5. EU Regulatory procedures for a marketing authorisation (MA)

Objections to recognition in the MRP and DCP can only be raised on the grounds of potential serious risk to public health. The issue, if not resolved between CMS, RMS and applicant, will be referred to the coordination group (CMD(h)) where within 60 days, MSs shall reach a consensus. In case this fails, the procedure is submitted to the EMA scientific committee (CHMP) for arbitration.

In the case that at least one of the concerned Member States objects to approve the assessment report or acknowledge the MA of the RMS on the grounds of a potential serious risk to public health, it shall give a detailed explanation of the reasons for its position to the RMS, to the other CMSs and to the applicant.

Based on Article 29 (2) of Directive 2001/83/EC as amended, a guideline has been adopted to set out in more detail in which exceptional cases a Member State concerned in a mutual recognition procedure or in a decentralised procedure can refuse to recognise a marketing authorisation or a positive assessment on the basis of a potential serious risk to public health.

In the following, this guideline (adapted)will be used to describe what can be considered a serious risk to public health and therefore would constitute the basis for a concerned Member State to raise major objections and to establish clearly and substantiated why the proposed authorisation (or refusal) should not be accepted.

Excerpt from: ‘Guideline on the definition of a potential serious risk to public health in the context of Article 29 (1) and (2) of Directive 2001/83/EC — March 2006 (2006/C 133/05):

Directive 2001/83/EC does not provide for a definition of a ‘potential serious risk to public health’. However, the following definitions are given in that Directive:

- The term ‘risk related to the use of the medicine’ is defined in point 28 of Article 1, first indent of Directive 2001/83/EC as ‘any risk relating to the quality, safety or efficacy of the medicine as regards to patients' health or public health’ (or any risk of undesirable effects on the environment).

- The term ‘risk-benefit balance’ is defined in point 28a of Article 1 of that Directive as ‘an evaluation of the positive therapeutic effects of the medicine in relation to the risks as defined in point 28, first indent’.

For the application of this guideline, the following definitions shall apply:

- A ‘risk’ is defined as the probability that an event will occur.

- A ‘potential serious risk to public health’ is defined as a situation where there is a significant probability that a serious hazard resulting from a human medicine in the context of its proposed use will affect public health.

- ‘Serious’ in this context means a hazard that could result in death, could be life-threatening, could result in patient hospitalisation or prolongation of existing hospitalisation, could result in persistent or significant disability or incapacity, or could be a congenital anomaly/birth defect or permanent or prolonged signs in exposed humans.

1. Potential serious risk to public health

The assessment of a potential serious risk to public health cannot be made in isolation but has to take into account the positive therapeutic effects of the medicine in question. Consequently, the term potential serious risk to public health as used in Article 29(1) of Directive 2001/83/EC has to be understood as relating to the overall benefit-risk assessment of the medicine.

Any major objection must be scientifically justified and consider the nature and degree of any hazards, the magnitude of the risks involved, the benefits associated with the use of the product and the feasibility and practicality of the implementation of any measures to mitigate the risks.

A potential serious risk to public health in relation to a particular medicine may mainly exist under the following circumstances:

1. Efficacy:

• • The data submitted to support therapeutic efficacy do not provide sound scientific justification for the claims for efficacy.
  • Adequate proof for bioequivalence demonstrated by generic medicines to the reference medicine is lacking.

2. Safety:

• • The evaluation of the non-clinical and clinical safety data and post-marketing data does not provide adequate support for the conclusion that all potential safety issues for the target population have been appropriately and adequately addressed in the proposed labelling.
  • The absolute level of risk from the medicine, in the context of its proposed use, is considered unacceptable.

3. Quality:

• • The proposed production and quality control methods cannot guarantee that a major deficiency in the quality of the product will not occur.

4. Overall benefit-risk:

• • The benefit-risk balance for the product is not considered to be favourable, taking into account the nature of the identified risk (s) and the potential benefit in the proposed indication (s) and target patient population (s).

5. Product Information:

• • The information is misleading or incorrect for either the prescribers or the patients to ensure the safe use of the medicine.

Any objection on the ground of a potential serious risk to public health cannot be justified by differences in national administrative or national scientific requirements, or internal national policies, unless the conditions above or Article 29(1) of Directive 2001/83/EC are fulfilled.

Legal basis:  Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC.