Complete Your CE Test Online - Click Here 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. 9. The FDA reviews information that goes on a drug’s professional labeling (information on how to use the drug). 10. The FDA inspects the facilities where the drug will be manufactured as part of the approval process. 11. FDA reviewers will approve the application or find it either “approvable” or “not approvable.” The quality of clinical data The FDA relies on data that sponsors submit to decide whether a drug should be approved. To protect the rights and welfare of people in clinical trials and to verify the quality and integrity of data submitted, the FDA’s Division of Scientific Investigations (DSI) conducts inspections of clinical investigators’ study sites. DSI also reviews the records of institutional review boards to ensure they are fulfilling their role in patient protection. DSI seeks to determine such things as whether the study was conducted according to the investigational plan, whether all adverse events were recorded, and whether the subjects met the inclusion/exclusion criteria outlined in the study protocol. Following each inspection, FDA investigators prepare a report summarizing any deficiencies. In cases where they observe numerous or serious deviations, such as falsification of data, DSI classifies the inspection as “official action indicated” and sends a warning letter or a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator, specifying the deviations that were found. The NIDPOE begins an administrative process to determine whether the clinical investigator should remain eligible to receive investigational products and conduct clinical studies. CDER conducts about 300 to 400 clinical investigator inspections annually. About 3 percent are classified in this “official action indicated” category. The FDA established an independent Drug Safety Oversight Board (DSOB) in 2005 to oversee the management of drug safety issues and communication to the public about the risks and benefits of medicines (FDA, 2016). The board’s responsibilities include conducting timely and comprehensive evaluations of emerging drug safety issues, selecting drugs to be placed on a drug watch website for health professionals and patients, and ensuring that experts both inside and outside of the FDA give their perspectives to the agency. Drug nomenclature Three name classifications of drugs are the chemical, or scientific name; the generic name; and the brand or trade name (Smith-Marsh, 2018): 1. Chemical (scientific) name: Drugs often have several names. When a drug is first discovered, it is given a chemical name, which describes the atomic or molecular structure of the drug. The chemical name is thus usually too complex and cumbersome for general use. Next, a shorthand version of the chemical name, or a code name (such as RU 486), is developed for easy reference among researcher. Page 44 Massage.EliteCME.com