Feedback from the Orthopaedic Device Forum
The U.S. Food and Drug Administration (FDA) has issued several guidances—documents that outline the agency's current thinking about regulatory policy—concerning physician-directed use of medical devices. Before a guidance is finalized, the agency releases a draft guidance to solicit feedback from stakeholders.

In January 2017, the FDA issued two new draft guidances, using a question/answer format. The first draft guidance addresses communications from drug and device manufacturers to payers, formulary committees, and similar entities and colloquially is called the "payer guidance." The second draft guidance focuses on ensuring that medical product communications are consistent with FDA-required labeling and is called the "consistency guidance."

In these drafts, the FDA proposed a set of criteria for publications discussing off-label use that can be disseminated to end users and the public by manufacturers. Both positive criteria (the publication must …) and negative criteria (the publication must not …) were outlined. During its last two meetings, members of the Orthopaedic Device Forum (ODF) discussed these guidances and raised some concerns. This article includes highlights of the guidances, as well as the comments and critiques of ODF members.

Proposed positive criteria
The following positive criteria are among those proposed by the FDA for publications that manufacturers can disseminate to end-users and the public on the off-label use of a drug or device. In each case, the publication must meet the outlined criterion.

1. Be peer-reviewed and published in accordance with the peer-review procedures of the organization.
2. Be in the form of an unabridged reprint or copy of an article.
3. Contain information that describes and addresses adequate, well-controlled clinical investigations that are considered scientifically sound by experts who have the scientific training and experience to evaluate the safety or effectiveness of the drug or device. In the case of devices, significant investigations other than adequate, well-controlled studies—such as meta-analyses—that are testing a specific clinical hypothesis and journal articles discussing significant nonclinical research (such as well-designed bench or animal studies) may be consistent with this guidance.
4. Be disseminated with the approved labeling. Articles covering medical devices reviewed under section 510(k) of the Food, Drug & Cosmetic Act must be disseminated with labeling for the indications in the product's cleared indications for use statement for each of the manufacturer's products included in the article.
5. Be disseminated with a comprehensive bibliography, when such information exists, of publications that discuss adequate, well-controlled clinical studies published in scientific journals, medical journals, or scientific texts about the use of the drug or medical device covered by the information disseminated (unless the information already includes such a bibliography).
6. Be disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use—especially when the conclusions of articles to be disseminated have been specifically called into question by another publication.
7. Be distributed separately from the delivery of information that is promotional in nature. For example, if a sales representative delivers a reprint to a physician in the physician's office, the reprint should not be attached to any promotional material also used or delivered during the office visit. If the recipients of the scientific or medical journal article have questions, the sales representative should refer them to a medical/scientific officer or department, which is independent of the sales and/or marketing departments. Similarly, although reprints may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, reprints should not be distributed in promotional exhibit halls or during promotional speakers' programs.

Proposed negative criteria
Similarly, the draft guidances propose negative criteria, outlining what the information may NOT include. The first of these negative criteria is that the information may not be false or misleading.

For example, a distributed journal article should not be characterized as definitive or representative of the weight of credible evidence derived from adequate and well-controlled clinical investigations if it is inconsistent with the weight of credible evidence or if a significant number of other studies contradict the conclusions set forth in the article. In addition, the distributed article should not have been withdrawn by the journal or disclaimed by the author and should not discuss a clinical investigation that the FDA has previously informed the company is not adequate and well-controlled.

The guidance also says that the distributed article must not contain information recommending or suggesting use of the product that makes the product dangerous to health when used in the manner suggested.

The following negative criteria were established for the distribution by manufacturers of scientific and medical journal articles about an unapproved use. These criteria are consistent with the recommended practices described in the guidance. In each case, the article should:

1. Not be in the form of a special supplement or publication that has been funded, in whole or in part, by one or more of the manufacturers of the product that is the subject of the article.
2. Not be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use. For example, if a sales representative summarizes or characterizes the article to emphasize portions of the article that suggest the manufacturer's drug may be safe or effective for an unapproved use during a sales call to a physician, this might be used as evidence of intended use.
3. Not be primarily distributed by a drug or device manufacturer. Instead, the article should be generally available in bookstores or other independent distribution channels (eg, subscription or Internet) where periodicals are sold.
4. Not be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer.
5. Not be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.
6. Not be attached to specific product information (other than the approved product labeling or the product's cleared indications for use statement).

The guidance also included examples of journal reprints that would not be considered consistent with the recommended practices outlined. These include letters to the editor, abstracts of a publication, reports of healthy volunteer studies, and publications consisting of statements or conclusions with little or no substantive discussion of the relevant investigation or data on which they are based.

ODF debate
During the most recent meeting of the ODF, members held a roundtable discussion about the draft guidances and raised some concerns. ODF members took issue with the evidence basis of the publications. Some stakeholders opined that the level of evidence of these journal articles should be a minimum of Level III data, possibly Level IV data in some cases.

ODF participants also thought that, depending upon the physician-directed use, in many instances the burden should be placed on surgeons (as the end-users) to ensure that these articles are appropriate for dissemination. This would possibly involve specialty society review of such literature and the establishment of a repository within the FDA of information vetted by specialty societies. Although not all physician-directed use articles could be reviewed by specialty organizations, members thought that these organizations would feel compelled to review specific topics, including some that represent an evidence-based standard of care, despite being off-label. One example discussed was the use of antibiotic bone cement for the treatment of an infected total joint arthroplasty.

The definition of physician-directed or "off-label" use was also an issue. Members pointed out that a difference exists between using a device or drug in an unapproved delivery route or application (eg, vancomycin powder in an instrumented spinal surgical case) and modifying the device on the back table (eg, carving a trabecular augmentation implant to fit a defect). In the latter application, under current practice, the surgeon would be considered a "manufacturer" of a new device and he or she would be considered as using a new device without approval, as opposed to truly physician-directed use of an existing device.

Most ODF members were uneasy about the dissemination of information to the general public. They thought that physicians and surgeons would be better gatekeepers of the information stream to patients, and that communications should come to patients through them rather than directly from manufacturers. Finally, members highlighted the need for transparency, scrutiny, and accuracy concerning the disclosures of authors on the disseminated information.

Conclusion
The regulation of physician-directed use is complex. Existing practice has safeguarded patient safety and encouraged ethical use of devices. New case law, concerns regarding freedom of speech, FDA draft guidances, and proposed legislation have created additional need for surgeon leadership, such as that provided by the ODF, to ensure safe and effective devices, appropriate labeling, and ethical physician-directed use when appropriate.

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

Katherine Sale, MPH, 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.

Editor's Note: Last month, the authors of the article, "Physician-Directed Use: Leadership from the Orthopaedic Device Forum," described the rapidly changing landscape of physician-directed use of orthopaedic devices, including existing practice and case law. This article considers recent draft guidances issued by the U.S. Food and Drug Administration and concerns raised by members of the Orthopaedic Device Forum.

References:

1. Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices—UCM387652.pdf. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM387652.pdf. (Accessed: 14th April 2017)
2. Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices—UCM285145.pdf. Available at: www.fda.gov/downloads/drugs/guidances/ucm285145.pdf. (Accessed: 14th April 2017)
3. Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities—Questions and Answers Guidance for Industry and Review Staff—UCM537347.pdf. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537347.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery. (Accessed: 14th April 2017)
4. Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers: Guidance for Industry—UCM537130.pdf. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537130.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery. (Accessed: 14th April 2017)