Understanding the Value of Case Reports and Studies in the Context of Clinical Research, Research Design, and Evidence-Based Practice

Case reports and studies may be defined as the non-experimental description of an individual or a few of cases in terms of new or unusual presentation of the diseases, an unexpected disease course or pathophysiology, and new effects (either beneficial or detrimental) of existing medications or procedures. Although they suffer from the non-experimental nature and other potential bias and errors, case reports and studies have played and will continue to play an important part in the advancement of medicine. They often serve as "primers" leading to discoveries of new diseases/disease pathophysiology as well as development of new preventive and therapeutic measures. Case reports and case studies are also employed as a platform for the training of medical students and/or resident doctors in scientific writing and critical thinking. Although the significance of case reports and studies in medicine has being recognized since the early stage of development of clinical medicine, their value needs to be appreciated in the context of modern clinical research design and the hierarchy of strength of evidence for guiding patient care. This paper discusses case reports and studies within the big picture of clinical research, research design, and evidence-based practice.

Globally, practice of medicine has been increasingly becoming evidence-based. Evidence-based practice means applying the best available research results (evidence) when making decisions about health care. Health care professionals who perform evidence-based practice use research evidence along with clinical expertise and patient preferences. The research evidence for evidence-based practice in general stems from biomedical research especially translational and clinical research (see Figure 1 for description of the scope of biomedical research and Figure 2 for the recent United States National Institutes of Health (NIH) definition of translational research [1]; the NIH definition of clinical research is given in the next section).

The term clinical research has been defined in various ways. In 1997, the NIH Director's Panel on Clinical Research issued a three-part definition of clinical research [2,3] (Figure 3). According to this definition, clinical research is classified into three categories: (1) patient-oriented research, defined as research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. (Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual). Patient-orientated research may include studies of mechanisms of human diseases, therapeutic interventions, clinical trials, and development of new technologies related to diseases; (2) epidemiological and behavioral studies aimed to examine the distribution of diseases, the factors that affect health, and how people make health-related decisions; and (3) outcomes and health services research which seeks to identify the most effective and most efficient interventions, treatments, and services. Based on this broad definition of clinical research, case reports and studies may be viewed as a form of patient-orientated research.

While all biomedical research provides some sort of evidence which could be potentially used to guide patient care, the quality and strength of the research evidence depend on the type of research or research design. As illustrated in (Figure 4), clinical research design includes 3 types of studies: (1) case reports and studies, (2) observational clinical research, and (3) experimental clinical research [4]. Observational research methodology includes the cohort study, case-control study, and cross-sectional study, while experimental clinical research design typically involves a Randomized Controlled Trial (RCT). If the RCT is carried out in a double blind manner, it is called double-blind randomized controlled trial. Case reports and studies can be informative in certain situations, but have limitations due to the low strength of evidence that they provide. Indeed, in evidence-based disease management guidelines from many professional organizations, such as the American Heart Association and the European Society of Cardiology, evidence provided by case reports and studies falls in the level C of the evidence categories (A, B, C) [5,6] (Figure 5). The low strength of evidence provided by case reports and studies results from multiple intrinsic characteristics of such studies, including (1) lack of appropriate controls; (2) limited sample size (one to a few individuals); and (3) lack of blinding. All these intrinsic characteristics bring about significant bias and random errors. Because of the above limitations, interpretation of the results of case reports and studies and discussion of their implications must be done with great caution. In contrast, in the hierarchy of evidence provided by the above three categories of clinical research design, the double-blind randomized, placebo-controlled trial (overall design shown in Figure 6) provides the strongest evidence for the safety and efficacy of a preventive or therapeutic modality [4]. The strength of evidence is further increased by systematic review and meta- analysis of multiple randomized controlled trials (Figure 7).

The strength and quality of the clinical research evidence determine the effectiveness and quality of evidence-based medical practice. In this context, recommendations in disease management guidelines from professional organizations are based on the best evidence currently available. In this context, randomized controlled trials, and their systematic review and meta- analysis are most frequently cited as the strongest evidence for disease management recommendations. In the absence of other studies, case reports and studies are also cited to provide information for health care providers. The usefulness of such information should be judged in the context of case reports and studies, and the value in guiding patient care must not be overstated. Regardless of the limited value of case reports and studies in proving direct evidence for medical practice, they, as also mentioned earlier, may serve as "primers" to lead to new discoveries that subsequently impact evidence-based practice. In this regard, the value of case reports and studies lies in their role of providing clues to new medical discoveries and the subsequent development of preventive and therapeutic measures to control human diseases, rather than directly providing first-line of evidence to guide medical practice (Figure 8).