What are Clinical Trial Phases?

In the United States, medications and medical devices can't reach patients without being approved by the Food and Drug Administration (FDA). Each potential new treatment must make its way through several clinical trial phases that test the treatments for safety and effectiveness. Clinical trials may also help researchers discover what medical approaches work best for certain groups of people.

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How do clinical trials work?

During a trial, volunteers receive an intervention based on a clinical trial protocol put together by the researchers running the study. This means they'll either receive the new treatment or device being tested, or they will receive a placebo (no active ingredients) or the current standard of care, depending on the condition. In some cases, participants may receive the standard of care and a placebo, if the trial is testing a treatment to alleviate side effects or a particular symptom. For life-threatening illnesses with available treatment, such as cancer, placebos are not used.

As the treatments are administered to the volunteers, the researchers measure outcomes — things like how the patient feels, changes in symptoms, decrease in spread of disease, etc. These measurements help them determine the efficacy of the trial — that is, whether the treatment or device being evaluated works to improve outcomes as anticipated. Researchers also keep careful track of how volunteers react to the treatments being tested in order to determine the safety of the intervention as well.

Preclinical studies: Before trials start

Before researchers begin testing a potential new treatment in people, extensive research is conducted to decide whether the drug is a good candidate for clinical trials. Testing includes in vitro (in a test tube or cell culture) as well as in vivo (animal) experiments. For some drugs, researchers are able to perform drug profiling using computer models that show how the drug will interact with the human body.

Preclinical research may take anywhere from one to six years. Researchers only take the most promising potential treatments to the next phase.

What is the goal of a clinical trial?

An investigational clinical trial will set out a goal before the trial launches. A trial's goal may be to compare effectiveness between an existing treatment and a potential new drug or device, to treat specific symptoms, or to delay or prevent disease progression. A trial may have a primary goal as well as a secondary goal. For example, the primary goal of a Parkinson's disease trial may be to treat a particular symptom such as tremor, but the secondary goal may be to slow disease progression, as well.

Beyond the overall goal of a clinical trial, each trial phase has goals to meet, as well, which we will outline in the next sections.

Phase 0

A relatively new step in the clinical trial process, this early stage is intended to quickly weed out ineffective drugs, or establish that a drug will work as expected in the body.

This stage only enrolls a few volunteers, who are given just 1% of the dose of the drug being researched. Phase 0 trials take no more than seven days.

These short trials give researchers a sense of how the drug will behave in the body. This phase is not required by the FDA, but is suggested particularly for drugs that aim to treat serious diseases.

Phase 1: Testing for safety

The first official stage of a clinical trial researches a potential new treatment for safety. These trials enroll around 20 to 100 volunteers, and last from a few months to a year. Because this phase measures safety by testing for any adverse side effects of the treatment, and not how effective the drug or device is, the trial may enroll only healthy volunteers without the condition. The trial may also enroll patients with the condition the trial aims to treat, but treating symptoms is not the goal of this phase.

During this phase, researchers start with small doses of the drug and measure how the body responds to determine the ideal dosing. They also check for side effects.

Because this is typically the first time the investigational drug is tested in humans, it is the highest-risk clinical trial to take part in. For that reason, Phase 1 trials are also the most common paid clinical trials.

If the researchers determine that the treatment is safe enough, it moves into the next phase. Around 70% of treatments in development move on to Phase II trials.

Phase 2: Testing for safety and effectiveness.

The next clinical trial phase continues to test for safety, while measuring the effectiveness of the treatment for symptoms, as well. Phase 2 trials enroll up to several hundred volunteers living with the condition. This phase can last from several months to a few years.

Phase 2 trials are typically randomized. This means that one group of participants receives the study drug, while others receive a placebo or the standard of treatment. Placebos are not used in Phase 2 cancer trials.

Most Phase 2 trials are also blinded, meaning that neither the researchers nor the participants know to which treatment branch patients have been assigned.

A potential treatment can only move on to the next phase if it is found to be effective. Around 33% of study drugs pass this phase.

Phase 3: Testing for safety and effectiveness with many patients

The largest clinical trial phase, these studies enroll hundreds of participants to test a potential treatment for effectiveness, while continuing to monitor safety and side effects. This phase may last for several years, as the FDA requires a large amount of information to weigh benefits against side effects.

Approximately 25 to 30% of treatments that enter this phase move forward in the approvals process. At this point, the drug or device sponsor applies for a New Drug Application (NDA) with the FDA.

The FDA decides whether or not to approve the NDA based on the results from all previous clinical trials. If the FDA determines that the benefits of the treatment outweigh the risks, the drug is approved, and the pharmaceutical company may begin marketing the drug.

Phase 4: Post-marketing trials

After a new treatment is approved by the FDA, the pharmaceutical or device company may want to continue monitoring patients to learn more about the treatment’s longer-term effects, while comparing the it against other already-approved options.

It may take time for long-term side effects to appear, making this an important phase, too.

Learning more: Phases 2b and 3b

Sometimes, researchers want to learn more about an investigational treatment before moving it into Phase 3 testing, the largest and most expensive phase. Phase 2b trials give sponsors the opportunity to rigorously demonstrate the effectiveness of a potential new treatment.

In some cases, a Phase 2 may be broken into two sections: the A trial investigates the best dosing for the treatment, then the B trial measures how effective the treatment may be.

For Phase 3 trials, 3a studies take place before FDA approval, and IIIb studies are conducted after. Post-approval studies may further research how the treatment impacts quality of life, for example.

How do medical device clinical trials work?

Medical devices must also be approved for use, but go through a somewhat different process. Devices are not tested on people without the condition. Instead, they are tested first for safety and performance in what is called a "pilot" or feasibility study with a small group of patients, typically 10 to 30. Next, a "pivotal" trial enrolls a larger population of patients, from 150 to 300 participants, to further test safety and effectiveness. Post-approval studies collect long-term information, like post-marketing studies for drug trials do.

Unlike drug trials, medical device trials are not able to use a placebo. Another difference is that many drug trials are blinded, in which neither the researcher nor the participant known which branch the patient is in. But for medical device trials, that is typically impossible to do. Instead, new medical devices are typically measured against the existing standard of care.

Not all new medical devices need to go through clinical trials. Some are quite simple and considered low-risk, such as new bandages or tongue depressors, which are both considered medical devices. Medical devices are broken into classes. Class I devices pose a minimal risk, Class II are Intermediate Risk, and Class III devices are Substantial Risk. Class III devices always require a clinical trial, and sometimes Class II devices do, as well.

What is the approval process for generic drugs?

When a new drug or device is first approved, the sponsor receives exclusivity on the drug for a period of time in order to recoup the cost of developing the drug. The length of time that a drug maintains exclusivity varies, but in most cases, a new brand-name drug receives exclusivity for five years. with the intention that the company will recoup the costs of developing the treatment.

After that, other companies are able to submit generic versions of the drug for approval. The company must show their manufacturing process for creating the drug, so the FDA can confirm that the manufacturer can make a high-quality product.

The FDA will also review results from additional clinical trials that test the generic drug against the brand-name drug, comparing data to ensure that the generic drug is safe, effective, and can be substituted for the original drug.

How long does clinical research take?

Including preclinical research, a new drug's journey from the lab to pharmacy shelves can take up to 11 years. Post-marketing research may add another few years to the process, as well.

Unfortunately, up to 80% of clinical trials are delayed because of recruitment challenges – that's why it's so important for interested patients to take part in research opportunities. Today, nonprofit research organizations, patient advocates, and organizations like Antidote are working to raise clinical trial awareness and connect patients with trials that are right for them.

Making the decision to participate

You may choose to consider the clinical trial phase when making your choice. Whether you’re searching for trials on ClinicalTrials.gov or using a clinical trial search tool like Antidote Match, the trial phase will be included in the listing, along with information about inclusion and exclusion criteria for the trial.

Different phases have different risks and benefits associated with them. For example, a Phase 1 trial is the most likely to offer financial compensation, but also has the most risk because there will have been little to no human testing done before the trial.

Phase 1 and 2 trials may also require less of a time commitment, because they tend to be shorter. The length of the trial will most likely be listed on the trial information page. If you’re talking to the study team, get all the information you can about the time commitment to participate to make sure it’s a good fit for your schedule.

For Phase 2 and 3 trials, you can also factor in the results from previous trials in making your decision. Try searching the name of the trial or study drug or device in Google to find published results from previous trials. These papers tend to be written for scientific audiences, rather than for patients, so consider talking about the results with your doctor, too. It’s important to include your doctor throughout your decision-making process, as they can give advice on whether it would be safe or advisable to change your treatment at that time. And whatever your decision, you’re always free to leave a clinical trial at any time, for any reason, once you join.

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