In drug development, pre-clinical development,
also named preclinical studies and nonclinical studies, is a
stage of research that begins before clinical
trials (testing in humans) can begin, and during which important
feasibility, iterative testing and drug safety data is collected.
The main goals of pre-clinical studies are to determine a
product's ultimate safety profile. Products may include new or iterated or
like-kind medical devices, drugs, gene therapy solutions, etc.
Types of preclinical research
Each class of product may undergo different types of
preclinical research. For instance, drugs may undergo pharmacodynamics
(what the drug does to the body) (PD), pharmacokinetics
(what the body does to the drug) (PK), ADME, and toxicity
testing through animal
testing. This data allows researchers to allometrically
estimate a safe starting dose of the drug for clinical
trials in humans. Medical devices that do not have drug attached will not
undergo these additional tests and may go directly to Good Laboratory Practices (GLP) testing
for safety of the device and its components. Some medical devices will also
undergo biocompatibility testing which helps to show whether a component of the
device or all components are sustainable in a living model. Most pre-clinical
studies must adhere to GLPs in ICH
Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in
the United States.
Typically, both in vitro
and in vivo
tests will be performed. Studies of a drug's toxicity
include which organs are targeted by that drug, as well as if there are any
long-term carcinogenic effects or toxic effects on mammalian reproduction.
Animal testing
The information collected from these studies is vital so
that safe human testing can begin. Typically, in drug development studies
animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.
Choice of species
The choice of species is based on which will give the best
correlation to human trials. Differences in the gut, enzyme
activity, circulatory system, or other considerations make
certain models more appropriate based on the dosage form,
site of activity, or noxious metabolites. For example, canines may not be good models
for solid oral dosage forms because the characteristic carnivore intestine is
underdeveloped compared to the omnivore's, and gastric emptying rates are
increased. Also, rodents can not act as models for antibiotic drugs because the
resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's
functional groups, it may be metabolized in similar or different ways between
species, which will affect both efficacy and toxicology.
Medical device studies also use this basic premise. Most
studies are performed in larger species such as dogs, pigs and sheep which
allow for testing in a similar sized model as that of a human. In addition,
some species are used for similarity in specific organs or organ system
physiology (swine for dermatological and coronary stent studies; goats for
mammary implant studies; dogs for gastric and cancer studies; etc.).
Ethical issues
Animal testing in the research-based pharmaceutical
industry has been reduced in recent years both for ethical and cost reasons.
However, most research will still involve animal based testing for the need of
similarity in anatomy and physiology that is required for diverse product
development.
No observable effect levels
Based on pre-clinical trials, No Observable Adverse Effect
Levels (NOAEL) on drugs are established, which are used to determine initial
phase 1 clinical trial dosage levels on a mass API
per mass patient basis. Generally a 1/100 uncertainty factor or "safety
margin" is included to account for interspecies (1/10) and
inter-individual (1/10) differences.
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