Medical Devices made of substances: opportunities and challenges

The new regulation recognizes and directly addresses a topic of utmost importance to pharmacologists, i.e. “Devices that are composed of substances or of combinations of substances”. In fact, as clearly stated in the paper by Racchi and Govoni, “The evolution of medical devices has led to an increasing number of products that include “substances” and which, due to their presentation (powders, liquids, tablets) and to their sites of application (i.e. gastrointestinal mucosae reached via oral administration), resemble those products which have historically been called medicinal products”. Furthermore, Regulation 2017/745, identifies a specific classification rule (Rule 21) for medical devices made of substances, that is even more intriguing for pharmacologists. Indeed, Rule 21 specifically states: “Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as:

— ….omissis.

The intended purpose for medical devices made of substances is a therapeutic effect (an MD is used for treatment or alleviation of disease); however it “does not achieve its principal intended action by pharmacological, immunological or metabolic means”. We can thus affirm that the Regulation 2017/745, by changing the legislation on MD, has built a structured system in the interest of the patient. In fact, clinical data required to claim any “intended purpose” have been straightened and the safety of the device should be confirmed by a post-market clinical follow-up.

This is a big challenge indeed for pharmacologists. Basic and clinical pharmacologists will be asked to address a series of relevant points:

• the «pharmacological mode of action» and the «non-pharmacological modes of action» should be defined as clearly as possible;
• an evolution of the interpretation of the mechanism of action of substances / complex substances is necessary, since they de facto do not fit the pharmacological model;
• pharmacologists can contribute to this evolution together with regulators, to ensure very best innovation in therapy, within the strictest safety and efficacy standards.

As the Italian Society of Pharmacology, we would like to accept this challenge, first of all by informing the pharmacological community of the changes and opportunities associated with Regulation 2017/745 and secondly by opening up a constructive forum of discussion. We certainly need to keep an open mind when approaching these topics and avoid to being held back simply by the fear of change or by prejudice. Instead, we need to continue to search and call for convincing scientific and clinical evidence. In fact, we all know that a huge number of people are using products of unproven efficacy and safety. We are also aware that the drug regulatory system is too rigid for products such as natural complex substances. In this respect, the regulation raises the standard of evidence required to demonstrate safety and efficacy for M.D., based on risk/benefit evaluations. Likely, the regulation will reduce the availability of products of unproven efficacy and will positively impact on the patient’s health. Basic and clinical pharmacologists should collaborate in order to describe and possibly clarify the inside of that “black box”, i.e. the “non- pharmacological mechanism”, responsible for the documented therapeutic effect of a medical device made of substances. This special issue of Pharmadvances, the official journal of the Italian Society of Pharmacology, aims to be the Forum for this discussion.

The issue contains an article by Racchi and Govoni and seven commentaries to their paper. Racchi and Govoni, distinguished pharmacologists at the University of Pavia (Italy), discuss how regulatory documents in the European Union, distinguish “medical devices” from “medicinal products” according to the principal mechanism of action of the product. The correct interpretation of terms such as “pharmacological, immunological and metabolic mechanism of action”, have important regulatory implications.Their main message is “to attract pharmacologists to design proper experimental paradigms to be applied to the rigorous and scientific interpretation of the correct mechanism of action of medical devices made of substances”.

Marcella Marletta, former Director at the Directorate General for Medical Devices and Pharmaceutical Services, Ministry of Health and Walter Ricciardi, President of the Istituto Superiore di Sanità in the years 2014-2018, both highlight the importance that this regulation has for the development of new, innovative, highly needed, low risk therapeutic products and how it will most likely increase and strengthen confidence in the Medical Devices safety among EU healthcare professionals, patients and consumers. They have followed Regulation 2017/745 in its complete evolution.

Paolo Sassone-Corsi, Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine (USA) discusses how recent technical advances in the field of omics- technologies-, will enable researchers to decipher biological phenomena and thus understand the consequences of the interaction of a complex substance with the human body on a systemic, holistic scale.

Salvatore De Masi, head of clinical research at the Meyer Pediatric Hospital (Florence, Italy) makes an interesting reflection on the gap between the mechanism of action and the therapeutic effect.