Clinical Trials: What are they and why are there “phases” to trials?

by John Stacy

Clinical trials differ from “pre-clinical” studies in that they involve human subjects. Often trials test new drugs, new combinations of drugs, new medical devices or surgical methods. They can also be designed to find new ways to use existing treatments or how to change behaviours to improve health quality of life.

Clinical trials help discover whether new treatment, prevention, and behavioural approaches are safe and effective in human volunteers. The first patients to receive a break-through treatment are the participants in trials where these treatments are tested. Clinical trials offer hope for many people and a chance to help researchers find better treatments for others in the future.

In the United States, clinical trials are a legally required pathway for a new drug, diagnostic test or medical device. That is, only those products that have received a license can be legally sold for the purpose of treating human disease. There are similar laws in this regard in most nations of the world. Agencies such as the FDA in the United States or the EMA in the European Union decide whether a medical product receives a licens to be used.  

In order for a product (i.e. drug, test, device, etc.) to be approved by the FDA or EMA, it has to move through three phases of trials (phase 1 to 3). There are usually several distinct trials of a product within each trial phase. Each trial is a study with in its own predefined experimental design. The institutions sponsoring trials will decide as these progress whether to continue with the product or to withdraw it from the process. If all three trial phases are completed to the satisfaction of the sponsor, the results of each trial (along with all supporting preclinical data) will be submitted to the agency to be evaluated.  

Phase 1: These are generally trials of a product (most often a drug candidate) previously untested in humans. There are usually only a couple of trials planned per new product, and only a small number of participants are recruited per trial (no absolute rule but usually around 20 to 30). They are designed to document side-effects (establish safety), discover optimum dosing and may also measure drug excretion and metabolism.  

Phase 1/2: Trials may be designed to move patients through a process depending on results. These may in effect bridge phases 1 and 2.  

Phase 2: Effectiveness is the outcome measure under focus in phase 2 trials. At this level, the drug being tested is usually compared to other therapeutic approaches. Phase 2 trials usually recruit upward of 100 participants.  

Phase 3: Once phase 1 and 2 trials have established safety and efficacy to the satisfaction of trial sponsors, they may decide to continue with the new drug to phase 3. At this level the aim is to see if what was learned in phases 1 and 2 holds in a larger group (often more than 1000 participants).  

Phase 4: Yes, there are “aftermarket” studies of drugs and other medical products that are already licensed for sale by the FDA or relevant agency. Here the point may be to continue to gather efficacy and safety data from the regular use of the drug (and in some cases other products). These studies can open up new insight into how the therapy might be best used. In some rare cases, phase 4 may discover safety or efficacy concerns that cause approval to be withdrawn.  

Phase not applicable: These are trials without FDA-defined phases, including trials of devices or behavioural interventions that are not seeking approval for marketing. There are a large number of trials that fall into this category. Some of these trials test aspects of treatments such as how instructions are  communicated or how a given procedure performs under different circumstances, etc.

Trial eligibility: Sponsors of clinical trials absolutely want participants, but that doesn't mean each case fits their need. Trial descriptions list specific criteria for the inclusion or exclusion of participants. The guiding principle to these criteria is that a participant should at least have some possibility of successful treatment with the therapy being tested.