PRECLINICAL DEVELOPMENT: AN OVERVIEW
Preclinical development is the essential stage of early drug development performed prior to first-in-man clinical trials.
This critical phase encompasses all the tasks required to advance a new drug candidate through manufacturing, formulation, pharmacology, pharmacokinetic and toxicology testing. All of these tasks must be performed in a sound, regulatory compliant manner to ensure the quality of data and the safety of future clinical trial participants.
CRITICAL TASKS IN THIS PROCESS INCLUDE:
Defining the clinical strategy
It is best to define the clinical needs as early as possible and to select the primary target indication. The product’s dosing schedule, administration route, as well as the characteristics of the targeted patient population, should be carefully considered.
Hit, lead and clinical candidate selection
The selection of hits, leads and, finally, a clinical trial candidate should be based on criteria including:
• Target specificity
• Minimal off-target effects
• In vivo efficacy and benchmarking
• Chemical feasibility
• IP issues
Chemistry, Manufacturing and Controls (CMC) and pharmaceutical development
The manufacture of the drug substance and of the investigational medicinal product, on a large scale, in a regulatory compliant industrial environment is an underestimated but critical aspect of non-clinical development. The corresponding activities start with clinical candidate selection and continue throughout clinical development. Development of an appropriate formulation should not be overlooked.
Both in vitro and in vivo studies are needed to demonstrate the efficacy of the product and to characterise the dose-effect relationship. They should be designed to confirm the mechanism(s) of action and provide preliminary safety data.
Bioanalytical method development
Specific bioanalytical methods must be developed for the species used and the types of samples tested in the pharmacology and GLP-compliant toxicology studies. They also need to be adapted for human samples. Validation studies should be undertaken as appropriate.
Toxicology and safety pharmacology
The toxicology and safety pharmacology studies should characterise the toxicity profile of the clinical candidate in relevant animal species. This allows the maximum tolerated and safe doses to be determined, as well as the target organs of its toxicity. Exposure-effect relationships should also be characterised (toxicokinetics). These studies will help determine the initial clinical dose.
Writing a compliant Clinical Trial Application
The key elements of a European clinical trial application dossier usually include:
• The Investigational Medicinal Product Dossier (IMPD)
• The Investigator's Brochure (IB)
• The clinical trial protocol
• The patient information leaflet and informed consent form