The FDA has issued significant new Draft Guidance on January 17, 2017 that touches on the hot-button issues surrounding manufacturer dissemination of off-label information about approved drugs and medical devices, titled Medical Product Communications That Are Consistent With the FDA-Required Labeling.
We say the Guidance “touches” on off-label information because what the Guidance actually covers is information about a drug or device that is not specifically included in the labeling, but which is consistent with the approved labeling. True “off-label” information, such as completely new unapproved indications or uses for a product, is not covered by the Guidance, and dissemination of such communications remains an important yet unresolved area of dispute between the Agency and regulated industry.
The key policy announced in the Guidance is that drug and device manufacturers’ “communications of information that is not contained in their product’s FDA-required labeling but that are determined to be consistent with the FDA-required labeling are not alone considered evidence of a new intended use,” and as such will not subject the company to liability for misbranding under the federal Food, Drug and Cosmetic Act. The Guidance thus affirms a policy position long advocated by many in the regulated industry, but which heretofore had not been formally adopted by the FDA. The announced policy comes with caveats, however, most notably that “a communication that is consistent with a product’s FDA-required labeling could nonetheless misbrand the product and subject a firm to enforcement action if the representations or suggestions made in the communication are false or misleading in any particular.”
The bulk of the Guidance sets forth, in Q&A format, details on how the Agency will evaluate whether product-specific information that is outside the approved labeling is nonetheless “consistent with” the approved labeling and is not otherwise false or misleading when used in promotional communications. As a threshold matter, the Guidance sets forth a three-factor test that will be used to determine a communication’s consistency with the approved labeling, as follows:
The three-factor test for consistency with approved labeling
Factor 1 is whether the information in the communication directly conflicts with information in the labeling. Within this first factor, the FDA takes into consideration four separate issues. If the product falls into any of these four categories, it will not be deemed to be consistent with the labeling:
- The content relates to a different indication than the ones reflected in the labeling
- The patient population represented or indicated in the communication is outside the approved or cleared patient population
- The content conflicts with the approved limitations or directions for handling, preparing, and /or using the product in the labeling or
- The representations or suggestions conflict with the approved dosage or use regimen set forth in the labeling.
Factor 2 is whether the information “increase[s] the potential for harm to health relative to the information reflected in” the approved labeling. This is a fairly subjective factor, where the FDA can find a communication is not consistent with FDA-required labeling if, for example, the communication “alters the benefit-risk profile of a product in a way that may result in increased harm to health.”
Factor 3 is “whether the directions for use in the FDA-required labeling enable the product to be safely and effectively used under the conditions represented/suggested in the communication − If the answer is no, that indicates the communication is not consistent with the FDA-required labeling.”
Failure to satisfy any of the above-mentioned factors would establish that the communication “is not considered consistent with the FDA-required labeling.” Further, as previously noted, medical product firms are still subject to the requirement that communications are not false or misleading. False or misleading communications are considered misbranding violations and could subject the company to enforcement action even if the communication satisfied the three factors and thus is consistent with the approved labeling.
Examples of communications that are consistent and not consistent with FDA-required labeling
The Guidance provides illustrative examples of types of communications that could be considered consistent with FDA-required labeling. These examples come with the further caveats that “not all representations or suggestions about a product that relate to the general categories described in this answer will be consistent with the FDA-required labeling for the specific product. That determination is fact-specific and is made by evaluating the particular representations or suggestions being made in a communication using the factors outlined [above].” That said, examples of potentially consistent outside-of-labeling information include:
- Comparative product information based on a head-to-head study with another medical product approved or cleared for the same indication
- Information that offers “additional context” about adverse reactions, including for example, how to mitigate such adverse reactions
- Information about the onset of action of the product for its approved or cleared indication and dosing or use regimen
- Information about the long-term safety and/or efficacy of the products such as may be available based on post-marketing data
- Information about the effects or use of a product in a specific patient subgroup that is within the approved patient population
- Information about patient-reported outcomes, such as treatment compliance/adherence or “patients’ perceptions of the product’s effect on their basic activities of daily living.” (This “basic activities of daily living” information sounds tantalizingly similar to quality-of-life (QOL) claims that historically have been subject to restrictive treatment by FDA. Unfortunately the Guidance does not discuss what, if anything, differentiates these two types of claims)
- Information concerning product convenience, such as a “convenient dosing schedule.” (Here, however, the Guidance does not explain what factors would make a dosing schedule “convenient.”) and
- Information that provides additional context about the mechanism of action (MOA) where the MOA is described in the approved labeling.
On the other end of the spectrum – communications that are considered not consistent with FDA-required labeling – the FDA provides the following examples:
- Information about using the product to treat or diagnose a difference disease or condition than approved for the product
- Information about treating or diagnosing a different patient population than is approved
- Information about the use of the product to treat a different stage, severity, or manifestation of the disease than is approved
- Information about the use of a product as monotherapy, where it is only approved or cleared for use with one or more other products
- Information about a different route of administration or use in a different tissue type than is approved
- Information about the use of a different strength, dosage, or use regimen than is approved or
- Information about the use of a different dosage than what is set forth in the labeling.
Considerations for evidentiary support, and the form and context of communications to avoid false or misleading representations
The last several Q&A sections of the Guidance discuss considerations for how companies should communicate “consistent” but outside-of-labeling information to avoid rendering the communications false or misleading. As a general matter, the Guidance states that “[a]ny data, studies, or analyses relied on should be scientifically appropriate and statistically sound to support the representations or suggestions made in the communication.” Another area of particular importance to medical product companies is the FDA’s views on the proper presentation of information or data from study results. The FDA expects a company’s communication to accurately represent the results or data by clearly and prominently displaying material aspects of the study’s design and methodology, as well as material limitations to the study design, methodology, and results. In addition to being accurate about favorable findings, the FDA expects companies to offer context to the audience by disclosing unfavorable or inconsistent data or findings. Thus, selective presentation of only positive findings would be at odds with this policy. Moreover, the Guidance recommends that information from the FDA-required labeling that relates to the representations or suggestions should be provided to give appropriate context.
The major takeaway from this draft guidance is that the FDA will not view communications that are consistent with, but not included in, FDA-required labeling as stand-alone evidence of a new intended use for purposes of bringing misbranding allegations against a drug or device manufacturer. Although the Guidance provides some useful clarification on how it will interpret and apply the policy, it also leaves a number of questions unanswered. And, because applying the Guidance’s policy to any particular communication(s) for any particular product will require a detailed and fact-specific analysis, companies should remain cautious when proceeding to disseminate new information covered under the Guidance.
More broadly, and arguably more importantly, the Guidance entirely avoids the crucial issue of when the Agency will accept the legitimacy of dissemination by manufacturers of truthful and non-misleading information that is more fundamentally off-label – i.e., new and different unapproved uses for approved products – to healthcare providers. The courts have weighed in repeatedly against FDA’s restrictive policies against such communications, and it remains to be seen whether this Guidance (along with the contemporaneous HCEI Guidance noted above) represents the first step in a gradual move toward FDA acceptance of the courts’ decisions, or an effort to claim that it has done all it can or intends to do with respect to off-label communications.