A young researcher's guide to a clinical trial
What is a clinical trial?
Clinical trials involve research conducted on humans that is designed to evaluate the effectiveness of a drug or treatment and add to medical knowledge. As per the National Institutes of Health (NIH), “Clinical trials are research studies that explore whether a medical strategy, treatment, or device is safe and effective for humans. These studies also may show which medical approaches work best for certain illnesses or groups of people.”
Clinical trials are usually medical or clinical studies in which human volunteers participate in carefully conducted investigations according to a pre-determined research protocol. The clinical trial program is a long drawn process taking up to 5-7 years or more to complete. A clinical trial is usually conducted as the final step of an extended research process. First, a new medical strategy, drug, treatment, or device is developed in the lab, then it is tested on animals, and finally tested on humans to see how safe or effective it is.
Types of clinical trials
Broadly speaking, clinical trials can be of two types:
Interventional: In this kind of trial, specific treatments or interventions are given to the participants by the investigators. The outcomes are then compared to a group that has been given a different treatment or no treatment.
Observational: In observational studies, the investigators or the researchers observe the treatments or management techniques that are given to a group of patients and note the outcomes. However, the researchers do not give the interventions.
Based on the purpose of the study, the NIH has classified clinical trials into the following types:
Treatment trials: These are designed to test new treatments, new combinations of drugs, new surgical approaches, or radiation therapy.
Prevention trials: The objective of these trials is to find ways to prevent a disease from occurring or relapsing. These often include medicines, vaccination, or lifestyle changes.
Screening trials: This type of study tests the best way to detect specific diseases or health conditions.
Diagnostic trials: These studies aim to come up with better tests or procedures for diagnosing a disease or health condition.
Quality of life trials: Also known as supportive care trials, these studies explore ways to improve the comfort and quality of life of people with a chronic illness.
Phases of clinical trials
The clinical trial program is a long drawn process taking up to 5-7 years or more to complete. Clinical trials are conducted in “phases,” and each phase has a different purpose. :
Phase I trials: In this phase, a new drug or treatment is tested on a small group of people (20–80) to evaluate its safety and identify the side effects, and to obtain early signs of effectiveness.
Phase II trials: The drug or treatment is given to a larger group of people (100–300). The purpose is to evaluate its effectiveness and obtain more information about side effects and risks.
Phase III trials: The drug or treatment is administered to very large groups of people (1,000–3,000). This is done to confirm its effectiveness, compare it with other modes of treatment, and evaluate the overall risk-benefit equation.
Phase IV trials: These studies are conducted after the drug’s approval and launch in the market with an aim to obtain additional information about its risks, benefits, and optimal use. These are also referred to as post-marketing surveillance studies.
Developing a research protocol
As mentioned earlier, a clinical trial needs a lot of careful planning. Since it involves human subjects, it has to abide by strict scientific standards and ethics that are designed to protect the rights and ensure the safety of the patients or participants who enrol for the trial. Once the research team is clear about the research idea and study design, it is time to start developing a research protocol.
A research protocol is a detailed research plan that serves as a roadmap when you are conducting the study. It is designed to answer specific research questions while at the same time safeguarding the health of the participants. Designing an efficient and effective research protocol is of utmost importance as institutional review boards (IRB) give their approval of a study on the basis of the research protocol.
A protocol is usually prepared by a panel of experts. All the investigators in the research team are expected to strictly observe the protocol. A research protocol should include the following elements:
1. Background and rationale
3. Informed consent
4. Subject selection criteria: Inclusion and exclusion criteria
5. Treatment plan and study procedures
6. Statistical analysis plan
7. Assessment of safety and efficacy
Participation in clinical trials is voluntary. To protect the rights of human subjects, potential participants are provided with information about the study so that they are aware of the process, potential benefits, and the risks involved before they decide to participate in the trial. This process is known as informed consent and the document providing the details is known as the informed consent document. Participants are required to sign the informed consent document before joining a clinical trial. In case of minor participants or participants whose decision making capacity is impaired due to clinical conditions, the consent of a parent or close relative is required. However, signing the informed consent document does not make it mandatory for the participants to go through the entire trial. Volunteers are free to withdraw from the study at any point of time, even if the study is not completed.
In the US, most clinical trials need to obtain the approval of an IRB before they can be started. An IRB is a committee comprising of physicians, nurses, researchers, statisticians, and members of the community that makes sure that a clinical trial is ethical, and that the rights and welfare of the participants are protected. The committee ensures that research risks are minimal and are worth the potential benefits. Outside of the US, an ethics committee is usually the equivalent of an IRB.
The IRB reviews the research protocol and the informed consent document. Once these two documents are completed, the investigators need to send an application to an IRB or an ethics committee. The proposal is then reviewed, and if it meets the expected ethical standards, it is approved.
Registration of clinical trials
The Declaration of Helsinki states that "Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.” Organizations like World Health Organization (WHO) and the International Committee of Medical Journal Editors (ICMJE) are strong advocates of clinical trial registration. All journals listed on the ICMJE website require registration of clinical trials in a public trials registry before the first patient is enrolled as a condition of consideration for publication. ClinicalTrials.gov run by the United States National Library of Medicine (NLM) is the world’s largest and most widely used clinical trials registry. The WHO maintains a clinical trials registry network. The ICMJE accepts registration in ClinicalTrials.gov or in any primary registry of the WHO International Clinical Trials Registry Platform (ICTRP). Once the clinical trial is over, the results data should be submitted to the registry. While the ICMJE encourages submission of results as a good practice, this is not mandatory.
Case report form for clinical trials
A case report form (CRF) is a paper or electronic questionnaire used in clinical trial research to record all protocol-required information on each subject/participating patient in the study. Case report forms contain data obtained during the patient's participation in the clinical trial. According to the International Conference on Harmonization Guidelines for Good Clinical Practice, a CRF is “A printed, optical or electronic archive intended to record the greater part of the protocol– expected data to present to the sponsor on every trial subject.” It encompasses the entire medical history including adverse events from the patient and is collected over a period of weeks or months.
The CRF should accurately represent the protocol of the clinical trial, as well as managing its production, monitoring the data collection and auditing the content of the filled-in CRFs. The CRF assists in obtaining the complete, comprehensive and standardized data collection that promotes efficient processing, analysis, and reporting of information, as well as the exchange of data across sites. The data from the CRF is further used by clinical research coordinators, biostatisticians, investigators, data managers or a programmer.
The main purpose of a CRF is to gather complete and accurate data in a clinical trial and to smoothly transcribe the data from the source document to a retrievable form. In other words, a CRF preserves and maintains the quality and integrity of data from a clinical trial. The structuring of the CRF should enable data collection of the highest quality. The sponsor/pharma company usually designs a CRF. The sponsor should ensure that the CRF represents the trial protocol; additionally, the sponsor is also responsible for management of the production, monitoring of the data collection and the auditing the content of the CRFs. However, the patient’s name and medical record number are usually de-identified before sending the details to the sponsoring agency.
You can download a list of 13 important considerations you should keep in mind when designing a CRF.
Reporting guidelines and manuscript structure
Once the study is over and data has been analyzed, it is time to write and submit the manuscript to a journal. There are some guidelines which need to be followed while reporting clinical trials. There are different reporting guidelines for different study designs, for example, CONSORT is used for randomized trials, STROBE for observational studies, and STARD for diagnostic studies. Following these guidelines ensures that all the required details of the study are covered in the manuscript.
As per the ICMJE guidelines, a clinical trial manuscript generally includes the following sections:
Title Page: The manuscript title page should the article title, author information, disclaimers, sources of support, word count, and sometimes the number of tables and figures.
Abstract: The abstract should accurately reflect the content of the article. Items identified as essential in the CONSORT guidelines should be included. The clinical trial registration number should be mentioned at the end of the abstract.
Introduction: The introduction includes background information about nature of the problem and its significance as well as the statement of purpose or research objective.
Methods: The Methods section covers all the details of how and why the study was conducted. Only information that was available at the time the protocol was designed should be included in this section; all information obtained during the trial should be described in the Results section. The Methods section should include the following subsections:
• Selection and description of participants
• Technical information
Results: The results should be presented logically, through text, tables, and figures. Data on all primary and secondary outcomes mentioned in the Methods section should be provided.
Discussion: This section emphasizes the main findings and compares the results with other relevant studies. It also mentions the limitations of the study and discusses implications for future research and clinical practice.
Clinical trials are an important research tool for advancing medical knowledge and healthcare. They provide the most valuable statistical evidence in medical and health research.
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