As a patient advocate, anytime I’m asked to be part of a new project, my first questions center on expectations. What can I expect, and what will you expect from me? It’s intimidating, perhaps even unwise, to sign up for something without really understanding what both parties can anticipate. In any clinical trial, the informed consent process should give patients very specific details about what they can expect, but having a basic understanding of trials in general can also give patients and their loved ones a much better idea of what researchers hope to learn, and how that will affect the patients in the study.
Clinical trials are described in four phases, and each phase has a distinct purpose. Phase 1 trials evaluate the safety of the drug and determine a dose that should be given to patients going forward. Phase 2 studies examine whether the drug works. Phase 3 trials are often much larger and compare the new treatment with other options for the condition. Phase 4 trials are usually conducted after the drug’s approval, and involve the collection of extra data to more thoroughly monitor safety and efficacy of a new drug in more patients and over a longer term.
Phase 1: Is the Drug Safe? What Dose Should Patients Receive?
While most patients enrolling on a phase 1 clinical trial are hoping for some benefit of taking a new drug, whether or not the drug works is not the goal in this “first in human” phase. This phase is all about safety and dose finding.
The first patients in a phase 1 trial are assigned a dose that is a fraction of what could safely be given to animals in preclinical studies (the laboratory studies where researchers learn more about drugs in animals before giving them to humans). As each group tolerates treatment with, at most, minimal side effects, the next group is given a higher dose. When too many patients experience serious side effects, the researchers say they have reached the maximum tolerated dose (MTD), which will be used to guide dosing decisions in subsequent trials. Researchers also study the pharmacokinetics (PK) of the drug — what the body does to the drug, how the drug is processed. They study how the body absorbs, distributes, metabolizes, and excretes the drug. And, they look at the pharmacodynamics (PD) of the drug — what the drug does to the body. Assessing blood counts, biomarkers, imaging, and side effects is important at each dose level.
The outcome of this phase is to determine the dose that should be used in trials going forward, and it gives doctors a better idea of what side effects to expect as they begin to treat more patients in future clinical trials. Patients on a phase 1 trial are monitored very closely to assess safety endpoints, PK, and PD, and so multiple visits to the clinic and many blood draws should be expected. If you are participating in a phase 1 trial, an important thing to remember is that some of the earliest patients on the trial receive a very low dose, which is unlikely to actually benefit the patient. In addition, some receive a very high dose that could lead to severe side effects. For this reason, especially in phase 1 trials, there are usually very specific stoppage rules in place so that if the side effects are too severe, the trial can be ended for the safety of the patients.
Phase 2: Is the Drug Effective?
Phase 2 actually starts getting at the question that most patients are interested in — does the drug work? In a phase 2 study, safety is still monitored, but therapeutic value is now the primary endpoint, therefore these trials focus on the patients who would ultimately receive the drug if it were approved. The researchers are looking for even small signs of benefit to the patients, as those on a phase 2 trial may have disease that has worsened on standard treatments, and so are harder to treat. This is the point at which investigators have to decide if they go ahead to much bigger and more expensive phase 3 trials, or abandon ship and divert resources to other drugs.
Phase 3: Is the Drug Better Than Other Available Options?
Phase 3 trials are much bigger and more expensive (upwards of $100K per patient by some industry estimates). They need to involve lots of patients in the ultimate target population to see if the new drug is better than the standard treatment or another option being considered. The gold standard for a phase 3 trial is the randomized control trial where patients are randomly assigned to receive either standard care or the investigational drug. This helps investigators determine whether the drug improves outcomes for patients. The FDA makes decisions on approval of the drug after the completion of one or more phase 3 trials.
Phase 4: What Happens After the Drug is Approved?
Sometimes, after analyzing the data from the first three phases of clinical trials, the FDA will approve a drug, but ask for a phase 4 trial where the sponsor follows patients who are prescribed the drug after its approval. This is also called a post-marketing study because it is used to learn more about a drug after it has been approved and is being marketed to patients. In order to be part of a clinical trial, patients must usually be relatively healthy, with few health problems apart from the one that’s landed them on the clinical trial. Once it’s approved, though, a drug is given to patients with many more health issues, and so a phase 4 trial allows the investigators to follow any adverse effects that were unexpected based on the initial trial population. It also allows the investigators to follow patients longer and monitor for side effects that might not become evident until long after the completion of treatment.
If you or someone you love is considering a clinical trial, you have the potential to be a critical part of a very important process! Still, it’s so important to know what to expect as a result of enrolling in the trial, and understanding the process can give you a lot more confidence as you decide whether being part of a clinical trial is the right decision for you. Not only can clinical trials be a great care option for some, but participants in a clinical trial are part of a living legacy for generations to come. They leave a gift to grateful patients just like me, whose clinical care was shaped by the clinical trial process.