When preparing the research methodology in clinical theses, precautions should be taken to avoid taking sides.
Blinding method
A case in which the treatments applied to the clinical research participants must be kept unknown is called the blinding method. If the participant does not know what they are receiving, it is called a single blind study; If even the investigator does not know, it is called a double-blind study. When there is a probability of knowing which drug is administered in the order of application, when uninformed staff administer the drug, it is called internal blinding.
In case the study drug is known in its pharmaceutical form, a dummy double-blinding test is performed. Intravenous drug is given to one group and a placebo tablet is given to the comparison group; then the placebo tablet is given to the group that received the intravenous drug and the comparison group is given the intravenous drug in addition to the placebo tablet. In this way, each group receives the intravenous and tablet form of the drug. In case a third party interested in the study is involved and also does not know the drug (along with the statistic), it is called third party blinding.
Randomisation method
The selection of patients for the study groups should be random. For this selection, randomization methods are used that avoid conscious or unconscious manipulations in the selection of patients. No factor pertaining to the patient should provide preference for one treatment over the other during randomisation. Randomization strengthens the study design and allows the determination of reliable scientific knowledge.
The simplest method is simple randomisation, eg. Eg determining the type of anesthesia to be administered to a patient by flipping a coin. In this method, when the number of samples is kept high, a balanced distribution is created. When the number of samples is low, there will be an imbalance between the groups. In this case, stratification and blocking should be added to the randomisation. Stratification is the classification of patients one or more times according to the prognostic characteristics determined by the investigator and blocking is the selection of a certain number of patients for each stratification process. The number of stratification processes should be determined at the beginning of the study.
Process limitations
As the number of stratification processes increases, it becomes difficult to carry out the study and balance the groups. For this reason, the characteristics and limitations of stratification must be effectively determined at the beginning of the study. Stratifications are not required to have equal intervals. Despite all precautions, an imbalance between the groups may occur before the investigation begins. In such circumstances, post-stratification or re-standardization can be performed according to prognostic factors. The main feature of the application of blinding (masking) and randomisation is the prevention of bias. Therefore, it is worthwhile to thoroughly examine the bias at this stage.
Bias
During the conduct of clinical investigation, errors can be introduced voluntarily or involuntarily in a number of stages, such as design, population selection, calculation of the number of samples, non-compliance with the study protocol, entry of data and selection of statistical method. Bias is taking sides with individuals according to their own ideological decisions, opinions, and preferences.
For an error to be biased, it must be a systematic error. Systematic errors in controlled studies generally cause the results of one group to move in a different direction compared to the other. It should be understood that scientific research is often prone to errors. However, random errors (or, in other words, “the luck factor”, in which the bias is unintentional, do not lead to bias. Another issue, which is different from bias, is trickery. It is defined as changing voluntary interventions, outcomes and patient data unethically or copying data from other studies.
Comparatively, bias may not be done consciously. In case unexpected results or outliers are found while analyzing the study If possible, such data should be re-included in the study, as the complete exclusion of the data from a study jeopardizes its reliability. In this case, the assessment should be done with and without outliers. It is negligible if not no difference is found. However, if there is a difference, the outlier results are re-evaluated. If there is no error, the outlier is included in the study (as the outlier can be a result). It should be noted that it is not possible to re-evaluate the data in anesthesiology.
Statistical Evaluation Methods in Clinical Theses
Statistical evaluation methods should be determined at the design stage in order not to find unexpected results in clinical research. Data should be evaluated before the end of the study and without going into detail in time-consuming investigations involving multiple samples. This is called interim analysis. The date of the interim analysis should be determined at the beginning of the study.
The purpose of doing an interim analysis is to avoid unnecessary cost and effort, as it may be necessary to conclude the investigation after the interim analysis, e.g. Eg studies in which there is no possibility of validating the hypothesis at the end or the occurrence of different side effects of the drug to be used. The precision of the hypothesis and the number of samples are compared.
The levels of statistical significance in the interim analysis are very important. If the data level is significant, the hypothesis is validated even if the result is insignificant after the date of the analysis. Another important point to consider is the need to complete the treatment of the participants within the period specified in the study protocol. When the study result is achieved earlier and unexpected situations develop, treatment is concluded earlier. In addition, the participant may leave the study of their own free will, may die, or unpredictable situations may develop (eg, pregnancy). The participant can also leave the study at any time, even if the study has not ended.
Expected Quality Level
In the event that the results of a study are contrary to the already known or expected results, the expected quality level of the study that suggests the contradiction may be higher than the studies that support what is known on that topic. This type of bias is called confirmation bias. The presence of well-known mechanisms and logical inference from them can create problems in evaluating the data.
This is called plausibility bias. Another type of bias is the expectation bias. If a result other than the known results has been achieved and it is against the publisher’s will, it can be challenged. Bias can be introduced during study publication, such as publishing only positive results, selecting study results in a way that supports an opinion, or preventing their publication.
Some publishers may only publish research that praises only positive results or desired results. The bias can be introduced for advertising or financial reasons. Financial pressure can be put on the publisher, particularly in case studies involving drugs and new medical devices. This is called trade bias.
Selection of the Research to be Conducted
The last stage in the methodology of clinical studies is the selection of the intervention to be carried out. The use of placebo occupies an important place in the interventions. In Latin, placebo means “I’ll be fine.” In the medical literature it refers to substances that are not curative, do not have active principles and have various pharmaceutical forms.
Although placebos do not have the active drug characteristic, they have shown effective analgesic characteristics, particularly in algology applications; furthermore, its use avoids bias in comparative studies. If a placebo has a positive impact on a participant, it is called a placebo effect; on the contrary, if it has a negative impact, it is called the nocebo effect.
Another type of therapy that can be used in clinical research is the simulated application. Although an investigator does not cure the patient, the investigator can compare those who receive therapy and undergo a simulation. Sham therapies have also been shown to exhibit a placebo effect. In particular, sham therapies are used in acupuncture applications.
Risk Assessment in Clinical Theses
Before human medical research is conducted, the risks, drawbacks, and predictable benefits to the individuals or groups participating in the study must be evaluated. Precautions must be taken to reduce the risk to a minimum level. The risks during the study must be followed, evaluated and recorded by the investigator.
Once the methodology for a clinical study is determined, dealing with the “Ethics Committee” is the next stage. The purpose of the ethics committee is to protect the rights, safety and well-being of volunteers who participate in clinical research, considering the scientific method and the concerns of society. The ethics committee examines the studies presented over time, in a comprehensive and independent manner, in matters of ethics and science; in accordance with the Declaration of Helsinki and following national and international standards on “Good Clinical Practices”.
The method to be followed in the formation of the ethics committee must be developed without any type of prejudice and examine the applications in matters of ethics and science within the framework of the ethics committee, Regulations for Clinical Trials and Good Clinical Practices (www.iku. com). The documents necessary to be presented to the ethics committee are the research protocol, voluntary consent form, budget contract, Declaration of Helsinki, curriculum vitae of researchers, samples of similar or explanatory literature, certificate of approval from the supporting institution and form of patient follow-up.
Members of the Ethics Committee
Only a sister / brother, mother, father, son / daughter and wife / husband can take charge in the same ethics committee. A rector, vice-rector, dean, vice dean, provincial director of health and chief physician cannot be members of the ethics committee. Members of the ethics committee can work as investigators or coordinators in clinical research.
However, during research meetings in which the members of the ethics committee are researchers or coordinators, they must leave the session and cannot approve decisions. If the number of ethics committee members for a particular research is so high that a decision is impossible, the clinical research is presented to another ethics committee in the same province.
If there is no ethics committee in the same province, an ethics committee is sought in the nearest settlement. Thereafter, the researchers must inform the participants using an informed consent form. This form should explain the content of the clinical study, the potential benefits of the study, alternatives, and risks (if any). It must be easy, understandable, compliant with spelling rules, and written in plain language that is understandable to the participant. This form helps participants make a decision regarding participation in the study. It should aim to protect the participants. The participant should be included in the study only after signing the informed consent form; the participant can leave the study when necessary, even when the study has not ended.
Bibliographic References
Rule S, LeGouill S. Bureaucracy is strangling clinical research. BMJ 2019. doi:10.1136/bmj.l1097.
Gobbini E, Pilotto S, Pasello G et al. Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer. Clin. Lung Cancer 2018; 19(2):191–198.
Cardone C, Martinelli E, Troiani T et al. Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer. ESMO Open 2019; 4(4):e000519.
Research Methodology in Clinical Theses
