Clinical Trial Phases, the Drug Approval Process, and Measuring Responses

This content was current as of the date it was released. In science and medicine, information is constantly changing and may become out-of-date as new data emerge.

Phase I Trial – Is the drug safe and what’s the best dose?

These are often the “first in human” clinical trials. There is no placebo arm. They tend to be small, with only a few dozen patients. The first few people in the study often get a very low dose of the treatment and are closely monitored. If there are no significant problems, the next group gets a higher dose. This process continues until a dose is found that is most likely to work while having an acceptable level of side effects. Because the numbers are small, some side effects may not be appreciated until more patients have used the drug. Phase I trials are specifically designed to check for safety, but efficacy is also important, especially with the final dosage that will be used in further trials. These trials are the highest risk for patients, as little is known about the safety and efficacy of the drug.


Phase II Trial – Does the drug work?

Phase II trials are medium size trials where there is no placebo or control arm and patients will always get the novel drug. There can be different arms using different combinations or sequencing of the drugs. These trials may look at response rates and survival outcomes.


Phase III Trial – Is it better than the standard of care?

Phase III trials are much longer trials, often involving several hundred participants and conducted at multiple sites where there is randomization to either a control arm of “standard of care” or the new therapy. Placebos may be used in some Phase III studies, but only if there is no other effective treatment option available, meaning that no treatment that would qualify as the “standard of care”. Some Phase III trials allow “crossover” where patients who progress on one arm may crossover to the other arm.


Submission for FDA approval – New drug application (NDA)

In the USA, when Phase III clinical trials, or sometimes after very strongly positive Phase II studies, demonstrate that a new drug is more effective and/or safer than the current standard of care, a new drug application (NDA) is submitted to the Food and Drug Administration (FDA) for public approval.

The approval usually closely reflects the protocol that was used in the registration trials.

In other words, if the drug was studied only in relapsed or refractory patients, that is likely the only population for which it would be approved. However, once a drug is approved, doctors can use it “off label” for other indications. Whether insurance will pay for it is less certain.


Phase IV Trial – What else do we need to know about this already approved drug?

Even though the drug may have been tested on thousands of patients, late or rare adverse events may still show up. That is the purpose of Phase IV trials. Although the drug is commercially available, in a Phase IV trial, it may be provided for free.


Response to Therapy

In order to be consistent, doctors and researchers have agreed on standard ways to describe responses to therapy. The definitions are actually quite technical and are evolving. This is a simplified version. We start with the worst and work towards the best.

Progressive disease (PD): As the name suggests, the cancer continues to grow despite the treatment. This is not good news.

Stable disease (SD): The cancer neither progresses nor recedes. This can be a durable and quite an acceptable circumstance, especially if the CLL is not causing problems.

Partial Remission (PR): The cancer has been knocked back, but there are still cancer cells to be found in the blood, bone marrow or nodes. PR requires at least a 50% reduction in the size of lymph nodes and in the number of lymphocytes in the peripheral blood stream.

Complete Remission (CR): The absence of clonal lymphocytes in the blood is one of the major criteria. All lymph nodes need to be normal size (<1.5 cm). There is some controversy that the 1.5 cm is not the best marker and 2.0 cm. might be better, but for now, in the US, < 1.5 cm is the standard. In a clinical trial, the confirmation of a CR usually requires a bone marrow biopsy that shows no CLL.

Undetectable Measurable (minimal) Residual Disease (uMRD): This is the best news with the longest duration of response. Special tests can be used to find a single CLL cell hiding among 10,000 (standard measure of MRD) or even one in a million cells (using next generation sequencing) in the blood or bone marrow. If no cells are found, you are undetectable MRD (uMRD), a very good thing. This does not mean there is no cancer left. It means that if there is any cancer left, the level is so low that it can’t be detected by present technology.

Just to confuse things, it is possible to be uMRD and be in a PR if your lymph nodes are still enlarged. In CLL, lymph nodes may not always shrink back to completely normal size after treatment, but they still may be cancer free. Learn more about MRD.