Guideline on the definition of a potential serious risk to human or animal health or for the environment in the context of Article 33(1) and (2) of Directive 2001/82/EC — March 2006
Date: 2006-06-07
Institutions: European Commission
Subjects: animal health, environmental protection, health risk, marketing, pharmaceutical legislation, public health, veterinary drug

C 132/32

EN

Official Journal of the European Union

7.6.2006

Guideline on the definition of a potential serious risk to human or animal health or for the en-
vironment in the context of Article 33(1) and (2) of Directive 2001/82/EC — March 2006

(2006/C 132/08)

1. INTRODUCTION

Based on Article 33(2) of Directive 2001/82/EC as amended (1) the scope of this guideline is to set out in
more detail in which exceptional cases a Member State concerned in a mutual recognition procedure as
referred to in Article 32(2) or in a decentralised procedure as referred to in Article 32(3) can refuse to
recognise a marketing authorisation or a positive assessment on the basis of a potential serious risk to
human or animal health or for the environment.

In the case that at least one of the Member States (2) concerned by the application cannot approve the
assessment report, the summary of product characteristics, the labelling and the package leaflet on the
grounds of a potential serious risk to human or animal health or for the environment, as set out in Article
33(1) of Directive 2001/82/EC, when requested to mutually recognise a marketing authorisation granted
by another Member State, it shall give a detailed explanation of the reasons for its position to the reference
Member State, to the other Member States concerned and to the applicant.

As the same pharmaceutical legislation forms the basis for the authorisation process in all Member States
and as all Member States have the same legal standards for quality, safety and efficacy, an authorisation
granted in one Member State should generally be recognized amongst Member States.

In the mutual recognition procedure, according to Article 32(2) of Directive 2001/82/EC, 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, the quality, safety and efficacy of the
product is sufficiently guaranteed and nor other or further reasons for refusal of the marketing authorisa-
tion according to Article 30 of Directive 2001/82/EC is given. 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 the risk-benefit balance is considered to be favourable, together with the
approved summary of product characteristics, labelling and package leaflet.

In the decentralised procedure, according to Article 32(3) of Directive 2001/82/EC, 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 product characteristics, package leaflet and labelling.

Article 33(1) of Directive 2001/82/EC describes the procedure to be followed if a concerned Member State
cannot approve the assessment report, summary of product characteristics, package leaflet and labelling as
prepared by the reference Member State. In Article 33(1) reference is made to Article 32(4), which in turn
refers to Article 32(2) and (3). These Articles 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, the summary of product characteristics, the package leaflet
and labelling from the reference Member State in a mutual recognition procedure or a draft assessment
report, a draft summary of product characteristics and a draft of the labelling and package leaflet in a
decentralised procedure.

The scope of this guideline is to define in which exceptional cases a concerned Member State can refuse to
recognise a marketing authorisation in a mutual recognition procedure, or a draft assessment report, a
draft summary of product characteristics and a draft of the labelling and package leaflet from the reference
Member State in a decentralised procedure on the basis of a potential serious risk to human or animal
health or for the environment. As a consequence this should also limit the variety and number of objec-
tions raised by Member States, which has been considered as one of the main obstacles to the attractiveness
and efficient functioning of the veterinary mutual recognition procedure.

(1) Amended by Directive 2004/28/EC; OJ L 136 30.4.2004, p. 58.
(2) Member States in this context refers to all countries of the European Economic Area

7.6.2006

EN

Official Journal of the European Union

C 132/33

Additionally, a concerned Member State has to provide a detailed and substantiated justification when
raising objections based on a potential serious risk to human or animal health or for the environment
taking into account the following definitions.

In this context, it should be considered that a Member State plays a different role when it is called upon to
approve the evaluation report, the summary of product characteristics, the labelling and package leaflet for
a veterinary medicinal product submitted to it by the reference Member State and the role that it plays
when it is the only one to issue a national marketing authorisation for a veterinary medicinal product that
has not yet been the subject of an application for authorisation in another Member State of the Com-
munity, or when it is itself the reference Member State.

In the latter case, the Member State is fully competent to determine the content of the marketing authorisa-
tion for the veterinary medicinal product in accordance with Directive 2001/82/EC. In the first case by
contrast, the authorisation/evaluation by the reference Member State should normally be recognised, so
that the role of the concerned Member States is not to decide whether or not the authorisation/evaluation
can be improved, but rather to establish clearly and in a well-argued fashion why the proposed decision on
authorisation/evaluation presents a potential serious risk to human or animal health or for the environ-
ment.

2. DEFINITION OF POTENTIAL SERIOUS RISK

A ‘risk’ is generally defined as the product of the size of a hazard and the probability of the hazard occur-
ring. The term ‘risk’ relating to the use of a veterinary medicinal product is further defined in Article 1(19)
of Directive 2001/82/EC as ‘any risk relating to the quality, safety or efficacy of the veterinary medicinal
product as regards animal or human health as well as any risk of undesirable effects on the environment’.
This definition is complemented by Article 1(20) of that Directive defining a risk/benefit balance as an
evaluation of the positive therapeutic effects of the veterinary medicinal product in relation to the risks as
defined in Article 1(19).

Directive 2001/82/EC does not provide a definition of a ‘potential serious risk to human or animal health
or for the environment’ but empowers the Commission to do so. Hence, the following definition shall
apply:

A ‘potential serious risk to human or animal health or for the environment’ is defined as a situation
where there is a significant probability that a serious hazard resulting from the use of a veterinary medic-
inal product will affect human or animal health or the environment and cannot be prevented, reversed or
avoided.

‘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 or animals, or which could realistically
cause these effects where the product enters the environment.

An isolated assessment of a ‘potential serious risk to human or animal health or for the environment’
cannot be made but has to take into account the positive therapeutic effects of the veterinary medicinal
product in question. Consequently, the term ‘potential serious risk to human or animal health or for the
environment’ as used in Article 33(2) of Directive 2001/82/EC has to be interpreted as relating to the
overall risk/benefit assessment of the veterinary medicinal product, taking into consideration the nature of
the identified risk(s) to human or animal health or for the environment and the potential benefit of the
proposed indication(s) for the target species.

To justify a potential serious risk to human or animal health or for the environment, it is not sufficient to
only refer to one of the situations mentioned in the following sections. It is necessary to demonstrate for
each individual case on the basis of a detailed and scientific justification that a potential serious risk as
defined generally is posed.

C 132/34

EN

Official Journal of the European Union

7.6.2006

2.1. Potential serious risk to human health

2.1.1. Potential serious risk for the consumer

The consumer of animal products should not be exposed to an undue and avoidable risk when consuming
foodstuffs of animal origin. In order to ensure consumer safety an assessment of the safety of residues of
all pharmacologically active substances contained in veterinary medicinal products for food-producing
animals in accordance with Council Regulation (EEC) No 2377/90, has to be carried out. This evaluation is
based on the determination of the Acceptable Daily Intake (1) (ADI) on which Maximum Residue Limits (2)
(MRLs) are subsequently based.

A potential serious risk to the consumer exists only if the withdrawal period (3), determined from the
results of suitable residue depletion studies for a veterinary medicinal product, does not provide a sufficient
degree of assurance that the concentrations of residues in foods derived from treated animals (meat, milk,
eggs and honey) are not above the permitted concentrations causing a possible exceeding of the Maximum
Residue Limits.

2.1.2. Potential serious risk for the user

A potential major hazard to human health (non-professional and professional user) must be regarded as
serious and the probability of it occurring in practice, following risk management measures, must be
minimal. Major effects (hazards) can only be tolerated if the devices and methods of administration as well
as the conditions for use, described in the summary of product characteristics of the veterinary medicinal
product, reduce the risk for human health to an acceptable level in relation to the expected beneficial effect
for the animal.

A potential serious risk for the user exists only if the extent to which the exposure of the user can be
reduced by a precautionary measure, alone or in combination with other protective methods, is not suffi-
cient to reduce the risk to an acceptable level (4).

2.2. Potential serious risk to animal health

A potential serious risk to animal health in relation to a specific veterinary 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 species
and proposed dosing regimen (as defined by proposed labelling), do not provide a sound scientific justi-
fication for the claims for efficacy or if adequate proof for bioequivalence demonstrated by generic
veterinary medicinal products to the reference veterinary medicinal product is lacking.

— Safety: the evaluation of the preclinical toxicity/safety pharmacology, clinical safety data and post-
marketing data does not provide adequate support for the conclusion that all potential safety issues for
the target species have been appropriately and adequately addressed in the proposed labelling or the
absolute level of risk from the medicinal product, in the context of its proposed use, is considered unac-
ceptable.

— Quality: the proposed production and quality control methods cannot guarantee that a major defi-

ciency in the quality of the product will not occur

(1) Acceptable Daily Intake (ADI): the estimate of the residue, expressed in terms of micrograms or milligrams per
kilogram of bodyweight, that can be ingested daily over a lifetime without any appreciable health risk (Volume 8:
Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products in foodstuffs of
animal origin http://pharmacos.eudra.org).

(2) Maximum Residue Limits (MRLs): the maximum concentration of residue resulting from the use of a veterinary
medicinal product (expressed in mg/kg or mg/kg on a fresh weight basis) which may be accepted by the Community
to be legally permitted or recognised as acceptable in or on a food as laid down in Council Regulation (EEC) No
2377/90 (http://pharmacos.eudra.org).

(3) Withdrawal period (as defined in Article 1 point 9 of Directive 2001/82/EC, as amended): the period necessary
between the last administration of a veterinary medicinal product to animals, under normal conditions of use and in
accordance with the provisions of the Directive, and the production of foodstuffs from such animals, in order to
protect public health by ensuring that such foodstuffs do not contain residues in quantities in excess of the
maximum residue limits for active substances laid down pursuant to Regulation (EEC) No 2377/90 (http://pharmaco-
s.eudra.org)

(4) CVMP Guideline on User Safety for Pharmaceutical Veterinary Medicinal Products (EMEA/CVMP/543/03-FINAL

http://www.emea.eu.int)

7.6.2006

EN

Official Journal of the European Union

C 132/35

— 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 species

— Product Information: a potential serious risk exists if information for the professional and non-profes-

sional user is insufficient to guarantee a suitable and safe use of the product in the animal

2.3. Potential serious risk for the environment

Applicants are required to submit a complete report which concludes with an Environmental Impact
Assessment (EIA) based on the characteristics of the product, its potential environmental exposure, envir-
onmental fate and effects as well as risk management strategies as appropriate. The report should take into
account the pattern of use, the administration of the product, the excretion of active substance and major
active metabolites as well as the disposal of the product.

Following the risk assessment as outlined in international agreed guideline (1) a potential serious risk for
the environment exists if:

— a major risk for one or more of the environmental compartments (e.g. air, water, soil) is identified,
taking into account different environmental conditions (e.g. climate, geo-hydrology) in the Member
States

— and it (they) cannot be mitigated by any risk management strategies ensuring that no unacceptable risk

is associated with the use and disposal of this product

Generally, any major objection must be scientifically justified taking into account the nature and degree of
any hazards, the magnitude of the risks involved, the benefits associated with the use of those veterinary
medicinal products, and the feasibility and practicability of implementing any measures that mitigate the
risks. The Member State intending to refuse the application for marketing authorisation for the veterinary
medicinal product should be prepared to support its grounds within the context of a coordination group
procedure and if failed in an arbitration procedure. This would also cover any existing knowledge of the
substance and specific risks in the concerned Member State which are not outlined in the dossier of the
veterinary medicinal product or the assessment report of the reference Member State and which are not
included in the summary of product characteristics during the mutual recognition or decentralised proce-
dure.

Member States have accepted common rules and guidelines relating to manufacturing, quality control,
evaluation of veterinary medicinal product efficacy, evaluation of its safety and quality assurance and label-
ling. These scientific guidelines give guidance for the evaluation of an application in general. However,
different interpretations cannot be excluded on a specific set of data. It has to be recognised that in these
circumstances a lack of compliance with scientific guidelines may not automatically result in a potential
serious risk to human or animal health or for the environment unless they fulfil the conditions as described
in section 2 of this guideline.

Any objection on the ground of a potential serious risk to human or animal health or for the environment
cannot be justified by differences in national administrative or national scientific requirements or internal
national policies, unless the conditions of Article 33(1) of Directive 2001/82/EC are fulfilled.

DG Enterprise and Industry will publish a list of examples related to the above definitions of issues which
normally would not be considered as grounds for a ‘Potential Serious Risk to Human or Animal Health or
for the Environment’. This list will be updated based on experience gained with the decentralised and
mutual recognition procedures

(1) CVMP Note for Guidance: Environmental Risk Assessment for Veterinary Medicinal Products other than GMO
Containing and Immunological Products (EMEA/CVMP/055/96-FINAL) Guidelines on environmental impact assess-
ment (EIAS) for veterinary medicinal products – phase I and II (CVMP/VICH/592/98-FINAL; CVMP/VICH/790/03-
FINAL http://www.emea.eu.int)