After developing a potential therapy, the next step is to conduct studies prior to testing the therapy in human volunteers to assess its potential harmful effects and safety. 

The FDA has developed regulations called good laboratory practices (GLP) that are required for preclinical studies.  These are designed to assure study safety and include items such as personnel, facilities, equipment used, operating procedures, and reporting.

Preclinical studies may be conducted in vitro (a laboratory environment) or in vivo (with a living organism) to obtain detailed information on dosing and toxicity to determine whether the therapy should be tested in humans.

Phase 1 trials are generally conducted in a small number of individuals and intended to assess the product’s safety, tolerability, and dosage of a therapy and for many new candidates researchers will conduct testing on normal volunteers (healthy people). The exception is if a new drug is intended for use in cancer patients, researchers may conduct Phase 1 trials in patients with that type of cancer.

Phase 1 trials are closely monitored and gather information and evaluate the effects of the product candidate on the body and what happens once administered.  Dosing is often adjusted based on preclinical data to determine side effects and the level the body can safely tolerate.

This safety and dosage information about the effectiveness of the therapy is used to determine the best way to administer the therapy to limit risks and maximize potential benefits. If an acceptable safety profile is demonstrated, the candidate is advanced to a Phase 2 trial. 

Phase 2 clinical trials are generally designed to study the safety and tolerability of the product candidate in a larger group of individuals and to evaluate the early efficacy in patients with the disease or condition for which the product is being developed.  For cancer trials, a placebo (inactive treatment) is typically not used in Phase 2 trials and outcomes may have an a broader assessment of the effectiveness of the treatment if there is a large unmet need.

The definition of success for Phase 2 cancer trials depends on the goal of the treatment. Aside from demonstrating safety, a positive outcome may mean the cancer shrinks, disappears, doesn’t grow or doesn’t return for an extended period of time. In addition, many clinical trials evaluate if the patients undergoing the new treatment live longer than most other patients with the same cancer do without the treatment. 

For some cancers the regulations may allow therapies for serious conditions that fill an unmet need to be approved more quickly through FDA special programs such as fast track, breakthrough therapy, accelerated approval, and priority review if the product candidate demonstrates early safety and a survival benefit over existing therapies.  

If a product candidate meets its Phase 2 endpoints (goals for safety and other criteria), a Phase 3 trial is conducted with a large number of participants to further determine efficacy and compare it to existing therapies or placebo.  In most instances, the Phase 3 trials compare the product candidate with the current standard of care, if available, and also continues to monitor side effects and collect safety data. Some Phase 3 trials also study the product candidate in combination with other FDA approved therapies.

If accelerated approval was not granted after Phase 2, this third phase is the final step before submitting an investigational product to a regulatory agency for market approval. The regulatory health authority, such as the U.S. Food and Drug Administration (FDA), will review the results of the clinical trials up to and including the Phase 3 trial to determine whether to approve a new product candidate.

Phase 4 clinical trials are part of Post-Market Safety Monitoring which is conducted once the investigational product candidate has been approved by FDA and other regulatory agencies. 

These trials continue to assess the safety and efficacy of the new product along with its long-term effects in a real world setting. They may take place over many years and usually involve a large number of participants.

Even though Phase 1, 2, and 3 clinical trials provide important information on an investigational product’s efficacy and safety, limitations exist and therefore the safety and effectiveness of a product continues to be monitored over the years of a product’s lifetime in the marketplace.