European Pharmacovigilance for Centrally Authorised Medicinal Products – Regulation (EC) No. 726/2004
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.
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’s obligations under Article 26 in relation to the publication of
guidance are discussed above.
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.
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.
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.
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.
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