Over the past several months I have encountered many questions relating to off-label data communication. In this article I am providing the three most asked questions on this topic and the summarized responses that I have provided.
What are the biggest issues related to off-label data communication that you see in the US and other countries?
The short answer is “knowledge”, or the lack thereof. To give more detail to this short and direct answer I will also provide the following.
In recent times, off-label marketing of medical devices and pharmaceuticals has remained a prime focus for government investigation. The issues surrounding off-label promotion are twofold: first, it is an illegal activity that violates federal law; second, it places individual employees and the corporation in jeopardy. Infractions for off-label promotion can include incarceration and heavy fines for individuals and corporations. As a byproduct, off-label communication may also impose ethical dilemmas on innocent bystanders when these types of known communications occur. Because this activity is illegal, any person contemplating reporting such acts may well shoulder a heavy personal and professional burden – they also may confront the thoughts and threats of retaliation.
The federal Food, Drug, and Cosmetic Act (FDCA) prohibits the “adulteration or misbranding” of any device or drug. One, under the law a drug or device is deemed misbranded if its label does not bear “adequate directions for use.” Two, because the labels 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 promoted 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. 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).
Medical device and pharmaceutical manufacturers should know that off-label promotion is prohibited by law. Organizationally, it can be difficult to identify and prevent the types of conduct that constitute off-label practices. Reports have indicated that some senior leaders may not want to bring attention to their own internal practices of labeling, or lack thereof. In many cases, some employees within these organizations have not been made aware of this legal fact. It is not uncommon that sales representatives are not fully aware of the legal implications of off-label promotion. To counter these knowledge gaps, companies should implement compliance programs aimed at preventing off-label activities. It is imperative that employees know what off-label promotion is, and what the indication, or indications for use are for the specific device or drug. Training employees to avoid off-label promotion, to avoid engaging in it, and to report it to management is fundamental to any off-label compliance effort.
Statements relating to off-label promotion occur when discussions drift away from the indication. This is one of the most common issues relating to off-label promotion. Frequently, statements made by sales representatives to customers result in off-labeling problems for device or pharmaceutical companies. Additionally, it must be noted that manufacturers can engage in off-label promotion through various other promotional mediums and marketing materials, such as; Web sites, sales brochures, direct-to-consumer advertising, and press releases.
The FDA and other government agencies may also look at and evaluate the following information sources to determine whether off-label promotion has occurred:
- Training materials that are presented by the company at professional conferences,
- Submissions to government agencies made in support of device reimbursement,
- Securities filings that include information about a product’s research and development or regulatory status.
Business Practices can also create off-label risk for a company. These practices include:
- Sales representative activities,
- Field medical activities,
- Reprint use,
- Third-party relationships,
- Consultant utilization,
- MSLs being utilized as an extension of Marketing and Sales to promote off-label use.
I have highlighted several internal issues that can be faced relating to off-labeling. I will add that external issues can also pose threats as well. One such example surrounds questions posed by physicians. 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. A few companies may direct their MSL to answer the question with the aforementioned in mind. The answer would also be directed to the one who is asking the question. Any inquiry must genuinely originate with the physician in order for the company to respond legally, as this is from the guidance document. Companies should implement compliance strategies aimed at preventing off-label activities that could lead to heavy fines and worse.
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.
Is there an algorithm an MSL should follow if asked about off-label medical information at a scientific or educational event when only a group of KOLs are listening?
I would first direct you to your individual policies and procedures. While there are off-label regulations and codes of practice in all countries, there are no black and white interpretations for MSLs. The guidance documents can be interpreted by different people and companies in a multitude of ways. This is one reason to have organizational SOPs put in place for its members. To be effective, SOPs should provide very clear guidance and direction to an MSL team within that company. The SOP sets a stage and precise framework in which the MSL should be working – it can be seen as the algorithm that should be followed by the MSL.
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. A few companies may direct their MSL to answer the question with the aforementioned in mind. The answer would also be directed to the person who is asking the question. Any inquiry must genuinely originate with the physician in order for the company to respond legally, as this is from the guidance document. Companies should implement compliance strategies aimed at preventing off-label activities that could lead to heavy fines and worse.
If a KOL starts speaking about off-label product information during their talk at the congress sponsored by the pharmaceutical company, what should the MSL do?
One program or activity to consider for an MSL team is not only to develop a speaker’s bureau, but train those speakers on the proper guidance and the risk of off-label promotion. This should be commonplace for any MSL that works with Key Opinion Leaders (KOLs) on behalf of a pharmaceutical or medical device company.
A formal program should be designed and implemented which includes collaborating and training a KOL with on-label messages and adherence to regulatory guidelines. With this in mind, a program book should be created with the essential educational steps and guidance for the KOL. This will assure the KOL is properly prepared to speak during a congress; but more importantly, how and why to avoid off-label promotion. This corporate booklet should also include any formal action taken at the congress, and may include interruption, clarification, or a more formal action provided by the MSL. The playbook should be retained in your individual speaker training file and signed by the KOL. After speaking with many global KOLs, most are unaware of the risks associated with off-label promotion. It is essential to be proactive and mitigate these risks that are associated with this type of promotion.
As a related topic I add the following information. 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. (1) In other words, these programs must pertain only to approved indications for the products being discussed. The FDA will view any discussions of off-label uses that aim to influence from the sponsoring company as violations of the FDCA.
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.
Companies should implement compliance programs aimed at preventing off-label data communication activities that could lead to heavy fines and worse.
- 62 Fed. Reg. at 64,074.
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.
Williams © 2016