FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
CELLULAR, TISSUE AND GENE THERAPIES ADVISORY COMMITTEE
Meeting, #54, November 17, 2011
BLA 125400 - QUESTIONS TO THE ADVISORY COMMITTEE
Product Quality - Cell Bank
Apligraf is manufactured using allogeneic keratinocytes and fibroblasts derived from
neonatal foreskin of human donors. Because expansion of the cell bank is limited, new
banks from new donor tissue must be generated on a periodic basis.
- Discussion Question: Please discuss the applicant's approach to qualify and demonstrate comparability for new cell banks used for Apligraf manufacture.
Product Quality – Potency
For Apligraf, product potency is determined by a set of histological parameters which
collectively assess the quality of the epidermal and dermal layers present in the product
after maturation. These parameters include epidermal coverage, epidermal development,
basal cell layer, suprabasal cell layer, dermal matrix thickness, fibroblast density and
matrix aspect. These parameters were shown to correlate with percutaneous water
absorption, GF/cytokine profile, cell metabolic activity by MTT, VEGF secretion and in vivo mouse assay.
- Discussion Question: Please discuss the use of H&E staining as a product potency measure for Apligraf.
21 CFR 601.25(d)(2) states that effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product, when used under adequate directions for use and warnings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man.
In the pilot study, Apligraf failed to meet non-inferiority margins for amount of attached
gingiva, compared to autogenous palate graft control. However, the sponsor found that
the width of keratinized tissue (KT) at the Apligraf site was numerically increased over
baseline and used this information to design their pivotal study.
In the pivotal study, 81/85 subjects (95.3%) met the primary endpoint of KT ≥ 2mm at
the Apligraf-treated site at 6 months (88.4%-98.7%, 95% CI). All 85 subjects met the
primary endpoint at the Control site. All 11 training subjects met this goal at both the
Apligraf and Control sites.
With respect to the secondary endpoints of the pivotal trial, Apligraf was statistically
significantly superior to control treatment for color matching, texture matching, and
patient preference and had a KT ≥ 1 mm success rate that was significantly > 80% (the
success standard for that secondary endpoint of the trial). There was no significant
difference between Apligraf and control with regard to sensitivity.
Apligraf has a theoretical advantage over a free gingival autograft due to the requirement
for harvesting a donor palatal site in the latter procedure. However, with respect to the
secondary endpoint of pain at Day 3 in the pivotal trial, there was no evidence of a
CTGTAC Briefing Document BLA 125400: Organogenesis Inc., Apligraf
difference between Apligraf and control, with 54/84 (64.3%) subjects reporting no pain at
either site and 18/84 (21.4%) reporting pain at both sites. (The remaining 12 subjects
were discordant in pain between the sites in roughly equal proportions.)
The proposed indication for Apligraf is for the "treatment of surgically created gingival
and alveolar mucosal surface defects in adults."
- Discussion Question: Please discuss the effectiveness of Apligraf for the proposed indication, particularly considering the study results for KT, appearance, texture, patient preference, pain, and attached gingiva.
- Voting Question: Based on the data provided, is Apligraf effective for the treatment of surgically created gingival surface defects in adults?
Studies 006-PER-002 and 005-PER-001 evaluated the use of the product in subjects with
an insufficient (≤ 1 mm) zone of attached gingiva, requiring soft tissue grafting, where
root coverage was not desired. The proposed indication is for the "treatment of surgically
created gingival and alveolar mucosal surface defects in adults." However, alveolar
mucosal defects were not studied in the pilot or pivotal trials.
- Discussion Question: Please discuss whether the results of these studies are applicable to the broader patient population as described in the proposed indication.
21 CFR 601.25(d)(1) states that safety of a licensed biological product means the relative
freedom from harmful effect to persons affected, directly or indirectly, by a product when
prudently administered, taking into consideration the character of the product in relation
to the condition of the recipient at the time. Proof of safety shall consist of adequate tests
by methods reasonably applicable to show the biological product is safe under the
prescribed conditions of use, including results of significant human experience during use.
Apligraf has been studied for the oral indication in three clinical trials. The period of
observation in these trials was six months. In addition, there are clinical safety data from
post-market use in chronic cutaneous wounds. The sponsor has also provided histological
data on seven clinical trial subjects, and DNA persistence data on two.
- Discussion Question: Please discuss the safety of Apligraf for the proposed oral indication, considering the available nonclinical and clinical study results, including both premarketing and postmarketing experience.
- Voting Question: Do the data presented demonstrate the safety of Apligraf for the proposed indication?