Clinical trials are a vital part of the medical research process. They rank high on the hierarchy of scientific evidence. They help determine if new treatments for diseases are safe and effective. Clinical trials are classified into four phases, which vary in the number of participants, duration, and type of study design. The phases are sequential and each phase has a specific focus and purpose.

Phase I clinical trials are the first stage of testing a new drug or treatment in humans. The purpose of phase I clinical trials is to identify any major safety issues with the drug and to see how drugs are tolerated. The primary endpoints focus on pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetics is how the drug is absorbed, distributed, metabolized, and excreted out of the body while pharmacodynamics is how the drug interacts with the body. If possible, you can also try to determine the maximum tolerated dose (MTD).

The route of administration, chemical properties of the agent, and biophysical differences in the patient’s population all influence PK and PD profiles of an investigational agent. For example, Cytochrome p450 is an enzyme that plays a key role in drug metabolism, but there different genetic variations that influence how drugs are metabolized.

If you are a poor metabolizer, then the enzyme has low activity and unable to clear a medication into it’s inert metabolites. That means you’ll have to decrease the dose to get the appropriate therapeutic response. If you are a rapid metabolizer, the enzymes breakdown the medication too quickly and you’ll need to increase the dose to get an appropriate therapeutic dose.

Typically, Phase I studies begin with a starting dose determined by preclinical toxicology studies. The study is constructed with a Single Ascending Dose (SAD) where subjects are given a small dose and closely monitored. After each cohort, a Dose Escalation Meeting (DEM) is held to determine the safety profile of the investigational drug. If the drug is deemed safe then the study continues with a higher dose but kept at a single dose.

If successful, the trial proceeds into a Multiple Ascending Dose (MAD) study. This time around, subjects receive multiple doses throughout the study. They are similarly monitored for safety considerations. The starting dose is based on the results from the SAD study. There are safety assessments after each cohort to determine the safety and viability of the investigational agent.

Phase II is usually conducted with a slightly larger sample size to provide preliminary evidence of efficacy and dosing. It also contributes supplementary data on drug safety. Phase II usually involves the target population of the investigational agent. The data collected is used to further refine research methods and protocols for a phase III landmark trial. The viability of the investigational drug is usually determined in Phase II. Approximately 33% of drugs move on to the next phase.

Phase III clinical trials test whether the treatment is better than current standard treatments. They are typically large trials involving multiple study sites and a large patient population. Colloquially, Phase III trials are considered landmark studies that serves as a true evaluation of an investigational product’s efficacy. 

Phase IV clinical research studies are also referred to as post-market studies. They investigate how well the treatment works in different populations or with different doses or regimens.