On Friday, the FDA issued a draft guidance document intended to provide ANDA holders with information about how and when to propose any necessary labeling updates to their drugs when the reference-listed drug (RLD) upon which the ANDA was approved is no longer on the market. FDA guidance documents are intended to provide the FDA’s current thinking on a topic, and, as such, are offered as recommendations for industry, unless specific regulatory or statutory requirements are cited. In general, the FDA’s guidance documents do not establish legally enforceable responsibilities.
Ordinarily, the holder of the NDA (that is the RLD) will propose any necessary changes to product labeling, and, upon FDA approval, ANDA holders will implement any approved changes. The FDA reiterates in this guidance that even after the NDA holder stops marketing the drug, the NDA holder remains responsible for proposing any necessary labeling changes. That duty lasts until the FDA makes a determination that the NDA was withdrawn from the market for reasons other than safety or effectiveness, at which point, the NDA holder’s federal labeling duties cease. The FDA’s draft guidance provides recommendations for proposing labeling changes to drug products after this point, where ANDAs remain on the market.
In its guidance, the FDA asks holders of ANDAs based upon withdrawn NDAs to look to various resources for potential information that might warrant a labeling change for an ANDA. The FDA’s examples of such resources include post-marketing data, published literature, labeling updates for drugs that contain the same active ingredient, and labels for drugs in the same pharmacologic or therapeutic class or that treat the same condition.
The FDA also provides examples of the kinds of labeling change proposals an ANDA holder may submit. According to the draft guidance, ANDA holders may submit labeling edits to reflect current disease terminology, or to add statements provided in regulations specific to certain modes of administration (such as parenteral drugs). Proposals may also include labeling revisions that remove contraindications where there is new evidence that the benefits outweigh the risk for a certain use or subpopulation, or to add warnings and other warning-related information where there is new evidence to support it.
The FDA makes clear in its draft guidance that any proposed changes must be submitted as a Prior Approval Supplement and may not be implemented before the FDA’s approval. Upon approval, the FDA will instruct all ANDA holders that rely upon the withdrawn NDA to implement the changes. This directive reinforces the longstanding statutory and regulatory requirements that any labeling changes—whether the ANDA approval is based upon an existing or a withdrawn NDA—must be approved by the FDA before the ANDA holder implements them.
The draft guidance not does address the status of the agency’s proposed generic labeling rule. Finalization of that rule, originally proposed November 13, 2013, and intended to give ANDA holders the ability to unilaterally implement labeling changes, prior to FDA approval, has been postponed to April 2017. Opposition to that proposed rule includes that it would permit generic drug companies to implement labels that differ from other ANDAs and the NDA holder’s labeling, which is at odds with the statutory directive of uniform labeling. Notably, the FDA takes the position in this draft guidance that prior approval for proposed ANDA labeling changes is required “to ensure that labeling remains uniform across generic drugs,” which may signal that the agency is reevaluating its approach to the generic labeling rule.
The FDA has invited comments on the draft guidance. Although interested parties can submit comments on a guidance document at any time, the FDA has asked that any comments be submitted by September 9, 2016 to ensure they are considered before the agency begins its final version of the guidance document. Please contact Sarah Frederick, Glenn Kerner or Rich Oetheimer with any questions.