FDA Approval Process
When the results from preclinical and clinical studies suggest that a potential new drug is safe and effective, a company will submit a new drug application (NDA) to the FDA.6 This application includes all of the preclinical and clinical data for the new drug, as well as its proposed labeling, directions for use, patent information, safety updates, and potential for drug abuse or misuse. Once the FDA receives the application, it decides whether the application is complete or not. Incomplete applications are not filed and are not reviewed. Complete applications must be reviewed and a decision issued by the FDA within 6 to 10 months.6
During the review of the NDA, members of the FDA review team with different specialties review the application sections.6 The review team evaluates the application for the quality of the data; and any fabrication, manipulation, or withholding of data. After they interpret the data, the FDA review team then makes a recommendation of whether the potential new drug should be approved or not, and a senior FDA official makes the final decision.
FDA approval is granted when the NDA shows a drug to be both safe and effective for its intended use.6 The prescribing instructions and labeling are refined. If the NDA does not contain sufficient information, or other questions arise, then the FDA may call an advisory committee. This committee is made up of external experts, who review the application and provide their advice to the FDA. The FDA may take the advisory panel’s recommendations into consideration when making a final determination.
Because the drug-development process can be long, and there is a great need for new safe and effective drugs, the FDA has several tracks that it employs that can expedite the drug-approval process, which enables a drug to be reviewed by FDA more quickly than through the traditional approval pathway. These pathways include a fast-track designation, a breakthrough therapy designation, an accelerated approval pathway, and a priority review designation.7 All of these tracks are designed to reduce the development and/or FDA review period and are typically reserved for compounds that are thought to show promise in preclinical and/or early clinical testing. These additional tracks are commonly used in oncology because cancer is a life-threatening disease and, particularly in metastatic disease, there is a great unmet need for new therapies.
Oncology drugs are the most common type to use the accelerated approval pathway, which frequently approves drugs based on a single, small clinical trial that may or may not be randomized with a control group.8 When drugs are approved through the accelerated approval pathway, the FDA requires that a confirmatory trial be conducted after approval to ensure efficacy and safety.
Once a drug is approved, the company is given permission to market its drug for the approved indication. When the company is ready to manufacture and distribute the drug, it is available to be prescribed by clinicians. Drug advertising is regulated by the FDA, and all advertisements must only be for the approved indication and must be truthful in regard to the drug’s effectiveness and potential side effects.9 The FDA also continues to review any problems or adverse events that may be reported about the drug and monitors drug manufacturing facilities both within the United States and in other countries.
Drugs prescribed according to the indications listed on their label are considered “on-label” uses. However, sometimes drugs are used for indications outside of those listed on the drug’s label, a practice that is known as “off-label” prescribing. A drug is approved for a specific indication because the FDA reviewed data that were specific to that indication.6 Therefore, when a drug is used off label, there are typically few data to support its use for that off-label indication. However, there is usually something about the drug, such as its mechanism of action, that suggests it could be an effective treatment approach for that off-label use. In some cases, clinical practice guidelines recommend the use of a drug off label because published preliminary studies suggest there could be a benefit.10
Off-label use is common in oncology: It is estimated that chemotherapies are used off label in 13% to 71% of patients, and that up to 62% of targeted therapies are used in this way.10 Although off-label agents are used throughout the field of oncology, they are most commonly used among patients with metastatic disease or those in palliative care, and among patients with cancer of the breast, pancreas, head and neck, or ovaries.10
Patients may also be treated with drugs that have not yet been approved by the FDA by enrolling in clinical trials. In addition, the FDA has a program that enables patients to have access to investigational drugs through compassionate use. In May 2018, the US government passed a “right-to-try” (RTT) law.11 This law allows patients who are unable to participate in clinical trials to use investigational drugs outside of the clinical trial setting, after they have tried all other established treatment options.12 Patients have the right to ask their clinician about investigational drugs, but clinicians are not required to help patients get access to these drugs. And, there is no guarantee that drug companies approve the request for the drug, or that insurance providers cover the expense of this investigational therapy.12
- U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Website. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Accessed July 11, 2019.
- Dhingra K. Oncology 2020: a drug development and approval paradigm. Ann Oncol. 2015;26:2347-2350.
- US Food and Drug Administration. The drug development process: step 1: discovery and development. Reviewed January 4, 2018. Accessed July 8, 2019.
- US Food and Drug Administration. The drug development process: step 2: preclinical research. Reviewed January 4, 2018. Accessed July 8, 2019.
- US Food and Drug Administration. The drug development process: step 3: clinical research. Reviewed January 4, 2018. Accessed July 8, 2019.
- U.S. Food and Drug Administration. The Drug Development Process: step 4: FDA Drug Review. Reviewed January 4, 2018. www.fda.gov/patients/drug-development-process/step-4-fda-drug-review. Accessed July 8, 2019.
- Sherman RE, Li J, Shapley S, Robb M, Woodcock J. Expediting drug development — the FDA’s new “breakthrough therapy” designation. N Engl J Med. 2013;369:1877-1880.
- Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318:626-636.
- US Food and Drug Administration. The drug development process: step 5: FDA post-marketing drug safety monitoring. Reviewed January 4, 2018. Accessed July 8, 2019.
- Saiyed MM, Ong PS, Chew L. Off-label drug use in oncology: a systematic review of literature. J Clin Pharm Ther. 2017;42(3):251-258.
- American Society of Clinical Oncology. ASCO in Action brief: right-to-try and expanded access to investigational drugs. Published May 9, 2018. www.asco.org/advocacy-policy/asco-in-action/asco-action-brief-right-try-and-expanded-access-investigational-drugs. Accessed July 8, 2019.
- Brown B, Ortiz C, Dubé K. Assessment of the right-to-try law: the pros and the cons. J Nucl Med. 2018;59(10):1492-1493.