About Clinical Trials

Phases of Clinical Trials

Medical research is primarily aimed at understanding the mechanisms underlying diseases. Once these mechanisms are identified, researchers work to find ways to influence them, such as by blocking harmful molecules, eradicating pathogens, or stimulating beneficial biological processes. During this stage, scientists create new compounds (molecules) that, in theory, could positively interfere with the disease mechanisms.

The journey of such compounds involves several stages to ensure both their safety and efficacy. Initially, computer models are used to identify promising molecular candidates, a process known as in silico testing. These candidates then undergo laboratory testing in vitro, where their reactions are studied outside a living organism. Following this, tests are conducted on laboratory animals selected for their biological responses that closely resemble those of humans. This phase, referred to as in vivo or pre-clinical trials, provides valuable insights into how the compound might behave in human systems. Only after these preliminary stages are complete does the compound move on to clinical trials, where it is administered to humans.

It is important to note that only a small fraction of the compounds developed by researchers make it to the clinical trial phase. Most fail to meet the required safety or efficacy standards during earlier stages and are subsequently discarded.

• Exploratory Clinical Trials: These trials encompass Phase I and Phase IIa studies, focusing on the initial safety testing and investigating early signs of efficacy. They aim to determine whether a compound has the potential for further development.
• Confirmatory Clinical Trials: Phase IIb and Phase III trials fall into this category. These stages confirm the optimal dosage that produces effective results while minimising side effects. At this point, the compound undergoes more comprehensive testing on larger groups of participants.

This systematic process ensures that any medicine reaching pharmacy shelves has undergone thorough evaluation and meets the highest standards of safety and efficacy, paving the way for advancements in healthcare and improved patient outcomes.

Clinical trials are conducted in sequential phases, each serving a distinct purpose in the development and approval of new medical treatments.

Phase 0:

Phase 0 trials, a relatively recent and optional exploratory stage, are also referred to as micro-dosing studies in humans. These trials aim to accelerate the development of promising drugs or imaging agents by rapidly assessing whether they perform in humans as expected, based on pre-clinical data. A unique feature of Phase 0 studies is the administration of single sub-therapeutic doses of the investigational compounds to a small group of subjects (typically 10–15 individuals). This phase gathers preliminary data on the pharmacokinetics of the compound—how the body absorbs, distributes, metabolises, and eliminates it.

Phase 0 trials do not provide data on safety or efficacy, as the doses are too low to produce any therapeutic effects. The data obtained helps researchers decide whether to proceed with development based on human models rather than relying solely on the variability of animal studies.

Phase I::

Phase I trials involve a small number of participants (usually 20–100), either healthy volunteers or individuals with a specific condition. Lasting several months, these studies focus on determining the safety of the investigational medicine, identifying safe dosing ranges, and monitoring potential side effects. The trial begins with the administration of a single dose to participants, followed by incremental increases in dosage to identify the optimal safe dose.

Phase I trials can be further subdivided:

Phase Ia (Single Ascending Dose): Small groups of participants receive a single dose of the investigational medicine. Safety is monitored closely, with the initial dose administered to a subset of two individuals—one receiving the active drug and the other a placebo (sentinel dosing). If no adverse effects are observed, subsequent participants are dosed to complete the cohort (usually 6–10 individuals). The dose is gradually increased until unacceptable side effects occur, at which point the dose escalation is halted, and the maximum tolerated dose is determined.

Phase Ib (Multiple Ascending Dose): These studies explore the safety and tolerability of repeated dosing, assessing pharmacokinetics (how the medicine behaves in the body) and pharmacodynamics (its effects on the body).

Phase II::

Phase II trials involve several hundred patients diagnosed with the condition targeted by the investigational medicine. These trials are not large enough to confirm the drug's full efficacy but instead focus on gathering additional safety and effectiveness data to refine subsequent trial designs. Phase II studies aim to determine whether the drug shows biological activity or clinical efficacy.

Phase II trials are divided into:

Phase IIa: These pilot studies focus on demonstrating clinical efficacy or biological activity, often referred to as “proof of concept” trials.

Phase IIb: These studies establish the optimal dosage that produces effective results while minimising side effects (“definite dose-finding” trials).

Some trials combine aspects of Phase I and Phase II to simultaneously assess safety, tolerability, and initial efficacy.

Phase III::

Phase III trials are conducted on a larger scale, involving thousands of participants over several years. The investigational medicine is administered to diverse populations to confirm its effectiveness, monitor for side effects that may only emerge with prolonged use, and compare the new treatment to existing therapies. Success in this phase often leads to approval for large-scale use.

Phase IV::

Phase IV trials, also known as post-marketing studies, occur after a treatment has been authorised for public use. These studies monitor long-term side effects or issues that may arise after extended use and evaluate the treatment’s performance in various prevention or therapeutic settings.

This phased approach ensures that medicines undergo rigorous evaluation, meeting high standards of safety and efficacy before becoming widely available. Clinical trials remain essential for advancing medical science and improving global healthcare.

Relevant Terms

The document that governs the conduct of a clinical trial and outlines all associated activities is referred to as the Study Protocol. This protocol includes detailed information about the purpose of the research, criteria for selecting study volunteers, the schedule of activities, methods and treatments, dosages, the duration of the study, and reporting procedures. Another critical document is the Investigator's Brochure (IB), provided by the Sponsor to investigators. This brochure contains pharmacological data and information from pre-clinical and clinical studies, covering both beneficial effects and any adverse events related to the investigational product.

Before a patient can participate in a clinical trial, they are required to sign an Informed Consent Form (ICF). Prior to signing, patients meet with one of the investigators, who explains the details of the study, including the tests involved, how often they will need to attend the clinic, any tasks required at home, and the potential risks or discomforts. Patients are also informed about the medication they will receive. They are encouraged to ask questions to ensure they fully understand what participation entails. This information is provided both verbally and in writing within the informed consent form.

During the informed consent process, investigators must:

• Provide potential participants with all relevant information about the study to help them make an informed decision regarding enrolment or, if already enrolled, continued participation should new information arise about the investigational drug.
• Ensure participants understand the potential risks, benefits, and alternatives to the research.
• Explain that participation is entirely voluntary and that participants may withdraw from the study at any time, as their agreement to participate does not constitute a binding contract.

The informed consent process protects participants and begins as soon as a potential volunteer requests information about the study. It continues throughout the duration of the trial, involving ongoing discussions between investigators and participants. Investigators address questions and provide clear, understandable written documentation about the study. The informed consent form is reviewed and approved by regulatory authorities and independent ethics committees before being distributed to potential participants. Signing this form is mandatory to enrol in a clinical trial.

The confidentiality of personal data for study participants is strictly upheld. Such data is accessible only to the research team, with all study-related records using participants' initials to protect their privacy.

The investigator (researcher) leading the trial is a qualified medical professional with substantial expertise in patient care and scientific knowledge. Investigators are typically specialists trained in clinical trial practices. When the study is conducted by a team at a given site, the lead investigator is designated as the Principal Investigator (PI), who oversees all aspects of the clinical research.

The conduct of clinical trials is governed by the Good Clinical Practice (GCP) Guidelines, which establish international standards for the design, management, monitoring, auditing, documentation, analysis, and reporting of trials. These guidelines ensure the reliability and accuracy of data and results while safeguarding the rights, integrity, and confidentiality of participants.

The Investigational Medicinal Product (IMP) refers to the drug substance or placebo tested or used as a reference in a clinical trial.

Clinical trial Sponsors—usually pharmaceutical companies or governmental organisations—develop strategies and provide financial support for conducting trials. If Sponsors lack the necessary internal resources to organise trials, they contract specialised companies, known as Contract Research Organisations (CROs), to manage trial implementation.

Clinical trials are conducted at various certified locations, including hospitals, medical clinics, physician practices, and teaching hospitals, all approved by relevant health authorities.

To initiate a clinical trial in any country, approval from two regulatory entities is required: the Health Authority (HA) and the Ethics Committee (EC). Only after obtaining these approvals, in accordance with applicable legislation, can the trial proceed.