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