What does each phase of a clinical trial determine?


With increasing complications, there is always a need for a new treatment.But, before adopting a new treatment, it is necessary to assess its impact on the population’s general health. The investigators, researchers, and drug sponsors should know how the new drug interacts with the system. It is also crucial to make the new treatment better than the standard treatment. To analyze drug treatment outcomes, it should undergo pre-clinical trials in
animal cell lines in-vitro; and different phases of clinical trials in humans. Are all trials similar to each other, or does each phase of a clinical trial define some activity independently?

What is the process of treatment discovery?

“To come up with a new treatment, researchers first study the disease and hypothesize the treatments. Later, they test it for success and refine it to compensate for the lack of efficacy.”

Initially, they characterize the disease by observations. They highlight its signs and symptoms and eventually find the causative organism and its pathology. They study the further complications of animal cell lines in-vitro.

With this information in hand, they propose a potential treatment and evaluate its effect in vitro in various experiments.

The primary goal of all these experiments is to determine its pharmacokinetics (Drug absorption to elimination), pharmacodynamics (effects), and toxicology (effect on major organs).

The protocol

When the pre-clinical trials appear safe and promising, the drug sponsor submits an investigational new drug (IND) application. This approval gives them permission for phased human trials. If phased trials are safe, they again submit a new drug application (NDA). If the FDA approves the NDA, the company can release it into the market for use.

What are the 4 phases of clinical trials?

The four phases define the safety and efficacy of a maximum tolerated dose (MTD). The goal progresses from testing the safety to determining the efficacy and efficiency through various stages.

Phase I clinical trial

This trial is conducted in a small number of healthy and/or diseased volunteers. Besides, the subjects misinterpret this treatment to be therapeutic — they expect a direct medical benefit. It is the responsibility of the investigators for informed consent before the trials.

It determines the initial safety data. This trial prefers safety over efficacy and efficiency. Since the new drug is “first in human,” the first administration is very low. If the subjects express no severe side effects, they increase the dose.

The investigators constantly note down the pharmacokinetic data on single and repeated doses for further analysis. If subjects express severe toxicity, further trial is halted.

Phase II clinical trial

It includes a slightly larger sample administered with doses judged safe in phase I trial. The subjects usually have the disease of interest. However, they also collect safety data systematically, along with pharmacokinetics and pharmacodynamics. This trial explores the therapeutic effect of the treatment. 

They screen for the desired outcome or a biomarker of the desired effect and abandon those that fail to demonstrate the specific activity.

It expresses preliminary evidence of efficacy by comparing it with standard therapies, examining different doses within the trial, and randomizing subjects with control groups. If the drug is primarily tested for its safety, the focus on efficacy is limited and calls on the phase III trial for further investigation.

The basis of the primary outcome is the most indicative clinical measure, a measure that the treatment might affect. It is then compared to the standard treatment group.

Phase III clinical trial

This trial is a large confirmatory study that gives more room to analyze the rare adverse effects. It is the therapeutic confirmatory and comparative efficacy. The randomization starts in this phase (Randomized controlled trials – RCTs). 

They divide the subjects into two groups — one receives the new treatment, while the other gets the placebo. Placebo also looks like the new drug but will not have any effect. It eliminates the bias between the groups; also sheds light on the impact of psychology. 

The randomization is blinded to make it unbiased in the artificial setting — single (Subject only), or double (subject and investigator), or triple (subject, investigator, and data analyst) blinded.

If the drug qualifies this phase, it indicates the adoption of therapy. Sometimes, though it meets its outcome, the treatment may be more restrictive than it was initially proposed due to high toxicity.

For example, there are two subpopulations, A and B. If A and B met its outcome in the combined sample, and B did not have an acceptable outcome when analyzed alone, it indicates a more robust benefit to A. For safety concerns, the focus is on making sure not to adopt harmful treatments. So, A might receive the new treatment, but additional data is necessary to prove that it is beneficial for B.

Phase IV clinical trial

After a successful phase III, the drug enters into phase IV. It deals with drug marketing. The goal is to identify rare side effects, drug effectiveness and evaluate the cost. It focuses on efficiency using the clinical outcomes expressed by the individuals likely to receive the new treatment. 

Phases of clinical trials: Efficacy vs. effectiveness

Phase II trials define the efficacy — defined by the subset of patients who would eventually receive the treatment. The outcome is usually the clinical benefit. Before randomization, the subjects are found to tolerate the new treatment, are compliant with controlled procedures, and relatively more likely to have a beneficial treatment effect. 

However, the care the subjects receive may not be standard of care the patient would receive in the typical medical setting. The primary outcome may not be the clinical outcome because the measures and schedules do not coincide with usual practice.

Phase III expresses effectiveness, which is an improvement in “general health” — as a whole. It enrolls a sample representative who would eventually receive the treatment. The eligibility criteria does not include the disease unless it is the ultimate indication

It compares the new treatments to the ones that the patients would otherwise receive. It evaluates the other changes associated with the treatment, timing of treatment, and the method of measurement of the outcome.

Since clinical trials are necessary for the world’s general health, you could be contributing by signing up for a study from https://clinicaltrials.gov/.

Related: Why is the world waiting for a vaccine? How does it work?

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