Pre-clinical development
Encyclopedia
In drug development
, pre-clinical development is a stage of research that begins before clinical trial
s (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 (also named preclinical studies and nonclinical 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. Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics
(PD), pharmacokinetics
(PK), ADME
, and toxicity testing through animal testing
. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trial
s in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to 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 Good Laboratory Practice
s (GLP) 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.
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. 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 drugs 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 studies; etc.).
Based on pre-clinical trials, No Observable Effect Levels (NOEL) 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.
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.
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
, pre-clinical development is a stage of research that begins before clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s (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 (also named preclinical studies and nonclinical 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. Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
(PD), pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
(PK), ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
, and toxicity testing through animal testing
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to 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 Good Laboratory Practice
Good Laboratory Practice
In the experimental research arena, the phrase good laboratory practice or GLP specifically refers to a quality system of management controls for research laboratories and organizations to try to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of chemical ...
s (GLP) 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
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
tests will be performed. Studies of a drug's toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
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.
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
Murinae
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. This subfamily is larger than all mammal families except the Cricetidae and Muridae, and is larger than all mammal orders except the bats and the remainder of the...
and canine
Beagle
The Beagle is a breed of small to medium-sized dog. A member of the Hound Group, it is similar in appearance to the Foxhound, but smaller, with shorter legs and longer, softer ears. Beagles are scent hounds, developed primarily for tracking hare, rabbit, and other game...
, although primate
Macaque
The macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
and porcine
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
are also used. The choice of species is based on which will give the best correlation to human trials. Differences in the gut
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, enzyme activity, circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, or other considerations make certain models more appropriate based on the dosage form
Dosage form
-Introduction:Dosage forms are a mixture of active drug components and nondrug components. Depending on the method of administration they come in several types. These are liquid dosage form, solid dosage form and semisolid dosage forms. A Liquid dosage form is the liquid form of a dose of a...
, 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
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired 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. If it results from an unsuitable or incorrect dosage or...
. Depending on a drugs 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 studies; etc.).
Based on pre-clinical trials, No Observable Effect Levels (NOEL) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...
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.
Animal testing
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...
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.