July 31, 2024

FDA Expands Practice of Permitting Population-Based Skinny Label “Carve-Ins”

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Axinn, Veltrop & Harkrider LLP

FDA recently doubled down on its approach of allowing new language in an ANDA label as the result of a section viii statement – a so-called “carve-in.” Section viii statements assert that an ANDA does not seek approval for a method of use covered by patent or exclusivity. This of course generally requires omitting protected information from the label. But in a recent response to a citizen petition, FDA permitted adding new language to an indication in conjunction with a section viii statement. There is some precedent for this. FDA previously allowed a “carve-in” that reverted to a previously approved indication covering a narrower patient population.^[1] But here, FDA endorsed excluding a protected population by adding new labeling language that is not present in the currently approved indication.

The drug at issue here is Entresto (sacubitril/valsartan), which is used for the treatment of chronic heart failure. In its initial clinical studies to support approval, the RLD holder only included patients with reduced left ventricular ejection fraction (“LVEF”). However, a subsequent study also included some patients with an LVEF within the normal range. FDA thus approved a new version of the indication that expanded the approved patient population. In addition to the three-year exclusivity associated with the new clinical trial (since expired) the RLD holder also listed patents in the Orange Book purporting to claim this new patient population. The RLD holder then filed the instant citizen petition asking, among other things, that FDA not approve any ANDA seeking to exclude the newly added patient population using section viii statements.

FDA rejected the action requested by the citizen petition and explicitly endorsed a labeling “carve-in” that ANDA applicants might use, as shown below:

Revisions to Entresto’s Previously Approved Adult HF Indication Statement

Entresto’s Current Approved Adult HF Indication Statement

FDA’s Suggested “Carve-in”

1.1 Adult Heart Failure
Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure (̶N̶Y̶H̶A̶ C̶l̶a̶s̶s̶ I̶I̶-̶I̶V̶)̶ a̶n̶d̶ r̶e̶d̶u̶c̶e̶d̶ e̶j̶e̶c̶t̶i̶o̶n̶ f̶r̶a̶c̶t̶i̶o̶n̶.̶

E̶n̶t̶r̶e̶s̶t̶o̶ i̶s̶ u̶s̶u̶a̶l̶l̶y̶ a̶d̶m̶i̶n̶i̶s̶t̶e̶r̶e̶d̶ i̶n̶ c̶o̶n̶j̶u̶n̶c̶t̶i̶o̶n̶ w̶i̶t̶h̶ o̶t̶h̶e̶r̶ h̶e̶a̶r̶t̶ f̶a̶i̶l̶u̶r̶e̶ t̶h̶e̶r̶a̶p̶i̶e̶s̶,̶ i̶n̶ p̶l̶a̶c̶e̶ o̶f̶ a̶n̶ A̶C̶E̶ i̶n̶h̶i̶b̶i̶t̶o̶r̶ o̶r̶ o̶t̶h̶e̶r̶ A̶R̶B̶.̶

Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)].

1.1 Adult Heart Failure
Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.

Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)].

1.1 Adult Heart Failure
Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.̶ and reduced ejection fraction. B̶e̶n̶e̶f̶i̶t̶s̶ a̶r̶e̶ m̶o̶s̶t̶ c̶l̶e̶a̶r̶l̶y̶ e̶v̶i̶d̶e̶n̶t̶ i̶n̶ p̶a̶t̶i̶e̶n̶t̶s̶ w̶i̶t̶h̶ l̶e̶f̶t̶ v̶e̶n̶t̶r̶i̶c̶u̶l̶a̶r̶ e̶j̶e̶c̶t̶i̶o̶n̶ f̶r̶a̶c̶t̶i̶o̶n̶ (̶L̶V̶E̶F̶)̶ b̶e̶l̶o̶w̶ n̶o̶r̶m̶a̶l̶.̶

L̶V̶E̶F̶Left ventricular ejection fraction (LVEF) is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)].

Indeed, at least one ANDA filer has already been approved with such a “carve-in.” MSN’s ANDA No. 213748 referencing Entresto was approved on July 24, 2024, the same day FDA issued its response to the citizen petition.^[2]

Overall, FDA’s approach here is consistent with its earlier Velcade decision. There, FDA allowed a “carve-in” with an older version of an indication with added language that limited the patient population to second-line lymphoma patients. Likewise, in this case, “the Agency does not believe it would be appropriate for the scope of patent protection for Entresto to be broadened due to the writing of labeling in a clear and concise manner.”^[3] Instead, FDA here permits some sparing modification of the current indication with additional terms. This is a slight extension of FDA’s approach in Velcade, which simply used a previously approved version of the indication. FDA’s response here may signal some flexibility by the Agency to consider novel “carve-in” labeling modifications as part of a section viii skinny labeling strategies.

^[1] See FDA Docket No. FDA-2017-P-3672, FDA Response to Citizen Petition regarding Velcade (bortezomib) (Nov. 6, 2017) (Velcade Petition Response), available at https://www.regulations.gov/document/FDA- 2017-P-3672-0022.

^[2] See also FDA Docket No. FDA-2022-P-2228, FDA Response to Citizen Petition regarding Entresto (sacubitril and cvalsartan), at 2 n.6 (Jul. 24, 2024), available at https://www.regulations.gov/document/FDA-2022-P-2228-0015.

^[3] Id. at 38 (cleaned up).

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