Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Lantidra: what flexibility did regulators accept, and why?
donislecel · Allogeneic pancreatic islets
Flexibility accepted
OtherAcceptedBeyond the letter
No nonclinical studies with the product; published islet-transplant literature in rodents and monkeys relied on instead
Why: Published literature supports mechanism of action and need for immunosuppression · Weight of evidence
“No nonclinical studies were conducted with LANTIDRA. Instead, the applicant referenced multiple publications and one manuscript in the BLA submission that evaluated biological activity, local (liver) distribution, and the local (liver) safety of transplanted allogeneic or syngeneic islets in combination with various immunosuppressive agents in diabetic rodent (mice, rats) and nonhuman primate (NHP) models.”
“Review of the nonclinical studies in the published literature provided overall support for the purported mechanism of action of LANTIDRA and the need for an immunosuppressive regimen.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; literature hepatic tumours in rats given low islet numbers judged low risk
Why: Tumours only with low islet numbers; translation of rodent data to the clinic not well understood · Weight of evidence
“Transplantation of high numbers of islets did not result in hepatic neoplasms. Per the proposed label, the recommended minimum clinical dose level for the target population is 4000-5000 EIN/kg.”
“In addition, the translation of these rodent data (rodent donors and recipients) to the clinical scenario is not well understood. Thus, the carcinogenic risk of LANTIDRA in transplanted patients is considered low.”
DARTVerdict not stated
No genotoxicity or developmental and reproductive toxicity studies
“No genotoxicity, carcinogenicity, or developmental and reproductive toxicity (DART) studies were conducted with LANTIDRA.”
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
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
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