Clinical Studies

I. General comments regarding clinical research

Quality clinical research is essential for bringing the advances of basic research to the bedside and for achieving high‐level patient care. Clinical research also has many practical advantages for the thoughtful practicing care giver who would like to advance the field of medicine and his/her career. The conduct of clinical research and reporting of results demand the same rigor and attention to details as those required by basic research studies, although the analytical methods and study design differ.

For clinical investigators, especially those who are new to the field, an awareness of the principles and ethics of clinical research is essential. The following statement from the U.S. Food and Drug Administration is useful advice: “Adherence to the principles of good clinical practices, including adequate human subject protection is universally recognized as a critical requirement to the conduct of research involving human subjects. Many countries have adopted good clinical practice principles as laws and/or regulations.”
(Clinical Trials and Human Subject Protection).

• diagnosis
• therapy
• cost effectiveness
• screening
• prevention
• prognosis
• risk assessment

• Clinical practice
  • uses established evidence-based diagnostic methods and treatment
  • relies on individual physician experience, which may not be proven by research
• Clinical research
  • searches for validation of the efficacy or effectiveness of practice methods.

• Comparative effectiveness (e.g., various chemotherapeutic regimens)
• Risk assessment and prediction (e.g., LDL and risk of myocardial infarction)
• Diagnostic tests (e.g., diagnostic value of alpha-fetoprotein, carcinoembryonic antigen, gene array, oncotype)

• Fewer resources needed
  • Lab or other advanced facilities
  • Funding
  • Training
• Research can be conducted as part of clinical practice
• Research results are immediately relevant and applicable to clinical practice (no “bench-to-bedside” delay)

• A curious mind and commitment to the advancement of clinical knowledge and practice
• Patients willing to participate in research studies
• Access to medical records--preferably electronic and available on an ongoing basis
Dedicated, uninterrupted time--usually only a few hours per week

• Academic advancement and stature
• Personal intellectual gratification
• Improvement in care and education of patients
• Satisfaction in the mentoring and development of trainees

II. Various kinds of clinical research studies

Much of the following text has been taken from the AMA Manual of Style. A Guide for Authors and Editors. 10th Edition. Oxford University Press, pp 835-848. ¹ The Manual of Style is an invaluable source that authors are strongly encouraged to consult as they plan and execute their clinical studies.

The following are some other useful resources on the various types of clinical research:

• What Are the Different Types of Clinical Research?
• Learn About Clinical Studies

Before embarking on a clinic research study the investigator must understand the various kinds of studies that are available. Commonly used concepts and methods:

• Experimental vs. observational studies
  • In experimental studies such as clinical trials, researchers assign the participants into different intervention groups (drugs, procedures, medical devices, diet, exercise, etc) and measure the outcomes. Randomized controlled clinical trials (RCTs) are considered the gold standard of study design, but it is not always possible to conduct RCTs.
  • In observational studies, researchers do not assign the participants into specific intervention groups but only observe what happens to different groups of participants. Participants may receive treatments as part of their standard medical care. Experimental studies offer a higher level of evidence than observational studies. However, because observational studies are based on the outcomes of a large range of people in realistic situations, they may add useful insights to disease processes as they occur beyond the limited conditions of RCTs.
• Prospective vs. retrospective studies
  Observational studies can be prospective or retrospective.Prospective vs. Retrospective Studies
  • A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). The study usually involves taking a cohort of subjects and watching them over a long period. All efforts should be made to avoid sources of bias such as the loss of individuals to follow up during the study. Prospective studies usually have fewer potential sources of bias and confounding than do retrospective studies.
  • A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Most sources of error due to confounding and bias are more common in retrospective studies than in prospective studies. For this reason, retrospective investigations are often criticized. If the outcome of interest is uncommon, however, the size of prospective investigation required to estimate relative risk is often too large to be feasible. You should take special care to avoid sources of bias and confounding in retrospective studies. Recall bias is common in all retrospective studies and is especially a concern when participants believe that a factor related to the independent variable may be associated with the outcome. If recall bias may have occurred, the authors should discuss how they addressed this possibility
• Case-Control studies vs. cohort studies
  These are two common types of observational studies.
  • A case-Control study compares those who have had an outcome or event (cases) with those who have not (controls), and attempts to determine what previous exposure may be associated with the outcome.
  • A cohort study follows a group of subjects before an outcome occurs, and compares those who have had an exposure with those who have not.

• Randomized controlled trials
  • RCTs generally lead to the strongest inferences about the effect of medical treatments.
  • RCTs assess efficacy of the treatment intervention in controlled, standardized and highly monitored settings.
  • Since the results of RCTs might not reflect the effects of a treatment in “real-world” settings they may need to be supplemented with observational studies.
  • The methods of RCTs must be described in detail to allow the reader to judge the quality of the study.
  • The CONSORT Statement³provides a checklist to help ensure complete reporting of RCTs. (The CONSORT Statement)
  • Flow diagram
    • Outlines the flow of participants in the study, including when and why participants were evaluated for the study endpoints.
    • Generally should be published with the study.
    • See AMA Manual of Style. A Guide for Authors and Editors. 10^th Edition. Oxford University Press, p. 840.
  • Intention-to-treat analysis
    • Final results are based on analysis of data from all the participants who were originally randomized, whether or no they actually completed the trial.
    • In reporting the data from RCTs it is usually best to report the results in intention-to-treat analysis.
  • Publication bias
    • The tendency of authors to submit and journals to preferentially publish studies that have statistically significant results
    • International Committee of Medical Journal Editors (ICMJE) requires, as a condition of publication, that a clinical trial be registered in a public trials registry.²

• Parallel design double-blind trials
  • Participants are assigned to only one treatment group of the study.
  • Designed to assess whether one or more treatments are superior to the others
  • Participants and those administering the intervention should all be unaware of which treatment individual participants are receiving (“double-blinding.”).
  • Ideally, those rating the outcomes should also be blinded to the treatment assignments (“triple-blinding.”).
• Cross-over trials
  • Participants receive more than one of the treatments under investigation, usually in a randomly determined sequence, and with a pre-specified amount of time (“washout period”) between sequential treatments
  • Often used for evaluating drug treatments
  • Each participant serves as his/her own control.
• Equivalence or non-inferiority trials³
  • Compare a treatment or intervention against a treatment or intervention that is already known to be effective when it would be unethical to expose participants to an inactive placebo.
  • Assess whether the treatment or invention under study is no worse than an existing alternative.

• Case Series
  Offer a lower degree of evidence than case-control and cohort studies.
  • Describe characteristics of a group of patients with a particular disease or who have undergone a particular procedure.
  • Not used to test a hypothesis because there is no comparison group
  • Case series are subject to several types of biases and therefore authors should be particularly careful about the kinds of conclusions that can be drawn from them.
• Meta-analysis
  • A systematic pooling of the results of two or more studies to address a question or hypothesis.
  • A more statistically powerful test of the null hypothesis than is provided by the separate studies because the sample size is substantially larger than those in the individual studies
  • To help standardize the presentation of meta-analyses, JAMA recommends use of the QUORUM flow diagram and check list for reporting meta-analyses of RCTs (The CONSORT Statement), and the MOOSE checklist for reporting meta-analyses of observational studies.
  • To ensure that the meta-analysis accurately reflects the available evidence, the methods of identifying possible studies for inclusion should be explicitly stated. Authors should state the dates that their search covered and the search terms used.
  • Authors should attempt to include the results of non-English-language articles.
  • A meta-analysis is useful only as long as it reflects current literature. Thus, meta-analyses should be updated as new studies are published.
  • Publication bias
    • See “Publication bias” in Randomized Controlled Trials, above.
• Calculating sample size
• For many clinical studies, it is important to calculate the sample size that will be needed for obtaining reliable results.
• The following is a good reference for sample size calculation: Das S, Mitra K, Mandal M. Sample size calculation: Basic principles. Indian J Anaesth. 2016 Sep;60(9):652-656.
• “Addressing a sample size is a practical issue that has to be solved during planning and designing stage of the study. The aim of any clinical research is to detect the actual difference between two groups (power) and to provide an estimate of the difference with a reasonable accuracy (precision). Hence, researchers should do a priori estimate of sample size well ahead, before conducting the study. Post hoc sample size computation is not encouraged conventionally. Adequate sample size minimizes the random error or in other words, lessens something happening by chance. Too small a sample may fail to answer the research question and can be of questionable validity or provide an imprecise answer while too large a sample may answer the question but is resource-intensive and may be unethical. More transparency in the calculation of sample size is required so that it can be justified and replicated while reporting.”
• Several sample-size calculators are also available on line.

References

1. AMA Manual of Style. A Guide for Authors and Editors. 10th Edition. Oxford University Press. http://www.amamanualofstyle.com/view/10.1093/jama/9780195176339.001.0001/med-9780195176339

2. DeAngelis CD, Drazen JM, Frizelle FA et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. JAMA.2004;292(11):1363-1364

3. Piaggio G, Elbourne DR, Altman DG, et al.; for the CONSORT group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;295(10):1152-1160.