The draft guidances create a grey area between “on-label” and “off-label” communications that will require careful navigation as manufacturers develop HCEI analyses and promotional communications.

In two recent draft guidances and a memorandum, the Food and Drug Administration (FDA) acknowledges a public health need for certain information outside the four corners of FDA-approved product labeling, signaling a new flexibility with respect to company communications with health care providers and payors. At the same time, the agency repeats its position that “off-label” communications remain unacceptable.

One draft guidance covers manufacturers’ communication of health care economic information (HCEI) — analysis of the “value” of a medical treatment (i.e., cost, efficacy, efficiency, etc.) — to payors, formulary committees and similar entities, as well as pre-approval communications with payors about investigational products.1 The other addresses manufacturers’ communications to health care providers that the FDA considers consistent with approved product labeling.2 The memorandum states the FDA’s position on First Amendment considerations related to “off-label” communications about unapproved uses of a product — a hotly debated issue between the FDA and industry.3 Together, these new statements provide a basis for both optimism and caution. While the FDA will accept the communication of some truthful and nonmisleading information that is outside the label, grey areas between permissible and impermissible communications remain.

Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities

This draft guidance clarifies that the FDA does not consider HCEI that “directly relates to an approved indication and is based on competent and reliable scientific evidence” to be false or misleading when accompanied by a “conspicuous and prominent statement describing any material differences” between the HCEI and the approved labeling. To be considered “related to an approved indication, HCEI analyses should relate to the disease or condition, manifestation of the disease or condition, or symptoms associated with the disease or condition in the patient population” for which the drug is approved. HCEI analyses may be considered “related” even if they incorporate information that does not appear within, and may vary from, information presented in the FDA-approved labeling.

The draft guidance provides several examples of analyses “related to” an FDA-approved indication that may be shared with payors. These include:

  • Validated Surrogate Endpoints — HCEI analyses may be derived from clinical data demonstrating an effect on a surrogate endpoint that is known to predict clinical benefit (e.g., blood pressure reduction as a validated surrogate endpoint for reduction in certain cardiovascular events pertaining to antihypertensive drugs).

  • Patient Subgroups — HCEI analyses may be derived from analyses of treatment effects in patient subgroups that are within the patient population for the approved indication, even if these subgroup analyses were not pre-specified in the approval studies.

  • Comparisons — HCEI analyses may be derived from studies comparing the safety or effectiveness of a drug for its approved indication to another drug or to no treatment.

HCEI analyses must be based on competent and reliable scientific evidence (CARSE). The FDA will consider an analysis to be based on CARSE if it has been developed using generally accepted scientific standards, appropriate for the information being conveyed, that yield accurate and reliable results. The draft guidance also describes the types of information that manufacturers should include when providing HCEI to payors, such as the limitations of the economic analyses, a statement describing the material differences from the FDA-approved labeling, omitted data sources or studies (including the results of a comprehensive literature search and an explanation of the methods used to determine which data to include or exclude), and any additional risk information related to variations from the FDA-approved labeling.

This draft guidance also permits companies to provide payors with certain kinds of information about unapproved investigational products, recognizing that payors may need some information ahead of approval for coverage and reimbursement planning. The FDA does not intend to object under the regulations prohibiting the promotion of investigational drugs and devices — provided (1) the information is “unbiased, factual, accurate, and non-misleading” and (2) the communication includes a clear statement that the product is investigational and that the safety or effectiveness of the product has not been established, together with information about the stage of product development. The guidance lists the kinds of information that can be communicated. This includes such information about the product as its class and design, the indications sought, and “factual presentations” of study results, with no characterizations or conclusions about the safety or effectiveness of the product.

Medical Product Communications That Are Consistent With the FDA-Required Labeling

This second draft guidance explains how the FDA evaluates medical product communications, including promotional materials, that include information not contained in the FDA-required labeling, but that may be consistent with the labeling. Information that is “consistent with” the labeling is limited to information about the approved or cleared uses of a product. All such information must be conveyed in a truthful, nonmisleading way. The FDA states that, if any representations are false and misleading, the communication would misbrand the product, regardless of whether it is consistent with the labeling. For example, pivotal study data showing an individual component of a composite primary endpoint should not be used to claim efficacy for the component if that analysis was not sufficiently powered.

The FDA describes three factors that it will consider in determining whether a communication is consistent with the FDA-required labeling.

  • Factor 1: How the information in the communication compares to the information about the conditions of use in the FDA-required labeling including:

    • Whether the representations relate to a different indication than those in the FDA-approved labeling

    • Whether the representations are outside the approved/cleared patient population in the FDA-approved labeling

    • Whether the representations conflict with the limitations or directions for handling, preparing or using the product in the FDA-approved labeling

    • Whether the representations conflict with the recommended dosage or use regimen, route of administration or strengths set forth in the FDA-required label.

  • Factor 2: Whether the representations in the communication increase the potential for harm relative to the information reflected in the FDA-required labeling.

  • Factor 3: Whether the directions for use in the FDA-required labeling enable the product to be safely and effectively used under the conditions represented or suggested in the communication.

The agency also provides several examples of information that would be “consistent with” the FDA-approved label. Some of these examples may expand the current boundaries on promotional communications. For example:

  • Information based on a comparison of the safety or efficacy of a medical product for its approved/cleared indication to another medical product approved/cleared for the same indication (e.g., a firm’s communication provides information from a head-to-head study indicating that its drug that is approved to treat high blood pressure in adults has superior efficacy to another drug that is also approved to treat high blood pressure in adults)

  • Information about the onset of action of the product for its approved/cleared indication and dosing/use regimen

  • Information that provides additional context about the mechanism of action described in the FDA-required labeling.

To be truthful and not misleading, communications “need to be grounded in fact and science and presented with appropriate context.” The evidentiary support should be “scientifically appropriate and statistically sound to support the representations or suggestions made in the communication.” To avoid a presentation that is false and misleading, the FDA recommends “accurately characterizing and contextualizing the relevant information, including by disclosing unfavorable or inconsistent findings” and providing any data or information from the FDA-required labeling that relates to what is represented in the communication.

Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products

In November 2016, the FDA held a public hearing to obtain input on issues related to communications regarding unapproved uses of approved or cleared medical products. The FDA’s recent memorandum provides additional background on the issues it is considering as it reviews its rules and policies on “off-label” communications, including First Amendment considerations. The FDA acknowledges that its current policies on communications about unapproved product uses implicate its interest in advancing the public health, including the development of robust safety and efficacy data; protecting against fraud, misrepresentation and bias; and protecting the integrity and reliability of promotional materials. The agency notes that the risk of adverse events is higher for unapproved uses and offers examples of cases where false and misleading marketing has caused patient harm.

Here, the FDA recognizes that companies’ communications regarding unapproved uses may advance public health by supporting informed decision-making for patient treatment and furthering scientific understanding and research. The agency also discusses the tension between its policies and First Amendment considerations, highlighting some of the merits of alternative approaches to harmonizing the competing interests implicated by these communications. While the memorandum outlines the circumstances where the FDA’s current approach permits discussion regarding “off-label” use (such as continuing medical education programs and presentations at scientific conferences) and describes the relevant First Amendment jurisprudence, it does not provide clarity on the policies the FDA intends to adopt.

Potential Implications for Drug and Device Manufacturers

Giving payors and physicians access to information that is “related to” or “consistent with” the FDA-approved label, but outside its four corners, serves the public interest, impacting both product accessibility and individual patient care. However, the draft guidances create a grey area between “on-label” and “off-label” communications that will require careful navigation as manufacturers develop HCEI analyses and promotional communications. For example:

  • As both draft guidances emphasize, whether a communication is false and misleading will be a fact-specific determination.

  • The FDA’s examples of permissible communications relate to areas that have traditionally been the subject of FDA enforcement actions, including comparative claims, use of validated surrogate endpoints in communications with payors, and claims related to a product’s mechanism of action.

  • The standards for the types of evidence that may support the communications are subjective.

While the FDA has not detailed the circumstances in which it will take enforcement action, it suggests that it will focus on the quality of the evidence supporting a company’s communications, whether the company addresses unfavorable or inconsistent findings, and whether the communication adequately describes material differences from the FDA-required labeling. Manufacturers should also consider what standard-setting role these draft guidances may play beyond FDA regulation — particularly in state government and private litigation, where plaintiffs are challenging marketing communications under state consumer protection statutes, the Lanham Act, and other advertising laws or in product liability claims.

Will the FDA continue to broaden the types of truthful, nonmisleading information that may be shared with payors and physicians? Or do these draft guidances and memorandum represent the outer limits of what information manufacturers may share beyond the FDA-approved label? As the FDA continues to refine its policies in this area, drug and device manufacturers should proceed cautiously in conveying scientifically appropriate information that is “related to” or “consistent with” the FDA-approved labeling to payors and health care providers.

The FDA has opened the comment period for these three documents for 90 days, until April 19, 2017. Please let us know if we can help you draft and submit your comment.