By: Avia M. Dunn and Elizabeth L. Berry (Skadden, Arps, Slate, Meagher & Flom LLP)
Editing By: Cynthia L. Meyer (Kleinfeld Kaplan & Becker LLP)
On November 9 and 10, 2016, the U.S. Food and Drug Administration (FDA) held a public hearing on drug and device manufacturers’ ability to communicate information about unapproved uses of medical products that have at least one approved or cleared indication, or “off-label communications.”[i] The two-day forum provided stakeholders with an opportunity to weigh in on policy issues FDA should consider as the agency re-examines its regulation of such communications in light of recent changes in the legal landscape. This article provides an overview of key issues discussed during the hearing and outlines several key takeaways and points for further consideration.
FDA currently permits manufacturers to engage in off-label communications in certain specific circumstances—including responses to unsolicited requests, sponsorship of continuing medical education events at which off-label uses are discussed, dissemination of peer-reviewed journal articles, medical texts, and clinical practice guidelines containing off-label information and, for drugs, health care economic data. However, the scope of FDA’s authority to restrict off-label communications has been successfully challenged in a series of recent court decisions that suggest companies may distribute truthful, non-misleading information about off-label uses of their products without violating the FDCA.[ii] Congress has also weighed in on the discussion; the Committee on Energy and Commerce issued draft statutory language that highlights the public health interest of sharing new data generated by real-world evidence after product approval.[iii]
Notwithstanding the significant First Amendment questions raised by courts regarding FDA’s current approach to off-label communications, an equally important—but often overlooked—consideration in the off-label discourse is whether the medical community is fully aware of the potential risks associated with off-label use and how this may impact the public health.
It is against this challenging backdrop that FDA called the two-day hearing, seeking stakeholder input to help ensure that agency regulation of off-label communications “best protects and promotes the public health in view of ongoing developments in science and technology, medicine, health care delivery, and constitutional law.”[iv]
THE PUBLIC HEARING
The public hearing was held at FDA’s White Oak Campus in Silver Spring, Maryland. Speakers were allotted eight minutes each to present their positions before a panel of senior FDA officials, including the FDA Commissioner, senior officials from the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, the Center for Devices and Radiological Health, the Center for Veterinary Medicine, the Office of Medical Products and Tobacco, the Office of Chief Counsel, the Office of Policy, and the Office of the Commissioner.
By our count, speakers were relatively evenly divided in their support for and opposition to FDA allowing more off-label communications. For organizational purposes, we grouped the speakers into several broad categories and provide below a brief overview of the general views presented by these speakers at the public hearing.
Manufacturers and Trade Organizations
Representatives from life science companies and the organizations that represent them called FDA to task for the agency’s continued delay in issuing comprehensive guidance on off-label communications. The speakers were uniform in their request for FDA to overhaul the current off-label framework. Industry members asked FDA to provide clear guidance that comports with the First and Fifth Amendments, including clear safe harbors under which manufacturers can communicate truthful and non-misleading off-label information without fear of enforcement action. While certain speakers noted that the Constitution is “agnostic” as to the audience of such communications, most industry speakers focused their comments and proposed recommendations on revised regulations that would permit manufacturers to share truthful and non-misleading off-label information with health care providers, payors, and other sophisticated audiences, such as formulary committees, in a timely manner. The speakers grounded their statements not only in a First Amendment right to disseminate truthful, not misleading information, but also in the risk to public health caused by manufacturers’ inability to share information they have collected over time about their products, including adverse event data, standard of care information, and other real-world information.
The speakers primarily advocated for FDA to define “scientific exchange” in a way that acknowledges that scientifically valid information comes in many forms, including real-world evidence, retrospective studies and meta-analyses. Industry speakers also urged FDA to clarify the standard by which to evaluate the types of health care economic information that can be shared pursuant to Section 114 of the 1997 Food and Drug Administration Modernization Act (FDAMA).
The medical device representatives emphasized the need for device-specific guidance that takes into account the complexity of certain devices and the unique relationship between device manufacturers and health care professionals, highlighting the public health risks caused by overbroad restrictions on off-label interactions and the need to provide off-label information in order to effectively provide technical support, during device training courses, and in the operating room during procedures that involve complex devices.
Several speakers presented specific recommendations on how to present off-label information. A particularly interesting proposal involved a recommendation to expand Section 14 of the Prescribing Information to include various types of studies and to assign a grade to those studies based on the robustness of the data used to generate the study results.
Representatives of healthcare payors advocated for increased off-label communications between drug manufacturers and payors. Notably, payor representatives stressed that off-label communication should occur between manufacturers and sophisticated audiences, making a distinction between the professional sector and the patient community.
Because payors typically make decisions about plan design, coverage and formulary placement well in advance of the plan’s effective date, payor advocates stated that they need a broad range of information on off-label uses and pipeline products even before FDA approval or clearance to better inform those decisions. The payors requested all available manufacturer information, both favorable and unfavorable, including clinical trial data, real-world evidence, investigational uses and projected indications. The payors stated that, as sophisticated decision makers, they would be able to judge the value and credibility of such off-label information.
The speakers went on to note that manufacturers are currently hesitant to discuss off-label information because of FDA’s current off-label regulatory framework. This communication gap, according to payors, can delay coverage or improperly skew decision making. Thus, in order to help guarantee value-based decision making, the payor advocates stressed the need for expanded communications of timely off-label information.
Most speakers from academia were against expanding off-label communications due to public health concerns, stating that any potential benefits do not outweigh the risks. The speakers argued that, without stringent FDA regulation of off-label communications, drug manufacturers would have less incentive to produce rigorous data showing that medical products are, in fact, safe and effective. The speakers from academia also stated the belief that any attempts to mitigate these issues, such as disclaimers, data and sales incentive transparency, and surveillance, would not be effective and largely entail action after the harm has been done. The academic discussion on the First Amendment focused on the narrowness of the recent First Amendment holdings, the limited precedential value of the decisions and the potential for FDA to reframe the Central Hudson[v]analysis to focus on the role FDA’s regulations play in compelling the production of quality data and information.
The academic arguments in favor of expanding off-label communications focused on the public health interest in equipping health care providers with the information needed to make informed, up-to-date treatment decisions. The arguments also focused on constitutional concerns, noting that both speaker-based restrictions and audience-based restrictions raise constitutional concerns and that the inconsistency of prohibiting off-label communications while sometimes requiring it (e.g., requiring disclaimers or posting of trials on clinicaltrials.gov pertaining to off-label information) is troubling.
Patient Advocacy Groups and Individuals
Patient advocacy groups and individuals speaking as patients or caregivers of patients prescribed off-label medical products also spoke at the forum. The positions taken by these speakers were mixed. Certain patient advocacy groups, including organizations that represent individuals with rare diseases or less common treatment options, supported an expansion of permitted off-label communication. Because there are a number of barriers to studying rare diseases through randomized and controlled trials, any information available on the potential treatments and risks is invaluable. These advocates generally supported increasing the flow of statistically sound information, which may go to health care providers or patients, provided the information includes appropriate disclosures or certification.
However, other patient advocacy groups and most of the individuals who spoke were generally against loosening any current FDA restrictions on off-label communications. The speakers stated that loosening restrictions would undermine FDA’s mission to protect the public health, with some speakers citing the public health risk implicated by a study that shows that off-label use is associated with increased adverse events. Several of the speakers shared individual accounts of death and other adverse events that occurred after off-label use of a drug or device, and indicated that patients are already rarely told when the drug or device recommended to them has not been approved or cleared by FDA for that particular use or that there may be serious adverse events associated with such use that are not well understood. One patient advocacy group asserted that, in many cases, doctors are not even aware they are prescribing off-label.
Similar to the patient advocacy groups, the policy organization speakers took different positions on off-label communications. The arguments in favor of restrictive off-label regulations focused on so-called “indication creep” and the unnecessary medical treatments resulting from a manufacturer’s ability to engage in off-label communications. The arguments against restrictive off-label communication regulations were based on First Amendment principles and cautioned against equating the truthful and not misleading standard with FDA’s standard for approval and the presence (or lack thereof) of adequate and well-controlled clinical trials.
Professional organizations were in support of increasing off-label communications. Generally, the organizations indicated that current regulations stifled the exchange of scientific information between manufacturers and health care providers, leading to fewer treatment options. They noted the FDA approval process for new indications is slow and cumbersome and supported an expedited process for the free flow of information that would allow health care providers to get information more quickly, ensuring they can provide the best treatment options for their patients. Certain speakers also emphasized that health care providers are capable of interpreting and understanding data and information drug manufacturers share. All of the organizations emphasized the need for health care providers to be informed of the best and most recent data available to best treat patients.
The issues raised during the meeting were varied and complex. Compelling arguments from both sides of the debate, we believe, lead to several noteworthy observations:
FDA has honed in on several key areas of focus. During the meeting, FDA made clear that the agency is in search of data-driven feedback on three key questions: how manufacturers’ incentives to conduct new clinical studies and seek FDA approval of new uses will be affected if permitted to discuss such uses without FDA approval; what evidence standards or other criteria should be used to evaluate off-label information; and who the appropriate arbiter of off-label communications should be. FDA repeatedly raised these questions during the meeting but did not receive fulsome responses, with several speakers promising to provide more information in their written comments.
FDA needs to act quickly to revise its off-label communication framework. FDA has grappled with many of the issues raised by the presenters for years, yet the current framework continues to be a hodgepodge of rules, draft guidances, court decisions, and health care fraud and abuse settlements. Speakers repeatedly emphasized the need for more clarity and the need to update the regulatory framework to account for the realities of modern medical decision making.
Off-label regulations should include well defined terms and standards. While a few speakers took the position that truthful and non-misleading should be the only standard by which to judge permissible off-label communications, the hearing discussions made clear that, given the breadth of communications available to manufacturers, FDA must clearly demarcate the line between scientific exchange and promotion, as well as the line between information and scientifically-valid evidence. By way of example, several speakers made persuasive arguments against the use of published peer-reviewed journals as a hallmark standard for scientific exchange, citing publication bias (meaning, positive trials are more likely to get published than trials with unfavorable results) and lack of transparency as to publication standards and retractions. In addition, speakers raised the issue of whether the agency’s current definitions of some terms, such as labeling and intended use, would need to be updated to account for the new regulatory framework.
The revised off-label framework should not be a one-size-fits-all approach. Given the significant public health and First Amendment issues at stake, the revised off-label framework should not be a one-size-fits-all approach. Rather, the framework should take into account the audience, timing of the communication, product type, and patient population. The regulations should include safe harbors that take into account the sophistication and needs of the intended audience (e.g., payor, health care provider, patients with few or no treatment options). Further differentiation is likely needed based on the scope of the off-label communication. A communication regarding dosing based on evidence collected over time might be more acceptable than a communication based on a new intended use. Finally, the regulation should take into account the unique characteristics of certain product types (e.g., Class III devices, in vitro diagnostics, and precision medicine).
Public sentiment may temper full application of First Amendment principles. Recent First Amendment cases dealing with truthful, non-misleading speech suggest that FDA needs to re-think its stance that off-label speech is presumptively suspect and must fit within an explicit safe harbor, yet many patient advocates told compelling stories of death and serious adverse events that occurred after off-label use of a drug or device. This places FDA in the unenviable position of trying to thread the proverbial needle between developing regulations that align with First Amendment jurisprudence and ensuring that its revised regulations do not enable practices that cause undue risk to the public health.
The role of health care providers requires greater scrutiny. Because FDA does not regulate the practice of medicine, malpractice risk is the primary protection afforded to patients who are prescribed a medical product off label. The effectiveness of this safeguard should be explored in greater detail as part of a broader public policy inquiry into whether additional controls—such as informed consent or FDA-to-health care provider training—are appropriate.
[i] FDA intends to make a full transcript of the hearing available within 30 days and will accept public comments to the docket until January 9, 2017.
[ii] See United States v. Caronia, 703 F.3d 149 (2d Cir. 2012); Amarin Pharma, Inc. v. FDA, 119 F. Supp. 3d 96 (S.D.N.Y. 2015); United States v. Vascular Solutions, Inc. et al., Case No. 5:14-CT-00926-RCL (W.D. Tex. Filed Nov. 13, 2014); see also Final Jury Instructions, Vascular Solutions, No. 5:14-CR-00926.
[iii] See Letter from Fred Upton, Chairman, and Frank Pallone, Jr., Ranking Member, Comm. on Energy & Commerce, to Sylvia Burwell, Sec’y, U.S. Dep’t of Health & Human Servs. (May 26, 2016), https://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/files/documents/114/letters/20160526HHS.pdf/.
[iv] 81 Fed. Reg. at 60300.
[v] Central Hudson Gas & Electric Corp. v. Public Service Commission, 447 U.S. 557 (1980).