Clinical Research: An Overview

Clinical research plays a crucial role in advancing our understanding of human health and disease. It aims to generate valuable insights that can help prevent illnesses, enhance treatments, and promote overall well-being (1). Essentially, any study exploring the various facets of a disease like symptoms, risk factors, or underlying mechanisms falls under the umbrella of clinical research (2). Clinical research generally takes two forms: observational and interventional. Observational studies focus on examining existing conditions or processes without assigning specific treatments to participants. These may include studies that analyse how therapies perform in real-world settings, research on healthcare economics, or qualitative studies that delve into patients’ experiences. On the other hand, interventional research involves carefully designed experiments such as clinical trials where participants are assigned to either treatment or control groups at the start. Interventions in such trials can range from medications, surgical procedures, and medical devices to behavioural therapies, radiologic techniques, and preventive care strategies, as outlined by the WHO’s International Clinical Trials Registry Platform (3). This field of research serves as a cornerstone for medical advancement, providing essential insights into the safety and efficacy of new interventions. The knowledge gained guides healthcare professionals in making informed decisions about patient care and treatment strategies. Importantly, clinical research fosters a continuous cycle of innovation, enabling us to address current healthcare challenges and anticipate future needs. By driving transformative discoveries, it has the potential to revolutionize how diseases are managed and how healthcare is delivered (4). This article highlights findings from various clinical studies that contribute to this ever-evolving body of knowledge, ultimately improving patient outcomes and shaping the future of medicine.

Historical Background

James Lind is often credited with carrying out the first clinical trial back in 1747. He conducted an experiment to uncover a treatment for scurvy, selecting individuals who shared similar symptoms, living conditions, and diets. He divided these participants into groups based on the treatment they received. Lind discovered that those who consumed lemons and oranges each day experienced full recovery, a remarkable finding that laid the groundwork for what we know today vitamin C is essential in combating scurvy. Fast-forward to the 19th century, and the concept of placebos entered the realm of clinical research. U.S. physician Dr. Austin Flint integrated this approach in his study on rheumatism treatment by having one group receive an herbal extract as a substitute for an actual remedy. Moving ahead to 1946, the first randomized controlled trial emerged. Researchers aimed to evaluate the efficacy of streptomycin in treating pulmonary tuberculosis. This milestone introduced key elements such as randomization, systematic enrolment criteria, and blinding which have profoundly shaped modern clinical research methodologies. The field has come a long way since those early steps. With more than 34,000 peer-reviewed journals actively publishing research on virtually every aspect of medicine, the continuous influx of knowledge propels advancements in healthcare and medical science every single day (5).

Types of Clinical research

Primary research can be divided into two categories: observational studies and interventional studies. Observational studies, often referred to as epidemiological studies, involve researchers observing participants without influencing them, focusing on the natural connections between variables and outcomes (6). On the other hand, interventional studies—also known as experimental studies—are designed for the researcher to actively introduce a variable or intervention to examine its effect on health outcomes. This category includes randomized controlled trials (RCTs) and clinical trials. RCTs are a specific type of clinical trial where participants are randomly assigned to either the treatment group or the control group, ensuring unbiased comparisons (4).

Ethical and Regulatory Consideration

In clinical research involving human participants, adhering to ethical principles is crucial to ensure the integrity and safety of the study.

Ethical conduct guidelines serve as a foundation for responsible and respectful research practices:

• Uphold honesty, fairness, and integrity at every stage of research—whether it's designing experiments, collecting and analysing data, or sharing results. Transparency and objectivity matter.
• Be diligent in reviewing your work with care, maintaining accurate records, and openly sharing findings, data, and resources to foster trust and collaboration within the research community.
• Value intellectual property by respecting patents, copyrights, and research methodologies—steering clear of plagiarism or unethical borrowing of ideas.
• Safeguard confidential information, publish thoughtfully to contribute meaningfully to your field, and aim to make a positive impact on society through your research.
• Embrace diversity, reject discrimination, follow laws and institutional regulations, and honour the dignity and autonomy of both human and animal subjects in your work.

The Influential Code of Research Ethics:

To understand how today system of regulatory oversight in research is came to be, it’s important to consider the various codes and guidelines developed over time to shape ethical clinical practices.

1. Nuremberg Code-The Nuremberg Code, created in 1947, stands as a landmark in modern research ethics. It was drafted by American judges during the trials of Nazi doctors accused of horrific crimes—murder, torture, and other inhumane acts falsely justified in the name of medical science. As part of their judgment, the war crimes tribunal in Nuremberg established 10 ethical principles for conducting experiments on human subjects. This code, now recognized globally, emphasizes the responsibility of physicians to avoid causing harm or injury to patients involved in their research [8-9]. The Nuremberg Code emerged as a pivotal outcome of the Nuremberg Trials, establishing vital principles for ethical research involving human subjects.  

• Researchers must ensure that participants fully understand and willingly agree to take part.
• Before involving humans, studies should first be conducted on animals to lay a proper foundation.
• Any risks to participants should be carefully weighed and justified by the expected advantages or outcomes.
• Scientists overseeing the research must be appropriately trained and qualified.
• Causing physical or emotional pain to participants must be strictly avoided.
• Experiments that might lead to death or severe injury should never be carried out.

The principles of Nuremberg code:

1. Participation in research must be entirely voluntary, with participants giving informed consent before taking part.
2. Research must aim to achieve meaningful results that benefit society and cannot be attained through other methods. The scope and nature of the study must be purposeful and not excessive.
3. Studies involving humans should be grounded in prior research, such as animal studies, and rely on established knowledge about the issue being addressed to justify the research.
4. The research process must avoid causing unnecessary physical or mental suffering to participants.
5. Research must not proceed if there is reason to believe it could result in severe injury or death, unless researchers themselves are also participants in the study.
6. The level of risk participants are exposed to must never exceed what is justified by the humanitarian value of the issue being studied.
7. Adequate precautions and facilities must be in place to minimize the risk of injury, disability, or death for participants.
8. Research should only be conducted by qualified professionals who maintain the highest levels of care and competence throughout the study.
9. Participants must have the freedom to withdraw from the study at any time if they feel they cannot continue.
10. Researchers have a duty to stop the study if they believe it could result in harm, disability, or death to participants.

2. Declaration of Helsinki-The Declaration of Helsinki, established in 1964 by the World Medical Association (WMA), is recognized as the second major milestone in research ethics. It was created to serve as a comprehensive ethical framework specifically for physicians conducting research.[8] The original Declaration of Helsinki emphasized the importance of distinguishing between two types of clinical research: one that primarily aims to provide therapeutic benefits to patients, and another that is purely focused on scientific objectives without offering any direct therapeutic value to participants. This distinction shaped the foundation of the document. In its original form and across its first four revisions, the Declaration was organized under the following sections:

• Introductory statements,
• Basic principles,
• Clinical research combined with patient care,
• Non-therapeutic clinical research.

This structure remained intact until the Edinburgh revision in 2000, when significant changes were introduced (9).

3. Belmont report- In 1979, the National Commission released the 10-page Belmont Report, named after the conference centre where the commission originally met. The report played a key role in shaping ethical standards for research in the United States. Its creation was largely driven by the widespread public outcry over the Tuskegee Syphilis Study, a deeply controversial and unethical study that had previously come to light. This report became a cornerstone in establishing ethical guidelines for research involving human participants. The Belmont Report emphasizes three key ethical principles that serve as guiding pillars in medical research and are integral to medical education:

1. Respect for Persons:

This principle underscores the importance of treating individuals with autonomy and dignity while offering additional protections to those with limited ability to make independent decisions.

• Informed Consent: Individuals must receive all the necessary information about the research and have the freedom to decide whether to participate, without any coercion.
• Protection for Vulnerable Groups: Special care must be given to protect those who cannot fully make informed choices, such as children or individuals with cognitive challenges.

2.  Beneficence:
   This principle charges researchers with the responsibility of prioritizing the welfare of participants. It emphasizes:

• Promoting Well-being: Taking deliberate actions to enhance the health and welfare of participants.
• Preventing Harm: Making every effort to safeguard participants from any potential harm, whether physical or psychological.

3.  Justice:
   This principle calls for fairness in how the benefits and burdens of research are distributed. It involves:

• Fair Selection of Participants: Ensuring that no group is unfairly burdened or excluded from participating in research.
• Equitable Sharing of Risks and Benefits: Balancing the risks and advantages of research to ensure fairness across different populations.

By centring on these principles, the report lays the foundation for ethical research practices that protect and respect all participants (10).

4. Indian Council of Medical Research (ICMR) guidelines- In October 2017, the Indian Council of Medical Research introduced the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants. These guidelines were created to protect the dignity, rights, safety, and well-being of individuals taking part in such research. They are essential for ensuring ethical practices and are mandatory for all parties involved, including institutions, ethics committees (ECs), researchers, and sponsors or funding organizations. In 2007, the Indian Council of Medical Research (ICMR) launched an online platform called the ‘Clinical Trial Registration-India’ (CTRI) to streamline and organize clinical trial registrations. The majority of these activities are concentrated in western and southern regions of India, with cities like Mumbai, Pune, Ahmedabad, Hyderabad, Bangalore, and Chennai playing key roles in conducting clinical trials (11). Guidelines:

• An ethics committee established by the Central Drugs Standard Control Organization must oversee research activities.
• These committees are responsible for thoroughly reviewing all submitted research proposals.
• They should meet regularly to assess the progress of ongoing trials, review any serious adverse events, and take necessary actions.
• Research involving vulnerable populations should only be conducted if it directly benefits them.
• Economically and socially disadvantaged individuals must not be exploited to benefit more privileged groups.
• Informed consent is mandatory for participants. If an individual cannot provide consent, approval must be obtained from their legal guardian.
• Participants can be compensated for their time and inconvenience. However, payments should be reasonable and not so high as to cloud their judgment.
• If a drug proves effective for a participant during a trial, the sponsor must ensure its availability to them after the trial concludes, either until it is marketed or at a reduced cost afterward.
• Any participants who experience physical injuries during the trial must receive financial or other forms of assistance. In the unfortunate event of death, their dependents are entitled to compensation.

5. Council for International Organisations of Medical Sciences (CIOMS) - The Council for International Organizations of Medical Sciences (CIOMS) is a global nongovernmental organization officially affiliated with the World Health Organization (WHO). Established in 1949 under the guidance of WHO and UNESCO, CIOMS is tasked with fostering collaborative relationships with the United Nations and its specialized agencies, particularly UNESCO and WHO. Its focus lies in health-related research involving human participants, such as observational studies, clinical trials, bio banking, and epidemiological research.

The CIOMS Guidelines have consistently been developed in partnership with WHO. For the current guidelines, this collaboration has been more structured, with both organizations agreeing to align with the recommendations of the WHO Guidelines Review Committee (GRC).

This Involves:

1. Defining the revision process prior to beginning any updates.
2. Ensuring the Working Group has diverse global representation, includes balanced participation from various regions and stakeholders, and follows a transparent procedure for addressing conflicts of interest.
3. Outlining the steps for evidence collection and synthesis during the guideline revision process.
4. Conducting an independent external peer review to validate the final guidelines (12).

6. International Council for Harmonisation- Good Clinical Practices (ICH-GCP) guidelines- The International Council for Harmonisation (ICH) was established in 1991 in Brussels, bringing together the USA, Japan, and European nations. Its expert working groups are dedicated to ensuring the quality, safety, and effectiveness of medicinal products, whether they are drugs or medical devices. Notably, back in 1982, the International Ethical Guidelines for Biomedical Research Involving Human Subjects were introduced by CIOMS in collaboration with the World Health Organization (WHO). These guidelines later contributed to the ICH-GCP (Good Clinical Practice) standards. Good Clinical Practice serves as a globally accepted ethical and scientific benchmark for planning, conducting, documenting, and reporting clinical trials that involve human participants. The key aim of the ICH-GCP guidelines is to establish a unified framework that supports mutual acceptance of clinical trial data by regulatory authorities across the European Union, Japan, and the United States.

The core principles of ICH-GCP set a standard framework for conducting ethical and reliable clinical trials:

1. Clinical trials must adhere to ethical principles rooted in the Declaration of Helsinki and align with GCP standards and applicable regulations.
2. Prior to starting a trial, the potential risks and inconveniences should be carefully assessed against the expected benefits for both individual participants and society. A trial should proceed only if the benefits outweigh the risks.
3. The rights, safety, and well-being of participants must always take precedence over scientific or societal interests.
4. Adequate non-clinical and clinical data on the investigational product must be available to support the trial.
5. Clinical trials should be well-structured, scientifically rigorous, and clearly outlined in a detailed protocol.
6. Trials should strictly follow an approved protocol that has received favourable review from an institutional review board (IRB) or an independent ethics committee (IEC).
7. Qualified physicians or, in some cases, dentists, should oversee the medical care of participants and make necessary medical decisions.
8. All personnel involved in the trial must be appropriately trained, educated, and experienced for their specific roles.
9. Informed consent must be voluntarily obtained from each participant before they join the trial.
10. All information related to the trial must be meticulously recorded, stored, and handled to ensure accurate reporting and interpretation.
11. Participant confidentiality must be safeguarded, with adherence to privacy and confidentiality regulations.
12. Investigational products must be manufactured, handled, and stored according to Good Manufacturing Practice (GMP) and used in line with the approved protocol.
13. Robust systems and procedures should be in place to ensure the quality of all aspects of the trial.

These principles collectively form the cornerstone of Good Clinical Practice, making the ICH-GCP guidelines a vital resource often referred to as the "Bible" of clinical trials (13).

7. Institutional review Board/ Independent Ethics Committee- An Institutional Review Board (IRB) is an independent committee made up of individuals with medical, scientific, and non-scientific expertise. These boards are established by organizations such as hospitals, research centres, or universities. Their main role is to safeguard the rights, safety, and welfare of individuals who volunteer to take part in biomedical or behavioural research. The IRB ensures that these protections meet the guidelines set by Title 38, part 16 of the U.S. Code of Federal Regulations, which aligns with Title 45, part 46, and Title 21, part 56. Similarly, committees like Independent Ethics Committees (IEC), which serve comparable purposes, are also categorized as IRBs.

• Responsibilities:

1. Protecting Trial Subjects: IRBs or IECs are responsible for ensuring the rights, safety, and overall well-being of individuals participating in trials, especially those belonging to vulnerable groups.
2. Document Review and Approval: These boards need to gather and review essential documents, including trial protocols, informed consent forms (and any updates), subject recruitment plans like advertisements, informational materials for participants, Investigator's Brochure (IB), safety details, compensation-related information, the investigator's qualifications, and other necessary documents for thorough evaluation. They must provide clear, written feedback, documenting approval, requested modifications, disapproval, or the suspension/termination of previous approvals.
3. Investigator Qualifications: They assess the investigator's credentials, supported by up-to-date CVs or other requested evidence, to ensure suitability for conducting the trial.
4. Ongoing Review: Trials are monitored at least annually, or more frequently if deemed necessary, depending on the level of risk posed to participants.
5. Additional Information: Any extra information required by the board should contribute meaningfully to protecting participants' rights and safety.
6. Non-Therapeutic Trials: When trials involve non-therapeutic procedures and require consent from legally acceptable representatives, IRBs/IECs must confirm that ethical concerns and regulatory standards are adequately addressed.
7. Emergency Situations: For trials where prior consent isn’t feasible, such as emergencies, the boards evaluate if ethical and regulatory requirements are fulfilled in the proposed protocols.
8. Payments to Participants: The boards examine payment methods and amounts to ensure participants are not subjected to coercion or undue influence. Payments should be distributed proportionately and not hinge entirely on trial completion.
9. Transparency in Payment: All payment-related details, including amounts, methods, schedules, and how they are prorated, should be clearly outlined in informed consent forms and other materials provided to participants.

• Composition:

An Independent Ethics Committee (IEC) is led by a chairperson who is independent of the institution and supported by a member secretary from a similar institution who oversees the committee's operations. The IEC consists of:

1. Chairperson
2. One or two professionals from basic life sciences
3. One or two clinicians from diverse institutes
4. A legal expert or retired judge
5. A social scientist or representative of a voluntary organization
6. A philosopher, ethicist, or theologian
7. A community representative (layperson)
8. Member Secretary

Meeting Requirements: A minimum quorum of five members is essential to proceed with a meeting. As specified by the revised Schedule Y of the Drugs and Cosmetics Act (amended in 2005), the quorum must include:

• A basic medical scientist (e.g., pharmacologist)
• A clinician
• A legal expert or retired judge
• A social scientist, representative of a voluntary organization, philosopher, ethicist, theologian, or similar individual
• A community representative

The members collectively aim to safeguard the well-being and interests of all parts of the community (14).

• Procedures:

1. Establishment and Composition: The IRB/IEC identifies its members, verifies their qualifications, and confirms the authority under which the committee is formed.
2. Meetings and Notifications: It schedules meetings, informs its members, and conducts these gatherings to review trial-related matters.
3. Initial and Ongoing Reviews: The committee undertakes both initial evaluations and periodic reviews of clinical trials.
4. Frequency of Reviews: It determines how often continuing reviews should be conducted, based on the specific risks associated with the trial.
5. Subject Enrolment: No participants may be enrolled in a trial until the IRB/IEC has issued its approval or favourable opinion.
6. Protocol Deviations: Investigators cannot make any changes or deviations to the trial protocol without first securing written approval from the IRB/IEC.
7. Reporting by Investigators: Investigators must promptly report the following to the IRB/IEC:
   • Any protocol deviations or modifications made to prevent immediate hazards to participants.
   • Changes that increase risks to participants or significantly affect the trial’s conduct.
   • Serious and unexpected adverse reactions observed during the trial.
   • New information that may negatively impact participant safety or the trial’s progress.

The procedures available for appealing the board’s decisions or opinions.This approach ensures trials are conducted ethically and participants' safety and rights are prioritized throughout the study.

Study Design and Methodology

The foundation of a successful clinical research study lies in its study design. Conducting clinical research demands a methodical approach that involves careful planning, precise execution, and strategic sampling. This ensures that the results are both trustworthy and validated. For researchers, a clear understanding of various research methodologies is crucial. The effective implementation of clinical research methodologies is influenced by several key elements, such as the study type, the objectives, the target population, the chosen study design, the techniques and methods applied, as well as the sampling strategies and statistical analyses employed (15).

1. Non-experimental Study Design: This type of research does not involve altering or controlling the independent variable. Instead, researchers observe and measure variables as they naturally occur, without any intervention. Non-experimental research is often chosen when a specific research question about a causal relationship between two variables is absent, or when manipulating the independent variable is not feasible.

This approach is particularly useful in the following scenarios:

• Participants cannot be randomly assigned to different groups or conditions.
• The research explores causal relationships, but the independent variable cannot be adjusted.
• The study is broad or exploratory in nature.
• The focus is on non-causal relationships between variables.
• Limited information is available about the topic being studied (16).

B. Cohort Studies- Cohort studies are research approaches designed to compare two distinct groups of participants—those who have a specific exposure or risk factor and those who do not—in order to investigate differences in the incidence of certain outcomes or diseases. The exposure being studied is clearly defined, but the potential outcomes can vary, allowing researchers to track multiple outcomes resulting from a single exposure. These studies can be either retrospective or prospective

• Retrospective Cohort Studies: These studies rely on historical data to identify groups of individuals who were exposed to the risk factor and those who were not. Researchers then assess whether these individuals had developed the disease or outcome by the time the study is conducted.
• Prospective Cohort Studies: These studies involve monitoring participants over a period of time, starting from the identification of the exposure or risk factor. Researchers follow these groups to observe the eventual development of the disease or outcome. While these studies provide valuable insights, they often require significant time and resources because outcomes may take years to manifest. Both retrospective and prospective cohort studies share a fundamental design principle: they aim to compare populations with and without the exposure or risk factor to track the development of specific outcomes or diseases.

C. Cross sectional studies- Cross-sectional studies involve conducting a one-time survey or observation of one or more groups of individuals. These studies primarily rely on surveys, making them ideal for measuring prevalence; however, they are not designed to identify causation. For example, researchers might use this approach to determine how common lung injuries are among patients with blunt chest trauma. This method can also be employed to explore the "natural history" of a condition, injury, or phenomenon by conducting multiple cross-sectional observations over time. The main strength of cross-sectional studies lies in their simplicity—they are straightforward to conduct while still offering higher quality data compared to retrospective studies. Additionally, they are particularly valuable for gathering preliminary information that can form the basis for more detailed and extensive research in the future.

2. Experimental study design-Experimental studies, also known as intervention studies, involve testing interventions through preclinical trials on animals and clinical trials in humans. These studies are designed to compare the impact of one intervention against another or against a placebo. This research approach provides researchers with a structured framework that enhances the clarity and transparency of their investigation, allowing them to achieve their research goals more effectively.

1. Randomised Clinical trial- Randomized clinical trials, also called parallel group randomized trials or randomized controlled trials (RCTs), are a widely used method in medical research. In these trials, participants are randomly divided into two groups: the experimental group and the control group. The experimental group receives the treatment being tested, while the control group may receive a different treatment, a placebo, or no treatment at all. This setup helps researchers assess the effectiveness of the new treatment. RCTs are commonly used in experimental clinical studies, involving either healthy volunteers or patients. Once a new drug successfully passes pre-clinical testing, RCTs are conducted to evaluate its safety and efficacy. However, organizing an RCT requires meticulous planning. Factors like study design, participant criteria, selection of the control group, randomization process, sampling methods, and whether treatments should be blinded or openly labelled all need careful consideration before the trial begins. This structured approach ensures reliable and meaningful results, contributing to advancements in medical science.

• Blinding: Blinding refers to the practice of hiding the assignment of participants to specific study groups in a clinical trial. It ensures that patients, observers, and researchers are unaware of who belongs to which group, reducing bias in the study. Randomized clinical trials can be either blinded or non-blinded, with blinding performed at the start of the experiment. There are three types of blinding:

• Single-blind trials: In these trials, participants (patients or healthy volunteers) are unaware of whether they are receiving the test treatment or a placebo.
• Double-blind trials: Here, neither the participants nor the researcher knows who is assigned to the control or experimental groups. Only the observer is aware of the group assignments.
• Triple-blind trials: In this case, none of the study participants—including subjects, observers, and researchers—knows the nature or labelling of the treatment being administered. This minimizes personal or intentional bias.

• Non- blinded Experiment- non-blinded experiments, also called open-label studies, are those in which all participants, including patients, physicians, observers, and researchers, are fully aware of the treatment being used. While this transparency can lead to bias, it is sometimes necessary due to ethical concerns. For instance, in situations where concealing a treatment is impractical or inappropriate, patients might even be allowed to choose the drug brand themselves. This balance between ethical considerations and reducing bias is essential in clinical research.

1. Quasi-experiments: These resemble randomized controlled trials in that the researcher assigns the intervention or treatment. However, participants are not randomly assigned to groups.
2. Field trials: These are extensive studies conducted to evaluate the effectiveness of interventions, such as the success of COVID-19 vaccines in preventing the disease. Because such trials often involve conditions with low disease occurrence in the population, large sample sizes are necessary to draw meaningful conclusions.
3. Community trials: In these studies, treatments or interventions are applied to entire communities rather than individuals. For example, to assess the impact of adding fluoride to drinking water, some communities were given fluoridated water, while others were not, allowing researchers to compare the outcomes between the groups.

Conduction of Clinical Trial

Clinical trials play a crucial role in advancing medical science by evaluating new treatments, techniques, and approaches. These studies aim to answer scientific questions while striving to find improved methods to prevent, diagnose, detect, or treat diseases. They often compare new treatments to existing ones to assess their effectiveness and safety. Broadly speaking, clinical trials involve structured research conducted on human participants to examine the safety and effectiveness of new drugs or medical interventions. In simpler terms, they are a series of tests carried out in medical research and drug development to gather data on how treatments impact humans. Clinical trials are regarded as the cornerstone of medical progress and the gold standard for evaluating potential advancements. These studies explore innovative approaches to preventing, diagnosing, or treating illnesses, as well as enhancing the overall quality of life. Clinical trials vary significantly in scope and cost, ranging from small, single-centre studies to expansive, multi-centre investigations conducted across several countries. Developing an approved drug can cost billions of dollars, reflecting the complexity and scale of such research efforts. Before any new drug can proceed to clinical trials, it must first undergo rigorous preclinical studies. These studies are conducted both in vitro, which refers to experiments carried out in a laboratory using test tubes or other controlled settings, and on animal subjects. A variety of dosages of the drug are administered either to these animal populations or to in-vitro substrates to gather essential preliminary data. This data typically includes information about the drug's effectiveness (efficacy), potential harmful effects (toxicity), and how it moves and behaves within a living system (pharmacokinetics) (18).

5.  Preclinical Studies-

Preclinical trials, also referred to as non-clinical studies, represent the initial stage of clinical research. This phase takes place before any testing on humans begins. During preclinical studies, a drug is developed and tested on cells and animals to predict its potential impact on the human body. These studies incorporate both in-vitro methods (experiments conducted in a lab setting, such as in test tubes) and in-vivo methods (tests involving living organisms, like animals or cell cultures). Key aspects of preclinical trials include:

• Laboratory experiments designed to assess whether a drug is effective and safe enough to progress to human testing. These are often conducted on animal models.
• The primary goal is to establish the drug's overall safety profile before moving forward.
• Initial experiments are commonly performed on small rodents, such as mice, rats, guinea pigs, or rabbits.
• Following successful outcomes, trials may advance to larger animals, including cats, dogs, or monkeys, for further evaluation.

5. Phases Of Clinical Trial-

1) Phase 0- Phase 0, also referred to as micro-dosing, is an early stage in drug development where a new drug is tested in very small doses before moving on to Phase I trials. In these trials, only a few individuals (around 10 to 15) are given sub-therapeutic doses of the drug. The goal is to collect initial information about how the drug behaves in the body (pharmacokinetics) and how it interacts with the body (pharmacodynamics). This approach helps researchers gather critical data without exposing participants to significant risks.

2) Phase I - Phase I trials mark the beginning of testing a drug in human participants. These studies typically involve a small group, generally 20 to 80 healthy volunteers. The primary goal is to evaluate the safety of the drug, including its tolerability, how it behaves in the body (pharmacokinetics), and its effects on the body (pharmacodynamics). To ensure close monitoring, these trials often take place in specialized inpatient clinics with full-time medical staff on hand. This phase also includes exploring the right dosage for effective treatment, commonly known as dose-ranging or dose escalation studies. Here, the range of doses tested is usually much lower than those shown to cause harm during earlier animal testing.

Phase I trials typically involve healthy volunteers. Within this phase, there are different types of trials:

• Single Ascending Dose Studies: In these studies, small groups of participants are given a single dose of the drug. They are monitored and tested over a set period of time. If no serious side effects are observed and the drug's behavior in the body aligns with predicted safety levels, the dose is gradually increased. A new group of participants receives the higher dose, and this process continues until either safety thresholds—determined through prior calculations—are reached or adverse side effects become intolerable. At this stage, the drug is considered to have reached its maximum tolerated dose (MTD).
• Multiple Ascending Dose Studies: These studies are conducted to gain deeper insights into how the drug acts in the body (pharmacokinetics) and its effects (pharmacodynamics) when administered in multiple doses.                                     

This systematic process helps researchers refine their understanding of the drug's safety and optimal dosage levels.

3)  Phase II - Phase II trials, often referred to as therapeutic exploration or dose-ranging studies, focus on further evaluating a drug's safety and determining its effectiveness. Unlike Phase I trials, these involve larger groups of participants—typically ranging from 100 to 400 patients—selected based on specific inclusion and exclusion criteria. The primary objectives are to establish the drug's therapeutic benefits, identify the appropriate dosage range, and assess its ceiling effect under controlled conditions. Tolerability and how the drug behaves within the body (pharmacokinetics) are also thoroughly examined. These trials may be conducted as either blinded studies, where participants and/or researchers do not know which treatment is being administered, or open-label studies, where the treatment details are fully disclosed. Generally carried out at two to four centres, Phase II trials can last anywhere from six months to several years. Unlike other phases, they do not use placebos or inactive treatments. Phase II trials are often split into two sub-phases: Phase IIA and Phase IIB. Phase IIA focuses on determining the optimal dosage—essentially, figuring out how much of the drug should be administered. On the other hand, Phase IIB concentrates on evaluating the drug's effectiveness, studying how well it works at the prescribed doses. These distinct stages help refine both the dosage and the therapeutic benefits of the drug.

4) Phase III - Phase III trials, often referred to as therapeutic confirmatory studies, and are designed to compare the effectiveness and safety of a new drug against the current standard-of-care treatment. These trials focus on determining which drug works better and evaluating the side effects of each. They involve large patient groups, typically ranging from 300 to 3,000 participants or even more, depending on the disease or medical condition under study. The trials are randomized, meaning participants are assigned to different treatment groups, known as trial arms, purely by chance. This randomization ensures that all groups are similar, allowing researchers to attribute the study results solely to the treatment itself rather than differences between the groups. A computer program is often used for this random assignment process. Phase III trials may include more than two treatment groups; the control group receives the standard treatment, while the other groups test the new drug. Participants, as well as their doctors, cannot choose their group, and they remain unaware of their group until the trial concludes. Every participant is closely monitored throughout the study, and the trial may be halted early if the new drug causes severe side effects or if one group shows significantly better results. Phase III trials are complex, costly, and time-intensive to design and conduct, particularly for treatments targeting chronic medical conditions. These trials are often a prerequisite for FDA approval, ensuring the drug is safe and effective for public use.

5) Phase IV - Phase IV trials, often referred to as Post Marketing Surveillance Trials, focus on monitoring the safety of a drug after it has been approved for sale. These trials involve pharmacovigilance—keeping a close watch on potential side effects—and providing ongoing technical support for the drug. Regulatory authorities may require these studies, or pharmaceutical companies may conduct them independently to explore new markets or address unresolved questions. For instance, the drug may not have been tested for interactions with other medications or for specific groups like pregnant women, who typically avoid participating in clinical trials. The primary goal of Phase IV trials is to identify rare or long-term side effects that may not have surfaced during earlier phases (Phases I-III) due to limited sample sizes or shorter trial durations. Phase IV trials play a vital role in identifying adverse drug reactions (ADRs), drug interactions, and even new applications for drugs. These trials begin immediately after the drug is introduced to the market. Their main objectives include:

• Verifying the drug's safety and effectiveness in real-world, large-scale populations.
• Detecting rare or previously unknown adverse reactions.
• Assessing the effects of over dosage.
• Discovering potential new uses for the drug.
• Refining treatment protocols, including exploring new formulations and optimizing dosages.

These studies are key to ensuring that the drug continues to meet safety and efficacy standards while potentially uncovering additional benefits or adjustments needed.

• Application Process

Before initiating investigational research, a formal request must be submitted to the relevant regulatory authorities. This research may involve exploring a new dosage form or identifying a new use for a drug that has already been approved for sale. Along with regulatory approval, the research protocol and informed consent documents must also receive authorization from an Institutional Review Board (IRB) or an Ethical Advisory Board. These measures ensure the study is conducted ethically and safely, with participants fully informed before consenting to participate. Applications like the New Drug Application (NDA) in the U.S. or the Marketing Authorization Application (MAA) in other countries are submitted to seek approval for marketing a new drug. These comprehensive documents compile all the data gathered during the drug development process, including evidence of the drug’s safety and effectiveness. Once preclinical and clinical testing is successfully completed, this series of documents is sent to regulatory agencies such as the FDA in the United States or the corresponding authority in other nations. The application must demonstrate convincing evidence that the drug will deliver the intended benefits when used under the recommended conditions. The process of obtaining approval to market a new drug typically takes anywhere from six months to two years.