Clinical trials are conducted to collect data regarding the safety and efficacy of new medication, health care processes and/or devices. There are several steps and stages of approval in the clinical trial process before a medication, process or device can be implemented in the regular treatment guidelines of a particular disease.
Medication, process or device development usually starts with the search for an improved treatment option with better outcome than the one in place. This development begins with extensive laboratory research, which can take many years of experiments in animal and human cells. If the initial laboratory research is successful, researches send the data to the competent healthcare authorities to obtain approval to continue the research in humans.
After approval, human testing can start and is mostly conducted in four phases (for medication, and at least three for devices and processes). Each phase is considered a separate trial and, after completion of a phase, investigators are required to submit their data again for approval to the competent authorities, before moving to the next phase. In this way, each step or phase builds on the results of the previous phase (see figure for visualization).
Phase I: is it safe?
Phase I trials assess the safety of a drug process or device. It is the first phase that involves humans. (Preclinical studies on petri dishes and animals have already been carried out.) Phase I studies are small and usually involve between 15 and 50 healthy volunteers. In phase I studies, researchers investigate:
- the best way to give a new treatment (as an injection or as a pill)
- how the drug is absorbed, metabolized and excreted in humans
- the highest dose that can be administered safely without serious side effects.
In phase I studies, researchers closely monitor participants and titrate the dose so they can define the amount that works best with the least acceptable side effects. This dose is usually used for all future tests in the subsequent phases.
Phase II: does it work?
Phase II studies test the efficacy of the new intervention. Phase II trials are slightly larger than Phase I trials and typically involve 25 to 200 patients. Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Researchers start with the dose and method proved best in Phase I. Phase II patients receive the new treatment and researchers observe whether the treatment is beneficial. The benefits that researchers are looking for may vary and depends on the objectives of the research:
- tumor is getting smaller
- tumor stops growing
- an increase in time before the cancer comes back
- longer survival time
- better quality of life
If a certain percentage of participants benefit from the treatment and the side effects are still acceptable, the new treatment will likely move to phase III.
Phase III: is it better than the current treatment options?
Phase III studies compare the safety and effectiveness of the new treatment with the current standard of care. Phase III studies are typically large (some include tens of thousands of participants) and are conducted at many locations (multi-centered) and often in different countries around the world (European, International, Global). A phase III trial is the final step before the competent authorities consider approval and grant market access.
Patients are usually randomly selected to receive the current standard treatment or the new treatment. If possible, the study is double-blinded, meaning that neither the researchers nor the participants know who receives which treatment. Double-blinded clinical trials help researchers understand the real benefits and side effects of treatment without distortion by external influences. Results from a randomized, double-blinded study are considered more credible than results from a non-randomized or double-blinded study.
As in Phase I and Phase II studies, participants in a Phase III trial are closely monitored to determine if there are any serious side effects. Treatment is stopped if side effects appear dangerous.
Phase IV: is it still beneficial over a longer period of time?
Phase IV studies, also called Post Marketing Surveillance Trials, typically review whether the treatment offers benefits or long-term side effects that have not been studied or observed during Phase II or Phase III. Phase IV studies are typically conducted after an intervention or treatment has been approved for use by the competent authorities. Phase IV studies are rarer than Phase I, II, or III studies and affect usually hundreds of thousands of patients addressing mainly the following:
- comparison to drugs already on the market or new treatment options.
- monitoring long-term effectiveness and impact on a patient's quality of life
- determine the cost-effectiveness relative to other traditional and new therapies.
Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study.