Paulo Bargo, PhD

This white paper addresses concerns raised by statisticians, statistical programmers, informatics teams, executive leadership, quality assurance teams and others within the pharmaceutical industry about the use of R and selected R packages as a primary tool for statistical analysis for regulatory submission work. When discussing validation of software systems two areas should be considered:

Infrastructure validation
Software validation
Infrastructure includes the server, OS… Show more

This white paper addresses concerns raised by statisticians, statistical programmers, informatics teams, executive leadership, quality assurance teams and others within the pharmaceutical industry about the use of R and selected R packages as a primary tool for statistical analysis for regulatory submission work. When discussing validation of software systems two areas should be considered:

Infrastructure validation
Software validation
Infrastructure includes the server, OS, necessary infrastructure software, etc… For example, a system may use a server running Redhat Enterprise Linux (RHEL) version 6 and several other infrastructure software pieces including proxy servers like Apache httpd. Documenting infrastructure (or the environment) is an essential part of the validation process and this validation could follow standard practices such as those proposed in GAMP5, particularly change control management. Discussions regarding infrastructure validation are not in scope of this paper.

The aim of this paper is to propose a possible risk-based approach for assessing R package accuracy within a validated infrastructure.

Many of the thoughts and ideas addressed in this paper are extracted, verbatim, from the R Validation Hub, a cross-industry initiative whose mission is to enable the use of R by the bio-pharmaceutical industry in a regulatory setting.

The paper reflects the current thinking of the R Validation Hub working group and may evolve over time. Additional detail will be provided via the website and future papers. Show less

List of publications

Erythema and pigment responses of human skin following an acute exposure to ultraviolet radiation (UVR) are frequently used to determine the photosensitivity of the skin. In this study we investigated the responses of the skin to a micro-scale area of UVR exposure (MiR) and compared the responses to a macro-scale area of exposure (MaR). The fluence required to produce a minimally perceptible erythema (MED) using the MiR was found to be higher than that for the MaR. The erythema response… Show more

Erythema and pigment responses of human skin following an acute exposure to ultraviolet radiation (UVR) are frequently used to determine the photosensitivity of the skin. In this study we investigated the responses of the skin to a micro-scale area of UVR exposure (MiR) and compared the responses to a macro-scale area of exposure (MaR). The fluence required to produce a minimally perceptible erythema (MED) using the MiR was found to be higher than that for the MaR. The erythema response extended beyond the exposed area and this became pronounced when the beam size was microscopic. Reflectance confocal microscopy in vivo revealed that MiR induced cellular alterations within a confined area of smaller dimensions than the area of exposure. Pigment responses were confined within the areas of cellular damage. The erythema expression of exposed skin recovered faster for the sites receiving MiR even when the applied fluence was higher than the MED for the MaR. Through the use of MiR we were able to visualize spatially dissimilar skin responses of erythema and pigmentation suggesting different cellular mechanisms. Show less

The stratum corneum (SC) serves a primary function of skin barrier and understanding the kinetics of SC formation may provide great insight for skin diagnosis and evaluation of therapies. Besides trans-epidermal water loss (TEWL), few methods have been characterized to assess skin barrier non-invasively in vivo, particularly for dynamic measurements on the same specimen over time. The objective of this study was to characterize alternative non-invasive methods to evaluate the dynamic processes… Show more

The stratum corneum (SC) serves a primary function of skin barrier and understanding the kinetics of SC formation may provide great insight for skin diagnosis and evaluation of therapies. Besides trans-epidermal water loss (TEWL), few methods have been characterized to assess skin barrier non-invasively in vivo, particularly for dynamic measurements on the same specimen over time. The objective of this study was to characterize alternative non-invasive methods to evaluate the dynamic processes involved in the recovery of normal human SC after total removal. TEWL, tryptophan fluorescence and reflectance confocal microscopy (RCM) were used to determine skin barrier function, cell turnover and epidermal morphology over a period of 10 days after total removal of the SC by tape stripping. The results show a biphasic recovery of TEWL over time, which contrasted with a linear increase of 2.3 μm/day in SC thickness. Tryptophan assessment of cell turnover also demonstrated a biphasic pattern attaining a maximum three to four times the levels of the control site 3 days after injury that slowly returned to baseline and displayed great correlation (R2 > 0.95) to viable epidermis thickness that also achieved a maximum about 3 days after injury with an approximate increase of 55%. When plotting the change of TEWL versus SC thickness, a single exponential function is observed [Δ-TEWL = 55 exp (−0.157×)] which contrasts with other proposed models. These methods were able to present rates for SC recovery processes beyond skin barrier (TEWL) that may provide new insights on kinetics of barrier formation for evaluation of skin conditions and treatments. Show less