Biomedical Engineering Reference
In-Depth Information
available at agency internet websites (
Cavagnaro, 2008;
Cosenza, 2008; Nakazawa, 2008; Ryle and Snodin, 2008;
Dulichand and Dureja, 2010
).
The US Food and Drug Administration's (FDA) role in
drug development, as an important example of such regu-
lation, begins when the drug's sponsor wants to test its
diagnostic or therapeutic potential in humans (Food and
Drug Administration (FDA), 2010
). The molecule is then
legally governed under the US Federal Food, Drug, and
Cosmetic Act and becomes a new drug subject to specific
requirements of the regulatory system. The investigation
new drug (IND) application must contain information in
three broad areas: animal pharmacology and toxicology
studies, manufacturing information and clinical protocols,
and investigator information (
Food and Drug Administra-
tion (FDA), 2011
). Nonclinical data from animal studies
permit an assessment as to whether the product is reason-
ably safe for initial testing in humans and assists in estab-
lishing the initial clinical dose level. US Federal law
requires that a drug be the subject of an approved marketing
application before it is transported or distributed across
state lines. An approved IND allows an exception to this
law, such that the drug can be shipped to sites conducting
clinical trials.
The new drug application (NDA)
and biological license
application (BLA) are the vehicles through which drug
sponsors formally propose that the FDA approve a new
pharmaceutical for sale and marketing in the US (
Food and
Drug Administration (FDA), 2009, 2010
). Data gathered
during animal studies and human clinical trials of an
Investigational New Drug (IND) become part of the NDA
or BLA. The NDA and BLA provide evidence on the drug's
safety and effectiveness obtained to meet FDA's require-
ments for marketing approval, and provides information on
manufacturing
medicine. Much of the lead optimization toxicology studies
are done in vitro and in vivo in rodents, but selected studies
may also be done in the large animal species (i.e. typically
nonhuman primate or dog). While not required, data from
these studies may be provided to regulatory agencies to
support the development rationale for clinical trials and
market approval. However, regulatory applications
(e.g. INDs, NDAs, BLAs) must be supported by good
laboratory practice (GLP) compliant animal toxicity
studies, which generally are not performed until the
compound development phase. The toxicity assessment of
biological molecules (i.e. large molecules such as proteins)
in the preclinical stage has a different nature than small
molecules since there generally are fewer, or even a single
molecule, to select from for development.
In compound development, toxicity assessments are
conducted according to regulatory requirements to ensure
that a benefit:risk assessment supports safe administration
of a drug to humans. Requirements dictate the types and
characteristics of studies to be conducted depending on the
human clinical trial to be conducted. A typical set of
nonclinical toxicology studies includes genetic toxicology
studies, subchronic (14
90 day) multidose in vivo toxi-
cology studies, safety pharmacology studies for assessment
of cardiovascular, central nervous system (CNS), and
respiratory pharmacological effects, chronic (6
e
12 month)
multidose in vivo toxicology studies, developmental and
reproductive toxicology studies (DART), and carcinoge-
nicity studies.
Regulatory oversight of nonclinical toxicity studies
addresses two main areas: (1) the assurance of quality and
integrity of the data from toxicity studies which is governed
by GLP (
Code of Federal Regulations 21, 1999
); and (2)
the generation and use of animal study data and interpre-
tations to determine the benefit:risk assessment for dosing
humans. An acceptable risk to patients will vary dependent
on the medical indication. Regulatory agencies, health care
providers, patients, and the public accept greater patient
risk for a drug developed for a life-threatening disease such
as cancer, than for non-life-threatening conditions such as
hair loss.
In the past, guidance for drug development by the USA,
Europe, and Japan differed in expectations, which resulted
in overlapping but not identical expectations. To bring
regional guidance into a common expectation, the Inter-
national Committee on Harmonisation (ICH) formed in
1990 to develop common acceptable practices for drug
development (see the ICH website
e
processes,
chemistry,
pharmacology,
medical, biopharmaceutics, and statistics.
Animal toxicity studies are also categorized as
preclinical safety studies, because in addition to deter-
mining the toxicity of a drug candidate, they provide
information to determine safe starting doses for the initial
clinical studies. Animal toxicity studies are done during
two distinct portions of drug discovery and development:
lead optimization and compound development, the latter of
which may be termed differently depending on the sponsor
organization. Lead optimization primarily applies to
chemical drugs (i.e. small molecules as discussed later). It
is a process by which a company selects a candidate (i.e.
drug candidate) to advance to compound development from
a few to a large number of potential drugs. Lead optimi-
zation often includes animal toxicity studies, which are
done at the discretion of the company in a nonregulated
environment. The objective of lead optimization is to select
drug candidates with the greatest probability of successful
development and potential
http://www.ich.org/
<
home.html
). The committee was comprised of regula-
tory agencies and pharmaceutical experts from U.S.,
Europe, and Japan. Harmonisation enabled pharmaceutical
companies to gather a common set of data for drug regis-
tration, thereby reducing redundant and unnecessary testing
and animal usage. This organization has clearly defined
>
to be the highest quality
