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How Do Clinical Trials Work?

How Do Clinical Trials Work?

In this episode, Dr. Fonseca details the process of clinical trials, as well as how patients and families can better understand what goes on during each of the main parts of the study.

How Do Clinical Trials Work?

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We’ve all heard about clinical trials, especially when it comes to cancer treatment. Perhaps you qualify for a clinical trial, or you’re curious about whether a clinical trial could help you. But what is a clinical trial? Read on to learn more about clinical trials, as well as how patients and families can better understand what goes on during each part of the study.

This article includes commentary from our interview with Dr. Raphael Fonseca, a practicing hematologist and myeloma specialist with almost three decades of experience who now serves as the interim executive director at Mayo Clinic. You can listen to the whole interview with Dr. Fonseca in the YouTube video below.

Thank you to Karyopharm for its support of our educational program. The Patient Story has full editorial control of our content.

The interview has been edited only for clarity.


What are clinical trials?

Clinical trials are a stage in medical research that tests the effectiveness of a treatment on human patients. The FDA allows researchers to conduct clinical trials once a treatment has shown promise in animals. Clinical trials can be used to find treatments that are better at helping a medical condition, or to determine if a new type of treatment is safer than the current standard of care.

At the minimum, they provide a very comprehensive approach for how we treat patients because patients have to be under such great scrutiny, and there’s a whole team that supports how they conduct the clinical trial that patients have and get more attention than they would ever get in any other way.

Dr. Rafael Fonseca
What do clinical trials study?

Clinical trials test new interventions -meaning treatments like drugs, or other procedures- that have potential to be more effective or safer than the current standard of treatment for a disease or condition. Researchers don’t yet know if the intervention used in a clinical trial works, and many treatments never make it past the clinical trial stage.

Without clinical trials, doctors would have no way of knowing if a better treatment exists for a disease. Clinical trials can result in new treatments or even cures for diseases that were previously considered terminal.

It’s important that patients understand that clinical trials aren’t a magic bullet — ultimately, only a small percentage of drugs in clinical trials will receive FDA approval.

The keyword is “pursuing” because we don’t know whenever you’re testing something new. You hope it works.You don’t know if it will, and you don’t know if it potentially could also be more toxic.

Dr. Rafael Fonseca
Are clinical trials safe?

When you elect to participate in a clinical trial, you will have the risks of the trial explained to you. Potential risks include uncomfortable treatment, treatment that is not better than the current standard of care, and the fact that you may end up in a control group (group that does not receive the experimental treatment, instead receiving a placebo or typical existing treatment).

In the past, clinical trials were sometimes unsafe and unethical. Now, clinical trials must adhere to very strict standards that protect patients. Modern-day clinical trials require explicit consent from the patient. Doctors will never involve you in a clinical trial without your consent, and you are allowed to end your participation in a clinical trial at any time.

Clinical trials are very explicit events where patients and families actively have to decide to participate… there were some transgressions in the past regarding clinical trials, but they are nowadays incredibly and highly regulated. Furthermore, there’s a great level of safety and there’s more scrutiny on clinical trials than there is on anything else in that clinic. You as a patient always have the option to say, “I don’t want to do it anymore,” for whatever reason, or for no reason at all… If for whatever reason, I think in a clinical trial that it is not in your best interest, then we’re going to stop the trial.

Dr. Rafael Fonseca

Clinical trials must also adhere to strict schedules. While this may mean your appointments are longer or not as flexible, it also means that you will know exactly when and for how long you are receiving treatment.

There’s a high degree of rigor. We can’t just go around and say, “Oh, I’m going to see you next week instead of this week.” If the clinical trial says something, we try to adhere to that as much as possible so that we have the high quality and the consistency of the data. You would know about it.

Dr. Rafael Fonseca

The Main Phases of a Clinical Trial

Phase I
Credit: FDA

Phase I trials test drugs that often have never been administered to humans. The purpose of a Phase I trial is to determine whether the new intervention has the potential to help more than harm. Researchers use Phase I clinical trials to find out what a safe human dosage is.

…This has a phase where you escalate from low doses towards higher doses. Now, there may be great laboratory exams that work with animal models or something where you say, “this is a good approach,” but it’s not until you test it in humans that you know. That’s what Phase I is. There’s no placebo comparison. 

Dr. Rafael Fonseca

Study groups in Phase I trials are usually very small. Participants are closely monitored for side effects. Phase I trials are not testing the effectiveness of a treatment — they are primarily focused on how safe the treatment is for humans.

Phase II
Credit: FDA

Interventions move on to a Phase II trial when they are determined to be safe in Phase I. The goal of a Phase II clinical trial is to see if the drug is effective at treating the target disease in humans.

Most of the time, what you measure is just a response rate. The better the drug, the higher the response rate.

Dr. Rafael Fonseca

Like Phase I trials, Phase II trials do not use placebos. Instead, participants either all receive the same dose, or receive a range of doses that researchers determined safe in Phase I in order to determine the optimal effective dose. Because more people are involved in Phase II trials, researchers will likely see side effects that did not occur in Phase I.

Phase III
Credit: FDA

If a drug shows promise in a Phase II clinical trial, it moves on to Phase III. Phase III trials test whether a drug or treatment is better than the current standard of care. For example, a new type of chemo might effectively kill cancer cells in Phase II — but does that mean it works better than the drug that is already used to treat that type of cancer?

Let’s say you take Drug A, and A is the standard of care. But, we think adding drug B might be good. If you do a Phase III trial, a frequent way of doing it is that everyone is going to get Drug A. That’s the standard of care… But then by a flip of a coin, we’re going to have half of the patients take Drug B, and the other half will take A.  Patients know this. It has to be a very explicit discussion.

Dr. Rafael Fonseca

Placebos are used in Phase III trials, but patients are not given an inactive treatment if a treatment that already works for the disease exists. Phase III trials are often very large, taking place concurrently at medical facilities across the country or world.

Phase III clinical trials are often the last step before new drugs are submitted for FDA approval. After a Phase III trial, drugmakers will submit a new drug application (or NDA) to the FDA. The FDA can then accept the application, or return it with a request for further study.

Phase IV

Once a drug is approved by the FDA, it may enter a Phase IV trial. Phase IV clinical trials look at the effects of treatments over a longer period of time, often several years. Drugs in Phase IV trials have already been proven safe and effective — there is little risk to the patient in a Phase IV trial. Instead, the point of Phase IV trials is to help researchers know more about the long-term effectiveness and side effects of the treatment.

What is the purpose of a double-blinded study?

In a double-blinded study, neither the doctors nor the patients know which treatment the patient is receiving. The purpose of this is to remove any bias on the doctor’s part and gauge the true effectiveness of the treatment.

[Doctors] may have preconceived ideas, and they might care for you differently. They might use two different things, or even gauge things differently on how you’re doing. That’s why we sometimes have double-blinded studies where there’s placebo pills that are identical to [Drug] B, but only half of them are active. Neither doctors nor patients know which of those pills are.

Dr. Rafael Fonseca

Double-blinded studies allow researchers to understand the effects of a treatment without worrying about whether doctors are treating patients with the experimental treatment differently.

And for those who participate in trials, thank you. It is only because of those trials that we’re able to advance the science.

Dr. Rafael Fonseca
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