Drugs: Preclinical Development
Preclinical development enables drug candidates to progress from research to development, by linking discovery in the laboratory to testing in humans. Analytical methodology and manufacturing processes are established and ramp up towards GMP compliance to support initial clinical trials. The product pharmacology, pharmacokinetic/ biodistribution, and toxicity profiles are explored, which ultimately aim to support the intended clinical trial design for first-in-human testing.
Pharmacology, pharmacokinetics, and toxicity are tested either In Silico, in vitro or in vivo in nonclinical studies – for some of them under a regulatory-compliant setting, which enables the extrapolation of animal data into humans – particularly to estimate a safe starting dose in the clinic.
This first stage of development also aims to identify the target clinical indication(s) and anticipated labeling claims, and to outline future development. A dialogue is often initiated with regulators on the regulatory strategy, manufacturing and controls, and nonclinical and clinical development programs. The Target Product Profile is primarily created as an aspirational document to guide initial development activities.
Key challenges encompass:
- For which indication to first develop the product?
- Is there an animal model and how relevant is it?
- Will the overall nonclinical program support the intended First-In-Man (FIM) clinical trial?
- Will the FIM trial answer the required questions?
- Is the manufacturing process adapted/able for future clinical development?
- Are all analytical methods necessary at this stage in place to assess quality?
- How realistic is the overall product development plan?
- What is the product time-to-launch?
- Understand the product’s market, regulatory environment, and payer adoption drivers
- Identify optimal therapeutic indication(s) and labeling claims
- Outline a preliminary Target Product Profile (TPP), including commercial and clinical considerations
- Identify the path to market
- Outline a high-level development plan
- Identify and assess product-related risks
- Define pre-clinical data necessary to enter the clinic
- Identify predictive models and alternatives to animal testing
- nonclinical product testing (including immunogenicity)
- Identify product-related risks to be assessed and managed, key requirements for analytical methods and manufacturing processes development, regulatory requirements to adapt manufacturing and controls to subsequent stages of development
- Select the most efficient predictive models and tools for linking manufacturing attributes with product specifications
- Develop and qualify analytical methods (including potency assays)
- Select, characterize and calibrate reference standard
- Identify applicable GMP, and GLP requirements
- Ensure compliance: initiate SOP writing, audit
- Seek regulators’ advice on nonclinical program, regulatory strategy, clinical development plan, manufacturing and testing approach
- Input regulators’ opinions and recommendations into the development program, anticipate development obstacles, maximize chances to obtain approval for the product to move along the development timeline