Before a new drug, surgical procedure, or therapy becomes available to the public, it must go through a rigorous testing process and be evaluated by the US Food and Drug Administration (FDA). This testing process consists of a series of clinical trials that are designed to test the safety and usefulness of the new
drug compared to the current standard treatment.
The clinical trials that make headlines are usually what are called phase III trials. These are large-scale tests with hundreds or thousands of patients. They are the culmination of earlier phase I and phase II trials that include many fewer people and still earlier preclinical experiments with animals. They are also the final tests in humans before the FDA is asked to authorize sale of new medicines.
Why Are Large-Scale Trials Needed?
Clinical trials are designed to test whether a drug is safe for humans, and whether the drug is effective in treating human diseases or conditions. Although the drug has generally gone through extensive animal testing before the trial begins, animal trials cannot always predict how new medicines will affect humans. Even the most painstaking tests with animals give only approximate indications of how people will respond to drugs. At some point, after thorough study in animals (and when the FDA is convinced human experimentation will probably be safe), tests with humans become necessary.
Not only is it necessary to test new drugs in humans, but they need to be tested in a large number of humans in order for the results of the trial to be clear. The reason so many volunteers are required is that people are highly variable in how they respond to drugs. It is not unusual, for example, for a drug be somewhat effective in only 30 percent of those who take it. For medical researchers to prove such a slight benefit requires testing the drug in as many as several thousand patients.
This extensive testing is part of what drives up the cost of new drugs – the average development time is over 10 years and costs from 500 to 700 million dollars.
What Goes on Prior to a Large-Scale Phase III Trial?
An enormous amount of testing has gone on by the time a drug is ready for phase III. In general, a new drug or treatment goes through preclinical testing in animals, then small phase I and phase II trials in humans before being ready for large-scale testing.
Preclinical testing
When a drug is discovered that seems to have medical potential, a drug company will test it exhaustively in animals, looking for signs it may be poisonous, cause cancer, or cause birth defects. Animal studies will also be used to estimate the initial drug doses to be tested in humans.
When animal experiments are finished, the company asks the FDA for permission to begin clinical trials. The FDA only grants approval once they are satisfied that the animal experiments are sound and that clinical trials are likely to be safe.
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Phase I
The first test of the drug in humans is known as phase I. It is designed to find out if the drug is safe rather than whether the drug is effective. Phase I is also used to learn what drug doses to use in later trials, how the drug is broken down in the body and excreted, and study short-term side effects.
A phase I trial rarely has more than 100 participants. Often healthy people are enrolled in phase I trials rather than patients on the assumption that if the drug has unexpected side effects, healthy people have the best chance of escaping permanent harm. But on other occasions, as with a drug treating a serious disease like cancer, phase I subjects may be patients who have failed standard treatments.
Phase II
If a drug passes the safety tests of phase I, it advances to a phase II trial with up to 200 participants. The goal of a phase II trial is to learn more about safety and side effects, sharpen estimates of proper doses, and get an early appraisal of whether the drug is going to work. This trial is often the first time a drug is tested in actual patients.
What Are the Different Types of Phase III Trials?
The phase III trial consists of hundreds or thousands of people. Commonly, phase III will be conducted at several medical centers to see if people treated in different locales have similar experiences. The central question of a phase III trial is whether the drug works. Phase III will also give doctors an extensive look at the drug’s side effects. There are many different ways of conducting a phase III trial.
Blinded, randomized trials
Many Phase III trials are randomized, double-blind trials. Randomized means people are assigned at random either to receive the new drug, the standard treatment for that disease, or a nonfunctional substitute (such as a sugar pill). This last group is often called the control group, or the placebo group. Because phase III must answer definitively whether the drug works, it’s important to compare people who receive it with others who do not.
A good example of how people are randomly assigned to study groups is the phase III trial for Herceptin, which treats a form of breast cancer. In this trial women either received the standard breast cancer treatment with Herceptin or the standard treatment without Herceptin. In this case, there was no control group who received just a sugar pill because to do so would be to not treat women with a potentially fatal illness. In this trial, the women who received Herceptin with the standard treatment became the test group; the others, the controls.
Women were assigned at random to the two groups. This means that the average age of the two groups was roughly similar as was the severity of their cancer so the results can be compared. If the two groups had differed considerably in age or health, researchers would not be able to tell if the drug itself was effective, or if the women in that group were just younger or healthier.
Herceptin’s trial was also considered double-blind, which means that neither the women nor their doctors knew who was receiving Herceptin. Of course, it is natural for doctors to want to know what treatments their patients are getting, and in single-blind trials they do. There, only the trial participants are unaware of which group they are in. But double-blind trials are considered better because they prevent doctors from acting on preconceived notions they may have about whether or not the drug works.
For example, a doctor in the Herceptin trial might have been tempted to offer extra treatment to participants that weren’t getting Herceptin. But the physician’s attempt to compensate for the fact that the participant wasn’t receiving the study drug would have collided with the requirement to keep groups comparable in everything except who received the new drug. Unintentionally, the doctor might have interfered with the trial, casting doubt on its conclusions. This is why it is considered good practice for phase III trials to be double-blind.
Open trials
Not every trial is blind. In unblinded trials, often described as open trials, both doctors and participants know what treatments are being given. Trials of surgical procedures and comparisons of medical devices are often by nature open. One of the problems with an open drug trial is that many participants may not want to take placebos, because they presume the drug will be better. Open trials, like single-arm trials (where all participants receive the same treatment), are more susceptible to bias. This is because the knowledge of the treatment being administered can influence both the participant’s reporting of symptoms and the researcher’s assessment of outcomes. This lack of blinding can make it difficult to objectively evaluate the true effectiveness of the treatment being studied.
Phase IV Trials
Phase IV trials, also known as post-marketing surveillance, occur after a drug or treatment has been approved by the FDA and is available to the public. While Phase I-III trials focus on safety and efficacy in controlled settings, Phase IV trials monitor the long-term safety and effectiveness of the treatment in a much larger and more diverse population. Because the drug is now being used in real-world clinical practice, researchers can gather information on:
- Rare or long-term side effects: Some side effects may not be apparent in the smaller, shorter-duration Phase I-III trials. Phase IV allows for the detection of less common adverse events.
- Effects in specific populations: The initial trials may not have included sufficient numbers of certain patient groups (e.g., elderly patients, pregnant women, or patients with specific comorbidities). Phase IV can provide data on how the treatment affects these populations.
- Drug interactions: When a drug is used in the general population, it is more likely to be used in conjunction with other medications, potentially leading to unforeseen drug interactions. Phase IV studies can identify these interactions.
- New uses for the drug: Sometimes, during Phase IV, researchers may discover that the drug is effective for treating conditions other than the one for which it was originally approved.
Information gathered during Phase IV trials is crucial for refining treatment guidelines, updating drug labels, and ensuring approved therapies’ continued safety and effectiveness. This phase is an ongoing process of monitoring and learning about the long-term impact of medical interventions.
