October is Health Literacy Month, a time for people to promote the importance of understandable health information. Throughout the month, we defined terms that are frequently used in clinical trials, posting a new word with its definition each day on Twitter. But a deeper understanding of these words comes with knowing how they relate to each other.
Clinical trials are an essential part of the process of testing and evaluating investigational drugs. A drug enters into this stage of development only after years of testing in the lab in preclinical research. Before a drug is tested in people, researchers determine things like how the drug should be administered (for example, by mouth or as an injection), what the formulation should be (for example, as a liquid or a pill) and early assessments of the drug’s safety. Once these parameters are established, testing in people can begin.
Clinical research is a scientific endeavor, but at the heart of it all is people. The people who volunteer to participate in clinical trials are the most essential. Yet it takes many other people to provide support to them: principal investigators and study coordinators at clinical research sites, and researchers and business people at the study sponsor company.
Phases of Drug Development
The first tests in people are designed as Phase 1 studies. These trials are generally (though not always) conducted in healthy volunteers. One exception is in Phase 1 cancer clinical trials (read more about early phase cancer studies). The main endpoints measured in Phase 1 studies are things like pharmacokinetics—how the human body breaks down, absorbs and excretes the drug—and pharmacodynamics—how the drug affects the body. Usually, Phase 1 studies evaluate only one treatment or combination of treatments, so they use an open-label design, meaning the study participants and the clinic staff know the volunteers are receiving the investigational drug. When Phase 1 trials are complete, we learn things like the maximum tolerated dose (what’s the highest safe dose that can be administered?) and food effects (should this medication be taken with food or on an empty stomach?).
Once the basics of drug metabolism are established in Phase 1, Phase 2 trials can begin. In Phase 2, we measure whether the drug has the intended effect on the disease it is designed to treat. In addition to this first assessment of efficacy, we also refine the dose. Where Phase 1 trials mainly assess the safest tolerated dose, Phase 2 trials help define the lowest effective dose. At all phases of clinical research, we measure the incidence of adverse events—things like headaches, nausea or more serious reactions. These events help us better understand the drug’s safety profile.
Phase 3 trials, in which the investigational drug is administered to many hundreds or even thousands of people, are considered the gold standard of clinical research. They allow us to confirm any safety or efficacy effects noted in Phase 2. On the safety side, adverse events sometimes happen so rarely that we don’t realize they may be of concern until larger numbers of people take the drug. On the efficacy side, we want to confirm that any indication of efficacy noted in Phase 2 persists among larger groups of people. The outcome of a Phase 3 trial might be that the new drug is better, or we might find that the standard of care is better.
These studies are carefully designed to reduce bias and ensure that any differences we see in comparing one group to another are because of the effect of the drug and not some other variable. One way to reduce bias is to randomize study participants to either the investigational drug or the standard of care using a double-blind approach, meaning that neither the study participants nor the research staff know which treatment the patient is receiving. (Check out this brief video illustrating the concept of randomization.) The number of people enrolled and the endpoints measured in the trial are also carefully calculated to be able to show whether one treatment is statistically significantly better than another.
Once Phase 3 studies are completed, the results are analyzed and reported to the U.S. Food and Drug Administration (FDA) or other similar regulatory agencies in other countries. FDA reviews all the data and decides whether to approve the new drug as a prescription medication. Details from all the clinical research are provided in the patient leaflet. In some cases, FDA can require that additional studies of the drug be completed in Phase 4 trials, after the drug is on the market. These studies allow for continued careful monitoring of the drug’s effects.
Required Documentation
Every clinical trial, at every phase of development, must have a study protocol, which provides detailed information about the entry criteria, data collection methods and the outcomes being measured. Key features of the study protocol are available to the public on websites like Lilly TrialGuide and ClinicalTrials.gov. Every protocol is assessed by an Institutional Review Board (IRB), to ensure the rights and safety of study participants. The study cannot begin until the protocol is approved by both the IRB and FDA in the U.S. or other similar regulatory agencies in other countries.
Another key document required for every clinical trial is the informed consent form. These forms must also be reviewed and approved by the IRB, and each study participant must read and sign the consent before they can begin the trial. The informed consent document includes all the essential information that participants need to understand about the trial in order to decide if they want to participate. It helps participants understand, for example, things like which concomitant medications are allowed or not allowed during the study and whether the study requires a wash out period (read more about why wash out periods are needed). While informed consent itself is a process, the form provides the substance for the discussion and is an essential piece of the clinical trial.
Tips for Learning More
People who are considering participation in clinical trials can search for published information about investigational drugs in peer-reviewed medical journals and can use shared decision making principles in conversations with their doctor.
To learn more about clinical trials, check out "what to expect" on Lilly TrialGuide.