drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regu ...

, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s (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 Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

of the product, which typically include new

medical device A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assura ...

prescription drug A prescription drug (also prescription medication, prescription medicine or prescription-only medication) is a pharmaceutical drug that is permitted to be dispensed only to those with a medical prescription. In contrast, over-the-counter drugs c ...

s, and

diagnostics Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". ...

. 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 In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...

to the stage of preclinical development becomes an

approved drug An approved drug is a Medicine, medicinal preparation that has been validated for a therapeutic use by a Regulation of therapeutic goods, ruling authority of a government. This process is usually specific by country, unless specified otherwise. ...

Types

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 ADME is the four-letter abbreviation (acronym) for absorption (pharmacokinetics), ''absorption'', distribution (pharmacology), ''distribution'', ''metabolism'', and ''excretion'', and is mainly used in fields such as pharmacokinetics and pharmacol ...

, and toxicology testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for

s in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to

good laboratory practice The Principles of Good Laboratory Practice (GLP) establish rules and criteria for a quality system that oversees the organizational processes and conditions in which non-clinical (non-pharmaceutical) health and environmental safety–or simply toxi ...

s (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 ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' 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 A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

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 The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

and canine, although

primate Primates is an order (biology), order of mammals, which is further divided into the Strepsirrhini, strepsirrhines, which include lemurs, galagos, and Lorisidae, lorisids; and the Haplorhini, haplorhines, which include Tarsiiformes, tarsiers a ...

and

porcine The pig (''Sus domesticus''), also called swine (: swine) or hog, is an omnivorous, domesticated, even-toed, hoofed mammal. It is named the domestic pig when distinguishing it from other members of the genus '' Sus''. Some authorities consid ...

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 Enzyme assays are laboratory methods for measuring enzyme, enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibitor, enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in Mo ...

circulatory system In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart ...

, or other considerations make certain models more appropriate based on the

dosage form Dosage forms (also called unit doses) are pharmaceutical drug products presented in a specific form for use. They contain a mixture of active ingredients and inactive components ( excipients), configured in a particular way (such as a capsule she ...

, site of activity, or noxious

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

. 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 An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...

. 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 Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

studies; etc.). Importantly, the regulatory guidelines of

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

, 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.

Ethical issues

Animal testing Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of animals, as model organisms, in experiments that seek answers to scientific and medical questions. This approach can be contrasted ...

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 level The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effe ...

s (NOAELs) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass

API An application programming interface (API) is a connection between computers or between computer programs. It is a type of software interface, offering a service to other pieces of software. A document or standard that describes how to build ...

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.

References