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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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Cash flow 'Valley of Death' diagram. The cash flow 'Valley of Death' as a function of development stage (time) with typical funding sources at various stages (adapted from [12]). RAID, Rapid Access to Interventional Development; SBIR, Small Business Innovative Research; RAPID, Rapid Access to Preventive Intervention Development; STTR, Small Business Technology Transfer.
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Figure 3: Cash flow 'Valley of Death' diagram. The cash flow 'Valley of Death' as a function of development stage (time) with typical funding sources at various stages (adapted from [12]). RAID, Rapid Access to Interventional Development; SBIR, Small Business Innovative Research; RAPID, Rapid Access to Preventive Intervention Development; STTR, Small Business Technology Transfer.

Mentions: The transition from research and preclinical development to the clinic is so perilous that it is frequently referred to as the 'Valley of Death' [11,12] (Figure 3). Funding challenges contribute to this bleak landscape. Successful transitioning often requires a combination of both private and public sector investments targeting the most promising drug candidates. Several public and private sources are available to provide funding for preclinical activities (Table 3)


The basics of preclinical drug development for neurodegenerative disease indications.

Steinmetz KL, Spack EG - BMC Neurol (2009)

Cash flow 'Valley of Death' diagram. The cash flow 'Valley of Death' as a function of development stage (time) with typical funding sources at various stages (adapted from [12]). RAID, Rapid Access to Interventional Development; SBIR, Small Business Innovative Research; RAPID, Rapid Access to Preventive Intervention Development; STTR, Small Business Technology Transfer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Cash flow 'Valley of Death' diagram. The cash flow 'Valley of Death' as a function of development stage (time) with typical funding sources at various stages (adapted from [12]). RAID, Rapid Access to Interventional Development; SBIR, Small Business Innovative Research; RAPID, Rapid Access to Preventive Intervention Development; STTR, Small Business Technology Transfer.
Mentions: The transition from research and preclinical development to the clinic is so perilous that it is frequently referred to as the 'Valley of Death' [11,12] (Figure 3). Funding challenges contribute to this bleak landscape. Successful transitioning often requires a combination of both private and public sector investments targeting the most promising drug candidates. Several public and private sources are available to provide funding for preclinical activities (Table 3)

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