Alofisel
darvadstrocel · Allogeneic adipose MSCNo reproductive and developmental toxicity studies
Abecma: what flexibility did regulators accept, and why?
idecabtagene vicleucel · BCMA CAR-T
Flexibility accepted
SpeciesVerdict not stated
No single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Why: Autologous human T cells do not graft in immunocompetent animals · No relevant species
“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.”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or carcinogenicity studies; vector integration site analysis of clinical lots and IL-2-independent growth assay instead
Why: No preferential integration near genes of concern and no transformation observed; tumorigenic risk negligible · Weight of evidence
“No traditional genotoxicity assays and carcinogenicity assessments were performed for bb2121. The safety of bb2121 was assessed by evaluating the integration profile of the lentiviral vector.”
“No tumorigenic transformation of T cells following transduction in the ide-cel manufacturing process was observed in the IL-2 independent growth study. Moreover, there were no substantial changes in CAR T cell phenotypes or CD4:CD8 ratio, or substantial decreases in clonal diversity under any condition tested.”
DARTAcceptedBeyond the letter
No animal reproductive and developmental toxicity studies
Why: Acceptable based on the product characteristics · Low-risk modality
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
BiodistributionVerdict not stated
No germline transmission studies
Why: EMA guideline: germline risk of genetically modified human cells is low; animal testing of human cells not meaningful · Within the guideline · Low-risk modality
“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.”
Safety pharmacologyAccepted
No dedicated safety pharmacology studies
Why: Nature of the product and in line with EMA gene therapy guideline · Within the guideline
“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.”
Same question, other cell therapies
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
Carvykti
ciltacabtagene autoleucel · BCMA CAR-TNo GLP-compliant formal toxicology studies and no repeat-dose study; no relevant animal species
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