Should the Best Pharmaceuticals for Children Act be Amended to Accommodate 505(b)(2) NDA Labeling Carve-outs?

March 16, 2017By Kurt R. Karst

There are many things that are unique to the 505(b)(2) NDA approval pathway. Some are good and some are . . . well, let’s just say that they have proven to be frustrating for  some 505(b)(2) applicants.   Perhaps one of the most nettlesome aspects of the 505(b)(2) NDA pathway arises by operation (or should we say by lack of operation?) of FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act (“BPCA”).

FDC Act § 505A(o), titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage Provision” (or Section 11 of the BPCA), allows an ANDA applicant to omit from its labeling certain patent- and/or exclusivity-protected information concerning the pediatric use of a drug, and to include a disclaimer with respect to the omitted information. (Such a disclaimer might state: “Pediatric use information is approved for [COMPANY’S BRAND-NAME DRUG]. However, due to [COMPANY’S] marketing exclusivity rights, this drug product is not labeled with that pediatric information.”)  Specifically, FDC Act § 505A(o) states:

(1) GENERAL RULE.— A drug for which an application has been submitted or approved under section 505(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 502 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 505(j)(5)(F) of this title.

(2) LABELING.— Notwithstanding clauses (iii) and (iv) of section 505(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 505(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.


(A) the availability or scope of exclusivity under this section;

(B) the availability or scope of exclusivity under section 505 for pediatric formulations;

(C) the question of the eligibility for approval of any application under section 505(j) that omits any other conditions of approval entitled to exclusivity under clause (iii) or (iv) of section 505(j)(5)(F); or

(D) except as expressly provided in paragraphs (1) and (2), the operation of section 505.

We’ve seen FDC Act § 505A(o) come into play before, and sometimes in court. The provision was at issue in litigation over generic CRESTOR (rosuvastatin calcium) (here and here) and generic ABILIFY (aripiprazole) (see our previous post here).

At this point you may be asking: “Why are you discussing 505(b)(2) NDAs in the context of a provision that concerns only ANDAs?” After all, FDC Act § 505A(o) is titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling” (emphasis added), and there’s no indication that FDA raised any concerns with the provision in a report submitted to Congress in July 2016.  But that’s precisely the point!  FDC Act § 505A(o) does not address 505(b)(2) NDAs.  The BPCA neither addresses the carve-out or retention of protected pediatric information from 505(b)(2) product labeling, nor does the BPCA address the use of disclaimers for protected pediatric use information that is carved-out of 505(b)(2) product labeling.

If FDA determines that the protected pediatric information is important safety information, and therefore, must be retained in 505(b)(2) product labeling for reasons of safe use, then a full approval for the affected 505(b)(2) product cannot be issued until pediatric exclusivity has expired. Instead, FDA could issue only a tentative approval, with final approval dependent on the expiration of exclusivity applicable to pediatric labeling information.  This is true regardless of how close a 505(b)(2) NDA product may be to an ANDA drug product (and which ANDA could be approved by operation of FDC Act § 505A(o)).  For example, a drug product that is essentially a generic version of a brand-name listed drug, but that is submitted under a 505(b)(2) NDA simply by virtue of the sponsor’s use of a so-called “non-exception excipient,” thus precluding ANDA submission (see our previous post here), may be blocked from obtaining final approval because FDC Act § 505A(o) does not accommodate 505(b)(2) NDAs.

With the growing popularity of 505(b)(2) NDAs, which the Tufts Center for the Study of Drug Development recently assessed, the inability of a 505(b)(2) NDA applicant to obtain final approval because of protected pediatric information is on the rise. We sifted through several 505(b)(2) NDA approval packages and found quite a few FDA assessments concerning the ability (or inability) of a 505(b)(2) applicant to omit protected pediatric information.  Sometimes FDA concluded that the 505(b)(2) NDA could be approved with a labeling carve-out, and sometimes FDA determined that only tentative approval could be granted because FDC Act § 505A(o) does not apply to 505(b)(2) NDAs.  Here’s a rundown of the FDA assessments we found:

  • NDA 022312 – Docetaxel Injection (Approved on January 11, 2012)
  • NDA 201811 – Argatroban Injection (Approved on March 23, 2015)
  • NDA 207963 – Palonosetron HCl Injection (Approved on August 22, 2016)
  • NDA 203049 – Argatroban Injection (Approved on January 5, 2012)
  • NDA 201743 – Argatroban Injection (Approved on May 9, 2011)
  • NDA 022485 – Argatroban Injection (Approved on May 9, 2011)
  • NDA 022434 – Argatroban Injection (Approved on June 29, 2011)
  • NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Approved on June 25, 2012)
  • NDA 200795 – Gemcitabine Injection (Approved on August 4, 2011)

We also came across some 505(b)(2) NDA tentative approval letters containing the standard language regarding exclusivity (i.e., “The listed reference drug product upon which you based your application is subject to a period of exclusivity protection and therefore final approval of your application under section 505(c)(3) of the Act (21 U.S.C. 355(c)(3)) may not be made effective until the period has expired.”) that we suspect is related to a period of pediatric exclusivity and where FDA has determined that a carve-out is not permissible:

  • NDA 022359 – Argatroban Injection (Tentatively Approved on July 28, 2010)
  • NDA 205122 – QUDEXY XR (topiramate) Extended-release Capsules (Tentatively Approved on April 15, 2016)
  • NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Tentatively Approved on August 18, 2016)
  • NDA 208645 – Bortezomib Injection (Tentatively Approved on October 20, 2016)

Congress is currently debating reauthorization of the Prescription Drug User Fee Act. As part of that process, Congress will likely also consider other changes to the law, including changes to provisions applicable to pediatric drug development (see, e.g., S. 456/H.R. 1231, the Research to Accelerate Cures and Equity for Children Act). Should another one of those issues for consideration be whether or not FDC Act § 505A(o) should be amended to accommodate 505(b)(2) NDAs.