As described in the outlook of the first post in October, the blog series by medXteam GmbH now addresses the first type of clinical trials with medical devices: basic research – other clinical trials (MDR Article 82).

Other clinical investigations with medical devices

1 Introduction

Basic research didn't begin with EU Regulation 2017/745 (Medical Device Regulation, MDR); quite the contrary. Generally, it's about investigating feasibility and clarifying fundamental questions. The goal of basic research is therefore:

• the exploration of technical fundamentals
• the research of medical fundamentals
• the integration into the development of new products

Most of these activities take place in the laboratory:

Figure 1: Feasibility research project

However, there are always questions that can only be answered through tests/studies on humans.

This case was not previously regulated in the German Medical Devices Act (MPG). The Act only addresses clinical trials for medical devices according to Sections 20 et seq.

The MDR now regulates this in Article 82 with the so-called “ clinical investigations ” , the implementation of which at national level in Germany is detailed in Chapter 4, Subsection 2, Sections 47 to 61 of the MPEUAnpG (Medical Devices EU Adaptation Act).

2. Clarification of the terms “medical device” and “prototype”

A medical device is defined in Article 2 of the MDR as follows:

„“Medical device” means an instrument, apparatus, device, software, implant, reagent, material or other article which, according to the manufacturer, is intended for use on humans and is intended, alone or in combination, to fulfill one or more of the following specific medical purposes:

• Diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of diseases,

• Diagnosis, monitoring, treatment, relief or compensation of injuries or disabilities,

• Examination, replacement or alteration of the anatomy or of a physiological or pathological process or condition,

• Obtaining information through in-vitro examination of substances from the human body

• including from organ, blood and tissue donations

• samples originating from the human body and whose intended main effect in or on the human body is not achieved by pharmacological or immunological means or metabolically, but whose mode of action can be supported by such means.“

The fundamental criterion for defining a product as a medical device is its intended purpose. According to Article 2, paragraph 12 of the MDR, this is “ …the use for which a product is intended in accordance with the manufacturer’s information on the labelling, in the instructions for use or advertising or sales material and the information provided during the clinical evaluation…”

The intended purpose must be formulated by the manufacturer as part of the technical documentation and is crucial in determining whether a product is simply a product or a medical device. For a product to be declared as a medical device, it must be able to fulfill its intended purpose under normal operating conditions and meet the definition mentioned above.

If the intended purpose of a product does not match the above definition and does not refer to any of the points mentioned above, it is not a medical device. In this case, the MDR requirements for development and initial use do not apply.

What constitutes a medical device and what does not? 

 

Table 1: Differentiation between medical device and product

A product designated as a "prototype" or "demonstrator" is a medical device in a very early stage of development. This means that it is a first test version of a new device, procedure, or concept that has never been clinically tested. Accordingly, there is no experience regarding its medical benefit, usability in everyday clinical practice, application/usage protocol, and potential risks associated with its use .

An initial study with such a prototype/demonstrator is intended to gather initial and fundamental experience. Furthermore, it aims to demonstrate the feasibility of the new concept/procedure and explore options for potential development as a medical device. The insights and experience gained will form the basis for any further development of the prototype/demonstrator into a medical device. This development process, in accordance with the MDR (Medical Device Regulation), may then involve numerous modifications to the design, features, technical functions, and configuration to achieve sufficient usability and clinical/technical performance. Only a product that meets the required safety and clinical performance standards can ultimately be placed on the market.

3. Clinical trials in humans – determining the appropriate study type

3.1 Clinical investigation to demonstrate conformity of products (Article 62 MDR) or other clinical investigation (Article 82 MDR)

To distinguish between a clinical investigation ( registration study ) according to Article 62 of the MDR and a feasibility study ( other clinical investigation ), the objectives of the regulatory requirements within the framework of the MDR must first be presented:

„Based on a high level of health protection for patients and users, this regulation aims to ensure a smoothly functioning internal market for medical devices, taking into account the small and medium-sized enterprises operating in this sector. Furthermore, this regulation establishes high standards for the quality and safety of medical devices, which are intended to address general safety concerns regarding these products.“

In this context, determining the safety and performance of a medical device plays a fundamental role as a prerequisite for placing it on the market. Placing on the market “ means the first making available of a product, with the exception of investigational products, on the Union market …” (MDR Article 2, paragraph 28). The only exception is the supply of the medical device for the purpose of a clinical investigation.

To be placed on the market, a medical device must bear a CE marking. The CE mark indicates that the medical device complies with legal requirements and that, during the assessment process, its safety and performance have been demonstrated in accordance with its intended purpose under everyday clinical conditions. This demonstration is provided by the manufacturer and is known as the conformity assessment procedure. This involves a clinical evaluation of clinical data, which are the product's safety and performance data. Unlike pharmaceutical law, this data can also be obtained from the literature. The prerequisite is that corresponding data for similar products are available and that the similarity to the manufacturer's own medical device can be demonstrated. This approach is also known as the literature route.

If this is not possible, performance and safety data must be generated by the manufacturer itself within the framework of a clinical investigation – previously the MPG investigation (§ 20 MPG) or the clinical investigation to demonstrate the conformity of products (Article 62 MDR). An MPG study is conducted in accordance with the "Regulation on the Conduct of Clinical Investigations with Medical Devices" (MPKPV), which, according to § 1 (1) of the Regulation, must always be applied when conducting clinical investigations in accordance with the MPG, the results of which are to be used for carrying out a conformity assessment procedure in accordance with the Medical Devices Regulation (MPV). After the MDR enters into force, this regulation will be replaced by Regulation (EU) 2017/745 of the European Parliament and of the Council (MDR), and the MPG will be replaced by the MPEUAnpG (Medical Devices EU Adaptation Act). Clinical investigations (Article 62 MDR) and other clinical investigations (Article 82 MDR) are then planned and carried out in accordance with the requirements of the MDR and the supplementary national provisions of the MPEUAnpG. The performance and safety of the medical device are also paramount in the clinical investigations under Article 62 of the MDR

“Clinical trial” refers to a systematic investigation involving one or more human participants and conducted to evaluate the safety or performance of a product

If the aim of a research project and its associated clinical application is not to assess the performance and safety of a product within the framework of a conformity assessment procedure according to the current Medical Devices Act (MPG) (in conjunction with the Medical Devices Clinical Trials Ordinance (MPKPV)) and the Medical Device Regulation (MDR), but rather to investigate the medical/technical fundamentals that may later be incorporated into the development of new medical devices (testing a prototype), then this does not constitute a "clinical investigation" within the meaning of the regulations. While both the MPG and the MDD lack a precise distinction and delimitation, this is provided by Articles 62 and 82 of the MDR, published since May 2017

Article 62: General requirements for clinical investigations carried out to demonstrate the conformity of products

1. to establish and verify that a product is designed, manufactured and packaged in such a way that, under normal conditions of use, it is suitable for one or more of the specific purposes listed in Article 2, point 1, and performs the intended function as specified ;
2. to determine and verify the clinical benefit of a product as claimed by its manufacturer;
3. to establish and verify the clinical safety of the product and to determine any undesirable side effects of the product that may occur under normal conditions of use, and to assess whether these represent acceptable risks compared to the benefits provided by the product.

Table 2: Aims and timing of clinical trials to demonstrate product conformity

Article 82: Requirements for other clinical trials (basic research, in vivo feasibility studies, …)

1. Clinical trials not carried out for one of the purposes referred to in Article 62(1) must comply with the provisions of Article 62(2) and (3), (4)(b), (c), (d), (f), (h) and (l) and (6).
2. In order to protect the rights, safety, dignity and welfare of trial participants and to ensure compliance with scientific and ethical principles in clinical trials not carried out for one of the purposes referred to in Article 62(1), each Member State concerned shall lay down appropriate additional requirements for such trials.

And the MPEUAnpG, which comes into force with the MDR, also provides a definition for other clinical investigations under § 3 sentence 4 Definitions:

"[...] a clinical trial that

1. not part of a systematic and planned process for product development or product monitoring by a current or future manufacturer,

2. carried with the aim of demonstrating the conformity of a product with the requirements of Regulation (EU) 2017/745,

3. serves to answer scientific or other questions and

4. outside of a clinical development plan as defined in Annex XIV Part A point 1 letter a of Regulation (EU) 2017/745."

Table 3: Other clinical trials

Thus, the appropriate study format clearly results from the objective of the clinical trial and the stage of development of the product to be used.

Therefore, if safety and performance data are to be collected for the purpose of conformity assessment of an existing prototype (i.e., the product must also be in a sufficiently mature state), the MPG/MDR legal framework applies and a clinical investigation must be carried out in accordance with MPKPV/MDR Article 62.

If, however, the product is still in an early research stage as a pre-prototype and first requires proof of the functionality and rationale of the underlying concept, and therefore initial evidence of the effectiveness of the new procedure as well as verification of the feasibility of a potentially subsequent clinical intervention study is to be provided, then this is not, in essence, a medical device study (MDR Article 62), and clinical application is also not carried out in accordance with the Medical Devices Clinical Trials Ordinance (MPKPV). The applicable requirements are described in the following chapter "Conducting a Feasibility Study".

Other clinical investigations are regulated in Article 82 of the MDR and in Chapter 4, Subsection 2, Sections 47 to 61 of the MPEUAnpG (Medical Devices EU Adaptation Act).

3.2 Timing of any other clinical trial

Other clinical investigations are always conducted when the focus is not on evaluating the performance and safety of the medical device. Instead, the focus is on answering scientific or other questions, and this can occur at any stage of the product lifecycle, even before the actual product (e.g., prototype, demonstrator). Therefore, it is entirely possible that " other clinical investigations are conducted within the scope of the intended purpose covered by the CE marking, " and thus, if the investigation were concerned with performance/safety and/or benefit, it would be a PMCF study or clinical investigation for products bearing the CE marking, according to Article 74 of the MDR.

3.3 Conducting a feasibility study

Other clinical trials are integrated into the process of gathering experience through various procedures for expanding knowledge and improving specific methods. At the very beginning of such developments, for example, is the idea, which must first be tested for its feasibility, usually within animal models (in vivo studies). In one of these testing phases, initial improvements and adaptations of the original idea take place, which are then tested again in the animal model. Thus, the realization phase of the idea can comprise several cycles. The transition to a feasibility study occurs when there is evidence that the idea contributes to an improvement in medical care (Kohnen, 2011).

Figure 2: Knowledge acquisition in the empirical science of medicine. (Kohnen, 2011)

The aim of such a clinical trial in humans is to provide initial evidence of the effectiveness of a procedure and to verify the feasibility of a possible subsequent clinical intervention study.

While such other clinical investigations were not considered in the MPG, the MDR now provides a clear definition in Article 82 (see above) and sets out unambiguous requirements for this form of clinical investigation:

The commissioning of a product is not a legal vacuum, but is subject to extensive safety checks (technical safety, electrical safety, biological safety, and compliance with standards), the so-called "essential requirements" (Annex I MDD) or "essential safety and performance requirements" (Annex I MDR), which must be verified by independent third parties. Furthermore, a comprehensive risk analysis and an ethically sound benefit-risk assessment must be submitted.

This also follows from Article 82 MDR with reference to Article 62 paragraph 4 letter l:

„(4) A clinical trial pursuant to paragraph 1 may only be carried out if all of the following conditions are met: […]

(l) The investigational product(s) in question complies(s) with the essential safety and performance requirements set out in Annex I, with the exception of those points that are the subject of the clinical investigation; with regard to these points, all necessary precautions have been taken to protect the health and safety of the trial participants. This includes, where appropriate, technical and biological safety checks and a preclinical evaluation, as well as provisions relating to occupational safety and accident prevention, taking into account the latest state of knowledge.“

Since other clinical trials are research projects that fall under the umbrella of basic medical research on humans, the general legal regulations and guidelines for medical research also apply. This applies to all other clinical trials, regardless of when they are conducted. Various requirements must be considered to protect patients, users, and third parties. These include the

• Declaration of Helsinki in its current version.

This ensures compliance with the ethical standards of medical research involving human subjects. Particular attention should be paid to the following points within the project:

1. Obtaining the patients' declaration of consent
2. Protection of patients incapable of giving consent
3. The well-being of the "test subject" is placed above the interests of science
4. Obtaining a positive opinion from the relevant ethics committee. This was included in the MDR in Article 82 as follows:

„Clinical trials not carried out for one of the purposes referred to in Article 62(1) must comply with the provisions of Article 62(2) and (3), (4)(b), (c), (d), (f), (h) and (l) and (6)

This means in particular:

Article 62, paragraph 3

„Clinical trials are designed and conducted in such a way as to ensure the protection of the rights, safety, dignity and well-being of the trial participants, which takes precedence over all other interests, and that the clinical data obtained are scientifically sound, reliable and robust.

Clinical trials are subject to scientific and ethical review. The ethical review is carried out by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by the ethics committees are compatible with the procedures laid down in this Regulation for the assessment of the application for authorization of a clinical trial. At least one layperson participates in the ethical review.“

Article 62, paragraph 4

„A clinical trial pursuant to paragraph 1 may only be carried out if all of the following conditions are met: […]

b) an ethics committee established under national law has not issued an adverse opinion regarding the clinical trial, which is valid under the national law of the Member State concerned for its entire territory;

c) the sponsor or its legal representative or a contact person referred to in paragraph 2 is established in the Union;

d) Vulnerable population groups and examination candidates shall be adequately protected in accordance with Articles 64 to 68;

(f) the candidate or — if the candidate is unable to give informed consent — his or her legal representative has given informed consent in accordance with Article 63;

h) the examinee's right to physical and mental integrity, privacy and protection of his or her personal data in accordance with Directive 95/46/EC remains protected.“

Furthermore, in accordance with Section 48 of the MPEUAnpG, the documents in accordance with Annex XV Chapter II of the MDR must be prepared and submitted to the Ethics Committee.

Subsection 2 with §§ 47 ff in the MPEUAnpG is dedicated to the topic of other clinical trials (requirements, procedures at the ethics committee, etc.) and provides clear national regulations on this subject.

Furthermore, it is recommended to consider the application of ISO 14155 for the standardized conduct of studies involving medical devices. While the standard focuses on clinical trials of medical devices and thus does not correspond to the intent of a feasibility study, much of its content can still be applied due to its relevance. Within the standard, ethical principles hold a prominent position, and Chapter 4 is dedicated to "Ethical Considerations." Since it is essential to protect the safety and well-being of study participants in accordance with the Declaration of Helsinki (participant insurance, supplementary healthcare), the standard provides valuable guidance in this regard.

Furthermore, the benefit-risk assessment and the justification for a "clinical trial" play a crucial role. According to the MDR and MPEUAnpG, ethical and safety-related requirements are considered binding.

For this purpose, ISO 14155 equates the terms "clinical trial" and "clinical study" with "clinical investigation." To justify a clinical investigation under the Medical Devices Act (MPG), an objective presentation of published and unpublished data, as well as a detailed risk analysis and benefit-risk assessment, must be conducted. The justification for a clinical investigation is documented in the study protocol and serves as an evaluation criterion for the ethics committee in its review for approval. This applies equally to other clinical investigations, although in these cases, due to the early phase and the lack of clinical experience, only a benefit-risk assessment with regard to the research project can be considered.

4. Outlook

The blog series on the types of clinical trials will be interrupted in December by our " Christmas Special ." With this special, we would like to provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year, so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections with further changes are added every week.

DiGA studies will continue in January.

5. How we can help you

At medXteam we clarify whether and if so which clinical trial needs to be carried out under what conditions and according to what requirements during the pre-study phase: In 3 steps we determine the correct and cost-effective strategy in relation to the clinical trial required in your case Data collection.

Do you already have some initial questions?

You can get a free initial consultation here: free initial consultation