A simple way of clinical research is the description of clinical cases, which may show unique or unusual features of the condition or outcome of therapy. Such case analyses are quite common in endodontic journals and at congresses. It is the only mean by which specific or even unexpected clinical events can be described and are therefore important as further examinations may be initiated. The limitation of case presentations is obvious. Information from a single case cannot be transferred to other patients because of the wide variation and many factors not controlled or checked for.

Series of cases provide better information. Larger groups of patients with a particular disease or condition subjected to treatment are studied. The involvement of chance can be checked by statistical analysis. Yet, the efficiency of the clinical procedure cannot be ascertained to be better or equal to any other method if no control group is available. Sometimes, inclusion of data from prior studies or other authors’ results is used for comparison purposes. However, this procedure will not bring particular strong evidence to the report, as the conditions, under which the studies were conducted, may not have been very similar.

Case-control studies also belong to the arsenal of methods of observational studies available for clinical research. A case-control study assesses persons with a condition (or another outcome variable) of interest and a suitable control group of persons without the condition (comparison group, reference group). The potential relationship of a suspected risk factor or an attribute to the condition is examined by comparing the affected and non-affected subjects with regard to how frequently the factor or attribute is present (or, if quantitative, the levels of the attribute) in each of the groups. For an example Kim et al. [3] studied the influence of a presence of an isthmus area when performing endodontic surgery in maxillary and mandibular first molars. Of the 106 teeth, 72 teeth had an isthmus, and 34 did not. The analysis revealed that the cumulative 4 years survival rate after surgery was 61.5 and 87.4%, respectively, when an isthmus was present and absent.

Retrospective studies of any nature will not do well as they suffer the risk of having limited or no control of a number of aspects relevant to outcome. To provide good evidence, clinical research requires being prospective. A type of clinical research design that has gained increased attention in recent years is the prospective cohort observational study [4]. Cohort refers to a group of patients. This study design implies that a large sample of patients can be treated and then be assembled for follow-up examinations. An important factor of such studies is that a fairly large number of clinics have to be included in order for the report to gain generalizability. Yet the study design has the advantage to allow inclusion of general dentists and therefore will give availability to aspects on endodontics at which we have very little understanding.

Randomized controlled trials (RCTs) are genuine clinical experiments. Two or more groups of subjects receive different measures, are followed forward in time and are compared using an outcome assessment. The distinguishing feature of an RCT is that patients are allocated to test and control procedures in a strictly randomized manner. This kind of study usually observes the effect of a single variable only. All other variables (background variables, confounders) are controlled by the chance effect in both the test and the control group. To be appropriate RCT requires further a precalculated minimal number of patients to be included in order to ensure that a statistical significant difference between the test and the control procedure can be ascertained. RCTs are indeed powerful tools as many of the biasses that affect nonrandomized trials can be eliminated.

In Fig. 9.2 the set-up of three different RCTs is sketched. From a scientific perspective, these would be highly desirable to implement in order to provide significantly better knowledge of the prognosis for apical periodontitis in root-filled teeth.

Yet, the long time they require to conduct and the high costs make RCTs difficult to perform. On a careful consideration, we must realize that RCTs may not attain evidence-based research very easily for important clinical questions for endodontic retreatment. In fact, RCTs are ideal for testing the effects of drugs because it can use placebo and be controlled double blinded. However, for assessment of important aspects of surgical interventions, such as endodontic retreatment procedures, several predicaments occur. For example, it would probably be difficult to enrol a sufficient number of root-filled teeth with apical periodontitis similar enough to be randomized to extraction and implant or non-surgical retreatment. But even if possible, it is likely that the values and expectations of the patients, the dentists and the evaluators could influence the assessment of the outcome since neither patients, dentists nor evaluators can be blinded to the allocated treatment (Fig. 9.2a, b). Another concern is the long follow-up time necessary to a meaningful outcome comparison assessment. If, for example, surgical or non-surgical intervention is compared to extraction implant placement in a randomized manner (Fig. 9.2b), the crucial and interesting comparison is at hand only after several years [6, 7].

Finally, RCTs for the most central clinical questions have ethical challenges. For example, perhaps the utmost important and vital RCT would be to randomly allocate individuals with asymptomatic apical periodontitis in root-filled teeth to retreatment or monitoring the condition without intervention (Fig. 9.2c). The many difficulties involved in investigating the most relevant clinical questions with an RCT design have resulted in a limited number of publications over the years. And most of them are investigating relatively trivial issues [7] but still without evidence-based answers even to these.

There are several approaches to summarize the scientific basis for clinical practice. In recent years, when thanks to developments of computer and IT technology, large amounts of data and literature can be both searched and retrieved within a very short period of time, so-called systematic reviews have become increasingly common. By definition the review must be conducted in a systematic way and contain at least four components:

Systematic reviews are a special type of review article, which can be considered to provide the highest level of evidence when several similar RCTs on the same clinical question are utilized. Meta-analysis is a specialized type of systematic review, where data are pooled for a quantitative rather than a qualitative analysis. This type of study can provide the highest level of evidence, if the report is limited to proper RCTs. However, a meta-analysis cannot give a higher-quality evidence than that which exist in the studies included in the analysis.

In assessing the scientific quality of a clinical research report, a number of factors are essential. These aspects sum up into an account of internal validity (the degree to which the results of a study are correct for the sample of patients being studied) and the extent of external validity (generalizability) (the degree to which the results of an observation hold true in other settings).