November 29, 2016
FDA Flash! Blog
By Li Feng, Ph.D.; Shana K. Cyr, Ph.D.
The Food and Drug Administration (FDA) recently published a final rule to amend regulations governing 505(b)(2) applications and abbreviated new drug applications (ANDAs). Abbreviated New Drug Applications and 505(b)(2) Applications, 81(194) Fed. Reg. 69580-69658 (Oct. 6, 2016) (to be codified at 21 C.F.R. pts. 314, 320) (Final Rule). The amendments will implement provisions of Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) and facilitate compliance with and efficient enforcement of the Federal Food, Drug, and Cosmetic Act (FDCA). Id. at 69580. The amendments will become effective on December 5, 2016, and will apply to new submissions received by FDA on or after that date. Id. This article summarizes many of the changes that will be made, organized according to the affected sections of Title 21 of the Code of Federal Regulations (CFR). Readers are encouraged to refer to the Final Rule and the CFR and to seek legal counsel as appropriate to determine how the amendments might affect them.
The new rule amends 21 C.F.R. §§ 314.3 and 320.1, which define various terms used in 21 CFR parts 314 and 320. Id. at 69636-39 (amending 21 C.F.R. § 314.3); id. at 69658 (amending 21 C.F.R. § 320.1). For example, amended § 314.3 now defines "180-day exclusivity period," "active ingredient," "bioequivalence," "pharmaceutical alternatives," and "therapeutic equivalents." Id. at 69636-39 (amending 21 C.F.R. § 314.3). Amended § 320.1 now provides that the definitions contained in § 314.3 apply to part 320. Id. at 69658 (amending 21 C.F.R. § 314.20).
The new rule amends 21 C.F.R. §§ 314.50 and 314.94, which set forth various content and formatting requirements for new drug applications (NDAs) and ANDAs, respectively. Id. at 69639-41 (amending 21 C.F.R. § 314.50); id. at 69649-51 (amending 21 C.F.R. § 314.94).
Amended § 314.50 contains provisions pertaining to 505(b)(2) applications. It provides that if, before the date of submission of an original 505(b)(2) application, there is a drug product approved in an NDA that is pharmaceutically equivalent to the proposed drug product, the application must include an appropriate patent certification or statement with respect to each patent that claims the drug substance, the drug product, or an approved use. Id. at 69640 (adding 21 C.F.R. § 314.50(i)(1)(i)(C)). It provides that a 505(b)(2) applicant is not required to submit a patent certification or statement to address a patent or patent information that is late-listed with respect to a pending 505(b)(2) application. Id. (amending 21 C.F.R. § 314.50(i)(4)). It provides that an NDA holder’s amendment to a use code is untimely unless submitted within 30 days of (1) patent issuance; (2) approval of a corresponding change to product labeling; (3) a decision by the U.S. Patent and Trademark Office (USPTO), the U.S. Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that is specific to the patent and alters the construction of a method-of-use claim of the patent. Id. (amending 21 C.F.R. § 314.50(i)(4)).
Amended § 314.50 specifies that if the FDA’s Orange Book reflects that an NDA holder has requested removal of a patent or patent information and one or more applicants are eligible for 180-day exclusivity, the patent will remain listed until any 180-day exclusivity based on that patent has expired or been extinguished. Id. at 69641 (amending 21 C.F.R. § 314.50(i)(6)(ii)). It provides that a 505(b)(2) applicant is not required to provide or maintain a certification to a patent or patent information remains listed only for purposes of a first ANDA applicant’s 180-day exclusivity. Id. (amending 21 C.F.R. § 314.50(i)(6)(ii)). It provides that a 505(b)(2) applicant must, however, submit an amended certification if an NDA holder’s removal of a patent from the Orange Book results in there being no patents listed for the listed drug identified in the 505(b)(2) application. Id. (amending 21 C.F.R. § 314.50(i)(6)(ii)). It further provides that a 505(b)(2) applicant must submit an appropriate certification or statement if, after submission of the 505(b)(2) application, USPTO issues a new patent that the applicant believes to the best of its knowledge claims a relied-upon listed drug or an approved use. Id. (adding 21 C.F.R. § 314.50(i)(6)(iii)(2)).
The new rule provides similar amendments to § 314.94 with regard to ANDAs. Id. at 69649-51 (amending 21 C.F.R. § 314.94).
The new rule amends 21 C.F.R. §§ 314.52 and 314.95, which require certain notices by 505(b)(2) applicants and ANDA applicants, respectively. Id. at 69641-43 (amending 21 C.F.R. § 314.52); id. at 69651-53 (amending 21 C.F.R. § 314.95).
Amended § 314.52 contains provisions pertaining to 505(b)(2) applications. It specifies that 505(b)(2) applicants must send a paragraph IV notice during the period that starts with the filing date of their application and ends 20 days after the postmarked date on the FDA’s paragraph IV acknowledgement letter. Id. at 69642 (amending 21 C.F.R. §314.52(b)). It adds that if the applicant alleges that the patent will not be infringed and seeks to preserve the option to later file a civil action for declaratory judgment, then the notice must be accompanied by an offer of confidential access to the 505(b)(2) application for the sole and limited purpose of evaluating possible infringement of the patent that is the subject of the paragraph IV certification. Id. (adding 21 C.F.R. § 314.52(c)(7)). It provides that a 505(b)(2) applicant must amend its application to document any paragraph IV notices it receives within 30 days of receipt of the last notice. Id. (amending 21 C.F.R. § 314.52(e)).
The new rule provides similar amendments to § 314.95 with regard to ANDAs. Id. at 69651-53 (amending 21 C.F.R. § 314.95).
The new rule amends 21 C.F.R. § 314.53, which requires submission of certain patent information by an NDA holder. Id. at 69643-47 (amending 21 C.F.R. § 314.53). Amended § 314.53 provides that for approved NDAs, the NDA holder’s description of a patented method must describe only the approved method(s) of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product. Id. at 69643 (amending 21 C.F.R. § 314.53(b)(1)). It provides that the NDA holder must identify with specificity the section(s) and subsection(s) of the approved labeling that describes the method(s) of use claimed by the patent submitted. Id. at 69643 (amending 21 C.F.R. § 314.53(b)(1)).
Amended § 314.53 provides that Forms FDA 3542a and 3542 must include dosage forms and routes of administration of the drug, and whether the applicant proposes to market the drug for prescription or over-the-counter use. Id. (amending 21 C.F.R. § 314.53(c)(2)(i)(F)); id. at 69644 (amending 21 C.F.R. § 314.53(c)(2)(ii)(F)). If the patent has been submitted previously for listing, the form must also identify all changes from the previously submitted patent information and specify whether the change is related to the patent or an FDA action or procedure. Id. at 69644 (amending 21 C.F.R. § 314.53(c)(2)(i)(K)); id. at 69645 (amending 21 C.F.R. § 314.53(c)(2)(ii)(L)). An applicant who submits information for a patent that claims one or more methods of using the drug product must also submit certain information regarding whether that patent also claims the drug substance and/or drug product. Id. at 69644 (adding 21 C.F.R. § 314.53(c)(2)(i)(O)(3)); id. at 69645 (adding 21 C.F.R. § 314.53(c)(2)(ii)(P)(4)). It provides that an NDA applicant who submits a supplement to change the formulation, add a new indication, or make certain other changes must also submit certain patent information. Id. at 69645-46 (amending 21 C.F.R. § 314.53(d)(2)(ii)).
Amended § 314.53 provides that the FDA’s Orange Book will include the NDA holder’s description of patented methods of use. Id. at 69646 (amending 21 C.F.R. § 314.53(e)). It specifies that any patent information submitted by an NDA holder and any requests by others to remove patents or patent information from the Orange Book may be subject to public disclosure. Id. (amending 21 C.F.R. § 314.53(e)).
Under the rule, an NDA holder who determines that a patent or patent claim no longer meets the listing requirements (including if there has been a final judicial finding of invalidity) must promptly notify FDA to amend or withdraw the patent or patent information. Id. (amending 21 C.F.R. § 314.53(f)(2)(i)). If a court order requires the NDA holder to amend or withdraw a patent or patent information, the NDA holder must submit an NDA amendment that includes a copy of the order within 14 days of the order. Id. (amending 21 C.F.R. § 314.53(f)(2)(i)). FDA will remove the information if there is no first applicant eligible for 180-day exclusivity or after the 180-day period has expired or been extinguished. Id. (amending 21 C.F.R. § 314.53(f)(2)(i)). If the term of a listed patent is extended, the NDA holder must within 30 days of receiving the certificate of extension submit on Form FDA 3542 a correction to the expiration date of the patent. Id. (amending 21 C.F.R. § 314.53(f)(2)(ii)). Changes or corrections other than withdrawal of a patent and requests to remove a patent from the list must be submitted on Form FDA 3542 or 3542a, as appropriate, in an amendment or supplement to the NDA. Id. (amending 21 C.F.R. § 314.53(f)(2)(iii)).
Under the new rule, a person other than the NDA holder can submit a written or electronic communication titled "314.53(f) Patent Listing Dispute" that includes a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for FDA to send to the NDA holder. Id. at 69646 (amending 21 C.F.R. § 314.53(f)(1)). For method-of-use patents, the statement of dispute must be only a narrative description of no more than 250 words of the person’s interpretation of the scope of the patent. Id. at 69646 (amending 21 C.F.R. § 314.53(f)(1)). The description must only contain information for which the person consents to disclosure because FDA will send the text of the statement to the NDA holder without review or redaction. Id. (amending 21 C.F.R. § 314.53(f)(1)).
For requests directed to the accuracy or relevance of a drug substance or drug product claim, the NDA holder has 30 days to either (1) confirm the correctness of the patent information with the required signed verification, or (2) withdraw or amend the patent information. Id. (adding 21 C.F.R. § 314.53(f)(1)(i)(A)). FDA will not change the information in the Orange Book unless the NDA holder withdraws or amends the patent information in response to the dispute. Id. (adding 21 C.F.R. § 314.53(f)(1)(i)(A)).
For requests directed to the accuracy or relevance of submitted patent information regarding an approved method of using the drug product, the NDA holder has 30 days to (1) confirm the correctness of its use code description, or (2) withdraw or amend the patent information. Id. (adding 21 C.F.R. § 314.53(f)(1)(i)(B)). In addition, the NDA holder must provide a narrative description of no more than 250 words of the NDA holder’s interpretation of the scope of the patent that explains why the existing or amended use code describes only the specific approved method of use claimed by the patent for which a claim of patent infringement cold reasonably be asserted. Id. at 69646-47 (adding 21 C.F.R. § 314.53(f)(1)(i)(B)). The description must only contain information for which the person consents to disclosure because FDA will send the text of the statement to the person who submitted the dispute without review or redaction. Id. at 69647 (amending 21 C.F.R. § 314.53(f)(1)(i)(B)).
If the NDA holder confirms the correctness of the patent information, and provides the required narrative description and signed verification within 30 days, FDA will not change the patent information in the Orange Book. Id. (amending 21 C.F.R. § 314.53(f)(1)(i)(B)(1)). If the NDA holder responds to the dispute with amended patent information, and provides the required narrative description and signed verification within 30 days, FDA will update the Orange Book to reflect the amended patent information. Id. (amending 21 C.F.R. § 314.53(f)(1)(i)(B)(2)).
Under the new rule, 505(b)(2) applications and ANDAs must contain an appropriate certification or statement for each patent even if a patent listing dispute has been initiated or completed with regard to such patent. Id. at 69647 (amending 21 C.F.R. § 314.53(f)(1)(ii)).
The new rule amends 21 C.F.R. § 314.54, which provides procedures for submitting 505(b)(2) applications that require investigations for approval of a new indication or other changes from a listed drug. Id. at 69647-48 (amending 21 C.F.R. § 314.54). Amended § 314.54 requires that the NDA holder’s use code description contain adequate information to assist 505(b)(2) and ANDA applicants in determining whether a listed method-of-use patent claims a use for which the applicant is not seeking approval. Id. at 69645 (amending 21 C.F.R. § 314.53(c)(ii)(P)(3).
The new rule amends 21 C.F.R. §§ 314.60 and 314.96, which provide rules about amending unapproved applications and ANDAs, respectively. Id. at 69648 (amending 21 C.F.R. § 314.60); id. at 69653 (amending 21 C.F.R. § 314.96). The new rule also amends 21 C.F.R. §§ 314.70 and § 314.97, which provides rules about supplementing or amending an approved application or ANDA, respectively. Id. at 69648-49 (amending 21 C.F.R. § 314.70); id. at 69653 (amending 21 C.F.R. § 314.97). Amended §§ 314.60, 314.70, 314.96, and 314.97 provide that an applicant may not amend or supplement a 505(b)(2) application or ANDA to seek approval of a drug that is different from the drug in the original submission of the 505(b)(2) application. Id. at 69648 (adding 21 C.F.R. § 314.60(e)); id. at 69648-49 (adding 21 C.F.R. § 314.70(h)); id. at 69653 (amending 21 C.F.R. § 314.96). Amended § 314.60 provides that an amendment to a 505(b)(2) application must contain an appropriate patent certification or statement for certain types of amendments. Id. at 69648 (adding 21 C.F.R. § 314.60(f)).
The new rule amends 21 C.F.R. § 314.90, which provides rules about waivers. Id. at 69649 (amending 21 C.F.R. § 314.90). Amended § 314.90 provides that if FDA grants the applicant’s waiver request with respect to a requirement under §§ 314.50 through 314.81, the waived requirement will not constitute a basis for refusal to approve an NDA under § 314.125. Id. (adding 21 C.F.R. § 314.90(c)).
The new rule also amends 21 C.F.R. § 314.99, which provides rules about other responsibilities of ANDA applicants. Id. at 69653 (amending 21 C.F.R. § 314.99). Amended § 314.99 provides that if FDA grants the applicant’s waiver request with respect to a requirement under §§ 314.92 through 314.99, the waived requirement will not constitute a basis for refusal to approve an ANDA under § 314.127. Id. at 69653 (amending 21 C.F.R. § 314.99(b)).
The new rule amends 21 C.F.R. § 314.93, which provides rules about petitions to request a change from a listed drug. Id. at 69649 (amending 21 C.F.R. § 314.93). Amended § 314.93 provides that if after approval of a petition and before approval of an ANDA submitted pursuant to the approved petition, a drug product is approved in an NDA for the change described in the petition, the petition and the listed drug identified in the petition can no longer be the basis for ANDA submission, irrespective of whether FDA has withdrawn approval of the petition. Id. (adding 21 C.F.R. § 314.93(f)(2)). An applicant seeking approval for such drug product must submit a new ANDA that identifies the pharmaceutically equivalent reference listed drug as the basis for ANDA submission and comply with applicable regulatory requirements. Id.
The new rule amends 21 C.F.R. § 314.101, which provides rules about filing an NDA and receiving an ANDA. Id. at 69653-54 (amending 21 C.F.R. § 314.101). Amended § 314.101, for example, provides that submission of a 505(b)(2) application or an ANDA is not permitted under certain sections of the FDCA. Id. at 69653-54 (amending 21 C.F.R. § 314.101).
The new rule amends 21 C.F.R. § 314.105, which provides rules about NDA and ANDA approval. Id. at 69654-55 (amending 21 C.F.R. § 314.105). Amended § 314.105, for example, provides that FDA will issue a tentative approval letter if an NDA or ANDA meets the requirements but cannot be approved because of certain exclusivity periods. Id. at 69654-55 (amending 21 C.F.R. § 314.105).
The new rule amends 21 C.F.R. § 314.107, which provides rules about the date of approval for a 505(b)(2) application or ANDA. Id. at 69655-57 (amending 21 C.F.R. § 314.107). Amended § 314.107 provides extensive amendments about the date of approval for 505(b)(2) applications and ANDAs. Id. at 69655-57 (amending 21 C.F.R. § 314.107).
The new rule amends 21 C.F.R. § 314.108, which gives rules about new drug product exclusivity. Id. at 69657-58 (amending 21 C.F.R. § 314.108). Amended § 314.108, for example, defines "bioavailability study" as one to determine the bioavailability of pharmacokinetics of a drug. Id. at 69657 (amending 21 C.F.R. § 314.108(a)).
The new rule amends 21 C.F.R. § 314.125, which gives rules about refusal to approve NDAs. Id. at 69658 (amending 21 C.F.R. § 314.125). Amended § 314.125 provides that FDA may refuse to approve an NDA if the 505(b)(2) application failed to contain a patent certification or statement with respect to each listed patent for a drug that approved in an NDA that is pharmaceutically equivalent and was approved before the original 505(b)(2) application was submitted. Id. (adding 21 C.F.R. § 314.125(b)(19)).
The new rule amends 21 C.F.R. § 314.127, which gives rules about refusal to approve ANDAs. Id. at 69658 (amending 21 C.F.R. § 314.127). Amended § 314.127 provides that FDA may refuse to approve an ANDA submitted pursuant to an approved petition if an NDA subsequently has been approved for the change described in the approved petition. Id. at 69658 (amending 21 C.F.R. § 314.127).
The new rule amends 21 C.F.R. § 320.23, which gives rules about measuring in vivo bioavailability and demonstrating bioequivalence. Id. at 69658 (amending 21 C.F.R. § 320.23). Amended § 320.23 provides that for drug products that are not intended to be absorbed into the bloodstream, bioequivalence may be demonstrated by scientifically valid methods that are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect. Id. (adding 21 C.F.R. § 320.23(b)(2)).
Originally printed in FDA Flash! Blog on November 29, 2016. This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. This article is only the opinion of the authors and is not attributable to Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, or the firm's clients.
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