Before a new drug, surgical procedure, or therapy becomes available to the public, the US Food and Drug Administration (FDA) must rigorously test and evaluate it. This testing process involves a series of clinical trials designed to assess the new drug’s safety and effectiveness compared with the current standard treatment.
The types of clinical trials that make headlines are usually phase III trials. These are large-scale tests with hundreds or thousands of patients. They build on earlier phase I and phase II trials involving far fewer people, as well as earlier preclinical experiments in animals. They are also the final human tests before the FDA is asked to authorize the sale of a new medicine.
Clinical trials test whether a drug is safe for humans and effective in treating human diseases or conditions. Although the drug has generally undergone extensive animal testing before the trial begins, animal studies 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.
New drugs must be tested in humans, and they must be tested in a large number of people to ensure the trial results are 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 to be somewhat effective in only 30 percent of those who take it. To prove such a slight benefit, medical researchers must test the drug in 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 range from 500 to 700 million dollars.
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There are several types of clinical trials.
These include:
A large amount of testing has occurred 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.
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 also help estimate the initial doses to test in humans.
After animal experiments, the company asks the FDA for permission to begin clinical trials. The FDA approves the application only after it is satisfied that the animal experiments are sound and that clinical trials are likely to be safe.
The first human test of a drug is called phase I. It is designed to determine whether the drug is safe, not whether it is effective. Phase I also determines which doses to use in later trials, how the drug is metabolized and excreted, and short-term side effects.
A phase I trial typically enrolls fewer than 100 participants. Phase I trials often enroll healthy people rather than patients, on the assumption that if the drug has unexpected side effects, healthy people are most likely to avoid 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.
If a drug passes phase I safety tests, 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 effective doses, and get an early appraisal of whether the drug will work. This trial is often the first time a drug is tested in actual patients.
Phase III trials involve hundreds or thousands of people. Phase III is often conducted across several medical centers to determine whether people treated in different locales have similar experiences. The central question of a phase III trial is whether the drug works. Phase III also gives doctors a broad view of the drug’s side effects. There are many ways to conduct a phase III trial.
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 those 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, no control group received just a sugar pill because to do so would be to not treat women with a potentially fatal illness. In this trial, women who received Herceptin with standard treatment were the test group; the others were the controls.
Women were randomly assigned to the two groups. This means the two groups had roughly similar average ages and cancer severity, allowing the results to be compared. If the two groups differed considerably in age or health, researchers could not tell whether the drug was effective or whether the women in that group were simply younger or healthier.
Herceptin’s trial was also double-blind, meaning neither the women nor their doctors knew who was receiving Herceptin. Of course, doctors naturally want to know what treatments their patients are getting, and in single-blind trials, they do. In those trials, only the 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 about whether the drug works.
For example, a doctor in the Herceptin trial might have been tempted to offer extra treatment to participants who weren’t getting Herceptin. But the physician’s attempt to compensate for the participant not receiving the study drug would have conflicted 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.
Not every trial is blind. In unblinded trials, often called open trials, both doctors and participants know which treatments are being given. Trials of surgical procedures and comparisons of medical devices are often open by nature. 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, such as single-arm trials (in which all participants receive the same treatment), are more susceptible to bias. This is because knowing which treatment is being administered can influence both participants’ symptom reporting and researchers’ assessment of outcomes. This lack of blinding can make it difficult to assess the treatment’s true effectiveness objectively.
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Phase IV trials, also known as post-marketing surveillance, occur after the FDA approves a drug or treatment and it becomes available to the public. While Phase I-III trials focus on safety and efficacy in controlled settings, Phase IV trials monitor the treatment’s long-term safety and effectiveness in a much larger, more diverse population. Because the drug is now being used in real-world clinical practice, researchers can gather information on:
Information gathered during Phase IV trials is crucial for refining treatment guidelines, updating drug labels, and ensuring approved therapies remain safe and effective. This phase is an ongoing process of monitoring and learning about the long-term impact of medical interventions.
Clinical trials give researchers an opportunity to explore new treatments that can improve outcomes across multiple diseases and conditions. Understanding the different types of clinical trials and how they work can help you know what to expect before joining one. If you decide to participate, the research team will share all the details upfront so you understand what to expect and feel comfortable moving forward.
If you’d like to see which clinical trials are currently seeking participants, visit BlackDoctor’s Clinical Trials Resource Center.
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