Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Kymriah: what flexibility did regulators accept, and why?
tisagenlecleucel · CD19 CAR-T
Flexibility accepted
SpeciesAcceptedBeyond the letter
No single-dose or standard toxicity studies: patient-specific human cell product cannot be given to immunocompetent animals
Why: Patient-specific product not appropriate to administer to immunocompetent animals · No relevant species
“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”
GLPAcceptedBeyond the letter
Nonclinical toxicology studies not GLP-compliant (no independent QA audit, non-GLP raw data storage)
Why: Standard toxicity studies could not be performed due to lack of a relevant animal model · No relevant species
“The nonclinical toxicology studies were not conducted in compliance with Good Laboratory Practice (GLP), because there was no independent Quality Assurance (QA) audit of integral study parts and raw data storage was not applied in compliance with GLP regulations.”
“The absence of GLP compliance is acceptable since standard single or repeat-dose toxicity studies could not be performed due to lack of a relevant animal model.”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or rodent carcinogenicity studies; lentiviral integration site analysis and in vitro/in vivo outgrowth data instead
Why: Rodent assays not appropriate for insertional mutagenesis of modified cells; no adequate alternative animal models · Other reason
“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products. No alternative adequate animal models are available (SmPC, section 5.3).”
BiodistributionAccepted
Risk of inadvertent germline transmission of the CAR construct not addressed nonclinically
Why: EMA germline transmission guideline: risk for genetically modified human cells is considered low · Within the guideline · Low-risk modality
“The risk of inadvertent germline transmission of the CD19 CAR construct has not been addressed; 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 to be low”
Efficacy modelAcceptedBeyond the letter
Pharmacology studies used ALL tumour cells only; no nonclinical pharmacology with DLBCL cells
Why: Clinical experience with the DLBCL indication · Human data
“The lack of non-clinical pharmacology studies with DLBCL cells is acceptable based on the clinical experience with this indication.”
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
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