Overview of Safe Harbors and Regulatory Compliance and the Impact on MSLs

Jennifer Williams PhD, JD, MBA, RN, MS

This information is for educational purposes only and should not be construed as legal advice or a legal opinion from the author. This information is my own opinion and not that of past or present employers.

During the past decade regulation has impacted the medical device and pharmaceutical industry; for better or worse this influence continues to change the environment. It is imperative that company executives stay in front of, and react to, increased complexities of change in the healthcare environment brought on by regulation. Observant business strategies are also necessary to eliminate the risk associated with common themed infractions. One such infraction is off-label promotion, as this remains a prime focus of government investigations within the medical device and pharmaceutical industry.

Alarm has mounted among government policymakers, patient advocates, physicians, and leaders in the industry that influence clinical practice, medical education, and medical research (1). The aforementioned have been the nexus of some practices of off-label promotion. Government enforcement actions, congressional hearings, and press coverage have generated intense scrutiny of the dubious financial relationships and questionable industry practices that persist in this area. With these actions patient care and medical advancements may suffer at the plight of over-regulation. By and large, the medical industry targets physicians with promotional efforts – these physicians often serve as the doorkeepers for medication prescription and medical device use. Companies also enter into financial agreements with physicians for consulting; in which these physicians speak at national conferences and provide clinical and marketing research as a professional service (2).

On some occasions off-label information is presented at conferences. There are two different scenarios or circumstances that surround such scientific meetings. First, that the presentation is regulated and under the control of the manufacturer. Second, that there is no manufacturer control. In order for the presentation to be lawful, the conference must be independent from the manufacturer. This means that a physician who presents off-label information must not be a representative of the manufacturer. Further, the manufacturer must not have influence over the conference speakers content, attendees, or have any sponsorship role at the educational program (3).

In determining independence, the FDA will consider the sponsor’s control over the speaker and content, meaningful disclosure, and the manufacturers relationship with the speaker. As a side note, the federal Food, Drug and Cosmetic Act (FDCA) includes a practice-of-medicine exemption that allows physicians to use devices in any manner they see fit. This also includes presenting off-label information to members of the general public – such as those in an audience at a conference. This is permissible only if this is not a controlled event. Finally, controlled communication should be regulated as promotional material and be consistent with the intended use. This would indicate that rules applicable for dissemination of written material, appropriate location, interaction with healthcare professionals and the speaker’s agreement must be followed (3).

Under the final guidance, the FDA asserts regulatory authority over any scientific or educational program supported by a pharmaceutical or medical device manufacturer in which the content of the program pertains to the sponsoring company’s products or competing products, and the program is intended to, or does, reflect the direct or indirect influence of the supporting company. The agency disclaims any regulatory authority over programs that are both independent and non-promotional per 62 Fed. Reg. at 64,074.

Educational speaker programs at conferences that are not independent, or may reflect some influence by the supporting company, “are not per se illegal, but they are subject to regulation” as the final guidance makes clear. (4) In other words, these programs must pertain only to approved indications for the products being discussed. Again, the emphasis here can be summed up with a single word: “independence.” If a scientific or educational program that pertains to research concerning potential new uses of a medical product is intended to be and is truly independent of any direct or indirect influence by the sponsoring company, the guidance suggests that the agency will not interfere. In contrast, the FDA will view any discussions of off-label uses that aim to influence from the sponsoring company as violations of the FDCA. The majority of the guidance is devoted to enumerating a lengthy and nonexclusive list of factors that the agency will weigh or balance in an unspecified manner to evaluate whether a program is truly independent (4).

The federal Food, Drug, and Cosmetic Act (FDCA) prohibits the “adulteration or misbranding” of any device or drug. Two major points stand out. One, under the law, a drug or device is deemed misbranded if its label does not bear “adequate directions for use.” Two, because the label on a device or drug relate only to approved uses, when either is promoted off-label, its label does not bear adequate directions for the new off-label use. Therefore, the drug or device is misbranded. In order to obtain FDA approval, the manufacturer must obtain the safety and effectiveness of the product for its intended uses. Therefore, promoting a drug or device outside of its approved indications constitutes the introduction of an unapproved new drug into interstate commerce in violation of the FD&C Act, 21 USC Sec. 331 (d).

The “intended use” of a drug or device refers to the objective intent of the persons legally responsible for the labeling of the product. This intent is determined by such persons’ expressions or by the circumstances surrounding the distribution of the article including, for example, labeling claims, advertising matter, or oral or written statements by such persons or their representatives. (See 21 CFR 201.128 and 801.4.) The agency, thus, regulates products based not only on information provided “with” the product (approved professional labeling), but also based on information disseminated by or on behalf of manufacturers in other contexts, such as scientific and educational meetings and symposia, books, reprints of articles from scientific journals, in part because all of these activities/materials can create new intended uses for the products, which must be reflected in the approved labeling of the products, 21 CFR 201.128 and 801.4.

WHAT IS SAFE HARBOR

In some cases, an off-label use of a drug or device may be the medical standard of care. A failure for a physician to use a drug or device in an off-label manner may constitute medical malpractice. This is one reason the FDA allows companies to provide physicians with the following type of off-label information about unapproved uses. These include:

Scientific and medical journals. Manufacturers may provide physicians with scientific and medical journal articles that discuss off-label uses of a product. To be able to provide this information legally, companies must adhere to a strict set of rules developed by the FDA. In January 2009, FDA published “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices” (often referred to as “Good Reprint Practices Guidelines.”) Since that time an updated draft dated February 2014, became available at ocod@fda.hhs.gov. These practices set forth the requirements for journal articles and the conditions under which they may be distributed. One can consult the FDA website for a copy of these guidelines.

Inquiries from physicians must be unsolicited requests for a company to respond to off-label uses. The response to any such unsolicited inquiry must be balanced—or include information about both the risks and benefits of the off-label use—and be commensurate with the scope of the question. It is not acceptable for sales personnel to encourage “inquiries” from physicians. Any inquiry must genuinely originate with the physician in order for the company to respond legally (6).

The purpose of establishing Good Reprint Practices was to describe the conditions under which medical or scientific literature concerning off-label use of a drug, biologic or medical device could be distributed without prompting the FDA to say the information misbranded a product that has an approved use. The Good Reprint Practices created a “safe harbor” for off-label use information that would otherwise be prohibited based on a misbranding charge. Manufacturers must adhere to the guideposts of “should” and “should not” when navigating within the safe harbor. FDA uses several factors to determine whether or not a medical or scientific journal article stays within the safe harbor. By following FDA’s guidance on what a manufacturer should and should not do, the FDA will not use the dissemination of the reprinted medical or scientific article as evidence of a manufacturer’s intent to promote and market an off-label use (6).

A manufacturer should consider the following before it disseminates a reprint of a medical or scientific article regarding an unapproved use according to the Good Reprint Practices:

1.The article should be published by an entity with an independent editorial board with relevant expertise and objectivity.
The article should appear in its unabridged form
The editors, authors and contributors associated with the article are subject to full disclosure of a conflict of interest based on a publicly stated policy.
The article should be peer-reviewed under the publishing organization’s established procedures.
The article should describe the information in the context of being derived from adequate and well-controlled clinical investigations.
The article should be disseminated with the product’s approved labeling.
A comprehensive bibliography should be disseminated with information from other publications that is contrary to the results.
The article should not be used in conjunction with or associated with any other promotional literature or activity (6).

In recent years, most of the enforcement actions for off-label promotion have been focused on drug companies. However, the FDA, the United States Office of Inspector General (OIG), and the Department of Justice are increasingly paying attention to off-label promotion in the device industry and will receive the same level of scrutiny as the pharmaceutical companies. These are considerations for observant executives to consider while implementing business strategies within their own company.

References

N.K. Choudhry et al., “Relationships between Authors of Clinical Practice Guidelines and the Pharmaceutical Industry,” JAMA 287, No. 5 (2002): 612-617; Association of American Medical Colleges (AAMC), Industrial Funding of Medical Education: “Financial Support of Continuing Medical Education,” JAMA 299, No 9 (2008).

T.A. Brennan et al., “Health Industry Practices That Create Conflicts of Interest: A Policy Proposal for Academic Medical Centers, “JAMA 295, No 4 (2006): 429-433.

62 Fed. Reg. at 64,074.

21 CFR 201.128 and 801.4.

The Food and Drug Administration (FDA) issued a revised draft guidance document in February 2014 entitled, “Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices.” The guidance updates the draft guidance issued in January 2009 entitled, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” The Food and Drug Modernization Act (FDAMA) (21 U.S.C. § 360aaa) amended the Food, Drug, and Cosmetic Act (FD&C Act) to include the regulatory conditions under which a reprinted published medical or scientific article may be distributed by a manufacturer to healthcare professionals and related healthcare businesses. The regulatory issue continues even though the FDAMA amendment is no longer in effect.