Rules? Where We’re Going, We Don’t Need Rules: FDA Goes Back to the Future With Recent Hatch-Waxman Policy Shifts; What’s a Company to do?

Tell me doctor, where are we going this time?  Is this the 90s, or 2025?  Apologies to both Robert Zemeckis, who directed the 1985 classic “Back to the Future,” and to Huey Lewis and the News, which played “Back in Time” for the feature film, for slightly altering the script and lyrics, but we couldn’t think of a backdrop more apropos for the topic of this post.

Before we move forward, however, let’s step back in time. . . .

It was just earlier this year in a dispute in the DC District Court concerning a 505(b)(2) NDA for Epinephrine Injection, 30 mg/30 mL (1 mg/mL), that we learned about a change—we think—in FDA’s application of the statutory 30-month stay provisions for certain supplemental applications.  It came out of left field, but as FDA explained in an April 5, 2024 Letter Decision made available in the litigation:

The Agency has identified examples in which FDA has recognized a 30-month stay for new strength supplements for abbreviated new drug applications (ANDAs) based on an infringement action brought for patents listed after the date the original ANDA was submitted.  To the Agency’s knowledge, the 30-month stays for these new strength supplements for ANDAs have either expired or have otherwise been terminated by a court and thus are moot.  In these examples, the Agency appears to have recognized a 30-month stay because a new strength supplement is referencing a new listed drug with separately listed patent(s) in the Orange Book.  However, the Agency looked more closely at these issues in the context of NDA 205029/S-013 and reevaluated the statutory language at section 505(j)(5)(B)(iii) of the FD&C Act. Section 505(j)(5)(B)(iii) of the FD&C Act does not exclude new strength supplements from the provision that limits the availability of a 30-month stay to patents for which the NDA holder submitted information to FDA “before the date on which the application (excluding an amendment or supplement to the application) . . . was submitted” and largely mirrors the language at section 505(c)(3)(C) of the FD&C Act.  As a result of this reevaluation, FDA intends to change its practice with respect to new strength supplements for ANDAs and bring it into conformity with the statutory text.  Going forward, the result will be that a 30-month stay will not be available for new strength supplements for ANDAs for patents submitted after the original ANDA was submitted (even where those patents were submitted before the submission of the new strength supplement).  Because it is not directly implicated by this decision, FDA has not yet completed its assessment of new strength amendments that may be implicated by this issue.  If FDA identifies any example in which FDA erroneously determined that there is an active 30-month stay either in the context of a new strength supplement or new strength amendment, it will review its decision to ensure that it conforms with the statutory text.

We say “we think” above because we don’t really know for sure where FDA currently stands on the issue.  There was a lot of flip-flopping during the litigation and much of the litigation record, including the resolution, remains sealed and confidential.  In fact, there was so much unexplained flip-flopping by FDA that DC District Court Judge Timothy J. Kelly, who was recently assigned to another Hatch-Waxman dispute involving 3-year new clinical investigation exclusivity (here and here), issued a pretty critical Memorandum Opinion stating, for example, that “FDA takes no position on whether it provided an explanation when it changed its position and gave final approval to Supplement 13. . . . That lack of opposition alone permits the Court to treat this argument as conceded. . . .  Here, when the FDA changed its position and approved Supplement 13, not only did it fail to provide a satisfactory explanation, it provided no explanation at all.”  (And moving back earlier in time, let’s not forget FDA’s July 2018 Determination of Suboxone Exclusivity where the Agency flip-flopped and suddenly determined that it would no longer require a Paragraph IV notice letter to perfect 180-day exclusivity eligibility, thus enabling later forfeitures of exclusivity eligibility.  We won’t dwell on that one here . . . see our earlier post on that doozy!).

FDA’s 2024 CDER Guidance Agenda does note that the Agency is working on a draft guidance, titled “30-Month Stay of Approval of an ANDA or 505(b)(2) Application;” however, who knows when the guidance will actually be issued.  In the meantime, brand-name and generic drug manufacturers don’t have a clear picture on how the 30-month stay provisions operate in the supplement context.  How can folks navigate the roads of Hatch-Waxman if they don’t have clarity from FDA on the rules of the road?!?

It turns out, however, that FDA’s unannounced flip-flopping in certain 30-month stay circumstances may be—and probably is—only the beginning.  Two cases make this point, and both stem from FDA’s August 26, 2024 update to the Agency’s Paragraph IV Certifications List.

First up is FDA’s so-called “valid Paragraph IV certification” regulation at 21 C.F.R. § 314.94(a)(12)(viii)(C)(1)(ii) for ANDAs.  It states:

An applicant must submit an appropriate patent certification or statement under paragraph (a)(12)(i) and/or (iii) of this section if, after submission of the ANDA, a new patent is issued by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to the best of its knowledge, claims the reference listed drug or that claims an approved use for such reference listed drug and for which information is required to be filed under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53.  For a paragraph IV certification, the certification must not be submitted earlier than the first working day after the day the patent is published in the list. [(Emphasis added)]

This regulation was promulgated in October 2016 as part of FDA’s final rule implementing certain portions of the 2003 Medicare Modernization Act (“MMA”), Pub. L. No. 108-173, 117 Stat. 2066.  It contradicts FDA’s regulation at 21 C.F.R. § 314.53(d)(5) (“Patent information will be considered to be submitted to FDA for purposes of paragraph (d)(3) of this section as of the earlier of the date the information submitted on Form FDA 3542 is date-stamped by the Central Document Room, or officially received by FDA in an electronic format submission that complies with § 314.50(l)(5)”), which states that once patent information is received by FDA it is considered submitted and Orange Book-listed . . . and thus available for a patent certification without the engineered delay of FDA’s MMA regulation at 21 C.F.R. § 314.94(a)(12)(viii)(C)(1)(ii).

Prior to the “valid Paragraph IV certification” regulation companies would submit so-called “serial Paragraph IV certifications” in hopes of being the sole first applicant eligible for 180-day exclusivity.  But as FDA explained in the preamble to the 2016 Final Rule:

The requirement that an ANDA applicant must not submit a paragraph IV certification earlier than the first working day after the day the patent or patent claim is listed in the Orange Book reflects FDA’s determination that selecting the first working day after the day on which the patent information is published creates a level playing field for all ANDA applicants (see §§ 314.94(a)(12)(viii)(C)(1)(ii) and 314.95(b)(2)). One court has determined, in the absence of a regulation to the contrary, that “reality matters” if a patent has been submitted to FDA, and an ANDA applicant can submit a paragraph IV certification even if the patent is not yet listed in the Orange Book (see Teva Pharms., USA, Inc. v. Leavitt, 548 F.3d 103, 105 (D.C. Cir. 2008)). However, FDA has determined that permitting serial submissions of amendments and multiple notices of paragraph IV certifications is overly burdensome to FDA and NDA holders. Such a practice makes it difficult to determine which paragraph IV certification and notice of paragraph IV certification is valid. Our decision to level the playing field for paragraph IV certifications in this manner is consistent with our authority to establish rules for the efficient enforcement of the FD&C Act (see section 701(a) of the FD&C Act).

That DC Circuit Court decision FDA cites is important.  In Teva Pharms., USA, Inc. v. Leavitt, 548 F.3d 103 (D.C. Cir. 2008) the Court said that “FDA is correct; both the statute and the Agency’s policies compel FDA to rely on the actual status of a patent (as indicated by the NDA holder) and not on the varying contents of a published reference guide.”

Despite the dubious nature of FDA’s “valid Paragraph IV certification” regulation, nobody has yet challenged it in court.  But they may no longer have to!  FDA seems to have abandoned it (or somehow modified it).  The evidence for this change in position is in FDA’s August 26, 2024 update to the Agency’s Paragraph IV Certifications List for generic versions of MULTRYS (Cupric Sulfate, Magnesium Sulfate, Selenious Acid, Zinc Sulfate) Injection (NDA 209376) and TRALEMENT (Cupric Sulfate, Magnesium Sulfate, Selenious Acid, Zinc Sulfate) Injection (NDA 209376).

The August 19, 2024 version of the Paragraph IV Certifications List identified the “Date of Submission” of the first Paragraph IV ANDA(s) for generic MULTRYS (the 60 mcg/mL, 3 mcg/mL, 6 mcg/mL, and 1000 mcg/mL strengths) as November 16, 2024 (and with three ANDAs submitted); for generic MULTRYS (the 0.3 mg/mL, 55 mcg/mL, 60 mcg/mL, and 3 mg/mL (1 mL) strengths) as November 16, 2023 (and with two ANDAs submitted; and for generic TRALEMENT (the 0.3 mg/mL, 55 mcg/mL, 60 mcg/mL, and 3 mg/mL (5 mL) strengths) as November 16, 2023 (and with one ANDA submitted).  At that time, there was information on a single patent listed in the Orange Book for both MULTRYS and TRALEMENT: U.S. Patent No. 11,786,548 expiring on July 1, 2041.  The Orange Book shows a November 14, 2023 “Submission Date” for the patent information, so it is reasonable to assume that the November 16, 2024 date is based on a scenario where the patent information was received by FDA on November 14, 2023, published in the Orange Book on November 15, 2023, and, under FDA’s “valid Paragraph IV certification” regulation, was first certified to on November 16, 2023.

That all changed with the August 26, 2024 update to the Agency’s Paragraph IV Certifications List.  The updated listings all now show November 14, 2023—the Orange Book submission date for U.S. Patent No. 11,786,548—as the “Date of Submission” of the first Paragraph IV ANDA(s) . . . and with three, three, and two ANDAs submitted on that November 14, 2023 date.  That’s one more than is on the August 19, 2024 list for TRALEMENT and one more for certain strengths of MULTRYS, presumably because one or more ANDA applicants serially certified but not through the working day after Orange Book listing of the patent information.  Of course, there could even be an entirely new set of Paragraph IV first applicant now eligible for 180-day exclusivity for generic MULTRYS and TRALEMENT depending on the facts.

This change, we understand, is not a mistake.  It was quite an intentional move by FDA.  It will presumably be followed by other updates to the Paragraph IV Certifications List to account for similar circumstances (are there are definitely a few of them).  But what the change seems to indicate is that FDA is flip-flopping—that is, abandoning (or is somehow modifying)—on its  “valid Paragraph IV certification” regulation and seems to be returning to a serial Paragraph IV certification scenario that is more in-line and consistent with the Agency’s Orange Book patent listing regulation at 21 C.F.R. § 314.53(d)(5).

Second up is FDA’s position on what constitutes a distinct drug product for ANDA 180-day exclusivity purposes.  This is one issue that the Association for Accessible Medicines raised in comments to FDA in 2020 concerning the Agency’s June 1, 2020 request for comment on the Orange Book.

By way of background, each brand-name drug product listing in the Orange Book has historically constituted a distinct drug product eligible for a separate period of 180-day exclusivity, provided, of course, patent information is listed in the Orange Book for the particular drug product.  That’s what the DC District Court indicated back in the 1990s—see Apotex, Inc. v. Shalala, 53 F. Supp. 2d 454 (D.D.C. 1999) (affirming that 180-day exclusivity is strength-by-strength).  Thus, separate entries—identified in the Orange Book as Product 001, Product 002, etc.—are assigned for each dosage form, route of administration, and strength (including changes to concentration or total drug content) approved under an NDA (though a change in the drug product from prescription use to over-the-counter use has special rules as we previously posted), and FDA recognizes each drug product as distinct for 180-day exclusivity purposes.

Similarly, if there is a single Orange Book listing (e.g., Product 001), but the brand-name drug is approved in, for example, different vial and pre-filled syringe presentations or ampule and vial presentations (all under the same Product 001 Orange Book listing), then FDA’s historical position has been that there is a single period of 180-day exclusivity for the first Paragraph IV ANDA applicant for either presentation (but not for both).  Indeed, FDA sent this blogger letter correspondence years ago stating just that:

FDA has never considered different presentations of the same dosage form and strength to be different listed drugs for 180-day exclusivity purposes.  FDA has long considered ampules and vials to be the same dosage form (injection) and has permitted ANDA applicants to change from one to the other without changing the listed drug they reference and without losing eligibility for exclusivity.  Examples of this practice include changes in presentation from ampule to vial for calcitriol and octreotide acetate. . . .  If there is only a single listed drug, only a single period of exclusivity can result.

In some instances, FDA has assigned a product code (e.g., Product 002) outside of the pharmaceutical characteristics noted above (i.e., dosage form, route of administration, and strength).  For example, in 2011, FDA explained in a Citizen Petition Response (Docket No. FDA-2011-P-0128) that two Bromfenac Ophthalmic Solution, 0.09%, drug products approved under NDA 021664 (XIBROM and BROMDAY) are different products because the NDA sponsor “itself has consistently treated Xibrom and Bromday as distinct drug products.”  Pointing to multiple labeling versions, different dosing instructions, and a difference in brand names, FDA noted that the Agency would also treat them as two distinct drug products.  FDA seems to have applied a similar analysis to KAPVAY and JENLOGA (clonidine hydrochloride) Extended-release Tablets, both approved under NDA 022331, in the same strengths, dosage form, and formulation but with different indications.  Each is listed separately on the Paragraph IV Certifications List, and each gave rise to a distinct period of 180-day exclusivity eligibility.

In more recent years, however, FDA has assigned a distinct product code in the Orange Book but has refused to recognize the drug product as a distinct drug product for 180-day exclusivity purposes.  Daptomycin for Injection, 500 mg/vial, is one example of this occurring.

FDA approved CUBICIN (daptomycin for injection), 500 mg/vial, on September 9, 2003 under NDA 021572.  On July 6, 2016, FDA approved a supplement to NDA 021572 for a reformulated Daptomycin for Injection, 500 mg/vial, drug product, CUBICIN RF, containing sucrose.  Upon approval of CUBICIN RF, the Orange Book included—and continues to include—a separate entry for CUBICIN RF, identifying it as Product 003 under NDA 021572.  Both drug products are listed as RLDs and were listed as Reference Standards before they were discontinued.  Moreover, each is listed with different patent information (U.S. Patent No. 8,003,673 for Product 002, and U.S. Patent No. 9,138,456 for Product 003).

FDA initially updated the Agency’s Paragraph IV Certifications List on October 22, 2018 showing August 30, 2018 as the Paragraph IV submission date for CUBICIN RF (daptomycin) Injection, 500 mg/vial (Product 003).  That listing inexplicably vanished when FDA updated the Paragraph IV Certifications List just two months later, on December 18, 2018.  Apparently, FDA did not believe that the approval of the supplemental NDA on July 6, 2016 for CUBICIN RF should give rise to a separate opportunity for 180-day exclusivity because CUBICIN RF is a reformulation of CUBICIN and does not represent a separate drug product from which 180-day exclusivity can arise.

A somewhat similar situation exists for RESTASIS (cyclosporine ophthalmic emulsion), 0.05%, and RESTASIS MULTIDOSE (cyclosporine ophthalmic emulsion), 0.05%.  Both pharmaceutically equivalent drug products are approved under NDA 050790 and appear in the Orange Book (with different patent listings) as Product 001 and Product 002, respectively.  Yet, FDA’s Paragraph IV Certifications List does not show a separate Paragraph IV ANDA submission listing for RESTASIS MULTIDOSE (and we know there has been one) that would give rise to a separate period of 180-day exclusivity.

Enter RELISTOR (methylnaltrexone bromide) Subcutaneous Injection, approved under NDA 021964, and FDA’s flip-flop on what constitutes a distinct drug product for ANDA 180-day exclusivity purposes.  As with FDA’s apparent reconsideration of the Agency’s “valid Paragraph IV certification” regulation, FDA seems to have gone Back to the Future with what constitutes a distinct drug product for ANDA Paragraph IV 180-day exclusivity purposes: Each drug product listing in the Orange Book.  (SIDE NOTE: If there was ever a drug proprietary name trying to make a name for itself in the Hatch-Waxman world, then you could hardly do better than RELISTOR!)

RELISTOR Injection is approved in two strengths—12 mg/0.6 mL and 8 mg/0.4 mL—but is available in three presentations: a 8 mg/0.4 mL mL single dose pre-filled syringe, a 12 mg/0.6 mL single dose pre-filled syringe, and a 12 mg/0.6 mL single dose vial.  Although the 12 mg/0.6 mL strength products are pharmaceutically the same, they are separately listed in the Orange Book.  We assume—and certainly hope, but cannot be sure at the moment—that the separate Orange Book listings are not merely a function of the different single dose pre-filled syringe and single dose vial presentations (i.e., packaging), but rather are a function of more substantive information in the RELISTOR Prescribing Information, which states: “The pre-filled syringe is only for patients who require a RELISTOR injection dose of 8 mg or 12 mg.  Use the vial for patients who require other doses of RELISTOR injection.”  Thus, there may be a condition of use basis explaining FDA’s decision to separately list each drug product in the Orange Book.

Despite the separate Product 001 and Product 003 Orange Book line items for Methylnaltrexone Bromide Injection, 12 mg/0.6 mL, and despite the submission of separate Paragraph IV ANDAs for each product, FDA’s Paragraph IV Certifications List has identified only a single Methylnaltrexone Bromide Injection, 12 mg/0.6 mL, drug product with a single first applicant having submitted its ANDA on July 22, 2015.  At least that was the case up through the August 19, 2024 version of the Paragraph IV Certifications List.

That changed with the publication of the August 26, 2024 update to FDA’s Paragraph IV Certifications List.  In that version of the list, FDA includes two Methylnaltrexone Bromide Injection, 12 mg/0.6 mL, drug product listings: (1) Methylnaltrexone Bromide Injection, 12 mg/0.6 mL Single Dose Vial, with a single first applicant and the prior July 22, 2015 Paragraph IV ANDA submission date; and (2) Methylnaltrexone Bromide Injection, 12 mg/0.6 mL Single Dose Prefilled Syringe, with a single first applicant and a September 8, 2015 Paragraph IV ANDA submission date.   The second listing appears to have come about as a result of FDA’s August 26, 2024 approval of ANDA 208112, which is presumably for the 12 mg/0.6 mL Single Dose Prefilled Syringe version of RELISTOR Injection (i.e., the addition made to the August 26, 2024 Paragraph IV Certifications List).

FDA’s recognition of separate 180-day exclusivity periods for Methylnaltrexone Bromide Injection, 12 mg/0.6 mL Single Dose Vial, and Methylnaltrexone Bromide Injection, 12 mg/0.6 mL Single Dose Prefilled Syringe seems to us to be a sign that the Agency has, in fact, reverted back to its position—that is, the Agency’s position prior to CUBICIN RF and RESTASIS MULTIDOSE—that each brand-name drug product listing in the Orange Book constitutes a distinct drug product eligible for a separate period of 180-day exclusivity.

Sooo . .  . . when was FDA planning on notifying the generic drug industry of these changes in policy and position?  Perhaps at an upcoming Hatch-Waxman 40th Anniversary party?  Or maybe in another upcoming guidance on new developments for 180-day exclusivity?  Who other than FDA knows . . . .  But the point is this: How are companies supposed to plan and coordinate submissions to new patent information to ensure first applicant status and eligibility for 180-day exclusivity when the rules for doing so are unclear and in flux?  How are companies supposed to plan for product launches that may be pegged to 180-day exclusivity eligibility when they don’t even know that they may be eligible for the exclusivity?  As we all know, 180-day exclusivity is a litigious area of the law.  These types of changes—presumably intended to shield FDA from litigation—will probably only attract litigation.