Gene therapy, somatic or stem cell therapy and tissue engineering are at the cutting edge of translational research – from bench to bedside. More so than with any other, 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 answer this call with a science-driven, risk-based approach, which involves continuous discussions between developers and regulators along 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 adapted control strategy.

The lack of 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 US regulatory classifications
  • Complexity of 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 actions 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