Table 2.

Features of the Development Programs for Six Approved Oncolytic and Gene Therapy Products

	Talimogene Laherparepvec	Tisagenlecleucel	Axicabtagene Ciloleucel	Voretigene Neparvovec	Onasemnogene Abeparvovec	Brexucabtagene Autoleucel
Indicationa to address unmet medical needs	recurrent melanoma	relapsed and refractory ALL	relapsed and refractory DLBCL	retinal dystrophy	spinal muscular atrophy	relapsed and refractory MCL
Serious disease	√	√	√	√	√	√
Rare disease	√	√	√	√	√	√
Product construct	oncolytic HSV with transgene for GM-CSF	Tb cells with CAR to CD19 transduced with LV vector	Tb cells with CAR to CD19 transduced with ɣ-RV vector	AAV2 vector with transgene for RPE65	AAV9 vector with transgene for SMN1	Tb cells with CAR to CD19 transduced with ɣ-RV vector
Route of administration	intralesional	intravenous	intravenous	subretinal	intravenous	intravenous
Significant modifications in product manufacturing during development	√	√	√	√	√	√
Product comparability studies completed	√	√	√	√	√	√
Non-clinical studies conducted	in vitro studies with the human product and in vivo (TB and non-TB rodents) studies with an analogous murine product to assess AT activity, safety, and BD after IT and IV administration	in vitro and in vivo (TB and non-TB rodents) studies to assess specificity, AT activity, safety, and BD after IV administration	in vitro studies with the human product and in vivo (TB rodents) studies with an analogous murine CAR construct to assess specificity, AT activity, and safety after IV administration	in vivo studies in RPE65 mutant and normal-sighted dogs, and normal-sighted NHP to evaluate POC,c safety, immunogenicity, and BD after single and repeat SR administration	in vivo studies in a murine spinal muscular atrophy model, healthy mice, and NHP to evaluate POC,d safety, and BD after single IV administration	in vitro studies with the human product and in vivo (TB rodents) studies with an analogous murine CAR construct to assess specificity, AT activity, and safety after IV administration
Clinical studies demonstrating the primary evidence of effectiveness [number of patients (n), study duratione]	one multicenter trial [n = 436, ∼3.75 years]	one multicenter trial [n = 88, ∼1.75 years]	one multicenter trial [n = 111, ∼2 years]	one two-center trial with crossover of control to treatment at 1 year followed up to 2 years of observation [n = 31, ∼4 years]	one multicenter ongoing trial with external control from natural history data [n = 21, ∼1.5 years]	one multicenter ongoing trial [n = 74, ∼3.25 years]
Open label	√	√	√	√	√	√
Randomized, two arm, with concurrent control	√			√
	product versus GM-CSF			product versus observation control
Single arm		√	√		√	√
Novel primary endpoint				√	√
Natural history data used				√	√
First-in-human study in children		√		√	√
Time from initial IND to approval	10 years	8 years	9 years	10 years	6 years	12 years
Type of initial IND	commercial	academic research	academic research	academic research	academic research	academic research
Fast Track designation at ∼years before approval	√ 4 years				√ 6 years
Breakthrough designation at ∼years before approval		√ 1.5 years	√ <2 years	√ 3 years	√ 3 years	√ 2 years
Orphan Product designation at ∼years before approval	√ 4 years	√ 3 years	√ 3 years	√ 1 year	√ 5 years	√ 4 years
Rare pediatric disease voucher		√		√	√
Accelerated approval						√
Review cycle duration	15 months	7 months	6.5 months	7 months	8 months	7.5 months
Approved in 1st review cycle	√	√	√	√	√	√
Post-marketing LTFU	√	√	√	√	√	√
PMR safety study	√	√	√			√
Risk evaluation and mitigation strategy		√	√			√

ALL, acute lymphoblastic leukemia; DLBCL, diffuse large B cell lymphoma; MCL, mantle cell lymphoma; GM-CSF, granulocyte-macrophage colony-stimulating factor; RPE65, retinal pigment epithelium protein; SMN1- survival motor neuron 1 protein; BD, biodistribution; IV, intravenous; IT, intratumoral; SR, subretinal; AT, antitumor; HSV, herpes simplex virus; CAR, chimeric antigen receptor; LV, lentiviral; RV, retroviral; AAV, adeno-associated viral; POC, proof-of-concept; TB, tumor-bearing; NHP, non-human primates; LTFU, long-term follow-up; PMR, post-marketing requirement.

^aOnly first approved indications are included.

^bAutologous.

^cCell targeting, vision, and behavior.

^dCell targeting, survival, and motor function.

^eStudy duration represents an approximate time from enrollment of the first subject to the data cutoff accepted for evaluation in the marketing application.