From discovery to medicine
Part two: Before a new medication can be used in patients, it must go through a gauntlet of tests to ensure it is safe and effective

In the second installment in our multi-part series on how a new medication moves from the lab to the doctor’s office, we take a look at clinical trials, a crucial step in this process. Stay tuned for part three, which will explore the exciting clinical research spearheaded by Van Andel Research Institute scientists and collaborators.

Dr. James Lind (1761–1794) is widely considered to be the first person, or at least one of the first, to have run a controlled clinical trial. While working on the British naval ship Salisbury, Lind was shocked by the high prevalence and mortality of scurvy among the sailors, a condition marked by pain, fatigue, malaise, bleeding gums and rashes.

Earlier on, others had suggested that eating citrus fruits (vitamins were not yet understood) could prevent or cure scurvy. Lind decided to do an experiment. He took 12 sailors with scurvy and divided them into six pairs. Two of those pairs received citrus (oranges and lemons or cider). Other pairs received various non-citrus treatments including elixir of vitriol, vinegar, seawater and spicy paste with barley water. The two sailors given oranges and lemons made full, or near full, recoveries. Those who had cider showed some improvement, while the other groups showed none. Lind’s findings eventually led to a new way to treat and prevent scurvy, and greatly improved the lives of seafarers around the world.

Lind’s experiment, while simple by today’s standards, illustrates the overall aim of clinical research, which is to demonstrate the effectiveness and safety of a treatment, medical procedure or device in humans.

Today, clinical trials are a much more refined and regulated process that typically is broken into three phases, each serving a distinct purpose.

Phase I

Phase I clinical trials are the first time a drug is used in humans, and as such are designed primarily to test the safety of a drug by evaluating the side effects and working to determine the optimal dose for humans. Researchers may also look into whether there is any need to change how the drug is made (formulation). These trials can also evaluate pharmacokinetics (how the drug travels through and is excreted from the body) and pharmacodynamics (how a drug affects an organism).

Before a Phase I trial can begin, an Investigational New Drug application must be filed and approved by the U.S. Food and Drug Administration (FDA), the federal regulatory body in charge of ensuring medication safety.

Typically, a group of healthy volunteers (usually fewer than 100) is recruited to participate in the study, which is conducted in a specialized research facility where participants can be observed by clinical staff. However, in some populations where the need for a new treatment is dire, patients with the target disease also may be included. For example, an experimental medication may be given to patients with advanced cancer for whom other treatments have failed and no other options exist.

Phase II

After determining the safety and dose of a new drug, a full evaluation of its biological effect can begin. Phase II studies are larger, and typically involve between 100–300 patients. The ultimate goal of Phase II studies is to demonstrate that the treatment works as intended and/or to determine which dose enables the drug to work as expected, with minimal side effects. Thus, drug safety evaluations continue in Phase II, within the larger patient group. Most drug failures occur in Phase II, which is why these studies are seen as key turning points in the life of a developmental drug.

Phase II trials are often designed as randomized controlled trials, wherein some patients receive the experimental treatment, while others get either placebo, or an existing, standard-of-care treatment.

Phase III

Phase III trials assess the effectiveness of the drug in comparison to the best currently available treatment and are the final step before a new drug can enter the market. Phase III trials are randomized controlled trials, typically conducted on larger patient groups (300–3,000 or even more if required). Because the number of patients is much larger, they are often conducted in multiple clinical trial centers (e.g., hospitals) simultaneously (these are known as multi-center trials). These studies are much more expensive and take longer than the other stages.

In order for a drug to be approved by the FDA, a successful Phase III trial typically must be completed, and in some cases, two must be completed. There are also some scenarios in which a drug can be approved after a Phase II study, but that is usually in cases where there is a tremendous need and the Phase II study demonstrated convincing evidence that the drug is effective at treating the disease.

Once the Phase III trial is complete, and assuming the drug was successful from an effectiveness and safety standpoint, the data from all trial phases is compiled into a New Drug Application and sent to the FDA for approval or rejection. The FDA monitors the progress of the trials through each phase of development and has the ability to put a halt to the trials at any time if it deems the drug not safe. With the New Drug Application, the FDA reviews the data and the drug’s usefulness in comparison to existing products and ultimately determines if it should be approved. It also dictates the “label” for the drug, which outlines exactly what the product is approved to treat, and in which patients specifically. The FDA may decide, if the results of the clinical trials are not conclusive or are borderline, that further trials are be required.

On a final note, it’s important to remember that none of this would be possible, without clinical trial participants, who volunteer to be part of these efforts. Their decision to take part ultimately helps future patients by ensuring new therapies are safe and effective and that they make it into the doctor’s office.

To learn more about how Van Andel Research Institute’s supports clinical trials, please visit vai.org/clinical-trials.