Laviv
azficel-T
Species
no relevant
Longest study
n/a
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
No preclinical or toxicology studies conducted with the product
“No preclinical studies were conducted with this product.”
Why that species
No suitable animal model for rhytids; prior human commercial experience cited instead
“The BLA states that due to this previous commercial experience in humans, and due to the lack of a”
Surrogate molecule
No product testing; only published rabbit analog-cell study reviewed (not equivalent to clinical process)
“The preparation of the rabbit analog cells used in this study did not duplicate the procedure that is used for IT preparation”
Species: general tox
None; no ICH toxicology studies (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Species: DART
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Species: carcinogenicity
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Surrogate used in
No sponsor studies with an animal cellular analog; only published analog-cell literature
“No preclinical studies were conducted by the sponsor with the clinical product, Isolagen Therapy™, or with an animal cellular analog in support of early phase to later phase clinical trials.”
Study lengthopen answer page →
Longest pivotal study
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Pivotal GLP studies
None; no GLP toxicology; reliance on ~1100 treated subjects of prior commercial use
“No preclinical studies were conducted with this product.”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted (autologous nature, prior human experience)
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
Carcinogenicity
Not conducted (autologous, minimally manipulated); tumorigenicity listed as a gap
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
Reproductive & developmental
Not conducted (autologous nature, prior human experience)
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
Safety pharmacology
Not conducted (autologous nature, prior human experience)
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
Genotox: Ames
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Genotox: in vitro mammalian
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Genotox: in vivo
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Carcinogenicity model
Not conducted; published nude-mouse study (two animals, 2 months) inconclusive for tumorigenicity
“Regarding the in vivo assessment of tumorigenic potential: 1) only two animals were used and 2) the study duration was only 2 months, therefore no conclusions can be made about this safety endpoint.”
Carcinogenicity timing
Not required: autologous, minimally manipulated cells judged unlikely to become tumorigenic
“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).”
hERG / QT
Not conducted (no safety pharmacology studies)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Laviv don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
NOAEL / key findings
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Not studied for IT (cell survival/migration listed as a gap); published rabbit study showed autologous fibroblast survival over 5 months
“the autologous cultured fibroblasts could survive in vivo for more than 5 months”
Modality-specific risk
Tumorigenicity/abnormal growth and tissue remodeling (scarring, keloids) not evaluated in vivo; reviewer-identified gaps
“The potential for tumorigenicity and/or other abnormal growth following in vivo administration of IT.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
None: no preclinical studies; prior human experience supported initial clinical studies
“No preclinical studies were conducted by the sponsor with the clinical product, Isolagen Therapy™, or with an animal cellular analog in support of early phase to later phase clinical trials.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Laviv don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no preclinical studies conducted)
“No preclinical studies were conducted with this product.”
Pivotal GLP studies
None; no GLP toxicology; reliance on ~1100 treated subjects of prior commercial use
“No preclinical studies were conducted with this product.”
DART package
Species: DART
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Reproductive & developmental
Not conducted (autologous nature, prior human experience)
“were not conducted by the sponsor due to the autologous nature of IT and the previous human experience.”
PPND / ePPND: when
Not conducted: autologous product with prior human experience
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (autologous product, prior human experience)
“Toxicology studies as described in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, 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 by the sponsor due to the autologous nature of IT and the previous human experience.”
Carcinogenicity model
Not conducted; published nude-mouse study (two animals, 2 months) inconclusive for tumorigenicity
“Regarding the in vivo assessment of tumorigenic potential: 1) only two animals were used and 2) the study duration was only 2 months, therefore no conclusions can be made about this safety endpoint.”
Carcinogenicity timing
Not required: autologous, minimally manipulated cells judged unlikely to become tumorigenic
“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).”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
NOAEL / key findings
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Efficacy evidenceopen answer page →
Efficacy evidence
Literature only: animal analog fibroblasts in immunocompetent animals and human fibroblasts in immunodeficient mice; product not tested
“The fibroblasts were administered to immune competent animals (animal analog cells) and to immunodeficient mice (human cells).”
Why that model
No suitable animal model for rhytids; prior commercial human experience
“The BLA states that due to this previous commercial experience in humans, and due to the lack of a ‘suitable’ preclinical animal model for rhytids, no preclinical studies using IT were performed.”
Reviewer's view of the efficacy data
Limited relevance: published studies used cell isolation, culture and formulation different from the product
“The cell isolation procedure, culture condition, passage number, and formulation for each experiment described in the various publications were different from what is used for IT.”
Test articleopen answer page →
Test article vs clinical lot
Published rabbit study used analog fibroblasts prepared by mincing and dispase, unlike the IT process. Bridging: None; rabbit analog cell preparation did not duplicate the IT procedure
“The preparation of the rabbit analog cells used in this study did not duplicate the procedure that is used for IT preparation; for example, the rabbit cells were separated from the skin biopsy by mincing and treating with dispase; however, only digestive enzymes are used to prepare IT.”
Genetically modified?
Autologous human dermal fibroblasts expanded ex vivo; not genetically modified
“Autologous fibroblasts (Human, dermal, Isolagen Technologies, Inc.) expanded ex vivo, administered intradermally.”
First approval
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
No preclinical studies of any kind with the product; relied on prior commercial human use and published literature
Why: Prior commercial human experience; no suitable animal model; autologous, minimally manipulated cells unlikely to become tumorigenic · Human data · Low-risk modality · No relevant species
“The BLA states that due to this previous commercial experience in humans, and due to the lack of a ‘suitable’ preclinical animal model for rhytids, no preclinical studies using IT were performed.”
“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).”
OtherCriticised but acceptedBeyond the letter
Reviewer-identified gaps (cell survival, tissue remodeling, tumorigenicity) not studied in animals; human biopsies recommended instead
Why: Dermal changes to be assessed via biopsies in human subjects · Human data
“This reviewer’s recommendations are as follows: 1) assessment of any changes in the dermal architecture of the injected wrinkle should be obtained via biopsies in the human subjects; however, if additional questions arise based on the biopsy data, the conduct of a murine xenograft study could be considered to potentially investigate these concerns”
Similar precedents
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