Education

Additional Clinical Trial Development Education Resources

Food and Drug Administration: From Test Tube to Patient
CISCRP: An Introduction to Clinical Trials

Overview of the Drug Development Process

Introduction

Of the thousands of molecules that begin the development process, only a few make it to the next stage of testing these new molecules in humans. The drug development process has evolved into an extremely complex procedure, typically taking in most countries an average of 10-15 years from the time experimental molecules are first discovered to when they become commercially available as a therapeutic option for patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

The discovery process usually begins using computer technology that can analyze tens of thousands of new molecules for their potential to treat or prevent various human diseases. Selected molecules must then undergo extensive preclinical (prior to human) testing or laboratory research that can include years of study involving animal subjects and human cells. This testing is intended to show biological activity of the molecules against the targeted disease and evaluate the molecule for safety. Data collected from these studies are then analyzed to determine and compare the potential risk of the molecule versus the potential benefit of treating (or preventing) the disease. If this stage of testing is successful, the data are provided to an appropriate government health agency (e.g., U.S. Food and Drug Administration [FDA], Agence Française de Sécurité Sanitaire des Produits de Santé [AFFSAPS]) requesting approval to begin testing the drug in humans. In the United States, this request is called an Investigational New Drug application (IND).

Controlled testing of potential new treatments in humans is performed in "clinical trials." These trials are designed to test whether the experimental medicines are safe and effective for use in humans. Testing also determines the most effective dose of the new medicine and the side effects that may be experienced. These trials usually test the investigational drugs against the current standard of care, other medicines currently available to treat the targeted disease, or to placebo (an inactive substance that looks like the investigational drug, sometimes referred to as a sugar pill). The purpose of these tests is to determine whether the experimental medicines have any advantage in safety or effectiveness compared to other pharmaceutical options.

Four Phases of Clinical Studies in Humans

Phase 1 Trials

Clinical trials are organized into four categories, called phases. Phase 1 trials are primarily concerned with assessing the drug’s safety and tolerability and are the first step in testing new investigational medicines in humans. The patients in these trials usually number 20-100 and the trials may last several months. In addition to studying the investigational drug’s safety profile including the safe dosage range, these trials are designed to determine what happens to the investigational drug in the human body and how the investigational drug is absorbed, distributed, metabolized, excreted, and its duration of action. A Phase 1 trial will also investigate side effects that occur as dosage levels are increased. Except for drugs used to treat cancer, Phase 1 clinical trials are usually conducted in normal, healthy individuals and are not intended to treat (or prevent) disease or illness. Because cancer can be such a life-threatening condition, Phase 1 trials with anti-cancer drugs are usually carried out in patients who already have the disease.

Phase 2 Trials

Once a drug has been shown to be safe, it must still be tested for efficacy; that is, whether or not the experimental medicine has a desired effect on the targeted disease. Phase 2 trials are therapeutic studies to evaluate efficacy and to assess short-term safety of the study drug in patients suffering from a disease or condition for which the study drug is intended. This phase also determines appropriate dose ranges/regimens and, if possible, clarification of dose-response relationships to provide an optimal background for the design of larger therapeutic trials. Phase 2 trials are usually randomized, meaning that patients receiving treatment are divided between those that are administered the investigational drug, some that receive a comparable drug currently used to treat the targeted disease, and those that receive no drug (commonly referred to as placebo, an inactive substance that looks like the investigational drug). These trials are usually "blinded," a term used to describe that the researchers and patients are not aware of which group of patients is receiving the experimental drug and which group is not. The reason for "blinding the study" is to prevent bias from the researcher and patient when determining the effect experienced from the study medicines. In this manner, the trial can provide the investigators and the regulatory agency (e.g., FDA) comparative information about the relative safety of the new drug and its effectiveness. The number of patients in this phase of development typically ranges from 100 to 500 volunteer patients with disease. Typically, Phase 2 trials last from several months to up to 2 years.

Phase 3 Trials

Phase 3 trials, also referred to as registration or confirmatory trials, are designed to demonstrate efficacy and safety of the investigational drug or line extension in a larger population of patients with the disease that the drug is intended to treat. This requires large trials with patients who have the disease and involves comparing the investigational drug to comparator drugs and/or placebo. These trials usually enroll between 1,000 and 5,000 patients, last for 3 years or longer, and are conducted in a hospital or clinic setting. Physicians monitor the patients closely to confirm efficacy and identify adverse events from long-term use. Phase 3 trials provide evidence on whether a drug “works,” what dose should be used, what the risks of the molecule are, which patients may benefit from the therapy, and other information in determining whether the drug should be used in humans. Once Phase 3 trials are successfully completed, they are submitted to regulatory health agencies (e.g., FDA, European Medicines Agency [EMEA]) for review and possible marketing approval. Results of Phase 3 trials will determine the product labeling/prescribing information and how physicians are instructed to use the drug.

Phase 4 Trials

Phase 4 clinical trials are often called "post-marketing" trials because they begin after the Phase 1, 2, and 3 trial results have been given to the regulatory agency for review and marketing approval. Phase 4 trials usually enroll between several hundred to several thousand patients and may be designed to further evaluate safety in large populations; to determine if the drug is effective against other disease states; to test different ways of taking the drug such as tablets, time-release capsules, or syrups; and/or to determine the cost-effectiveness of the new drug relative to traditional other new therapies. Phase 4 trials typically occur throughout the life cycle of the approved medicine and are often required as a condition of marketing approval.

The following table is a summary of the different stages of the drug development process.

The Drug Discovery, Development, and Approval Process

It takes 10-15 years on average for an experimental drug to travel from the lab to US patients.
Only five in 5,000 compounds that enter preclinical testing make it to human testing.
One of these five compounds tested in people is approved.

Reference: “The Drug Discovery, Development and Approval Process,” Pharma New Medicine, (October 2004), page 43.