The European Medicines Agency (EMA) has demonstrated a commitment to a consultative and accommodating approach in an important scientific guideline on investigational advanced therapy medicinal products (ATMPs)[1].
The guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials went through two extensive consultation rounds before being finalized in January this year.
During the second round of feedback, PharmaLex experts in CMC (chemistry, manufacturing and controls) and in clinical development provided impactful stakeholder comments during the second consultation round on several crucial issues.
Key among these were that the guideline makes some important concessions to industry, most notably with regard to the acceptance criterion for replication competent virus (RCV) in replication-deficient viral vectors. This had been a sticking point with industry which pointed out that demonstrating absence of RCV was technically challenging given advances in analytics and associated sensitivity for detecting RCV[2]. While EMA noted it accepted the comment after the first round, the wording had not been changed when the draft guideline update was issued last year, as we previously highlighted.
During the second round of feedback, PharmaLex highlighted this issue, again urging EMA to adapt its stance. When the EMA released its final guidelines and comments from the second public consultation, it was pleasing to see that the acceptance criterion has now been modified. It now states: “For replication-deficient viral vectors, the absence or a justified and minimised upper limit of RCV should be demonstrated using a suitably validated assay[3].”
Secondly, the categorical requirement of clinical validation of surrogate efficacy biomarkers was removed to allow for a scientifically driven justification for the surrogate endpoints. Such a strict approach would have severely compromised development of therapeutics for slow-progressing orphan conditions addressing the unmet need.
These are welcome concessions for industry and PharmaLex is delighted to have played a role, together with other stakeholders, in bringing this important issue to EMA’s attention.
Throughout the robust consultation process, the agency has shown a willingness to accept feedback from a diverse set of stakeholders. A total of 25 stakeholders provided feedback during the second public consultation, including consultancies, scientific consortia, academia, industry, animal rights groups, and individuals.
EMA has long made clear its willingness to collaborate with all stakeholders. The final guideline serves to demonstrate the agency is staying true to its stated objectives.
About the author:
Pam Dhadda is an Associate Director, CMC Cell and Gene Therapy at PharmaLex. She has more than 10 years of experience in the development and manufacture of ATMPS, working extensively in CMC regulatory affairs for cutting-edge cell and gene therapies.
Tiina Palomäki is director, principal consultant, at PharmaLex. She is a geneticist with more than 15 years of pharmaceutical regulatory experience at the national and at the EU level and 13 years in biotechnological and biomedical research. Tiina has in-depth scientific knowledge and regulatory experience with various cell-based and gene therapy products in the areas of immune-oncology, CAR-T products, regenerative therapies, and gene editing.
[1] Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials – Scientific guideline, EMA. 7 January 2025. https://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials-scientific-guideline#:~:text=This%20guideline%20provides%20guidance%20on%20the%20structure%20and,confirmatory%20trials%20with%20advanced%20therapy%20investigational%20medicinal%20products.
[2] Overview of comments received on ‘ Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials ‘ (EMA/CAT/852602/2018). https://www.ema.europa.eu/en/documents/comments/overview-comments-received-draft-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials-first-version_en.pdf
[3] Overview of comments received on ‘Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials’ (EMA/CAT/123573/2024) – second public consultation, EMA. https://www.ema.europa.eu/en/documents/comments/overview-comments-received-guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials-ema-cat-123573-2024-second-public-consultation_en.pdf
