Section 6: The Last Words

Off-label drugs and the impact of the Food and Drug Administration in the treatment of retinal disease

George A. Williams, M.D

CHAPTER

51

INTRODUCTION

The pharmacotherapy of blinding retinal disease is replete with examples of off-label drug use (Table 51.1). The history of this off-label drug use is testimony to the innovation, persistence, and even courage of ophthalmologists in their continuing efforts to improve vision for those afflicted with retinal disease. Sometimes, off-label drug use is employed to treat relatively rare conditions such as endophthalmitis or uveitis, for which a Food and Drug Administration (FDA) label is unlikely. Other times, off-label drugs are used to treat common disorders such as diabetic retinopathy or age-related macular degeneration when approved therapies are suboptimal. Off-label drug use is also employed in combination therapy with approved treatments. Regardless of the indication, the use of off-label drugs may prove to be the best available treatment for an individual patient. However, off-label retinal pharmacotherapy places additional regulatory, legal, and economic burdens upon the ophthalmologist. This chapter will discuss the regulatory, legal, and coverage implications of off-label retinal pharmacotherapy.

OFF-LABEL DRUG USAGE AND THE FOOD AND DRUG ADMINISTRATION

HISTORICAL PERSPECTIVES

The advent of ocular photodynamic therapy with verteporfin in 2000 initiated a new era in the management of age-related macular degeneration. Although this novel therapy provided a safe and effective treatment for many patients with previously untreatable subfoveal choroidal neovascularization, the FDA label restricted its use to predominantly classic neovascular lesions. This limited label was used as the basis for the Centers for Medicare and Medicaid Services (CMS), coverage as outlined in a National Coverage Determination (NCD).1,2 Although this NCD was the first exposure for many ophthalmologists to the confusing and arcane regulations that govern off-label drug use, most ophthalmologists had been using approved drugs off-label for years for the treatment of endophthalmitis, uveitis, proliferative vitreoretinopathy, and cystoid macular edema. Even the use of preoperative and post­ operative antibiotics for endophthalmitis prophylaxis is off-label.

FDA APPROVAL PROCESS

An understanding of the issues involving off-label drug use requires a review of the FDA approval process.3 The FDA is a public health agency whose mission is to oversee the use and marketing of regulated medical products. The FDA reviews the toxicology and clinical research from phase I, phase II, and phase III studies which is presented in an investigational new drug (IND) application and, when appropriate, approves a drug for use and marketing. When a drug is approved, the FDA issues a label that describes and defines the drug’s specific medical indication(s), dose, dosage form, side-effects, and chemical structure. For some drugs, the FDA may include a “black box” warning in the label to emphasize potential complications associated with severe morbidity or mortality. The format of the FDA label has received

widespread criticism for its confusing and almost impenetrable structure and syntax. Recently, FDA announced a more “user-friendly” format designed to facilitate use by both patients and physicians.4 Although this new format is an improvement, it remains difficult.

THE CONCEPT OF “OFF-LABEL”

Any use of a drug not listed in the label is considered off-label. Off-label uses include giving an approved drug for a disease or indication other than that for which it is approved; at a different dose, frequency, or route of administration than specified in the label; or to treat a child when the product is approved to treat only adults. However, the use of an approved product by physicians is not restricted by the FDA to the limitations of the label. Physicians are allowed to use FDA-approved drugs in the treatment of an individual patient as medical practice. The FDA recognizes that off-label use of drugs by physicians is often appropriate and may represent the standard of care. The most obvious example of off-label drug use constituting the standard of care in ophthalmology is the use of intravitreal antibiotics for endophthalmitis despite the fact that no antibiotics are approved for intravitreal injection or for the treatment of endophthalmitis. The FDA has issued specific guidance on off-label drug use:

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 medical judgment. 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 on the product’s use and effects. Use of a marketed product in this manner when the intent is in the practice

of medicine does not require the submission of an Investigational New Drug Application … or review by an Institutional Review Board (IRB). However, the institution at which the product will be used may, under its own authority, require IRB review or other institutional oversight.4

In addition to the FDA, medical organizations such as the American Medical Association (AMA) and the American Academy of Ophthalmology are on record supporting off-label drug use when there is appropriate evidence-based medicine, expert consensus opinion, or unmet medical need.5,6 The AMA policy on off-label drug use is “The AMA confirms its strong support for the autonomous clinical decisionmaking authority of a physician and that a physician may lawfully use an FDA-approved drug product or medical device for an unlabeled indication when such use is based on sound scientific evidence and sound medical opinion.”5

If the FDA recognizes off-label drug use as appropriate and if the FDA does not regulate medical practice in the treatment of an individual patient, what role does the FDA play in off-label drug use? One important role is that the FDA precludes drug sponsors from marketing drugs to physicians or patients for off-label use. “Pharmaceutical manufacturers cannot proactively discuss off-label uses, nor may they distribute written materials (promotional pieces, reprints of articles,

Table 51.1  Common off-label retinal pharmacotherapies

etc.) that mention off-label use.”6 Therefore, the FDA label has important marketing implications because pharmaceutical companies are not allowed to market drugs for off-label use. Currently, this limitation applies to any formal marketing such as media advertising or drug detail information. Recently, the FDA has proposed a controversial relaxation on the restrictions for the marketing of off-label indications.7 Regardless of the status of off-label marketing, the FDA does not restrict other parties such as physicians or specialty societies from discussing off-label uses or distributing written materials concerning them.8,9

“INVESTIGATIONAL USAGE OF DRUGS”

The FDA also becomes involved in off-label drug use when the drug is in “investigational use.” The term “investigational use” suggests the use of an approved drug in the context of a clinical study protocol. When the primary intent of the investigational use is to develop information about a drug’s safety or efficacy, or if the off-label use involves a route of administration or dosage level or use in a subject population or other factor that significantly increases the risks associated with the use of the drug, submission of an IND is required. Physicians can obtain the IND application (form 1571) from the internet.3 The application process is self-explanatory, though rather tedious. Most investigational review boards will require an IND for a clinical trial involving off-label drug use.

COMPOUNDING PHARMACIES

Another regulatory issue involving off-label drugs is the formulation of ophthalmic preparations by compounding pharmacies. Any drug product prepared by a compounding pharmacy is considered by the FDA to be either off-label or a new drug. Compounding pharmacies are licensed by individual states to provide drugs to individual patients at the prescription request of a physician. In ophthalmology, compounding pharmacies provide multiple drugs for retinal pharmacotherapy, such as antibiotics, corticosteroids, and bevacizumab. Compounding pharmacies prepare approved drugs at dosages which are relevant for ocular administration and prepare preservative-free drugs. Although the FDA states: “Traditional compounding typically is used to prepare medications that are not available commercially”, the

FDA has recently expressed concerns about the legality of some compounding pharmacy practices related to retinal pharmacotherapy.10 These issues are related primarily to the marketing of compounded retinal drugs and the need for a patient-specific prescription for each dose. The role of the FDA in regulating the state-controlled compounding pharmacies is also a concern. At the time of this writing, these issues are under litigation. As a result, legislation has been introduced in Congress to clarify the role of the FDA in the regulation of compounding pharmacies. The implications of this legislation to retinal pharmacotherapy are unknown.

RISK MANAGEMENT ISSUES

The legal implications of off-label drug use primarily involve risk management issues. The keys to addressing these risk management issues are patient selection and informed consent. As discussed above, FDA approval status does not necessarily define appropriate medical practice, nor does the FDA regulate medical practice. Medical practice is the therapeutic relationship between a physician and an individual patient. The physician must decide what the appropriate medical care is for each patient and this decision must fall within the standard of care. The question then becomes: “When does off-label drug use become the standard of care?” The answer depends on who is defining the standard of care. Payers may use specific definitions of the standard of care to establish coverage determinations, which will be discussed later. From a risk management perspective involving malpractice, a jury, judge, or arbitrator determines whether treatment is within the standard of care. This determination is based upon factors such as supporting authoritative literature, expert consensus, scientific rationale, and local or national medical practice patterns.

INFORMED CONSENT

An important factor in establishing the standard of care is informed consent. This is particularly critical with off-label drug use. The Ophthalmic Mutual Insurance Company (OMIC) recommends that physicians inform patients about the off-label status of a proposed treatment.11 This discussion should include the known and potential unknown risks as well as the rationale for the off-label drug use. The physician should also discuss why any available FDA-approved or CMS-covered therapies are not appropriate. This discussion should be well documented in the chart. OMIC also recommends that a specific off-label informed consent be used. OMIC provides a specific consent for bevacizumab and triamcinolone acetonide with useful suggestions concerning patient selection, preparation of the medication, and informed consent and documentation.11

MEDICAL PAYMENT/COVERAGE

Perhaps the most difficult issue concerning off-label drug use concerns coverage for the drug and associated services. In ophthalmology, this often means coverage by Medicare. Coverage by Medicare can be established either by the local Medicare carrier via a local carrier decision (LCD) or by the CMS as an NCD. The Medicare Benefit Policy Manual provides that individual carriers may establish on a case-by-case basis coverage for off-label drug use based upon their assessment of the medical indication as reasonable and necessary.

FDA-approved drugs for indications other than what is indicated on the official label may be covered under Medicare if the carrier determines the use to be medically accepted, taking into consideration the major drug compendia, authoritative medical literature and for accepted standards of medical practice12

Some carriers have outlined criteria they consider when determining coverage of off-label drug use on a case-by-case basis. These criteria consider the following factors:

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