Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Carvykti: what flexibility did regulators accept, and why?
ciltacabtagene autoleucel · BCMA CAR-T
Flexibility accepted
SpeciesAccepted
No GLP-compliant formal toxicology studies and no repeat-dose study; no relevant animal species
Why: No relevant animal model; single IV infusion of a patient-specific product unsuitable for immune-competent animals · No relevant species · Within the guideline
“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.”
“The lack of repeat-dose toxicity studies is acceptable based on the fact that cilta-cel will be administered as a single IV infusion, and since cilta-cel is a patient specific product which is not appropriate to administer to immune competent animals.”
GLPVerdict not stated
Only a non-GLP pilot in cynomolgus monkeys with autologous surrogate CAR-T cells, without control groups
“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.”
GenotoxicityCriticised but acceptedBeyond the letter
No classical genotoxicity studies; integration site analysis on final product rather than ex vivo cells
Why: Mature T cells are highly resistant to oncogenic transformation, as documented in the literature · Low-risk modality
“Although the use of ex vivo cilta-cel would have been more suitable for the detection of dominant cell clones, the use of final product for integration analysis is considered acceptable based on the high resistance of mature T cells to oncogene transformation, which is well documented in the literature.”
BiodistributionAccepted
Inadvertent germline transmission risk not addressed by the applicant
Why: EMA guideline: germline transmission risk from genetically modified human cells is low and animal testing not recommended · Within the guideline · Low-risk modality
“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”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Product type, target antigen expression pattern and no relevant animal model · No relevant species · Pharmacology or kinetics
“The lack of any non-clinical reproductive and developmental toxicity studies is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
Same question, other cell therapies
Alofisel
darvadstrocel · Allogeneic adipose MSCNo reproductive and developmental toxicity studies
Amtagvi
lifileucel · TIL therapyNo nonclinical pharmacology studies with the product; published data on similar murine and human tumor-derived T lymphocytes cited instead
Aucatzyl
obecabtagene autoleucel · CD19 CAR-TNo general toxicity studies; no pharmacologically relevant species for human CAR T cells
Breyanzi
lisocabtagene maraleucel · CD19 CAR-TNo pharmacologically relevant species; no conventional single- or repeat-dose toxicity, local tolerance or other traditional studies
ChondroCelect
characterised viable autologous cartilage cells · Autologous chondrocytesAll nonclinical studies non-GLP, run as combined pharmacodynamic/distribution/toxicity studies in nude mice, sheep and goats
Ebvallo
tabelecleucel · EBV-specific allogeneic T cellsNo single- or repeat-dose toxicity studies; no relevant animal model for an HLA-restricted human T-cell product
Encelto
revakinagene taroretcel · CNTF (encapsulated RPE cell implant)No carcinogenicity/tumorigenicity studies; waived on toxicological risk assessments of rhCNTF and residual medium
Gintuit
allogeneic cultured keratinocytes and fibroblasts in bovine collagen · Allogeneic keratinocytes + fibroblastsICH toxicology package (chronic toxicity, genotoxicity, carcinogenicity, DART, safety pharmacology, immunotoxicity) not conducted; partly covered by device biocompatibility testing
Holoclar
autologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem cellsNo in vivo toxicity studies (single dose, repeat dose, immunogenicity); no suitable animal model
Kymriah
tisagenlecleucel · CD19 CAR-TNo single-dose or standard toxicity studies: patient-specific human cell product cannot be given to immunocompetent animals
Lantidra
donislecel · Allogeneic pancreatic isletsNo nonclinical studies with the product; published islet-transplant literature in rodents and monkeys relied on instead
Laviv
azficel-T · Autologous fibroblastsNo preclinical studies of any kind with the product; relied on prior commercial human use and published literature
MACI
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesNo carcinogenicity/tumorigenicity studies
Omisirge
omidubicel · Expanded cord blood HPCIn vivo studies described as GLP lacked QA statements, facility information and deviation reports
Provenge
sipuleucel-T · PAP-GM-CSF (autologous APC)No conventional toxicology or pharmacokinetic studies; risk-based approach justification instead
Rethymic
allogeneic processed thymus tissue · Allogeneic thymus tissueNo nonclinical toxicology studies: no relevant animal species or model
Ryoncil
remestemcel-L · Allogeneic BM-MSCNonclinical studies used surrogate animal-derived MSC and human MSC from an early manufacturing process, not the commercial product
Spherox
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsNo long-term toxicity data: pivotal 9-month GLP sheep study failed through loss of the implants
StrataGraft
allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen · Allogeneic keratinocytes + fibroblastsToxicity assessed only in immunodeficient mice, with significant study design and data limitations
Tecartus
brexucabtagene autoleucel · CD19 CAR-TNo relevant animal model; no GLP formal toxicology studies, only safety observations in a syngeneic mouse surrogate model
Tecelra
afamitresgene autoleucel · MAGE-A4 TCR-TNo in vivo single- or repeat-dose toxicity studies; no appropriate animal model for human TCR-engineered T cells
Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T) · Allogeneic Treg + HSPC + TconNo nonclinical toxicology studies; safety supported by clinical data with a similar cell product
Yescarta
axicabtagene ciloleucel · CD19 CAR-TNo toxicology studies with the product; no relevant animal model, murine surrogate CAR-T used for pharmacology
Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsNo conventional toxicology studies; safety read from two immunodeficient-mouse GvHD pharmacology models
Zemcelpro
dorocubicel · UM171-expanded cord blood CD34+UM171 toxicity studies in rats (single dose) and monkeys (three doses) not GLP-compliant