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The basics of preclinical drug development for neurodegenerative disease indications.

Steinmetz KL, Spack EG - BMC Neurol (2009)

Bottom Line: Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines.A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s).Increasingly, private foundations are also funding preclinical work.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biosciences Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. karen.steinmetz@sri.com

ABSTRACT
Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial.

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Related in: MedlinePlus

Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. These preclinical activities provide the basis for an Investigational New Drug (IND) application to the FDA for permission to initiate clinical testing in humans. ADME, absorption, distribution, metabolism, and excretion; API, active pharmaceutical ingredient; PK, pharmacokinetics; Prep, preparation; Tox, toxicity.
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Figure 1: Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. These preclinical activities provide the basis for an Investigational New Drug (IND) application to the FDA for permission to initiate clinical testing in humans. ADME, absorption, distribution, metabolism, and excretion; API, active pharmaceutical ingredient; PK, pharmacokinetics; Prep, preparation; Tox, toxicity.

Mentions: Once a lead candidate is identified, a typical preclinical development program consists of six major efforts: manufacture of drug substance (DS)/active pharmaceutical ingredient (API); preformulation and formulation (dosage design); analytical and bioanalytical methods development and validation; metabolism and pharmacokinetics; toxicology, both safety and genetic toxicology and possibly safety pharmacology; and good manufacturing practice (GMP) manufacture and documentation of drug product for use in clinical trials (Figure 1) The IND application summarizes the results of the above activities for submission to the US Food and Drug Administration (FDA). Table 2 outlines the general organization of an IND application and lists many of the relevant Code of Federal Regulations (CFR) sections for each key component. These activities are seldom discrete and sequential; rather, they are interrelated and often concurrent, with results from each activity informing the other steps as the drug candidate progresses through characterization and optimization (Figure 2).


The basics of preclinical drug development for neurodegenerative disease indications.

Steinmetz KL, Spack EG - BMC Neurol (2009)

Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. These preclinical activities provide the basis for an Investigational New Drug (IND) application to the FDA for permission to initiate clinical testing in humans. ADME, absorption, distribution, metabolism, and excretion; API, active pharmaceutical ingredient; PK, pharmacokinetics; Prep, preparation; Tox, toxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2697630&req=5

Figure 1: Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. These preclinical activities provide the basis for an Investigational New Drug (IND) application to the FDA for permission to initiate clinical testing in humans. ADME, absorption, distribution, metabolism, and excretion; API, active pharmaceutical ingredient; PK, pharmacokinetics; Prep, preparation; Tox, toxicity.
Mentions: Once a lead candidate is identified, a typical preclinical development program consists of six major efforts: manufacture of drug substance (DS)/active pharmaceutical ingredient (API); preformulation and formulation (dosage design); analytical and bioanalytical methods development and validation; metabolism and pharmacokinetics; toxicology, both safety and genetic toxicology and possibly safety pharmacology; and good manufacturing practice (GMP) manufacture and documentation of drug product for use in clinical trials (Figure 1) The IND application summarizes the results of the above activities for submission to the US Food and Drug Administration (FDA). Table 2 outlines the general organization of an IND application and lists many of the relevant Code of Federal Regulations (CFR) sections for each key component. These activities are seldom discrete and sequential; rather, they are interrelated and often concurrent, with results from each activity informing the other steps as the drug candidate progresses through characterization and optimization (Figure 2).

Bottom Line: Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines.A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s).Increasingly, private foundations are also funding preclinical work.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biosciences Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. karen.steinmetz@sri.com

ABSTRACT
Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial.

Show MeSH
Related in: MedlinePlus