A pivotal, dermal, in-vivo bioequivalence study performed by confocal Raman spectroscopy (CRS)

The EMA guideline on quality and equivalence of locally applied, locally acting cutaneous products, endorses the use of the stratum corneum (SC) sampling technique (Tape Stripping, TS) in lieu of an expensive and resource-intensive clinical endpoint study. However, alternative methods, like CRS are not yet approved. As we have already shown the correlation of TS and CRS results, we consider non-invasive CRS with its microscale resolution for fully quantifiable API data and its ease of use, as the superior method for future dermal bioequivalence studies for products with Raman-active drug substances. To provide pivotal data and demonstrate the suitability CRS for dermal bioequivalence assessment, we conducted an in-vivo study using four formulations containing salicylic acid(SA). The study design included a reference, a test, and a control formulation to validate discriminatory power. CRS measurements were performed in 12healthy volunteers at two defined time points - 1 h (uptake, that is in diffusional steady-state) and 4 h after product removal (clearance) - using a 785 nm laser to acquire SC penetration profiles down to a depth of 15 µm. We could demonstrate that the penetration data meet all EMA bioequivalence requirements. Thus, the supposedly bioequivalent products were confirmed to be bioequivalent, as their 90 % confidence intervals (CIs) fell entirely within the acceptance range of 80.00---125.00 %, in accordance with the average bioequivalence (ABE) approach. As this was, to our knowledge, the first dermal, in-vivo bioequivalence study conducted with the advantageous CRS method, fully following the recommendations of the EMA guideline. The pivotal data obtained thus shows the suitability of the CRS method. This should help with its establishment as a means to obtain bioequivalence data, also with reference to recognition in a subsequent guideline update.