Initial investigation of a therapy in humans starts with a phase I clinical trial. Phase I is extremely preliminary. Its purpose is really just to verify whether the therapy can be used in humans at all. It identifies the safe range for therapy dosage and any side effects patients may experience. In phase I, a therapy is given to a very small number of people, tens of people as opposed to thousands like clinical trials in later phases.
In phase I studies, you often see many diagnoses being tested at once. For example, it is not unusual for phase I cancer trials to look at solid tumors. There could be dozens of reasons for a patient to have a cancerous solid tumor. Phase I studies are small. But when they look at several different diseases, you get an even smaller number of patients. For example, let’s say a phase I cancer trial is looking at testing New Drug X in patients with solid tumors. A total of twenty patients will participate in this study. Of those twenty patients, five may have non-small cell lung cancer and two may have colorectal cancer. So you are looking at tiny numbers of people. You are trying to prove that this therapy can be used in humans at all rather than looking at how well it works on a particular disease.
Phase II is when you start to get into the real meat of trialing a therapy. In this phase, a few hundred people are recruited. At this point, the targeted diseases are clearly defined. You don’t see tons of diagnoses being trialed like you might see in Phase I. The goals of a phase II trial are to figure out which dose is the best for treating a disease and to identify any side effects or toxicities a patient may experience from taking the therapy.
In phase II trials, trial design is less uniform. This means that not all phase II trials follow the same pattern. They are sometimes divided into two parts, called phase IIa and phase IIb. Phase IIa trials are usually dedicated to figuring out what dosage should be given to patients. In phase IIb, the studies investigate what dosage gives the best result for patients and cause the lowest level of toxicity and complications, called adverse events.
Most people are familiar with the clinical trial format where some patients get the therapy and some patients get a placebo, and neither the patients nor the investigators know who gets what until the end. This doesn’t always happen, especially in oncology and rare disease trials. For very aggressive diseases, the reason is that getting the placebo and therefore not receiving any treatment would be fatal. In such instances, some patients might get the new therapy while others would get an older therapy that is currently used for people with that disease. When a treatment plan is typically prescribed for patients with a particular diagnosis, that treatment is called the standard of care (SoC). When you read through trial data or articles about trials, you might see something like “[drug name] vs SoC”. This means that some patients get the new therapy and some get the old therapy. The patients may or may not know which therapy they are getting. This depends a lot on the disease and how the new therapy and the standard of care are administered. For example, a new therapy might be given intravenously twice a month. The standard of care could be radiation therapy once a month. For obvious reasons, patients and investigators will know what therapy they are getting. But if both treatments are given via IV twice a month, the patients may not know. The investigators may or may not know depending on the trial design.
In certain situations, a phase II trial might be designed not to compare a new therapy to standard of care, but instead to demonstrate that a therapy can be given safely at a particular dose and have the intended effect upon a disease. This might happen if there is no standard therapy available for a disease. It also happens in rare disease studies because they want to get as much data on how a therapy affects patients with the rare disease and, by nature, there aren’t a lot of patients with that rare disease. So in a study for Rare Disease Y, instead of giving 100 patients the new therapy and 100 patients the standard of care, the investigators may choose to give all 200 patients the new therapy so that they can get as much data as possible on how this drug affects patients with this rare disease.
After phase II studies, the data collected and analyzed is submitted to the regulatory body for countries where the investigators want to be able to use the drug. In the US, this is the FDA. The data is reviewed and the regulatory body will decide what the next step is to be able to use the therapy in people.
There are several possible paths from this point. The regulatory agency may decide that the data is not strong enough to show that the drug works at a particular dose safely in patients while helping their disease. They could tell the investigators to extend their phase II trial, or to design a new trial and try again. They could tell the investigators that they feel the therapy is dangerous and not eligible for use in humans. They could agree the data supports the use of the therapy in this patient population, but want to see more data on a larger population. In this instance, the next step is a phase III trial.
In scenarios where the therapy is demonstrably effective against a disease and relatively safe to use in humans, the regulatory body could also elect to approve the therapy for use immediately. In this case, no phase III trial would be needed to approve the therapy for a particular disease indication. This happens mostly in situations where there is no effective therapy currently for a disease. This has happened in rare disease trials.