Abecma
idecabtagene vicleucel · BCMA CAR-TNo single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Breyanzi: what flexibility did regulators accept, and why?
lisocabtagene maraleucel · CD19 CAR-T
Flexibility accepted
SpeciesAccepted
No pharmacologically relevant species; no conventional single- or repeat-dose toxicity, local tolerance or other traditional studies
Why: No species cross-reactivity; immunodeficient xenograft mouse models judged appropriate for autologous cell products · No relevant species · Within the guideline
“JCAR017 T product is an autologous T-cell based treatment characterised by the lack of species cross-reactivity. In this light, traditional toxicity, including single and repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance studies were deemed of negligible utility and thus were not conducted.”
“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”
GenotoxicityAcceptedBeyond the letter
No traditional genotoxicity assays; lentiviral integration site mapping and long-term growth assays used instead
Why: Lentivirus does not preferentially integrate at oncogenic sites; insertional events carry minimal risk of oncogenic transformation · Weight of evidence
“The risk of insertional mutagenesis with lentiviral transduction of the T cells, leading to malignant transformation, was studied using unbiased, genome-wide bioinformatics methods.”
“These data support the conclusion that any insertional events resulting from lentiviral transduction methods used to generate JCAR017 have minimal risk for oncogenic transformation.”
CarcinogenicityAccepted
No carcinogenicity studies; non-conventional 60-day in vitro IL-2-independent proliferation study instead
Why: ICH S9 for anticancer products; cell counts below LLOQ without IL-2 after 60 days · Within the guideline · Weight of evidence
“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”
“Taken together, the applicant provided data supporting the absence of a carcinogenicity potential of JCAR017 T cells, since most samples in the absence of IL-2, after 60 days of culture, resulted below the LLOQ for cell concentration.”
DARTVerdict not stated
No developmental and reproductive toxicity studies
Why: No survival in immunocompetent rodents; graft-versus-host disease in immunocompromised mice · No relevant species
“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”
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
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