Page 129 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

96 SECTION | I General

VetBooks.ir The DES (diethylstilbestrol) proviso provides an excep- label must include, among other things, the drug name
and active ingredient, product claim(s), pharmacology,
tion to the Delaney Clause of the FFDCA, which allows
adverse effects, precautions, warnings, and contraindica-
for the use in food-producing animals of new animal
drugs, food additives, and color additives that induce can- tions. Sections of 21 CFR Parts 200 and 201 describe the
cer in animals or humans, if (1) the compound does not various sections and requirements for animal drug labels.
adversely affect the animal, and (2) analytical methods A Freedom of Information (FOI) summary is prepared
approved by FDA do not detect residues of the compound and published on the CVM website. The FOI summary is
in any edible tissues from the treated animal. If FDA a public document describing the safety and effectiveness
determines, on the basis of the results of the chronic can- information that supports the CVM’s decision to approve
cer bioassays and other information, that the sponsored the drug. It includes summaries of studies that were done
compound caused cancer in man or animals, then the and explains the basis for approval. After approval, the
compound is regulated as a carcinogen under the Delaney drug is monitored through periodic and special industry
Clause DES proviso and is subject to 21 CFR Part 500, drug experience reports submitted to the CVM by the
Subpart E, to meet the FDA operational definition of no sponsor, including adverse drug experience (ADE) reports
residue. that may result in label changes related to product safety.
The FDA will calculate the concentration of a residue
of carcinogenic concern in the total human diet that repre- POSTAPPROVAL SURVEILLANCE
sents no significant increase in the risk of cancer to the
ACTIVITIES
human consumer, termed S o . The FDA assumes this S o
will correspond to the concentration of test compound in Overview of the CVM’s Pharmacovigilance
the total diet of test animals that corresponds to a maxi- Program
mum lifetime risk of cancer in the test animals of 1-in-1
million (21 CFR y500.82). The no-residue regulations Although the CVM has a rigorous preapproval process for
describe not only the calculation of a concentration of the animal drugs, well-conducted, randomized, controlled
residue of carcinogenic concern that corresponds to a clinical trials may not be of sufficient size to identify
maximum lifetime risk to the test animal of 1-in-1 million every safety problem, especially ones that are rare and
(21 CFR y500.84), but also the possibility of a waiver of unexpected. Once a product is marketed, there is a sub-
requirements, which allows alternative procedures to pro- stantial increase in the number of patients exposed to the
vide the basis for ensuring that the approval of the com- drug, including animals with coexisting medical condi-
pound satisfies the anticancer provisions (21 CFR tions and those being treated with concomitant medica-
y500.90). Generally speaking, for a genotoxic carcinogen tions and biologic agents such as vaccines. There are
or in the absence of information establishing threshold- potential food interactions as well. Additional information
able mode of action for carcinogenesis for a particular about medical product safety and effectiveness is obtained
compound, FDA assumes that a threshold for carcinogen- after a product is marketed and used under actual field
esis cannot be determined and determines an S o using a conditions in large diverse populations of animals. This
default 1-in-1-million linear-at-low-dose statistical extrap- information is used to complete the safety profile of a
olation procedure (Gaylor and Kodell, 1980; Farmer product and helps to ensure that drug product labeling is
et al., 1982) based on the tumor incidence in the observed adequate and accurate. Ultimately, this information will
species. For a nongenotoxic carcinogen, alternative assist practitioners in making informed decisions to mini-
approaches for deriving the acceptable tissue residue con- mize risks while maximizing benefits of the drugs used in
centrations (such as a threshold for carcinogenic effects animals.
based on the mode of action for carcinogenesis) can pro- Pharmacovigilance, as defined by the World Health
vide a basis for ensuring that the anticancer provisions of Organization (WHO), is “the science and activities relat-
the FFDCA are satisfied. ing to the detection, assessment, understanding, and pre-
vention of adverse effects or any other drug-related
problems” (WHO, 2017a). In general, the role of a phar-
Approval
macovigilance program is to identify safety signals that,
After all requirements for approval have been met, the upon further evaluation, may lead to the discovery of pre-
product can be legally marketed and promoted as a new viously unidentified or unrecognized adverse drug events
animal drug. As part of the preapproval process, the CVM and associated risk factors that were not identified in the
reviews the language and formatting that will be on each preapproval evaluation of the product. These adverse
part of the drug’s labeling. The labeling must provide all events may be related to previously unrecognized pharma-
necessary information to use the drug safely and effec- cological effects of the drug, idiosyncratic effects, drug-
tively, including the risks associated with the drug. The drug interactions, drug-food interactions, drug-disease