Preclinical evaluation of a Madical Device: focus on substance-based devices

Di Sofia Tamini - Regulatory Affairs Manager

Regulation (EU) 2017/745 on medical devices (MDR) emphasizes in several points the importance of conducting an appropriate preclinical evaluation of the medical device.

The objective of the preclinical evaluation is to provide a solid basis on the safety of the medical device, in terms of biocompatibility and toxicological risk assessment, as well as performance and efficacy, including the definition of the mechanism of action through which the device achieves its intended purpose.

This type of evaluation must be based on documentary evidence and on sufficient data, which can derive from a critical and systematic review of the existing scientific preclinical literature and must be consolidated by preclinical tests conducted on the device. Preclinical tests include in silico, in vitro, ex vivo and in vivo tests.

Specifically, the preclinical evaluation serves as the means of demonstrating compliance with the general safety and performance requirements outlined in the MDR in Annex I, and in particular those relating to Chapter II. In fact, this chapter outlines the requirements regarding the design and the manufacturing of the device, which can only be satisfied through preclinical evaluation.

Moreover, referring to Annex II of the Regulation, regarding the content of the technical documentation, in point 6.1 it is clearly stated that the preclinical data concern and include:

  • “Results of tests, such as engineering, laboratory, simulated use and animal tests, and evaluation of published literature applicable to the device, taking into account its intended purpose, or to similar devices, regarding the pre-clinical safety of the device and its conformity with the specifications;
  • Detailed information regarding test design, complete test or study protocols, methods of data analysis, in addition to data summaries and test conclusions regarding in particular:
  1. the biocompatibility of the device including the identification of all materials in direct or indirect contact with the patient or user,
  2. physical, chemical and microbiological characterisation,
  3. electrical safety and electromagnetic compatibility,
  4. software verification and validation […],
  5. stability, including shelf life; and
  6. performance and safety. […]

Where no new testing has been undertaken, the documentation shall incorporate a rationale for that decision. An example of such a rationale would be that biocompatibility testing on identical materials was conducted when those materials were incorporated in a previous version of the device that has been legally placed on the market or put into service.”
And for substance-based medical devices, it is added in point 6.2 (a):  “Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as referred to in the first subparagraph of Article 1(8), a statement indicating this fact. In this case, the documentation shall identify the source of that substance and contain the data of the tests conducted to assess its safety, quality and usefulness, taking account of the intended purpose of the device.”
And in point 6.2 (c): “In the case of devices that are composed of substances or combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, detailed information, including test design, complete test or study protocols, methods of data analysis, and data summaries and test conclusions, regarding studies in relation to:

  • absorption, distribution, metabolism and excretion; 
  • possible interactions of those substances, or of their products of metabolism in the human body, with other devices, medicinal products or other substances, considering the target population, and its associated medical conditions; 
  • local tolerance; and
  • toxicity, including single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, as applicable depending on the level and nature of exposure to the device. 

In the absence of such studies, a justification shall be provided.”

Therefore, considering what is reported in the MDR, how should the Manufacturers proceed with the preclinical evaluation of their medical devices, in order to correctly respond to the requests and requirements of the Regulation and confirm its compliance?
Based on the characteristics of the device and in particular the nature and duration of contact of the device with the end user, each Manufacturer must proceed with the evaluation of the preclinical efficacy and the mechanism of action of their medical devices, together with the assessment of its biological safety.

For substance-based devices, in both cases, the initial step is always the characterization of the formulation of the device. This requires specifying the exact qualitative and quantitative composition of all ingredients (as % w/w), defining their origin and function within the formula, and identifying which ingredients are the functional substances and which are excipients.

Evaluation of preclinical efficacy
According to Article 2(1) of the MDR, a medical device does not achieve its principal intended action by pharmacological, immunological or metabolic (FIM) means, in or on the human body, but which may be assisted in its function by such means.
Typically, the primary intended action of the medical device is achieved by physical, mechanical, or chemical means, e.g. physical barrier action with creation of a protective film, lubrication, heat transfer, radiation, ultrasound, organ replacement or support or bodily functions, etc. Additionally, hydration or dehydration and pH modification may be means by which a medical device achieves its primary intended action. Therefore, FIM-type mechanisms of action are not contemplated for medical devices, unless they are solely of an ancillary nature.
The Manufacturers will therefore have to demonstrate the efficacy and preclinical performance, defining the mechanism of action of their device. Initially, by conducting a comprehensive and precise literature search, evaluating the existence of relevant and pertinent preclinical studies, such as those derived from equivalent devices, which can provide data to support the preclinical performance of their device.
For substance-based medical devices, since it is very difficult to demonstrate equivalence, it is possible to rely on the literature to analyze in detail the individual ingredients of the medical device. By identifying the components to which the mechanism of action is attributed, it will be possible to focus the bibliographic research on the functions they perform, and with which means these effects are achieved, in order to draw the appropriate conclusions on the device in its entirety.
If the device contains an ingredient with a potential FIM-type action, the Manufacturer must demonstrate that such activity cannot be achieved by the substance in question, as present in the device. Alternatively, if such action is achieved, it must be proven that the effectiveness of the medical device is not dependent on this action but only has an ancillary function.

If the literature is not sufficient to fully support the definition of the mechanism of action and the demonstration of preclinical efficacy, or even the exclusion of any type of FIM means, the Manufacturer will have to plan the conduct of specific tests.
Currently, a wide range of in vitro tests and cellular models available, enabling the replication of the actual conditions of use of the device, on the designated target area, resulting in robust and representative outcomes. The tests that can be conducted either demonstrate the mechanism of action and efficacy, such as a barrier efficacy test, or exclude FIM-type activity, such as a test to verify the absence of anti-inflammatory properties.

Preclinical safety evaluation
The objective of the preclinical safety evaluation, or biological evaluation, of medical devices is to examine the behavior of the constituents of the device under conditions similar to the biological environment. The reference standard for the biological assessment is ISO 10993-1, which is currently in its fifth revision, published in 2018.
The biological evaluation is closely connected to the risk management process, which is why ISO 10993-1 incorporates aspects of ISO 14971, relating to the application of risk management to medical devices.

Biological safety must be assessed during the product design and development phase, especially with regards to the choice of raw materials, packaging materials, the production process and, when applicable, sterilization methods. However, the biological assessment process does not stop here, but it continues as a device must maintain its safety and performance characteristics throughout its entire life cycle. This results in the definition and control of the correct conditions and duration of storage, transport conditions, and the safety of use of the medical device.

Both ISO 10993-1 and ISO 14971 emphasize the need and the importance of planning assessment activities, and in the context of preclinical safety assessment, through the drafting of a specific biological evaluation plan (BEP). The BEP is the set of activities that define the biocompatibility profile of a device in relation to its specific biological risk for the final user, and takes into consideration all available data, particularly those derived from bibliographic research and those already available for the device. According to the ISO 10993-1 standard, and depending on the type of device, the nature, and the duration of contact between the device and the final user, the BEP defines the endpoints that must be evaluated to confirm the biocompatibility of the device. If the information available is not sufficient to cover the endpoints identified, an appropriate testing plan is proposed in the BEP, in order to minimize the risk related to the use of the device and guarantee the safety of the final user. The considerations that emerge in the BEP, as well as the results of the biocompatibility tests, are discussed and adequately commented and contextualized in the biological evaluation report (BER), in which it will be possible to draw overall conclusions on the biocompatibility of the device and, consequently, on its safety.

Nonetheless, it should be noted that conducting biocompatibility tests, or some biocompatibility tests, may not always be necessary. For instance, the systematic literature review, which is a fundamental component of biological evaluation, could allow the collection of sufficient information, thus avoiding the conduction of unnecessary tests. Obviously, each situation must be appropriately analyzed with an in-depth and case-by-case approach.

As regards substance-based medical devices, as mentioned above in point 6.2 of Annex II of the MDR, as well as in point 10.1 (b), the biological safety assessment must also include the analysis of the toxicokinetics of the medical device, which is the study of the absorption, distribution, metabolism, and excretion (ADME) of substances within the organism.
As absorption is the starting point of the toxicokinetic evaluation, the definition of the absorption profile of the components of the medical device, carried out through the appropriate research of relevant and pertinent literature data, can define the possible kinetic behavior of the product in its entirety. This assessment will be crucial in determining the necessity to deepen the toxicokinetic evaluation. In fact, in the event that the device cannot be absorbed, the information regarding distribution, metabolism and excretion would be unnecessary because not pertinent and applicable.
If, despite the data collected from the bibliographic research, it is not possible to fully evaluate the potential absorption of the device or to exclude the possibility of absorption of one or more of its constituents, then the Manufacturer will be required to proceed with the complete evaluation of the ADME or, alternatively, to perform an in vitro percutaneous/permucosal absorption test. Depending on the test results, the absence of absorption will be demonstrated or, in the case of documented absorption, a complete evaluation of the ADME will be required.

The first choice is to conduct a bibliographic ADME evaluation. Through literature data, it will be possible to establish whether the substance or substances, once absorbed, will pose a toxicological risk to the final user. In the rare instances where it is not possible to define the ADME based on the published literature data, in vivo toxicokinetic studies should be considered.

PRINEOS, a Strategic Consulting Company for Medical Devices and Pharma, bases its customers satisfaction on the high quality of the services provided. Conducting a precise and comprehensive preclinical evaluation is of fundamental importance; therefore, PRINEOS assist and supports Manufacturers in drafting the documents and defining the most effective approach to demonstrate the safety and the preclinical efficacy of medical devices.