Legal Aspects of Medical Therapy

The US Food and Drug Administration (FDA) has statutory authority to approve the marketing of prescription drugs and to specify the uses of these drugs. The FDA’s Office of Prescription Drug Promotion reviews and regulates prescription drug advertising and promotion through surveillance activities and issuance of enforcement letters to pharmaceutical manufacturers, whereas the Federal Trade Commission regulates advertising and promotion for over-the-counter drugs. The FDA has created a 3-step process for human testing of new drugs before they are approved for marketing:

• Phase 1: After animal and in vitro studies, human testing begins. This process involves trials with 10–80 people for collection of toxicology data and pharmacokinetic data on dosage range, absorption, and metabolism.

• Phase 2: Randomized controlled clinical trials involving a minimum of 50–100 affected people are conducted to determine safety and effectiveness of the drug.

• Phase 3: Controlled and uncontrolled trials evaluate the overall risk–benefit relationship and provide an adequate basis for physician labeling. The data gathered from these tests are then submitted as part of a new drug application for marketing.

The FDA’s approval of each drug and its specific uses (“on-label” prescribing) are based on documentation submitted by manufacturers that supports the safety and efficacy of the drug. Although the FDA is committed to making drugs available as rapidly as possible, the process of bringing a new product to market requires extensive research and development and millions of dollars.

Once approved for a specific use(s), a drug may be prescribed by individual physicians for other indications and/or patient populations. For example, doxycycline, typically prescribed to treat infection, can also be used to treat ocular rosacea (based on its inhibition of matrix-metalloproteinases). Off-label drug use, defined as prescribing a drug for an indication or employing a dosage or dose form that has not been approved through the FDA process, is common. An off-label use may even be the predominant treatment option for a given clinical condition. Although off-label use of a drug may already be the standard of care for a certain medical condition, drug proprietors may never seek FDA approval for the new indication because of financial reasons.

In ophthalmology, many common drugs are used off-label. Some examples are listed in Table 16-1. One of the most commonly used medications, topical prednisolone, has not been approved by the FDA for postoperative care. Use after cataract surgery is thus an off-label application.

Although off-label drug use per se does not violate federal law, prescribing physicians remain liable to malpractice actions with their use. In particular, unapproved use of a drug that does not adhere to an applicable standard of care places a practitioner in a difficult legal position. However, if other physicians, similarly situated, would have prescribed in the same manner, a standard of care can be met in most jurisdictions. In equivocal cases where standard of care is uncertain, informed consent should be considered.

Expanded access refers to the clinical use of investigational new drugs (INDs) prior to FDA approval. Clinical use of INDs in this setting is typically requested for patients with terminal conditions who either do not qualify for the clinical trial or may succumb to their illness before the drug obtains approval. The treating physician must ensure that the company is willing to provide the drug/device and agrees with the treatment plan.

Table 16-1 Common Drugs Used Off-label in Ophthalmology

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.