Clinical Trials

Phase 1 studies are the initial introduction of an investigational drug into humans. Participants usually comprise a small group of healthy volunteers who are closely monitored, ideally in a hospital setting. Phase 1 studies are typically conducted as “open-label” studies that are not randomized, blinded, or controlled. 

Dose escalation schemes are employed to examine the short-term toxicity and define the maximum tolerated dose. Side effects are monitored as dosage increases. The long-term toxicity, however, is not yet identified at this point of the investigation. 

Phase 1 studies also determine the pharmacokinetics of the drug in humans. Drug concentrations are measured by obtaining blood samples at specified time intervals and collecting urine or other body fluids or tissues. Assessment of pharmacodynamics is done through the measurement of laboratory tests, noninvasive tests, vital signs, and other clinical assessments. The pharmacokinetic and pharmacodynamic data give researchers an idea of the dose range for efficacy testing in later, phase 2 trials.

One of the projects of the Anti-Dengue Drug Development program is a Phase 1 safety and dose-escalation trial conducted by Pharmalytics Corporation which administered a fixed-dose combination capsule of select herbal plants. After the establishment of the safety and tolerability of the drug, the study proceeded to the phase 2/3 trial which aims to determine the safety and efficacy of the drug in the treatment of dengue without warning signs.

Phase 2 clinical trials occur once the initial safety of the study drug has been confirmed in Phase 1 trials. Phase 2 trials are performed on larger groups of participants (up to a few hundred) with the disease or condition under study to assess how well the treatment works, as well as to continue assessments on safety and toxicity in Phase 1 studies. A key focus of Phase 2 studies is determining the optimal dose of a drug candidate in order to determine how best to administer the drug to maximize possible benefits while minimizing risks.

Most phase 2 studies are randomized and are often double-blind. Randomization means that participants are assigned randomly to receive either the experimental treatment or a placebo (treatment or substance with no therapeutic value). Those who receive the placebo are called the control group. Meanwhile, double-blinding means that treatment allocation is not known to both participant and physician.

Since larger numbers of participants receive treatment in phase 2 studies than in phase I studies, there is a greater chance to observe and compile adverse effect/adverse drug reaction information.

Phase 3 clinical trials are large confirmatory studies meant to establish the treatment’s safety and efficacy in order to gain regulatory approval for a precisely defined indication. Evidence from phase III studies that strongly support the proposed indication will generally lead to the adoption of therapy. 

Phase 3 study designs are mostly randomized and double-blinded. Sample sizes usually range from hundreds to thousands to have a high probability of ruling out the possibility of ineffective therapies and to estimate the treatment effect with high statistical precision. Since phase 3 employs a larger sample size, there is a better opportunity to detect rare serious toxicities. 

Once safety and efficacy are demonstrated, the sponsor can submit a New Drug Application (NDA), which contains all of the data and information gathered at every phase of the trial, as well as other information required by the applicable regulatory authority. The NDA is submitted to the FDA for consideration for marketing approval.

Phase 4 clinical trials are post-marketing trials that take place after the FDA has issued regulatory approval for use of the treatment. Guidelines on revised post-marketing surveillance requirements are detailed in FDA Circular No. 2021-020. 

A treatment’s effectiveness and safety are monitored in large, diverse populations. This way, rare but serious adverse effects that cannot be assessed in smaller phase 3 studies can be evaluated. 

It is important to distinguish between the efficacy and the effectiveness of an intervention. Efficacy is defined by how the intervention performs in ideal and controlled conditions, such as in phase 1 to 3 clinical trials, as opposed to effectiveness which refers to how well an intervention works in real-world conditions. While phase 3 trials focus on efficacy by demonstrating the treatment benefit of prevention through some surrogate biomarker of the disease, phase IV trials focus on effectiveness by using the clinically relevant outcome in a population-based sample of individuals who receive the adopted treatment. Since populations are not homogenous in their characteristics and individual behavior affects the efficacy of treatment, postmarketing trials also seek to evaluate these factors.