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Regulatory Considerations in Veterinary Toxicology Chapter | 6  93




  VetBooks.ir  countries, which are the United States, the countries of the  information, such as toxicokinetic data, may also be col-
                                                                lected if deemed necessary.
             European Union, and Japan (VICH, 2017).
                The components of the TAS technical section are very
             briefly described below. For some drugs, each of these  Other Laboratory Safety Studies
             components will be necessary, while for others, for which
                                                                Additional safety studies may be needed in order to
             a lot of information is already available and drug action
                                                                answer specific safety questions in the intended target
             and safety are well understood, less information may be
                                                                species or class of animal. Examples of such specialized
             needed. Margin of safety and other laboratory safety stud-
                                                                studies include reproductive safety studies; specific ani-
             ies must be performed in conformity with the principles
                                                                mal class safety studies (e.g., neonatal, geriatric); injec-
             of Good Laboratory Practices (GLP), codified in 21 CFR
                                                                tion/administration-site safety studies; and mammary
             Part 58. The GLP regulations address nonclinical labora-
                                                                gland safety studies.
             tory studies and ensure that methods and procedures for
             collecting, processing, and reporting data are standard-
             ized, allowing for an adequate level of accuracy and qual-  Safety Information From Field Effectiveness
             ity control for the studies and data submitted for review.  Studies
             In addition, the GLP regulations assure that records are  Additional safety information needed is gathered from
             available to provide assurance that the study was actually  field (clinical) effectiveness studies. Unlike the margin of
             conducted as described in the study protocol and final  safety studies, the field studies are conducted under clini-
             study report.                                      cal conditions representative of the intended use of a new
                                                                animal drug (e.g., client-owned diseased animals of vari-
                                                                ous breeds, classes, and ages). These studies allow detec-
             Pharmacologic/Toxicologic Characterization
                                                                tion of some adverse findings that occur at a low
             The pharmacologic/toxicologic characterization includes  frequency and may have been missed in small-scale mar-
             any information submitted by the sponsor that may help  gin of safety studies. More importantly, these studies pro-
             design the pivotal TAS study. In addition, it can help to  vide data on drug safety in diseased animals. Good
             better predict and understand any potential adverse effects  Clinical Practice (GCP) Guidance offers the FDA’s cur-
             that may occur in the target animal. Data in the pharma-  rent best thinking on the conduct of effectiveness studies
             cologic/toxicologic characterization package may include  (FDA/CVM, 2011a).
             published literature and preliminary studies, including
             various target and nontarget laboratory animal studies as  Safety Data From Foreign Approvals
             well as pharmacokinetic, pharmacodynamic, and toxicol-
                                                                If an investigational drug is already approved in other
             ogy studies.
                                                                countries, the CVM will also evaluate foreign adverse
                                                                reports, if available, to learn about these adverse findings
             Pivotal Margin of Safety Study                     under clinical conditions of use.
             Margin of safety studies have historically been used to
             support the safety of an investigational new animal drug.  Human Food Safety Assessment
             These studies are generally characterized by a small sam-
                                                                General Considerations
             ple size, relative homogeneity of study animals, limited
             study duration, and the use of healthy young animals.  For drugs used in food-producing animals, human food
             Although the use of multiple doses is commonly needed  safety assessment of drug residues is required to ensure
             in order to extrapolate safety findings of new animal  that there is reasonable certainty of no harm to human
             drugs to their use under various clinical conditions, the  consumers with respect to human exposures to potential
             actual multiples of the 1X dose in a margin of safety  residues in edible tissues (muscle, liver, kidney, fat, and
             study are not strictly defined. Most typically, however,  when applicable, milk, eggs, and honey) of animals trea-
             the margin of safety is demonstrated in a 0X-, 1X-, 3X-,  ted with the drug product. FDA is normally concerned
             and 5X-dose study with the drug administered for 3X the  with intermittent and chronic exposure of people to rela-
             intended duration. The product safety is then established  tively low concentrations of drug residues, including the
             by demonstrating an acceptable level of safety (above 1X  parent drug and its metabolites. Some compounds need
             dose) and identifying (if present) the toxic syndrome.  only a minimum of testing, while others may need more
             Variables that are typically assessed in a margin of safety  studies in various toxicological testing species. The CVM
             study include physical examinations and observations;  has published draft revised GFI #3 to inform sponsors of
             various clinical pathology tests (hematology, blood chem-  the scientific data and/or information that may be required
             istry, and urinalysis); necropsy; and histopathology. Other  to provide an acceptable basis to determine that the
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