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In the News: October 2020 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

Unpacking the (Black) Box: Antares Licenses Urology Product with Boxed Warning

When the FDA requires a product’s labeling to include a boxed warning (also called a “black box warning” because the text is surrounded by black border), the potential market value of the drug often drops severely. Avadel Specialty Pharmaceuticals, for example, was forced into bankruptcy when its Noctiva® (desmopressin acetate) nasal spray was approved in 2017 with a boxed warning highlighting the risk of hyponatremia, or low blood sodium levels. Originally approved for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void, the product has since been discontinued.

In October, Antares Pharma licensed Ferring Pharmaceuticals’ Nocdurna® (desmopressin acetate) sublingual tablet, which was approved in 2018 for the same indication as Noctiva and has a boxed warning highlighting the same risks. Presumably, Antares’ long-established 90-person urology sales force can achieve pull-thru of this drug product.

Labeling regulations prohibit reminder ads for products with boxed warnings, which the FDA requires when a drug product has very serious risks. Since reminder ads are mostly associated with direct-to-consumer advertising, the impact of a boxed warning generally has the greatest downward value effect when consumers need to be made aware of a drug’s existence, so that they’ll be motivated to see their healthcare providers or pharmacists. The negative media exposure that comes with boxed warnings and adverse scientific publications can also impede new prescriptions.

The root cause of a boxed warning is often related to the formulation. Examining boxed warnings and identifying formulation changes that might result in the removal of the boxed warning can reveal drug improvement opportunities for sponsors. Camargo has helped several clients to reformulate products in order to avoid a boxed warning.

Court Decision to Spell Problems for “Skinny” Labels?

In October, the U.S. Court of Appeals for the Federal Circuit reversed a district court patent dispute decision in GlaxoSmithKline Beecham Ltd. Vs Teva Pharmaceuticals USA, Inc. At 58 pages, almost half of which is a dissent, the case may not be on everyone’s reading list, but it has at least the potential to be an issue for ANDA applicants.

Most ANDA applicants are aware that when (a) the Orange Book lists multiple drug product method of use patents for a Reference Listed Drug (RLD) and (b) the patents expire at different times, it may be possible to employ a “Section VIII carve-out” or “skinny label.” This allows sponsors to gain ANDA approval following the expiration of one of the patents but prior to the expiration of the other.

While there were a number of factors at play in the case, the interesting point is that, unlike the district court, the appellate court concluded that Teva had infringed on an unexpired method of use patent in spite of Teva’s use of a “skinny label” for the product. The “skinny label” has been used many times previously to enable ANDA applicants to reach the market in similar circumstances.

This decision has caused a good amount of consternation in the generics industry, but it should be noted that this in only one appellate circuit. Still, navigating such patent issues during drug development can be difficult, and Camargo can assist in finding a safe course.

Approval of the Month: Companion Diagnostic for Bayer’s Vitrakvi Should Lead to Improved Patient Outcomes

In November 2017, Foundation Medicine received approval for FoundationOne CDx™, a genomic profiling test for solid state tumors, which paved the way for partnerships with pharma companies’ therapeutics. In 2019, Foundation Medicine and Bayer Healthcare Pharmaceuticals, Inc. announced a collaboration to develop a companion diagnostic for Vitrakvi® (larotrectinib) NTRK (neurotrophic tropomyosin receptor kinase) inhibitor, approved in the U.S. for patients with NTRK fusion cancer across all solid tumors.

In October, less than 18 months later, the FDA approved the companion test, which will allow physicians to better identify target eligible patients. Prior to the availability of this test, Bayer struggled to find patients for its new drug.

The speed of the submission in January 2020 and approval in October 2020 was attributed to the retrospective testing of available tumor tissue samples from patients enrolled in three clinical trials that led to the accelerated approval of larotrectinib. Results showed maintained efficacy of larotrectinib among patients with NTRK fusion-positive tumors identified by the FoundationOne CDx test.

Guidance Issued on Referencing Approved Drug Products in ANDA Submissions

The FDA recently issued the guidance “Referencing Approved Drug Products in ANDA Submissions,” clarifying the use of the RLD and reference standard (RS) in an ANDA submission and defining which to reference in the basis of the submission.

The ANDA application must contain a basis of submission specifying the RLD, and the applicant must show that the proposed generic drug is the same as the RLD with respect to active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics. The generic drug must also have the same labeling as the RLD (except for differences permitted under the Agency regulations).

The guidance clarifies the differences between an RLD and an RS for use during in vivo bioequivalence studies to support an ANDA and how the Agency determines the appropriate RS to designate in the Orange Book.

The document also reinforces the importance of identifying the correct RLD to use as the basis of the submission for an ANDA and distinguishing between the RLD and RS to determine bioequivalence. Camargo can help sponsors ensure that the correct RLD and RS are identified and correctly defined within the basis of submission to ensure a successful ANDA application.


Jenny Fielder
Manager of Regulatory Compliance

Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President of Regulatory Operations