Risk-Assessment Procedures

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Chapter: Pharmacovigilance: Spontaneous Reporting in Germany

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-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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