drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured. When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete, for example, if some required studies are missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA’s Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of new drug applications for standard drugs no later than 10 months after receiving the application. The review goal is six months for priority drugs. There is also continuous interaction throughout the review process. For example, over roughly six years, the sponsor, Merck Research Laboratories of West Point, Pa., and the FDA had several face-to-face meetings and about 28 teleconferences regarding the asthma drug Singulair (montelukast sodium). Reviewing applications Though FDA reviewers are involved with a drug’s development throughout the IND stage, the official review time is the length of time it takes to review a new drug application and issue an action letter – an official statement informing a drug sponsor of the agency’s decision. Once a new drug application is filed, an FDA review team – medical doctors, chemists, statisticians, microbiologists, pharmacologists and other experts – evaluates whether the studies the sponsor 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 the study design or analyses. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need additional information to make a decision. Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors and office directors, depending on the type of application. Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency. Sometimes, the FDA calls on advisory committees made up of outside experts, which help the agency decide on drug applications. Accelerated approval Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available. Instead, less traditional measures, called surrogate endpoints , are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti- retroviral drugs. Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA’s orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three
large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood. Most drugs used to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don’t confirm the initial results, the FDA can withdraw the approval. Because the pre-market review can’t catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a post-marketing surveillance program. Bumps in the road If the FDA decides that the benefits of a drug outweigh the risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA, or if more information is necessary to make that determination, the FDA may decide that a drug is “approvable” or “not approvable.” A designation of approvable means that the drug can probably be approved, provided that some issues are resolved first. This might involve the sponsor and the FDA coming to a final agreement on what should go on the drug’s labeling, for example. It could also involve more difficult issues, such as the adequacy of information on how people respond to various dosages of the drug. A designation of “not approvable” describes deficiencies significant enough that it is not clear that approval can be obtained in the future, at least not without substantial additional data. Common problems include unexpected safety issues that crop up or failure to demonstrate a drug’s effectiveness. A sponsor may need to conduct additional studies including perhaps studies of more people, different types of people, or for a longer time period. Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices , and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn’t ready for inspection, approval can be delayed. Any manufacturing deficiencies found would need to be corrected before approval. The FDA outlines the justification for its decision in an action letter to the drug sponsor. When the action is either approvable or not approvable, CDER gives the sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the sponsor can choose to ask for a hearing or correct any deficiencies and submit new information, or they can withdraw the application. Drug review steps Preclinical (animal) testing: 1. An investigational new drug application (IND) outlines what the sponsor proposes for human testing in clinical trials. 2. Phase 1 studies (typically involve 20 to 80 people). 3. Phase 2 studies (typically involve a few dozen to about 300 people). 4. Phase 3 studies (typically involve several hundred to about 3,000 people). 5. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet. 6. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval. 7. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. 8. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
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