From Randomization to Regulation: Navigating the Landscape of Clinical Trials

1. Introduction and Background

A clinical trial is a structured approach used to evaluate the safety, effectiveness, and potential benefits of a drug or medical device in the treatment, prevention, or diagnosis of diseases or health conditions [1,2] Clinical trials are typically divided into different phases: Phase 0 (micro-dosing), Phase 1, Phase 2, Phase 3, and Phase 4 [3]. Among these, Phases 0 and 2 are considered exploratory, while Phase 1 is often referred to as the non-therapeutic stage. Phase 3 is known for confirming therapeutic effectiveness, and Phase 4 focuses on monitoring the drug’s safety and efficacy after it has been approved for market use.

Phase 0, also known as the micro-dosing phase, was traditionally conducted on animals. However, it is now performed in human volunteers to gather preliminary information about pharmacokinetics and dose tolerability before progressing to Phase 1, which involves healthy subjects. A summary of the various phases of clinical trials is presented in Table 1.

2. The Phases, Types, and Nature of Clinical Trial Studies [4,5]

Clinical trials are divided into different phases, each designed to evaluate specific aspects of a new drug’s development.

Phase 0

Phase 0 is a preliminary exploratory stage where extremely low doses (about 1/100th of the therapeutic dose) are administered to a small number of human volunteers. The aim is to understand the drug’s pharmacokinetics and to inform dosing for later phases. While such studies were previously conducted only on animals, they are now carried out in humans.

Phase I

Phase I trials, which are non-therapeutic, involve fewer than 50 healthy volunteers and focus on determining the safety profile, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of the drug. These trials are often conducted at a single site. Phase Ia includes single ascending dose (SAD) studies to identify MTD using groups of 3–6 participants. Phase Ib involves multiple ascending dose (MAD) studies where the dosing is refined, typically using three groups of eight individuals.

Phase II

Phase II trials are exploratory and include 5 to 100 patients, aiming to establish the effective therapeutic dose and assess the drug’s efficacy. These trials often involve multiple centers. Phase IIa determines the ideal dosage over a few weeks or months in about 20–30 patients. Phase IIb explores the dose-response relationship, drug interactions, and comparisons with placebo.

Phase III

Phase III trials are confirmatory and involve a large number of participants, usually between 300 to 3000, across multiple centers. This stage confirms the drug’s effectiveness and safety in a larger patient population. The drug is compared to existing treatments or placebos, and any side effects or adverse reactions are recorded. This phase also prepares the drug for submission to regulatory authorities such as the FDA through a New Drug Application (NDA).

Phase IV

Phase IV is the post-marketing phase, carried out after regulatory approval. It involves long-term monitoring of the drug in a wider population to detect rare or delayed side effects and interactions with other medications, ensuring continued safety and efficacy during general use.

Clinical trial designs, their advantages, and disadvantages [6,7,8]

In clinical trials, different study designs are selected based on the research objectives and the type of condition being examined.

Parallel Randomized Design

One of the most widely used methods is the parallel randomized design, where participants are assigned to separate groups, each receiving either the investigational treatment or a placebo (an inactive substance). A downside of this design is that the placebo group does not get the actual treatment, potentially missing out on its therapeutic effects.

Crossover Randomized Design

The crossover randomized design involves participants receiving all treatments at different periods, allowing each person to act as their own control. This method minimizes bias and is efficient in terms of sample size, but it is generally not appropriate for conditions that require urgent or immediate treatment.

Factorial Design

A factorial design, which may or may not be randomized, examines the effect of two or more interventions simultaneously. It can reveal how treatments interact with one another, but its complex structure can make analysis and interpretation challenging.

Randomized Withdrawal Design

In the randomized withdrawal design, participants begin with the active treatment, and some are later switched to a placebo. This helps evaluate how long the treatment remains effective, especially for chronic conditions.

Matched Pairs Design

Lastly, the matched pairs design is often used in post-marketing studies. It involves pairing participants with similar characteristics to reduce variability and enhance the accuracy of treatment comparisons.

3. Different Types of Randomizations in Clinical Trials [9,10,11]

Various types of randomization methods are used in clinical trials to reduce bias and ensure balanced treatment groups.

Simple Randomization

In simple randomization, participants are assigned randomly to treatment or control groups using methods like coin tossing or computer-generated sequences. This approach is straightforward but may sometimes result in unequal group sizes, especially in small samples.

Block Randomization

Block randomization ensures that treatment and control groups remain balanced in size by dividing participants into small blocks, within which equal numbers are assigned to each group. This method is especially helpful in trials with smaller sample sizes.

Stratified Randomization

In stratified randomization, participants are grouped based on certain characteristics—such as age or disease severity—before being randomly assigned to different treatment arms. This ensures that these key variables are evenly distributed across groups.

Covariate Adaptive Randomization

Covariate adaptive randomization, also called minimization, is a dynamic method where each new participant is assigned to a treatment group in a way that balances selected covariates across groups. It helps maintain comparability between groups as the trial progresses.

Split-Body Trials

Split-body trials, or randomization by body halves or paired organs, involve applying one treatment to one side of the body (e.g., one arm or one eye) and a different treatment or control to the other. This allows for direct comparison within the same individual, minimizing inter-personal variation.

Cluster Randomization

In cluster randomization, entire groups or clusters—such as hospitals, schools, or communities—are randomized rather than individuals. This is particularly useful when the intervention could spill over to others in the same setting, preventing contamination.

Randomized Consent Design

Lastly, randomized consent design, also known as Zelen’s design, involves assigning patients to a treatment arm before obtaining their consent. This can reduce selection bias and enhance recruitment but raises ethical concerns, especially when consent is sought only after randomization.

4. Clinical Trial Methods and Terminologies [12,13]

Clinical trials can be categorized based on how they are designed and executed.

Randomized Clinical Trial

In a randomized clinical trial, participants are assigned to different treatment groups through a random process, which helps eliminate selection bias and ensures fairness in comparison.

Open-Label

An open-label trial is one in which both the researcher and the participant are fully aware of the treatment being administered, making the process transparent but potentially introducing some bias.

Single-Blind Study

In a single-blind study, the participant does not know whether they are receiving the experimental treatment or a control, helping to reduce expectation-related bias.

Double-Blind Trial

A double-blind trial takes this a step further by keeping both the participants and the investigators unaware of the treatment allocations, which enhances the objectivity of the study outcomes.

Placebo

A placebo is a substance designed to look like the actual medication but contains no active ingredients; it is used to measure the true effect of the experimental drug.

Add-On

In add-on studies, a second medication is provided along with the study drug to some participants, allowing researchers to observe any potential combined effects or improvements in therapy.

Single-Center Studies

Single-center studies are carried out at one research site, which can make monitoring and coordination easier but may limit the diversity of the participant pool.

Multi-Center

In contrast, multi-center studies take place across several sites or institutions, allowing for more varied participant demographics and broader applicability of the results.

5. Ethics and Concerns in Clinical Trial/Research [14−20]

Ethical conduct is a cornerstone of clinical research due to the involvement of both human participants and animals. The significance of ethics in medical research became more evident after the unethical treatment of war prisoners in experiments following World War II. To address such abuses, the Nuremberg Code was established in 1947. This code laid out specific ethical standards for conducting medical experiments on humans. One of its primary requirements is obtaining voluntary informed consent from all research participants. Individuals involved must be fully informed about the purpose, expected duration, procedures, and any known or potential risks related to the study. They also reserve the right to withdraw from the study at any time and to consult a doctor in case of any health complications.

Other key points from the Nuremberg Code include ensuring that the research offers benefits to society, that it is based on prior animal research for justification, that it avoids unnecessary harm or discomfort, and that the risks involved do not threaten the lives of participants. The code emphasizes human welfare, proper medical care for those involved, and the involvement of only well-qualified researchers.

In 1964, during the 18th meeting of the World Medical Association in Helsinki, Finland, further ethical principles were introduced—now known as the Declaration of Helsinki. This document reinforced the idea that the rights and welfare of human subjects must always take priority over the interests of science or society. Subsequently, in 1974, the United States introduced the National Research Act, mandating that all human research proposals be reviewed by Institutional Review Boards (IRBs) to ensure ethical standards are met.

Later, in 1979, the Belmont Report was issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This report identified three core ethical principles: respect for persons, beneficence, and justice. These principles serve as the foundation for ethical decision-making in clinical studies involving human subjects.

On a global level, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) developed the Good Clinical Practice (GCP) guidelines. These were introduced in 1991 in Brussels as a joint effort among the USA, Europe, and Japan to establish unified standards for drug development and testing. ICH conferences, held biennially, bring together representatives from member countries, regulatory bodies such as the WHO and EFTA, and stakeholders from both academia and the pharmaceutical industry. The goal of ICH is to maintain high standards in terms of drug safety, quality, and efficacy.

Despite existing guidelines like the Nuremberg Code, Belmont Report, and ICH-GCP, additional ethical protections were deemed necessary. In 1982, the Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the WHO, introduced ethical guidelines specifically for biomedical research involving human subjects. These guidelines pay special attention to protecting vulnerable populations and promoting ethical research practices, especially in developing countries.

In the Indian context, the Indian Council of Medical Research (ICMR) released ethical guidelines for biomedical research involving humans in 2000, later updated in 2006. As of 2013, any clinical trial conducted in India must be approved by an IRB that is recognized by the Drug Controller General of India (DCGI), ensuring greater accountability and adherence to ethical standards.