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7.3 Authorisation of Clinical Trials in the EU 145
Tabl e 7. 1 (Continued)
Document no. Topic Title of guidelines
GL54 Safety: Acute reference dose
(ARfD)
Studies to Evaluate the Safety of Residues
of Veterinary Drugs in Human Food:
General Approach to Establish an Acute
Reference Dose (ARfD)
GL55 Biologicals: TABST Live
vaccines
Harmonisation of criteria to waive target
animal batch safety testing for live vaccines
GL56 MRK: Residues in honey Studies to evaluate the Metabolism and
Residue Kinetics of Veterinary Drugs in
Food-producing Species: Study Design
Recommendations for Residue Studies in
Honey for establishing MRLs and
Withdrawal Periods
GL57 MRK: Residues in sh Studies to evaluate the Metabolism and
Residue Kinetics of veterinary drugs in
food-producing species: Marker residue
depletion studies to establish product
withdrawal periods in aquatic species
GL58 Stability: Climatic Zones III
and IV
Stability Testing of New Veterinary Drug
Substances and Medicinal Products in
Climatic Zones III and IV
GL59 Biologicals: LABST
Veterinary vaccines
Harmonisation of criteria to waive
laboratory animal batch safety testing for
vaccines for veterinary use
As with human GCP, the guideline addresses:
● the duties and requirements of sponsors and investigators,
● the preparation of trial protocols and supporting standard operating procedures,
● the recording, storage and reporting of data,
● the notication of adverse events and
● the monitoring and quality assurance auditing of the trial.
Unlike human trials, Institutional Review Boards/Independent Ethics Commit-
tees are not involved, while informed consent is only required from the owner of the
trial animals. In addition tothe standard items associated with human trials, aspects
such as management and housing of animals, diet, and disposal of trial animals and
their products should be included in the trial protocol. Studies may be blinded from
the investigators to avoid bias in the reporting of animal observations.
7.3 Authorisation of Clinical Trials in the EU
Regulation (EU) 2019/6 stipulates that veterinary clinical trials within the EU may
only be undertaken if approved by the national competent authority of the EU
member state in which the clinical trial is to be undertaken. The regulation also
146 7 Authorisation of Veterinary Medicines
stipulates that such approval can only be granted if participating food-producing
animals (or their produce) do not enter the food chain unless an appropriate
withdrawal period has been set by the competent authority. Design and execution of
such clinical trials must be in accordance with the international guidelines on good
clinical practice of the International Cooperation on Harmonisation of Technical
Requirements for Registration of Veterinary Medicinal Products (VICH). Individual
national competent authorities (e.g. the HPRA in Ireland) each produce their own
trial application forms, fee details, etc. which are invariably published on their
websites.
7.4 Authorisation of Clinical Trials in the US
The US regulates animal trials mainly through the requirement to inform the
authorities before non-approved veterinary pharmaceuticals are shipped to trial
sites. Depending on whether it is classied as a drug or a biologic, information
must be submitted to either the FDA Center for Veterinary Medicines (CVM) or the
United States Department of Agriculture (USDA) Center for Veterinary Biologics
(CVB).
Before shipping an animal drug, a ‘Notice of Claimed Investigational Exemption
for a New Animal Drug’ must be submitted to the CVM on FDA Form 3458,
accompanied by the information outlined in Figure 7.1. The specic regulations
are contained in 21 CFR Part 511, New Animal Drugs for Investigational Use. The
investigational drug product must be labelled with the following warning:
Caution. Contains a new animal drug for use only in investigational animals
in clinical trials. Not for use in humans. Edible products of investigational
animals are not to be used for food unless authorization has been granted
by the U.S. Food and Drug Administration or by the U.S. Department of
Agriculture.
Produce from trial animals may not enter the food chain unless authorised by the
CVM on the basis of data showing that residues will be either safe or not present in
1. The identity of the new animal drug.
2. Labelling and other pertinent information supplied to investigators (study protocols,
non-clinical laboratory data, etc.).
3. The name and address of each clinical investigator.
4. Approximate number of animals to be treated or quantities of drug to be shipped.
5. If food-producing species, a commitment that produce will not be used without prior
authorisation, the approximate start and nish date of the trials and information on the
dosage and animals.
6. Information on Contract Research Organisations, if involved.
7. Environmental assessment or exemption declaration.
Figure 7.1 Information supplied to the CVM in support of a Notice of Claimed
Investigational Exemption (NCIE) for an Investigational New Animal Drug (INAD).
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7.5 Maximum Residue Limits (MRLs) 147
1. Permit or letter of authorisation issued by the state where each trial will be conduced.
2. Tentative list of proposed recipients.
3. Description of product and available preliminary information on safety and ecacy.
4. Copies of labels.
5. Study protocol.
6. Data showing that the product is unlikely to adversely aect food produce from the
animals.
7. Commitment from investigator to provide additional information before movement of
food-producing animals, if applicable.
8. Information on possible environmental impact.
Figure 7.2 Information supplied to the CVB in support of a request for authorisation to
ship an experimental biologic product.
products from animals treated at the maximum dosage with the minimum allowed
withdrawal period. The CVM must be notied of the date and place of slaughter
at least 10 days prior to each shipment for slaughter. The regulations also address
the retention of records and the competence of study investigators. Records of drug
shipments must be maintained for at least two years after the date of shipment. Data
and results of trials must be retained for either two years after completion of the
trial, or approval of the drug, whichever is relevant. The sponsor must ensure that
the investigator is suitably qualied and experienced to conduct the studies.
Regulations covering experimental biologic products are contained in 9 CFR
Part 103 Experimental Production, Distribution and Evaluation of Biological
Products Prior to Licensing. In this case, authorisation must be obtained from
the CVB before product is shipped. Requests for authorisation must be supported
by the information outlined in Figure 7.2. Experimental biologics should not
be manufactured in the same facility as licensed biologics unless authorized
by the authorities on the basis that adequate measures are in place to prevent
contamination of licensed products. Product labels must bear the statement:
Notice! For Experimental Use Only--Not For Sale.
Animals may not be moved for 14 days after administration of the experimental
product and records on the disposition of trial animals must be retained for two
years. Bio-security issues will be of particular concern to the environmental impact
assessment where trials involve live organism or genetically modied organisms,
either in vaccine challenge studies or as experimental products.
7.5 Maximum Residue Limits (MRLs)
A unique feature of the development of veterinary medicines for food-producing
species is the need to consider the establishment of MRLs for the drug or its
metabolites in food produce. European Union Regulation (EC) No. 470/2009
refers to a MRL as: the maximum concentration of a residue of a pharmacologically
148 7 Authorisation of Veterinary Medicines
active substance that may be permitted in food of animal origin and “residues of
pharmacologically active substances” means all pharmacologically active sub-
stances, expressed in mg/kg or μg/kg on a fresh weight basis, whether active
substances, excipients or degradation products and their metabolites which remain
in food obtained from animals.
The requirement to establish MRLs stems fromconcern that residues of veterinary
pharmaceuticals may have undesirable toxicological or pharmaceutical eects in
humans if present in food. With antibiotics in particular, it is known that residues
can present a risk to human health by favouring the emergence of antibiotic
resistance in bacteria of the human gut ora, or by disrupting the normal healthy
intestinal ora that provide a colonisation barrier against less desirable organisms.
MRLs are generally not considered necessary for biopharmaceutical substances
such as vaccines, although pharmacologically active excipients, adjuvants, or
preservatives used in such products, will need to be assessed.
MRLs are derived using a two-stage process. The rst step is to establish an
acceptable daily intake (ADI), which represents the quantity of substance and/or
its residues, expressed as μg or mg per kg bodyweight, that can be ingested daily
over a lifetime without any appreciable health risk to exposed individuals. This will
be based on a review of the various pharmacological, toxicological, microbiological
and other tests undertaken to demonstrate the safety of the substance. This usually
permits identication of the no observed (adverse) eect level (NO(A)EL) or, in
certain cases the lowest observed (adverse) eect level (LO(A)EL), with respect to
the most sensitive parameter in the most sensitive appropriate test species, or in
some cases, in humans. An uncertainty factor or safety factor is then applied to take
account of the inherent diculties in extrapolating animal toxicity data to humans
and the variations between humans.
Once an ADI has been established, it can be used to estimate MRLs for dierent
food commodities that provide assurance that the likely dietary intake of residues
will remain below this threshold. Typically, calculations are based on an arbitrary
average human bodyweight of 60 kg and an assumed average daily consumption of
500 g of meat (made up of 300 g of muscle, 100 g of liver, 50 g of kidney and 50 g
of fat) together with 1.5 l of milk and 100 g of eggs or egg products. Consideration
must also be given to residue depletion patterns and the possibility of persistence in
specic organs when proposing MRLs. The process should result in the proposal of
MRLs for all the following food commodities from all species intended for human
consumption; meat ofmammals and poultry (muscle, fat, (fat and skin where appro-
priate) liver and kidney), meat of n sh (muscle and skin in natural proportions),
milk, eggs and honey.
At international level, a Joint Expert Committee on Food Additives (JECFA)
under the auspices of the United Nations Food & Agriculture Organisation (FAO)
and the World Health Organisation (WHO) have undertaken safety evaluations of
residues of veterinary medicines among other contaminants in food products. As a
result, MRLs for a number of common veterinary drugs have been published in the
‘Codex Alimentarius’. As these have been developed in the interests of safe food and
fair trade, World Trade Organisation and other international agreements promote
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7.6 Authorisation of Veterinary Medicines in the EU 149
the use of such limits by national authorities unless there is strong scientic
justication to the contrary. For new drugs, proposals as regards residues will have
to be addressed as part of the authorisation process.
7.6 Authorisation of Veterinary Medicines in the EU
The authorisation of veterinary medicines containing a new chemical entity for use
in food-producing animals involves a two-stage application process – an application
to establish MRLs and an application for marketing authorisation.
7.6.1 Applications to Establish MRLs
Regulation (EC) 470/2009 lays down the rules and procedures for the establishment
of MRLs. The regulation is supported by, three implementing regulations that can
be found in The Rules Governing Medicinal Products in the European Union, Vol-
ume 8 – MRLs detailed guidance
● Regulation (EU) 2017/12 (regarding the form and content of the applications and
requests for the establishment of MRLs).
● Regulation (EU) 2018/782 (establishing the methodological principles for the risk
assessment and risk management recommendations).
● Regulation (EU) 2017/880 (laying down rules on the use of a maximum residue
limit(MRL) established for a pharmacologically active substance in a particular
foodstu for another foodstu derived from the same species and a MRL estab-
lished for a pharmacologically active substance in one or more species for other
species).
Moreover, the EMA publishes extensiveadviceand guidance on MRLs onitswebsite,
with many of the guidelines being those developed and adopted through the VICH
process described earlier in the chapter.
Applications to establish MRL’s for new pharmacologically active substances
must be submitted to the EMA at least six months in advance of an application for
a marketing authorisation. To avoid delays, manufacturers are advised to submit
an application once all the necessary data is available, as a product authorisation
cannot be granted unless MRL’s have been established, if appropriate. The EMA
should be notied of the intent to submit an application three to four months
in advance of the anticipated date so that a rapporteur and co-rapporteur can be
appointed from among the members of the Committee for Veterinary Medicinal
Products (CVMP).
Applications must be submitted using the form shown in Figure 7.3, and
supported by a technical dossier, primarily consisting of a safety le and a residue
le. The contents of the dossier (as specied in Regulation (EU) 2017/12) are
outlined in Figure 7.4. The safety le focuses on providing information on pharma-
cological and toxicological studies that leads to a proposed ADI for the substance
or its metabolites. The residue le provides data to indicate how the residues
150 7 Authorisation of Veterinary Medicines
Figure 7.3 MRL application form.
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7.6 Authorisation of Veterinary Medicines in the EU 151
Figure 7.3 (Continued)
152 7 Authorisation of Veterinary Medicines
Figure 7.3 (Continued)
will be distributed and depleted together with proposed MRLs and validated
analytical methods for detection of the residues in food commodities. As with
marketing applications, signed expert reports that provide a critical assessment and
commentary on the data form a fundamental part of the les.
7.6.2 Review of Applications and Establishment of MRLs
The review of MRL applications is similar to that for centralised marketing
authorizations conducted by the EMA, in that rapporteurs are responsible for the
hands-on evaluation, which is then reported back to the CVMP for consideration.
Guidance in relation to the assessment criteria used, particularly in relation to
scientic risk assessment and establishment of risk management recommenda-
tions relevant to MRL applications, are outlined in Regulation (EU) 2018/782.
If there are outstanding issues a list of questions is forwarded to the applicant
for his response. Otherwise, a formal opinion is prepared and presented to the
Commission for legal implementation as a decision. The maximum time allowed to
deliver a CVMP opinion is 220 days unless the medicine is urgently required in the
interests of public health or animal welfare, in which case an accelerated review
period of 120 day is mandated. These limits exclude time taken for initial validation
of the application and review of responses form the applicant where necessary. The
review will result in one of four outcomes:
Establishment of a MRL
Establishment of a provisional MRL (pending further data) the absence of the
need to establish a MRL
A prohibition on administration of the substance
The European Commissionconrms the classication of the substance by includ-
ing it in the annex to Commission Regulation (EU) No. 37/2010. Some illustrative
sample MRL annex entries are presented in Table 7.2. Upon approval, the EMA
then also publish an MRL assessment report (EPMAR), which outlines the CVMP
evaluation and basis for their opinion.
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7.6 Authorisation of Veterinary Medicines in the EU 153
Chapter 1: Administrative Information
(details of substance, the applicant, summary of evaluation and ndings,
MRLs proposed and method of analysis proposed)
Chapter 2: Data for scientic risk assessment:
A. Safety le
A.0. Detailed and critical summary (expert report)
A.1. Precise identication of the substance concerned by the application
Names (INN, IUPAC, CAS) Therapeutic & Pharmacological class, Structural & molecular
formulae, impurities, Description of physical properties
A.2. Pharmacology
A summary of the results of the various pharmacological studies, with particular emphasis
on results which may berelevantto the evaluation of the safety of residues of the substance.
A.2.1 Pharmacodynamics
A.2.2 Pharmacokinetics
A.3. Toxicology (in laboratory species)
3.1 Single-dose toxicity
3.2 Repeat-dose toxicity
3.3 Tolerance in the target species
3.4 Reproductive toxicity, including developmental toxicity
3.4.1 Study of the eects on reproduction
3.4.2 Embryotoxicity/foetotoxicity, including teratogenicity
A.4. Other requirements
(Immunotoxicity, Neurotoxicity, Microbiological properties of residues, Potential eects
on the human gut ora, Potential eects on the micro-organisms used for industrial food
processing, Observations in humans)
A.5. Determination of ADI or alternative limit
B. Residue File
B.0. Detailed and critical summary (expert report)
B.1. Metabolism and residue kinetics
B.2. Monitoring and exposure data (if relevant)
B.3. Residue analytical method
Chapter 3: Risk Management Considerations
Figure 7.4 Outline of the MRL dossier.
Table 7. 2 Some sample entries taken from the annex of regulation (EU) No. 37/2010 regarding maximum residue limits (MRL) approved for the indicated
veterinary medicine (pharmacologically active substance).
Pharmacologically
active substance Marker residue Animal species MRL Target tissues
Other provisions
(according to Article 14(7)
of Regulation (EC) No. 470/2009)
Therapeutic
classification
Albendazole Sum of albendazole
sulfoxide, albendazole
sulphone, and
albendazole 2-amino
sulphone, expressed as
albendazole
All ruminants 100 μg/kg Muscle NO ENTRY Antiparasitic
agents/Agents
against
endoparasites
100 μg/kg Fat
1000 μg/kg Liver
500 μg/kg Kidney
100 μg/kg Milk
Aloe vera gel and
whole leaf extract
of Aloe vera
Not applicable All food producing
species
No MRL
required
Not applicable For topical use only. No Entry
Amoxicillin Amoxicillin All food-producing
species
50 μg/kg Muscle For n sh the muscle MRL
relates to ‘muscle and skin in
natural proportions’.
MRLs for fat, liver and kidney do
not apply to n sh.
For porcine and poultry species
the fat MRL relates to ‘skin and
fat in natural proportions’.
Not for use in animals from
which eggs are produced for
human consumption.
Anti-infectious
agents/Anti-biotics
50 μg/kg Fat
50 μg/kg Liver
50 μg/kg Kidney
4 μg/kg Milk
Cefapirin Sum of cephapirin and
desacetylcephapirin
Bovine 50μg/kg Muscle No entry Anti-infectious
agents/Anti-biotics
50 μg/kg Fat
100 μg/kg Kidney
60 μg/kg Milk
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