Navigating the Borderline Products: Regulatory Challenges of Substance-Based Medical Devices

Introduction

Devices that are composed of substances or combinations of substances, also called “Substance-based medical devices” (SBMD), represent a category of products within the medical device industry, often seen as “borderline products”. In fact, being composed of substances, these products can fall within the pharmaceuticals or medical devices regulatory frameworks, based on their principal mode of action. As they continue to gain recognition, understanding their role, regulatory pathway, and impact on healthcare is essential. 

What Are Substance-Based Medical Devices?

SBMD fall within the Regulatory Framework of the MDR. The MDR clearly states that previous Medical Device Directives failed to fully consider the invasiveness and toxicity of absorbable devices. Therefore, new classification rules were implemented in the MDR, focusing on the site of the body where the device acts, where it is applied, and whether its substances or metabolic by-products are systemically absorbed.  

Nevertheless, “Substance” or “combination of substances” are not defined in the MDR, while these are given in other regulatory frameworks, such as the Medicinal Product Directive (MPD – Directive 2001/83/EC) [2].  

To provide a clear understanding of this scenario, The Medical Device Coordination Group (MDCG) issued the Guideline MDCG 2022-5 [3]. A substance is also understood as any matter irrespective of origin which may be human, animal, vegetable, or chemical obtained by chemical change or synthesis. SBMDs are defined as medical device which are composed of substances that are permitted in a medical device (i.e., excluding viable biological material, viable organisms, animal tissues, human tissues), and do not achieve its principal intended action by pharmacological, metabolic or immunological means. 

Therefore, SBMDs are expected to be primarily composed of substances and achieve their intended purpose through a physical mode of action. Unlike drugs, they do not rely on chemical interactions to treat or diagnose conditions. Instead, these devices may form barriers, lubricate tissues, or create a physical environment conducive to healing. 

Examples of SBMDs include: 

• Hyaluronic acid gels used in joint pain relief or wound healing. 

• Topical creams that protect or provide a barrier to the skin. 

• Inhalation products that clean and humidify the respiratory tract. 

Qualification of a Product as a SBMD

SBMDs are impacted by dedicated general safety and performance requirements (GSPRs) in Annex I of the MDR (e.g., GSPRs 12.2, 13.3, 23.2(r), 23.4(t)). They are also regulated by a classification rule (Rule 21) and a specific certification procedure (Annex IX 5.4). 

Like all other Medical Devices regulated by the MDR, the first milestone of the development of a SBMD is its qualification as a Medical Device. Ensuring the Mechanism of Action falls within those means permitted by the MDR is imperative (no pharmacological, metabolic or immunological actions!). in fact, the primary differentiator lies in the mode of action: 

• Pharmaceuticals act through chemical, metabolic, or immunological means. 

• Medical Devices operate via physical mechanisms, even if they contain active substances. 

The Manufacturer has to prove that the substances in the medical device are not supporting the intended principal action via the “prohibited” mechanisms. This can be achieved through literature assessment of each constituent or through experimental evidence.  

Depending on the risk associated with the device, SBMDs can fall into different classes (Class I, IIa, IIb, or III), with Class III being the highest risk and subject to the most stringent regulatory requirements. 

Preclinical and Clinical Data

Key challenge for SBMDs manufacturers is to provide details on the preclinical and clinical safety and effectiveness of the products.  

Preclinical safety encompasses producing preclinical tests, including biocompatibility data. For SBMDs, dedicated protocols may apply, since in some cases these devices are not suitable for extraction techniques. Moreover, information in the technical documentation on absorption, distribution, metabolism and excretion (ADME) of the final device, as per the requirement of Annex II, clause 6.2 (c). in this framework, at least the substances concurring to the principal mode of action should be assessed, to exclude any systemic absorption and related risks. This evaluation needs a deep knowledge of each single constituent ADME profile. 

Manufacturers must provide clinical data supporting the safety and performance of the device. This often involves clinical trials or equivalence data comparing the new device to a previously approved one. The procedure of collecting clinical data is part of the mandatory Clinical Evaluation required by the MDR. 

SBMDs face unique challenges in their development process. Unlike traditional medical devices, which often involve mechanical or electronic components, these products must undergo rigorous testing to ensure that their physical actions are both safe and effective. For example, achieving the right consistency and stability for the substance to perform its intended action is one of the hardest challenges. Demonstrating efficacy through preclinical or clinical trials tailored to the physical mode of action, may require innovative trial designs. 

Case Studies

To illustrate the impact of substance-based medical devices, consider the following examples: 

Hyaluronic Acid for Osteoarthritis: 

• Hyaluronic acid-based injectables provide lubrication to the joints, reducing pain and improving mobility without the systemic effects of oral medications. 

Film-Forming Barrier Creams: 

• Used in dermatology, these creams create a protective layer on the skin, preventing irritation and aiding in the treatment of conditions like eczema. 

Nasal Sprays for Allergies: 

• Nasal sprays containing saline solutions act physically to clear nasal passages, providing relief from allergic symptoms without the use of antihistamines. 

Endnote 

Substance-based medical devices play a crucial role in the future of healthcare, offering safe, effective, and versatile solutions for a wide range of medical conditions. As the regulatory framework continues to evolve and technology advances, these devices will likely become increasingly important in both clinical and consumer settings. For healthcare providers, patients, and manufacturers, staying informed about the development and application of these innovative devices is essential to fully realise their potential in improving health outcomes. 

References

Regultion (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC 

Directive 2001/83/EC on the Community code relating to medicinal products for human use  

MDCG 2022 – 5 Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices – April 2022 

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