Gene and cell therapies, collectively known as Advanced Therapy Medicinal Products (ATMPs), represent one of the most exciting and challenging frontiers in modern medicine. These therapies have the potential to treat, and even cure, diseases once considered untreatable.
But with innovation comes complexity. The regulatory landscape for ATMPs is highly specialized, evolving, and globally fragmented. Successfully bringing an ATMP to market requires a deep understanding of the unique requirements set by the FDA, EMA, MHRA, and other authorities, as well as a robust strategy for quality, safety, and long-term follow-up.
1. What Are ATMPs?
ATMPs are a class of biological products that include:
– Gene Therapy Medicinal Products (GTMPs): Introduce or modify genetic material to treat or prevent disease.
– Somatic-Cell Therapy Medicinal Products (CTMPs): Use cells that have been manipulated or processed to achieve therapeutic effects.
– Tissue-Engineered Products (TEPs): Repair, regenerate, or replace human tissue.
These therapies often combine biological, device, and manufacturing challenges, making their regulation more complex than conventional biologics or drugs.
2. The Global Regulatory Landscape
While the core principles — safety, efficacy, and quality — are universal, the regulatory frameworks differ across regions.
U.S. – Food and Drug Administration (FDA)
– Regulated under 21 CFR Parts 1271 and 312 (for clinical trials) and 21 CFR Part 601 (for Biologics License Applications, or BLAs).
– Overseen by the Center for Biologics Evaluation and Research (CBER), Office of Tissues and Advanced Therapies (OTAT).
– Pathways: IND → BLA, with pre-IND and Type B meetings strongly recommended.
– Expedited programs include RMAT (Regenerative Medicine Advanced Therapy), Breakthrough Therapy, and Fast Track designations.
European Union – European Medicines Agency (EMA)
– Governed by Regulation (EC) No 1394/2007 on ATMPs.
– Reviewed through the Committee for Advanced Therapies (CAT) and Committee for Medicinal Products for Human Use (CHMP).
– Centralized authorization is mandatory for all ATMPs.
– Early dialogue options: Scientific Advice, Innovation Task Force (ITF) meetings, and PRIME designation for accelerated development.
United Kingdom – MHRA (Post-Brexit)
– Follows the EU framework but has its own ATMP classification and approval process.
– Offers Innovative Licensing and Access Pathway (ILAP) to accelerate time to market.
Japan – PMDA
– Regulated under the Pharmaceuticals and Medical Devices Act (PMD Act).
– Includes conditional and time-limited approval system for regenerative medicine products.
– Supports parallel scientific consultations for global harmonization.
3. Step-by-Step: Navigating an ATMP Submission
Step 1 – Determine ATMP Classification Early
In both the U.S. and EU, sponsors can request formal classification to confirm whether their product qualifies as an ATMP (and which subtype).
– This step determines the applicable regulatory pathway, preclinical expectations, and required documentation.
Step 2 – Plan Preclinical and Clinical Strategy
ATMPs often lack traditional animal models, so regulators expect scientifically justified, product-specific approaches.
– Include data on biodistribution, tumorigenicity, immunogenicity, and genotoxicity.
– For gene therapies, define the vector design, transgene stability, and off-target effects early.
Step 3 – Request Early Regulatory Engagement
– Engage FDA or EMA early through pre-IND, Type B, or scientific advice meetings.
– Discuss manufacturing controls, potency assays, and long-term follow-up.
– Early feedback reduces rework and delays later in development.
Step 4 – Establish GMP-Compliant Manufacturing
The manufacturing process for ATMPs is often complex and product-specific.
– Follow ICH Q5A–Q5E, Annex 2 (EU GMP for Biologics), and FDA’s CMC guidance for gene and cell therapy products.
– Validate critical raw materials, including cell banks and viral vectors.
– Maintain chain of identity and chain of custody for patient-specific (autologous) therapies.
Step 5 – Prepare the Submission Dossier
The submission follows the Common Technical Document (CTD) structure but requires ATMP-specific content:
| CTD Module | ATMP-Specific Focus |
|---|---|
| Module 1 | Administrative and regional information |
| Module 2 | Quality Overall Summary, nonclinical and clinical overviews |
| Module 3 | CMC data, characterization, comparability studies, and viral vector details |
| Module 4 | Nonclinical studies (biodistribution, immunogenicity, etc.) |
| Module 5 | Clinical trials, long-term follow-up plans, and safety monitoring |
Step 6 – Leverage Expedited Programs
Regulators recognize the urgent medical need for ATMPs and offer accelerated programs:
– FDA RMAT or Breakthrough Designation
– EMA PRIME or Conditional Approval
– PMDA Sakigake or Conditional Early Approval
These programs enable rolling submissions, priority reviews, and closer regulatory collaboration.
Step 7 – Plan for Post-Approval Commitments
Approval is not the finish line. ATMP sponsors must commit to:
– Long-term follow-up studies (often 15 years for gene therapy).
– Postmarket safety reporting (per ICH E2E, GVP Modules).
– Ongoing GMP compliance and product comparability data for process changes.
4. Common Pitfalls to Avoid
– Insufficient CMC data: The leading cause of regulatory delays for ATMPs.
– Inadequate potency assays: Regulators expect validated, product-relevant assays.
– Incomplete comparability studies: Especially after manufacturing changes.
– Lack of traceability: Missing documentation of donor cells or vector lots.
– Delayed regulatory interaction: Waiting too long to request advice or meetings.
Early planning, clear communication, and risk-based documentation are essential to success.
How Avendium Can Help
At Avendium, we help life science and biotech companies navigate ATMP development and regulatory submissions from concept through approval.
Our experts support:
– ATMP classification and regulatory strategy development.
– CMC gap assessments and comparability documentation.
– Pre-IND, EMA Scientific Advice, and PMDA consultation preparation.
– Quality and compliance system design for cell and gene therapy facilities.
– Postmarket safety reporting and long-term follow-up program setup.
Contact us today to learn how we can help guide your ATMP submission strategy.