Clinical and Pre-clinical trials for Veterinary Medicinal Products

Safety concern the knowledge of the possible adverse effects and the safety margin (dose titration studies), to which a VMP can be safely administered any evaluates what would happen if the drug is given at a higher dose or for a longer duration than indicated use. Safety concern also the use of the VMP in particular animal physiological status (i.e. pregnancy, lactation, aging, sex, particular sensitive race etc..). In food producing animals, the residue study is a must to establish the NOEL of VMP residue in meat, milk, eggs; thus, all the edible production of an animal farmed for food production. 

One more concern in the safety issue is the environmental impact of the excreted VMP, in grazing animal or animal that are feed on pasture, also this is an expensive study that must be performed in those target species. 

Once safety is evaluated, the efficacy of the drug must be evaluated. Efficacy ensures that a drug act as claimed.  

Efficacy studies can be performed by comparison with those from the target animal species that have received a veterinary medicinal product already authorised in the EU (thus a confirmation of the same efficacy), or in comparison with placebo or no treatment. 

According to the need can be performed in a blind (or masked) mode in order to do not have any influence of the evaluator on the results obtained. 

How do veterinary clinical trials differ from human ones? One key point is that veterinary medication clinical trials focus on a target animal when analysing the drug, or on the race of animal at which the drug is aimed. The big difference is that there are many animals’ species and in all them a clinical study to confirm the safety or the efficacy have to be performed. 

In Human being the clinical trials commonly begin with studies in laboratory animals and then move to humans. Lab animals are also used in veterinary preclinical trials, to establish as said above the dose titration, the safety on pregnancy, lactation carcinogenicity mutagenicity etc.  

Regulatory Basis for clinical trials 

Several directive and regulation govern the authorization to run a clinical trial. 

Clinical trials in Europe are ruled under Reg. (EU) 2019/6, article 9. It requires an authorization from the competent authority of the state where the study take place and underline that the clinical trials must be carried out taking into account of the international guidelines on good clinical practice (GCP) of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (‘VICH’). 

The Directive 2010/63/EU of the European Parliament and of the Council lays down provisions on the protection of animals used for scientific purposes based on the principles of replacement, reduction and refinement. Clinical trials for veterinary medicinal products are exempted from the scope of that Directive, but new regulation 2019/6 underline that the design and performance of clinical trials, which provide essential information on the safety and efficacy of a veterinary medicinal product, should take into account those principles of replacement, reduction and refinement. In fact, these principles concern the care and use of live animals for scientific purposes, and should be optimised in order to provide the most satisfactory results whilst using the minimum number of animals.  

The procedures of such clinical trials should be designed to avoid causing pain, suffering or distress to animals and should take into account the principles laid down in Directive 2010/63/EU, including the use of alternative test methods wherever possible, and the guidelines of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (‘VICH’). 

The country competent authority, where the study take place, must authorize the clinical trial for Veterinary Medicinal Product registration. 

Type of studies 

Preparing the VMP dossier, based on new molecules, authorization procedure and target species, different studies must be performed to be included in part 3 and part 4; the table below resume them: 

Dossier requirements 

Pre-clinical and Clinical trials mainly affect part 3 and 4 of the dossier for a veterinary medicinal products. Clinical trial are conducted for the evaluation of the Tolerance in the target animal species where the local and systemic tolerance of the veterinary medicinal product shall be investigated in the target animal species. The purpose of these studies is to characterise signs of intolerance and to establish an adequate margin of safety using the recommended route(s) of administration. This may be achieved by increasing the therapeutic dose and/or the duration of treatment. The report on the trials shall contain details of all expected pharmacological effects and all adverse reactions. 

The Regulation 2019/6 reports that: “The purpose of clinical trials is to demonstrate or substantiate the effect of the veterinary medicinal product after administration at the proposed dosage regimen via the proposed route of administration and to specify its indications and contra-indications according to species, age, breed and sex, its directions for use as well as any adverse reactions which it may have.” 

All the efficacy data obtained in Clinical trials will be reported in VMP’s dossier part 4 and the safety data obtained will be reported in VMP dossier part 3.3 as data obtained during the “tolerance studies in target species”. 

Companies’ investment protection 

Tests, pre-clinical studies and clinical trials represent a major investment for companies which they need to make in order to submit the necessary data with the application for a marketing authorisation or to establish a maximum residue limit for pharmacologically active substances of the veterinary medicinal product.  

That investment should be protected in order to stimulate research and innovation, in particular on veterinary medicinal products for minor species and antimicrobials, so that it is ensured that the necessary veterinary medicinal products are available in the Union. For that reason, data submitted to a competent authority or the Agency should be protected for a certain period of time before the possibility to refer to such as data by other applicants in order to apply for a generic or equivalent VMP’s.  

That protection, in fact is limited in time in order to allow for competition. Similar protection of investments should be applied to studies supporting a new pharmaceutical form, administration route or dosage that reduces the antimicrobial or antiparasitic resistance or improves the benefit-risk balance. 

Further, the new legislation provides for an extended data protection period of technical documentation of 10, 14, or 18 years, depending on the type of VMP.  These measures intend to stimulate the development of new VMPs, for example for rare diseases. 

Quality in Veterinary studies 

VICH have developed different guidelines for the management of clinical trials in veterinary medicine and those need to be respected performing trial for VMP application in EU. The respect of the quality is the base of each guidance and will guaranties the validity of founding. 

The list of the applicable guidance is reported on EMA or VICH websites; these guidance cover all the safety issue: Environmental safety, Toxicology, Metabolism and kinetic studies, target animal safety, environmental safety study as well the user safety risk assessment and antimicrobial safety; and all efficacy issues with good clinical practices, anthelmintic specific guidance and bioequivalence for generic VMPs. 

Conclusion 

Pre-clinical and clinical studies are the most challenging phase of a new drug for the Veterinary companies. If you need support, PQE can help you defining the best regulatory strategy and selecting the CRO that will support you during the studies. For more information visit our website.