Holoclar
autologous corneal epithelial cells containing limbal stem cells
Sources:EMA assessment report ↗
Species
no relevant
Longest study
none
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 animal species; abridged programme of in vitro tumorigenicity assays and literature
“Conventional non-clinical studies were generally not considered appropriate for Holoclar as a cell-based medicinal product (CBMP).”
Why that species
Lack of relevant animal models due to differences in ocular structure; xenograft and primate concerns
“the lack of relevant animal models due to differences in the ocular structure of most other mammals.”
Surrogate molecule
No surrogate; published rat/rabbit literature considered supportive only
“published non-clinical data were only considered supportive.”
Species: general tox
None; classical single- and repeat-dose animal toxicity studies omitted (no suitable animal models)
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
Species: DART
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Species: carcinogenicity
Not conducted; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
Surrogate used in
No surrogate used; homologous animal model judged unnecessary
“in vivo studies in a homologous animal model were considered by the CAT not to be necessary and the absence of non-clinical PD data was accepted.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“in vivo studies in a homologous animal model were considered by the CAT not to be necessary”
Pivotal GLP studies
No in vivo tox; in vitro karyotype, growth factor dependence and soft agar assays
“in order to investigate the proliferative capacity of the 3T3-J2 feeder cells, the applicant performed in vitro karyotype analysis and soft agar assays.”
Route in tox
Topical ocular (no animal dosing); in vitro only
“the product is intended for administration to the eye where it remains locally at the site of application”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (classical); in vitro karyotype analysis of cells
“The analysis demonstrated a consistent karyotypic profile throughout the tested cell cultures.”
Carcinogenicity
Not conducted (conventional); in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
Instead of genotoxicity
Not applicable: cells not genetically modified
Reproductive & developmental
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible”
Safety pharmacology
Not conducted; local ocular administration
“conventional pharmacodynamic safety and drug interactions studies were not conducted.”
Genotox: Ames
Not conducted (conventional non-clinical studies not appropriate for this CBMP)
“Conventional non-clinical studies were generally not considered appropriate for Holoclar as a cell-based medicinal product (CBMP).”
Genotox: in vitro mammalian
Karyotype analysis (50 metaphases, six batches): no chromosomal aberrations; negative
“The karyotype analysis included chromosomal counts and the frequency of hyperploidy, hypoploidy, polyploidy, breaks and structural abnormalities in 50 metaphasic cells in six batches cultured from the drug product.”
Genotox: in vivo
Not conducted (no classical animal toxicology studies)
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
Carcinogenicity model
Not conducted; three in vitro tumorigenicity assays (karyotype, growth factor dependence, soft agar) indicated low risk
“tumourigenicity of Holoclar drug substance and product was investigated in three different in vitro approaches, all of which pointed towards a low risk of tumour formation.”
Carcinogenicity timing
Not required: conventional carcinogenicity not performed; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
hERG / QT
Not conducted (no safety pharmacology studies; local ocular use)
“conventional pharmacodynamic safety and drug interactions studies were not 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 Holoclar 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 animal tox. In vitro: no chromosomal aberrations, soft agar negative (EMA assessment report, p. 18)
NOAEL / key findings
No NOAEL; no animal tox. In vitro: no chromosomal aberrations, soft agar negative
“No evidence of chromosomal aberrations or minor chromosomal damage was detected”
Risksopen answer page →
Immune & cytokine safety
No immunogenicity studies; no significant adaptive immune response in clinical setting
“no significant adaptive immune response was observed after repeated transplantation in the clinical setting”
Biodistribution & persistence
No biodistribution studies; cells remain on ocular surface, supported by clinical histology
“classical absorption, distribution, metabolism and excretion studies were not considered relevant for a human CBMP”
Modality-specific risk
Tumorigenicity of proliferative cells; murine 3T3-J2 feeder cell microchimerism
“One of the main concerns with the use of any cell therapy, in particular those comprising a heterogeneous population of cells including cells with proliferative potential, is the formation of tumours.”
Anti-drug antibodies: animals
Not conducted; animal immunogenicity studies omitted
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
Anti-drug antibodies: patients
No significant adaptive immune response after repeated transplantation; incidence not given
“no significant adaptive immune response was observed after repeated transplantation in the clinical setting”
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 Holoclar 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 animal tox. In vitro: no chromosomal aberrations, soft agar negative (EMA assessment report, p. 18)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; animal toxicity studies omitted (no suitable animal model)
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
Pivotal GLP studies
No in vivo tox; in vitro karyotype, growth factor dependence and soft agar assays
“in order to investigate the proliferative capacity of the 3T3-J2 feeder cells, the applicant performed in vitro karyotype analysis and soft agar assays.”
DART package
Species: DART
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Reproductive & developmental
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible”
PPND / ePPND: when
Not conducted: reproductive toxicity testing omitted (autologous, no systemic exposure)
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
Carcinogenicity model
Not conducted; three in vitro tumorigenicity assays (karyotype, growth factor dependence, soft agar) indicated low risk
“tumourigenicity of Holoclar drug substance and product was investigated in three different in vitro approaches, all of which pointed towards a low risk of tumour formation.”
Carcinogenicity timing
Not required: conventional carcinogenicity not performed; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
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 animal tox. In vitro: no chromosomal aberrations, soft agar negative
“No evidence of chromosomal aberrations or minor chromosomal damage was detected”
Efficacy evidenceopen answer page →
Efficacy evidence
No product-specific pharmacology studies; published rat LSCD studies with similar fibrin-cultured limbal cells as proof of principle
“support for the proof of principle was available from published non-clinical studies in rats which showed that ex vivo expanded limbal cells cultured on a fibrin support can be used to replace and regenerate corneal epithelium lost due to LSCD”
Why that model
No relevant animal models: species differences in ocular structure, xenograft complications, ethical concerns with primates
“the lack of relevant animal models due to differences in the ocular structure of most other mammals. Furthermore, complications may arise from the xenograft setting of such studies and due to ethical concerns with primate models.”
Reviewer's view of the efficacy data
CAT accepted absence of non-clinical PD data given clinical data; literature rabbit/rat data only supportive
“However, since the products used in studies described in the literature were not identical or sufficiently comparable to Holoclar, published non-clinical data were only considered supportive.”
Test articleopen answer page →
Test article vs clinical lot
Six batches cultured from the drug product, tested in vitro (karyotype)
“The karyotype analysis included chromosomal counts and the frequency of hyperploidy, hypoploidy, polyploidy, breaks and structural abnormalities in 50 metaphasic cells in six batches cultured from the drug product.”
Genetically modified?
Autologous human corneal epithelial cells including stem cells
“The non-clinical development programme of Holoclar, a transparent sheet of autologous human corneal epithelial cells including stem cells, comprised an evaluation of published studies from the scientific literature”
First approval
2014 (EMA, CHMP positive opinion)
“During the meeting on 18 December 2014, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a conditional Marketing Authorisation to Holoclar.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No in vivo toxicity studies (single dose, repeat dose, immunogenicity); no suitable animal model
Why: No suitable animal models; clinical safety data available · No relevant species · Human data
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
CarcinogenicityAcceptedBeyond the letter
No conventional carcinogenicity or in vivo tumorigenicity study; tumour risk assessed with in vitro assays
Why: Three in vitro approaches all pointed towards a low risk of tumour formation · Weight of evidence
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
“tumourigenicity of Holoclar drug substance and product was investigated in three different in vitro approaches, all of which pointed towards a low risk of tumour formation.”
DARTAcceptedBeyond the letter
No reproductive toxicity studies
Why: Autologous product with no expected systemic exposure; negligible reproductive risk · Low-risk modality · Pharmacology or kinetics
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Efficacy modelAcceptedBeyond the letter
No product-specific nonclinical pharmacology; in vivo homologous animal model studies not performed
Why: Clinical data available · Human data
“Therefore, and in light of the availability of clinical data (see section 2.5. ), in vivo studies in a homologous animal model were considered by the CAT not to be necessary and the absence of non-clinical PD data was accepted.”
BiodistributionAcceptedBeyond the letter
No nonclinical biodistribution studies; lack of cell spread supported by patient corneal histology
Why: Immunohistology of corneal sections from treated patients supports lack of biodistribution · Human data
“The main support for a lack of biodistribution, however, was provided by clinical data including an immunohistological analysis of corneal sections derived from Holoclar-treated patients who had perforating keratoplasty.”
“In light of the available clinical data, the CAT agreed that no additional non-clinical biodistribution data were needed.”
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