The Orthopaedic Device Forum is a unique venue in which multiple stakeholder groups meet twice annually to debate and shape the future of orthopaedic device technology and policy. Surgeons are represented by the AAOS and its Board of Specialty Societies. Orthopaedic device manufacturers are represented by the Orthopedic Surgical Manufacturers Association (OSMA). Federal agencies are represented by senior officials from the U.S. Food and Drug Administration (FDA). Standards bodies are represented by ASTM International.

In 1996, the Device Forum “was established to permit regularly scheduled interactions among representatives of the scientific and clinical orthopaedic community, the FDA and other governmental agencies, and representatives of the industry related to musculoskeletal health and disease.” The Device Forum is the premier organization for these groups to have open discussions concerning device-related matters that can directly affect the ways orthopaedic surgeons bring forth safe and effective care to patients.

During its last two meetings, the Device Forum took a leadership role in the debate over the rapidly evolving landscape of physician-directed use of orthopaedic devices. Physician-directed use of a medical device is defined as use judged by the physician to be in the best interest of a patient within that physician’s clinical practice of medicine.

A physician-directed use, also called an off-label use, is not part of the intended use for the device as reflected on its label as approved or cleared by the FDA. In 2017, multiple new elements have been added to this already complex topic, including two new FDA draft guidance documents. Understanding the newest developments requires a review of established practices regarding physician-directed use and the historical context of the recent case law.

Existing practice in physician-directed use
The Federal Food and Drug and Cosmetic Act (FDCA) states that a manufacturer or distributor may sell and promote products only for cleared or approved intended uses. Physicians, however, may practice medicine by using or prescribing a lawfully marketed product for unlabeled uses. This is the source of the debate.

When can a manufacturer of a drug or device promote its product for use in a manner that was not approved by their premarket application (PMA) or premarket submission (510[k])? Where do the boundaries lie between imparting information and promoting a product to the end user or to the public?

Manufacturers can disseminate (in a nonpromotional manner) information about off-label uses of their products through several pathways. For some pathways, the FDA has indicated that such activity will not be used as evidence of the manufacturer’s intent to promote the off-label use, if the manufacturer satisfies the specific criteria under each policy. For other pathways, FDA has indicated that it does not intend to regulate such activities under the advertising and labeling provisions of the FDCA.

The main dissemination pathways are as follows:

• reactive dissemination in response to an unsolicited request from a healthcare provider
• proactive dissemination to healthcare providers via the Good Reprints practices
• sponsorship of independent continuing medical education programs
• “scientific exchange” of specifically related data

Case law
During the spring 2017 Orthopaedic Device Forum meeting, Jennifer A. Henderson, JD, MPH, an attorney at Hogan Lovells, provided a history of court decisions concerning off-label use made during the past three decades (Table 1). These rulings have shaped the current environment, which now allows manufacturers to conduct free speech as long as the speech is scientifically sound and truthful.

One example is the recent U.S. Supreme Court decision concerning Sorrell v. IMS Health Inc. The case stemmed from a law passed in 2007 by the state of Vermont that banned the sale, transmission, or use of prescriber-identifiable data for marketing or promoting a prescription drug without the consent of the prescriber. Ultimately, the Supreme Court was asked to decide whether the Vermont statute unconstitutionally restricted the free speech rights of drug/device manufacturers.

The U.S. Supreme Court decided that it did infringe on freedom of speech rights. Writing for the majority, Justice Anthony M. Kennedy noted: “Vermont’s statute, which imposes content- and speaker-based burdens on protected expression, is subject to heightened judicial scrutiny.” However, in the dissenting view, Justice Stephen G. Breyer, joined by Justices Ruth Bader Ginsburg and Elena Kagan, wrote: “The First Amendment does not require courts to apply a special ‘heightened’ standard of review when reviewing such an effort.”

The dissenting view also stated that “in any event, the statute meets the First Amendment standard this Court has previously applied when the government seeks to regulate commercial speech.” Even though this case does not specifically deal with off-label promotion, it established that speech in the aid of marketing of a medical product constitutes protected speech, setting the framework for subsequent off-label speech decisions.

In 2012, the 2nd U.S. Circuit Court of Appeals heard the case United States v. Caronia, concerning Orphan Medical, Inc., and its drug Xyrem. The drug was approved for treatment of narcolepsy, but had serious side effects, “including difficulty breathing while asleep, confusion, [and] abnormal thinking.” If abused, the drug could lead to coma or death. The FDA had approved the drug with a “black box” warning, which is the highest warning given in product labeling, and the drug was not approved for patients younger than age 16.

Alfred Caronia, a former sales representative for Orphan Medical was accused of organizing speaker functions that promoted Xyrem for use in non-approved patient subpopulations and for non-approved indications. The government charged Caronia with two criminal offenses, sparking the eventual 2nd Circuit ruling. In a 2–1 decision, the appeals court vacated the conviction stating, “it does not follow that prohibiting the truthful promotion of off-label drug usage by a particular class of speakers would directly further the government’s goals of preserving the efficacy and integrity of the FDA’s drug approval process.”

In 2015, the case of Amarin Pharmaceuticals v. FDA was brought to the U.S. District Court, Southern District of New York. The court enjoined the FDA from prohibiting Amarin from making proactive, truthful, and nonmisleading statements about clinical data for its fish oil drug, and the FDA eventually settled the case with Amarin in 2016. The FDA agreed to the following:

• Amarin may engage in truthful and nonmisleading off-label speech.
• Such speech may not trigger prosecution for misbranding.
• Proposed statements, as modified by the ruling, were truthful and nonmisleading.

Conclusion
The topic of safe and ethical physician-directed use is complex. This article highlights existing and traditional practices, the history of case law leading to the current evolution of physician directed use, and the leading role that the Orthopaedic Device Forum and its stakeholders have taken within this debate. Next month, we will describe in detail the current state of two new FDA draft guidances, how the proposals within those documents may change existing practice, and the comments and critiques at the Device Forum roundtable regarding these important changes.

William M. Mihalko, MD, PhD,chairs the Orthopaedic Device Forum. He can be reached at wmihalko@campbellclinic.com.

Katherine Sale is manager of biomedical research and regulation at AAOS. She can be reached at sale@aaos.org.

S. Raymond Golish, MD, PhD, MBA,chairs the AAOS Biomedical Engineering Committee. He can be reached at ray@golish.com.