Digital Health Technology (DHT) in European Clinical Trials, How to Improve the Status-Quo of the Regulatory Landscape?

Digital health technology (DHT) is increasingly used to facilitate the conduct of clinical drug trials. The European regulatory environment would benefit from some adjustments to realize the full potential of DHTs. Considering current discussions such as the European Accelerating Clinical Trial Initiative (ACT EU), we propose four concrete adjustments to this regulatory landscape to introduce risk-based qualification approaches for DHTs. In our view, these changes would have the potential to facilitate the use of DHT in clinical research and thus provide access to innovative therapies in Europe.

Digital Tools-Regulatory Considerations for Application in Clinical Trials.

During the last few years, the pharmaceutical industry has adopted digital technologies/digital health technology (DHT) to improve the drug development process and the commercialization of new products. Technological advances are strongly supported by both the US-FDA and the EMA, but the regulatory landscape in the US seems to be more suitable to promote innovation in the digital health sector (e.g. Cures Act). In contrast, the new Medical Device Regulation sets high hurdles for Medical Device software to pass regulatory scrutiny.On both sides of the Atlantic, a digital tool must be fit-for-purpose for the intended use in the clinical drug trial. Irrespective of its status as a Medical Device, at least the basic safety and performance requirements according to local regulations should be met, quality system and surveillance requirements should be fulfilled, and the sponsor must ensure conformity with GxP and the local data privacy and cybersecurity legislations.There is an overlap in technical and clinical validation for drug development tool qualification in both regions to ensure that the digital tools deliver reliable data with tangible clinical benefits. Based on an analysis of the regulatory framework of the FDA and the EMA, this study proposes regulatory strategies for a global pharma company: It would be prudent for drug development companies to a) use approved solutions or b) consider qualification of drug development tools early and in parallel to clinical development. Early engagement with the FDA and the EMA/CA is recommended to define evidentiary standards and corresponding regulatory pathways for different contexts-of-use and to clarify regulator's expectations as to what extent data collected by digital tools are acceptable to support marketing authorization applications (MAA).Hence a harmonization of the partly disparate regulatory requirements in the US and the EU accompanied by further development of the regulatory landscape in the EU, could further foster the use of digital tools in drug clinical development. The outlook for the use of digital tools in clinical trials is hopeful.

Digital Medical Device Companion (MyIUS) for New Users of Intrauterine Systems: App Development Study.

BACKGROUND: Women choosing a levonorgestrel-releasing intrauterine system may experience changes in their menstrual bleeding pattern during the first months following placement. OBJECTIVE: Although health care professionals (HCPs) can provide counseling, no method of providing individualized information on the expected bleeding pattern or continued support is currently available for women experiencing postplacement bleeding changes. We aim to develop a mobile phone-based medical app (MyIUS) to meet this need and provide a digital companion to women after the placement of the intrauterine system. METHODS: The MyIUS app is classified as a medical device and uses an artificial intelligence-based bleeding pattern prediction algorithm to estimate a woman's future bleeding pattern in terms of intensity and regularity. We developed the app with the help of a multidisciplinary team by using a robust and high-quality design process in the context of a constantly evolving regulatory landscape. The development framework consisted of a phased approach including ideation, feasibility and concept finalization, product development, and product deployment or localization stages. RESULTS: The MyIUS app was considered useful by HCPs and easy to use by women who were consulted during the development process. Following the launch of the sustainable app in selected pilot countries, performance metrics will be gathered to facilitate further technical and feature updates and enhancements. A real-world performance study will also be conducted to allow us to upgrade the app in accordance with the new European Commission Medical Device legislation and to validate the bleeding pattern prediction algorithm in a real-world setting. CONCLUSIONS: By providing a meaningful estimation of bleeding patterns and allowing an individualized approach to counseling and discussions about contraceptive method choice, the MyIUS app offers a useful tool that may benefit both women and HCPs. Further work is needed to validate the performance of the prediction algorithm and MyIUS app in a real-world setting.

Examinations of the antioxidative properties of the topically administered drug bufexamac reveal new insights into its mechanism of action.

The effect of bufexamac on UV-irradiation-induced lipid peroxidation was investigated. Linolenic acid was used as a model lipid. Bufexamac was shown to be capable of reducing the amount of lipid peroxidation. The quantification was carried out by the thiobarbituric acid assay. Irradiation experiments were also performed using HaCaT keratinocytes as a model system. The oxidative changes were quantified by DNA synthesis measurements and cell viability determinations. Bufexamac was found to act antioxidatively again. To investigate free radical involvement, electron paramagnetic resonance studies were carried out. The influence of bufexamac on the concentration of hydroxyl radicals generated by the Fenton system was examined using the spin trapping technique. Moreover, the hydroxamic acid's ability to react with stable radicals was checked. The quantification assay of 2,2-diphenyl-1-picrylhydrazyl hydrate showed no concentration changes of the stable radical caused by bufexamac. In the Fenton assay antioxidative effects were measured after the addition of the drug. The qualitative changes after irradiating bufexamac were studied at a molecular level by electrospray mass spectrometry. Multiple-stage mass spectrometry experiments enabled the establishment of fragmentation schemes. Phenolic degradation products were detected. The results suggest a new interpretation of the controversially debated mechanism of action of bufexamac and indicate possible reasons for its eczema provoking potential.

Relevance of reactive oxygen species in the induction of 8-oxo-2'-deoxyguanosine in HaCaT keratinocytes.

There is growing evidence that solar radiation-induced oxidative DNA damage may play an important role in carcinogenesis of the skin. One substantial modification in this context is the oxidation of the guanine base to 8-oxo-2'-deoxyguanosine. Using HaCaT keratinocytes, measurement of the 8-oxo-2'-deoxyguanosine content in this study was performed by flow cytometry on whole cells. Hydrogen peroxide and hydroxyl radicals seem not to be involved in the process of this DNA alteration. However, our results demonstrate that ultraviolet A can cause DNA damage at guanine sites primarily via photosensitized reactions. Although singlet oxygen can also lead to 8-oxo-2'-deoxyguanosine, the major mechanism seems to be based on formation of the guanylcation radical through excited riboflavin and can therefore proceed without the involvement of reactive oxygen species.

Evidence for a role of nitric oxide in the mediation of antiproliferative UVA effects in keratinocytes.

Using cultured human keratinocytes, the present study investigates the role of nitric oxide (NO) in the mediation of the antiproliferative effects of ultraviolet light A (UVA). UVA treatment of cells (3-21 J cm (-2)) caused a time- and dose-dependent increase in nitrite formation in a micromolar range. This effect was accompanied by a decrease in DNA synthesis by 53.5%. Moreover, UVA treatment slightly reduced cell viability by 23.8%. Preincubation of keratinocytes with the NO scavenger 4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO, 10-100 microM) or the NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA, 30-300 microM) significantly diminished the UVA-induced increase in nitrite. PTIO as well as l-NMMA partially protected keratinocytes from UVA-induced antiproliferative effects and increased DNA synthesis by 67 or 49% of the control. The co-application of UVA irradiation (10 J cm (-2)) and the essential cofactor of NO synthases tetrahydrobiopetrin (BH4, 500 microM) led to an overadditive increase in the release of nitrite as well as to a decrease in DNA synthesis. These results imply that NO is involved in the antiproliferative UVA effects in keratinocytes.

Is the photoprotective effect of vitamin E based on its antioxidative capacity?

Vitamin E (alpha-tocopherol) is widely used in the prevention of ultraviolet (UV)-induced skin damages. Mostly, the photoprotective effect of vitamin E is attributed to its radical scavenger capacity. We discuss here other possible explanations for its preventive potential.