Announced as another effort to improve patient access and address drug pricing, FDA recently finalized two guidance documents intended to facilitate better communication and negotiation with payors, formulary committees, and others:
The guidance documents were published initially in draft form in January 2017 and have since been revised to provide even further clarity in response to stakeholder comments. The guidance documents provide valuable insight into FDA’s current thinking regarding communication of product information, and Commissioner Gottlieb hopes that they “encourage competitive contracting based on measures of value that matter most to purchasers and patients . . . .” FDA, Press Release, Statement from FDA Commissioner Scott Gottlieb, M.D., on new efforts to advance medical product communications to support drug competition and value-based health care (June 12, 2018).
Promotional Communication Guidance
The Promotional Communication Guidance further explains FDA’s views on manufacturer communication of information that is not in, but is consistent with, the FDA-required labeling. As in the draft guidance, this information is limited to approved or cleared uses of the product. This final version of the Promotional Communication Guidance is similar to the initial draft, but makes some meaningful changes. The same three-factor test as the draft is included in the final version, but includes much more detail. As a reminder, this three-factor test is integral to the determination of whether a communication is consistent with the FDA-required labeling:
- Factor 1: Different Conditions of Use; whether information in a medical product communication is different from the information in the FDA-required labeling regarding:
- Patient Population;
- Limitations and Directions for Handling, Preparing, and/or Using the product;
- The recommended dosage or use regimen or route of administration.
- Factor 2: Increases the Potential for Harm; whether the representations or suggestions in a medical product communication negatively alter the benefit-risk profile of the product.
- Factor 3: Prevents Safe and Effective Use; whether the medical product can still be used safely and effectively in accordance with the directions for use in the FDA-required labeling, given the representations or suggestions in a medical product communication.
Given the potential for overlap in the three factors, FDA explains that factor 1 primarily addresses situations where information about the conditions of use described in the labeling and in a firm’s communication conflict with one another. If a firm’s communication suggests use of its product in a way that does not conflict with the FDA-required labeling but nevertheless increases the potential for harm to health, the communication would not be consistent with the FDA-required labeling under factor 2. Similarly, if a firm’s communication suggests use of a product in a way that does not conflict with the information in the FDA-required labeling but the FDA-required labeling would not provide adequate information to enable the product to be safely or effectively used under the conditions represented in the communication, the communication would not be consistent with the FDA-required labeling under factor 3.
As discussed in the draft, communications that are consistent with the FDA-approved labeling will not be relied upon to establish a new intended use; however, FDA explains throughout the final version that this policy should not suggest that these communications are excluded from consideration altogether. If, for example, there is other evidence of a new intended use, these communications, even though consistent with the labeling, may be part of the overall material reviewed in evaluating the firm’s conduct. Conversely, a determination that a product communication is not consistent with that product’s labeling does not necessarily mean the communication will be relied on to establish a violation.
FDA also adds a discussion of devices to this guidance, including 510(k)-cleared devices. FDA explains that for 510(k)-cleared devices, firms should analyze communications in accordance with 21 C.F.R. § 807.81(a)(3) (change that requires a premarket notification) and FDA’s guidance Deciding When to Submit a 510(k) for a Change to an Existing Device (510(k) Modifications Guidance). Communications that trigger the need for a new 510(k) are considered inconsistent with FDA-required labeling; those that do not trigger the need for a new 510(k) are considered consistent with the labeling. For 510(k)-exempt devices, firms should analyze communications in accordance with the appropriate exemption and classification regulation.
While most of the examples and analyses remained the same, we note that FDA provided more specific information in the example involving effects of a product on patients under Question 4. “Patient-reported outcomes,” a term used in this example in the Draft Guidance, is no longer mentioned in the final guidance. Although the example still includes information about compliance/adherence as consistent with the FDA-required labeling, it no longer includes this information within the context of a patient perception. In addition, the Draft Guidance had included broad language suggesting that information related to patient perceptions of a product’s effect on their “basic activities of daily living” would be consistent with FDA-required labeling. When originally published in January 2017, this example represented a more radical departure for FDA on its approach to “patient testimonials,” which had often been the subject of enforcement action. The final guidance no longer includes this language; however, it includes a more limited example relating to a patient’s perception of a known adverse reaction related to the product.
In addition, information about the tolerability of a product when used concomitantly with another product for a co-morbid condition was added as an example of a consistent communication in response to Question 4.
The final Promotional Communication Guidance also attempts to clarify that the amount and type of evidence needed to support a particular promotional communication depends on the communication. FDA explains that different evidence is needed to support different types of claims or representations, but is not clear about how to determine which evidence is required. Evidence must be scientifically appropriate and statistically sound, but FDA provides no clarification of those terms, particularly within the context of examples otherwise provided, including patient perceptions and retrospective analyses, as consistent with the FDA-required labeling.
Further, FDA cautions firms to be careful not to overstate the findings or conclusions that may be drawn from evidence or fail to disclose material limitations. In the Draft Guidance, FDA included information in Q.6/A.6 relating to promotion of individual items included in a composite endpoint and cautioned that if the trial was not adequately powered to determine treatment effect on the individual component and there was no control for multiplicity, a representation that there was an effect would be false or misleading. In the final Promotional Communication Guidance, FDA provides a helpful example of how a firm might communicate this information in a truthful and non-misleading way, and includes the components of a disclaimer that might help contextualize such a presentation, (“the firm could explain that because these analyses were not prespecified and appropriate multiplicity adjustments were not applied, the results on the individual components need cautious interpretation and could represent chance findings.” Promotional Communication Guidance at 13).
Finally, the Promotional Communication Guidance provides for additional flexibility in communicating information that is not consistent with FDA-required labeling. In the Draft Guidance, FDA cites only to its draft guidance on responding to unsolicited requests and its guidances on scientific publication dissemination as mechanisms to communicate information about unapproved uses of approved products. In its final guidance, FDA uses these guidances as examples but otherwise makes clear that a communication that is not consistent with FDA-required labeling does not necessarily mean the communication is one that FDA would rely on as relevant to establishing a violation.
Payor Communication Guidance
The Payor Communication Guidance addresses common questions regarding communications to payors to allow a better exchange of truthful and non-misleading information, which FDA hopes will lead to quicker coverage decisions and beneficial pricing structures. The final version emphasizes that its intent is to assist manufacturers in ensuring that their communication of Health Care Economic Information (“HCEI”) to payors about both approved or cleared and unapproved medical products is truthful and non-misleading.
Substantively, the Payor Communication Guidance appears largely the same as the draft version, but is significantly more expansive. While the draft version of the guidance applied only to drugs and investigational devices, the final version explicitly applies its recommendations to approved or cleared devices. These devices are addressed in a newly-added section covering device-related questions, but we note that this section is notably devoid of detail. The analysis, in its entirety, provides that communications for devices may not be false or misleading and that “if a device firm disseminates HCEI that complies with the recommendations [for drugs], FDA does not intend to consider such information false or misleading or evidence of a new intended use.” Payor Communication Guidance at 17.
Further, the guidance expands its scope to cover not just investigational drugs and devices, but also unapproved uses of approved drugs and devices and new drugs and devices not yet approved for any use, as this information may help payors plan and budget for future coverage or reimbursement decisions. The draft guidance defined the term “investigational product” narrowly to refer to drugs and devices that are not yet approved or cleared by FDA for any use (this includes products intended to be submitted or already submitted in a marketing application). In the final version, recommendations are expanded beyond these types of investigational products to communications by firms regarding unapproved uses of already approved or cleared products. This is a significant change, as these discussions are tantamount to off-label discussions; these types of discussions with Medicare and Medicaid providers could raise False Claims Act questions.
FDA does explain in a new question addressing additional considerations about unapproved products and unapproved uses of approved, cleared, or licensed products that it has adopted this approach in an effort to balance competing public health interests to advance overall health. Because payors are a sophisticated audience, FDA believes that the recommendations and limitations set forth in the guidance appropriately balance the competing government health interests with firms’ interests. However, FDA makes clear that these types of communications about unapproved products or uses raise additional or different considerations beyond the scope of this guidance. Regardless of these new, more permissive guidelines, industry should be careful of suggesting an unapproved use for an approved product.
Additionally, FDA makes the following other revisions to the Payor Communication Guidance:
- In the table following A.A.4, Examples of HCEI Analyses That Relate to an Approved Indication, the final version of the guidance adds “Compliance/Adherence” as an example. HCEI analyses may be derived from studies assessing patient compliance/adherence with a drug for its approved indication.
- In A.C.1, factual presentations of results from clinical studies now includes bench tests that describe performance and includes detailed examples on ways to present results from studies. Targeting marketing strategies is also removed as information about an unapproved product that may be provided under the guidance.
- In A.C.2, other information that should be communicated about unapproved products or unapproved uses now includes a recommendation that firms describe material aspects of study design and methodology and full findings, as well as a prominent statement disclosing the indication(s) for which FDA has approved, cleared, or licensed the product and a copy of the most current FDA-required labeling.
Importantly, section 502 of the Federal Food, Drug, and Cosmetic Act provides that the substantiation standard for health care economic information is competent and reliable evidence. In the final version of the guidance FDA provides a flexible approach to this standard, stating that evidence must be developed “using generally accepted scientific standards, appropriate for the information being conveyed, that yield accurate and reliable results.” Payor Communication Guidance at 10.