EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL
Consumer goods
Pharmaceuticals
Brussels/DG ENTR
Proposal for a
Guideline on the definition of a potential serious risk to
public health
February 2005
Discussion in MRFG
Contribution EFPIA, EGA, AESGP
Commission Draft
Date of implementation
February – July 2004
April-October 2004
February 2005
November 2005
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1. Introduction
Based on Article 29 (2) of Directive 2001/83/EC as amended the scope of this guideline is to
set out in more detail in which exceptional cases the Member State concerned can refuse to
recognise a marketing authorisation/assessment on the basis of a potential serious risk to
public health.
Member States can raise grounds that a medicinal product for human use presents a serious
risk to public health when requested to mutually recognise a marketing authorisation granted
by another Member State. If a Member State does not, it has to give a detailed explanation of
the reasons for its position in order to ensure that they do not act as an indirect and artificial
hindrance to the free movement of goods.
A thorough evaluation of the operation of marketing authorisation procedures has led to an indepth revision of the Mutual Recognition Procedure in order to improve the opportunities for
cooperation between Member States. The cooperation is aiming at supporting the principle of
full (“real”) mutual recognition, promoting an efficient use of regulatory resources and
consequently eliminating remaining obstacles to the free movement of safe medicinal
products for human use in the Community.
As the same pharmaceutical legislation forms the basis for the authorisation process of a
medicinal product in all Member States and as all Member States have the same legal
standards for quality, safety and efficacy, the Marketing Authorisation should generally be
recognized amongst the Member States.
In the Mutual Recognition Procedure, according to Article 28(2) of Directive 2001/83/EC as
amended, the reference Member State will assess the data in the dossier and issue a national
marketing authorisation provided the risk-benefit balance of the product is considered to be
favourable and the quality of the product is sufficiently guaranteed. For the process of mutual
recognition the reference Member State has to provide an assessment report that is sufficiently
detailed to explain to the Member State concerned why this risk-benefit balance is considered
to be favourable. In the decentralised procedure, according to Article 28(3) of Directive
2001/83/EC as amended, no prior national procedure is intended and no existing marketing
authorisation is in place at that time. After receipt of a valid application it is the duty of the
Reference Member State to prepare within 120 days a draft Assessment Report together with
the draft Summary of Products Characteristics, Package leaflet and labelling.
Article 29(1) of Directive 2001/83/EC describes the procedure to be followed if a concerned
Member State cannot agree to the documents as prepared by the reference Member State. In
Article 29 reference is made to Article 28(4), which in turn refers to paragraphs 2 and 3.
These paragraphs concern both Mutual Recognition Procedure and decentralised procedure.
Consequently, the grounds for refusal are the same irrespective of whether the concerned
Member State evaluates an Assessment Report, Summary of Products Characteristics,
Package leaflet and labelling from the reference Member State in a Mutual Recognition
Procedure, or a draft Assessment Report, Summary of Products Characteristics, Package
leaflet and labelling from the reference Member State in a decentralised procedure.
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By defining in which exceptional cases the concerned Member State can refuse to recognise a
marketing authorisation on the basis of a potential serious risk to public health this will also
concurrently limit the variety and number of objections raised by Member States.
A concerned Member State raising objections has to provide a detailed and substantiated
justification when based on a potential serious risk to public health.
2. Definition of potential serious risk to public health
The term “risk” relates to the use of a medicinal product and is defined in Article 1 (28, first
indent) of Directive 2001/83/EC as ‘any risk relating to the quality, safety or efficacy of the
medicinal product as regards to patients’ health or public health’ and in Article 1 (28a) ‘an
evaluation of the positive therapeutic effects of the medicinal product in relation to the risks
as defined in point 28, first indent’.
A risk is defined as the product of the size of a hazard and the probability of the hazard
occurring. A ”potential serious risk to public health” is where there is a high probability that a
serious hazard could result in severe negative effects with regard to the use of the human
medicinal product that cannot be prevented, reversed or avoided. The assessment process does
identify the potential to cause harm to public health and that it will actually be expressed in
practice.
“Serious” in this context means a hazard that could result in death, could be life-threatening,
could result in significant disability or incapacity, could be a congenital anomaly/birth defect,
or which could result in hospitalisation or permanent or prolonged signs in exposed humans.
A serious risk to public health in relation to a specific medicinal product can mainly be
considered to exist under the following circumstances:
• Efficacy: the data submitted to support therapeutic efficacy in the proposed
indication(s), target population(s), and proposed dosing regimen (as defined by
proposed labelling), do not provide adequate scientific justification for the claims for
efficacy
• Safety: evaluation of the preclinical toxicity/safety pharmacology and clinical safety
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 or the absolute level of risk from the product is considered
unacceptable.
• Quality: the proposed production and quality control methods cannot guarantee that a
major deficiency in the quality of the product will not occur, that might have a
negative impact on the safety or efficacy of the product
• Overall risk-benefit: the risk-benefit 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)
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• Product Information: information for prescribers and patients could result in serious
harm to public health.
Examples of issues related to the above categories which would not be considered as grounds
for a serious risk to public health are set out in the Annex.
3. Conclusion
The assessment of an application of a human medicinal product by a Member State should
carefully cover all essential risk-benefit aspects based on a complete and correct set of data
presented in the dossier. Therefore, only a very limited number of exceptional cases should
arise where the concerned Member State can refuse the product during the process of mutual
recognition.
Any objection must be scientifically justified. Its consistency should be demonstrated with
reference to current relevant legislation. The Member State concerned raising the concern
should be prepared to support its grounds within the context of an arbitration procedure. This
would also cover any existing knowledge of the substance and specific risks in the Member
State concerned which are not outlined in the dossier of the medicinal product or the
Assessment Report of the reference Member State and which are not included in the
Summary of Products Characteristics during the Mutual Recognition Procedure or
decentralised procedure.
The withdrawal of the application by the applicant will not prevent a referral procedure if
Member States consider that the medicinal product presents a potential serious risk to public
health.
Member States have accepted common rules and guidelines relating to manufacturing, quality
control, labelling, evaluation of medicinal product efficacy, evaluation of medicinal product
safety and quality assurance. Therefore, no serious risk to public health should be raised
without providing actual proof of discrepancy with official rules relating to efficacy, safety,
quality or labelling. Since the labelling and the package leaflet are now part of the Mutual
Recognition Procedure and decentralised procedure, it is essential that agreement is reached
by the Member State concerned during the procedure.
It has to be recognised that a lack of compliance with current Guidelines does not
automatically result in a serious risk to public health, as this is based on the evaluation of
safety, quality and efficacy.
Any objection linked to national administrative medical practices, or national scientific
requirements, going beyond the framework of rules governing medicinal products in the
European Union, cannot justify a potential serious risk in the sense of this guideline.
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Annex
Examples of issues which would not be considered as grounds for a Serious Risk to
Public Health
Efficacy:
• The absence of an active comparator study versus a specific medicinal product
• The absence of clinical trials in non-target populations: the elderly
• The absence of evidence demonstrating added therapeutic value of the new medicine in
comparison to existing medicines
• The length of the treatment various according to national medical practices in the
various Member States
Safety:
• The targeted population is too narrow, and should include patients who are allergic or
intolerant to medicinal products approved for the same indications
• A Member State requires a special interaction study with a medicinal product that is
not usually prescribed or used together with the new medicinal product
Quality:
• The requirement to use alternative analytical methods if the methods proposed in the
documentation have demonstrated their suitability
• The requirement to use complementary analytical tests if these tests do not provide any
additional results in terms of product safety
• The request for physico-chemical parameters testing for in-use stability data which are
not relevant to the pharmaceutical form of the product
• The request to tighten the limits of the active ingredient for the shelf-life specification of
the finished product
Overall risk-benefit:
• Issues not related to the scientific requirements to demonstrate efficacy, safety and/or
quality (e.g. issues related to pricing and reimbursement)
• For products with well-established medicinal use the posology is based on “systematic
and documented use” and the safety is based on pharmacovigilance data
• Reference to a Note for Guidance that is still a draft version
Product Information:
• The claimed indication cannot be granted because this would trigger the need of
harmonising Summary of Products Characteristics of the other products approved at a
national level
• The absence of a contra-indication for a non-target population (children, elderly,
patients with renal or hepatic insufficiency). According to the Summary of Products
Characteristics guideline, these populations should be mentioned in Section 4.4 of the
Summary of Products Characteristics (Special warnings and precautions for use)
• The absence of contra-indications from other medicinal products of the same class, if
the scientific data provided in the documentation gives no reason to believe that the
same contra-indications apply to the new medicine
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