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the background Innovation in drug therapy often occurs in the unregulated “o=-label” use of drugs. The term off-label comes from the FDA’s regulation of what uses a drug is approved for and what claims a pharmaceutical company is allowed make about any approved drug. Because all of this information is included in the drug’s labeling , using a drug for an unapproved purpose has come to be called “o=-label use.” Central to the FDA’s marketing approval process is the approval of a drug’s labeling, which technically includes the label a;xed to the drug’s container, a package insert that accompanies the drug and contains full information about its e=ects, and certain advertising. The label information, whether on the container, on the package insert, or in any advertising or promotion, is limited to describing the drug’s use only for the approved doses and routes of administration for the approved medical condition. The use of a drug under circumstances not included in the labeling is considered to be a nonapproved, or o=-label, use. Pharmaceutical companies are forbidden by law to promote o=-label drug use unless they follow narrow “safe harbor” conditions.1 However, because the FDA does not regulate the practice of medicine, physicians may prescribe a drug for an o=-label use if it seems reasonable or appropriate. Physicians possess a largely unfettered professional prerogative to use approved drugs for any medically reasonable purpose, and a significant amount of o=-label drug use is introduced as medical practice innovation and not as research. O=-label use can start when a physician guesses, based on what is known about a drug and/or a disease, that a Innovation in the O=-Label Use of Drugs chapter three drug might also be useful for another medical condition. Physicians also obtain information about o=-label use from the medical literature (physicians sometimes write case reports of nonapproved uses) and from colleagues, who often relate their experiences with o=-label use at professional meetings. It is easiest to explain o=-label use of drugs with an example. One involved the use of theophylline for patients with a lung condition called chronic obstructive pulmonary disease (COPD), the major symptom of which is shortness of breath. Theophylline was known to relax and dilate the airways in patients with asthma and was approved for use in patients with that condition. The drug was also widely used for decades in adults with nonasthmatic COPD. Even though there was no pharmacologic reason to believe that the drug would work and it was known that the drug could be quite toxic, many physicians prescribed theophylline for COPD because many patients had reported that it helped their breathing. Finally , research was conducted which showed that, at su;cient blood levels, the drug improved lung function compared with placebo treatment and was tolerable (Eaton et al. 1980). During the years that theophylline was being prescribed for COPD without any research data to support its use, many patients undoubtedly benefited. This example explains why many physicians would object if the FDA interfered with their professional judgment to use an approved drug for an unapproved purpose. Regulation, they say, would stifle the significant advances that can be made with drug treatments. Conversely, proponents of regulation believe that unresearched o=-label drug use is risky and needs oversight, because no research has advised the physician about whether a drug works consistently. Also, o=-label drug use, even if widespread, does not serve to inform the medical community about the full consequences of the use—what conditions maximize its benefit and minimize its toxicity. Only systematic and controlled research can accomplish that goal, they argue. In the theophylline example, research showed doctors that doses of the drug below certain levels produced no clinically significant improvements in lung function while subjecting the patient to the risk of toxicity. Finally, some who would change the status quo are troubled by the fact that most patients are not told by their physicians that the drug they have been prescribed has not been approved for use in their condition (Beck and Azari 1997; Salbu 1999; Zindrick 2000). If research and regulation do not govern the o=-label use of drugs, what does? Physicians are held to the “standard of care” within the medical community. Legally, the standard of care is determined by what expert physicians will testify is considered generally accepted practice by other...

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