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June 14, 2018

FDA Finalizes Guidance Documents on Payor Communications and Communications Consistent with Labeling


On June 12, 2018, the US Food and Drug Administration (FDA) issued revised, final versions of two guidance documents, "Drug and Device Manufacturer Communications with Payors, Formulary Committees and Similar Entities—Questions and Answers"1 (hereafter the "Payor Guidance") and "Medical Product Communications That Are Consistent With the FDA-Required Labeling—Questions and Answers"2 (designated by FDA as the "CFL Guidance"). FDA published draft versions of these documents in January 2017, which we previously summarized here and here.

Comments on the guidance documents must be submitted to FDA by July 13, 2018.3

Industry and other stakeholders have eagerly anticipated the revisions to these final guidance documents, which provide additional flexibility for manufacturers to communicate information not contained in a product labeling and which provide FDA's views on manufacturer communications with payors, including under Section 502(a) of the Federal Food, Drug, and Cosmetic Act as amended by Section 3037 of the 21st Century Cures Act (Section 114 of the Food and Drug Administration Modernization Act (FDAMA 114)).

FDA Commissioner Scott Gottlieb, M.D. issued a press release announcing the final guidance documents as part of the Agency's "new efforts to advance medical product communications to support drug competition and value-based health care." Citing the Trump Administration's Drug Pricing blueprint, which we summarized here, Commissioner Gottlieb emphasized "the importance of linking payments for drugs to their value" and "removing regulatory obstacles to value-based purchasing by payors." To achieve these goals, Commissioner Gottlieb acknowledged the need for FDA to provide "clear guidance to pharmaceutical companies about open, responsible communication with payors, formulary committees and others." With respect to the CFL Guidance, Commissioner Gottlieb emphasized that the guidance will facilitate the sharing of information, such as post-market study data, that "may help inform decision-making regarding patient care." Commissioner Gottlieb noted that FDA believes the two guidance documents "will provide clarity to companies as they develop communications about their medical products and help ensure that patients, providers and insurers have access to a range of relevant, truthful and non-misleading information from companies about medical products."

The Payor Guidance

The Payor Guidance sets forth FDA's current position on manufacturer-payor communications, and, in particular, FDAMA 114 and communications related to healthcare economic information (HCEI) with payors across a product's lifecycle, providing recommendations to firms to help them ensure that their HCEI and other communications to payors are truthful and non-misleading and that appropriate background and contextual information is provided to enable payors to make informed decisions. In the Payor Guidance, FDA expressly recognized that payors are a "sophisticated audience" and generally "possess financial resources and motivation to closely scrutinize information about medical products as part of their decision-making process, including an evaluation of the limitations and reliability of that information." 

Significantly, FDA clarified that it would not take enforcement action under 21 C.F.R §§ 312.7(a) or 812.7(a) (FDA's regulations prohibiting pre-approval promotion) or otherwise, for manufacturer communications to payors regarding information about an unapproved use of an approved/cleared/licensed product. FDA stated that such communications "can allow payors to provide coverage for these new products and new uses more quickly after FDA approval or clearance." The draft guidance had limited FDA's enforcement discretion to only investigational products with no FDA approved/cleared/licensed use.

FDA revised the structure of the guidance to separate Q&A for approved drugs (Section III.A), approved/cleared devices (Section III.B),4 and medical products not yet approved/cleared for any use or unapproved uses of approved/cleared products (Section III.C).  While FDA recognized that FDAMA 114 applies only to drugs, FDA stated that the recommendations in III.A are "generally applicable to firms' communications of HCEI to payors about devices as well, and can help ensure these communications are not false and misleading."5

FDA also retained its position from the draft guidance that "communication of HCEI about drugs under [section 502(a)] is promotional labeling," and thus subject to FDA postmarketing reporting requirements that apply to all promotional labeling—including submission to OPDP on FDA Form 2253 at the time of initial dissemination or initial publication.6 Additional changes include (bold denotes newly added text):

  • HCEI Definition: FDA added that HCEI "pertains to the economic consequences (including, but not limited to, monetary costs or resource utilization) related to the clinical outcomes of treating a disease (or specific aspect of a disease) or of preventing or diagnosing a disease." 
  • Audience: FDA clarified that the appropriate audience to receive HCEI includes both public and private sector payors, formulary committees, and related entities, including "third party administrators" responsible for selection/coverage of drugs.
      • FDA also elaborated that while the Payor Guidance is not applicable to healthcare providers (HCPs) making individual patient prescribing decisions or patients (e.g., public websites), HCEI communications are permitted to HCPs "when they are carrying out their professional responsibilities for selection of drugs for coverage or reimbursement."

  • Competent and Reliable Scientific Evidence (CARSE): FDA did not substantively change this Q&A, but noted that its examples of authoritative bodies was non-exhaustive and also listed the Agency for Healthcare Research and Quality (AHRQ).

  • Information That Should be Included When Disseminating HCEI: As noted above, FDA emphasized that firms must provide payors "appropriate background and contextual information when disseminating HCEI" and such information "should be presented clearly and prominently."
      • FDA explained that the "disclosure of pertinent information can be concise so long as all material information (such as the source(s) of data used, the outcome measures used, the type of analysis, the limitations of the analysis, and the generalizability of the findings) is provided." 
      • FDA recommended that this contextual information be presented in "conjunction with the information within the HCEI presentation to which it relates or that the HCEI presentation include a prominent reference to where the information can be found within the presentation."
      • FDA also clarified that its recommendations are not meant to suggest "duplicate disclosures" of background/contextual information that may already be required by certain authoritative bodies (e.g., AMCP dossier).Otherwise, FDA's examples of such information (e.g., study design and methodology, generalizability, limitations, etc.) largely remain unchanged from the draft guidance.7
  • Conspicuous and Prominent Statement Describing Material Differences: FDA provided new examples of instances in which HCEI may have "material differences" from the FDA-approved labeling, and thus, the HCEI must present a conspicuous and prominent statement describing such differences. Specifically: "new or increased risks, different dosing/use regimens, different endpoints, [and] more limited/target patient populations." FDA further elaborated: if an HCEI presentation "is based on real-world data where actual patient use of the drug falls outside of the recommended dosing/use regimen in the FDA-approved labeling," FDA recommended using the following statement "in conjunction with the HCEI presentation and in a font size comparable to that used for the other information in the presentation":

The dosing regimen used in this study varies from the dosing regimen in the FDA-approved labeling8

FDA explained that it will evaluate whether a statement is conspicuous and prominent based on factors such as "location of the statement, the font size and style of the statement text, the contrast between text and background, and the white space between and around text."

  • Risk-Sharing/Value-Based Contracts: FDA reiterated that it does not regulate contract terms between firms and payors, but also added that risk-sharing and value-based contracts "are not subject to FDA reporting requirements." However, in a change from the draft guidance and consistent with Dr. Gottlieb's statements, the Payer Guidance confirms that communications made in connection with the negotiation and implementation of value-based contracts are covered by the Payer Guidance.

Communications Regarding Investigational Products/Uses

As noted above, the Payor Guidance clarifies that FDA will not take enforcement action under 21 C.F.R §§ 312.7(a) or 812.7(a), or otherwise, for guidance-compliant manufacturer communications to payors regarding information about an unapproved use of an approved/cleared/licensed product. FDA added one new type of information manufacturers can communicate: "patient utilization projections (e.g., epidemiological data projection on incidence and prevalence); and removed "targeting/marketing strategies." In addition, FDA provided specific examples 9 of appropriate and inappropriate factual presentations of results from clinical studies.10

FDA recommended that firms include a clear statement that the product or use is not approved/cleared/licensed, and that the safety or effectiveness of the product or use has not been established. FDA revised the types of other information that firms should include when communicating about unapproved products/uses. 

  • FDA clarified that firms should include information on the status of studies and how the data presented relates to the overall product development plan and whether a marketing application for the product or new use has been submitted to FDA or when such a submission is planned. 
  • For communications that include factual presentations of results from studies (as noted above), FDA recommended that firms: (1) "describe material aspects of study design and methodology and also disclose material limitations related to the study design, methodology, and results; and (2) "ensure that results are not selectively presented (e.g., both positive and negative or null findings should be presented)." 
  • For communications regarding unapproved uses of approved/cleared/licensed products, FDA recommended including a prominent statement disclosing the FDA approved, cleared, or licensed indication, as well as a copy of the most current FDA-required labeling. 
  • For communications regarding an unapproved product or an unapproved use of an approved/cleared/licensed product, FDA recommended including a clear statement that the product or use is not approved/cleared/licensed and that the safety or effectiveness of the product or use has not been established. 

FDA also stated that firms should provide follow-up information to payors, but clarified that only if the previously communication information "becomes materially outdated" as a result of significant changes or new product information. 

FDA concluded that the Payor Guidance recommendations with regard to unapproved uses of approved or cleared medical products "appropriately balance the[se] competing interests" of FDA and interested stakeholders. FDA also confirmed that the "risk that payors will be misled is relatively low" if firms follow the recommendations in the guidance. FDA noted that communications to other audiences about unapproved products or uses are beyond the scope of the Payor Guidance. 

CFL Guidance

The CFL11Guidance addresses FDA's current thinking with respect to medical communications that present information not contained within the FDA-required labeling of a medical product. Significantly, the CFL Guidance provides that FDA will exercise enforcement discretion with respect to manufacturer communications that meet three factors, and offers specific examples of instances of manufacturer communications that would and would not meet the criteria set forth in FDA's three-factor test. Although the CFL Guidance is substantially similar to the draft guidance that FDA previously published, FDA did make a few changes that are worth noting. Those changes are summarized below.  

First, FDA amends language from the draft guidance that previously suggested that FDA does not intend to rely on communications consistent with the FDA-required label "alone" as evidence of a new intended use. Importantly, the final version of the CFL Guidance includes an explicit acknowledgement that "if a firm communicates information that is not contained in its product's FDA-required labeling but that is determined to be consistent with the FDA-required labeling, FDA does not intend to rely on that communication to establish a new intended use."12 However, the Agency clarifies that these edits are not intended to suggest that these communications must be excluded from consideration altogether. Rather, FDA explains that "if there is other evidence of a new intended use for a product, product communication that are consistent with the FDA-required labeling may be part of the overall material that is evaluated in assessing the firm's conduct."13

Additionally, the CFL Guidance clarifies the applicability of the CFL framework to 510(k)-cleared devices and 510(k)-exempt devices. With respect to 510(k)-cleared devices, FDA explains that there is no need to separately analyze communications under the CFL Guidance, but rather that they should be analyzed under the regulatory provisions governing when a new 510(k) is required for changes to a cleared device (21 C.F.R. § 807.81(a)(3)) and FDA's guidance document titled "Deciding When to Submit a 510(k) for a Change to an Existing Device." FDA notes that the risk-based assessment required by FDA regulations and interpreted by FDA guidance on device product changes is consistent with the principles of the CFL Guidance. As to 510(k)-exempt devices, FDA recommends that firms analyze communications in accordance with the applicable limitations of exemptions regulation, adding that the Agency views communications that trigger the need for a 510(k) as inconsistent with the FDA-required labeling while viewing those that do not trigger the need for a 510(k) as being consistent with the FDA-required labeling. The Agency further states that although it is not necessary for manufacturers to analyze 510(k)-cleared and exempt devices under the CFL Guidance framework, the recommendations contained in the guidance may nonetheless be useful to help firms convey information in a truthful and non-misleading way. 

The CFL Guidance also finalizes the three factors that FDA will consider in determining whether a firm's communication about a medical product is consistent with the FDA-required labeling for that product. The three factors are:

  1. How the information contained in the communication compares to information in the FDA-required labeling. In particular, FDA will review information in the communication related to indication; patient population; limitations and directions for handling/use; and dosing or use regimen/administration.
  2. Whether the information in the communication about the use of the product increases the potential for harm to health relative to the information in the FDA-required labeling. By way of example, FDA states that it may assess "the risks of abuse or misuse of certain products, the potential for harm to the health of humans from certain animal drug uses, or the potential for harm to health from secondary exposure to certain medical products."
  3. Whether the directions for use in the FDA-required labeling enable the product to be safely and effectively used as represented/suggested in the manufacturer communication.  

In discussing the three factors for determining whether a product communication is CFL, FDA clarifies that because the FDA-required labeling is not intended to "exhaustively address every possible scenario a firm could suggest in its communications," simply analyzing whether there is a conflict between the information in a communication and the FDA-required label is not always sufficient for determining whether a communication is consistent with the label. Rather, if a firm's communication suggests use of a product in a way that does not conflict with the label but that nonetheless increases the potential for harm to health relative to the information reflected in the label or that would not provide adequate information to enable the safe and effective use of the product, the communication would not be considered consistent with the label.

By way of illustration, FDA added to the final guidance an example in which the Dosage and Administration section of the approved labeling for a drug indicates that the dosage modifications may be needed based on individual safety and tolerability, but does not provide specific dose modification instructions. Where a firm's communication for the drug sets forth a specific modified schedule for patients who have tolerability issues that would result in the patients receiving a sub-therapeutic dose of the drug, the communication would not be considered consistent with the label because the FDA-required labeling would not provide adequate information to enable effective use of the product under the dosing conditions represented in the communication.

In discussing the second factor for determining whether a product communication is CFL (i.e., whether the communication increases the potential for harm to health relative to the information reflected in the FDA-required labeling), the final guidance clarifies that where a firm has submitted a changes being effected (CBE) supplement for a safety-related labeling changes, firm communications that reflect the changes to the labeling described in the pending CBE supplement would be considered consistent with the label provided the communications are otherwise consistent with the framework described in the CFL guidance.

FDA also added additional examples of communications that would be considered consistent with FDA-required labeling. One of the examples addresses a firm’s product communication for its prosthetic hip (approved to treat mobility-limiting joint disease caused by osteoarthritis), which provides information regarding the effect of the device on relieving patients' symptoms associated with the disease at an interim point in time before a primary endpoint of improvement in function.  Another example is a firm's communication conveying that its drug, which is administered by subcutaneous injection, is more convenient than another product with the same active ingredient indicated for the same condition which is administered through an intravenous infusion, by providing information that its subcutaneous injection requires an average of 3 hours in the clinic versus an average of 10 hours in the clinic for infusion of the other product.

As to examples involving communications that would not be considered consistent with the label, FDA deleted an example in which a device is cleared for use in individuals with cystic fibrosis (CF) for diagnosing a specific CF-gene mutation and the firm's communication provides information about using the device in individuals who do not have CF to determine if they are carriers of the CF gene. FDA appears to have replaced this example with one where a device is indicated for the quantitation of hepatitis B virus (HBV) DNA in human blood samples of previously diagnosed HBV-infected individuals as an aid in the management of patients with chronic HBV infection undergoing anti-viral therapy, and a firm's product communication provides information about using the device to make an initial diagnosis of HBV infection in previously undiagnosed patients. FDA opines that the firm's communications in this example would not be consistent with the FDA-required labeling.

The CFL Guidance continues to emphasize that to be considered consistent with the FDA-required labeling, firm communications must be truthful and non-misleading and must be based on appropriate evidentiary support. With respect to evidentiary support, the CFL Guidance retains the "scientifically sound and statistically appropriate" standard set forth in the draft guidance that will be used for establishing whether there is adequate evidentiary support for a communication such that it will not be considered false or misleading.

Importantly, FDA also clarifies that the amount and type of evidence needed to support a particular CFL promotional communication depends, in part, on the topic addressed by the communication, as well as on the particular representations or suggestions made in a communication (i.e., different evidence would be needed to support a long-term efficacy presentation versus a mechanism of action presentation). FDA understands that firms are interested in including information from a variety of types of studies and analyses in their product communications, and the Agency believes a variety of types of studies and analyses can provide useful additional information about a medical product for its approved/cleared conditions of use. The Agency adds, however, that some of these studies or analyses do not, in and of themselves, allow for reliable conclusions to be drawn about the effects of the product, and that, to be considered truthful and non-misleading, firms'product communications should not overstate the findings of or the conclusions that can be drawn from such studies or analyses, or fail to disclose their material limitations.

By way of example, FDA added to the CFL Guidance a scenario in which analyses of pivotal trial data elaborate on the data in the product label by providing information from separate analyses of individual components of a composite endpoint that was used as the primary endpoint, but where the pivotal trial was not adequately powered to determine treatment effect on the individual components of the composite endpoint and/or type 1 error was not controlled for. FDA explains that, in this circumstance, the firm could present the results from these analyses of the individual components of the composite endpoint descriptively, without p-values and without claiming that the results on the individual components demonstrate additional effects of the drug. However, FDA recommends that the firm should also include contextual information in such communications to describe the material limitations of the data, such as that because the analyses were not prespecified and multiplicity adjustments were not applied, the results on the individual components warrant cautious interpretation and could represent chance findings.

The CFL Guidance sets forth recommendations for firms to consider when developing their communications consistent with the FDA-required labeling. In particular, the Agency recommends that :

  • CFL promotional communications should accurately represent the data and information presented. For example, study design and methodology should be "clearly and prominently" disclosed in firms' CFL communications.
  • CFL promotional communications should accurately characterize and contextualize relevant information presented. For example, a firm should not selectively present only positive efficacy results.
  • CFL promotional communications should include information from the FDA-required labeling if such information is related to the information presented in the CFL communication. For example, if a CFL communication includes information about the types and rate of occurrence of adverse events observed in practice, the communication should include any information from the FDA-required labeling related to the types and rate of occurrence of adverse events.  

FDA concludes that, if a manufacturer "wishes to present this information in a CFL promotional communication, it must do so in a truthful and non-misleading way."  Nevertheless, in the CFL Guidance, FDA emphasizes that it would not necessarily rely on a communication that is not consistent with that product’s FDA-required labeling "as relevant to establishing a violation of FDA-administered legal authorities." 

*          *          *          *          *

Both guidance documents provide valuable additional clarity to medical product manufacturers and related stakeholders regarding their promotional communications.  However, application of FDA's guidance will require case-by-case analysis. Companies should carefully consider the implications of both the Payor and CFL Guidance documents on their marketing, managed markets, and medical communication strategies, internal policies and procedures, promotional review processes, and compliance programs.

© Arnold & Porter Kaye Scholer LLP 2018 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.

  1. Available here.

  2. Available here.

  3. Payor Guidance (Docket No. FDA-2016-D-1307); CFL Guidance (Docket No. FDA-2016-D-2285).

  4. If a device firm disseminates HCEI that complies with the recommendations in section III.A Payor Guidance, FDA "does not intend to consider such information false or misleading or evidence of a new intended use."

  5. FDA explained that while HCEI applies only to drugs, the general requirement in section 502(a) that labeling not be false or misleading applies to devices as well as to drugs. FDA clarified, however, that device firms are not subject to the same postmarket reporting requirements to submit promotional materials to FDA upon initial dissemination or publication.

  6. See 21 C.F.R. § 314.81(b)(3)(i). In making this clarification, FDA added a brief summary of the Kordel v. United States case, to expand upon why product communications constitute labeling. See pp. 3-4, n. 11. FDA also noted that it considers HCEI communications about devices to be promotional labeling. See id.

  7. FDA clarified that data sources for outcomes measures could include "real-word data" from administrative databases. FDA also revised examples of the types of limitations.

  8. FDA said this example is "not intended to suggest this is the only way" to present this statement.

    • Example 1: A firm intends to submit a marketing application for a product for management of severe pain and wants to communicate to payors.
        • Appropriate: "In a X-week randomized controlled trial comparing PRODUCT to placebo, a statistically significant improvement was observed on the primary endpoint of reduction in mean pain scores from baseline" in conjunction with a graph and/or table summarizing the numerical study result.
        • Inappropriate: "PRODUCT allows health care providers to optimize pain relief" or "PRODUCT has been demonstrated to provide potent pain relief."
    • Example 2: A firm recently completed a phase 3 trial evaluating its product, Drug X, for the treatment of metastatic non-small cell lung cancer, and intends to submit a marketing application for this use and wants to communicate to payors:
        • Appropriate: "In a randomized, multi-center trial of Drug X versus {active control} in patients with metastatic non-small cell lung cancer, Drug X met its primary endpoint of improving progression-free survival compared to {active control}."
        • Inappropriate: "Drug X shows superior efficacy to {active control}" or "We expect Drug X to be the drug of choice for non-small cell lung cancer."

  9. FDA also clarified that results can include "clinical studies of drugs or devices or bench tests that describe device performance."

  10. FDA uses the acronym "CFL" as shorthand for the phrase "consistent with the FDA-required labeling."

  11. In the draft guidance, FDA had stated that "{i}f a firm's communication is consistent with the FDA-required labeling, that communication alone is not viewed by FDA as providing evidence of a new intended use." (emphasis added)

  12. We note that FDA's proposed revisions to the definition of "intended use" have been indefinitely delayed. See 83 Fed. Reg. 2092 (Jan. 16, 2018).