Page 126 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

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