Preclinical

development

In drug development, preclinical

development (also termed preclinical
studies or nonclinical studies) is a stage of
research that begins before clinical trials
(testing in humans) and during which
important feasibility, iterative testing and
drug safety data are collected, typically in
laboratory animals.
The main goals of preclinical studies are
to determine a starting, safe dose for first-
in-human study and assess potential
toxicity of the product, which typically
include new medical devices, prescription
drugs, and diagnostics.

Companies use stylized statistics to

illustrate the risks in preclinical research,
such as that on average, only one in every
5,000 compounds that enters drug
discovery to the stage of preclinical
development becomes an approved
drug.[1][2]

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 toxicology 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
preclinical 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 drug toxicity
include which organs are targeted by that
drug, as well as if there are any long-term
carcinogenic effects or toxic effects
causing illness.

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.).

Importantly, the regulatory guidelines of

FDA, EMA, and other similar international
and regional authorities usually require
safety testing in at least two mammalian
species, including one non-rodent species,
prior to human trials authorization.[3]

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 preclinical trials, no-observed-

adverse-effect levels (NOAELs) 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.

See also

Drug development

Preclinical imaging

Phases of clinical research

References

1. Emanuel EJ (9 September 2015). "The

Solution to Drug Prices" (https://www.nyti
mes.com/2015/09/09/opinion/the-solutio
n-to-drug-prices.html?_r=0) . New York
Times. "On average, only one in every
5,000 compounds that drug companies
 discover and put through preclinical
testing becomes an approved drug. Of the
drugs started in clinical trials on humans,
only 10 percent secure F.D.A. approval. ..."

2. "Drug Approvals - From Invention to

Market...12 Years!" (https://www.medicine
net.com/script/main/art.asp?articlekey=9
877) . MedicineNet. Retrieved 2021-04-21.

3. Atanasov AG, Waltenberger B, Pferschy-

Wenzig EM, Linder T, Wawrosch C, Uhrin P,
Temml V, Wang L, Schwaiger S, Heiss EH,
Rollinger JM, Schuster D, Breuss JM,
Bochkov V, Mihovilovic MD, Kopp B, Bauer
R, Dirsch VM, Stuppner H (December
2015). "Discovery and resupply of
pharmacologically active plant-derived
natural products: A review" (https://www.n
 cbi.nlm.nih.gov/pmc/articles/PMC474840
2) . Biotechnology Advances. 33 (8):
1582–1614.
doi:10.1016/j.biotechadv.2015.08.001 (htt
ps://doi.org/10.1016%2Fj.biotechadv.201
5.08.001) . PMC 4748402 (https://www.nc
bi.nlm.nih.gov/pmc/articles/PMC474840
2) . PMID 26281720 (https://pubmed.ncb
i.nlm.nih.gov/26281720) .

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