Indian Dermatol Online J. 2019 Sep-Oct; 10(5): 601–605. Clinical trials looking at which treatment is better must have certain checks in place. Appropriate “control” selection while comparing the investigating agent to the “control group is essential to rule out selection bias. Randomization is another step to
minimize variability or “confounders.” By randomization, research participants have an equal chance of being selected into any treatment group of the study, generating comparable intervention groups, thereby distributing the confounders. A trial can be “open labeled” or “blinded.” By the process of blinding, we make the participant and/or assessing physician unaware of the treatment he/she is going to receive. Thus, the element of bias which can creep in owing to personal preference or
subjective component to the assessment of outcome can be eliminated. Concealment of allocation is done as the participant enters the trial. Concealment secures randomization and prevents “selection bias”. Keywords: Allocation concealment, blinding, clinical trial, control, randomization, SNOSE Clinical trials or interventional
studies are to be designed in such a way that it gives a comprehensive idea about the effectiveness/efficacy or safety of any new agent introduced for the treatment of any clinical condition. To understand the fact that the improvement (or deterioration) is not happening by chance, it is essential that the treatment modality is compared against another modality of treatment (active control) or no treatment (placebo control). Thus, the role of having control is paramount, and it decides
the level of evidence of any trial and in-turn decides the grade of recommendation. Apart from having control, there is another important factor which can affect the interpretation of result in any clinical trial, and this factor is “bias.” The bias can be while selecting the participant and the control (selection bias), owing to the confounding factors (confounding bias) and also while assessing the outcome (assessment bias). Randomization is the method adopted to eliminate the
bias of selection and confounder. It has got two steps; generation of random number and concealment of the random number from the dispensing physician (allocation concealment). For eliminating the assessment bias, the method adopted is blinding and it can be done at a different level using the participant of the trial, assessing physician, and even the statistician analyzing the results. The article will attempt in elaborating on these facets of clinical trial and impart
practical clues to implement the same. A. Selection of control- The “control” is used in clinical trials to nullify the effect of known or unknown factors (other than the factor being tested) on the research outcome and hence, to increase the reliability of the results. For example, if a new topical medication is shown to be effective in psoriasis patient, the inclusion of “control” in the study allows the investigator to conclude that the new medication is truly
effective and improvement did not happen by chance. While choosing control, two principles should be followed:[1] The control or the comparison group should be representative of the source population from which cases are derived The controls should be
independent of the exposure, i.e., less likely to have the exposure of interest. For e.g., to test the role of “topical corticosteroids causing the unresponsiveness to standard antifungal therapy” it is essential that case (those who have used steroid) and control (those who have not) be chosen from the same socio-cultural strata to eliminate the confounders such as hot and humid working environment, cleanliness, etc. This prevents “selection bias.” Thus, a control
minimizes the effects of variables other than the variable under evaluation. In making a decision about a new treatment, the control arm is usually taken as the “gold standard treatment” (or the “best available treatment”). Comparison between the “test” arm (or “experimental” arm) and the “control” arm in such clinical studies makes a fruitful assessment of the new treatment compared with the previous
one and increases the reliability of the study. Placebo control: A placebo is an inactive substance that looks like the drug or treatment being tested.[2] A placebo control may be used where no standard treatment exists or else using a placebo control becomes unethical and substandard care in patients with active disease, where there is an approved treatment. Guidelines state that
there should be a condition of “clinical equipoise” before a placebo-controlled trial is started. Clinical equipoise assumes that there exists not one better intervention either for the control or experimental group during the design of the trial, e.g., a trial on systemic sclerosis by using an experimental drug understanding the fact that there is no gold-standard therapy for systemic
sclerosis.[3] The use of “active” control or “historical” control (stated below) can address this issue. Participants who are going to receive placebo are not going to benefit from the trial. This therapeutic misconception should be eliminated during the informed consent process. Dose-response control: A new dose for a known drug makes it a “new
drug.”[4] During its clinical trial, the control is usually the previously used dose. For e.g., 10 mg levocetirizine compared to 5 mg levocetirizine Active control: Here, the control is an active drug, usually the standard therapy or known effective treatment Historical control: Such control uses data from previously conducted studies and administrative databases. The
studies that can be chosen for historical control can be a prospective natural history study or a control group from a previous randomized controlled trial. B. Randomization Minimizing variability of evaluation is the core of conducting good research or experiment. This variability is also known as “confounders.” Confounders can be known or unknown. Confounders have the possibility of generating erroneous results because of the unknown
effects of unmeasured variables. The process by which confounders can be reduced is known as “randomization.” By randomization, research participants have an equal chance of being selected into any treatment group of the study, generating comparable intervention groups, thereby distributing the confounders. The confounders can, therefore, be ignored. Thus, the difference in outcome and results can be explained by treatment alone. However, if one wants to gain greater experience using a new
treatment or drug, one may opt for “Unequal randomization”- randomization in 2:1 ratio (2/3 of patients on new treatment). The power of the study does get reduced [power decreases from 0.95 (for 1:1) to 0.925 (for 2:1)], but this technique is statistically feasible and is especially suited to phase II randomized trials. Balances the treatment groups with respect to baseline variability, known, and unknown
confounding factors, thus eliminates “confounding bias” Eliminates “selection bias.” Selection bias occurs when the researcher voluntarily or involuntarily steers the less sick patients to the treatment he feels is better and vice versa Forms the basis for statistical tests. How to randomize?
What is not randomization?
Techniques for randomization
C. Blinding A trial can be “open labeled” or “blinded”. By the process of blinding, we make the participant and/or assessing physician unaware of the treatment he/she is going to receive. Thus, the element of bias which can creep in owing to personal preference or subjective component to the assessment of outcome (e.g., a tool like physician global score is used to assess the outcome) can be eliminated. The process has now been further extended to include the statistician analyzing the result to make it fool proof. Thus, blinding is helpful in eliminating intentional or unintentional bias, increasing the objectivity of results, and ensuring the credibility of study conclusions. Types of blinding:
However, instead of expressing whether the trial is single, double, or triple blinded, it is more pertinent to specify who exactly is going to be blinded. Masking: It is a term used interchangeably with “blinding” and is usually used by ophthalmologists. Advantages of blinding:
Procedures of blinding a trial:
Assessment of the efficacy of blinding:There might be untoward effects in which the trial can be unblinded. The curiosity of participants or staff, differences in taste and smell of the drug, and placebo or a cross-over study are such instances. Ideal placebos are not always easy to procure or manufacture. Thus, the assessment of blinding should be done prior to the decoding of randomization. The participants, investigators, and staff are asked to guess what the participants had received. If the guess is 50% in each group, blinding has been maintained. If the guess is >50%, there had been a breach in blinding. If guess is <50% a suspicion about non-admittance of breach of blinding should be made. Instances when blinding may be broken:
Instances when blinding is not possible or difficult to achieve:
What to do if blinding is not possible or ethical:
D. Allocation concealment Concealment of allocation is done as the participant enters the trial. Concealment secures randomization and prevents “selection bias.” Every researcher tries to prove his hypothesis as correct. This can lead to conscious or unconscious steering of certain “good” patients to the desired group and others to the alternate group. If the investigator knows the randomization, such bias can lead to an imbalance in the study and wrong conclusions can be drawn. Such bias can be avoided by the following allocation of concealment techniques:
E. Differences between allocation concealment and blinding
ConclusionTo conclude, a randomized controlled trial (RCT) is the gold-standard study design to evaluate any therapeutic method and carries the highest level of evidence (Level I b). Undoubtedly, as a researcher, we all are interested in conducting an RCT and contribute to the knowledge of the scientific world. Choosing the correct control group and avoiding biases are the most important aspect of any RCT. There can be a situation where blinding is not possible because of operational issues, but in every trial, effort should be thrust on randomization, which can eliminate two major biases: the bias of selection and confounding bias. Proper randomization would ensure that the baseline confounders are balanced lest; complex statistical methods are called for balancing them (e.g., multivariate analysis). This article is an attempt to provide practical tips for the researchers interested in a clinical trial, so that the data generated is more valid and credible. Financial support and sponsorshipNil. Conflicts of interestThere are no conflicts of interest. References3. Cook C, Sheets C. Clinical equipoise and personal equipoise: Two necessary ingredients for reducing bias in manual therapy trials. J Man Manip Ther. 2011;19:55–7. [PMC free article] [PubMed] [Google Scholar] 4. Definition of new drug. Rule 122E. Schedule Y of Drugs and Cosmetics Act, 1940 and Rules, 1945. Central Drugs Standard and Control Organization [homepage on internet]. India. [Last accessed on 2019 Mar 25]. Available from: http://cdsco.nic.in/html/D&C_Rules_Schedule_Y.pdf . 5. Altaman DG, Bland JM. Statistics notes. Treatment allocation in controlled trails: Why randomize? BMJ. 1999;318:1209. [PMC free article] [PubMed] [Google Scholar] 6. Parikh MN, Hazra A, Mukherjee J, Gogtay N. New Delhi: Jaypee Brothers Medical Publishers; 2010. Research Methodology Simplified Every Clinician A Researcher. [Google Scholar] 7. Suresh KP. An overview of randomization techniques: An unbiased assessment of outcome in clinical research. J Hum Reprod Sci. 2011;4:8–11. [PMC free article] [PubMed] [Google Scholar] 8. Lal NR, Sil A, Gayen T, Bandyopadhyay D, Das NK. Safety and effectiveness of autoinoculation therapy in cutaneous warts: A double - blind, randomized, placebo - controlled study. Indian J Dermatol Venereol Leprol. 2014;80:515–20. [PubMed] [Google Scholar] 9. Roy K, Sil A, Das NK, Bandyopadhyay D. Effectiveness and safety of clofazimine and pentoxifylline in type 2 lepra reaction: A double-blind, randomized, controlled study. Int J Dermatol. 2015;54:1325–32. [PubMed] [Google Scholar] Articles from Indian Dermatology Online Journal are provided here courtesy of Wolters Kluwer -- Medknow Publications What is a Non experimental study that quantifies the degree to which events measures or variables are associated?Correlational research is a type of nonexperimental research in which the researcher measures two variables and assesses the statistical relationship (i.e., the correlation) between them with little or no effort to control extraneous variables.
Which of the following refers to participants in an experimental study who do not receive the treatment under investigation?In experimental research, some subjects are administered one or more experimental stimulus called a treatment (the treatment group ) while other subjects are not given such a stimulus (the control group ).
Which of the following research methods provides an in depth analysis of the behavior of one person or a small group of people?Single-subject research is a type of quantitative research that involves studying in detail the behavior of each of a small number of participants.
What is the term to describe when the participants expectations lead them to experience some change even though they receive an empty or fake treatment?Placebo Effects - Occur when participants' expectations lead them to experience some change even though they receive empty, fake or ineffectual treatment.
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