StrataGraft
allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen
Species
Mouse
Longest study
20 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 only (immunodeficient wound model)
“The following toxicology study was conducted to evaluate the safety profile of STRATAGRAFT® following administration in an athymic (immunodeficient) murine wound model:”
Why that species
Human cells would elicit xenogeneic response in immunocompetent animals; nude mice have reduced T-cell response
“STRATAGRAFT® is composed of human cells, thus the potential for elicitation of a xenogeneic response following administration in immune competent animals exists.”
Surrogate molecule
No surrogate; clinical human-cell construct applied to nude mice
“Strain/Breed nude mice”
Species: general tox
Athymic (immunodeficient) mouse wound model
“The following toxicology study was conducted to evaluate the safety profile of STRATAGRAFT® following administration in an athymic (immunodeficient) murine wound model:”
Species: DART
Not conducted; acceptable given product characteristics and safety profile
“No animal reproductive or developmental toxicity (DART) studies were conducted with STRATAGRAFT, which is acceptable, considering the product characteristics and safety profile.”
Species: carcinogenicity
No carcinogenicity study; tumorigenicity in immunodeficient mice (topical construct 20 weeks; s.c. NIKS keratinocytes 23 weeks)
“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.”
Surrogate used in
No surrogate used; human-cell construct tested in nude mice to avoid xenogeneic response
“STRATAGRAFT® is composed of human cells, thus the potential for elicitation of a xenogeneic response following administration in immune competent animals exists.”
Study lengthopen answer page →
Longest pivotal study
20 weeks
“no apparent local or systemic toxicity was observed out to 140 days following topical application of STRATAGRAFT® to immunodeficient mice with an existing wound.”
Pivotal GLP studies
Non-GLP 8+ week subchronic study NCREP.001 in 26 nude mice, single topical application, sacrificed to 140 days; retrospective tumorigenicity analyses to 421 days
“Minimum Eight Week Transdermal Subchronic Toxicity Study with STRATAGRAFT® Skin Tissue in Nude Mice”
Route in tox
Topical application on full-thickness wound bed (single administration)
“Route of Administration (ROA) Topical application on the wound bed”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genotoxicity studies were conducted.”
Carcinogenicity
No carcinogenicity study; tumorigenicity assessed in nude mice and in vitro, no tumors
“No tumor formation was observed for the 20-week study duration.”
Instead of genotoxicity
Not applicable: cells not genetically modified
“No genotoxicity studies were conducted.”
Reproductive & developmental
Not conducted
“No DART studies were conducted.”
Safety pharmacology
Not conducted
“No nonclinical safety pharmacology studies were conducted”
Genotox: Ames
Not conducted
“No genotoxicity studies were conducted.”
Genotox: in vitro mammalian
Not conducted
“No genotoxicity studies were conducted.”
Genotox: in vivo
Not conducted
“No genotoxicity studies were conducted.”
Carcinogenicity model
Tumorigenicity only: topical StrataGraft on immunodeficient mouse wounds 20 weeks and s.c. NIKS keratinocytes 23 weeks; no tumors
“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.”
Carcinogenicity timing
No standard carcinogenicity study; immunodeficient-mouse tumorigenicity studies (20-week topical, 23-week s.c. NIKS cells) completed before the marketing application, no tumors
“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.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No nonclinical safety pharmacology studies were conducted”
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 StrataGraft 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; no local or systemic toxicity to 140 days; wound site showed normal healing (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
No NOAEL; no local or systemic toxicity to 140 days; wound site showed normal healing
“No test article-related findings were observed in the examined tissues.”
Risksopen answer page →
Immune & cytokine safety
Xenogeneic response possible in immunocompetent animals, so athymic mice used; no immunogenicity studies reported
“STRATAGRAFT® is composed of human cells, thus the potential for elicitation of a xenogeneic response following administration in immune competent animals exists.”
Biodistribution & persistence
No PK/cell distribution studies; clinical biopsy DNA analysis at 3 months in 85 subjects found no allogeneic DNA
“A total of 85 subjects in the Phase 1 and Phase 3 clinical trials were evaluated at 3 months for persistence of allogeneic STRATAGRAFT DNA at the treatment site.”
Modality-specific risk
Tumorigenicity of immortalized NIKS keratinocytes; no tumors in nude mice up to 421 days
“No animal exhibited evidence of tumor formation.”
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
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 StrataGraft 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; no local or systemic toxicity to 140 days; wound site showed normal healing (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study: single topical application in nude mice, followed to 140 days
“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.”
Pivotal GLP studies
Non-GLP 8+ week subchronic study NCREP.001 in 26 nude mice, single topical application, sacrificed to 140 days; retrospective tumorigenicity analyses to 421 days
“Minimum Eight Week Transdermal Subchronic Toxicity Study with STRATAGRAFT® Skin Tissue in Nude Mice”
DART package
Species: DART
Not conducted; acceptable given product characteristics and safety profile
“No animal reproductive or developmental toxicity (DART) studies were conducted with STRATAGRAFT, which is acceptable, considering the product characteristics and safety profile.”
Reproductive & developmental
Not conducted
“No DART studies were conducted.”
PPND / ePPND: when
No DART studies conducted; acceptable given product characteristics and safety profile
“No animal reproductive or developmental toxicity (DART) studies were conducted with STRATAGRAFT, which is acceptable, considering the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
No carcinogenicity study; tumorigenicity in immunodeficient mice (topical construct 20 weeks; s.c. NIKS keratinocytes 23 weeks)
“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.”
Carcinogenicity model
Tumorigenicity only: topical StrataGraft on immunodeficient mouse wounds 20 weeks and s.c. NIKS keratinocytes 23 weeks; no tumors
“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.”
Carcinogenicity timing
No standard carcinogenicity study; immunodeficient-mouse tumorigenicity studies (20-week topical, 23-week s.c. NIKS cells) completed before the marketing application, no tumors
“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.”
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; no local or systemic toxicity to 140 days; wound site showed normal healing
“No test article-related findings were observed in the examined tissues.”
Efficacy evidenceopen answer page →
Efficacy evidence
No nonclinical pharmacology studies; efficacy claims rest on clinical data
“However, no nonclinical pharmacology studies were conducted; please refer to the clinical review memo for confirmation of these claims.”
Why that model
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.
Reviewer's view of the efficacy data
FDA deferred efficacy claims to the clinical review; no nonclinical deficiencies and data support approval
“There are no nonclinical deficiencies identified in this submission. There are no outstanding requests for additional nonclinical data for evaluation of STRATAGRAFT®.”
Test articleopen answer page →
Test article vs clinical lot
STRATAGRAFT batches from earlier development processes that differed from the commercial process. Bridging: Differences from the commercial process were listed; the batch reflecting each change was not specified
“Per the applicant, the STRATAGRAFT® manufacturing process was being refined as the product development program progressed. The applicant cited the following differences between the manufacturing process of STRATAGRAFT® for Studies #1 and #14 and the commercial process.”
Genetically modified?
Allogeneic immortalized NIKS keratinocytes on allogeneic dermal fibroblasts in collagen
“The construct is composed of an epidermal layer of fully-stratified allogeneic immortalized near-diploid human keratinocytes (NIKS® keratinocytes) grown on a dermal equivalent (DE) consisting of allogeneic normal human dermal fibroblasts (NHDFs) in a rat tail collagen-rich matrix.”
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
OtherCriticised but acceptedBeyond the letter
Toxicity assessed only in immunodeficient mice, with significant study design and data limitations
Why: Human cells would elicit a xenogeneic response in immune-competent animals · No relevant species
“Reviewer’s Conclusion: 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.”
“Note: STRATAGRAFT® is composed of human cells, thus the potential for elicitation of a xenogeneic response following administration in immune competent animals exists.”
Efficacy modelVerdict not stated
No nonclinical pharmacology studies; claimed wound-healing mechanisms deferred to clinical data
“However, no nonclinical pharmacology studies were conducted; please refer to the clinical review memo for confirmation of these claims.”
BiodistributionVerdict not stated
No pharmacokinetic or cell distribution studies; persistence assessed in three completed clinical trials
Why: Persistence evaluated in three completed clinical trials · Human data
“No PK studies were conducted. The applicant refers to the three completed clinical trials: STRATA2011, STRATA2014, and STRATA2016.”
DARTAcceptedBeyond the letter
No reproductive or developmental toxicity studies
Why: Product characteristics and safety profile · Low-risk modality
“No animal reproductive or developmental toxicity (DART) studies were conducted with STRATAGRAFT, which is acceptable, considering the product characteristics and safety profile.”
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