Summary Basis of Decision for Tissueblue

Health Canada considers that the benefit-harm-uncertainty profile of Tissueblue is favourable for use as an aid in ophthalmic surgery by selectively staining the internal limiting membrane (ILM).

The vitreous body of the eye undergoes several biochemical changes through aging, which cause progressive liquefaction of the vitreous gel. This may eventually result in a posterior vitreous detachment (PVD), which can lead to the development of a macular hole or an epiretinal membrane (ERM) when adhesions along the vitreoretinal interface occur in the macular area. These conditions may be treated by releasing the tractions between the vitreous body and the macula. Three tissues in the eye are of interest for this type of surgery: the posterior hyaloid, the ERM, and the ILM. All three tissues are thin and transparent, and therefore difficult to visualize. The use of vital dyes during the surgery facilitates the procedure and improves safety by improving contrast between the ILM and the remaining retina.

Brilliant Blue G (BBG) is a common laboratory reagent used for protein visualization during gel electrophoresis. It has been marketed in the European Union since 2007. The dye stains the ILM by forming a stable, negatively charged complex with the basic amino acid residues of proteins (mainly arginine and aromatic amino acids). Retinal toxicity has been reported with BBG and is a factor of exposure time and concentrations. The concentration used in the proposed product (0.25 mg/mL) is considered safe with an exposure of less than 3 minutes, as is expected with retinal surgery.

The New Drug Submission (NDS) for Tissueblue was filed as a Submission Relying on Third-Party Data (SRTD). The evidence of safety and efficacy is based heavily on published literature and other publicly available references, rather than on original clinical data. The published literature submitted by the sponsor included 13 articles supporting the efficacy of Tissueblue for the proposed indication, two of which were considered pivotal: Carpenter et. al., 2013, and Mohr et. al., 2013.

In the study by Carpenter et. al. (2013), surgeons conducted a specific procedure using three different dyes containing BBG, one of which was Tissueblue. The dyes were used at two stages during the procedure. The surgeons assessed the status of the ILM at each stage, and reported on the usefulness of each dye for visualization. The dyes were applied to 98 eyes from 92 patients. In 37% of cases, the surgeon was unable to determine the status of the ILM before the second staining. In the remaining cases (29 out of 61 cases), the surgeon's opinion often changed following the second staining. Surgeons reported a 100% rate of "utility for visualization" for Tissueblue, indicating that there were no staining failures with the product in this study.

The study reported by Mohr et. al. (2013) was a prospective multicentre cohort study in patients undergoing ERM removal. One of the dyes used in these procedures was a solution of 0.25 mg/mL BBG and 4% polyethylene glycol, as contained in Tissueblue. This solution was used in 64 eyes, and surgeons reported adequate visualization and removal of the membranes in 95% of patients (61 out of 64 eyes). In three patients (5%), the staining effect obtained was insufficient and Indocyanine (IC) Green was used as a backup stain. The second dye was a dual dye solution (containing two active ingredients) consisting of 0.15% Trypan Blue, 0.25 mg/mL BBG, and 4% polyethylene glycol. This solution was used in 63 eyes, and 97% reported adequate visualization (61 out of 63 eyes).

Collectively, the pivotal and supportive studies submitted included a sufficient number of patients exposed to an identical product to determine that Tissueblue is effective when used according to the approved indication.

Clinical safety data were collected from 51 peer‑reviewed articles including data from 2,627 patients in whom staining agents were administered to 2,645 eyes. Major treatment types included ILM‑Blue, BBG, IC Green, and Trypan Blue.

A total of 284 adverse events were reported across all treatment groups. Adverse events were reported in 133 out of 1,145 subjects (12%) who received BBG from any source. The most commonly reported adverse event in subjects treated with BBG was cataract development or progression (69 subjects; 6%). Vitreous detachment, transient ocular hypertension, and retinal hemorrhage were also reported in approximately 1% each of subjects. All reported adverse events are common with the ophthalmic surgical procedures that were performed, and are frequently attributed to the vitrectomy itself.

Adverse events that only occurred in the BBG group included retinal break/tear and hemorrhage, cystoid macular edema, transient ocular hypertension, and cataract formation. These adverse events are also frequently attributed to the vitrectomy procedure. No serious, long‑term or delayed adverse events, or deaths were reported in the safety database. No differences were identified between population subgroups, including age or race.

The Mohr et. al. (2013) article reported that residual staining and dye remnants in the eye could not be detected in the month after surgery, which was of special interest and supported transient local action of BBG.

More than 275,000 units of the product have been distributed worldwide since the initial approval in 2010 in the European Union. No post‑marketing adverse reactions have been reported to the manufacturer since the product was launched.

A Risk Management Plan (RMP) for Tissueblue was submitted by Dutch Ophthalmic Research Center International BV to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Tissueblue Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for Look‑alike Sound‑alike attributes, was conducted and the proposed name Tissueblue was accepted.

Tissueblue has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tissueblue Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.