Off–Label Promotion Or Scientific Exchange? A Multimillion Dollar Question

By Saul B. Helman, M.D., and Sharon Kvistad, Navigant Consulting

Medical device industry headlines have been dominated in recent months by the significant regulatory oversight applied to promotional claims made for medical products, as well as the penalties imposed when manufacturers run afoul of those regulations.

Following a rigorous clinical trial process and submission of clinical data to the U.S. Food and Drug Administration (FDA), manufacturers are granted marketing authorization. However, the legal and regulatory landscape around promotional messaging can be confusing, and the confusion applies to everyone: Manufacturers of medical devices, biotech product developers, and pharmaceutical manufacturers all are subject to the same amalgam of federal statutes, FDA guidance, and case law. In fact, four separate U.S. government agencies contribute to the regulatory landscape: FDA, the Centers for Medicare and Medicaid Services (CMS), the Office of the Inspector General (OIG) for the U.S. Department of Health and Human Services, and the U.S. Department of Justice (DOJ).

The FDA recently asserted in a draft guidance that, while it recognizes the value of truthful and non-misleading scientific or medical publications on unapproved new uses, both to health care professionals (HCPs) and payers, such information is in no way a substitute for FDA’s premarket review process.¹ Meanwhile, the agency also has indicated a willingness to reconsider some of its off-label policies.² 

Faced with the threat of large off-label promotion settlements,³ manufacturers must take FDA oversight on messaging seriously, creating stark separation between official, on-label promotional messages and scientific exchanges, which contain unapproved, off-label information. This separation results in similar yet separate policies, processes, approvals, and situational uses for promotional exchanges and scientific exchanges.
 
In this article, we outline best practices for companies wishing to proactively install safeguards between scientific and promotional exchanges with physicians and other HCPs.

What Is Scientific Exchange, And When Is It Appropriate?
The FDA historically has held the view that off-label promotion of a device, or any medical product, is misbranding under the Food, Drug, & Cosmetics Act. Other federal laws⁴ and agency guidances⁵ address off-label promotion, but FDA never explicitly defines what constitutes scientific exchange, though it has been attempting to do so.⁶  Still, companies can infer FDA’s definition of scientific exchange through the “safe harbors” present in agency guidances: FDA permits manufacturers to disseminate off-label information as part of “scientific exchange” under prescribed circumstances.

The key to scientific exchange is that it is clearly non-promotional, conducted by individuals who are scientifically trained professionals and in a forum or context that is conducive and reflective of scientific discussion. Scientific exchange could be proactive or reactive in nature. The reactive exchange is in response to an unsolicited inquiry for information, which could include off-label information, and the scientific exchange would be directed toward addressing that inquiry. Proactive scientific exchange could include publications, medical education, company sponsored clinical study discussions, and pre-approval disease state discussions.

Physicians need scientific information to help inform their decision-making around patient care, and the manufacturer of the product is probably most qualified to provide the correct information. However, the compliance control environment needs to be established to support the individuals associated with scientific exchange (and the individuals involved in promotional activity) to ensure the appropriate behaviors prevail.

Clearly Separating Scientific Exchange From Promotional Messaging
To mitigate the risk of noncompliance and to inform employees of appropriate interactions, businesses should implement policies and procedures and refresh them regularly to reflect evolving government and industry guidance. Training, auditing, and monitoring the separation between scientific exchange and promotional messaging are important aspects of an effective compliance program. The following fundamental principles should be incorporated into each manufacturer’s policies and procedures to ensure separation between promotional and scientific exchanges, despite unclear government guidance.

Promotional Materials

• Product effectiveness claims included within promotional materials must be in the proper context and balanced with information about product risks and contraindications.
• Promotional materials must be reviewed and approved by a committee consisting of medical, legal, and regulatory representatives. Individuals in a commercial role should not be the sole approvers of promotional materials.

Promotional Interactions With HCPs

• Promotional messaging must be consistent with a product’s FDA-approved labeling, and must not be used as a tacit recommendation, inducement, or advocacy of unapproved, off-label usages.
• Products must not be promoted to HCPs whose specialty/subspecialty would make it unlikely to prescribe the product for its labeled use. Sales representatives and other commercial employees should be educated to understand that off-label promotion is inclusive of the message delivered and the audience to whom it is delivered.

Medical Interactions With HCPs

• Only scientifically trained personnel (e.g., medical science liaisons, medical information) may engage in responses to unsolicited off-label inquiries, and all scientific exchanges must be documented, ideally within a centralized system to retain evidence of the inquiry and resulting response.
• Scientifically trained personnel may not be evaluated, compensated, or involved in promotional discussions or activities with HCPs.

Payer/Formulary Access Interactions

• Payers and/or formulary committees at a provider level will dictate meeting requirements in terms of timing and frequency (i.e., limit a company to a single meeting). This requires a combined commercial and scientific exchange.
• Compliance policies and procedures need to be developed for these scenarios that are quite different from an HCP/sales representative interaction.
• Company attendees to these meetings need to have a clear understanding of their roles — commercial vs. scientific — and stick to their respective roles in a clear and transparent fashion.

Publications

• All publications must align with a corporate publication plan. The publication plan should be jointly developed, and should not be approved solely by commercial personnel. Authors must maintain full control over the publication without any undue influence by manufacturers.
• Publications must not be utilized as a means of distributing scientific information to authors that might support off-label use.

Grants And Continuing Medical Education (CME)

• CME funding decisions must be approved by a review committee consisting of representatives from the legal and medical departments, and must not be influenced or voted on by a commercial representative.
• CME funding must align with a predetermined educational strategy, and must not be used to opportunistically distribute off-label information.

Investigator Initiated Studies (IIS)

• The selection of IIS proposals must be made by medical affairs and/or R&D personnel solely to advance scientific knowledge, not to foster commercial goals or physician prescribing habits.
• The role of commercial personnel must be limited to referring the grant requester to the appropriate portal for grant submission and/or to the local medical liaison for appropriate handling. Medical liaisons must avoid any undue influence to ensure investigators are acting independently.

Post-Marketing Studies

• Post-marketing studies should be pursued to answer a legitimate scientific question, and should not be pursued to advance commercial objectives. 
• The results of all post-marketing studies must be disseminated according to the appropriate requirements guiding the publication of clinical trial data, and must not be released preemptively to advance commercial initiatives.

The complexities of engaging in appropriate scientific exchange, when combined with a paucity of clear guidance by FDA and other government agencies, create a risky situation for manufacturers. In order to mitigate this risk, manufacturers must have effective compliance controls in place. Manufacturers must ensure they have a sufficient firewall to separate scientific exchanges from promotional messaging in order to maintain the independence of those scientific exchanges.  The efficacy of this firewall can only be assessed through ongoing auditing and monitoring of activities that implicate scientific exchange; absent this, manufacturers cannot deem their compliance controls effective and may, therefore, be operating at risk.

Resources

1. Distributing Scientific and Medical Publications on Unapproved New Uses—Recommended Practices (Draft Guidance, 2014)
2. “FDA to Consider Expanding Scientific Exchange” 
3. "Medtronic to Pay $2.8 Million to Settle Off-Label Promotion Charges" 
4. For example, Section 401 of the Food and Drug Administration Modernization Act of 1997, which sunset in 2006
5. Significantly, 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 (Final Guidance, 2009) and its replacement (still in draft form), Distributing Scientific and Medical Publications on Unapproved New Uses—Recommended Practices (Draft Guidance, 2014); and Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices (Draft Guidance, 2011)
6. See, for example, Docket No. FDA-2011-N-0912, Communications and Activities Related to Off-Label Uses of Marketed Products and Use of Products Not Yet Legally Marketed

About The Authors
Dr. Saul Helman is a Managing Director at Navigant and is the Life Sciences Disputes, Regulatory, Compliance and Investigations Practice leader.  He provides support in investigations, litigation, and compliance integration matters involving healthcare and life sciences companies. Helman’s experience spans over two decades in life sciences, both in management and consulting roles. He also has significant international experience in healthcare, biopharmaceutical, and medical device companies.

Sharon Kvistad is an Associate Director in Navigant's Healthcare and Life Sciences Disputes, Regulatory, Compliance, and Investigations practice, focusing on FDA regulatory matters. Kvistad has over 30 years of experience in U.S. and global regulatory affairs as they relate to medical devices, with domestic submission preparation experience including IDE, PMA, PMA/S, HUD/HDE, and 510(k).