Why Clinical Trials Should Be Well-Controlled

“We are what we repeatedly do. Excellence, then, is not an act, but a habit.” This famous quotation from one of the greatest thinkers, Aristotle, best describes how people’s characters are defined by what they consistently perform or achieve. From this powerful line, it can be inferred that excellence, or “results”, can be achieved through habit, or “process”.

The same principle can be applied in Clinical Trials. In order to achieve results, CTs should undergo several processes. Whatever the Trial or Research is studying, it could be a new treatment, drug, method, or device, results are only obtained through a series of carefully monitored and executed processes.

According to Danielle Kirsh, in the article “What Makes a Well-Controlled Clinical Trial?” (2018), “The goal of a well-controlled experiment is for it to be repeated many times with the same or statistically similar results.” Based on the aforementioned analogy, the significance of results being repeated has already been established. However, in the CTs (Clinical Trials), by the virtue of its nature being scientific experiments, certain interventions are introduced to the Clinical Study at hand according to the research plan. So, from the introduction of these interventions in Clinical Research, questions would arise. For example, “What is the purpose of these interventions?” and “How can it be controlled?”

Significance of Control

According to Torday and Baluska, in the article “Why Control an Experiment?” (2019), “controlling an experiment is critically important to ensure that the observed results are not just random events.” Furthermore, according to Dr. Saul McLeod, in the article Controlled Experiment (2019), “Scientists use controlled experiments because they allow for precise control of extraneous and independent variables. This allows a cause  and effect relationship to be established. Based on these statements, it can be implied that control in an experiment or study must be established to set parameters and keep the experiment on track in relation to the original research plan.

As stated by Malay, MPH & Chung, MD, in the article “The Choice of Controls in Providing Validity and Evidence in Clinical Research” (2013), “the appropriate conduct of the study and its result are not only dependent upon the intervention of interest but also on the thoughtful selection of controls. It is therefore essential that investigators employ control groups, when possible, to test the validity of their treatment effect.” So, the success of a Clinical Trial or Study is not measured by a random introduction of an intervention. It is measured by the careful examination and deliberation of controls that would be introduced to a study in accordance with the research plan to examine its sustainability and effectiveness.

Official Standards

According to 21 CFR 314.126, the FDA published a document to give the regulations on “Adequate and Well-controlled study” and it states that a study should have:

• • A comprehensible statement of the objectives of the study and a summary of the proposed methods of analyses in the protocol.
  • A design and use it to allow a valid comparison with a control to provide a quantitative assessment of the effect.
  • A methodology of subject selection that provides enough assurance that the subject has a disease or condition that the treatment or experiment is directed at.
  • A methodology of putting patients in control groups and treatment to minimize bias and assure comparability of groups.
  • Sufficient measures undertaken in order to minimize bias of the subjects, observers, and the analysts.
  • Methodologies of evaluation of subjects' responses that are well-defined and reliable.
  • Evaluation of research results that is sufficient to assess the effects of the treatment, drug, or device being studied.

As per the guidelines that the FDA layed out, a Clinical Trial should have documents that enlist all of the procedure, methods, and approaches to really distinguish, explain, and signify all of the variables being studied in order to maintain standardized and efficient research study.

Characteristics of a Well-Controlled Study

According to 21 CFR 314.126, the FDA published a document to give the regulations on “Adequate and Well-controlled study” and it states that a study should have:

• • • An experiment is well-designed if it is simple and could be easily replicated. It upholds strict control on all variables
    • The design of the variables in the experiment prove or disprove causal relationships between dependent and independent variables. For example, drug or device versus the patient or subject’s condition.
    • Control is an important element of a well-thought-of study. There needs to be a way to rule out the influence of extraneous variables other than the dependent and independent variables.

A Clinical Study can’t be justified unless it produces results that are scientifically accurate and reliable. Controls serve as the baseline determinants of the effectiveness of a study.

Control Groups

Control groups are classified depending on the type of treatment and the method that would be used in studying the subjects within a group.

Randomization and Blinding

Randomization and Blinding are the 2 most common methods in minimizing the risk of bias and ensuring the treatment is the same throughout the Clinical Trial.

Randomization is the division of participants in a Clinical Study in 2 groups; experimental and control.

Blinding eliminates bias in conducting a Clinical Trial. All participants are treated the same except when receiving test and control treatment.

There are 2 types of blinding: Single-blind and Double-blind.

Double-blind is the most commonly used in a Clinical Trial. It pertains to the unawareness of both the participants and the researchers about the intervention being introduced to the test subjects.

Types of Control Groups

There are 4 common types of Control Groups: Placebo Concurrent Control Group, No Treatment Concurrent Control, Dose-Response Concurrent Control, Active (Positive) Concurrent Control.

In a Placebo Concurrent Control Group, participants are given a dummy treatment to study and prove the efficacy and effectiveness of investigational treatment.

No Treatment Concurrent Control is used if it is impossible to double-blind and only if the final results are guaranteed to be objective and not influenced by other factors.

Dose-Response Concurrent Control is a randomized, fixed-dose control group where participants either take a fixed dose or raised dose that aims to compare during the final dose.

Active (Positive) Concurrent Control has 2 objectives: to show efficacy of the investigational treatment by proving that it is effective as the accepted treatment and shows the investigational treatment is more effective than active control.

Conclusion

In order for a Clinical Study to be characterized as being well-controlled, the experiment can be repeated several times and still obtain the same statistical result. After all, Aristotle was right. In order to achieve excellence (results), replication of actions should be done (processes).

References

1. https://www.massdevice.com/what-makes-a-well-controlled-clinical-trial
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776925
3. https://www.simplypsychology.org/controlled-experiment.html
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461178/
5. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.126
6. https://novotech-cro.com/faq/importance-control-groups-clinical-trials