Scientific Evidence

The approval of EU Regulation 2017/745 has created a regulatory framework capable of consolidating an entire category of therapeutic products, that of Substance-based Medical Devices. The Regulation creates the conditions required to promote innovation in therapeutics, both for the so-called “minor illnesses” as well as for important “unmet medical needs”. At the same time, it significantly raises the standards for evaluating their efficacy and safety. Among the different kinds of Substance-based Medical Devices, those made of natural complex substances offer a special opportunity. In this new regulatory context, natural substances can be made available to the patient within an “evidence-based” context, guided by the principles of Systems Biology and Systems Medicine, and under the control of the healthcare sector. Substance-based Medical Devices are already an important product in the European therapeutic market and will likely play an increasing role in the years to come.

The novel Regulation 2017/745/EC on medical devices introduces and strengthens the role of “medical devices made of substances”, which mostly include substances of natural origin. Natural products may follow different regulations, from food to therapeutics. Concerning their isolated constituents, extracts are characterized by a complexity that is not easily tackled from both a scientific and a regulatory point of view, but more importantly, from a therapeutic point of view. The evidence-based approach applied to isolated molecules requires appropriate evidence of quality, efficacy, and safety. The same needs must be reached for complex substances by finding appropriate methods to generate this evidence, and in addition, defining an appropriate regulatory field for them. From a scientific point of view, new methods, such as those proposed by systems biology, are available and applicable to complex substances. From a regulatory point of view, Directive 2001/83/EC on medicinal products seems to be modeled on single (or combinations of single) molecule products. On the other hand, Regulation 2017/745/EC on medical devices seems to apply to complex substances without derogating on quality, efficacy, and safety. The regulation specifically names and strengthens medical devices that include substances, mostly of natural origin, introducing the official term “medical devices made of substances”. This paper discusses and proposes an interpretation of important terms connected to this legislation, regarding both scientific and regulatory issues, and the opportunities the regulation may give for innovation and therapeutic improvement with natural complex substances.

The evolution of medical devices has led to the introduction of medical devices that include “substances” and which, due to their presentation and sites of application may resemble medicinal products. The difference between substance-based medical devices and medicinal products lies in the proper definition of the principal mechanism of action. The major problem at the moment is the lack of a proper procedure for the demonstration of a mechanism that is “not pharmacological, immunological or metabolic.” We aimed to design an experimental set up to demonstrate the difference between the mechanism of action of two substances used commonly for the treatment of constipation, lubiprostone (example of medicinal product) and glycerine (example of medical device). By implementing cellular models and molecular analyses we demonstrate the difference in their mechanism of action. This set up can be considered an example on the possibility to define a paradigm for the case by case study of the mechanism of action of substances and combination of substances in medical devices.

Introduction: Medical devices comprise apparatus/instruments, software, and materials with therapeutic activities obtained by principal mechanisms of action different from pharmacological, immunological and metabolic, which are proper of medicinal products. In this context the key for the distinction between medicinal products and devices lies in the correct interpretation of these terms, which, although defined in a guideline, are still not univocally interpreted.
Areas covered: This article discusses the definitions of pharmacological and non-pharmacological mechanisms of action, such as the chemical and physical means. The aim is to give insights on the correct definition these terms in order to contribute to build the desired synergy between scientific and regulatory fields and promote a correct interpretation of the European regulatory framework as well as sustainable health and innovation.
Expert commentary: We propose a series of definitions and a method to interpret those definitions within possible decision tree paradigm. Specifically, we propose to define the difference between the terms ‘action’ of a medical device compared to the ‘mechanism of action’ of such device. In any decisional procedure the correct interpretation of these and other correlated terms is needed to correctly assess whether a substance is a medicinal product or a medical device.