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