The Food and Drug Administration (FDA) has acknowledged for years that “good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.” According to a recent article in Forbes, this knowledge has increasingly begun to consist of off-label prescriptions, which are sometimes necessary for the practice of good medicine.
As the agency’s website recognizes, “if physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.”
In addition, the American Medical Association (AMA) believes that “physicians have the training and experience necessary to determine the best or preferred method of treatment,” including off-label prescribing, which is often be considered “reasonable and necessary medical care, irrespective of labeling.” In fact, doctors can be subject to malpractice liability if they do not use drugs for off-label indications when doing so constitutes the standard of care.
Before a drug can be sold in the U.S., it must be certified by the FDA as safe and effective for a specific, or “on-label,” use. Once approved, although physicians may legally prescribe it for any other purpose (off-label), the manufacturers of such drugs are only legally able to educate and inform physicians about the “on-label” use. Companies can re-apply through the FDA to have the original drug approved for additional uses.
But with companies recently dealing with huge settlements involving off-label fraud (Pfizer; Eli Lilly; and AstraZeneca), how exactly do physicians find this “firm scientific rationale” and “sound medical evidence?” It is especially hard for physicians and patients to learn about off-label usages of drugs because the FDA, with support from many in Congress, has sought repeatedly to limit physicians’ and patients’ discretion about treatment decisions, including restricting physicians from prescribing drugs off-label. Forbes described two examples.
First, the Food and Drug Administration Amendments Act (FDAAA), which took effect on March 25, 2008, gave the FDA sweeping new powers, which included the ability to require a Risk Evaluation and Mitigation Strategy (REMS) for any newly approved drug. According to the FDA, a REMS is “a strategy to manage a known or potential serious risk associated with a drug or biological product,” which could be said to encompass virtually any medicine. FDA noted that a REMS can include a Medication Guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system, and must include a timetable for assessment of the REMS.”
Essentially, REMS made “off-label prescribing much more cumbersome and difficult” because for safe use of a drug, FDAAA consisted required that:
– Health care providers who prescribe the drug have particular training or experience, or are specially certified;
– Pharmacies, practitioners or health care settings that dispense the drug are specially certified;
– The drug is dispensed to patients only in certain health care settings, such as hospitals;
– The drug is dispensed [only] to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
– Each patient using the drug is subject to certain monitoring; and
– Each patient using the drug is enrolled in a registry.”
In addition to these requirements that reduce physicians’ off-label prescribing, FDA also restricts drug manufacturer promotion of off-label uses, which encompasses any and all contact with health professionals or patients. Manufacturers are only able to send peer-reviewed medical journal articles and excerpts from medical textbooks to physicians and are permitted to answer questions asked directly by physicians only under certain circumstances.
The second problem arose from an October 2009 lawsuit with Allergan drug Botox, which was approved for treating muscle spasms, but has been “widely used off-label” for other medical issues. The company argued that the FDA is not authorized by the Federal Food, Drug and Cosmetics Act to “ban the distribution of truthful information about safe and effective off-label uses of medicines” because it would be an unconstitutional abridgment of commercial free speech. The federal District Court for the District of Columbia will hear oral arguments from the parties later this year, and a final decision could take years.
The trouble for Allergan and other companies was that FDA ordered the company to send detailed safety updates to physicians who prescribe Botox for both on-label and off-label indications. As a result, “the company felt that regulators had placed it in a Catch-22 situation: Complying fully with the order could violate the FDA ban on promoting drugs for off-label uses,” and result in significant fines that would threaten the company and its employees with criminal penalties.
FDA’s off-label policies have raised concerns over the past decade. In fact, “a federal district court held that the near-blanket ban on disseminating truthful and non-misleading information about off-label uses was an unconstitutional restriction of commercial speech.” The regulations were only maintained because FDA “claimed that the rules merely established a “safe harbor” under which manufacturers would be automatically deemed in compliance with the law, but that the regulations did not really prevent all off-label promotion.” Then in 2009, the agency issued a guidance document that acknowledged explicitly that drug and device firms may sometimes distribute medical journal articles and text book excerpts to physicians.
It should also be noted that FDA has issued Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices. FDA also has Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices. Both of these documents provide significant resources and guidance for companies regarding off-label promotion of drugs.
Conclusion
With recent opinion polls by the Pew Research Center showing that Americans are dissatisfied with their government, the regulation of off-label prescriptions becomes an important issue because of how many patients it affects. It is estimated, “on the basis of articles in medical journals and information gleaned from conferences” that doctors use off-label prescriptions almost “100 million times a year.” By some estimates, at least 20% of all prescriptions written are off-label, and those uses often constitute the accepted standard of care. For example, “the practice is well known in cancer and cardiac treatment, where as many as half of all prescriptions are for off-label uses. In the absence of off-label prescribing, physicians would have fewer treatment options and many patients would die or suffer needlessly.”
Moreover, a “series of national surveys commissioned by the Competitive Enterprise Institute has shown that a large majority of physician specialists–including oncologists, cardiologists, emergency room doctors, orthopedic surgeons and neurologists–believe the FDA’s policies have made it more difficult for them to learn about new uses for drugs and medical devices, and that the agency should not restrict information about off-label use.” The authors recommend that the FDA should maintain a database of information about off-label uses of drugs to make it easier for physicians and safer for patients.
Doctors should not have to worry about being sued for not using drugs for off-label indications when doing so constitutes the standard of care, and they should not be restricted from learning about them either. As the authors correctly assert, “these FDA policies compromise physicians’ ability to learn about and use new pharmaceuticals,” and should be revised to reflect the important role off-label prescribing plays in the daily practice of numerous physicians. FDA should also consider how 100 million prescriptions are going to get filled without off-label prescriptions, and who is going to pay the legal costs for doctors who are prohibited or prevented from prescribing off-label usage of drugs.
Perhaps the term off label has the wrong label, perhaps it should be referred to as investigational use.