least every 6 months after authorisation and until the placing on the market;

·    immediately upon request or at least every 6 months during the first 2 years following the initial placing on the market; and

·    once a year for the following 2 years.

After this period, the PSURs must be submitted at 3-yearly intervals or immediately upon request. There is a specific provision that states that a marketing authorisation holder may not communicate informa-tion relating to pharmacovigilance concerns to the general public without giving prior or simultaneous notification to the Agency. In any case, the marketing authorisation holder must ensure that all such infor-mation is presented objectively and is not misleading. If a marketing authorisation holder fails in this duty, the Member States are under an obligation to apply effective, proportionate and dissuasive penalties.

As can be seen, the considerations for a market-ing authorisation holder are effectively the same, whether the product is authorised centrally or nationally/mutually recognised.

QUALIFIED PERSON

Article 23 of Regulation (EC) No. 726/2004 is similar to Article 103 of Directive 2001/83/EC and requires holders of centralised marketing authorisations to have an appropriately qualified person, responsible for pharmacovigilance, permanently and continuously at their disposal. This qualified person shall reside in the Community (or EEA, according to Volume 9) and is responsible for:

• establishing and managing a system which ensures that information about all suspected adverse reac-tions, reported to people within the company and medical representatives, is collected, evaluated and collated so that it may be accessed at a single point within the EU;

• preparing the reports required of the marketing authorisation holder for the competent authorities and the Agency;

• ensuring a full and prompt response to any request from the competent authorities for additional infor-mation (including information about volume of sales or prescriptions) necessary for a risk/benefit evaluation of a medicinal product; and

• providing the competent authorities with any other relevant information about the benefits, and risks of a medicinal product, including information on post-authorisation safety studies.

MEMBER STATES

Article 22 requires the competent authorities of Member States to ensure that all relevant informa-tion about suspected adverse reactions to centrally authorised products are brought to the attention of the Agency. Where the suspected adverse reactions are classified as serious, Article 25 requires the Member States to record and report them to the Agency and the marketing authorisation holder within 15 days of receipt of the information.

CLINICAL TRIALS DIRECTIVE

In addition to the pharmacovigilance requirements for authorised medicines, Directive 2001/20/EC on the approximation of the laws, regulations and admini-strative 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 introduced reporting requirements for adverse events and serious adverse reactions that occur during clinical trials. Investigators are required to report all serious adverse events immediately to the sponsor, other than those that the protocol or investi-gator’s brochure identify as not requiring reporting. The sponsor shall keep detailed records of all adverse events that are reported to him by investigators, and these records shall be submitted to the Member States in whose territories the clinical trials are being conducted, if the Member States so request.

The sponsor shall ensure that all information related to suspected serious unexpected adverse reactions that are fatal or life threatening is recorded and reported as soon as possible to the competent authorities in all Member States concerned, and to the ethics commit-tee, no later than 7 days after the sponsor receives such information, and any relevant follow-up information should be communicated within an additional 8 days. Other suspected serious unexpected adverse reac-tions should be reported to the competent authorities concerned and to the ethics committee within 15 days of first knowledge of the sponsor. The sponsor shall also inform all investigators.

Once a year throughout the clinical trial, the sponsor should provide the Member States in whose territo-ries the clinical trials are being conducted, and the ethics committee, with a listing of all suspected seri-ous adverse reactions which have occurred over the period, and a report of the subjects’ safety. Member States shall ensure that all suspected unexpected seri-ous adverse reactions to investigational medicinal products are entered into a central database.