One of CVM’s greatest challenges is to expeditiously approve safe, effective, and properly labeled new animal drug products through a science-based approach in a regulatory environment. The Center is also facilitating the introduction of innovative products and processes, thus increasing the certainty of the regulatory pathway for those products.
Significant Approvals During the Fiscal Year
The fiscal year 2012 significant approvals for new and supplemental new animal drug applications are listed in Appendix C of this report. Included in the 38 significant approvals this year are 11 original NADA approvals, 8 original ANADAs, and 19 supplemental approvals. The new chemical entity approvals included:
- RECUVYRA (fentanyl) Transdermal Solution– An original approval of a long lasting opioid analgesic, for the control of postoperative pain associated with surgical procedures in dogs. RECUVYRA is a Schedule II controlled substance. It will be distributed under a voluntary post-approval Risk Minimization Action Plan (RiskMAP) and its use is limited to certified veterinarians.
- RILEXINE (cephalexin monohydrate) Chewable Tablets – An original approval for the treatment of secondary superficial bacterial pyoderma in dogs caused by susceptible strains of Staphylococcus pseudintermedius.
- ZUPREVO (tildiprosin) 18% Injectable Solution—An original approval for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytical, Pasteurella multocida and Histophilus somni in beef and non-lactating dairy cattle, and for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD associated with Mannheimia haemolytical, Pasteurella multocida and Histophilus somni.
- AIVLOSIN (tylvalosin tartrate) Water Soluble Granules—An original approval for the control of porcine proliferative enteropathy (PPE) associated with Lawsonia intracellularis infection in groups of swine in buildings experiencing an outbreak of PPE.
- ALFAXAN (alfaxalone) intravenous injectable – An original approval for the induction and maintenance of anesthesia and for induction of anesthesia followed by maintenance with an inhalant anesthetic in dogs and cats.
- OVUGEL (triptorelin acetate) Gel –An original approval for the synchronization of time of insemination in weaned sows to facilitate a single fixed-time artificial insemination.
Responding to Antiparasitic Resistance
Resistance to drugs to treat parasitic worms in livestock and equines is a worldwide problem, and treatment failures are becoming increasingly common. In an effort to minimize the development of resistance and preserve effectiveness of antiparasitics, animal owners and veterinarians should work together to combine management practices and diagnostic tests with appropriate drug administration.
The Antiparasitic Resistance Management Strategy (ARMS), a new ONADE initiative, was adopted in response to information presented at FDA’s Public Meeting on Antiparasitic Drug Use and Resistance in Ruminants and Equines, held in March 2012. This Public Meeting also served to enhance communication between FDA and the animal drug industry as one of ten workshops agreed to as part of the goals associated with the Animal Drug User Fee Amendments of 2008.
This proactive initiative will address the developing problem of antiparasitic resistance in cattle, small ruminants, and equines in the U.S. through collaboration across offices, the center, and the agency, as well as with outside parties such as universities and professional national and international veterinary organizations. The long-term goal of ARMS is to protect animal health and the food supply by promoting sustainable use of antiparasitic drugs through education, exploring new developments in the field of antiparasitic resistance through research, and developing a regulatory framework that allows for the approval of sustainable antiparasitic products in cattle, small ruminants, and equines.
New Tool on the Horizon to Facilitate Drug Development and Evaluation
In September 2012, ONADE entered into a Cooperative Research and Development Agreement (CRADA) with Simcyp (now Certara) to further develop the Simcyp Dog model for the evaluation of drug products intended for use in different canine breeds. (A CRADA is an agreement between one or more FDA laboratories and one or more non-Federal parties under which the FDA laboratory provides personnel, services, facilities, equipment, or other resources toward the conduct of specified research or development efforts.)
This CRADA involves modelling and simulation research and development (from Simcyp), expertise in canine physiology and the associated variables that can influence the absorption, distribution, metabolism, and elimination of therapeutic moieties in the dog (pharmacokinetics), and the regulatory evaluation of drug products intended for use in dogs (provided by FDA).
This five year project aims to deliver physiologically-based pharmacokinetic (PBPK) dog models intended to help streamline the process of veterinary drug product development and evaluation. This will be accomplished by facilitating the use of pharmacokinetic principles as a tool for addressing complex questions associated with the design and interpretation of target animals safety studies and clinical field studies. It will also enable the integration of model predictions with data from safety and effectiveness studies to support the development of informative product labels. Furthermore, these models will be invaluable when determining label recommendations for the duration of human-pet contact restrictions for pets undergoing chemotherapeutic interventions (e.g., anti-cancer drugs).
The ultimate goal of this project is to develop a simulation platform for PBPK modelling and population predictions.
The Public Master File (PMF) Webpage
Public Master Files contain publicly available studies or other non-proprietary information intended to support drug approvals, often for minor use or minor species drugs. PMFs are established to provide access to this information and to enable public partners to share resources. Multiple sponsors can use these studies to support their approvals.
The PMF webpage consists of a front webpage with two tables that highlight public master files and public work that has been completed for use in obtaining drug approvals. The front page describes what PMFs are and what they typically include. One of the tables references public master files that have supported new animal drug approvals, and the other table references PMFs that are still in development. The table of PMFs supporting approvals includes a list of approvals that were supported by public master files, and provides links to the relevant Freedom of Information Act (FOIA) summaries of the bases for approval. For public master files still in development, the tables link to the technical section “complete” letters for the critical aspects of a drug approval (target animal safety, effectiveness, human food safety and environmental impact) that are available for use under that file. The webpage is important because it:
- provides greater transparency by making accessible information that is publically available for a specific drug or indication;
- facilitates collaboration between public, private, and international sponsors and provides another tool for collaboration between sponsors and stakeholders;
- recognizes work by public sponsors that has supported current drug approvals; and
- supports efforts to obtain minor species and minor use drug approvals.
Draft Guidance on Active Controls in Studies to Demonstrate Effectiveness
In June 2012, the agency made available the draft guidance for industry # 204, “Active Controls in Studies to Demonstrate Effectiveness of a New Animal Drug for Use in Companion Animals.” This guidance advises industry on the use of active controls (known effective therapies) in studies intended to provide substantial evidence of effectiveness of new animal drugs for use in companion animals. The intent of the guidance is to provide information to clinical investigators who conduct studies using active controls and have a basic understanding of statistical principles.
Final Rule Regarding Regulation of Carcinogenic Compounds in Food-Producing Animals
In August 2012, the agency published a final rule changing certain definitions in its regulations regarding compounds of carcinogenic concern used in food-producing animals. The change is intended to enable CVM to consider allowing the use of alternative procedures to satisfy the “DES Proviso” without requiring the development of a second, alternative set of terminology. (The “DES Proviso” refers to clauses in the Food, Drug and Cosmetic Act that prohibit approving substances shown to induce cancer in man or animals.) The agency believes the original intent of the regulation implementing the DES Proviso was to place an emphasis on no significant increase in the risk of cancer to the human consumer, rather than on the specific 1 in 1 million risk of cancer to the test animals, an approach that had previously been used.