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Quality management for Class I medical devices

At medXteam, clinical data is our core focus. As a CRO, we not only conduct clinical investigations of medical devices in accordance with the MDR and ISO 14155, but also offer all other options and forms of data collection. This time, however, the focus is not on clinical data itself, but on a foundation for medical device manufacturers in general, and specifically for manufacturers of Class I devices. The MDR requires a quality management system (QMS) for all medical device manufacturers. Therefore, Class I manufacturers must now also have one.

What are the special features? Are there any differences compared to manufacturers of higher-classified products? We will address this topic in this blog post.

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

QMS quality management system

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Devices Implementation Act (MPDG)

1 Introduction

The development and manufacture of medical devices are subject to strict regulations to ensure safety and efficacy. The Medical Device Regulation (MDR) sets out clear requirements, particularly for manufacturers of Class I medical devices, which are often classified as low-risk. Article 10(9) of the MDR mandates a quality management system (QMS) for all medical devices – regardless of their risk class.

For Class I products, this means that the QMS must fully comply with the requirements of the MDR and the ISO 13485 standard. This standard has previously formed the basis for quality management systems in the medical device sector and now, together with the specific requirements of the MDR, including articles and relevant annexes, forms the basis for quality management systems.

A key difference compared to higher-grade medical devices is that the QMS for Class I devices does not need to be certified. Instead, the focus is on actively maintaining the system – that is, continuously improving it and responding to regulatory changes. The established processes must be implemented and adhered to so that the products meet the quality standards accordingly.

In the following sections, we will examine in more detail how an effective and compliant QMS for Class I products is established and operated to meet the requirements of the MDR. From the fundamental principles to practical implementation, you will gain a comprehensive insight into the specific characteristics and challenges of quality management for this product class.

2. Requirements for a quality management system (QMS)

2.1 Requirements of Article 10 (9) MDR

Article 10(9) of the MDR describes the comprehensive requirements for a quality management system (QMS) that manufacturers of medical devices, including Class I devices, must implement and maintain. The aim of the QMS is to ensure that the requirements of the Regulation are continuously met, even during serial production.

A key component of this approach is the ability to promptly and appropriately address changes in product design, properties, or relevant regulatory requirements. This also includes the continuous improvement of the QMS, which is aligned with the risk classes and specific characteristics of the products.

Comprehensive requirements for the QMS

The quality management system must encompass all organizational areas of a manufacturer that influence the quality of processes, procedures, and products. This includes, among other things:

  • Structure and responsibilities: Clear definition of tasks and responsibilities within the company.
  • Processes and procedures: Development and application of effective workflows for all relevant business areas.
  • Management resources: Ensuring the availability of expertise, personnel, and financial resources.

Aspects to be considered at a minimum

According to the MDR, the QMS must cover a wide range of aspects, including:

  • Regulatory compliance: adherence to conformity assessment procedures and the management of product changes.
  • Risk management: Implementation of a systematic risk management process in accordance with Annex I, Section 3 of the MDR.
  • Clinical evaluation: Conducting and updating clinical evaluations and post-market clinical follow-up.
  • Product realization: Covering all phases, from planning and manufacturing to delivery.
  • Post-market surveillance (PMS): Building a robust system for collecting and analyzing market surveillance data.
  • Communication: Ensuring the exchange of information with authorities, notified bodies and other stakeholders.

Significance for manufacturers of Class I products

Even though the QMS of Class I manufacturers does not need to be certified, its implementation and continuous maintenance are crucial. It serves as proof of compliance with regulatory requirements and forms the basis for safe and efficient product development and delivery.

2.2 Requirements of ISO 13485

ISO 13485 is the internationally recognized standard for quality management systems (QMS) in the field of medical devices. It already existed under the Medical Devices Directive (MDD) and forms an essential basis for compliance with regulatory requirements. With the introduction of the MDR, ISO 13485 remains of central importance: A QMS must meet both the MDR requirements and continue to comply with those of ISO 13485.

ISO 13485 focuses on fulfilling regulatory and customer-related requirements throughout the lifecycle of a medical device – from development to post-market support. Key requirements include:

  • Risk management: Systematic identification, assessment and control of risks throughout the entire product life cycle.
  • Process-oriented approach: Structuring the QMS along defined processes that are linked together and geared towards quality and safety.
  • Documented procedures: Clear definition and documentation of all essential procedures and processes.

The standard requires a comprehensive system aimed at continuous improvement and compliance with safety and performance standards. Therefore, the standard's requirements are divided into various process groups, which together ensure an effective quality management system (QMS).

Management processes

Management processes create the strategic basis for the QMS and contribute to continuous improvement:

  • Management review: Regular review of the QMS by management to ensure its suitability, adequacy and effectiveness.
  • Corrective and Preventive Action (CAPA): Procedures for the systematic investigation and correction of nonconformities and for preventing future errors.
  • Internal audits: Scheduled evaluations of QMS processes to identify weaknesses and highlight potential for improvement.

Core processes

Core processes are directly related to the development, manufacture and provision of medical devices, for example (list is not exhaustive):

  • Change management: Controlling product or process changes to ensure that all requirements continue to be met.
  • Sales: Control and documentation of product provision, including compliance with delivery conditions and regulatory requirements.
  • Complaints: Handling customer feedback including root cause analysis and evaluation, and potentially transferring it to further processes (change management, problem solving)
  • Purchasing: Buying products from suppliers, selecting and monitoring suppliers to ensure that purchased materials or services meet the specified requirements.
  • Development: Structured planning, execution and monitoring of the development process, including the review and validation of product designs.

Support processes

Support processes ensure the smooth operation of the QMS. These include, for example, document control: it serves to ensure the timeliness, availability, and traceability of all quality-relevant documents. This encompasses the approval, distribution, and monitoring of changes to the documentation.

ISO 13485, alongside the MDR, ensures that a QMS not only meets MDR requirements but also provides a proven foundation for quality, safety, and regulatory compliance. Management, core, and support processes are closely integrated, forming a robust system that enables manufacturers to meet the high standards of the medical device industry.

3. Requirements of the MDR and ISO 13485 for manufacturers of Class I products

Manufacturers of Class I products face the challenge of establishing a comprehensive quality management system (QMS) that meets the requirements of both the MDR and ISO 13485. Despite the comparatively low risk class of these products, the expectations for the structure and implementation of the QMS are no less than for higher risk classes.

An effective QMS requires manufacturers to define, implement, and actively maintain all required processes. These include, in particular:

  • Management review: Regular review by management to ensure the adequacy and effectiveness of the QMS.
  • Internal audits: Systematic control and evaluation of internal processes to identify weaknesses and utilize potential for improvement.

In addition to the basic structuring of the QMS, the operational processes are also of central importance, including:

  • Complaint handling and customer feedback: An effective system for recording, analyzing and processing complaints and feedback, which serves as a basis for improvement measures.
  • Corrective and Preventive Action (CAPA): Processes for analyzing errors, addressing their causes, and preventing future problems.
  • Post-market surveillance (PMS): Establishment of a robust PMS system in accordance with MDR Article 83, which also includes vigilance, i.e., the reporting and handling of serious incidents.

The close link between QMS and technical documentation plays a central role. Data and insights from processes such as PMS, complaint handling, and vigilance must be directly incorporated into the technical documentation to ensure its accuracy and completeness. This is crucial for the ongoing conformity of the product with regulatory requirements.

For manufacturers of Class I products, implementing the MDR and ISO 13485 requirements therefore means that they must operate a QMS that is just as comprehensive and dynamic as that of manufacturers of higher risk classes. The active maintenance and operation of the system – through regular assessments, internal audits, and the consistent implementation of operational processes – is just as crucial as being prepared for inspections by regulatory authorities, which are now regularly carried out at Class I product manufacturers to ensure that all requirements are met.

Such a QMS is not certified by the Notified Body, but it is regularly inspected by the competent authority.

4. Conclusion and Summary

The requirements for a quality management system (QMS) are the same for all manufacturers of medical devices – regardless of their risk class. Manufacturers of Class I devices therefore face the same responsibilities as companies developing higher-risk products. The MDR and ISO 13485 standards require a comprehensive QMS that must not only be documented but also actively implemented.

However, a key difference for Class I manufacturers is that their QMS does not need to be certified by a Notified Body. While this saves costs and resources compared to higher-class products, it does not change the obligation to effectively establish, regularly review, and continuously improve the QMS.

Regulatory oversight remains an integral part of the regulatory framework. Official inspections and the review of technical documentation ensure compliance with requirements. A quality management system (QMS) that is not merely a formal entity but actively integrated into processes forms the basis for the ongoing conformity and marketability of products.

For manufacturers of Class I products, establishing and maintaining a functioning QMS is therefore crucial. The lack of certification by a Notified Body should not obscure the fact that the requirements are comprehensive and must be fully met. A well-structured, actively used QMS is not only a regulatory obligation but also a decisive factor for the quality, safety, and market success of the products.

5. How we can help you

We are happy to support you in setting up and implementing your QMS. As an external QMS manager, we also handle the implementation and active operation of QMS systems for leading manufacturers, involving you in the process. Because ultimately, you, the manufacturer, are the one who lives and breathes the QMS, not us.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and execution, right up to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end.

Do you already have some initial questions?

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

The path to biosafety of medical devices

In this blog post, we focus on the biological evaluation of medical devices, a crucial step in ensuring biocompatibility and patient safety. The post guides you through the fundamentals of biocompatibility, highlights the requirements of the MDR, and explains the significant role of the comprehensive EN ISO 10993 series of standards, which comprises many parts and addresses various aspects of biological safety. The most important and fundamental part is EN ISO 10993-1, which specifies the general requirements and procedures for biological evaluation.

Furthermore, we offer a detailed insight into the latest changes to the standard as well as the strategic steps for test planning and risk assessment. This article demonstrates what a modern test strategy can look like, taking into account material characterization and alternative methods for reducing animal testing, and provides practical guidance on complete documentation in the Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER). Our aim is to impart sound knowledge to effectively implement the complex requirements of biological evaluation while simultaneously ensuring the highest safety standards for medical devices.

Underlying regulations

EU Regulation 2017/745 (MDR)

EN ISO 10993-1

1 Introduction

Biocompatibility—the ability of a material to avoid adverse reactions when in contact with the human body—is a crucial factor for the safety of medical devices. Whether a product comes into direct contact with tissue, blood, or other bodily fluids, or acts indirectly on organs and systems, biological safety must always be guaranteed. Ultimately, the patient's well-being depends on it. The challenge for manufacturers is to ensure that every material, substance, and combination of components used has no undesirable effects on the human organism. This includes not only direct physical interactions but also chemical interactions that can arise from degradation products or changes within the body. Safety during repeated use is also important, as some products remain in contact with the human body for extended periods.

The Medical Device Regulation (MDR) sets out strict requirements for this, obligating manufacturers to conduct comprehensive biological assessments and document them carefully. Annex I, section 10.2, specifies the essential safety and performance requirements that every medical device must meet to ensure safe use. Annex II, section 6.1, further requires complete documentation of the biological assessment as part of the technical documentation.

"The products are designed, manufactured and packaged in such a way as to minimize the risks to patients from harmful substances and residues, taking into account the intended purpose of the product, as well as to transport, storage and handling personnel. Particular attention is paid to tissues exposed to these harmful substances and residues, as well as to the duration and frequency of exposure." (MDR Annex I, paragraph 10.2)

“Detailed information on the test setup, complete test or study protocols, methods of data analysis, in addition to data summaries and test results, in particular regarding the biocompatibility of the product, including the identification of all materials in direct or indirect contact with the patient or user […].” (MDR Annex II, paragraph 6.1)

2. The standard EN ISO 10993-1

EN ISO 10993 is the basic standard in a comprehensive series of standards for the biological evaluation of medical devices. This series comprises many specific parts, each covering different aspects of biocompatibility. The most important and fundamental part of this series is EN ISO 10993-1, which defines the general requirements and procedures for biological evaluation. This standard plays a crucial role in the approval process, as it provides manufacturers with clear guidelines on how to identify, minimize, and document potential biological risks. Compliance with EN ISO 10993-1 is therefore often a prerequisite for meeting the safety and performance requirements of the MDR (Medical Device Regulation).

The new version of EN ISO 10993-1:2020 introduces several changes and additions to make the assessment even more precise and reliable. Particular emphasis is placed on the need for integrated risk management that considers not only the chemical composition of the product, but also potential long-term effects and degradation products in the body.

A further, updated version of EN ISO 10993-1 is currently in draft form and introduces significant innovations designed to make the biological assessment process even more comprehensive and specific. These changes include new wording and more precise definitions intended to ensure more consistent interpretation. In addition, a new section is being introduced that describes specific requirements for the entire life cycle of a product, thus supporting a more holistic approach to biological safety.

The standard itself aims to provide manufacturers with a structured procedure for biological assessment that covers all relevant aspects of biocompatibility. Its scope encompasses all medical devices that come into direct or indirect contact with the human body – from skin contact and implantable products to products that enter the bloodstream. Key terms and definitions therefore include central concepts such as biocompatibility , risk analysis , and material compatibility , ensuring a common language and uniform testing standards.

The fundamental principles of EN ISO 10993-1 are based on a risk-based approach: First, the product design is analyzed to assess potential contact with the body and the material composition. Then, depending on the risk profile, specific biological tests are defined – from cytotoxicity and sensitization to long-term tests. This structured approach helps manufacturers to systematically identify and minimize all biological risks in order to ensure product safety throughout its entire life cycle.

3. Biological assessment and testing strategy

The biological evaluation and testing strategy for medical devices is a structured process designed to ensure the safety and biocompatibility of a product throughout its entire life cycle. This systematic approach to biological evaluation is clearly illustrated in Figure 1 of EN ISO 10993-1.

Figure 1: Systematic approach to biological evaluation (According to Figure 1 from EN ISO 10993-1)

A key aspect of biological assessment is now material characterization according to EN ISO 10993-18. Detailed physicochemical characterization of materials and their potential degradation products allows many risks to be identified and minimized early on. This reduces the need for extensive in vivo testing and supports the use of alternative testing methods.

Annex A of EN ISO 10993-1 describes specific biological endpoints that must be evaluated depending on the type and application of the medical device. The product is first assigned to a category:

  • Medical devices that only come into contact with the body surface,
  • Products that come into external contact with the body's interior
  • Implantable medical devices

Furthermore, the contact will be determined:

  • Medical devices that only come into contact with the body surface:
    • Intact skin
    • Mucosa
    • Injured or damaged skin areas
  • Products that come into external contact with the body's interior
    • Blood vessel system, indirectly
    • Tissue/Bone/Dentin
    • Circulating blood
  • Implantable medical devices
    • Tissue/bone
    • blood

and the contact duration is defined, which is divided into levels A (≤24 h), B (>24 h to 30 d) and C (>30 d).

This detailed categorization helps to define a specific testing strategy for each product. The choice of tests depends not only on the type of contact but also on the expected long-term effects and the potential risks posed by degradation products. A comprehensive risk analysis can often demonstrate that certain tests are unnecessary, thus avoiding unnecessary animal testing.

Figure 2: Example table from Annex A of EN ISO 10993-1:2020 for medical devices that come into contact with the body surface

These endpoints must be evaluated in detail in the Biological Evaluation Report (BER). However, this does not mean that all endpoints must necessarily be tested like a checklist. EN ISO 10993-1 also allows the use of existing data, such as scientific literature or other validated information, to cover certain endpoints. This provides a basis for justifying why some tests can be omitted, provided the available data support the biological safety assessment. This enables a targeted and resource-efficient evaluation that still meets all relevant safety requirements.

This enables a flexible assessment that meets both safety requirements and ethical considerations by minimizing animal testing as much as possible. The integration of alternative testing methods, such as in vitro procedures and computer-based simulations, is an essential component of modern biological assessment.

4. Documentation and reporting

A crucial component of the biological safety assessment of medical devices is meticulous documentation, ensuring that all assessment and testing processes are recorded in a traceable and transparent manner. Two key documents play a vital role in this: the Biological Evaluation Plan (BEP) and the Biological Evaluation Report (BER).

The Biological Evaluation Plan (BEP) defines the strategy for the biological evaluation of the product:

  • Product description: Details on components, materials and manufacturing processes.
  • Intended use and type of contact: Information on the intended use and type of physical contact.
  • Manufacturing process: Description of the manufacturing process and the auxiliary materials used.
  • Reusable products: Information on cleaning and/or sterilization.
  • Physical/chemical information: Existing data for characterizing the medical device and the materials it contains.
  • Risk assessment: Identification of biological endpoints.
  • Existing biological safety data: Existing biological tests.
  • GAP analysis: A gap analysis to identify missing information in current security data.
  • Test strategy: Selection and justification of the necessary tests, including physicochemical characterization according to EN ISO 10993-18 (if not already available).

The Biological Evaluation Report (BER) documents the execution and results of the evaluation and includes:

  • Product description: Details on components, materials and manufacturing processes.
  • Intended use and type of contact: Information on the intended use and type of physical contact.
  • Manufacturing process: Description of the manufacturing process and the auxiliary materials used.
  • Reusable products: Information on cleaning and/or sterilization.
  • Physical/chemical information: Existing data for characterizing the medical device and the materials it contains.
  • Risk assessment: Identification of biological endpoints.
  • Material and product characterization: Details of the physicochemical characterization and test results.
  • Test results: Description of the tests, results and interpretation of in vitro and in vivo tests, including cytotoxicity tests.
  • Conclusions: Overall assessment of biological safety and recommendations.
  • Determining further steps: If additional tests or assessments are required.

5. Conclusion

The biological evaluation of medical devices is a complex and multifaceted process that plays a crucial role in ensuring patient safety. The requirements of the MDR and EN ISO 10993-1 provide manufacturers with a sound regulatory framework that enables a structured and risk-based assessment. Material characterization according to EN ISO 10993-18, along with clearly defined biological endpoints, helps to identify risks early and address them effectively. The systematic approach, supported by precise categorization of contact type and duration, ensures that only necessary and relevant tests are performed.

A key advantage of the modern approach to biological evaluation lies in its flexibility to incorporate existing data and, where necessary, replace tests with scientifically sound arguments. This enables not only resource-efficient but also ethically responsible product evaluation, as the burden on laboratory animals is minimized. Detailed documentation in the BEP and BER ensures that all steps are traceable and compliance with regulatory requirements is transparently documented. Thus, biological evaluation not only provides safety for patients but also strengthens trust in medical devices and their responsible development and approval.

6. How we can help you

At medXteam, we provide comprehensive support for the biological evaluation of your medical devices and compliance with regulatory requirements. Thanks to our expertise in the analysis and evaluation of clinical data, we offer tailored solutions for creating the Biological Evaluation Plan (BEP) and the Biological Evaluation Report (BER). Our team helps you develop an effective testing strategy that covers all relevant biological endpoints while maximizing the use of clinical data and scientific literature to avoid unnecessary testing.

We guide you through the entire process – from material characterization according to EN ISO 10993-18 to the assessment and documentation of all biological risks in accordance with the MDR. Our experts are at your side to ensure that your products meet the highest safety standards and fulfill all regulatory requirements for approval. Let's work together to systematically address the biological risks of your products and achieve clinically sound, reliable results. Contact us to learn more about how we can support you in your next project.

Do you already have some initial questions?

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

At medXteam, the focus is on clinical data. In this context, as CRO we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection. This time, in this context, the topic of clinical trials in the dental sector is again the focus. Since this topic is very extensive, we have divided it into two parts. In the first part of the blog post we looked at basic study design considerations in dental studies. As an example of a topic in dental research, we have taken a closer look at the endpoints in periodontal clinical trials. Part 2 continues with periodontal study designs with endpoints that are used for specific clinical situations, e.g. B. in the treatment of localized gum recession, missing keratinized gingiva or furcation defects. Finally, we turn to the endpoints in implant research.  

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Devices Implementation Act (MPDG)

Sources

WV Giannobile, NP Lang, MS Tonetti, eds.: “Osteology guidelines for oral and maxillofacial regeneration: clinical research”. Quintessence Publishing, 2014.

1. Endpoints in studies evaluating the treatment of localized gingival recessions

The case definition of localized gingival recession is when the loss of the periodontal attachment affects the buccal surface of the tooth, with the attachment to the interdental tissues being partially or not affected. The extent of recession is measured by probing to determine the distance between the CEJ (cemento-enamel junction) and the gum line. The aim of regenerative therapies is therefore to treat these lesions by completely covering the buccal root surface and returning the gingival margin to the cementoenamel junction (=CEJ) or above. Achieving this goal is referred to as "root coverage" and therefore the ultimate end point of these procedures is the achievement of 100% root coverage.

Achieving 100% complete coverage is considered the primary outcome of these procedures. This primary result is usually expressed as a percentage and can be expressed as a percentage of root coverage, namely

  1. between the baseline and the end of the study period or
  2. as a percentage of sites where full coverage could be achieved.

Strictly speaking, the actual result requires evidence of complete regeneration of the soft tissue attachment at the root, which can only be determined histologically.

Therefore, there are specific surrogate endpoints that are commonly used in evaluating the effectiveness of these regenerative procedures. These are assessed by linear measurements using clinical probing and the key findings are:

  • Gain in clinical attachment (CEJ – PPD / cementoenamel border - pocket bottom)
  • Reduction of clinical recession (CEJ – GM / cementoenamel junction - gingival margin)
  • Gain in width of the keratinized gingiva (GM-MGJ / gingival edge - mucogingival border)

Several factors may be important when it comes to fully covering recession defects, such as: B. plaque levels, smoking status and surgical procedure used. From the patient's perspective, the main reason for recession coverage surgery is usually to improve the aesthetic appearance or reduce root hypersensitivity or pain. Therefore, capturing patient-related outcomes is very important when evaluating these interventions. The aesthetic result is usually assessed by the patients themselves using questionnaires. Likewise, the assessment of changes in pain and sensitivity by the patient is carried out using questionnaires or more objective assessments, e.g. B. with visual analogue scales (VAS). A composite index also exists to evaluate the aesthetic results of these procedures (Root Coverage Esthetic Score [RES]) by calibrated assessors. This score is based on the assessment of five variables: (a) the level of the gingival margin, (b) the marginal contour, (c) the soft tissue surface, (d) the position of the MGJ (mucogingival junction), and (e) the gingival color.

2. Endpoints in studies evaluating soft tissue augmentation procedures:

These procedures aim to increase the dimension of the keratinized gingiva or mucous membrane in specific areas or in places where it is present to a small extent or not at all. The primary outcome of these studies is the assessment of the increase in the width of the keratinized tissue, measured by probing from the GM (gingival margin) to the MGJ (mucogingival junction).

Surrogate outcomes are often used in these studies:

  • Changes in the width of the attached gingiva or mucosa, that is, the width of the keratinized gingiva or mucosa minus the probing depth of the sulcus or pocket (mm)
  • Changes in gingival thickness (mm)
  • Changes in vestibular depth (mm)

3. Endpoints in studies evaluating periodontal regeneration procedures for furcation defects

Unlike infraalveolar lesions, the extent of these furcation lesions is assessed horizontally rather than vertically, and the degree of horizontal impairment is used to classify furcation lesions into grades I, II, and III.

Therefore, the change in the degree of furcation is usually used as the primary endpoint.

Other surrogate endpoints to evaluate the efficacy of regenerative methods to resolve furcation infestation are changes in horizontal attachment levels. This result is measured by inserting the periodontal probe horizontally at the entrance to the furcation and assessing the probing depth. The remaining surrogate and secondary endpoints described in regeneration studies for infraalveolar defects can also be used in the evaluation of furcation defects.

4. Endpoints in studies on implant therapy

Over the past 20 years, this therapy has become the most important and widespread measure for restoring lost teeth.

The success of this form of therapy is based on achieving what is known as “osseointegration”, i.e. direct contact between the surface of a functioning implant and the bone. And of course maintaining that contact over time. Similar to periodontal therapy, it is not ethically possible to comprehensively assess osseointegration in humans histologically across studies, and therefore the true clinical endpoint is maintenance of the implant in function, with no apparent pathology, no symptoms, and no significant bone loss.

In clinical research, this endpoint is assessed using various success criteria, including those described by Albrektsson et al. (2009) are the most commonly used criteria. Success rates are expressed as the percentage of implants that achieve success over time.

Many clinical studies have reported the effectiveness of implant therapy using less stringent criteria, assessing only the presence of the implant in the mouth and functioning over a period of time. This result is expressed as a percentage (%) of implants surviving (remaining functional) or as a survival rate. It is also expressed in lifetime analysis using Kaplan-Meier survival curves. This endpoint has been and continues to be heavily criticized because it does not assess the status of the peri-implant tissue, but only the presence of the implant in the oral cavity.

In principle, it should be noted in implant studies that - unlike in dental studies - there is no fixed orientation point for measurements (e.g. the cementoenamel junction). This means that, for example, markings (e.g. incisal edge) on the remaining teeth or an acrylic stent must be used for precise and reproducible measurements.

4.1 Primary surrogate endpoints

The primary endpoints in implant research are the assessment of crestal bone level through radiological assessment. As with periodontal regeneration studies, assessment of crestal bone level changes requires standardization of radiographic technique.

The digitalized images obtained are used to record the distance from the implant shoulder to the most coronal implant-bone contact. The changes in these values ​​between baseline and the end of the study period are typically the primary outcome of clinical trials evaluating the effectiveness of dental implants. Depending on the study design, two different baseline values ​​can be used. Either the value of the initial radiographic examination is made at the time of implantation or at the time of insertion of the restoration. In the latter case, physiological bone remodeling after the surgical insertion of the implant is avoided and, as a rule, less bone loss will take place. However, this so-called remodeling process seems to depend on the implant design; therefore, the recommendation should be to assess bone levels at both time points and then in subsequent study periods.

In implant therapy, although maintaining implant-bone anchorage in the oral cavity depends on maintaining crestal bone levels, it is also important to assess the health parameters of the peri-implant tissue.

Examples would be here:

  • Probing depth: at six locations per implant using a pressure-calibrated probe
  • Bleeding on probing: A dichotomous score can be used at six sites per implant (0, no bleeding; 1, bleeding)
  • Presence/absence of suppuration after probing (Yes/No)
  • Width of the keratinized gingiva (distance gingiva to the mucogingival border)

4.2 Secondary surrogate endpoints:

The health of the peri-implant tissue depends on various etiological and risk factors that may influence the long-term effectiveness of dental implants and therefore should be controlled in any long-term clinical trial evaluating the effectiveness of implant therapy. The most commonly used are:

  • Presence of plaque at the peri-implant mucosal edge (usually assessed dichotomously and expressed as a percentage).
  • History of the patient's previous periodontal disease (also assessed dichotomously and expressed as a percentage).
  • Patient's current and past tobacco use.
  • Stability of the implant. This is measured by resonance frequency analysis (RFA) and expressed in RF units. It is an indirect measure of implant-bone contact and is used to evaluate primary implant stability at the time of implantation and during the osseointegration process (from primary to secondary stability).

5. Endpoints in clinical research evaluating bone regenerative therapies

Ideally, a dental implant is placed in a location where there is sufficient crestal bone to ensure good primary stability and ensure the osseointegration process. In reality, the situation is unfortunately different, as patients often wait before therapy so that bone loss has already occurred at the insertion site.

For these situations in which there is not enough bone, there are various augmentative, bone regenerative therapies. These therapies can be performed in conjunction with implant placement or before implant placement. Socket preservation techniques aim to prevent resorption of the alveolar walls. Lateral augmentation techniques build the jaw ridge laterally, vertical techniques create a vertical gain in bone.

5.1 Jaw chamber posture techniques

Basically, the primary endpoint in these studies is the measurement of the extent of vertical and horizontal resorption of the alveolar walls after tooth extraction.

Fabrication of acrylic templates with fixed landmarks enables a reproducible method for measuring horizontal and vertical dimensional changes of the alveolar ridge. Measurements are taken from these templates at standardized points on the bone crest after a small flap is raised. The most commonly taken horizontal measurement is the mid-buccal width of the bone ridge. Additional measurements can be taken on the mesial and distal sides of the donor sites. The same points can be used for the vertical measurements. The horizontal and vertical changes between baseline (tooth extraction) and the end of the study period (usually the time of implantation) are then calculated.

Similar measurements can be made indirectly using plaster models by measuring the horizontal and vertical changes at various standardized locations. This method involves taking silicone impressions before tooth extraction and at various times after extraction. This method can be used to quantify both vertical and horizontal changes in the alveolar ridges.

5.2 Lateral bone augmentation

Various surgical techniques exist for the treatment of bone defects around implants, partly because these defects have different dimensions and shapes (dehiscences, fenestrations, etc.). However, the common goal of these procedures is to increase the bone volume around the implant. The specific endpoints of these procedures are the assessment of the increase in bone volume between the procedure and the last follow-up. The direct linear measurements are taken with a periodontal probe in mm and recorded intraoperatively using the following reference points:

  • Defect height (mm), measured from the implant shoulder or edge to the first bone-implant contact (BIC)
  • Defect width (mm) measured from the mesial to distal tips of the bone crest
  • Defect depth (mm) measured from the bone crest to the implant surface in a direction perpendicular to the long axis of the implant
  • Infraalveolar defect height (mm), measured from the bone crest to the first bone-to-implant contact (bone-to-implant contact).

The comparison between the second surgical procedure, which usually occurs 3 to 4 months after the implant placement, and the bone grafting can be expressed in “mm” or as a percentage, reaching 100% when the contact between the bone and the implant is at the level of the implant shoulder.

To evaluate the volumetric changes, three-dimensional digital images can be recorded with optical scanners and measured with the appropriate software. The key advantage of this technique is its non-invasive nature, although this endpoint represents the combination of soft and hard tissue changes. Similar volumetric assessments can be made on plaster models that are then scanned. The captured images can be measured using a special CAD/CAM system by merging and superimposing the before-and-after images in a coordinate system and thus evaluating the increase in volume. The 3D changes in hard tissue volume must be evaluated radiographically using digital volume tomography (conebeam, CBCT) images.

5.3 Vertical bone augmentation

These procedures are usually before implantation, so the implant cannot be used as a reference. The same volumetric and radiographic techniques as described above can be used to evaluate vertical and horizontal changes between the regenerative procedure and follow-up. A special feature of these procedures are those in which the maxillary sinus is used for vertical bone augmentation (sinus lift procedure).

The effectiveness of vertical bone augmentation is often examined histologically. The biopsies are usually taken during implantation using a trephine drill. This procedure is ethically harmless because the trephine drill has the same diameter as the implant and the implant bed would have had to be prepared anyway.

 The following parameters are recorded histologically:

  • Percentage of new bone
  • Percentage of remaining bone substitute material or augmented autologous bone
  • Percentage of soft tissue or empty space remaining.

Assessment of vertical bone formation can be measured by standardized periapical radiographs immediately after the procedure and usefully 6 months after the procedure. If the sinus lift is performed in conjunction with implant placement (simultaneous approach), a similar assessment of vertical bone formation can be made on standardized periapical radiographs.

6. Endpoints in clinical research evaluating implant prosthetics

The specific parameters for evaluating the outcome of implant-supported restorations are:

  • Changes to the gingival margin by measuring the distance between the edge of the restoration and the most apical point of the soft tissue margin on the buccal side of the implant bed.
  • Changes in papillary filling by measuring the degree of soft tissue filling on the mesial and distal aspects of the implants. This is usually done according to the criteria of Jemt et al. (1997) described papilla index system (grades O to 4), where the grade O stands for no filling of the papilla, 1 for a filling of < 50%, 2 for a filling of > 50% and 4 for a complete filling Filling of the papilla.

In addition to these specific endpoints, other secondary outcomes that have been shown to contribute to the results of restorative procedures should also be assessed and reported, such as plaque accumulation, smoking status, bleeding on probing, gingival thickness, keratinized gingival width.

Important indices allow an objective and comprehensive assessment of the aesthetic results; These include the Pink Esthetic Score (PES) (Furhauser et al., 2005), the Implant Crown Aesthetic Index (Meijer et al., 2005) and the modified PES/White Esthetic Score (WES) (Belser et al., 2009) . The implant crown esthetics index is based on the anatomical shape, color and surface condition of the crown as well as the anatomical shape, color and surface condition of the peri-implant soft tissues. The modified PES/White Esthetic Score (WES) system complements the PES system with general tooth shape, clinical crown outline and circumference, color, surface finish and translucency.

These indices should be assessed on standardized clinical photographs by calibrated examiners.

7. Conclusion

In summary, many factors must be taken into account in clinical studies of periodontal regeneration to achieve reliable and meaningful results. The defect category, the choice of surgical technique and methodology, and the patient's smoking habit play an important role. In addition, secondary endpoints such as plaque accumulation and gingival inflammation should be carefully evaluated as they may significantly influence the study outcome. These factors contribute to ensuring the effectiveness and safety of the treatment methods studied and ultimately improving the periodontal health of patients. As we see in this Part 2, the choice of the correct endpoint also plays a crucial role in the design and planning of clinical trials with medical devices in the dental sector.

8. How we can help you

We would be happy to support you with successful planning and implementation of dental studies. Thanks to our comprehensive expertise in this area with the special features that need to be taken into account, we generate the clinical data you need for your medical device. 

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

Clinical research in the oral and maxillofacial area

At medXteam, the focus is on clinical data. In this context, as CRO we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection. This time the topic in this context is clinical trials in the dental sector. Since this topic is very extensive, we have divided it into two parts. This Part 1 focuses in particular on the study types, design and special endpoints for medical devices used in dental studies.  

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Devices Implementation Act (MPDG)

Sources

www.ebm-netzwerk.de : accessed on August 26, 2024 at 7:49 a.m

BA Just, H Rudolph, R Muche: “Clinical trials in dentistry – and what lies behind them - Clinical Trials in Dentistry – What lies behind”. ZWR - The German Dental Journal 2012; 121(10): 478-486. DOI: 10.1055/s-0032-1330863

WV Giannobile, NP Lang, MS Tonetti, eds.: “Osteology guidelines for oral and maxillofacial regeneration: clinical research”. Quintessence Publishing, 2014.

1 Introduction

Clinical research in the oral and maxillofacial area does not differ in its basic principles from biomedical research in other areas of the human body.

Dental clinical studies can also generally be divided into experimental and epidemiological, prospective and retrospective studies based on the procedure (see also our previous blog posts).

2 .  Dental studies

2.1 Experimental studies

In an experimental study, an experiment (or therapy) is carried out repeatedly, with the number and selection method of study subjects (test participants, patients) as well as the type and extent of information to be collected being determined before the start of the study. The aim of an experimental study is generally to demonstrate causal relationships. In an epidemiological study (observational study), only repeated observations are made without intervening in the process; this type of study is also possible retrospectively. The aim of an epidemiological study is generally to identify and evaluate connections.

However, the following study design is specific to dentistry and is very popular for various reasons:

Split mouth design

The split mouth design is an experimental model in dentistry in which two or more different therapies are administered to a study participant in different areas of the oral cavity. As a rule, the form of therapy is randomly assigned to the area of ​​the oral cavity. This special form of study design eliminates the differences that exist between two patients. Each patient acts as a test and control at the same time. In contrast to study designs that compare different patients with each other, the split-mouth design improves the comparability of different forms of therapy, which may mean that the number of cases can be smaller. However, since the information content obtained is so-called “connected” data, special, “connected” statistical tests are necessary.

2.2 Validity of the data 

The principles of all clinical studies apply to the validity of dental studies: it is a qualitative measure of the validity of a research result - but not a mathematical measure like reliability. Here too, a distinction is made between internal and external validity. Internal validity stands for the clarity of the interpretation of the results and is influenced by systematic errors (bias), such as errors in the design of the study, its implementation, the data collection or errors in the evaluation and analysis of the results.

2.3 Evidence

The same rules apply to clinical studies in the oral and maxillofacial region as to other clinical studies for the classification into evidence classes, randomization, sample size planning and statistical evaluation.

2.4 Good Clinical Practice

GCP or “Good Clinical Practice” refers to internationally recognized, ethical and scientific quality standards and rules for the conduct of clinical studies on humans. Compliance with the GCP serves to ensure the protection and informed consent of study participants (ethical aspect) as well as the collection of credible, valid data. Of course, dental clinical studies also fall under “good clinical practice”.

2.5 Areas

Dentistry is a field in which many medical devices are used. Think, for example, of drills for removing carious lesions, filling materials, orthodontic aligners and also implants. Therefore, MDR and ISO14155 regulate the regulatory approach and conduct of clinical studies.

An area in which many clinical studies are located is periodontics and dentoalveolar surgery. The following sections therefore primarily refer to these two research fields.

3. Endpoints in clinical trials

The basis of clinical research is to establish a clinically relevant hypothesis that can be validated or refuted using scientific methods. With this method, a targeted and clinically relevant question can be systematically defined, measured and analyzed to obtain an answer that is reported in the form of endpoints or results. The results are therefore the consequences or effects of interventions in clinical studies as well as the effects of the biological processes examined in prospective observational studies.

An endpoint is the parameter or variable measured in an intervention or observational study; The result of this measurement provides the answer to the research question or the validity of the tested hypothesis. These endpoints may be assessed and assessed by the patient or subject themselves (patient-assessed endpoints) or by the investigator or clinician on specific aspects of disease progression or response to treatment (investigator-assessed endpoints). True endpoints are also defined as those that represent a tangible impact on the patient (e.g., tooth loss).

In the study methodology of clinical research, surrogate endpoints (intermediate endpoints) are understood to be endpoints that are not themselves of direct importance for the patient, but can represent important endpoints (e.g. reduction in blood pressure as a surrogate parameter for preventing a stroke). Surrogate endpoints are often physiological or biochemical markers that can be measured relatively quickly and easily and are considered to have a predictive function for later clinical events. The prerequisite for reliable statements about the effectiveness of a treatment is a close causal relationship between surrogate parameters and the actual endpoint. It is therefore expected that the measured significant changes in the surrogate outcome as a result of the tested intervention will also significantly influence the true endpoint. This answer is controversial in many respects, especially in the study and treatment of chronic diseases with multifactorial etiology, such as: B. Periodontitis, where evaluation of one aspect of the disease does not exclude a different outcome via a different pathway or the influence of other confounding factors not identified by the surrogate under study.

Clinical research results are also divided into “primary” and “secondary” results. Primary results are those that serve to answer the research question or validate the hypothesis being tested. They are therefore at the forefront of data analysis and serve to provide the conclusions of the study. They must also be used to calculate the sample size of the study. The ideal situation for clinical research would be to use real results as primary outcomes, but as previously mentioned, real results in clinical research are typically difficult to evaluate in short- to medium-term intervention or observational studies.

Secondary outcomes are typically measures of behaviors or lifestyles that significantly influence the outcome of the actual outcome (e.g., tobacco smoking, plaque control). Their assessment is therefore important for controlling the relevant factors that may influence the studied response to an intervention or the onset or progression of a disease process.

The results can also be divided into “qualitative” or “quantitative”. Quantitative results are those that can be expressed using numerical continuous variables, which can usually be subjected to parametric statistics. Qualitative outcomes are verbal or categorical representations of a non-quantifiable variable and can be further classified as nominal (e.g. gender) or ordinal if they can be expressed in categories (e.g. plaque index). Before being used in clinical research, any quantitative or qualitative variable must be evaluated for its validity and reliability in assessing the outcome under study, as well as for its sensitivity and specificity in representing a true result.

In oral clinical studies of tissue regeneration, both real endpoints and surrogate endpoints are used, depending on the question, to evaluate the effectiveness of treatments.

Of course, to ensure the quality of a clinical trial, the endpoints should be applicable to the vast majority of patients and diseases. They should also be clearly defined and easy to validate. Furthermore, high sensitivity/specificity is important for disease diagnosis and disease progression.

Below we present the endpoints and outcomes most commonly used in periodontology and oral surgery, with a focus on tissue regeneration.

3.1 Endpoints in periodontology

Endpoints in periodontal research are used to understand the periodontal disease process and examine the effectiveness of various therapeutic measures. In order to study the disease process, it is important to establish a clear case definition for the periodontal disease being studied (gingivitis, chronic periodontitis, aggressive periodontitis, etc.). Although there are various case definitions in the literature, the most widely accepted is the European Federation of Periodontology (2017) International Classification of Periodontal Diseases and Conditions).

Chronic periodontitis usually progresses slowly, and if no preventive or therapeutic measures are taken, its natural course eventually leads to tooth loosening and even loss of the tooth. However, this progression is usually slow, with periods of loss of periodontal attachment followed by periods of quiescence or even tissue regeneration, which depends on many factors (genetic susceptibility, lifestyle and behavioral risk factors, etc.) affecting the interactions between host and bacteria involved in the pathogenesis of tissue destruction.

When examining the various prevention and therapeutic approaches, the effectiveness of the various measures with regard to their influence on the periodontal attachment level is determined using various endpoints:

through

  • the prevention of attachment loss and thus the maintenance of periodontal health (prevention),
  • the interruption of the destructive disease process and
  • the maintenance of a healthy but reduced periodontium (cause-related therapy) or
  • through the application of regenerative technologies that aim to achieve a new attachment of the periodontium to a previously diseased root surface (regenerative therapies).

In periodontal research, there are two real endpoints: one is the histological evidence of loss of periodontal attachment, and the other is tooth loss, the end result of the disease process.

Histology is the only method available to detect periodontal regeneration and periodontal destruction. However, this technique is limited to preclinical research because for histological evaluation, the affected tooth must be removed in a block with the associated soft tissue for histological preparation. Nevertheless, histological results have historically been used in studies evaluating regenerative technologies. To demonstrate the extent of regeneration, new cementum and connective tissue attachment must be identified coronal to the apical extent of the disease process along the root. In addition to assessing the presence of new cementum and connective tissue attachment as a qualitative histological result to demonstrate periodontal regeneration, histometric analysis was used for quantitative microscopic tissue determination of the attachment (new cementum, connective tissue and epithelium). A notch made during the surgical procedure at the apical extent of the attachment loss was used as a fixed landmark. However, for obvious ethical reasons, these histological results can only be examined in experimental studies, so the evaluation of regenerative therapies must be done in human studies with surrogate results.

Another true end point is tooth loss, as it represents the definitive end of the disease process and the clear failure of any intervention trial. This endpoint is rarely used in clinical trials because this event is rare and takes a long time. However, its assessment is very important in long-term population studies, as well as in longitudinal studies to evaluate the long-term effectiveness of preventive and therapeutic measures, since it allows a true assessment of dental survival and allows the assessment of the risk factors that influence this outcome.

3.2 Primary surrogate endpoints in periodontology

As previously mentioned, the primary endpoints in periodontal research are the assessment of clinical attachment level by periodontal probing and bone level by radiographic examinations.

3.2.1 Periodontal probing

Periodontal probing is the most commonly used non-invasive diagnostic method to assess the progression of periodontitis and evaluate the level of periodontal attachment. This is usually done by carefully inserting the probe into the gingival sulcus and measuring the distance between a fixed reference point, the cemento enamel junction (CEJ), and the point where the probe will be inserted at a certain pressure ( about 25 g) (bottom of the sulcus or pocket). This measurement, called the clinical attachment level (CAL), is not always easy to evaluate because the CEJ is not always available for visual inspection when it is below the gum line. For this reason, the CAL level is usually determined together with the probing pocket depth (PPD) level and the recession level (REC). The PPD values ​​indicate the distance between the gingival margin and the floor of the sulcus/pocket, the REC values ​​indicate the distance between the gingival margin and the CEJ. The addition of PPD and REC expresses CAL; However, in health, gingivitis and early periodontitis there is no recession because the gingival margin is usually above or at the level of the CEJ, meaning that PPD and CAL have similar values. In periodontal research intervention studies, the three measurements (CAL, PPD and REC) must be recorded at baseline and after treatment to evaluate the effects of therapy on disease progression. In these studies, the primary outcome must therefore be the increase in clinical attachment and reduction in probing pocket depth.

Although periodontal probing is the most commonly used assessment method in periodontal research, this measurement has many sources of error that should be minimized in clinical examinations. Their validity and reproducibility depends on the inclination of penetration into the sulcus, on the force of insertion, on the ability to read the measurements correctly (usually within 1 mm), and on the accuracy of correctly transmitting the results. Various strategies to reduce this variability have been recommended, such as: B. the use of constant force probes, stents to guide the probe and electronic reading systems. Furthermore, to ensure the reproducibility of the exploratory measurements in any clinical trial, it is essential to perform calibration studies to ensure that inter-examiner variability is kept as low as possible. Ideally, a single calibrated operator should perform all measurements. If other examiners are used, it is even more important to conduct calibration studies between examiners.

In the past, in clinical trials for periodontal regeneration, intraoperative probing measurements were performed on the treated infraalveolar lesions. In this study design, baseline measurements are taken during the intervention once the defect is completely debrided (cleaned), and the distance between the cemento-enamel junction (CEJ) and the deepest point of the defect is recorded. To evaluate the outcome, a surgical re-entry is required to register this distance (CEJ low point of the defect) after lifting a flap. For obvious ethical reasons, these re-entry studies are now rarely performed unless the second surgical procedure is required to remove a non-absorbable barrier membrane (e.g. e-PFTE).

3.2.2 Bone level x-rays

The use of periapical radiographs is the most common method to detect changes in interdental alveolar bone position relative to a fixed reference point on the tooth (e.g. CEJ). This measurement, similar to the CAL value, provides important information when studying the progression of periodontal disease (loss of bone level), or when studying periodontal regeneration (increase in bone level), or in studies simply attempting to evaluate periodontal therapy , to stop the disease process (stability of the bone level). To detect these changes in bone level, two or more x-rays taken at different times must be compared. Similar to clinical measurements, the most commonly calculated distances are the distance between the CEJ and the deepest root-bone contact. The data is typically expressed in the form of linear measurements of bone formation or loss. Similar to periodontal probing, the validity and reproducibility of radiographic assessment of bone level is subject to many sources of error.

This includes:

  • the x-ray projection,
  • the position of the plate or sensor,
  • X-ray recording and processing as well as the
  • Examiner's ability to interpret the images.

In clinical research, it is therefore important to control these sources of variability by taking periapical radiographs with the correct parallelization technique and using individual radiographic film holders containing impressions of the patient's occlusal surfaces. This ensures a reproducible X-ray angle across the entire series of images. Most of the current X-ray diagnostic systems use digitized images that allow image correction and direct linear measurements by software, improving the reproducibility of these measurements. Ideally, the evaluation of bone level changes is done electronically via digital subtraction analysis; this requires very precise X-ray technology to enable correct overlay of the images.

Assessment of changes in bone level can also be done directly in clinical studies by measuring the distance between the CEJ and the deepest bone contact with the root surface (bone probing). This must be done intraoperatively, and then again at a later reintervention after lifting a flap and cleaning the residual defect. As mentioned above, these invasive reintervention procedures are not recommended for obvious ethical reasons. The use of study impressions of the defect to evaluate the three-dimensional changes in the lesion after the tested regenerative procedure is also conceivable. . Intrasurgical impressions should be taken both at the time of surgery after debridement of the defects and at the end of the study period (usually one year). These prints should provide information about:

(i) number of tooth surfaces affected;

(ii) the depth of the 1-, 2-, and 3-wall components of the defect; and

(iii) the defect perimeter, estimated as the width of the angle and measured to the nearest 30 degrees.

These endpoints also require a re-entry procedure and should be viewed critically for the same reasons as described above.  

3.3 Secondary surrogate endpoints

When conducting clinical trials in periodontics, there are several endpoints that do not necessarily evaluate the main objective of the study or the outcome of the treatment being tested, but which are known to have a secondary influence on the study outcome and which should therefore be evaluated and taken into account. The most commonly used secondary endpoints are plaque accumulation and gingival inflammation. Both measurements are linked, one provides information about the patient's compliance with oral hygiene measures (plaque accumulation) and the other about the degree of infection control (gingivitis), which is usually carried out in the therapy phase that occurs before periodontal regeneration therapy. Plaque accumulation can be measured, for example, with the Full Mouth Plaque Score (FMPS), which dichotomously assesses the presence of visible plaque in 4 to 6 locations per tooth (0, no visible plaque at the soft tissue edge; 1, visible plaque at the soft tissue edge). . It is expressed proportionally and good patient compliance is considered to be achieved when this value is below 15%. Similarly, gingival inflammation can be assessed using the full mouth bleeding score (FMBS), which assesses the presence of visible bleeding on probing in 4 to 6 sites per tooth. It is also expressed proportionally and it is estimated that adequate infection control is achieved when this value is below 15%.

There are other indices to evaluate plaque accumulation and inflammation of periodontal pockets (plaque index, gingival index, etc.), but these are mainly used for therapies aimed at reducing plaque and gingivitis and in which these indices become the main endpoint of the study, which is clearly not the case in regenerative studies.

Another important factor is the patient's smoking habit. Ideally, subjects should be non-smokers, but if this is not possible, the smoking factor should be taken into account during randomization so that the number of smokers in the treatment groups is balanced.

The choice of surgical technique and methodology is another important factor. There are specific surgical techniques for regenerative procedures that are primarily aimed at preserving interdental tissue. These techniques should be clearly described in the research protocol and appropriate training and calibration should be performed before the study begins.

The defect category plays another role. Particularly in periodontal regeneration studies where different approaches are taken to treat infra-alveolar defects, the anatomy of the defect may influence the regeneration outcome, and therefore measurement of this anatomy should be used as a secondary surrogate. This is usually done intraoperatively by direct measurements of the defect with a periodontal probe after the lesion has been completely cleaned. These measurements should include the number of bony walls defining the defect, the infra-alveolar component of the defect, and the defect angulation. The infracosseous component of the defect, as well as the defect angulation, can also be measured radiographically, although the accuracy requires good radiographic technique.

4. Conclusion

In summary, many factors must be taken into account in clinical studies of periodontal regeneration to achieve reliable and meaningful results. The defect category, the choice of surgical technique and methodology, and the patient's smoking habit play an important role. In addition, secondary endpoints such as plaque accumulation and gingival inflammation should be carefully evaluated as they may significantly influence the study outcome. These factors contribute to ensuring the effectiveness and safety of the treatment methods studied and ultimately improving the periodontal health of patients.

To be continued: Look forward to part 2 of our blog series, in which we will delve into further important aspects of clinical research in periodontology. Stay tuned!

5. How we can help you

We would be happy to support you with successful planning and implementation of dental studies. Thanks to our comprehensive expertise in this area with the special features that need to be taken into account, we generate the clinical data you need for your medical device. 

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

FDA - MDR: Transfer of the approval strategy to the US market

At medXteam, the focus is on clinical data. In this context, as CRO we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection. This time the topic in this context is the approval strategies on the US market. Regulatory requirements also apply here and clinical data is sometimes required. But this time the focus is on the question: How can I transfer my MDR approval strategy to the US market with the highest level of efficiency?

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

QMS quality management system

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Device Implementation Act (MPDG)
Federal Food, Drug and Cosmetic Act (FD&C Act)
Code of Federal Regulations (CFR), Title 21
Quality System Regulation (QSR) – 21 CFR Part 820
Medical Device Reporting (MDR) – 21 CFR Part 803
Unique Device Identification (UDI) – 21 CFR Part 830
Postmarket Surveillance – 21 CFR Part 822

1 Introduction

The global medical device market faces numerous regulatory challenges and requirements that vary across regions. Two of the most important regulatory frameworks are the European Union's Medical Device Regulation (MDR) and the US Food and Drug Administration (FDA) approval processes. Both regulatory authorities have the primary goal of ensuring the safety and effectiveness of medical devices, but their requirements and processes differ significantly.

The MDR, which finally came into force in May 2021, replaced the previous Medical Device Directive (MDD) and brought with it significant changes and stricter requirements. It ensures that medical devices sold in the EU meet the highest safety and performance standards. The MDR requires comprehensive technical documentation, rigorous clinical assessments and continuous post-market surveillance. These stricter requirements pose a challenge for manufacturers who must ensure their products comply with the new regulations.

On the other side is the FDA, which plays a central role in regulating medical devices in the United States. The FDA classification of medical devices into different risk classes determines the approval process that a product must go through before it comes onto the market. The most common approval routes are the 510(k) Premarket Notification, the Premarket Approval (PMA), the Investigational Device Exemption (IDE) and the De Novo Classification. Each of these pathways has specific requirements for documentation and clinical data that must be submitted.

Transferring the MDR approval strategy to the US market is a complex process that requires careful planning and extensive knowledge of the regulatory requirements of both systems. Companies that want to successfully complete this transfer must understand the differences and similarities between the MDR and FDA regulations and adapt their documentation and processes accordingly. This includes identifying synergies, adapting technical documentation and reports, and taking specific FDA requirements into account in risk management and conformity assessment.

With this blog post we would like to create the basis and context for transferring the MDR approval strategy to the US market. We will examine the essential requirements and processes of the MDR and FDA, identify the main differences and similarities and discuss the specific challenges and solutions for the transfer process. The aim is to give companies practical insights and concrete recommendations for action in order to make the transfer process efficient and successful.

2. Medical device approval under the MDR

The MDR requires comprehensive technical documentation covering all aspects of the product life cycle, including design, manufacturing and clinical data. The process involves submitting this documentation to a Notified Body, which carries out a conformity assessment and, if successful, issues a CE marking. Medical devices that fall into class I under the MDR are excluded from the submission process.

Technical documentation under the MDR must contain detailed information about the medical device, including risk management reports, clinical assessments and evidence of compliance with all relevant standards. According to MDR, manufacturers must implement a robust risk management system that includes the identification, assessment and control of risks. Clinical evaluation is a continuous process that uses clinical data to confirm the safety and performance of the device throughout its life cycle. In addition, it is now mandatory for every manufacturer of a medical device to implement a complete quality management system with all relevant processes.

3. Medical device approval under FDA

The FDA categorizes medical devices into three classes (I, II, and III) based on their risk. Depending on the classification, manufacturers must submit either a 510(k) Premarket Notification, a PMA (Premarket Approval), or an IDE (Investigational Device Exemption). Each procedure has specific documentation and clinical data requirements.

The 510(k) Premarket Notification is intended for Class II products that must demonstrate that they are similar to a product already on the market. The PMA (Premarket Approval) is for Class III products that pose a higher risk and require evidence of extensive clinical data on safety and effectiveness.

The IDE (Investigational Device Exemption) makes it possible to carry out clinical studies with Class III products that have not yet been released on the market. The De Novo process provides a way to classify new products that do not have a similar approved product but pose a low to medium risk.

Even under the FDA, it is essential for manufacturers to implement a robust quality management system in accordance with the requirements (21 CFR Part 820) to ensure the quality and consistency of the products.

4. Comparison of the approval processes: MDR vs. FDA

Both systems have the common goal of ensuring the safety of medical devices, but differ in their approaches. The MDR requires strict post-marketing surveillance and ongoing clinical evaluations for each type of medical device, while the FDA offers different approval pathways based on the risk of the product.

MDR approval can be time-consuming and costly as extensive clinical data and detailed technical documentation are required depending on the type and risk class of the product. FDA approval can vary depending on the process (510(k), PMA), with PMA (Premarket Approval) processes typically being more expensive and lengthy than 510(k) submissions.

The MDR requires extensive technical documentation and ongoing clinical assessments. The FDA also requires detailed documentation, but specific requirements may vary depending on the approval route and product classification. Clinical trials are often necessary for PMA (Premarket Approval) and IDE (Investigational Device Exemption), while 510(k) relies on existing clinical data.

5. Transfer of the MDR approval strategy to the US market

When transferring the MDR approval strategy to the US market, much of the data and documentation that has already been collected can be reused. However, it is important to recognize the differences in regulatory requirements and make adjustments accordingly. The technical documentation prepared for the MDR may need to be adjusted to meet FDA's specific requirements. This may include reformatting reports, additional testing, or creating new documents required by the FDA.

The existing ISO 14971 risk management system can be retained in many aspects, but may need to be expanded to meet specific FDA requirements. The conformity assessment must comply with the FDA regulatory framework.

6. Challenges and Opportunities

Typical challenges include differences in regulatory requirements, additional documentation requirements, and the need for additional clinical data. These issues can lead to delays and increased costs.

Successful strategies include planning the transfer process early, working closely with regulatory experts, and carefully adapting existing documentation to FDA requirements. Constant monitoring of regulatory updates and changes is essential as these can impact approval requirements and processes. Companies should remain flexible and adapt their strategies accordingly.

7. Conclusion and conclusion

Transferring the approval strategy from the European Medical Device Regulation (MDR) to the requirements of the US Food and Drug Administration (FDA) is a complex but feasible process. Both regulatory systems have the same goal of ensuring the safety and effectiveness of medical devices, but they differ in their specific requirements, processes and documentation requirements. The success of such a transfer depends on a thorough analysis of the differences and similarities between MDR and FDA, as well as careful adaptation of existing documentation and processes.

An important aspect of the transfer is the identification of synergies where existing data and reports from the MDR process can be used to meet FDA requirements. At the same time, manufacturers must consider FDA's specific requirements, including adapting risk management, clinical evaluations and technical documentation. Implementing a robust quality management system in accordance with 21 CFR Part 820 and complying with Unique Device Identification (UDI) requirements are additional critical elements that must be considered.

Manufacturers going this route should consider the following key strategies:

  • Early planning and analysis of differences and similarities
  • Use synergies of existing data and documentation
  • Make specific adjustments to the technical documentation (e.g. risk management)
  • Review the quality management system with regard to FDA requirements (21 CFR Part 820).

Transferring the approval strategy from the MDR to the US market presents a challenge, but also offers the opportunity to expand market access in the US and promote global growth. With a careful and well-planned strategy, manufacturers can successfully navigate this process

8. How we can help you

We would be happy to support you with a successful and efficient transfer of your MDR approval to the US market. The first step is to decide on an approval process that is suitable under the FDA. We will then work with you to develop strategies with which you can get the most out of your existing documentation and existing clinical data in order to adapt them to the regulatory requirements on the US market in a cost- and time-efficient manner.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

  1. Statistical Significance vs. Equivalence: What Clinical Investigations Really Show
  2. How is a clinical assessment based on performance data created?
  3. What routes of clinical evaluation of medical devices are there?
  4. Why is clinical strategy so important in medical device development?
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