What flexibility did FDA and EMA accept for approved gene therapies?

“No in vivo proof-of-concept studies were conducted as no relevant animal disease model for TDT and SCD exists that could be used for evaluation of exa-cel.”

“However, the significance of the in vivo model used for addressing the tumorigenic risk associated with potential off-target editing and/or chromosomal translocations induced during the editing process of the CD34+ hHSPCs is limited, as the validity of the model remains questionable.”

“However, as the likelihood of detecting chromosomal translocations using other methods such as CAST-Seq is expected to be low, omission of additional chromosomal translocation studies is acceptable.”

“The dose level of 1 x 106 CD34+ hHSPCs/mouse administered in the single dose toxicity study is acceptable, despite the fact that there is only a 1.6-fold safety margin as compared to the max. human dose level of 20 x 106 cells/kg.”

“No DART studies were conducted with CTX001. The applicant’s rationale for not conducting DART studies include: i) no CTX001-related pathologic findings were observed in reproductive organs in the completed toxicology study (Study Report No. 1016-2465), ii) very low distribution of CTX001 to reproductive organs was reported in the completed biodistribution study (Study Report No. 1016-2475),”

“As in mice a dose of ~≥ 2.2 fold the clinical dose results in mortality, a safety study in an animal species more close to human would have been helpful to determine the safety profile of the product in relation to the dose.”

“The clinical relevance of the observed Zolgensma related effects in animals, with special attention to occurrence of tissue lesions (primarily liver and ventricle) already found in doses 0.7- to 1.4-fold the clinical dose and the striking mortality in mice at doses 2-3 the clinical dose required discussion.”

“Neither studies on vector integration nor a justification for omission of such studies has been provided in the dossier.”

“The low but persistent levels of vector DNA observed in gonads should have triggered further non-clinical analyses in accordance with the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors (EMEA/273974/2005).”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“As the proposed indication (high grade Bacillus Calmette-Guerin unresponsive non-muscle invasive bladder cancer) is not an advanced cancer indication, the omission of carcinogenicity evaluation needed to be supported with a weight-of-evidence (WoE) approach for both the vector and the novel excipient.”

“Developmental and Reproductive Toxicity studies were not conducted using rAd-IFN/Syn3 or Syn3 alone based on the transient rAd-IFN DNA levels detected in the gonads in the biodistribution analysis of rAd-IFN/Syn3”

“Absence of genotoxicity assessment of rAd-IFN was justified with literature information on the potential for adenoviral integration in the host genome from (bladder) cells of NMIBC patients treated with Adstiladrin (after treatment with BCG).”

“In a GLP cynomolgus monkey study, tissue distribution of rAd-IFN was studied following intravesical administration, but only for bladder, liver, kidney and gonad tissue. A full tissue analysis of the presence and persistence of rAd-IFN has not been performed.”

“These data support the conclusion that transduction of HSCs with BB305 LVV has a low risk for oncogenic transformation. Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”

“Developmental and Reproductive Toxicology Studies: Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered murine beti-cel, based on the results of Study #4”

“Even if not fully compliant to GLP principles, these four in vivo combined studies allowed the assessment of both primary pharmacodynamics and toxicity.”

“No safety pharmacology studies were performed which is considered acceptable as there was no evidence of adverse effects on the circulatory, respiratory, neurologic or digestive systems observed in any of the in vivo studies conducted.”

“AMT-060 instead of etranacogene dezaparvovec was used in several toxicological studies provided. This is regarded acceptable as AMT-060 differs only in two base pairs/one amino-acid to the final GTMP AMT-061”

“As haemophilia B is almost exclusively limited to male patients, and as the current MAA only comprises adult patients, dedicated EFD and PPND studies are not required. Assessment of juvenile toxicity is not warranted in the presented setting.”

“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”

“The dorsal root ganglia analysis was not included in the histopathology, but is to be investigated in juvenile NHP studies as part of the future PIP.”

“No in vivo pharmacology studies were carried out in support of this application, and this is acceptable. The applicant refers to studies published in the literature as supportive information.”

“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”

“No specific developmental and reproductive toxicology studies were conducted by the applicant with eladocagene exuparvovec, in agreement with CHMP. Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”

“Based on the data obtained in the initial RoA study demonstrating superior expression in the target putamen region with iPut administration despite using a 10-fold lower dose as compared to ICV and IT administration, a waiver (EMEA-002435-PIP01-18-M02 [eladocagene exuparvovec]) for the second study was submitted to PDCO and accepted 16 December 2020.”

“The CHMP previously gave scientific advice that such studies would not be needed if ‘biodistribution data in two species and two sexes demonstrate lack of vector distribution to the gonads’. The applicant considers its dataset to be in line with this advice from CHMP.”

“The position at the conclusion of these was that the applicant need provide no experimental data with voretigene neparvovec and that a discussion could suffice, if judged adequate.”

“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”

“Separate safety pharmacology studies were not conducted and are not deemed to be necessary.”

“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”

“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”

“Locally administered adenovectors (SC or intramuscular) have a well-defined and predictable BD profile that is consistent despite differences in vector serotypes, transduction methods, payload, and manufacturing processes; thus, PRGN-2012 is expected to behave similarly to human .”

“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern. In addition, previous data indicates adenovirus has not demonstrated a significant risk for tumorigenicity in humans.”

“The safety data from immune-deficient mice are considered less relevant in predicting the human situation. When it comes to cell therapies, it is well established that animal models are poor predictors of safety in humans.”

“Traditional carcinogenicity studies were not conducted for eli-cel. However, integration site analysis (ISA) was performed on Lenti-D transduced pre-transplant human CD34+ HSCs and post-transplant engrafted bone marrow cells (BMCs) from animals in the GLP toxicology study harvested at 29 and 92 days.”

“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”

“Given that the cells are transduced ex vivo with a replication-incompetent vector and no residual free viral particles are present in the Lenti-D Drug Product, the risk for germ line transmission is considered regarded very limited and rather theoretical.”

“This study did not evaluate the intended clinical product. Animals in this study were administered an AAVRh74var vector encoding the canine factor IX gene. However, safety and activity data resulting from administration of this surrogate would be expected to be representative of BEQVEZ.”

“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”

“Dedicated studies on carcinogenicity were not conducted with fidanacogene elaparvovec. Results obtained from integration analyses might not raise any specific carcinogenicity concern so far.”

“Per the applicant, developmental and reproductive toxicology studies have not been conducted with SRP-9001 for the following reasons:”

“Per the applicant, carcinogenicity/tumorigenicity studies have not been conducted with SRP-9001 for the following reasons: • AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”

“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”

“Accordingly, the SmPC states that carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.”

“The doses administered provide only safety margin of approximately half the highest dose administered in humans (20 x106 CD34+ cells/kg).”

“Preparation of the test items (transduced and mock-transduced) was performed by MolMed and was not conducted to GLP.”

“The applicant argued that there is no existing study design that would be accepted as relevant to assess insertional mutagenesis and the risk of oncogenicity: the validity of any study design is questionable.”

“The CAT did not fully agree with the applicant’s justification for lack of further experimental evidence to compare the effect of a control adeno-associated virus and AMT-011 to study the significance of LPL overexpression.”

“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by sponsor showed no evidence of tumorigenicity in the in vivo studies performed or preferential integration near proto-oncogenes in the integration site analysis (ISA).”

“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”

“As the transduction of the cells occurs ex vivo, the risk for transduction of the gametes and consequently the risk from germline transduction is limited and rather theoretical.”

“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”

“Carcinogenicity Studies: No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”

“Developmental and Reproductive Toxicology Studies: Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered mBMCs transduced with BB305 LVV”

“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”

“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the intracochlear route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”

“As concerns fertility, dedicated fertility studies/embryofoetal studies have not been performed; the applicant argued that males comprise the majority (>99%) of the patient population to be treated with BMN 270”

“The impossibility of using autologous human cells in animal models limits the scope of possible nonclinical studies.”

“Developmental and reproductive toxicity The absence of standard developmental and reproductive toxicity studies with Telethon003 is acceptable in view of the patient population, nature of the gene therapy, and preconditioning regimen with developmental toxicants.”

“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”

“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”

“No carcinogenicity, genotoxicity, or repeat dosing were conducted for OAV101B. These studies are not necessary based on the intended ROA, dosing regimen (i.e., single infusion), known product characteristics, and overall safety profile for this class of product.”

“As the vector backbone is claimed to be non-integrating and non-replicating, it is accepted that the risk for potential germline transmission is negligible and additional DART studies are not required.”

“Studies to evaluate the safety pharmacology, genotoxicity, and carcinogenicity of TUDRIQEV were not conducted. These studies are not warranted based on the product characteristics and safety profile.”