Gintuit
allogeneic cultured keratinocytes and fibroblasts in bovine collagen
Species
MouseRabbitOther
Longest study
52 wk
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
Athymic (nude) mice for pharmacology; rabbits, guinea pigs, mice for biocompatibility
“Species: Athymic mice, 6-8 weeks old; the number, strain and sex were not provided in the study report”
Why that species
Immunodeficient mice used so human cells could engraft and persist; no species rationale stated
“The transplanted Apligraf® remained durable, as demonstrated by the persistence of human keratinocytes and fibroblasts, for at least one year in the nude mice.”
Surrogate molecule
No surrogate; clinical construct (Apligraf) grafted onto nude mice
“Apligraf® appeared to function as a skin graft (i.e., healing by primary intention) in the nude mouse full-thickness wound model.”
Species: general tox
Not conducted (no chronic toxicology); ISO-10993 biocompatibility tests only
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Species: DART
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Species: carcinogenicity
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Surrogate used in
No surrogate used; clinical product (Apligraf) grafted in nude mouse wound model
“Apligraf® appeared to function as a skin graft (i.e., healing by primary intention) in the nude mouse full-thickness wound model.”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“Grafts were harvested at 7, 14, 28, 56, 100, 180, 232, and 365 days after grafting.”
Pivotal GLP studies
No GLP repeat-dose tox; GLP ISO-10993 biocompatibility tests (systemic, subchronic subcutaneous in rabbits) and non-GLP nude mouse graft studies
“The potential toxicity of Apligraf® was evaluated via studies that reflect the initial medical device framework (i.e., biocompatibility testing in conformance to ISO-10993 standards).”
Route in tox
Topical graft (mouse); intraperitoneal, intravenous, intracutaneous, subcutaneous extracts in biocompatibility
“Sub-chronic Toxicity (Subcutaneous Injection Test – Subchronic)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (nature of product and clinical experience)
“The toxicology study designs as discussed in the International Conference on Harmonisation (ICH) Safety (‘S’) guidelines, consisting of pharmacokinetics, acute toxicology, chronic toxicology, genotoxicity, carcinogenicity, reproductive and”
Carcinogenicity
Not conducted (nature of product and clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“The toxicology study designs as discussed 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”
Reproductive & developmental
Not conducted (nature of product and clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Safety pharmacology
Not conducted (nature of product and clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Genotox: Ames
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Genotox: in vitro mammalian
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Genotox: in vivo
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Carcinogenicity model
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Carcinogenicity timing
Not required (nature of product and extensive clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
hERG / QT
Not conducted (safety pharmacology not done)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
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 Gintuit 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 ↗
This product's starting point
NOAEL / key findings: No NOAEL; biocompatibility testing showed no findings of significant biological concern (FDA pharmacology/toxicology review, p. 49)
NOAEL / key findings
No NOAEL; biocompatibility testing showed no findings of significant biological concern
“This biocompatibility testing paradigm did not reveal any findings of significant biological concern.”
Risksopen answer page →
Immune & cytokine safety
No alloimmune response in vitro; indirect allorecognition not evaluated; xenogeneic reaction to subcutaneous injection in rabbits
“The potential for Apligraf® to induce an alloimmune response by indirect allorecognition was not evaluated.”
Biodistribution & persistence
Human keratinocytes and fibroblasts persisted at least 1 year in nude mice; did not persist in humans
“The grafted keratinocytes and fibroblasts persisted for at least 1 year after grafting.”
Modality-specific risk
Alloimmune response and graft persistence/integration; hypertrophic scarring
“Apligraf® did not integrate or show long-term persistence following application to cutaneous wounds in humans; the mechanism for this species difference was not explored.”
Anti-drug antibodies: animals
No ADA data; xenogeneic immune tissue reaction at subcutaneous implant site in rabbits
“The subcutaneous injection of Apligraf® into rabbits resulted in tissue reaction at the implanted site due to the xenogeneic immune response.”
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.
Label warnings
- Hypersensitivity Reactions
- Wound Infection
- Malignancies
- Transmission of Infectious Diseases
- Sterility Testing
Hypersensitivity & infusion reactionsInfectionsSecondary malignancy
US prescribing information, Warnings and PrecautionsDailyMed ↗
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
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.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Gintuit 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 ↗
This product's starting point
NOAEL / key findings: No NOAEL; biocompatibility testing showed no findings of significant biological concern (FDA pharmacology/toxicology review, p. 49)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (ICH chronic toxicology not conducted; nature of product and clinical experience)
“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.”
Pivotal GLP studies
No GLP repeat-dose tox; GLP ISO-10993 biocompatibility tests (systemic, subchronic subcutaneous in rabbits) and non-GLP nude mouse graft studies
“The potential toxicity of Apligraf® was evaluated via studies that reflect the initial medical device framework (i.e., biocompatibility testing in conformance to ISO-10993 standards).”
DART package
Species: DART
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Reproductive & developmental
Not conducted (nature of product and clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
PPND / ePPND: when
Not conducted; nature of product and extensive clinical experience
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Carcinogenicity model
Not conducted (nature of product and clinical experience)
“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 nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
Carcinogenicity timing
Not required (nature of product and extensive clinical experience)
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications.”
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
No NOAEL; biocompatibility testing showed no findings of significant biological concern
“This biocompatibility testing paradigm did not reveal any findings of significant biological concern.”
Efficacy evidenceopen answer page →
Efficacy evidence
Full-thickness wound in athymic (nude) mice grafted with Apligraf
“The purpose of this study was to characterize the in vivo tissue maturation, remodeling, and cellular persistence of Apligraf in a full-thickness wound in athymic mice.”
Why that model
Already approved as a device (PMA) for ulcers, so limited additional preclinical studies were done
“Apligraf®, which is identical to Apligraf® (oral), is approved under a PMA filing (reviewed by CDRH) for the treatment of venous leg and diabetic foot ulcers; therefore, limited additional preclinical studies were conducted in support of this BLA.”
Reviewer's view of the efficacy data
Murine wound models did not directly support the proposed healing-by-secondary-intention mechanism; graft behaved as a skin graft
“Although the sponsor’s hypothesis is that Apligraf® functions to enhance wound healing by secondary intention, the results from the in vivo studies in the murine wound models did not provide direct evidence to support this position.”
Test articleopen answer page →
Test article vs clinical lot
Apligraf, stated to be identical to Apligraf (oral). Bridging: Apligraf used in the studies is identical to Apligraf (oral)
“Apligraf®, which is identical to Apligraf® (oral), is approved under a PMA filing (reviewed by CDRH) for the treatment of venous leg and diabetic foot ulcers; therefore, limited additional preclinical studies were conducted in support of this BLA.”
Genetically modified?
Allogeneic keratinocytes and dermal fibroblasts
“In vitro analysis of the cellular components of Apligraf®, allogeneic keratinocytes and dermal fibroblasts, did not show induction of an alloimmune response”
First approval
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
ICH toxicology package (chronic toxicity, genotoxicity, carcinogenicity, DART, safety pharmacology, immunotoxicity) not conducted; partly covered by device biocompatibility testing
Why: Nature of the product and extensive clinical experience in the cutaneous indications · Human data · Other reason
“The toxicology study designs as discussed 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”
“were not conducted due to the nature of Apligraf® and the extensive clinical experience in the cutaneous indications. In addition, some aspects of these studies were captured in the biocompatibility testing.”
OtherAcceptedBeyond the letter
No additional preclinical studies on conversion to the BLA pathway; relied on the identical PMA-approved cutaneous product
Why: Clinical data already existed; identical product approved under a PMA · Human data
“Although this product was converted to a BLA regulatory pathway, additional preclinical studies were not conducted because clinical data existed by that time.”
Efficacy modelQuestioned
Nude mouse wound model showed skin-graft behaviour, not the proposed healing by secondary intention; species difference not explored
“Although the sponsor’s hypothesis is that Apligraf® functions to enhance wound healing by secondary intention, the results from the in vivo studies in the murine wound models did not provide direct evidence to support this position.”
OtherVerdict not stated
Alloimmune response by indirect allorecognition not evaluated
“The potential for Apligraf® to induce an alloimmune response by indirect allorecognition was not evaluated.”
Similar precedents
LavivCell therapy · azficel-T · Autologous fibroblastsNo relevant species · n/aRethymicCell therapy · allogeneic processed thymus tissue · Allogeneic thymus tissueNo relevant species · 39 wkRyoncilCell therapy · remestemcel-L · Allogeneic BM-MSCMonkey + rodent · 26 wkStrataGraftCell therapy · allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen · Allogeneic keratinocytes + fibroblastsRodent only · 20 wkChondroCelectCell therapy · characterised viable autologous cartilage cells · Autologous chondrocytesOther species · 53 wkMACICell therapy · autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesOther species · 53 wk