505(b)(2) NDA and ANDA Amendments: Don’t Forget to Meet the New Verification Requirement

FDA’s October 6, 2016 Final Rule implementing certain provisions of the December 8, 2003 Medicare Modernization Act (“MMA”), Pub. L. No. 108-173, 117 Stat. 2066, ushered in a lot of changes for NDA and ANDA applicants and sponsors (see our previous post here).  The new regulations went into effect on Monday, December 5, 2016, and FDA immediately began to enforce them.

While we’re likely to see controversy and various issues crop up in the years to come as the new MMA rules are tested, one of the new requirements in particular has come up over and over again in the weeks since December 5, 2016. It concerns ANDA amendments and new 21 C.F.R. § 314.96(d).  (The corresponding regulation applicable to 505(b)(2) NDA applicants is at 21 C.F.R. § 314.60(f).)  This regulation states:

(d)(1) Patent certification requirements.  An amendment to an ANDA is required to contain an appropriate patent certification or statement described in Sec.  314.94(a)(12) or a recertification for a previously submitted paragraph IV certification if approval is sought for any of the following types of amendments:

(i) To add a new indication or other condition of use;

(ii) To add a new strength;

(iii) To make other than minor changes in product formulation; or

(iv) To change the physical form or crystalline structure of the active ingredient.

(2) If the amendment to the ANDA does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in paragraph (d)(1) of this section.

New Subsection (d)(1) codifies FDA’s position, developed over the past decade or so, that certain changes proposed in an ANDA amendment require an applicant to recertify to patent information listed in the Orange Book for the brand-name RLD, and, in the case of a Paragraph IV certification, to provide a new notice of Paragraph IV certification. A patent infringement lawsuit filed in response to such a renotification can result in the imposition of a superseding 30-month litigation stay on ANDA approval.  We previously blogged on that issue here, and there are various FDA Citizen Petition Decisions discussing the issue (Docket No. FDA-2012-P-0943; Docket No. FDA-2011-P-0127; Docket No. FDA-2010-P-0223; Docket No. FDA-2010-P-0632), as well as instances in which the issue has been raised in patent infringement litigation because of a product change in an amendment (See, e.g., Alza Corp. et al. v. Impax Laboratories Inc. et al., Case No. 1:10-cv-01024 [here]; Alza Corp. et al. v. Impax Laboratories, Inc. et al., Case No. 1:11-cv-00395 [here]; Teva Branded Pharmaceutical Products R&D Inc. et al. v. Perrigo Pharmaceuticals Co. et al., Case No. 13-cv-01441 [here]).

New Subsection (d)(2) is a new requirement. FDA explains in the preamble to the MMA Final Rule that “if the amendment to the 505(b)(2) application or ANDA does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in Sec. Sec. 314.60(f)(1)(i) through (iv) and 314.96(d)(1)(i) through (iv).”  And when FDA says “must,” the Agency really means “must.”

Immediately after the December 5, 2016 effective date of the new regulations, FDA’s Office of Generic Drugs (“OGD”) provided ANDA applicants with a courtesy reminder (often by phone) that any ANDA amendment, if it does not contain a patent certification (or section viii statement), must include a verification statement pursuant to 21 C.F.R. § 314.96(d)(2). The verification statement can be rather simple, and may be included in a cover letter to the ANDA amendment.  For example, “This amendment does not seek approval for a change listed in 21 C.F.R. § 314.96(d)(1),” or “I verify this amendment is not listed in 21 C.F.R. § 314.96(d)(1).”

In recent weeks, OGD appears to have stopped providing courtesy reminders by phone to ANDA applicants. Instead, OGD is sending out more official correspondence saying that an amendment submitted without a verification is deficient.  Here’s an example of such correspondence:

This is in reference to your abbreviated new drug application (ANDA) XXXXXX for [DRUG]. Your amendment dated [DATE], was submitted to the Agency on or after December 5, 2016, the effective date of the final rule on Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69580 (Oct. 6, 2016).  This rule revised 21 CFR 314.96(d), which concerns amendments to unapproved ANDAs.  In part, the rule now requires an amendment to an unapproved ANDA to contain an appropriate patent certification or section viii statement described in 21 CFR 314.94(a)(12), or a recertification for a previously submitted paragraph IV certification, if approval is sought for changes described in any of the following types of amendments:

(i) To add a new indication or other condition of use;

(ii) To add a new strength;

(iii) To make other than minor changes in product formulation; or

(iv) To change the physical form or crystalline structure of the active ingredient.

If an amendment to an unapproved ANDA does not contain a patent certification or section viii statement, or a recertification, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described above.

Your amendment is deficient under 21 CFR 314.96(d). It currently does not contain (1) a patent certification or section viii statement, (2) a recertification, or (3) a verification statement.  As appropriate, please submit a patent certification or section viii statement, a recertification, or a verification statement (referencing your amendment dated [DATE]).

For future reference, to comply with the requirement of 21 CFR 314.96(d), we recommend that a patent certification or section viii statement, or recertification be referenced in the cover letter of an amendment to an unapproved ANDA and included in module 1.3 of such unapproved ANDA. Similarly, we recommend that a verification statement be included in the cover letter of an amendment to an unapproved ANDA.  For inquiries related to this requirement please contact the Patent and Exclusivity Team at CDER-OGDPET@fda.hhs.gov.

Avoiding such a deficiency letter is relatively simple: Remember to incorporate the verification in any template correspondence for an ANDA amendment.

We’ll probably see more from FDA and other interested parties on the new verification requirement as new scenarios crop up. (And we’re likely to see a lot of ink spilled on what types of amendment changes might trigger the patent certification/recertification requirement.  After all, the phrase “other condition of use” at 21 C.F.R. § 314.96(d)(1)(i) seems pretty ambiguous.) In fact, we’ve already come across one instance that seems to run contrary to the “either/or” choice FDA explains in the preamble to the MMA Final Rule (i.e., “if the amendment to the 505(b)(2) application or ANDA does not contain a patent certification or statement, the applicant must verify. . . .”). In the case of a timely-listed later-listed Orange Book patent, an ANDA applicant must certify to the patent in an amendment; however, the amendment may not be for one of the changes listed at 21 C.F.R. § 314.96(d)(1), and thus requires a verification under 21 C.F.R. § 314.96(d)(2).