Drugs: Early Stage Clinical Development
Early clinical development initiates testing in humans, corresponding to Phases 1 and 2a exploratory studies. The investigational product is administered to small groups of healthy volunteers or patients to assess safety and to determine a safe dosing range. A clinical safety system is established to monitor the product’s safety profile and assess significant findings for reporting to regulatory authorities.
Concomitantly, subsequent trials are outlined and readied. Safety, clinical endpoints, patient populations, biomarkers and relevance of comparators are the principal topics of scientific advice meetings with regulators at this stage. Reimbursement environment analysis is undertaken in order to begin to apprehend reimbursement or access challenges, current perceptions of standard of care, defining unmet need and typical treatment pathways. Manufacturing processes are scaled up to provide sufficient drug product for larger clinical trials.
Key Challenge Encompass:
- Should healthy volunteers or patients be recruited for phase 1?
- What are the cost and timeline to complete the program?
- Is the dose-range finding plan in Phase 1/2a studies adequate to identify the optimal dose for pivotal studies?
- Is a pediatric development plan necessary? What is the right time for this?
- When and how to scale-up manufacturing processes?
- Is all the CMC information available to assemble the IMPD?
- Extrapolate animal data to humans for designing clinical protocols (including drug schedule, route of administration, subject/patient follow-up)
- Outline clinical development up to marketing, with for each trial: synopsis, endpoint(s) and surrogate marker(s), patient populations, designs, study feasibility in the targeted countries
- Organize clinical advisory board
- Design development plan for companion diagnostic and/or delivery device
- Identify opportunities for early access (US expanded access / EU compassionate use programs)
- Anticipate process transfer if needed and manufacturing campaign
- Anticipate product release (identify testing labs, methods needed)
- Obtain regulators’ input on manufacturing plan, analytical testing, nonclinical and clinical development, regulatory strategy, (Scientific Advice/Protocol assistance, Pre-IND meetings, End-of-Phase 1 meeting, End-of-Phase 2 meeting, parallel advice)
- Obtain clinical trial approval from US FDA and Institutional Review Boards, EU Competent Authorities, and Ethics Committees (Investigational New Drug applications, Clinical Trial Applications, respectively)
- Obtain feedback from payers – possibly jointly with regulators – on late-stage clinical design
- Develop IND / CTA, Investigational Medicinal Product Dossier, protocol, Case Report Forms (CRFs) Informed Consent Forms and Investigator Brochure(s)
- Assemble and submit IND / CTA packages
- Protocol amendments
- Interim data analysis
- Execution and audit of clinical trial
- Set up a lean clinical safety system, that will accommodate clinical-stage requirements and adapt to a post-marketing pharmacovigilance setting in full compliance with ICH, US and EU requirements
- Manage and report safety cases (expedited and periodic reporting)
- Monitor safety profile, organize Data Safety Monitoring Boards (DSMB)
- Provide support and recommendations for scale-up of manufacturing processes, integrate Quality-by-Design (QbD) potential
- Drug product formulation development
- Product characterization, specifications, and associated analytical methods
- Support process and method transfer, scale-up of manufacturing processes and design of comparability strategy
- Design quality and GMP compliance (drug substance and drug product, from suppliers to product release, through analytical laboratories)
- Collect stability data
- Prepare for audits and GMP inspections
- Define the burden of illness
- Scan and anticipate competitive environment
- Outline economic models
- Ensure that clinical trials address payers requirements