The basic appeal of clinical trials for patients is the ability to gain access to potentially powerful new drugs which are not yet approved and may be unavailable in hospitals or clinics for years. However, consent to participate in a clinical trial should never be given lightly. As a patient, you need to be aware of the objectives of the trial, basic information about the drug, how likely the trial's researchers believe you might benefit from what they want to put into your body, and what the potential side effects and negative consequences of treatment might be.
This, of course, is true of approved therapies as well. What is particularly important to understand in the clinical trial context is what the researchers themselves aren't sure about. Ethically, researchers must have at least a reasonable belief that what they are doing may be beneficial. However, at the end of the day your best advocate will always be yourself.
Phase I
The first level of trials for a drug are referred to as Phase I trials. This is not actually where drug testing begins: well before it is tested in humans, it will normally have shown effectiveness in the laboratory, and then been given to animal test subjects. These are the smallest trials, typically involving at most several dozen patients.
The sole scientific objective of a Phase I trial is to determine whether a drug is safe and, if so, at what levels side effects become serious enough to stop treatment (the maximum tolerated dose). When a Phase I trial involves the first use of the drug in humans (as opposed to first use against a particular disease), the trial typically begins at a very small fraction of dangerous dose levels for animals like mice or rats, and escalates from there. Obviously the severity of side effects is relative to the drug's expected role: for instance, side effects which are considered acceptable in the chemotherapy context would be absolutely unacceptable in the non-prescription decongestant or headache relief setting.
Because the sole purpose of a Phase I trial is safety, a drug may "succeed" at Phase I, and move to Phase II below, even if no patients show any improvement in their condition. Obviously, however, the most effective drugs also work in Phase I trials, and reports of these trials often highlight drug effectiveness where possible. Phase I trials for drugs treating non-lethal conditions often use healthy volunteers, who may be paid for their participation. Drugs for lethal conditions, like cancer, are usually given to the highest-risk patients, who have already attempted and/or failed all available treatment options. This reflects the reasoning that patients with no other treatment available have the most to gain, and the least to lose, from trying out a new drug.
Phase II
The second level of clinical trials take the tolerable dose level established at Phase I and give it to a somewhat larger body of patients, between several dozen and several hundred. Oftentimes these are recruited as part of a combined study known as a Phase I/II trial. Sometimes they also contain randomized treatment and control groups, discussed in Phase III below (which always contains comparison groups).
The chief goal of the Phase II trial is to judge whether a drug is effective. At this stage, patients may not be fully representative of the overall population, and the results usually do not attempt to make a fair comparison between the new drug and any existing alternatives. A drug which shows sufficient promise at the Phase II level may then be moved to a Phase III trial, which compares its effectiveness and safety with standard alternative drugs.
Most drugs that fail do so at the Phase II level, when it is shown that their side effects turned out to be much more severe than anticipated, or their effectiveness to be much less than hoped for.
Phase III
The final stage before drug approval is a much larger, comparative trial, typically involving hundreds or even thousands of patients. A Phase III trial aims to confirm the safety and effectiveness of the drug as established in previous trials, but, more importantly, to compare its effectiveness with other drugs commonly used to treat the same condition.
As patients enter the trial, they are randomly assigned ("randomized") to receive either the experimental new treatment or one or more standard treatments or a placebo (referred to as "controls"). These groups are referred to as "arms." In less serious cases, they may receive a placebo with no therapeutic ingredients, such as a sugar pill. When life-threatening diseases like cancer are involved, often the control group receives a standard treatment. There may also be more than one control arm. For instance, one current Phase III trial is comparing bendamustine + rituximab (the experimental combination) with two standard combinations, R-CHOP and R-CVP.
Phase III trials are especially important because, at least in theory, they can objectively establish whether a drug is safer and/or more effective in a given setting than other drugs already available. A drug may still be desirable if it is no more effective, but is much safer. Obviously, the best new drugs are both safer and more effective. A Phase III trial which shows that a drug is less effective, or equally effective but more dangerous, is generally seen as a drug failure.
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