Clinical trials are the first step in trying an investigational drug in humans to test its safety and effectiveness (efficacy). Before a drug reaches clinical trials, it is rigorously tested in preclinical studies both in cells (known as in vitro research) and in animal models (known as in vivo research).1 While these studies can help determine whether a drug may work as researchers predict, they cannot exactly mimic how it works in humans. The U.S. Food and Drug Administration (FDA) requires that all investigational drugs undergo the clinical trials process to ensure that they are both safe and effective in humans.
There are three phases of clinical trials, each with its own set of expectations and protocols for studying a new drug.2 After the drug moves through clinical trials, it is reviewed by the FDA for final approval. In total, only around 12 percent of drugs that enter the clinical trials process are approved by the FDA.3 Following approval, a drug may be monitored for several years in a phase 4 clinical trial to look for any rare side effects and ensure it is safe for use in the general public.2
How Are Clinical Trials Set Up?
After a company or sponsor has completed its preclinical research, it files an Investigational New Drug (IND) application with the FDA.4 The company/sponsor is required to provide the details and results of preclinical studies in animals to prove that the drug does not have any major toxic side effects. They also provide information on how the drug is manufactured and their detailed plans for clinical trials.
A team of scientists, medical doctors, and managerial staff at the FDA reviews the IND application to make sure it meets the federal standards. This team includes a:2
- Medical officer: Reviews clinical study data and plans before, during, and after the trials
- Pharmacologist: Reviews the data from laboratory and animal studies
- Pharmacokineticist: Reviews the preclinical data to understand how the drug is absorbed, broken down, and cleared by the body for dosing information
- Chemist: Reviews the drug’s composition and manufacturing process, and ensures it is safe to use in clinical trials
- Microbiologist: Reviews preclinical data for antimicrobial drugs
- Statistician: Evaluates the clinical trial design and ensures the protocols and data meet FDA standards
- Project manager: Coordinates the IND team throughout reviews and interacts with the company/sponsor that submitted the application
After the review team looks over the application and approves it, the company/sponsor can begin to recruit participants for the first of the clinical trial phases.
The company/sponsor will chose sites to conduct the study. Those sites will have their own personnel such as physicians, nurses, research coordinators and pharmacists.
What Is a Phase 1 Clinical Trial?
Phase 1 clinical trials are not designed to study how effective an investigational drug is. Instead, they mainly focus on whether or not it is safe to use in humans. Phase 1 trials usually include a small group of healthy volunteers, typically between 20 to 100 people. With certain types of treatments, such as cancer drugs, people with the disease participate.2 Oftentimes in cancer drug clinical trials, participants are people who have tried other treatments but whose cancer has returned and cannot be treated with available therapies.5
One of the purposes of phase 1 clinical trials is to determine the dosage of the investigational drug. Investigators will start with a low dose based on the preclinical animal studies to help ensure the participants do not have any major reactions to the drug. They will then slowly increase the dose in other participants in what is known as a dose-escalation study.6 The purpose of this study is to find a safe dose that does not cause too many unwanted side effects.
Investigators will also learn how the investigational drug and body interact. These findings help them adjust dosing during the trial to select the best dose. They can also be used to determine the best way of administering a drug, whether it is by mouth, injection, or infusion. Information gathered can include:2
- How the body breaks down the drug
- How fast the drug is cleared from the body
- The side effects participants experience
Phase 1 clinical trials can take several months to complete. After the data is gathered, the investigators will submit the data to the FDA review team in order to proceed to phase 2 clinical trials. If the drug is found to be safe in humans, it will move on. However, many drugs do not pass these initial studies — according to the FDA, around 30 percent of drugs do not pass phase 1 trials.2
What Is a Phase 2 Clinical Trial?
After a phase 1 clinical trial, the investigators can begin a phase 2 trial. A phase 2 clinical trial focuses on treating a larger population with the disease or condition to begin studying the investigational drug’s effectiveness and to identify less common side effects not seen in phase 1 trials. Depending on the type of drug being studied, between 25 and a few hundred participants may be chosen.2 Scaling up the study population can help investigators see how the drug works in a wider variety of people who are living with the disease/condition.
Typically, phase 2 trials treat all participants with the same dose to confirm their findings from phase 1 trials. However, some studies may be set up by splitting participants into different groups who receive different treatments. The first group, known as the control group, receives a placebo or “fake” treatment that mimics the drug, such as taking a sugar pill or receiving an injection with saline. With investigational cancer drugs, the control group will receive the standard of care—or a currently available therapy—so they can continue to manage their disease over the course of the study. The other groups receive various doses of the investigational drug to further study side effects, dosing, and potentially efficacy.7 Sometimes, phase 2 studies are not large enough for investigators to know whether or not a drug helps improve a disease/condition.2
Phase 2 clinical trials may last from several months to a few years, depending on the trial setup. The investigators will then compile the data from the trials and use it to make decisions on their setup for phase 3 trials.
According to the FDA, only 33 percent of investigational drugs move on to phase 3 trials. The most common causes of failure in phase 2 trials include:8
- The drug does not work as well as investigators expected
- The drug has too many toxic side effects
- There is little ability to sell the drug on the market because similar medications already exist
What Is a Phase 3 Clinical Trial?
A phase 3 clinical trial is the largest study of an investigational drug. This is the last step in the clinical trials process before a drug is approved by the FDA and made available to be prescribed to patients among the general public. Phase 3 trials recruit between 300 to 3,000 participants who have the disease/condition being treated by the investigational drug. The main goal of these studies is to determine whether or not it is safe and effective at treating the disease/condition, and if it is better than any existing therapies.2,9
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Phase 3 trials are typically randomized trials, meaning that participants are randomly divided into either a control group or study group. As with phase 2 trials, the control group will receive either a placebo or the standard of care for the disease/condition. The study group will receive the investigational drug at the final selected dose based on previous studies. In most of the studies, both the doctor and participant are unaware of whether they are administering/receiving the placebo or investigational drug. This is called a double-blind trial, which helps prevent bias in the study.10
Overall, phase 3 clinical trials are the longest studies, lasting from one to four years. The FDA reports that 25 to 30 percent of drugs move past phase 3 trials to then be submitted for FDA approval.2 However, even if an investigational drug completes the trial, it does not mean that it will be approved.
New Drug Application (NDA) and Final Review
After the phase 3 clinical trial is complete, the company/sponsor then submits a new drug application (NDA) to the FDA.11 This application is the final step to gaining approval from the FDA to sell and market a new drug. The NDA tells the overall story of the investigational drug, from the very beginning in cells and animals up through the final studies in humans. The information provided includes:12
- Preclinical data from the IND
- Clinical trial data from all three phases of studies
- Proposed packaging and labeling for the drug
- Directions on how to use the drug
- Information on the potential for drug abuse
- Safety updates from the clinical trials
- Data from studies conducted outside the United States
After the FDA receives an NDA, the review team who approved the IND then determines whether to approve or reject the drug. The team has six to 10 months to review the NDA and make a final decision.11 During this time, each member looks over the data to ensure it is accurate and that the investigators did not manipulate or fabricate results.
Occasionally, the review team may request that the company/sponsor answer some questions about their data or conduct other studies to gather more information. Most of the time, however, the NDA has enough data for the FDA to move forward with the approval process. After the review team completes their review, the data is compiled together into an “action package” that is sent to a senior FDA official. This official then makes the final decision to approve or deny a drug.11
Post-Market Safety Monitoring
Post-market safety monitoring is done after a drug is approved to monitor its use in the general public.13 Clinical trials cannot capture every possible side effect or problem that may occur with a drug. With this, the FDA continues to monitor reports on drugs in the following months to years after approval.
Phase 4 clinical trials may also be conducted to determine the long-term effects and look for any rare side effects. These trials follow thousands of patients who are receiving an approved drug to treat the intended disease/condition.2 For example, a phase 4 clinical trial may answer questions such as, “This approved cancer drug helps shrink tumors, but does it improve patients’ survival?” and “What are the side effects of taking the drug for several years?”6 This continued monitoring helps ensure that the drugs available on the market continue to be safe and effective in the long term.
The information provided in this article is not a substitute for the advice of qualified healthcare professionals. While we strive to publish accurate information, it is not possible to cover all potential scenarios, including drug or treatment effects, interactions, or usage. You should not rely solely on this article to determine whether a particular treatment, drug, or clinical trial is suitable for you or any other individual. Always consult a healthcare professional before starting or changing any treatments.