FDA Approval and "Off-Label" Use

By JAMES M. BECK and ELIZABETH D. AZARI
Partners in the law firm of Pepper Hamilton LLP, Philadelphia, PA.

Excerpted from: http://www.fdli.org/pubs/Journal%20Online/53_1/art9.pdf
(see link for full text and legal references)

    The notion that off-label use is itself a "risk" is one of two common misperceptions addressed in this article. The second is that all off-label treatment is ipso facto "investigational" or "experimental."
    It is an accepted principle that once FDA determines that a drug or device can be marketed, a physician’s discretionary use of that product (the practice of medicine) is not restricted to the uses indicated on FDA-regulated labels.
    Off-label use is widespread in the medical community and often is essential to giving patients optimal medical care, both of which medical ethics, FDA, and most courts recognize. Even so, the public (and an occasional court) mistakenly presumes that all off-label treatment is investigational or experimental and that physicians therefore should inform their patients of this whenever an off-label use is proposed.
    All medical treatments, including off-label treatments, have medical risks; and patients must be informed of medical risks. There is no question that patients should be advised if a proposed treatment is truly investigational or experimental, as those concepts are understood as a matter of medical ethics or food and drug law. The mere fact of off-label use, however, is a matter solely of FDA regulatory status and cannot logically be considered a medical risk of a drug or medical device. Nor is off-label use inherently experimental or investigational, the latter being an FDA term of art. Because FDA regulatory status of medical devices and drugs is irrelevant to the nature, risks, benefits, or alternatives of medical procedures, there is and should be no legal or ethical obligation for physicians to discuss FDA regulatory status issues with their patients. Expanding the doctrine of informed consent beyond medical matters — the nature of the treatment, how it may help the patient, what might go wrong, and possible alternative therapies — would confound patient decision making by diverting attention to medically irrelevant information. In addition, such a rule would force physicians to learn and discuss legal/administrative (rather than medical) facts — potentially to their detriment and to the detriment of their patients. Rather than use FDA regulatory status as a sort of proxy (a seal of approval) for medical risks and benefits, the law quite properly requires physicians to discuss these issues with their patients directly.

A.  Off-Label Use is Legal, Common, and Necessary

FDA never has had authority to regulate the practice of medicine; physicians may use legally marketed drugs or devices in any way that they believe, in their professional judgment, will best serve their patients.  Courts have repeatedly recognized the propriety of off-label use, and several states statutorily recognize off-label use in various contexts.  New Jersey is typical of such states, in that it requires medical  insurers to pay "for treatments other than those stated in the labeling approved by the FDA."  The New Jersey legislature found that off-label use "is legal when prescribed in a medically appropriate way," "conform[s] to the way in which appropriate medical treatment is provided," and is often "necessary and appropriate treatment."  FDA itself recognizes the value and propriety of off-label use. In 1982, the FDA Drug Bulletin informed the medical community that "once a [drug] product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling."  The agency went on to state that "unapproved" or more precisely "unlabeled" uses may be appropriate and rational in certain circumstances, and may, in fact reflect approaches to drug therapy that have been extensively reported in medical literature . . . . Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations.
    The policy set forth in that Drug Bulletin has been reaffirmed by the agency on numerous occasions.  In 1993, responding to questions regarding off-label use of certain bone screws, FDA stated that in practice, surgeons often use orthopedic screws which FDA has cleared for other purposes . . . as pedicle screws. Such use of medical devices for non-approved purposes has traditionally been regulated by the hospitals in which the physicians practice and not by the FDA.  In a letter to Joseph Barton, Chairman of the Subcommittee on Oversight and Investigation of the House Committee on Commerce, FDA recently reiterated to Congress that the agency does not regulate the practice of medicine.

"Off-label" use of FDA-approved drugs provides efficacious drugs at a lower cost. To require that all appropriate uses of a drug undergo approval by the FDA may substantially increase the cost of drugs and delay or even deny patients’ ability to obtain medically effective treatment. FDA approval for each use would require substantial expenditure and time to undergo the clinical trials necessary to obtain FDA approval.
   Off-label use is not only legal and ethical, but is a common and integral feature of medical practice.  The pace of medical discovery invariably runs far ahead of FDA’s regulatory machinery, and off-label use is frequently "state-of-the-art treatment."  New uses for drugs are often discovered after FDA approves the package inserts that explain a drug’s approved uses. Congress would have created havoc in the practice of medicine had it required physicians to follow the expensive and time-consuming procedure of obtaining FDA approval before putting drugs to new uses. Thus Congress exempted the practice of medicine from the FDCA (Food Drug and Cosmetics Act) so as not to limit a physician’s ability to treat his patients.  Thus, undue restrictions on off-label use would have adverse health consequences.  FDA understands this, and has acknowledged the importance of off-label use at FDLI meetings and elsewhere.
    The medical community also has emphasized the need for off-label use.   For example, the editor of the Journal of the American Medical Association testified before Congress that prescribing FDA-approved drugs for off-label (unlabeled) uses often is necessary for optimal patient care. For a product to have the most effective potential benefits, law and regulation should and must follow, not precede, science. There are too many variations in clinical circumstances and too much time delay in regulations to allow the government to impede the physician’s ability to practice in these regards when it is medically appropriate.
    Off-label uses of medical devices and drugs perform an important therapeutic role in many, if not most, areas of medical practice. Prescriptions for off-label uses of drug products "may account for more than 25% of the approximately 1.6 billion prescriptions written each year, with some recent estimates running as high as 60%."  Examples of medical conditions whose standard treatments involve or have involved extensive off-label use include cancer, heart and circulatory disease,  AIDS, kidney diseases requiring dialysis, osteoporosis, spinal fusion surgery, and various uncommon diseases.80 Pediatric uses also are mostly off-label.  Thus, "in some cases, if you didn’t use the drug in the off-label way, you’d be guilty of malpractice." 

B.  Off-Label Use is Neither "Research" Nor "Experimental"

    The mere fact that a product is used off-label to treat a patient does not make that use research. As a matter of medical ethics, there is a distinction between the "practice of medicine" and "research."  Medical therapy aims at relieving the suffering of people and restoring them to health. It attempts to cure diseases, correct disorders, and bring about normal bodily functioning. Its focus is on the individual patient, and his or her welfare is its primary concern. Medical research, by contrast, is a scientific enterprise. Its aim is to acquire a better understanding of the chemical and physiological processes that are involved in human functioning. It is concerned with the effectiveness of therapies in ending disease . . . . But this concern is not for the patient as an individual. Rather it is directed toward establishing theories. The hope, of course, is that this theoretical understanding can be used as a basis for treating individuals. But helping a particular patient get well is not a goal of medical research.
    Thus, when devices and drugs are used off-label as part of the practice of medicine, "the primary purpose . . . is to benefit the individual patient."  These distinctions were explained by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in its 1978 Belmont Report, prepared for the President of the United States.
    It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other.
    For the most part, the term "practice" refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success.   By contrast, the term "research" designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge . . . . Research is usually described in a formal protocol that sets forth an objective and a set of procedures to reach that objective. Nor does a physician’s use of medical devices or drugs off-label convert them into experimental or investigational products.  "A treatment found to be in accordance with generally accepted standards of medical practice would hardly be experimental."  As one leading medical ethicist explained, "many drugs and devices approved for use by the FDA are prescribed for uses that are not listed on the FDA-approved package label. This does not mean that all such uses must be made the object of a formal study designed to establish safety and efficacy."  Because FDA pre-market review of drugs and medical devices involves extensive scrutiny, the agency ordinarily has reasonable assurance that marketed products are safe, both for their labeled uses and for general use.
    ... Accordingly, the consensus position is that off-label use of medical devices and drugs by physicians seeking the optimal treatment for their patients is not equivalent to research, investigational, or experimental treatment. "The mere fact of a departure from the manufacturer’s recommendation where such departure is customarily followed by physicians . . . does not make that departure an ‘experiment.’ There was in this case no evidence of experiment and the instructions concerning ‘experiment’ should not have been given."  "Off-label" is merely a regulatory description of the use of a medical device or drug — a legal status, not a medical fact.  A product’s regulatory status can change over time.   If FDA were to allow a labeling change for a drug or medical device that added a use that is currently off-label, that regulatory decision would not make any patient’s treatment more likely to succeed; nor would it reduce the risk of any complication. "The status of the drug with the FDA does not alter the relationship between drug manufacturer, physician and patient."
    Unfortunately, terminology problems persist. It is common parlance to say that a drug or device is FDA "approved" for a given use if that use appears on the label.  The converse proposition, however, (which is decidedly not true) would be that such products are "unapproved" for all unlabeled uses. This erroneous concept of unapproved use takes on derogatory connotations if divorced from a regulatory context, as would be the case in an informed consent discussion. To those unfamiliar with FDA regulation, a group that includes most patients, unapproved suggests "disapproved" — that is, some affirmative determination by FDA that an off-label use is actually unsafe or too risky to appear on labeling.  FDA ordinarily looks to a manufacturer’s intended uses when considering how a drug or device is to be marketed and labeled.
    Thus, absent a labeled contraindication, unindicated uses cannot be considered unapproved; they simply have not been reviewed at all.  Nor can it be assumed that off-label uses are unproven or unsafe because they have escaped FDA scrutiny. Nothing in the FDCA or the conforming regulations suggests that FDA is to conduct its own evaluations of uses other than those proposed by a manufacturer.