The Food and Drug Administration (FDA) only approves drugs that have been demonstrated to be safe and effective. To determine whether a new drug is truly safe and effective, the drug sponsor conducts clinical trials which are carefully controlled experiments that test the impacts of new drugs on volunteers. While the phrase “clinical trials” can describe studies examining medical devices, tests, procedures, or changes to participants’ behavior (e.g., diet), this page will focus on clinical trials studying new drugs. Many of the principals will be similar for other therapeutics (e.g., biologics).
Once a new drug is ready to be tested, standard FDA procedure prescribes three phases of clinical testing:
- Phase 1: The first trial tests a drug in a small number of volunteers focused on toxicity.
- Phase 2: The second trial involves a larger number of volunteers than phase 1 and tests a drug’s effectiveness in treating a disease.
- Phase 3: The third trial is the largest in scale. and gathers additional information on safety and effectiveness. Often, this trial compares the new therapy to the standard of care to show a benefit over already approved drugs. In oncology drug development, clinical trials often involve a smaller number of participants due to the rarity of the disease and the urgency of addressing unmet medical needs. The closer a drug gets to market, its trials demand a greater investment of human, structural, and financial resources. Only a small portion of all potential drugs are sufficiently safe and effective to be worth the high burden of Phase 3 testing.
Some drugs also require post-market studies to further confirm safety, efficacy, and optimal use.
Clinical Trial Design
The primary goal of a clinical trial used for regulatory approval is to determine whether or not a new therapy is safe and effective. Drug Sponsors and the FDA also attempt to ensure that promising new treatments reach patients in need as efficiently as possible and can do so by expediting their path to market through Expedited Pathways. The FDA must balance these goals against the unique needs of different drugs. As a result, there is a great deal of variety among clinical trial structures and designs. Here are a few major elements of clinical trial design:
- Number of Patients: The more patients enrolled in a clinical trial, the greater the statistical power, or ability to accurately predict a drug’s effects. This is why Phase 3 trials, which offer the final study of a drug’s impact before it is submitted to the FDA for approval, tend to be so large. Some drugs have unique attributes, such as very small target populations, that make large trial sizes impractical or impossible. In these cases, developers must find ways to achieve statistical confidence with fewer enrolled patients.
- Controls: Data on a drug’s impact are more interpretable when compared with that of a control group–an otherwise similar group of patients who did not receive the new drug. In clinical trials, control groups generally receive either treatment at level of the standard of care. Each group of patients receiving a distinct treatment in a clinical trial is referred to as an “arm.” Often, if it becomes clear that one arm of a trial is producing superior results, the trial will be stopped to minimize the number of patients receiving the less beneficial treatment.
- Randomization: If researchers are directly comparing an experimental drug to a control, they often assign the two drugs to patients at random. This helps to prevent bias on the part of those selecting patients, which would compromise the accuracy of the study. Where trials involve small target populations, randomization can be impractical. In these cases, researchers may employ a “single-arm” trial, in which all patients receive experimental therapy.
- Blind, Double-Blind, and Non-Blind Trials: Bias can also result from the behavior of patients and researchers who know which treatment patients receive. A study is “blind” if patients are unaware of which drug they are receiving. In a “double-blind” study, researchers are also unaware of which drugs patients are receiving and only the pharmacist knows which drugs have been assigned to which patients. “Non-blind” or “open-label” trials can be unavoidable in cases where the administration of two drugs is radically different (e.g., if a medication is being compared with physical therapy).
- Endpoints: An endpoint is the outcome that researchers measure during a clinical trial in order to determine whether or not an experimental therapy is effective. Researchers select endpoints based on clinical trial design, the nature of the condition being treated, and the anticipated effect of the drug being tested. Many trials testing cancer drugs, for example, measure how long a patient survives on a particular drug (Overall Survival), Response Rate, Progression Free Survival, and Disease Free Survival.
Developers, regulators, and patient advocates are constantly looking for ways to design more efficient trials without jeopardizing safety or accuracy. One novel approach is the Master Protocol trial design, which aims to test several drugs simultaneously by screening a central group of patients for biomarkers and assigning them to the drugs most likely to impact their unique conditions.
Participating in a Clinical Trial
Clinical trials rely on the voluntary participation of patients. While clinical trials involve more risk than FDA-approved treatments, participants are under close supervision by researchers. Participating in a clinical trial offers access to cutting-edge drugs that have yet to reach the market. Clinical trial participation is a critical part of drug development and essential to advancements in medical research and treatment of cancer.
