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.