To speed promising new stem cell or gene therapies to patients who need them, the California Institute for Regenerative Medicine (CIRM) supports work at every phase of clinical trials, from early discovery research through clinical testing.

CIRM currently supports more than 100 clinical trials in California, conditions that range from rare diseases to cancers and neurological conditions like Alzheimer’s disease and Parkinsons. (You can search on this dashboard for both CIRM-funded and non-CIRM-funded stem cell and gene therapy clinical trials in the state.)

Those clinical trials are crucial because, before any new treatment reaches a patient, scientists must demonstrate that it’s both safe and effective at the intended dose. They do that through rigorous clinical trials. Each stage of the process, from the preclinical to the three main phases of clinical trials, is carefully monitored and generally meant to determine a specific goal.

Here’s a helpful breakdown of each phase; note that sometimes a phase may also be split into parts A and B. There’s a more complete look on CIRM’s website as well as an explainer on the FDA website. The University of California also offers a good primer on Clinical Trials here.

Preclinical Research: Laying the Groundwork

Every potential therapy begins in the lab, where researchers attempt to understand how a therapy might work before testing in cells and in animal models. The goal is to understand how a new treatment works and whether it appears safe enough to move into human studies.

Before anything even gets to the clinical trials stage, there are early stages of research beginning with the discovery stage, during which scientists first attempt to identify therapeutic candidates. Then, researchers move on to developing those candidates through something called “translational research,” during which they explore whether they’ve identified the right candidate and can make the treatment.

At some point, if researchers intend to begin a clinical trial, they must submit an Investigational New Drug (IND) application to the Food and Drug Administration. Usually, before they’ve readied that application, they’ve done pre-IND work that involves a lot of back and forth with the FDA to understand better what kind of preclinical work needs to be part of their application.

Even at this very early stage, there is a rigorous review. The reviewers at the FDA look at early data from animal studies, other study data, and the protocols for how researchers intend to conduct a future clinical trial in humans. The FDA reviewers also want to look at whether there have been any prior human studies of the treatment that indicate how people will respond to the proposed new therapy.

Only a a few of these early concepts reach human trials, and of those that do, most never reach approval becuase they may have severe side effects, lack effectiveness, or not perform better than current treatments.

Phase 1: Is the therapy safe?

After receiving approval from the FDA for their IND filing, scientists can move forward with a Phase 1 trial. While scientists have often invested years of research into a specific therapy before Phase 1 trials, this is the first time the treatments are tested in people.

At this stage, usually only a small number of patients receive the treatment — typically between 20-and-80 — but in the case of very rare diseases, it may be less than 10.  The scientists are testing whether a treatment is safe and, if so, at what dose. In addition, they’re trying to determine if there are side effects. Researchers closely monitor the clinical trial, recording any side effects and what happens at different dose levels.

Between 60 and 70 percent of all types of treatments combined move to the next stage, but for cell and gene therapy the percentage is much lower, according to data from the FDA. Fewer than half of gene and cell therapies get beyond Phase 1, an important an milestone that suggests the treatment is safe enough to move forward.

Phase 2: Does the treatment work?

Once scientists know a treatment is safe, they will begin Phase 2 clinical trials to look for early signs of effectiveness.

This stage involves larger groups of patients, often hundreds of participants who might be in more than one location. The scientists continue to monitor for safety and side effects. Along with safety, scientists look for early signs of effectiveness at the best dose they’ve identified from the Phase 1 trial.

Between 30 and 40 percent of treatments make it to Phase 3, but for cell and gene therapy it’s about 50 percent.

Phase 3: Does the treatment work better than current treatments?

At this stage, scientists have shown that a treatment is relatively safe and may be effective. Phase 3 trials add another layer of scrutiny to determine whether it’s any better than what’s currently available.

To do that, scientists must enroll many more people, sometimes thousands of participants across multiple sites, in this clinical trial phase.

Again, they continue to monitor for safety and side effects, and they’re comparing this new treatment to current treatments for the condition. The researchers want to confirm the effectiveness of a new treatment while evaluating potential side effects. All the while, they are collecting data and reporting back for regulatory approval.

 Almost 50% of treatments succeed in Phase 3 trials and go on to be submitted for FDA approval to market the drug. 

FDA Review and Approval: Is the treatment ready for patients?

Once the FDA determines a new treatment is safe and effective, it will approve its use. For cell and gene therapies, 80 percent of treatments that have made it past Phase 3 receive approval.

At each step, a new treatment must meet stricter standards. At the same time, only a small number of early ideas make it through. Years of data and rigorous testing go into every approval. By the time a treatment reaches patients, researchers have examined it from every angle, from safety to dosing to effectiveness, and how it compares to existing options.

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