Marketing approvals for cell and gene therapy products in oncology: Current review of EMA and FDA approvals.

Abstract

e15189 Background: Cell and gene therapies (CGT) are emerging as potentially game-changing treatments for relapsing and refractory cancer. To date, there are 9 CGTs approved for different cancers across the US and EU, majority focused on autologous CAR-T cell therapies for hematological cancers. In addition, there are ~1500 CGTs in preclinical and clinical development for treatment of cancers utilizing diverse approaches. The risks involved with CGTs differ from small molecule and biologics, and therefore the data required to demonstrate their safety are also different. To get an insight into what regulatory agencies are looking for demonstrating safety for anticancer CGTs, we analyzed the supporting nonclinical studies for the currently approved therapies. Methods: We reviewed of the European Public Assessment Reports (EPAR) and FDA Summary Basis for Approval (SBA) documents for the 9 approved anticancer CGTs. In particular, we looked into approaches that were accepted by the regulatory agencies and the justification provided. Results: Of the 9 approved CGTs included in the review, there were 6 autologous CAR-T cell therapies for the treatment of different hematological malignancies, 1 PBMC-based cell therapy for prostate cancer, 1 gene therapy treatment for bladder cancer, and 1 oncolytic virus for melanoma. Of the different cell therapies, only for Carvykti was a non-human primate study conducted with autologous CAR-T cells. The absence of toxicity studies for the other cell therapies was justified by the lack of relevant animal models since autologous human cells do not work in immune competent animals. Safety data was gathered along with pharmacology studies and clinical studies. As stated in ICH guideline S9, genotoxicity and carcinogenicity studies are not essential to support clinical trials for therapeutics intended to treat patients with advanced cancer. However, there is a theoretical risk of insertional mutagenesis with gene therapies. This was addressed with the approved gene therapies using studies for integration site analysis and IL-2 independent growth, together with review of published literature and clinical data. Conclusions: The risks associated with each cell and gene therapy are unique. As the science continues to evolve, together with new technologies and approaches, existing regulatory guidance may not cover the nonclinical study requirements for all products. It is therefore crucial for drug developers to take a risk-based approach in determining the need for appropriate nonclinical safety studies. The application of 3Rs to reduce animal use is widely encouraged and therefore regulatory agencies accept lack of non-relevant animal models as well as other science-based justifications for not conducting conventional animal studies.