Clinical study design is the formulation of trials and experiments, as well as observational studies in medical, clinical and other types of research (e.g., epidemiological) involving human beings. The goal of a clinical study is to assess the safety, efficacy, and / or the mechanism of action of an investigational medicinal product or procedure, or new drug or device that is in development, but potentially not yet approved by a health authority (e.g. Food and Drug Administration). It can also be to investigate a drug, device or procedure that has already been approved but is still in need of further investigation, typically with respect to long-term effects or cost-effectiveness.
Some of the considerations here are shared under the more general topic of design of experiments but there can be others, in particular related to patient confidentiality and ethics.
Outline of types of designs for clinical studies
When choosing a study design, many factors must be taken into account. Different types of studies are subject to different types of bias. For example, recall bias is likely to occur in cross-sectional or case-control studies where subjects are asked to recall exposure to risk factors. Subjects with the relevant condition (e.g. breast cancer) may be more likely to recall the relevant exposures that they had undergone (e.g. hormone replacement therapy) than subjects who don't have the condition.
The ecological fallacy may occur when conclusions about individuals are drawn from analyses conducted on grouped data. The nature of this type of analysis tends to overestimate the degree of association between variables.
Conducting studies in seasonal indications (such as allergies, Seasonal Affective Disorder, influenza, and others) can complicate a trial as patients must be enrolled quickly. Additionally, seasonal variations and weather patterns can affect a seasonal study.
- The term retrospective study is sometimes used as another term for a case-control study. This use of the term "retrospective study" is misleading, however, and should be avoided because other research designs besides case-control studies are also retrospective in orientation.
- Superiority trials are designed to demonstrate that one treatment is more effective than a given reference treatment. This type of study design is often used to test the effectiveness of a treatment compared to placebo or to the currently best available treatment.
- Non-inferiority trials are designed to demonstrate that a treatment is at least not appreciably less effective than a given reference treatment. This type of study design is often employed when comparing a new treatment to an established medical standard of care, in situations where the new treatment is cheaper, safer or more convenient than the reference treatment and would therefore be preferable if not appreciably less effective.
- Equivalence trials are designed to demonstrate that two treatments are equally effective.
- When using "parallel groups", each patient receives one treatment; in a "crossover study", each patient receives several treatments but in different order.
- A longitudinal study assesses research subjects over two or more points in time; by contrast, a cross-sectional study assesses research subjects at only one point in time (so case-control, cohort, and randomized studies are not cross-sectional).
A case-control study is a type of observational study in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute. Case-control studies are often used to identify factors that may contribute to a medical condition by comparing subjects who have that condition/disease (the "cases") with patients who do not have the condition/disease but are otherwise similar (the "controls"). They require fewer resources but provide less evidence for causal inference than a randomized controlled trial. We only get odds ratio from a case control study which is an inferior measure of strength of association as compared to relative risk.
The case-control is a type of epidemiological observational study. An observational study is a study in which subjects are not randomized to the exposed or unexposed groups, rather the subjects are observed in order to determine both their exposure and their outcome status and the exposure status is thus not determined by the researcher.
Porta's Dictionary of Epidemiology defines the case-control study as: an observational epidemiological study of persons with the disease (or another outcome variable) of interest and a suitable control group of persons without the disease (comparison group, reference group). The potential relationship of a suspected risk factor or an attribute to the disease is examined by comparing the diseased and nondiseased 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 (diseased and nondiseased)."
For example, in a study trying to show that people who smoke (the attribute) are more likely to be diagnosed with lung cancer (the outcome), the cases would be persons with lung cancer, the controls would be persons without lung cancer (not necessarily healthy), and some of each group would be smokers. If a larger proportion of the cases smoke than the controls, that suggests, but does not conclusively show, that the hypothesis is valid.
The case-control study is frequently contrasted with cohort studies, wherein exposed and unexposed subjects are observed until they develop an outcome of interest.
Control group selection
Controls need not be in good health; inclusion of sick people is sometimes appropriate, as the control group should represent those at risk of becoming a case. Controls should come from the same population as the cases, and their selection should be independent of the exposures of interest.
Controls can carry the same disease as the experimental group, but of another grade/severity, therefore being different from the outcome of interest. However, because the difference between the cases and the controls will be smaller, this results in a lower power to detect an exposure effect.
As with any epidemiological study, greater numbers in the study will increase the power of the study. Numbers of cases and controls do not have to be equal. In many situations, it is much easier to recruit controls than to find cases. Increasing the number of controls above the number of cases, up to a ratio of about 4 to 1, may be a cost-effective way to improve the study.
Strengths and weaknesses
Case-control studies are a relatively inexpensive and frequently used type of epidemiological study that can be carried out by small teams or individual researchers in single facilities in a way that more structured experimental studies often cannot be. They have pointed the way to a number of important discoveries and advances. The case-control study design is often used in the study of rare diseases or as a preliminary study where little is known about the association between the risk factor and disease of interest.
Compared to prospective cohort studies they tend to be less costly and shorter in duration. In several situations they have greater statistical power than cohort studies, which must often wait for a 'sufficient' number of disease events to accrue.
Case-control studies are observational in nature and thus do not provide the same level of evidence as randomized controlled trials. The results may be confounded by other factors, to the extent of giving the opposite answer to better studies. A meta-analysis of what were considered 30 high-quality studies concluded that use of a product halved a risk, when in fact the risk was, if anything, increased. It may also be more difficult to establish the timeline of exposure to disease outcome in the setting of a case-control study than within a prospective cohort study design where the exposure is ascertained prior to following the subjects over time in order to ascertain their outcome status. The most important drawback in case-control studies relates to the difficulty of obtaining reliable information about an individual’s exposure status over time. Case-control studies are therefore placed low in the hierarchy of evidence.
One of the most significant triumphs of the case-control study was the demonstration of the link between tobacco smoking and lung cancer, by Richard Doll and Bradford Hill. They showed a statistically significant association in a large case-control study. Opponents argued for many years that this type of study cannot prove causation, but the eventual results of cohort studies confirmed the causal link which the case-control studies suggested, and it is now accepted that tobacco smoking is the cause of about 87% of all lung cancer mortality in the US.
Case-control studies were initially analyzed by testing whether or not there were significant differences between the proportion of exposed subjects among cases and controls. Subsequently, Cornfield pointed out that, when the disease outcome of interest is rare, the odds ratio of exposure can be used to estimate the relative risk (see rare disease assumption). It was later shown by Miettinen in 1976 that this assumption is not necessary and that the odds ratio of exposure can be used to directly estimate the incidence rate ratio of exposure without the need for the rare disease assumption.
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- Stolley, Paul D.; Schlesselman, James J. (1982). Case-control studies: design, conduct, analysis. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-502933-X. (Still a very useful book, and a great place to start, but now a bit out of date.)