Around the world, updated legislation and regulatory guidance have heightened the focus on New Approach Methodologies (NAMs) as drug developers increasingly seek alternatives to in vivo testing models. This shift, guided by the 3Rs (Replacement, Reduction, Refinement), has progressed gradually for decades, but new technologies have accelerated the transition. Researchers are using NAMs in their testing more than ever, and regulators are seeking to mandate their use wherever possible.
One of the most mature NAMs is the skin irritation and corrosion test based on the Reconstructed Human Epidermis Model (RhE). Its evolution has played a key role in ushering in this new era of testing and serves as a useful blueprint for introducing NAMs across the drug development timeline.
What is the Reconstructed Human Epidermis Model?
The RhE model refers to a highly differentiated, three-dimensional skin tissue engineered by culturing human epidermal keratinocytes under specific conditions via in vitro culture techniques. It consists of the stratum basale, stratum spinosum, stratum granulosum, and a multi-layered stratum corneum, each of which is highly similar to those found in the human body, enabling it to simulate the barrier, penetration, and response functions of human skin when exposed to external substances.
Examples of well-established international RhE models include LabCyte, SkinEthic, and EpiDerm, which have been incorporated into OECD guidelines and are officially recognized as standardized methods for skin irritation and corrosion tests.
The History of Skin Irritation and Corrosion Testing Method Based on RhE Models
Skin irritation refers to the reversible damage to the skin after exposure to a substance. Skin corrosion refers to the irreversible damage to the skin, manifested as visible necrosis through the epidermis and into the dermis, following the application of a test substance. Historically, in vivo testing was used for skin irritation and corrosion tests, but with the advancements of the 3Rs principles and new regulations, the development of RhE models has been driven forward.
Concept to model prototype (1959-1990s): In 1959, Russel and Burch proposed the 3Rs principles, laying the ethical and scientific foundation for the introduction of NAMs. But it wasn’t until the 1990s that technology caught up with the ambition of the principles, as commercial RhE models such as EpiDerm and EpiSkin were successfully launched, providing a foundation for subsequent validation studies.
Validation and regulatory acceptance for skin corrosion test methods (1996-2004): Between 1996 and 1998 the European Centre for the Validation of Alternative Methods (ECVAM) initiated pre-validation studies, which supported the use of EpiDerm and EpiSkin for corrosion prediction for the first time Large-scale formal validation studies followed between 1998 and 2002, and in 2004, the OECD released Test Guideline (TG) 431, and officially recognized RhE-based corrosion test methods. This marked the first entry of in vitro corrosion tests into regulatory application.
Validation and regulatory acceptance for skin irritation test methods (2003-2010): Between 2003 and 2008, EXCVAM validated irritation testing for EpiDerm SIT, EpiSkin, and SkinEthic RhE models. In July 2010, the OECD released TG 439 In Vitro Skin Irritation Test: Reconstructed Human Epidermis Test Method, and the RhE model became a globally accepted standard method for the irritation test.
Method Optimization (2013-present): OECD revised TG 431 and TG 439 in 2013-2014, and added models such as SkinEthic. During this time, the organization also issued the Integrated Approach to Testing and Assessment (IATA) guideline for skin corrosion and irritation, promoting the integration of multi-model data and enhancing classification accuracy. From 2019 to the present, regulatory authorities have fully accepted RhE model data for the registration of cosmetics and chemicals. Research and development into improved RhE models is now being advanced worldwide to enhance predictive capability.
A NAM-Enabled Future
NAMs like RhE models offer four main advantages. The first is human relevance. Human-derived models eliminate species differences, allowing direct application of results to humans and avoiding the uncertainty of extrapolating from other species.
Standardization is another advantage, as models exhibit high batch-to-batch consistency and controllable test conditions. This greatly improves the reliability and comparability of data. NAMs also boast high efficiency and flexibility.
Compared with traditional methods, NAMs also have a shorter test cycle and can detect multiple substances simultaneously, accelerating the research and development process. Finally, NAMs also align with consumers’ increasing ethical expectations.
These advantages will only compound as technology improves. And as these new methodologies become increasingly prevalent, developers and sponsors must proceed with confidence and intention to make the most of them, while ensuring safety and efficacy remain at the highest levels possible.
A Final Word
The success of skin irritation and corrosion tests based on RhE models has demonstrated the benefits and inevitability of a NAM-enabled future, in which new methodologies are increasingly used in place of in vivo testing models. The scale of this shift should not be underestimated. We are now entering a new era of drug testing. Developers and sponsors must take steps to stay ahead of the curve by engaging a trusted partner with the experience and know-how to navigate this evolution.
