Table of Contents

Chapter 10: Participating in Clinical Trials

a. The Phases of Clinical Trial Development

Before a new therapy can be approved for use by the FDA, it goes through three different types of clinical trials in people to determine whether it is safe, whether it is effective in the disease for which it’s being tested, and whether it is at least as good—if not better—than what’s already being used. It typically takes up to eight years to go through the three different steps. In some cases, it can take less time, but can also often take much longer.

Before the therapy gets to the point of being tested in people, there can be years and years of preclinical work, which tests it in vitro, in the lab using cells in a test tube, and in vivo, in animals. Although researchers usually have a general idea of how the therapy works based on earlier experience, they often don’t know exactly how well it will work against different types of cancers. Animal studies, in particular, can be important, because unlike cancers in humans, cancers in animals can grow very rapidly, so the results of the research can be realized quickly. Preclinical studies are therefore often used to get a better sense of exactly how the drug works so the researchers will have more insight into where it might work.

Once a new therapy has been shown in the lab to stop the growth of cancer cells or to slow them down, it will be first tested in human in what is known as a phase 1 clinical trial.

The phase 1 clinical trial for the new therapy will be designed to see whether it is safe in people with different types of cancer. The lab work might have shown that the drug can stop one particular step in cancer cell growth, but that step might be important to the growth of breast, colon, and prostate cancers. So researchers will give the therapy to a group of people with different types of cancers, carefully monitoring its effects on the tumors, and gaining further insight into where it might prove most effective. There are usually 10-20 people enrolled in this type of study, so that just a handful of people have each of the different cancer types being tested.

It is at this phase of clinical development where the dosages of the drug are worked out as well. Figuring out the optimal dose can be tricky: a higher dose might kill more cancer cells, but it might also cause more side effects. With any therapy, there’s always a trade-off between safety and efficacy, and researchers—and the FDA—know that most people would be willing to put up with some significant side effects if it means that the therapy can beat back their cancer. But striking exactly the right balance between the two is very difficult, and many drugs that don’t make it to the clinic ultimately fail because the side effects outweigh the benefit.

Enrolling in a phase 1 trial sounds risky and very experimental, but a new therapeutic regimen will only make it to a phase 1 study if both the researchers and the FDA believe that there is a good chance it’ll be effective in people with cancer.

If the new therapy was shown to be safe and a safe dose is determined, it can move on to the next step. Typically, the phase 2 trial of the new therapy would enroll 50-250 people with one type of cancer from different institutions, all of whom would receive the study drug at the dosage that was established during the phase 1 trial. The goal of this step is to determine how effective the therapy is in a particular disease setting, and to get a better sense of its side effects. Although the therapy was deemed safe to move ahead after the phase 1 study, it is assumed that additional side effects will show up when given to a larger group, so the study participants are monitored very carefully to see how they react to it.

If it passes through the phase 2 trial and is shown to be effective at slowing or stopping cancer growth with no or few unexpected or severe side effects, the therapy can move to the next step. The phase 3 clinical trial is typically the most robust, and can have anywhere from 100 to 1000 people or more enrolled in the study at 10-50 or more institutions. The goal of this trial is to determine whether the new therapy is at least as effective—if not more effective—than the current standard of care.

In some cases, there is no accepted form of therapy for a particular type of cancer, so the new therapy will be tested against best supportive care, which might include ensuring adequate fluids, rest, and pain medications. This was more commonly seen in the late 1980s and early 1990s. But since then, the drug development process has advanced far enough in most cancers that there is usually at least one therapy or therapy regimen that is considered the standard of care against which any new therapy is tested.

However, if active surveillance is the standard of care, such as when your PSA is rising during hormone therapy but no metastases have been detected, a new therapy might be tested against a placebo, an inactive treatment that looks similar to the treatment being tested. The goal of a placebo-controlled trial in this setting is to determine whether the new therapy being tested is better than active surveillance.

In order to test whether a new therapy is better than the old, the entire study group is typically divided in half,with one half receiving the new therapy and the other half receiving the old. The rates at which the two study groups respond to the two different drugs are then compared.

Once results from all studies of the new therapy are in, the FDA reviews the data and considers whether the availability of the new drug will improve outcomes in people with cancer.

If the answer is yes, the therapy will be approved, and the label or prescribing information will be written. The label gives very specific instructions to doctors about how the therapy works and how it should be given, so doctors can know how best to use it. (This is why the use of a drug for a disease other than for what it was approved is known as an off-label use—it’s not being used as written in the drug’s label.)

Because new cancer drugs are so desperately needed, even if the FDA isn’t convinced that there is enough evidence of a benefit to warrant approval, it’s unlikely that the drug will be tossed out completely. Rather, the FDA will mandate additional clinical trials to better assess its efficacy. For example, a trial for a new prostate cancer therapy might show that it is more useful in men with particular tumor characteristics, like Gleason scores less than 7, or in men with specific clinical characteristics, like age younger than 70. In these cases, the FDA will require additional studies to see whether a particular group of men can be identified as the optimal group to receive the therapy.

Even if the drug is approved, that doesn’t mean the testing is over. The FDA might be concerned about a particular set of side effects, and will therefore mandate that phase 4, or post-marketing, clinical trials be conducted. Most often, the results from these studies will result in minor changes to the label, giving doctors more information about the way people react to the therapy and what sort of side effects they should be looking out for.

Not all therapies go through these studies in exactly the same way. There can be a combination phase 1 and phase 2 trial; a phase 2 trial that’s designed more like a phase 3 trial and that compares two different therapies in two groups of people; a phase 3 trial in which the two groups are intentionally divided unevenly; a phase 3 trial in which more than one regimen of a new therapy is tested against the old drug; or a phase 3 trial that compares three different therapies against each other. But regardless of how the trials are designed, they all have to prove the same three elements: that the new therapy is safe, that it is effective in the disease for which it’s being tested, and that it is at least as good—if not better—than what’s already being used.