Processed Nerve Allograft

AVANCE is an acellular nerve scaffold indicated for the treatment of adult and pediatric patients aged one month and older with:

• Sensory nerve discontinuity (≤25 mm). ( 1 )
• Sensory nerve discontinuity (>25 mm). This indication is approved under accelerated approval based on static two-point discrimination (s2PD) at 12 months in sensory nerve gaps ≤25 mm, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 , 14 )
• Mixed and motor nerve discontinuity. This indication is approved under accelerated approval based on s2PD at 12 months in sensory nerve gaps, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 , 14 )

1.1 Sensory Nerve Discontinuity (≤25 mm) AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with sensory nerve discontinuity ≤25 mm.

1.2 Sensory Nerve Discontinuity (>25 mm) AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with peripheral sensory nerve discontinuity >25 mm. This indication is approved under accelerated approval based on improvement in static two-point discrimination (s2PD) at 12 months in sensory nerve gaps ≤ 25 mm, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. [see Clinical Studies ( 14 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory clinical trials.

1.3 Mixed and Motor Nerve Discontinuity AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with mixed and motor nerve discontinuity. This indication is approved under accelerated approval based on improvement in s2PD at 12 months in sensory nerve gaps, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. [see Clinical Studies ( 14 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

AVANCE will vary in color from white, off-white, pink, pale pink, and yellow to pale yellow. AVANCE is a sterile, surgical implant and is intended for administration to a single patient. The available sizes of AVANCE are provided in Table 1 . AVANCE is available in 16 combination sizes with the following dimensions:

• Lengths: 15 mm, 30 mm, 50 mm, and 70 mm
• Diameters: 1 to 2 mm, 2 to 3 mm, 3 to 4 mm, and 4 to 5 mm AVANCE may vary in color from white, off-white, pink, pale pink, and yellow to pale yellow. ( 3 )

None. None. ( 4 )

• Procedural Complications – Monitor for procedural complications, including pain, hyperesthesia, infection, implant site swelling, adhesions, hypertrophic scar formation, impaired motor or sensory function, bleeding, and neuroma formation, and manage accordingly. ( 5.1 )
• Transmission of Infectious Diseases – Because AVANCE is made from human donor tissue, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases, vCJD, or CJD have ever been identified for AVANCE. All infections thought to be transmitted by AVANCE should be reported to Axogen Corporation at 1-888-296-4361. ( 5.2 )

5.1 Procedural Complications Procedural complications have occurred with the AVANCE implantation procedure and have included pain, hyperesthesia, infection, implant site swelling, adhesions, hypertrophic scar formation, impaired motor or sensory function, bleeding, and neuroma formation [see Adverse Reactions ( 6 )] . Additional procedural complications may include risk of bleeding and complications related to anesthesia. Monitor patients for procedural complications with AVANCE implantation and manage accordingly.

5.2 Transmission of Infectious Diseases Transmission of infectious diseases or agents may occur with AVANCE administration, as it is manufactured using tissues from human cadaveric donors. Donors are screened and tested for Human Immune-deficiency Virus 1 (HIV-1); Human Immune-deficiency Virus 2 (HIV-2); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); and Syphilis (Treponema pallidum). Additional testing for Human T-cell Leukemia-lymphoma Virus 1 (HTLV-1) and Human T-cell Leukemia-lymphoma Virus 2 (HTLV-2) may be performed as required by local regulatory authorities in US states. Only screening was performed for Creutzfeldt-Jakob disease (CJD). These measures do not eliminate the risk of transmitting these or other infectious diseases or agents. All infections thought to be transmitted by AVANCE should be reported to Axogen Corporation at 1‑888-296-4361.

The most common adverse reactions (incidence ≥2%) were procedural pain (4%) and hyperesthesia (3%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Customer Care at 1-888-296-4361 or customercare@axogeninc.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety database described in this section reflects exposure to AVANCE in the RECON Study. A total of 112 patients received AVANCE and 108 patients received NeuraGen ® (bovine nerve cuff) and were followed for a duration of 12 months. [see Clinical Studies ( 14 )] . A serious adverse reaction occurred in 1 patient, which was wound dehiscence. Table 2 lists the most common adverse reactions that occurred in ≥ 2% of patients in the RECON Study. Table 2. Adverse Reactions occurring in > 2% of Patients in the RECON Study Adverse Reactions AVANCE n = 112 n (%) Bovine Nerve Cuff n = 108 n (%) Implant site hyperesthesia 3 (3) 5 (5) Procedural pain 4 (4) 0 Other clinically significant adverse reactions that occurred in <2% of patients in AVANCE group include: implant site swelling (n=2), paraesthesia (n=2), hypertrophic scar (n=2), pyogenic granuloma (n=2), grade 3 neuroma (n=1), wound dehiscence (n=1), tendon adhesion (n=1), implant site nodule (n=1), osteomyelitis (n=1), and dermal cyst (n=1).

6.2 Postmarketing Experience Adverse Reactions from Observational Studies The safety of AVANCE was evaluated in an ongoing, multicenter, observational registry study in patients undergoing nerve repair. The registry assessed repairs using the Medical Research Council Classification (MRCC) across nerve types (sensory, motor, and mixed), gap lengths (5–210 mm), and body regions (upper extremity, head and neck, torso including breast, and lower extremity). Adverse reactions reported in the study include neuroma, seromas, implant site infection, tissue necrosis, nerve regeneration failure, hyperesthesia, hypoesthesia, AVANCE implantation error, and hematoma.

8.1 Pregnancy Risk Summary There are no data on the use of AVANCE in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with AVANCE to assess whether it can cause harm to the mother or fetus when administered to a pregnant woman. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary There is no data on the effect of AVANCE on human milk, the effect on the breastfed infant, or the effect on milk production.

8.4 Pediatric Use The safety and effectiveness of AVANCE have been established in pediatric patients aged one month and older. The use of AVANCE in pediatric patients for the treatment of nerve discontinuity was supported by extrapolation of adult data from the RECON Study. [see Clinical Studies ( 14 )].

8.5 Geriatric Use There were 8 patients (4%) who were 65 years of age and older in the RECON Study. Clinical studies of AVANCE did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger subjects.

AVANCE is an acellular nerve scaffold intended to restore nerve function in the distal tissue. AVANCE provides structural and biochemical cues for axonal regeneration. The structural cue is provided by the intact endoneurial tubes. The biochemical cue is provided by the basement membrane proteins of the endoneurial tubes. The basement membrane of the endoneurial tubes includes many proteins, such as collagen, laminin, fibronectin, and proteoglycans. The laminin lining the endoneurial tubes of AVANCE has been shown in in vitro assays and animal studies to be bioactive by supporting Schwann cell migration, axon growth cone interactions, and neurite extension. Without the specific bioactive laminin composition, the neuroregenerative capacity is hindered. However, the exact mechanism of action is unknown.