Gene therapy, somatic or stem cell therapy and tissue engineering are at the cutting edge of translational research, also known as Advanced Medicinal Therapy Products (ATMP). The intrinsic complexity of this class of drugs requires new approaches in the demonstration of a positive benefit/risk ratio. While requirements for quality, safety and efficacy apply for these innovative products as for all other drugs, regulators apply a science-driven, risk-based approach, which involves continuous discussions between developers and regulators along with nonclinical and clinical development.
Mainly based on starting materials of human origin and often produced with sophisticated manufacturing processes, these advanced therapy medicinal products involve complex procurement, testing, processing, preservation, storage, and distribution. They require sequential testing and release from raw and starting materials to the drug product, as well as an adapted control strategy.
The lack of a relevant comparator or the difficulty to obtain sufficient data (in particular considering that advanced therapies are often indicated in orphan conditions, or are autologous) often hinders a meaningful comparison with therapeutic alternatives and makes more complex the determination of a reimbursed price. Therefore, payers need to be engaged early enough to develop innovative approaches for suitable pricing schemes.
Key challenges encompass:
- Regulatory classification and strategy, differences in EU and the US
- The complexity of the procurement framework
- Product characterization (identity, viability, purity, potency, viral safety)
- Release testing (due to short shelf life and limited sample availability)
- Sterility assessment (with results often not available prior to infusion to patient)
- Complex mode of action and challenges to develop relevant potency assays
- Definition of product heterogeneity versus impurity
- Process and analytical development/validation, comparability and process reproducibility, cGMP alignment
- Donor testing (US/EU differences)
- Relevance of animal models, biodistribution, in vivo cell persistence, immunotoxicity, tumorigenicity
- “Safe dose” for First-in-Human, long-term clinical follow-up (cells/viral vector persistence)
- Market access strategy and value demonstration to payers
VCLS offers a broad range of services to cell and gene therapy developers
VCLS worked hand in hand with EMA to create the 1st regulatory guidance on ATMP in 2000. We provide end-to-end solutions and targeted services from regulatory strategy, CMC/quality, nonclinical, clinical development, market access to post-approval regulatory life cycle management.
Regulatory strategy and submission:
- Preparation and submission of CTAs and INDs, including country-specific GMO authorizations
- Protocol review
- Gap analysis/conversions from the US to/from the EU
- Orphan Drug Designation (ODD)
- Paediatric Investigation Plans (PIP, PSP)
- Regulatory Agency Meetings at all stages of development (pre-IND, End-of-Phase 2, Innovation Task Force Meetings, Scientific Advice)
- Authoring of MAA and BLA
CMC:
- Manufacturing process review, design & scale-up
- Raw material testing
- DS vs. DP classification
- Potency assays, release testing
- Impurity/purity
- Viral safety control
- Control strategy
- Interface with CMO
- Technology Transfer
- Comparability planning
- IMPD / Module 3
Nonclinical Development:
- Gap analysis
- Elaboration of the nonclinical development plan
- Investigator’s brochure authoring, studies report
Pharmacovigilance:
- Eudravigilance registration
- Safety database hosting
- Case management / Reports
Solutions 
