When is a Period Not a Period? The Curious Case of Ivabradine and Pediatric Exclusivity

FDA’s interpretation and application of the Best Pharmaceuticals for Children Act (“BPCA”), which provides for a 6-month add-on period of pediatric exclusivity has piqued our interest more than once over the years, leading to several posts (see, e.g., here, here, and here).  We now have another interpretation to add to the collection . . . .

By way of background, FDC Act § 505A provides an additional 6 months of patent and non-patent exclusivity to pharmaceutical manufacturers that conduct acceptable pediatric studies of new and currently-marketed drug products identified by FDA in a Written Request for which pediatric information would be beneficial.  Pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity (e.g., 5-year, 3-year, and 7-year orphan drug exclusivity) an application holder may have under the FDC Act, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.

An important aspect of pediatric exclusivity is that it provides additional marketing exclusivity not just for the pediatric indications or formulations, but for all protected indications and formulations of that sponsor’s drug.  Thus, pediatric exclusivity attaches to the patent and non-patent marketing exclusivity for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted, and not to a specific drug product.  See National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999).

In particular, FDC Act 505A(c), titled “Market Exclusivity For Already-Marketed Drugs,” states:

(1) IN GENERAL.—Except as provided in paragraph (2), if the Secretary determines that information relating to the use of an approved drug in the pediatric population may produce health benefits in that population and makes a written request to the holder of an approved application under section 505(b)(1) for pediatric studies (which shall include a timeframe for completing such studies), the holder agrees to the request, such studies are completed using appropriate formulations for each age group for which the study is requested within any such timeframe, and the reports thereof are submitted and accepted in accordance with subsection (d)(4)—

(A)(i)(I) the period referred to in subsection (c)(3)(E)(ii) of section 505, and in subsection (j)(5)(F)(ii) of such section, is deemed to be five years and six months rather than five years, and the references in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, fifty-four months, and eight years, respectively. . . .

The exception referred to above (i.e., “Except as provided in paragraph (2)”) states:

(2) EXCEPTION.—The Secretary shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.

The exception provision was added to the statute in September 2007 with the passage of the FDA Amendments Act (“FDAAA”).  Specifically, Title V of FDAAA reauthorized and amended the 2002 BPCA (Pub. L. No. 107-109, 115 Stat. 1408) to add the 9-month exception and remove (with some exceptions included in a FDAAA transition provision) former FDC Act § 505A(e), which permitted FDA to delay the acceptance or approval of an ANDA (or a 505(b)(2) NDA) by up to 90 days if an NDA sponsor submitted study results in response to a Written Request immediately prior to the expiration of any applicable period of patent or non-patent market exclusivity.  Former FDC Act § 505A(e) allowed sponsors to obtain a period of de facto pediatric exclusivity while FDA reviewed study results even if the Agency ultimately determined that the studies did not meet the terms of the Written Request.

FDA’s implementation of the exception provision at FDC Act § 505A(c)(2) (and its sister provision at FDC Act § 505A(b)(2)) has been relalatively free from controversy.  But a recent set of circumstances has raised some eyebrows.  In what appears to us to be a case of first impression, FDA granted a period of pediatric exclusivity shortly before the so-called “NCE-1” (New Chemical Entity) ANDA Paragraph IV submission date for a drug, resulting in a new NCE-1 submission date 6 months later.

The drug at issue is CORLANOR (ivabradine), 5 mg and 7.5 mg, Tablets, which FDA approved on April 15, 2015 under NDA 206143 and granted a period of 5-year NCE exclusivity that initially expired on April 15, 2020.  FDA issued the NDA holder a Written Request for pediatric studies in April 2015 (see here), and it appears, based on a very recent update to the Orange Book, that the NDA holder fairly responded to the Written Request and that the Agency granted pediatric exclusivity shorly before April 15, 2019.  That resulted in an extension to the NCE exclusivity period (identified in the Orange Book as “NCE *PED”) until October 15, 2020.

But should the exception at FDC Act § 505A(c)(2) also apply to the period that is the April 15, 2019 NCE-1 Paragraph IV submission date?  According to FDA, the answer is “No,” even though there was less than 9 months of term remaining in the NCE-1 period as of the date FDA granted pediatric exclusivity.

So what gives?  Well, it turns out that FDA does not consider the NCE-1 date to be a “period” under the statute, but rather a “reference.”

Let’s turn back to the language of the statute.  It says that if pediatric exclusivity is granted, then, for a drug product with 5-year NCE exclusivity, “the period referred to in subsection (c)(3)(E)(ii) of section 505, and in subsection (j)(5)(F)(ii) of such section, is deemed to be five years and six months rather than five years, and the references in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, fifty-four months, and eight years, respectively. . . .”  The exception provision says that FDA “shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.”

Thus, according to FDA, there are “periods” and “references” (or referenced periods?) under the statute that must be treated differently because the exception provision mentions only “the period.”  Thus, according to FDA, if pediatric exclusivity is granted immediately before the NCE-1 date, which is more than 9 month before the expiration of NCE exclusivity, then pediatric exclusivity will apply to the NCE-1 date (by operation of it applying to the NCE expiration date), and prevent ANDA Paragraph IV submission for an additional six months.  Any company that submits an ANDA beforehand will receive a rejection letter.