Phase IV
Phase IV clinical trials, also known as post-marketing surveillance trials, collect real-world data and occur after FDA drug approval. A Phase IV trial is typically part of a safety surveillance program (pharmacovigilance) once a drug is on the market. A Phase IV trial typically has the fewest risks for participants because the drug has been studied in several other earlier phase clinical trials. Typically, participants do not have to enroll in a Phase IV clinical trial, and they receive all of the usual disease treatments. Another advantage of a Phase IV trial is that it collects data from many different patient populations who receive care at dozens of different sites, thus increasing the robustness of the drug’s overall clinical trial data. A Phase IV study may be required by the FDA to fill in knowledge gaps, or it may be initiated by the sponsor to gather more information about the drug and how its use might be expanded. The goal of a Phase IV trial is to collect long-term safety and efficacy data in large groups of people and to identify rare adverse events that may not have been seen in smaller earlier phase studies. In addition, a sponsor may initiate a Phase IV trial to collect data to expand the label of the drug to different groups with the same disease or for new indications in other diseases with a similar pathophysiology, to obtain quality of life data, to evaluate drug-drug interactions, to compare the drug to other drugs on the market, and to analyze the cost-effectiveness of the drug. Because one of the goals is to collect information on rare adverse events, these trials often capture data on large numbers of study participants for long periods of time (2 to 5 years or more). For example, the Phase IV data from lumacaftor/ivacaftor demonstrated that 17% of people discontinued the drug within 6 months of starting it compared to only 4% of participants in the randomized control trials, and 39% of people with severe lung disease (FEV1 percent predicted < 40%) demonstrated higher rates of serious adverse events (39% vs. 17% in RCTs) and had higher rates of discontinuation of the drug(50). These examples highlight the importance of why sponsors must ensure a Phase IV trial is not under-powered. In addition, significant adverse events may be identified during a Phase IV trial that result in the drug being removed from the market.