Biomedical Engineering Reference
In-Depth Information
requirements for adequate assessment of new compounds
through a number of published guidance documents. These
documents are used by the member parties in their review
of preclinical study data supporting Investigation New
Drug (IND) submissions (Food and Drug Administration
(FDA), 2011).
In 1938, the USA passed the Federal Food, Drug, and
Cosmetic Act, which requires toxicity and safety testing. In
1962, the FDA first required the use and reporting of animal
safety data prior to administration of drugs in clinical trials
through the Kefauver-Harris Amendments. These required
proof of safety and efficacy prior to approval of new drugs
and established procedures that serve as the basis for the
IND regulations. The general principles of the IND
submission are to assure the safety and rights of subjects,
and to help assure that the quality of the scientific evalua-
tions of drugs is adequate to permit the evaluation of the
drug's effectiveness and safety.
The regulation of animal care and use for drug devel-
opment is described in Chapter 2. While regulatory struc-
tures vary between regions and countries, they usually
provide for an ethical review process reflecting the princi-
ples of replacement, reduction, and refinement of the use of
animals in experimental procedures.
Scientific Approach
All studies and research are done according to good
scientific principles in compliance with animal welfare
regulations. Disease mechanism and efficacy studies are
hypothesis driven. Safety and toxicity evaluations are also
hypothesis driven, but the hypothesis is determined by the
regulatory agency. Essentially, the premise is that all drugs
are toxins if given at high enough doses for sufficient
duration. This hypothesis addresses one of the fundamen-
tals of toxicology as originally stated by Paracelsus,
considered the father of toxicology, in the 1500s: “What is
there that is not a poison? All things are poison and nothing
is without poison. Solely the dose determines that a thing is
not a poison” (
Madea et al., 2007
). Under regulatory
guidance for development of the drug, the expectation is to
identify what the toxicity is, where it occurs, the dose
(plasma level) at which it occurs, when it occurs, and if
possible, why it occurs. Answers to these questions are
determined by an extensive prescribed set of studies and
parameters that guarantee at a minimum a thorough base-
line assessment of drug-induced effects in healthy animals.
Results from animal and other studies are extrapolated to
humans to estimate the benefit:risk relationship and starting
dose, stopping criteria, biomarkers, and dosing plan for
clinical studies/trials.
Species Needs for Drug Development
Minimum requirements for drug toxicity testing in
nonclinical studies are regulated by agencies worldwide, the
most prominent of which are the FDA in the USA,
Committee for Medicinal Products for Human Use (CHMP)
in Europe, and Ministry of Health, Labor and Welfare
(MHLW) in Japan. Guidance documents from ICH provide
a common approach and direction for these agencies. The
emergence of drug development in China and India may
result in greater influence of these countries on setting
international standards and expectations in the future.
ICH guidances require testing drugs in two relevant
animal species for multidose toxicity studies. ICH M3 (R2)
(Guidance on Non-Clinical Safety Studies for the Conduct
of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals;
International Conference on Harmo-
nisation, 2010
) pertains to traditional small molecule drugs
and addresses the type and duration of nonclinical safety
studies and their timing to support the conduct of human
clinical trials and marketing authorization for pharmaceu-
ticals. ICH S4 (Duration of Chronic Toxicity Testing in
Animals [Rodent and Non-Rodent Toxicity Testing];
International Conference on Harmonisation, 1998
)
harmonizes the duration of repeat dose toxicity studies in
the rat from 12 to 6 months. ICH S6 (R1) (Preclinical
Safety Evaluation of Biotechnology-Derived Pharmaceu-
ticals;
International Conference on Harmonisation, 2009
)
addresses the use of animal models of disease, determina-
tion of when genotoxicity assays and carcinogenicity
studies should be performed, and the impact of antibody
formation on duration of toxicology studies for large
molecules. Additional ICH guidance addresses other
aspects of nonclinical drug development (see the ICH
website
Historical Perspective for Drug
Development Animal Usage
During the history of drug development, there have been
tragic events in humans that have resulted in death, organ
damage, birth defects, and decreased quality of life. Some
of these have been due to inadequate generation of quality
data that interfered with developing an accurate and
complete risk assessment. These events combined with the
overall ethical need to protect test subjects in clinical trials,
and all patients, have initiated pivotal regulatory responses
to govern drug development in humans. One of the most
cited is the thalidomide tragedy. Thalidomide, marketed in
the late 1950s in Europe as a sedative, was withdrawn due
to teratogenicity and neurotoxicity that caused thousands of
cases of birth defects worldwide (
Perri and Hsu, 2003
).
More recent clinical tragedies include FIAU-induced liver
injury and death and TeGenero TGN1412-induced multiple
organ failure which are discussed later.
http://www.ich.org/home.html
).
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