Regulatory Issues in Veterinary Medicinal Product Development

Ciriaco Maraschiello - PhD, Director, Global Veterinary Services, Contract Research Services

By definition, a Veterinary Drug is a drug used by veterinarians in the treatment of animal diseases. Most drugs are subject to regulations with special reference to the safety of drugs and residues in edible animal products.

The development program for a new veterinary medicinal product (VMP) can be as complex as that performed for a new investigational drug proposed for the treatment of a human disease.

As with human drugs, a veterinary pharmaceutical can be a generic drug (and therefore not innovative) or a totally new chemical entity with a defined therapeutic activity. However, in contrast with human drugs, a veterinary drug can be developed for the treatment/prevention of a disease in one or more species, either for companion animals or for farm animals. In general, the veterinarian's pharmaceutical arsenal is the counterpart of drugs treating human diseases, with dosage and administration adjusted to the size, weight, disease, and idiosyncrasies of the species.

According to current guidelines, there are four parts that constitute the marketing authorisation file for a new VMP. PART I contains the summary of the dossier including the Summary of Product Characteristics (SPC). PART II contains all the information related to the chemistry of the active principle and should include all the processes for manufacturing the final formulation to be used for the intended treatment. The regulatory preclinical development of a new veterinary medicinal product would constitute PART III of the marketing authorisation dossier that has to be submitted to the authorities. PART IV would encompass the clinical development including the justification of the chosen dose (e.g. PK/PD studies in the target species) and the demonstration of the efficacy against the targeted disease and in accordance with the proposed dosing regimen.

Marketing authorisation file for Veterinary Medicinal Products (VMP)
PART I Summary of the dossier
PART II Quality
PART III Safety (and residue) file*
PART IV Efficacy
*Most of the investigations constituting PART III have to be carried out under Good Laboratory Practices

The present communication will focus on PART III and will address some particular issues related to the safety and residue documentation that have to be included in the dossier in the case of a VMP containing a pharmacologically active principle.

PART III includes all the information related to the safety profile of the active principle. This section of the dossier should include a complete description of the investigations (or referenced literature) performed to characterise the active principle of the VMP in terms of toxicological effects following acute and chronic exposure in laboratory animals and of course in the target species (TAS - Target Animal Safety). The most important data are generated using the same route of administration proposed for the new VMP, which should permit the establishment of a No Observed Effect Level (NOEL).  This is of the utmost importance in the case of VMPs used in the treatment/prevention of diseases affecting food-producing animals. The genotoxic potential, the effect on reproductive function and other effects (e.g. drug-drug interactions) of the active principle should be also reported in this section of the dossier.

PART III should also include a thorough description of the absorption, distribution, metabolism and excretion of the active principle after oral or parenteral treatment. The metabolism and tissue distribution of the active principle should be elucidated and often require the use of the 14C-labelled analogue.

The ecotoxicity section of PART III should report a thorough evaluation of the extent of exposure of the VMP, its active principle and/or relevant metabolites to the environment including, when appropriate, specific investigations of fate/degradation in the environment and effects on aquatic and other non-target organisms.

The evaluation of user safety during the handling of the veterinary medicinal product or active principle is another important section of PART III. Indeed, the results obtained from the evaluation will lead to specific recommendations that have to be adopted to ensure safe handling of the product by the user (e.g. the veterinarian, a pet owner, the worker in a manufacturing plant, a farmer etc…). These recommendations will be stated in the labelling and package insert of the VMP.

If the application relates to food producing species and if the active substance of the VMP has been included in one of the annexes to Regulation (EC) 470/2009 [repealing the previous Regulation (EEC) No 2377/90], then a residue file has to be produced to complete PART III. PART III would therefore be formed by PART IIIA (Safety file) and PART IIIB (Residue file). The documentation should first state if a Maximum Residue Limit (MRL) has been defined by the EMEA for the active principle and for each of the excipients of the VMP. If the active principle is a new chemical entity, then all the available pharmacological and toxicological information will be used to establish an MRL for its inclusion in Annex I of Regulation (EC) 470/2009.

A maximum residue limit (MRL) is the level of drug residue that can safely remain in the tissue or food product derived from a food-producing animal that has been treated with a veterinary drug.

The NOEL will be used to calculate a toxicological/pharmacological or microbiologicala Acceptable Daily Intake (ADI) that is the basis for calculating the MRL, together with the kinetics of residue depletion in the edible tissues (liver, kidney, muscle and fat(+skin)) of the target species treated with the VMP at the recommended dosing regimen for the proposed indication. The MRL, expressed in µg/kg of tissue, is defined for the marker residue of the pharmacologically active substance. The marker residue can be the parent compound and/or a main metabolite or the sum of metabolites (e.g. in the case of metabolically unstable compounds). Depending on the accumulation and depletion kinetics of the marker residue in the target species, one to four target tissues are defined and are each characterised by an MRL.b

Regulations 470/2009 and 2377/90

Regulation 470/2009 replaced Regulation 2377/90 (the MRL Regulation) on 6 July 2009. Like Regulation 2377/90, Regulation 470/2009 allows medicines to be administered to food animals only if the substances are listed in Annexes I to III of Regulation 2377/90. These 3 annexes are detailed lists of pharmacologically active substances and the animal species in which they may be used; a fourth annex lists banned substances.

  • Annex I is a list of substances for which MRLs have been fixed
  • Annex II is a list of substances for which MRLs are not necessary
  • Annex III is a list of substances with provisional MRLs
  • Annex IV is a list of substances for which no MRLs can be fixed because they are a hazard to human health at whatever level

The residue file (PART IIIB) should include a thorough description of the pharmacokinetics/ADME profile of the active principle in the target species (despite the fact that this information can overlap some information already stated in PART IIIA).

The residue file must include the studies performed to investigate the depletion of the marker residue in the target edible tissues and include a proposal for withdrawal time of the VMP in accordance with the proposed indications for the treatment of a given disease in the target species.

The Withdrawal Time is defined as the interval between the time of last administration of the drug and the time when the animal can be safely slaughtered for food purposes. At that time, the concentrations of the veterinary drug are below the specific MRL established for each target tissue. The WT is calculated by statistical regression analysis as recommended by the guideline EMEA/CVMP/036/95.

Despite its implicit involvement in the pharmacokinetics and toxicology studies described in PART IIIA, bioanalyticsc has a privileged place in PART IIIB and is the subject of an entire section. The bioanalytical method used to determine the marker residue in the target tissues is a key process since the method used must provide reliable results used to calculate a withdrawal time that guarantees consumer safety. If applicable, the bioanalytical section of PART IIIB should include a bibliographical review of the bioanalytical methods reported in the literature for the active principle and a thorough description of the validation of the bioanalytical method actually used for the quantification of the marker residue.

At HARLAN Laboratories Inc., we understand the difficulties that can be encountered during the development of a VMP, especially regarding the fulfilment of the regulatory requirements of PART III. We can meet all of your expectations in terms of quality and scientific expertise to support you in submitting a successful safety and residue file. Modern GLP facilities for the conduct of target animal safety studies, PK/bioavailability and residue depletion studies are available at our centre of excellence for Veterinary Pharmaceuticals in Barcelona and supported by a state-of-the-art bioanalytical facility featuring UPLC®-MS/MS and Ion trap support for metabolism studies.

References

  1. Maraschiello C. Maximum Residue Limits and Residue Depletion Studies. Researcher, 2006; 26: 12-13.
  2. Maraschiello C, Ramirez D. Services for Veterinary Drug Development. Researcher, 2007; 26: 10-11.

Footnotes

  1. Sometimes more relevant than the toxicological ADI especially in the case of antimicrobials due to their negative effects on the endogenous intestinal flora after oral treatment.
  2. The applicant has to submit an “MRL application” prior to or at the same time as the marketing authorisation application.
  3. The toxicology and pharmacokinetic studies should be supported by validated bioanalytical methods, which must be summarised in PART IIIA.

Selected guidelines and regulations

  • VOLUME 8 of The Rules Governing Medicinal Products in the European Community. Notice to Applicants and Note for Guidance. Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products in foodstuffs of animal origin. European Commission, June 2003.
  • Guideline on target animal safety for veterinary pharmaceutical products (2008). European Medicines Agency, Veterinary Medicines and Inspections, VICH Topic GL43, EMEA/CVMP/VICH/393388/2006.
  • Guideline for the validation of analytical methods used in residue depletion studies (2009). European Medicines Agency, Veterinary Medicines and Inspections, VICH Topic GL49, EMEA/CVMP/VICH/463202/2009-CONSULTATION.
  • Guidance for Industry. Bioanalytical Method Validation (2001). U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), May 2001.
  • Note for Guidance: Approach towards harmonisation of withdrawal periods (1995). The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, EMEA/CVMP/036/95.
  • Guidance for Industry. General principles for evaluating the safety of compounds used in food-producing animals (2006). U.S. Department of Health and Human Services, Food and Drug Administration, Center for Veterinary Medicine (CVM), Guideline 3.
  • Guideline on user safety for pharmaceutical veterinary medicinal products. The European Agency for the Evaluation of Medicinal Products (EMEA), Veterinary Medicines and Inspections, EMEA/CVMP/543/03.
  • REGULATION (EC) No 470/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 May 2009 laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin, repealing Council Regulation (EEC) No 2377/90 and amending Directive 2001/82/EC of the European Parliament and of the Council and Regulation (EC) No 726/2004 of the European Parliament and of the Council.
  • COMMISSION REGULATION (EU) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin.