What tox package did approved cell therapies have, from first-in-human to approval?

“A first-in-human, two-part, nonrandomized, open-label, multicenter, dosing finding Phase 1 study to evaluate the safety, efficacy, cellular kinetics/pharmacokinetics of a single dose of ABECMA in subjects with relapsed/refractory multiple myeloma (RRMM) (Study No. CRB-401, supportive study).”

“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”

“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”

“Conventional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals and thus, in vivo nonclinical general safety, genotoxicity, carcinogenicity, developmental safety or reproductive safety studies were not conducted.”

“In the first phase 1 single arm trial CAR T cells in patients with relapsed/refractory MM (Legend -2), ORR for the total population was 87.8%, with 64% CR and 56.8% MRD negative, VGPR was 10.8%, PR was 12.2%, CR (64%) and ORR (87.8%) in patients that had relapsed following IMiDs and PI treatment.”

“No repeat dose toxicity has been performed given there is no relevant nonclinical species and that cilta-cel is administered as a single dose to patients and is anticipated to undergo expansion and persistence following administration.”

“No non-clinical reproductive and developmental toxicity studies have been conducted, which is acceptable based on the type of product and the BCMA expression pattern.”

“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat advanced cancer.”

“Note: No IND(s) is associated with this file. All clinical studies were conducted outside of the United States (OUS).”

“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”

“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”

“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”

“a Phase 1, first-in-human, cell dose escalation and expansion study (ADP-0044-001) in HLA-A*02 patients with MAGE-A4-positive unresectable locally advanced or metastatic tumors.”

“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”

“No animal reproductive and developmental toxicity studies were conducted with TECELRA which is acceptable based on the product characteristics and safety profile.”

“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”

“Dosing of the conditioning chemotherapy agents and Yescarta was based on the results NCI study 09-C￾0082, a Phase 1 open label study of the safety and feasibility of anti-CD 19 CAR T-cells in subjects with advanced B-cell malignancies.”

“No toxicology studies with KTE-C19 were conducted.”

“No studies have been conducted to evaluate the effects of YESCARTA on fertility, reproduction and development. This is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”

“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted. To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors.”

“Study-001 is a prospective, single-arm, multicentre, open-label phase I-II dose de-escalation study of ECT-001-CB in patients who need an allogeneic hematopoietic stem cell transplant but lack a suitable donor. The study was conducted at 2 study sites in Canada and is completed.”

“Repeat dose studies were not conducted and are not relevant for the product as it is applied only once.”

“The applicant contended that such studies are unnecessary as ECT-001-CB is not recommended for use in pregnant women, and only minimal residual amounts of UM 171 were detected in dorocubicel. The absence of such studies is considered acceptable.”

“The applicant did not perform any carcinogenicity studies, which is in line with ICH S9 since the product is to be used in patients with advanced cancer.”

“Two repeat-dose toxicity studies were conducted with human eASC in male and female athymic nude rats (Crl:NIH-Foxn1rnu) via the perianal route, a study with a 3-month post-dose observation period and a study with a 6-month post-dose observation period.”

“Reproductive and developmental toxicity studies have not been performed for Alofisel because preclinical biodistribution studies indicated no migration and integration of eASC into reproductive organs following administration of eASC via different routes.”

“In in vivo tumourigenicity tests, nude mice administered a subcutaneous injection of eASC at various population doubling levels, equal to levels of product for clinical use, all survived to scheduled sacrifice and no tumour-formation was observed.”

“No toxicology studies were conducted for AMTAGVI.”

“No DART studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”

“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for AMTAGVI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”

“The applicant has not performed general toxicity studies with their product.”

“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”

“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (advanced cancer).”

“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.”

“JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice; therefore, traditional DART studies were not conducted.”

“Consistent with regulatory guidance under “Nonclinical Evaluation for Anticancer Pharmaceuticals” (ICH S9, 2009) carcinogenicity studies were not conducted.”

“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.”

“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.”

“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”

“Single and repeat dose toxicity studies were not conducted as due to the species-specific nature of tabelecleucel these studies would yield no additional information to aid in the understanding of its potential toxicity in humans.”

“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”

“Tabelecleucel has not demonstrated, and is not anticipated to have, carcinogenic potential and as stated in ICH S6(R1), standard carcinogenicity bioassays are generally inappropriate for”

“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study in 4–8-month-old minipigs, 4–10-year-old pigs, and catastrophic device failure of NT-501 was evaluated by ITV injection of unencapsulated NTC-201-6A cells into 8-9 month old minipigs.”

“In female rats administered rhCNTF at dose levels of 0, 10, 100, or 300 μg/kg/day SC for 2 weeks prior to mating to postpartum Day 21, mating performance, fertility and gestational parameters were normal. No adverse effects on fetuses or pup postnatal development were reported.”

“This reviewer agrees with the rationale provided in the TRAs for not conducting carcinogenicity/tumorigenicity studies.”

“toxicology, chronic toxicology, genotoxicity, carcinogenicity, reproductive and developmental toxicity, safety pharmacology, and immunotoxicity (http://www.ich.org/cache/compo/276-254-1.html) were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”

“reproductive and developmental toxicity, safety pharmacology, and immunotoxicity (http://www.ich.org/cache/compo/276-254-1.html) were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”

“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”

“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”

“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”

“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”

“The lack of repeat-dose toxicity studies is acceptable based on the fact that tisagenlecleucel will be administered as a single IV infusion, and since tisagenlecleucel is a patient specific product which is not appropriate to administer to immune competent animals.”

“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”

“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products.”

“No toxicology studies with LANTIDRA were conducted. The applicant provided publications assessing the overall safety of islet allografts following intraportal transplantation in Module 4 of the BLA.”

“No DART studies with LANTIDRA were conducted.”

“No carcinogenicity/tumorigenicity studies with LANITDRA were conducted. The applicant cited two publications that examined the potential for hepatic carcinogenicity following intraportal transplantation of allogeneic islets in diabetic rats.”

“No preclinical studies were conducted with this product.”

“reproductive and developmental toxicity, safety pharmacology, and immunotoxicity (http://www.ich.org/cache/compo/276-254- 1.html) were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”

“The pharmacology/toxicology review of the original IND submission supported the sponsor’s decision, noting that these cells are autologous, minimally manipulated, highly unlikely to change in phenotype, dedifferentiate, migrate or become tumorigenic (see Attachment I).”

“To assess the safety of the CF + NF cells following a single intravenous infusion into irradiated NOD-SCID mice.”

“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no test article-related toxicity findings in reproductive organs as assessed by histopathological analyses”

“No carcinogenicity or reproductive and developmental toxicity studies were conducted with OMISIRGE. These studies are not warranted based on the product characteristics and safety profile.”

“consisting of pharmacokinetics, acute toxicology, chronic toxicology, genotoxicity, carcinogenicity, reproductive and developmental toxicity, safety pharmacology, and immunotoxicity (http://www.ich.org/cache/compo/276-254 1.html) were not conducted due to the autologous nature of Sipuleucel-T”

“Conventional reproductive and development toxicity studies were not considered relevant given the nature and the intended clinical use of this autologous cell therapy product.”

“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T.”

“Per the applicant, based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal models, no nonclinical toxicology studies with RVT-802 were conducted.”

“In vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity studies were not conducted with RETHYMIC, nor were they indicated.”

“In vitro or in vivo genotoxicity, carcinogenicity, or developmental and reproductive toxicity studies were not conducted with RETHYMIC, nor were they indicated.”

“In a 90-day GLP repeat dose toxicity study, rats received 2×106, 10×106 or 20×106 rat ceMSC/kg administered in a 5mL/kg dosing volume by tail vein injection over a two-minute period twice per week for 4 weeks and weekly thereafter for a total of 13 dose administrations.”

“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”

“Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies were not performed for RYONCIL. These studies are not warranted based on the product characteristics and safety profile.”

“In the in vivo studies, a single dose of spheroids was either injected or implanted into a knee joint or administered subcutaneously in the back of the animal.”

“Reproductive and developmental toxicity studies were not conducted. In line with guidelines on cell-based medicinal products (EMEA/CHMP/410869/2006), the applicant has provided an acceptable justification for omitting these studies”

“No genotoxicity, conventional carcinogenicity and reproductive- and developmental toxicity studies were performed which is in line with the guideline on cell-based medicinal products (EMEA/CHMP/410869/2006).”

“Within the significant limitations of the study design and data provided, no apparent local or systemic toxicity was observed out to 140 days following topical application of STRATAGRAFT® to immunodeficient mice with an existing wound.”

“No animal reproductive or developmental toxicity (DART) studies were conducted with STRATAGRAFT, which is acceptable, considering the product characteristics and safety profile.”

“No tumor formation was observed for the 20-week study duration. In addition, following a single subcutaneous injection of NIKS keratinocytes in immunodeficient mice, no tumor formation was detected for the 23-week study duration.”

“KTE-X19 is intended to be administered as a single infusion treatment therefore no repeat-dose toxicities study was conducted.”

“The lack of non-clinical reproductive and developmental toxicity studies is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”

“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”

“No toxicology studies were conducted for TREGZI. This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”

“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”

“No genotoxicity, carcinogenicity, and developmental and reproductive toxicity (DART) studies were conducted for TREGZI. These studies are not warranted based on the product characteristics, biological activity, and safety profile.”

“Single dose toxicity has been assessed in the immunodeficient animal models in the pharmacodynamic studies. Repeat dose toxicity Repeat-dose toxicity studies were not submitted (See discussion on non-clinical aspects).”

“Conventional toxicology, carcinogenicity, mutagenicity and reproductive toxicology studies have not been performed, which is considered acceptable.”

“The MM-TK DP is a species specific product and therefore standard carcinogenicity studies using rodents or non-human primates as described in the ICH guidelines are not appropriate.”