What flexibility did FDA and EMA accept for approved cell therapies?

“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”

“The risk of inadvertent germline transmission of the CD19 CAR construct has not been addressed; however, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors, EMEA/273974/2005 indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered to be low”

“The applicant has chosen immunocompromised athymic rats to perform the biodistribution, toxicology and tumourigenicity studies. The applicant considers that this was done in order to minimize the immune recognition and potential rejection of human eASC in the experimental animal models and to extend Cx601 persistence”

“Studies conducted in horses and rabbits compared ACI-Maix or empty defects to analogous products consisting of ACI-Maix seeded with rabbit or horse cells.”

“In line with guidelines on cell-based medicinal products (EMEA/CHMP/410869/2006), the applicant has provided an acceptable justification for omitting these studies: Spherox contains autologous cells with a local mechanism of action, and the risk for biodistribution of cells is limited.”

“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”

“The MM-TK DP is a species specific product and therefore standard carcinogenicity studies using rodents or non-human primates as described in the ICH guidelines are not appropriate.”

“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”

“Further, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors, EMEA/273974/2005 indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered to be low and, as animal testing of human cells may be difficult or not meaningful, non-clinical germline transmission studies of human genetically modified cells are not recommended.”

“No dedicated Safety pharmacology and Pharmacodynamic drug interactions studies have been performed. Based on the nature of the product and in line with the Guideline on the quality, non­clinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014), this was considered acceptable.”

“Similar to the pharmacokinetic evaluation, the non-clinical safety evaluation of cilta-cel was limited due to the lack of a relevant animal model. Therefore, no GLP-compliant formal toxicology studies were performed.”

“It is unclear if changes in complete blood counts were related to cyclophosphamide pretreatment or NHP cilta-cel because the study did not include cyclophosphamide only and/or vehicle control groups.”

“The risk of inadvertent germline transmission of the cilta-cel has not been addressed by the applicant. However, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors, EMEA/273974/2005, indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered low”

“Per the applicant, conventional nonclinical toxicology studies were not conducted because they do not yield clinically relevant information for a CAR T cell product.”

“Traditional non-clinical pharmacokinetic studies (absorption, distribution, metabolism, excretion and in vitro drug-drug interaction) have not been conducted because obe-cel is an autologous gene therapy product and there is no pharmacologically relevant species. This is agreed.”

“As the observation period of the single dose studies described above were up to 12 weeks in mice, 14 weeks in sheep and 53 weeks in goats, these studies are considered to be sufficient to assess the long-term effects of ChondroCelect.”

“Taking into account the nature of the product and its intended clinical use the risk for reproductive and developmental toxicity is considered to be negligible.”

“A battery of genotoxicity studies was conducted to support licensure of NT-501 in keeping with ISO-10993, guidance for biological evaluation of medical devices.”

“The device used in this study is an early prototype that is 11 mm in length (the proposed clinical device is 6.5 mm). Thus, this study is preliminary regarding assessing the overall pharmacology of the product, NT-501.”

“Although the sponsor’s hypothesis is that Apligraf® functions to enhance wound healing by secondary intention, the results from the in vivo studies in the murine wound models did not provide direct evidence to support this position.”

“The potential for Apligraf® to induce an alloimmune response by indirect allorecognition was not evaluated.”

“However, no nonclinical pharmacology studies were conducted; please refer to the clinical review memo for confirmation of these claims.”

“No PK studies were conducted. The applicant refers to the three completed clinical trials: STRATA2011, STRATA2014, and STRATA2016.”

“The risk of inadvertent germline transmission of the CD19 CAR construct has not been addressed; however, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors (EMEA/273974/2005) indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered to be low”

“To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors. The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”

“No genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with LANTIDRA.”

“In line with Annex I, part IV of Directive 2001/83/EC applied to ATMP, a risk-based approach discussion was provided by the applicant to further justify the extent of non-clinical data provided in the dossier and particularly the lack of pharmacokinetic and toxicity studies.”

“Based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal species/models, no nonclinical toxicology studies with RVT-802 were performed.”

“JCAR017 T product is an autologous T-cell based treatment characterised by the lack of species cross-reactivity. In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”

“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”

“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”

“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”

“Safety pharmacology studies were not conducted due to the species-specific nature of tabelecleucel and the limited applicability of non-human toxicology models.”

“Conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable for tabelecleucel as described in the CHMP’s 2006 Guideline on human cell based medicinal products (EMEA/CHMP/410869/2006).”