Feature Articles
Clinical Trials and FDA Review Safety and Effectiveness of New Drugs
New drugs are an important part of today’s healthcare. These new drugs make millions of people's lives better every day. For over 90 years, the U.S. Food and Drug Administration (FDA) has been responsible for protecting the public health, by ensuring that these new drugs and all prescription and nonprescription medications are “safe and effective”. Before any new drug can be sold, the drug's manufacturer must prove this safety and effectiveness to the FDA and receive “FDA approval”.
An evaluation by the FDA, called a review, ensures that drugs meet standards for safety, effectiveness and quality. It takes on average 12 years and over $500 million to get a new drug from the laboratory onto the pharmacy shelf.1 In 2008, a total of 98 new drugs were approved by the FDA.2
Preclinical Testing
If you are a patient interested in learning about how trials test the safety and effectiveness of new drugs and treatments or are intersted in participating in a clinical trial, read some of the basic FAQs in the new Clinical Trials section for patients.
Once a company develops a drug, it undergoes about 3 years of laboratory testing before an application is made to the FDA to begin testing the drug in humans. The drug company must show the FDA results of preclinical testing they've completed in laboratory animals and what trials they propose for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans. Only about one in 1000 of the drugs that enter preclinical laboratory testing will ever make it to human testing. If the FDA grants its approval, the "investigative" drug will then enter the three phases of clinical trials.
What is a Clinical Trial?
A clinical trial or study is a type of research study that tests how well new medical approaches work in people. These trials evaluate the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people. The results describing how well a drug performed at treating a specific condition are often compared against any existing or standard treatments currently approved for those patients. Within this comparison, there are four possible outcomes for a clinical trial:
• Positive trial – The clinical trial shows that the new treatment has a large beneficial effect and is superior to standard treatment.
• Non-inferior trial – The clinical trial shows that the new treatment is equivalent to standard treatment. Also called a non-inferiority trial.
• Inconclusive trial – The clinical trial shows that the new treatment is neither clearly superior nor clearly inferior to standard treatment.
• Negative trial – The clinical trial shows that a new treatment is inferior to standard treatment.
The Phases of Clinical Testing
• Phase 1 studies are usually conducted in healthy volunteers. These studies determine the most frequent side effects of the drug and how the drug is used, broken down and excreted from the body. The number of subjects typically ranges from 20 to 80. If the drug’s side effects are found to be unacceptable, development of this drug stops here. If Phase 1 studies are acceptable, and do not reveal unacceptable side effects, Phase 2 studies may begin.
• Phase 2 studies investigate whether the drug works in people who have a certain disease or condition. Patients receiving the drug are usually compared with similar patients receiving a different treatment – usually an inactive substance called a placebo. These trials will determine if the new treatment has a beneficial effect and if it is superior or equivalent to standard treatment. Safety continues to be evaluated and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300. If the drug’s side effects are found to be unacceptable, or if the drug is not effective, development of this drug ends here. If Phase 2 studies have positive results and show evidence of the drugs effectiveness, the company begins to plan for Phase 3 studies. At the end of Phase 2, the FDA and the drug company meet to determine how many people will be included in the phase 3 studies.
- Preclinical testing on animals (3 years)
- Investigational new drug application outlines human clinical trials
- Phase 1 studies on 20 to 80 healthy people (1 year)
- Phase 2 studies on dozens to 300 patients (2 years)
- Phase 3 studies on hundreds to 3,000 patients (3 years)
- Meetings between manufacturers and FDA
- Submission of New Drug Application (NDA) for FDA approval
- FDA has 60 days to decide if it will review the NDA
- If accepted, FDA assigns a review team to the NDA (2.5 years)
- FDA reviews the drug’s proposed labeling
- FDA inspects the manufacturer’s facilities
- FDA review team finds the drug “approvable” or “not approvable”
All times are approximate.3
• Phase 3 studies gather more information about safety and effectiveness by testing the drug in much larger groups of people. Researchers look at different populations, different dosages and how the drug works in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the drug’s side effects are found to be unacceptable or if the drug is not effective, development of this drug ends here. If Phase 3 studies have positive results and show evidence of the drugs effectiveness, the company prepares to submit a New Drug Application (NDA). This is the formal step a drug manufacturer takes to ask for FDA approval to sell and market the drug in the United States.
The FDA Review and Approval Process
An NDA includes all animal and human data and analyses of all the information, along with information about how the drug behaves in the body and how it is manufactured. The company then submits the application (usually about 100,000 pages) to the FDA for approval, a process that can take up to two and a half years. Once a new drug application is filed, an FDA review team consisting of medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts evaluates whether the studies the manufacturer submitted show that the drug is safe and effective for its proposed use.
No drug is absolutely safe; all drugs have side effects. "Safe" in this sense means that the benefits of the drug appear to outweigh the risks. The review team analyzes study results and looks for possible issues with the application, such as weaknesses of study design or analyses. Reviewers determine whether they agree with the manufacturer's results and conclusions, or whether they need any additional information to make a decision.
Post-marketing Testing
If the drug receives final approval, it becomes available for physicians to prescribe. At this stage, the drug company will continue to report cases of adverse reactions and other clinical data to the FDA. Often the FDA will require the company to perform additional studies after the drug is approved in order to gather additional information about a drug's safety, effectiveness or optimal use. These are referred to as Phase 4 or post-marketing study commitments.
The Drug Label
The Food and Drug Administration (FDA) is an agency within the Department of Health and Human Services that assures the safety, effectiveness, and security of medical drugs and devices, our nation’s food supply, cosmetics, and products that emit radiation.
The agency is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.5
The FDA requires numerous clinical trials to prove a drug's safety and effectiveness in treating a given disease or condition. If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language for the drug’s label, including how the drug is given to patients, what sized doses are given, and other information for physicians to properly administer the drug to patients. The FDA will approve each drug only for one or more specific indications (diseases and conditions), and the use of the drug for these reasons is referred to as “on-label”. The use of a drug for a purpose other than what is in the drug's approved label is known as “off-label” use.
“Off-Label” Prescribing
Once a drug has been approved for one purpose, physicians are free to prescribe it for any other purpose that – in their professional judgment – is both safe and effective. They are not limited to official, FDA-approved indications printed on the label. This off-label prescribing is done when medications have been found to be effective for new uses but have not had the formal (and often costly) applications and studies required by the FDA to approve the drug for these new indications.4 However, when physicians use a drug to treat a different indication there is usually extensive medical literature to support the off-label use. Erythropoietin and darbepoietin, for example, are commonly prescribed off-label for various types of anemia including anemia of chronic disease, anemia in the elderly, and postpartum anemia.
The FDA has an elaborate clinical process that examines new drugs for distribution to the public with its seal of approval. Currently, FDA approves drugs after they are studied in many more patients and undergo more detailed safety evaluation than ever before. FDA grants approval to drugs after a manufacturer demonstrates that their benefits outweigh their risks for a specific population and a specific use, and that the drug meets standards for safety and effectiveness. This intricate, expensive, and lengthy procedure is in place to ensure patient safety and provide enough evidence for doctors to make sound medical decisions.
References
- U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Improving public health through human drugs, 2007 Update. Link. Accessed: July 15, 2009.
- U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Drugs@FDA. Original New Drug Application (NDA and BLA) Approvals. Link. Accessed: August 19, 2009.
- U.S. Food and Drug Administration. The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective. Link. Accessed: July 15, 2009.
- Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006 Mar-Apr;25(2):420-28. Link.
- U.S. Food and Drug Administration. About FDA. What we do. Link. Accessed: August 12, 2009.
Last Updated: August 19, 2009
Last Updated: October 28, 2009
