Summary

The US Food and Drug Administration (FDA) recently held a two-day public meeting on Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (off-label communications), which offered insight into the areas on which FDA may focus forthcoming (and long-awaited) guidance on off-label communications.

In Depth

The US Food and Drug Administration (FDA) recently held a two-day public meeting on Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (off-label communications), which offered insight into the areas on which FDA may focus forthcoming (and long-awaited) guidance on off-label communications.

As discussed in our pre-meeting commentary, FDA convened the public meeting to obtain public input as it develops draft guidance on the communication of off-label information. A broad array of stakeholders, including manufacturers, trade organizations, payers, and consumer safety and patient advocates, offered comments at the meeting and responded to questions from the agency. As outlined below, several themes emerged from the meeting:

Factors Influencing Standards for Off-Label Communications

During the meeting, the FDA and various stakeholders identified and discussed several factors that may be relevant when assessing the extent to which manufacturers should be permitted to disseminate off-label information. In particular, FDA questioned whether the audience or recipient of information; the nature, quality and source quality of information; the nature of the disease or condition; and/or who evaluates communications should be considered when establishing standards for off-label communications.

Audience or Recipient

Payers, health care providers, and patients are all potential recipients of off-label information.

Given the relative sophistication of the payer audience, increased payer access to off-label information seemed relatively non-controversial. To this end, the agency’s questions appeared to be aimed at articulating the boundaries of permissible communication—e.g., what types of data payers need to make decisions, and how far in advance payers need information before product roll-out—as opposed to whether such communication should occur.

Section 114 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) (Pub. Law No. 105-115), which amended Section 502(a) of the Federal Food, Drug, and Cosmetic Act (FDCA), permits manufacturers to provide payers and formularies health economic information directly relating to a drug’s approved indication for formulary decision making. While the Section 114 pathway has not been widely used, commenters expressed an interested in a revised safe harbor that would allow manufacturers to convey clinical information and health economic information regarding unapproved indications to payers and formularies to advance the same purposes, i.e., to allow population-level decision-making related to disease burden and overall cost.

Considerably more discussion surrounded the parameters for disseminating such information to health care providers. Some commenters supported relaxed agency standards that would facilitate the dissemination of off-label information to trained medical professionals. Other commenters, however, questioned whether providers have the time and/or expertise required to digest and understand novel clinical data. Commenters further questioned whether manufacturer-driven communications were the correct vehicle to provide such information to providers, given the potential for manufacturers to focus solely on favorable information. Other commenters noted, however, that manufacturers may be able to more quickly identify patterns of successful off-label use of their medical products, allowing them to notify health care providers that they may consider the off-label use as a viable treatment option for a particular condition.

Few commenters explicitly discussed the provision of off-label information to patients, and the provision of information to patients did not appear to be a priority for industry. Certain commenters noted, however, that the availability of truthful, non-misleading off-label information—particularly in patient populations for which all or virtually all treatments are used off-label (e.g., pediatric cancers)—could benefit the public health by, for the first time, giving patients an institutional resource to access such data.

Nature, Quality and Source of Information

Commenters and the FDA suggested that the nature, quality and source of scientific information may also be relevant considerations. For example, the agency and/or commenters explicitly considered:

• Whether studies that are peer-reviewed should have different requirements for dissemination than those that are not

• Whether peer-reviewed publications adequately disseminate clinically relevant data on off-label uses, or if there is a need for manufacturer participation to effectively disseminate such materials

• Whether the peer-review process is a sufficient control on the quality of evidence available to payers, providers and patients

• Whether data from clinical trials that constitute a higher level of evidence (e.g., randomized controlled trials) should be treated differently than information from lower-quality study designs (e.g., retrospective reviews, case reports)

Several presenters remarked that limiting dissemination to published peer-reviewed studies limits access to quality clinical evidence that may, for whatever reason, not have been published in the clinical literature. While FDA expressed concerns regarding the transparency of clinical information that had not undergone the peer review process, it appears open to a regulation defining “valid scientific evidence” that parallels the device regulation, 21 C.F.R. § 860.7, potentially expanding communication of information even in the absence of well-controlled investigations.

The agency asked several questions about criteria for judging “weak” or “incomplete” versus “complete” evidence in the absence of clinically significant results, i.e., objective or widely accepted thresholds for statistical or practical significance. The agency also asked how to distinguish and contextualize the differences between “evidence” that has clinical significance versus mere “information” or “data” that may not demonstrate the safety or effectiveness of a medical product, if any.

FDA questioned the extent to which disclaimers describing limitations of information are effective and whether data supports the effectiveness of such disclaimers. Finally, the agency questioned whether looser restrictions on off-label communications will disincentivize manufacturers from generating data or continuing to generate more robust data, or whether it will disincentivize manufacturers from seeking FDA approval or clearance for new uses altogether.  

Nature of Disease or Condition

FDA also entertained whether the nature of the clinical condition(s) addressed in the information should merit greater flexibility. For example, the risk-benefit analysis for the dissemination of off-label information regarding treatments for serious or life-threatening illnesses and rare diseases may weigh in favor of enhanced access to such information, particularly insofar as the affected provider and/or patient population may be more likely to understand such information.

Evaluation of Communications

FDA also considered the process for evaluating whether information meets potential standards for off-label communications. Specifically, issues on which the agency expressed interest in receiving comments included:

• Who should decide whether information is “truthful and non-misleading”

• Whether and when the FDA should review such communications before dissemination

• Whether the source (e.g., manufacturer versus independent researcher) of the information affects whether a communication is “truthful and non-misleading”

• Whether information omitted from a communication could cause patient harm

Boundaries to “Scientific Exchange”

FDA reaffirmed that its regulatory oversight is limited to promotion of medical products, and that it does not have the authority to regulate the practice of medicine. While neither “promotion” nor “scientific exchange” is defined, in its “Off-Label and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices - Information Sheet” guidance, FDA states that physicians must be “well informed about [a] product” and “base [the product’s] use on scientific rationale and on sound medical evidence.” To that end, the agency appears willing to consider defining or establishing more concrete parameters around the concept of scientific exchange to distinguish it from promotion. Several stakeholders’ presentations and FDA questions focused on the distinction between “scientific exchange” and “promotion,” who may participate in “scientific exchange,” and whether scientific exchange is limited to communications between academics and health care providers or extends to communications to formularies and payers.

Potential Revisions to Labeling

A number of stakeholders argued that current labeling is largely outdated and not the primary mode through which information is transmitted and raised the possibility of updating labeling to include an off-label information section with appropriate context (e.g., study design, limitations, statistical analysis) and disclaimers.

FDA also questioned what responsibilities manufacturers have to make sure audiences are given new or updated information, via periodically revised labeling or otherwise.