Risk-to-benefit assessment is a complex challenge. It is not only restricted to mere safety data, i.e. number of single case reports, incidences or odds ratios.
RISK-ASSESSMENT PROCEDURES
Risk-to-benefit
assessment is a complex challenge. It is not only restricted to mere safety
data, i.e. number of single case reports, incidences or odds ratios. In the
process of assessment and preparation of a decision, other aspects must be
regarded and considered as well. Therefore, other opinions and views on the
problem perhaps from people outside the agency’s pharma-covigilance unit should
be requested and reflected.
The
pharmacovigilance unit meets regularly once a month with representatives from
BfArM’s licens-ing units to exchange information on new safety issues, ongoing
risk-to-benefit assessments, internal and external decisions, e.g. from the
Committee for Medicinal Products for Human Use’s (CHMP) Phar-macovigilance
Working Party. These meetings allow the co-ordination of actions and procedures
within the agency. This is important because, for instance, there may be
licensing applications under discussion with substances that are under review
because of new safety information. Such meetings also are held with
representatives from the herbal products department, the narcotics department
and the legal or pharmaceu-tical administrative departments.
In
general, BfArM and PEI may take regulatory deci-sions according to four main
types of procedures. Type 1 is the Urgent Safety Restriction that leads to an
immediate change of the licence followed by a Type II Variation procedure
according to EU Regula-tions 1084/2003/EC or 1085/2003/EC. Type 2 is one of the
formal referrals according to Article 31 or 36 of Directive 2001/83/EC as
amended or Article 20 of Regulation 726/2004/EC, irrespective of whether
rapporteurship has been given to one of the two agen-cies or not. Type 3 may be
a class review outside a formal European referral resulting in changes of the
Summary of Product Characteristics (SmPC) or Patient Information Leaflet (PIL)
or establishing risk-management plans. Type 4 is a purely national risk
assessment that is not extended to other Member States because of lacking
community interest. What-ever procedure is chosen or started, BfArM or PEI
initiate a formal national procedure, the so-called ‘Two-Step Procedure’ that
helps to exchange informa-tion with the stakeholders, to implement once agreed
regulatory actions, and to communicate.
Once
a safety issue has been identified and action for minimising the risk is
considered necessary, the principal type of actions, the scope of the
regulatory action, i.e. which drugs are included, and the informa-tion from
relevant data sources available (preclinical data, clinical data and
post-licensing experiences) are compiled. A team including in-house experts in
the field drafts a list of questions to the MAHs (all who hold a licence with
the substance under review). This normally relates to active substances, but might
even concern an excipient or group of excipients, or appli-cation forms or
modes of application. The request to the MAHs explains why the agency has, on
the basis of new data or information, concerns whether the risk-to-benefit
balance is still acceptable (step one of the Two-Step Procedure). The MAHs have
to submit all relevant data requested but have also the opportunity to comment
on the concerns and the proposed regu-latory action, to submit supportive or
divergent data and to propose voluntary action for minimising the risk. The
time frame for responses should be adequate and depends on the severity and
urgency of the issue.
The
MAH’s response is evaluated and presented in an agency’s pharmacovigilance
meeting. The agreed regulatory actions are ordered formally to the MAHs, and
detailed reasons are given (step two). In princi-pal, the MAHs have the right
to appeal against the decision, however, an appeal cannot lift the decision
unless there are exceptional circumstances.
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