Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
MACI: what flexibility did regulators accept, and why?
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytes
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity/tumorigenicity studies
Why: Local implantation site, no systemic distribution, membrane not genotoxic · Pharmacology or kinetics · Weight of evidence
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration, and the lack of genotoxicity or mutagenicity observed for the ACI-Maix membrane in biocompatibility tests.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Local knee administration with minimal systemic entry; autologous, terminally differentiated cells · Pharmacology or kinetics · Low-risk modality
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically. As MACI is derived from autologous, mature, terminally differentiated cells, the concern for potential DART, as well as adverse effects on lactation, are mitigated.”
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
OtherVerdict not stated
Pivotal safety and activity studies used analogous products (rabbit or horse cells on the same membrane); combined pharmacology-toxicology horse study
“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.”
GLPCriticised but acceptedBeyond the letter
Non-GLP in vitro fibrin glue toxicity study poorly designed and reported; only summary information provided
Why: Study not critical given the other nonclinical and clinical data · Weight of evidence · Human data
“This in vitro study to assess the toxicity of various fibrin glues/sealants on human chondrocytes was poorly designed, conducted, and reported. Thus, this reviewer is not able to independently verify the study sponsor’s conclusion.”
“Only summary information from this study was provided. However, since this study is not critical for determining the safety and activity of MACI in the context of the other non-clinical and clinical data submitted, a complete study report was not requested.”
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
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
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