Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
ChondroCelect: what flexibility did regulators accept, and why?
characterised viable autologous cartilage cells · Autologous chondrocytes
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
All nonclinical studies non-GLP, run as combined pharmacodynamic/distribution/toxicity studies in nude mice, sheep and goats
Why: Specificity of the development programme for this product · Other reason
“These studies were non-GLP which is not in conformity with the pharmaceutical standards. However, these deficiencies were considered by CHMP to be tolerable in view of the specificity of the development programme for this particular product.”
“The implications of this deficiency to the validity and significance of the safety data collected in the pivotal goat study are considered tolerable.”
Study lengthAccepted
No repeat-dose toxicity study; single-dose implantation studies with observation up to 12 weeks (mice), 14 weeks (sheep), 53 weeks (goats)
Why: Long single-dose observation periods; omission in line with cell-based product guideline EMEA/CHMP/410869/2006 · Within the guideline · Weight of evidence
“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.”
“Therefore the omission of repeat-dose toxicity studies is in line with the EMEA guideline EMEA/CHMP/410869/2006.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity study in vivo; in vitro senescence study of serially passaged human chondrocytes instead
Why: No immortalisation during limited in vitro culture; tumorigenic risk negligible · Weight of evidence
“In order to address the carcinogenic potential of ChondroCelect, the Applicant performed an in vitro study to evaluate senescence of human articular chondrocytes after serial passaging, using ChondroCelect culture conditions.”
“The results provide sufficient evidence that immortalisation of human chondrocytes during limited time in in vitro culture conditions would not occur, and that the risk of tumorigenic growth is negligible. In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
DARTAccepted
No reproductive or developmental toxicity studies
Why: Nature of the product and its intended clinical use make the risk negligible · Low-risk modality · Within the guideline
“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.”
“Therefore, the omission of reproductive and developmental toxicity studies in the development program for ChondroCelect is acceptable and in line with the EMEA guideline EMEA/CHMP/410869/2006.”
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
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