GESTIÓN EN SALUD PÚBLICA: FDA Law Blog: FDA Issues Final Hatch-Waxman Regulations to Implement Some of the Provisions of the 2003 Medicare Modernization Act

FDA Law Blog: FDA Issues Final Hatch-Waxman Regulations to Implement Some of the Provisions of the 2003 Medicare Modernization Act

FDA Issues Final Hatch-Waxman Regulations to Implement Some of the Provisions of the 2003 Medicare Modernization Act

Posted: 06 Oct 2016 03:14 AM PDT

By Kurt R. Karst –

A mere 1 year and 8 months after FDA’s February 6, 2015 publication of a Proposed Rule to implement certain provisions of the December 8, 2003 Medicare Modernization Act (“MMA”), Pub. L. No. 108-173, 117 Stat. 2066, and 12 years and about 10 months after the MMA’s enactment, we finally have new Hatch-Waxman regulations. On October 6, 2016, FDA published in the Federal Register a Final Rule, titled “Abbreviated New Drug Applications and 505(b)(2) Applications,” that will forever alter the Hatch-Waxman landscape, and that will likely fuel controversies and provide fodder for litigation for years to come. The Final Rule is the latest – and most significant – in a series of actions intended by FDA to preserve the balance struck with the September 24, 1984 enactment of the Hatch-Waxman Amendments between benefits from the availability of low-cost and high quality generic drugs and the need to reward those manufacturers who bring innovative (i.e., brand-name) drug products to market.

While the focus of the Final Rule is only about 10 pages of MMA statutory text, the document spans 79 triple-column pages in the Federal Register, including about 22 pages of regulations that will be codified in the Code of Federal Regulations as of December 5, 2016. Several proposals FDA made in February 2015 (see our previous post here) are retained in the Final Rule, while a few have been dropped (either because of court decisions, or because FDA decided to move in a different direction). Perhaps most significant is FDA’s decision to drop (at least for now) a proposal to defer to a 505(b)(2) or ANDA applicant’s interpretation of the scope of a patent that it does not own (and, in particular, for a method-of-use patent that is identified in the Orange Book with a patent use code and narrative). Instead, FDA will institute a patent listing dispute mechanism whereby the “NDA holder must provide a narrative description (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 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.”

As you can imagine, we’re still poring over the Final Rule. We’ll probably put together a Summary and Analysis. But for now, below are some highlights (courtesy of FDA) of the changes compared to the Proposed Rule (including references to the relevant section in the Final Rule). Also, we’ve put together a 100-page Regulation-by-Regulation Redline of the new regulations compared to FDA’s existing regulations. We hope you find it helpful in navigating the vast waters of FDA’s Final Rule.

Final Rule Description of Change From Proposed Rule

21 C.F.R. § 314.3

Definitions (§ 314.3(b))

Revises the definition of 505(b) applications to clarify that it is an NDA for which “at least some of” the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right o f reference or use (see section V.P. 3).
Revises the definition of “acknowledgment letter” to delete the reference to 505(b)(F) applications and limit the applicability of this term to ANDAs (see section V.A.1).
Revises the definition of “commercial marketing” to clarify that it includes the introduction or delivery for introduction into interstate commerce of the reference listed drug by the ANDA applicant (see section V.A.2).
Revises the definition of “date of approval” to incorporate section 505(x) of the FD&C Act (see section V.A.3).
Revises the definition of “listed drug” to clarify that a drug product is deemed to be a listed drug on the “date of approval” of the NDA or ANDA (see section V.A.3).
Revises the definition of “substantially complete application”- to describe an ANDA that on its face is sufficiently complete to permit a substantive review and clarify that “sufficiently complete” means that the ANDA contains all the information required under section 505(j)(2)(A) of the FD&C Act and does not contain a deficiency described in § 314.101(d) and (e) (see section V.A.5).
Revises the definition of “tentative approval” to include a notification that an NDA or ANDA otherwise meets the requirements for approval under the FD&C Act but cannot be approved because there is a period of exclusivity under section 505E of the FD&C Act (see section V.A.7).

21 C.F.R. § 314.50

Patent claiming drug substance, drug product or method of use (§ 314.50(f)(1)(i)(C))

Clarifies that the requirement for a 505(b)(2) applicant to provide an appropriate certification or statement for each patent listed in the Orange Book: for a pharmaceutically equivalent drug product applies to one such pharmaceutically equivalent drug product approved in an NDA before the date of submission of the original 505(b)(2) application and not a resubmission or a supplement (see section V.H).

Method-of-use patent (§ 314.50(i)(l)(iii)(A))

Clarifies that a 505(b)(2) applicant may submit a statement under section 505(b)(2)(B) of the FD&C Act if the applicant is not seeking approval for an “indication or other condition of use claimed by a method-of-use patent rather than “any” indications or other conditions of use claimed by the method-of-use patent (see section V.C.1).

Untimely filing of patent information (§ 314.50(i)(4))

Provides that an amendment to the description of the approved method(s) of use claimed by the patent will not be considered timely filing of patent information if the amendment is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent, and the amendment contains a copy of the decision (see section V.B.2.b).

21 C.F.R. § 314.52

Sending the notice of paragraph IV certification (§ 314.52(b))

Requires that a 505(b)(2) applicant send a notice of a paragraph IV certification on or after the date of filing described in § 314.101(a)(2) or (3), but not later than 20 days after the date of the postmark on the “paragraph IV acknowledgement letter” (see section V. D.1.a).
Removes the requirement for a 505(b)(2) applicant to submit an amendment at the time it sends notice of a paragraph IV certification and permits submission of a single amendment that contains all required information within 30 days of the date on which the last notice is received (see section V.D.3.b).

Content of a notice of paragraph IV certification (§ 314.32(c))

Omits the proposed requirement that notice of a paragraph IV certification must contain a statement that the 5O5(b)(2) applicant has received the paragraph IV acknowledgement letter (see section V.D.1.a).

Amendment or supplement to a 505(b)(2) application (§ 314.52(d))

Requires that after the date of filing of a 505(b)(2) application the applicant must send notice of a paragraph IV certification included in an amendment or supplement at the same time that the amendment or supplement is submitted to FDA (see section V.D.1.b).

21 C.F.R. § 314.53

General requirements and Reporting Requirements (§ 314.53(b)(1) and (c)(2))

Clarifies that if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, the NDA holder’s use code must describe only the specific approved condition 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 (see section V.B.1.c).
Clarifies that the NDA ho1der submitting information on the method-of-use patent 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 (see section V.B.1.c).

Other Reporting Requirements (§ 314.53(r)(2))

Omits the proposed requirement for an NDA holder to include information on whether a patent is a reissued patent of a patent previously submitted for listing (see section V.B.1.e.).
Maintains the current requirement for an NIDA holder to include information on whether the patent has been submitted previously for the NDA (see section V.B.1.d).
Adds the requirement for an NDA holder to identify, for a patent that has been submitted previously for listing, all changes from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action (see section V.B.2.b).

Supplements (§ 314.53(d)(2))

Omits the proposal to require an NDA holder to submit a statement with an NDA supplement if the NDA holder is not received to resubmit patent information pursuant to § 314 53(d)(2)(ii)(A) (see section V.B.2.a).

Where to send submissions of Forms FDA 3542a and 3542 (§ 314.53(d)(4)

Designate the CDER Central Document Room, rather than the OGD Document Room, as the official repository for submission of Form FDA 3542 and clarifies that Form FDA 3542 can be submitted electronically (see section V.B.2.c).

Submission date of patent information (§ 314.53(d)(5))

Establishes that the submission date of patent information is the earlier of the date on which Form FDA 3542 is date-stamped by the CDER Central Document Room or officially received by FDA in an electronic format submission that complies with § 314.50(1)(5) (see section V.B.2.d).

Requests by persons other than the NDA holder (§ 314.53(f)(1))

Requires that a person submitting a patent listing dispute for a method-of-use patent include a statement of dispute that is only a narrative description (no more than 250 words) of the person’s interpretation of the scope of the patent (see section V.B.4.a).
Requires that a person submitting a patent listing dispute directed to a drug substance, drug product, or method-of use patent only include information in the statement of dispute for which the person consents to disclosure because FDA will send the text of the statement to the applicable NDA holder without prior review or redaction.
Requires that the NDA holder’s response to a patent listing dispute directed to a drug substance, drug product, or method-of-use patent include a signed verification of the accuracy and completeness of the response (see section V.B.4.a).
Requires that the NDA holder’s response to a patent listing dispute for a method of use patent also include a narrative description (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 method 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. Requires that the narrative description only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction (see section V.B.4.a).
Provides that FDA will promptly post information on its Web site regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the patent listing dispute (see section V.B.4.a).
Omits the proposal to review a proposed labeling carve-out with deference to the 505(b)(2) and/or ANDA applicant(s)’ interpretation of the scope of the patent in certain circumstances, which is not being finalized at this time (see section V.B.4.a).

21 C.F.R. § 314.54

Procedure for submission of a 505(b)(2) application requiring investigations for approval of a new indication for, or other change from, a listed drug (§ 314.54(a)(l))

Clarifies that the requirement for a 505(b)(2) applicant to identify one pharmaceutically equivalent drug product approved in an NDA as a listed drug (or an additional listed drug) relied upon applies before the date of submission of the original 505(b)(2) application and not a resubmission or a supplement (see section V.H.).

21 C.F.R. § 314.60

Patent certification requirements (§ 314.60(f))

Requires that if an amendment the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not: (1) A new indication or other condition of use; (2) a new strength. (3) an other-than-minor change in product formulation; or (4) a change to the physical form or crystalline structure of the active ingredient (see section VF.1).

21 C.F.R. § 314.70

Patent certification requirements (§ 314.70(i))

Omits proposed § 314 70(i) on patent certification requirements for 505(b)(2) supplements, which is not being finalized at this time (see section V.F.2).

21 C.F.R. § 314.90

Waivers (§ 314.90)

No substantive changes from the proposed rule (see section V.L.).

21 C.F.R. § 314.93

Petition to request a change from a listed drug (§ 314.93)

No substantive changes from the proposed rule (see section V.I).

21 C.F.R. § 314.94

Method-of-use patent (§ 314.94(a)(12)(iii)(A))

Clarifies that an ANDA applicant may submit a statement under section 505(j)(2)(A)(viii) of the FD&C Act if the applicant is not seeking approval for “an” indication or other condition of use claimed by a method-of-use patent rather than “any” indications or other conditions of use claimed by the method-of-use patent (see section V.C.1).

Untimely filing of patent information (§ 314.94(a)(12)(vi))

Provides that an amendment to the description of the approved method(s) of use claimed by the patent will not be considered untimely filing of patent information if the amendment is submitted within 30 days of a decision by the USPTO or a Federal court that is specific to the patent and alters the construction of a method-of-use claim(s) o f the patent, and the amendment contains a copy of the decision (see section V.B.2.b).
After request to remove a patent or patent information from the list (§ 314.94(a)(12)(viii)(B)).
Omits the proposed requirement for a first applicant to lawfully maintain a paragraph IV certification to an original patent that has been reissued, which is not being finalized (see section V.B.1.e and V.E.3).

21 C.F.R. § 314.95

Sending the notice of paragraph IV certification (§ 314.95(b))

Deletes the reference to an “acknowledgment letter” in § 314.95(b)(1) and (b)(2) because an ANDA applicant will now receive a “paragraph IV acknowledgment letter” if the ANDA contains a paragraph IV certification before the ANDA is received (see section V.D.1 a).
Removes the requirement for an ANDA applicant to submit an amendment at the time it sends notice of a paragraph IV certification and permits submission of a single amendment that contains all required information within 30 days of the date on which the last notice is received (see section V.D.3.b).

21 C.F.R. § 314.96

Patent certification requirements (§ 314.95(d))

Clarifies that a paragraph VI certification to a patent or patent claim for which an ANDA applicant previously submitted a paragraph IV certification is a “recertification” rather than an “amendment” of the paragraph IV certification (see section V.F.3).
Requires that if an 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: (1) a new indication or other condition of use; (2) a new strength; (3) an other-than-minor change in product formulation; or (4) a change to the physical form or crystalline structure of the active ingredient (see section V.F.1).

21 C.F.R. § 314.97

Patent certification requirements (§ 314.97(c))

Omits proposed § 314.97(c) on patent certification requirements for ANDA supplements, which is not being finalized at this time (see section V.F.2).

21 C.F.R. § 314.99

Other responsibilities of an applicant of an ANDA (§ 314.99)

No substantive changes from the proposed rule (see section V.L.).

21 C.F.R. § 314.101

Receiving an ANDA (§ 314.101(b))

Clarifies current Agency practice that following a refuse-to-receive decision, an ANDA applicant may: Withdraw the ANDA under § 314.99; correct the deficiencies and resubmit the ANDA; or take no action, in which case FDA may consider the ANDA withdrawn after 1 year (see section V.J.2).
Omits the proposed administrative consequence for ANDA applicants who fail to send notice of paragraph IV certification within the statutory timeframe (see section V.J.3).

NDA or ANDA deficiencies (§ 314.101(d))

Clarifies that FDA will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA in determining whether an ANDA is incomplete on Its face (see section V.J.2).
Regulatory Deficiencies (§ 314.101(e))
Clarifies that FDA will refuse to file a 505(bX2) application or refuse to receive an ANDA if submission is not permitted under sections 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the FD&C Act (see section V.A.7).

21 C.F.R. § 314.105

Approval of an NDA and an ANDA (§ 314.105)

Removes the proposed statement that an NDA is approved on the date of the issuance of the approval letter, and clarifies that a new drug product may not be marketed until the “date of approval,” rather than the “date of the approval letter” (see section V.A.3).
Clarifies that approval of a 505(b)(2) application or ANDA also may be delayed by a period of exclusivity for the listed drug under section 505E of the FD&C Act (see section V.A.7)

21 C.F.R. § 314.107

Disposition of patent litigation (§ 314.107(b)(3))

Revises § 314.107(b)(3)(v) to more dearly describe the timing of approval o f a 505(b)(2) application or ANDA when a preliminary injunction is entered by a Federal district court before the expiration of a 30-month stay (or 7-1/2 years where applicable) (see section V.M.2.g).
Clarifies that the 30-month period (or 7-1/2 years where applicable) will be terminated if the court(s) enter(s) an order of dismissal without a finding of infringement in each pending suit for patent infringement brought within 45 days of receipt of the notice of paragraph IV certification sent by the 505(b)(2) or ANDA applicant (see section V.M.2.j).
Delay due to exclusivity (§ 314.107(d)).
Clarifies that approval of a 505(b)(2) application or ANDA also may be delayed by a period of exclusivity for the listed drug under section 505E of the FD&C Act (see section V.M.4).

Notification of court actions or written consent to approval (§ 314.107(e))

Requires submission of a copy of any “written consent to approval” by the patent owner or exclusive patent licensee, rather than any “.documented agreement,” and clarifies that a copy of any order entered by the court terminating the 30-month or 7-1/2.-y ear period includes an order described in § 314.107(b)(3)(vii) and (vii) (see section V.M.5).
Provides that all information required by § 314 107(e)(1) must be sent to the applicant's NDA or ANDA rather than to OGD or the appropriate division in OND (see section V 3.1.5).

21 C.F.R. § 314.108

New drug product exclusivity(§ 314.108)

No substantive changes from the proposed rule.

21 C.F.R. § 314.125

Refusal to approve an NDA (§ 314.125)

Clarifies that FDA may refuse to approve a 505(6)(2) application if it does not contain a patent certification or statement pith respect to each listed patent for a drug product approved in an NDA that is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted and that was approved before the original 505(b)(2) application was submitted (see section V.H).

21 C.F.R. § 314.127

Refusal to approve an ANDA (§ 314.127)