FDA recently published a Federal Register (FR) Notice [Docket No. FDA-2024-N-3945] announcing the publication of a draft strategy document, for public comment, outlining specific actions FDA plans to take to facilitate the use of innovative manufacturing technologies.

This FR Notice and draft strategy document are part of FDA’s commitment under the Prescription Drug User Fee Act (PDUFA) Reauthorization Performance Goals and Procedures for Fiscal Years 2023-2027 (PDUFA VII), wherein FDA committed to advance the use and implementation of innovative manufacturing.

“Innovative manufacturing” is a somewhat ill-defined term, but the agency uses it to refer to any novel manufacturing that can increase product development speed, bolster supply chains, or prevent drug shortages.  This would include continuous manufacturing, distributed manufacturing, modern aseptic manufacturing equipment and novel analytical methods.

In connection with this effort, on June 8, 2023, FDA participated in a public workshop on the use of innovative manufacturing technologies and discussed potential barriers to their adoption.  It was at this workshop that the agency committed to issuing a draft strategy document, for public comment.

At the workshop, stakeholders also shared feedback on their interactions with CDER’s Emerging Technology Program (ETP) and CBER’s Advanced Technologies Team (CATT), which were designed to guide sponsors on submissions which incorporate innovative manufacturing technologies.

Based on the exchanges during this workshop FDA developed the draft strategy document which outlines the specific activities FDA intends to undertake to facilitate the use of innovative manufacturing technologies.  They include the following:

1. Continuing to enhance CDER’s ETP and CBER’s CATT as mechanisms to support innovation.
   • Regarding CDER’s ETP, the current ETP guidance document, originally published in 2017, will be updated by the end of 2026, and will include details on communicating the type of products and stages of development for which a requestor can approach the ETP. In addition, by the end of 2026 FDA will issue a report summarizing the activities performed by FDA’s Emerging Technology Team (ETT), which includes relevant representation from all FDA pharmaceutical quality functions. Finally, the ETT will establish program goals and performance measures for the ETP.
   • Regarding CBER’s CATT, the center is currently revising its internal procedures, referred to as CATT 2.0, with the goal of providing better service to stakeholders interested in early engagement regarding innovative manufacturing technologies. This will include, by November 2024, a more streamlined process, tracking, more timely review of meeting requests, and communication with requesters by providing periodic updates.  In addition, the CATT website will be revised by November 2024 to provide additional clarity about the CATT meeting process, sponsor eligibility, meeting request content, timelines, and potential outcomes of CATT engagements.
2. Supporting and utilizing ongoing initiatives for advanced manufacturing to address potential barriers.
   • Given that a major regulatory barrier to the adoption of innovative manufacturing is a lack of international harmonization in regulatory requirements, FDA will continue to explore mechanisms for harmonization, including guidances, such as those developed by the International Conference on Harmonization (ICH), and pilot programs such as those created by the International Coalition of Medicines Regulatory Authorities (ICMRA).
3. Implementation of the Advanced Manufacturing Technology Designation Program.
   • In 2023, FDA published a draft guidance entitled Advanced Manufacturing Technologies Designation Program. It provides recommendations to sponsors interested in participating in FDA’s Advanced Manufacturing Technologies Designation Program, which is intended to facilitate the development of drugs manufactured using AMT. The draft guidance outlines the eligibility criteria for AMT designation, the submission and assessment process for requests, and the benefits of an AMT designation.  FDA intends to finalize the guidance on Advanced Manufacturing Technologies Designation program by the end of 2024.

“Inter Partes Review” and “Section 101” are not terms you typically run into on this all-things-FDA blog, but we have talked about such patent-related issues before (here and here), and they are important legal (patent) principles, particularly in the context of drug and biological products (and the Hatch-Waxman Amendments and the Biologics Price Competition and Innovation Act (“BPCIA”)).  And because of that, we try to stay abreast of such things (while staying in our “FDA lane”), especially when Congress gets involved to change the law.  To that end, we were recently alerted to the fact that the Senate Committee on the Judiciary has scheduled an Executive Business Meeting for Thursday, September 19, 2024 to mark-up, among other things, two bills of interest: (1) S. 2220, the Promoting and Respecting Economically Vital American Innovation Leadership Act  (“PREVAIL Act”); and (2) S. 2140, the Patent Eligibility Restoration Act of 2023 (“PERA Act”).

The PREVAIL Act

In short, the PREVAIL Act is intended to, among other things, reform the Inter Partes Review (“IPR”) process created by the 2011 Leahy-Smith America Invents Act.  IPRs have become an important tool used by generic drug and biosimilar manufacturers to try and clear patent thickets covering brand-name products prior to or during the pendency of an ANDA or aBLA submission.

Reading through the “Findings” section of S. 2220, introduced by Senators Chris Coons (D-DE), Thom Tillis (R-NC), Richard Durban (D-IL), and Mazie Hirono (D- HI), as well as the August 2023 press release accompanying the bill’s introduction, the PREVAIL Act sounds pretty good on paper.  After all, who could say “No” to this?

This bill supports inventors, encourages investments in intellectual property, secures U.S. global technology leadership, and protects economic and national security. The PREVAIL Act updates and improves on legislation that Senator Coons previously introduced to ensure that our patent system protects this essential property right.

Or to this from The Inventor’s Project:

The PREVAIL Act makes commonsense reforms to the [Patent Trial and Appeal Board] to promote fair treatment for inventors, improve efficiency, and ensure that the USPTO has the resources it needs to effectively administer a patent system that incentivizes American innovation and enables U.S. inventors to compete.

But there’s another side to this story.  As noted by the Association for Accessible Medicines (“AAM”) in a March 2024 letter opposing the bill:

The PREVAIL Act includes a prohibitive standing requirement, making it a “necessary condition[]” that an entity must be sued or charged with infringement before filing a petition for IPR.  This provision would prevent timely IPR challenges of pharmaceutical patents, and would chill the feasibility of such IPR challenges altogether. . . .

The PREVAIL Act’s proposal that, absent “exceptional circumstances” subsequent petitions cannot challenge the same patent, uniquely harms generic and biosimilar companies.  The Hatch-Waxman Act and [BPCIA] make it highly likely that multiple generic and biosimilar companies will be interested in invalidating the same patents, though not always at the same time, particularly where companies are at different stages of product development. With multiple companies interested in challenging the same patents, there are numerous circumstances in which a subsequently-filed petition may be warranted. . . .  The PREVAIL Act improperly impedes the IPR pathway for such subsequent petitioners, forcing these companies to defer to the arguments presented by their competitors.

The PERA Act

Like the PREVAIL Act, the PERA Act, introduced by Senators Thom Tillis (R-NC) and Chris Coons (D-DE) and intended to address patent eligibility under 35 U.S.C. § 101, also seems pretty good on paper.  Consider this June 2023 press release on the bill’s introduction:

There is now widespread bipartisan agreement in Congress and across all recent administrations that reforms are necessary to restore the United States to a position of global strength and leadership in key areas of technology and innovation, such as medical diagnostics, biotechnology, personalized medicine, artificial intelligence, 5G, and blockchain.

The Patent Eligibility Restoration Act achieves this critical goal by restoring patent eligibility to important inventions across many fields while also resolving legitimate concerns over the patenting of mere ideas, the purported discovery of which already exists in nature, and social and cultural content that everyone agrees is beyond the scope of the patent system. In short, this system is aimed at promoting technology-based innovation.

And again from The Inventor’s Project:

[D]esigned to clear up the confusion caused by recent court rulings on what can be patented under section 101 of the U.S. Code.  The Act aims to eliminate all judicial exceptions to patent eligibility, maintaining the current categories of what can be patented while adding specific exclusions.  Importantly, it clarifies that sections 102, 103, and 112 will still dictate the requirements for getting a patent, but these requirements won’t affect the initial eligibility decision.  This change is meant to make things more straightforward for everyone involved in the patent process, from inventors to judges to patent officials.

But as AAM notes in a March 2024 letter opposing S. 2140:

Section 101 is critically important to AAM and its members.  Because of two statutory schemes, the Hatch-Waxman Act and the [BPCIA], generic and biosimilar companies generally must address patent issues before launching a product through costly and protracted patent litigation.  Eliminating invalid patents under § 101 enables generic and biosimilar companies to streamline pharmaceutical litigation.  Because § 101 can be addressed at the outset of a case, § 101 is a useful tool for generic and biosimilar companies to avoid burdensome discovery and trim the number of asserted patents, which in some cases amounts to dozens.  This in turn can allow generic and biosimilar companies to launch their products sooner, providing patients with earlier access to more affordable medications.

The PERA Act would not only minimize these benefits of § 101, but it would make it easier for brand-name biologic companies to obtain less innovative patents, leading to higher drug prices. . . .  The PERA Act would abolish § 101’s careful test for eligibility and would open the floodgates to non-innovative patents.

So . . . beware of Roger “Verbal” Kint.  Who you ask?  You might know him better as: Keyser Söze.

While we hope readers of the Blog, as our clients and friends, come out of any FDA inspection with a clean bill of health, we know that based on FDA FY2024 data to date, approximately 40% of inspections of medical device companies end up classified as voluntary or official action indicated (VAI or OAI).  These classifications usually result from observations listed on the FDA investigator’s report (a Form 483).

When an establishment receives a Form 483, FDA’s Compliance Program Manual for Inspection of Medical Device Manufacturers indicates that “Corrections and corrective action proposals and plans, including evidence of corrections implemented, should be submitted by the firm in writing within 15 business days of the inspection close, detailing the action(s) taken or to correct the deviations within a specified time frame.” Fifteen business days go by quickly!  Although the timeline is short, developing and submitting a strong response is critical to reduce the chance that FDA takes further action from the inspection, like the issuance of a warning letter or other enforcement action.

So, what makes for a strong response?  Ideally, you will be able to investigate each observation, identify a root cause, take corrective action, make corrections, and explain with written evidence that you completed these actions.  While this may be possible for some observations, most of the time the issues that rise to the level of ending up on a Form 483 are challenging problems that take more than 15 business days to address.

Regardless of whether the company can complete activities by the time the initial 483 response is due, or simply sets forth its plan for how it intends to get there, a well-organized response is important.  The readers of your response at FDA typically include individuals who were not at the inspection, and even if the original investigator is reviewing your response, they may not remember all of the details given the number of other inspections on their plate.

Given this, most companies will start the response for each observation by reiterating the actual language in the Form 483.  Device companies often have a procedure that requires that a corrective or preventive action (CAPA) record is opened for each audit finding, including FDA observations.  If you are able to get through the process and have a solid CAPA record before your initial 483 response is due, you should include it as an attachment to the response document.  If the actions within the CAPA are still a work-in-progress, the response should include a reference to the CAPA number, and the complete record can be submitted to FDA as part of a later update to the company’s 483 response or made available for review during a future inspection.

An effective 483 response usually looks similar in structure to a CAPA record.  First, the company should describe how you have or how you plan to investigate the issue.  Will you interview employees, review procedures, review records, and/or use investigative tools such as 5-whys or fishbone diagrams?  Be specific.  If you have had time to at least start the investigation, describe what you have learned.  If continued investigation is planned, describe the next steps and timeline.  If you have identified the root cause, or causes, identify them in the 483 response and note that you have completed the root cause investigation.

The next paragraph, or section, of the 483 response should describe any corrective actions you have identified to address the root cause, or if you have not yet completed your root cause investigation by the time your 483 response is due, you should set forth a plan to identify corrective actions based on the results of the investigation.  It is important to include targeted completion dates for these activities (more on this below), and if you already have implemented any corrective actions, describe them and provide evidence of completion.

Another important piece to include in your initial 483 response is your corrections to any specific records that FDA identified in the observation.  Most companies reflexively do this and assume that is adequate to address the FDA’s concern.  FDA expects that the company not only correct the specific finding, but that it conducts a broader retrospective review of other similar records (usually going back two years) to find and correct any other records with the same problem.  There is a natural tendency to want to do this first, and sometimes that is the right approach, but often it is best to wait until you have fixed any procedural gaps so that you can apply the improved procedures when correcting regulatory records. For implemented procedural changes, consider providing evidence of training records for those functions impacted by the change. For manufacturing and product-related observations especially, don’t forget to do a “right-left look” to identify if a similar issue has occurred with another product line offered by the company.

Going back to timing, we cannot stress enough the importance of providing reasonable deadlines in your response to give FDA the assurance that you are prioritizing remediation of the observations.  We have seen some companies be too aggressive or aspirational with their timelines, and then must explain to FDA in a later update why they missed a deadline.  And we have seen some companies include deadlines that are too long and drawn out, which then leads to follow-up questions from FDA.  If the 483 response identifies a longer-term plan to address an issue, the company should develop a timeline for completion of each step of the process and share that with FDA.

This means that the frenetic 15 business days to develop a robust response is not the end of the matter.   We typically recommend that if a company’s initial 483 response contains outstanding action items, the company should commit to providing FDA with regular updates about progress, usually on a bimonthly basis, until all actions have been completed.  We recommend, as part of your initial response or in the first update, providing FDA with a table identifying each observation, listing the corrections and corrective actions, and showing which have been completed or the targeted due dates for completion. This table can then be updated easily for the periodic updates and makes it easier for FDA to see the company’s progress towards completion of committed activities.

FDA can take several actions on a 483.  If satisfied with your written response, and subsequent updates, FDA may notify you that it will review the corrective actions at the next inspection, which may be scheduled based, in some part, on the timelines provided in responses to the 483.  A repeat finding in another 483 not only reopens the 15-business day cycle to prepare a response, but it is more likely to result in the issuance of a warning letter or enforcement action (like an injunction).  All of this headache can be avoided through a robust, strategic plan being developed and submitted in the initial 483 response.

* Credit to the country music fans out there who know this Keith Urban diddy.

Last week, FDA revised one of its two guidances relating to nitrosamines, Control of Nitrosamine Impurities in Human Drugs. Nitrosamines are impurities that can form during drug manufacturing and are considered potentially potent carcinogens. One specific kind of nitrosamines called N-nitrosamine drug substance-related impurities, or NDSRIs, are especially vexing to FDA and to industry because they mimic the structure of the specific active pharmaceutical ingredients (API), making them difficult to detect.

The new final guidance includes a description of some of the various circumstances under which nitrosamines form. It’s these varied scenarios that give quality managers nightmares. For example, depending on the manufacturing process for a specific human drug, the use of some specific solvents, reagents, and catalysts may trigger the formation of these possible carcinogens. But risk also lurks from vendor-sourced raw materials containing nitrosamine impurities, or from simple deviations in temperature or pH.

The revised guidance that was published last week aims to offer some new tools to help industry address these issues. FDA starts by setting the limit of what it views as acceptable intake (AI) limits, so that manufacturers and applicants can know what targets they should hit. Using the guidelines found in the ICH M7(R2), FDA set an AI threshold of 1.5 micrograms per day “for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects.” FDA says that highly potent compounds – again, as defined in ICH M7(R2) – pose risks below that limit.

We note that the other FDA guidance document on nitrosamines addresses NDSRIs. We wrote about 2023’s Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs), which also advised on how to review drug products and take appropriate action. This new revision acts as a companion piece to that guidance, providing additional details on identifying potential root causes and mitigation strategies.

FDA’s latest guidance has three key aspects: assessment, control, and reporting. First, firms should undertake risk assessments of their APIs, finished products, and products under approved or pending applications. We’ve seen this measure well underway at many impacted companies. Second, the guidance provides some new tactics for industry to control nitrosamine impurity risks through, for example, sensitive, product-specific chromatographic testing. Third, FDA offers new recommendations on how to report revised specifications that assessment and control might affect, which might include making amendments to approved or pending applications or drug master files where appropriate. Note here that those initial risk assessments need not be reported, but FDA recommends that firms do report resulting changes to drug specifications like stability or bioequivalence.

Last week’s guidance is featured on FDA’s new nitrosamines webpage and recommends that manufacturers implement revisions to control measures by August 1, 2025, noting that manufacturers and sponsors of approved products were expected to complete evaluations for small molecule nitrosamines last year. The revisions due in 2025 include testing for NDSRIs.

FDA recognizes that nitrosamine detection and remediation are complicated undertakings for quality managers. However, in light of its detailed and newly revised guidances, we doubt the Agency will offer too much in the way of leniency for firms that don’t respond with substantial effort.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is proud to announce that 16 of the Firm’s attorneys have been selected to the 2025 edition of The Best Lawyers in America®.  Founding Director Paul M. Hyman has been rightfully chosen as a 2025 “Lawyer of the Year.”  Additionally, Kalie E. Richardson, James E. Valentine and Sarah L. Wicks have been named to the “Best Lawyers: Ones to Watch” list for Health Care Law and Administrative/Regulatory, respectively.

Recognized attorneys include:

• “Lawyer of the Year” Award — Paul M. Hyman, FDA Law
• Michelle L. Butler, FDA Law
• Ricardo Carvajal, Food and Beverage Law
• Robert A. Dormer, FDA Law
• Douglas B. Farquhar, FDA Law
• Jeffrey N. Gibbs, FDA Law
• Gail H. Javitt, FDA Law
• Kurt R. Karst, FDA Law
• Sara W. Koblitz, FDA Law
• Dara K. Levy, FDA Law
• Allyson B. Mullen, FDA Law
• Josephine M. Torrente, FDA Law
• Anne K. Walsh, FDA Law

Best Lawyers — Ones to Watch® in America:

• Kalie E. Richardson, Health Care Law
• James E. Valentine, Health Care Law
• Sarah L. Wicks, Administrative/Regulatory Law

The Best Lawyers in America® publication is based entirely on annual peer-review and has earned the respect of the profession, the media, and the public as the most reliable, unbiased source of legal referrals.  Recognition by The Best Lawyers in America® is widely regarded by both clients and legal professionals as a significant honor conferred on a lawyer by his or her peers.

Thank you to readers of this blog. We received incredible feedback on our August 19 post analyzing the number of decision summaries that have been posted for De Novos.

We are happy to report that fifteen new decision summaries have been posted as of August 28. Notably, two decision summaries were posted for De Novos that had been granted in 2020 and two were posted for De Novos granted this year. Thus, the new summaries bracket a wide range in time.

Some other noteworthy observations:

• More than half (8/15) of the recently posted decision summaries were from 2023.
• There were no new summaries published for De Novos granted in 2021.
• The leader, with five summaries, was OHT7. OHT1 earned the silver medal with its four summaries.
• Not counting the two recent De Novo decisions that were not part of the original analysis, the total number of decision summaries posted for De Novos granted between CY 2022 and 2024 YTD is now 45/101 (43%). This represents an improvement, but there are still lots of De Novos for which the summaries are not yet available.
• On our list of the Top Ten De Novos with the greatest number of days elapsed between when they were granted and the lack of a decision summary, seven now have decision summaries posted for them.

We are cautiously optimistic more decision summaries will be posted soon. Given the high rate of innovation in the device industry, including the evolving field of AI, we expect more manufacturers to either submit De Novo classification requests or rely on those for their 510(k) devices. Timely access to these decision summaries will help manufacturers, FDA, and provide greater transparency to the public.

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.

As readers of this blog know (see, e.g., here), the Affordable Generics (and Biosimilars) Act has been floating around in Congress for the better part of two decades. That bill, addressing drug (and later biological product) patent settlement agreements (pejoratively referred to as “reverse payment agreements” by their opponents), was first introduced by Senator Herb Kohl (D-WI) in June 2006 as S. 3582—well before the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) established the biosimilar biological product licensure pathway, and years before the U.S. Supreme Court declined to hold, in FTC v. Actavis, Inc., 133 S. Ct. 2233 (2013), that so-called reverse payment settlement agreements are presumptively unlawful.

As originally proposed, the legislation would have amended the Federal Trade Commission Act (“FTC Act”) to effectively kill drug patent settlement agreements by providing that:

It shall be considered an unfair method of competition affecting commerce under subsection (a)(1) for a person, in connection with the sale of a drug product, to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim in which—

(A) an ANDA filer receives anything of value; and

(B) the ANDA filer agrees not to research, develop, manufacture, market, or sell the ANDA product for any period of time.

Though the bill also included narrow exceptions:

Nothing in this subsection shall prohibit a resolution or settlement of patent infringement claim in which the value paid by the NDA holder to the ANDA filer as a part of the resolution or settlement of the patent infringement claim includes no more than the right to market the ANDA product prior to the expiration of the patent that is the basis for the patent infringement claim.

S. 3582 went nowhere; and many additional unsuccessful attempts to get a similar bill passed followed over the years. For example, see our posts here, here, here, and here.

The push for legislation—restyled as the Preserve Access to Affordable Generics and Biosimilars Act with the enactment of the BPCIA—seemed to have waned a bit in recent years, perhaps coinciding with an end to the Federal Trade Commission’s (“FTC’s”) annual reports on “Agreements Filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003” and waning activity from FTC in the space (according to information published on FTC’s website).  But like cockroaches, some pieces of legislation are resilient and never seem to die.

The latest iteration of the Preserve Access to Affordable Generics and Biosimilars Act making its way through Congress is Senator Amy Klobuchar’s (D-MN) S. 142.  Like previous iterations of the bill, it would amend the FTC Act to add new Section 27, which provides, in part, that:

(A) In general.—Subject to subparagraph (B), in such a proceeding, an agreement shall be presumed to have anticompetitive effects and shall be a violation of this section if —

(i) an ANDA filer or a biosimilar biological product application filer receives anything of value, including an exclusive license; and

(ii) the ANDA filer or biosimilar biological product application filer agrees to limit or forgo research, development, manufacturing, marketing, or sales of the ANDA product or biosimilar biological product, as applicable, for any period of time.

And like its predecessor bills, S. 142 includes narrow exceptions:

(B) Exception.—Subparagraph (A) shall not apply if the parties to such agreement demonstrate by clear and convincing evidence that—

(i) the value described in subparagraph (A)(i) is compensation solely for other goods or services that the ANDA filer or biosimilar biological product application filer has promised to provide; or

(ii) the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.

. . . . As well as some exclusions:

(b) Exclusions.—Nothing in this section shall prohibit a resolution or settlement of a patent infringement claim in which the consideration that the ANDA filer or biosimilar biological product application filer, respectively, receives as part of the resolution or settlement includes only one or more of the following:

(1) The right to market and secure final approval in the United States for the ANDA product or biosimilar biological product at a date, whether certain or contingent, prior to the expiration of—

(A) any patent that is the basis for the patent infringement claim; or

(B) any patent right or other statutory exclusivity that would prevent the marketing of such ANDA product or biosimilar biological product.

(2) A payment for reasonable litigation expenses not to exceed—

(A) for calendar year 2023, $7,500,000; or

(B) for calendar year 2024 and each subsequent calendar year, the amount determined for the preceding calendar year adjusted to reflect the percentage increase (if any) in the Producer Price Index for Legal Services published by the Bureau of Labor Statistics of the Department of Labor for the most recent calendar year.

(3) A covenant not to sue on any claim that the ANDA product or biosimilar biological product infringes a United States patent.

In recent years and iterations of the Preserve Access to Affordable Generics and Biosimilars Act, additional provisions have been added (compared to the more ancient versions of the bill).  In particular, provisions have been added to expressly provide for the FTC to obtain forfeiture and civil penalties in an administrative proceeding initiated by the Commission.  The penalty provisions provide, in relevant part:

(e) Penalties.—

(1) FORFEITURE.—Each party that violates or assists in the violation of this section shall forfeit and pay to the United States a civil penalty sufficient to deter violations of this section, but in no event greater than 3 times the value received by the party that is reasonably attributable to the violation of this section. If no such value has been received by the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer, the penalty to the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer shall be sufficient to deter violations, but in no event shall be greater than 3 times the value given to an ANDA filer or biosimilar biological product application filer reasonably attributable to the violation of this section. Such penalty shall accrue to the United States and may be recovered in a civil action brought by the Commission, in its own name by any of its attorneys designated by it for such purpose, in a district court of the United States against any party that violates this section. In such actions, the United States district courts are empowered to grant mandatory injunctions and such other and further equitable relief as they deem appropriate. . . .

(3) CIVIL PENALTY.—In determining the amount of the civil penalty described in this section, the court shall take into account—

(A) the nature, circumstances, extent, and gravity of the violation;

(B) with respect to the violator, the degree of culpability, any history of violations, the ability to pay, any effect on the ability to continue doing business, profits earned by the NDA holder, the biological product license holder, the ANDA filer, or the biosimilar biological product application filer, compensation received by the ANDA filer or biosimilar biological product application filer, and the amount of commerce affected; and

(C) other matters that justice requires.

These civil penalty provisions—likely viewed by proponents of the legislation as hallmark provisions—may now be the legislation’s final death knell even if, unlike its predecessors, the bill actually makes it through Congress.  As we noted in a blog post published shortly after the Supreme Court’s decided SEC v. Jarkesy, 144 S. Ct. 2117 (2024) was released, that landmark decision “ruled that the Securities and Exchange Commission (SEC) may not impose fines to penalize securities in its administrative proceedings because that practice violates the Seventh Amendment ‘right of trial by jury’ in all ‘suits at common law.’”

While Jarkesy addressed only the SEC’s authority to impose fines, the underlying jury trial is not limited to that context: It applies to any claims that seek to impose civil penalties or other forms of monetary relief.  As the Court explained in Jarkesy, Congress’s imposition of civil penalties as a remedy is “all but dispositive” in determining that the Seventh Amendment right to a jury trial will attach, including in actions brought by a federal agency.

The Preserve Access to Affordable Generics and Biosimilars Act (S. 142) cannot be squared with Jarkesy’s interpretation and application of the Seventh Amendment.  As discussed above, the bill expressly provides for the FTC to obtain civil penalties—the exact type of claims the Supreme Court held are subject to Seventh Amendment protections—without a jury trial at any step of the process.  Rather, the bill is structured so that liability is fully determined by an Administrative Law Judge (“ALJ”) in an administrative proceeding without a jury, with “conclusive” factual findings made by that ALJ.  Then, in a follow-on action in court to impose civil penalties, the liability findings made by the ALJ are treated as “conclusive” and a judge—not a jury—assesses penalties in a bench trial.

That structure directly conflicts with the Supreme Court’s holding in Jarkesy.  First, S. 142 removes the jury entirely from both steps of its delineated process for assessing civil monetary penalties.  Second, by having an ALJ “conclusively” determine liability—and without a jury—it impermissibly takes away from the jury its core function of finding facts.  Just as it is unconstitutional to side-step the jury in an action seeking civil penalties for fraud (as in Jarkesy), so too is it impermissible in an action seeking civil penalties for unfair competition.  Both types of claims are analogous to common-law claims that fall squarely within the scope of Seventh Amendment protections.

Where does this leave us?  Well, Congress can move forward and pass the bill, but it would likely be immediately challenged in court as unconstitutional.  And with the Jarkesy decision, it seems almost certain that an enacted version of the Preserve Access to Affordable Generics and Biosimilars Act would be invalidated by a court because its entire remedial structure is contrary to the Seventh Amendment.  That means legislators will either have to go back to the drawing board or drop the issue all together.  Hopefully, the cockroach is dead.  After all, as we have written before in other contexts (i.e., the BLOCKING Act), “[I]f you limit a generic drug manufacturer’s ability to settle cases, that manufacturer does not settle fewer cases, it submits fewer Paragraph IV ANDAs.  And fewer ANDAs means less, not more, generic drug competition.”

The American Conference Institute (“ACI”) will hold (virtually) its 4th Annual Passport to Proficiency on the Essentials of Hatch-Waxman and BPCIA from October 8-24, 2024.  This virtual three-week program is designed to give new lawyers and executives a solid foundation in the essentials and intricacies of Hatch-Waxman and BPCIA litigation and regulation.

Gain a comprehensive understanding of Hatch-Waxman and BPCIA essentials—critical competencies for legal and business professionals in the biopharmaceutical sector.  Everyone in the life sciences industry must be well-versed in the regulatory components and intellectual property nuances integral to patenting products.

This year’s co-chairs include Fangli Chen, Ph.D. (Partner, Proskauer Rose LLP) and Jason Murata (Partner, Axinn, Veltrop & Harkrider).  Hyman, Phelps & McNamara, P.C. Director Sara W. Koblitz will speak during Module 5 on various Hatch-Waxman and BPCIA topics.  The series, held virtually on Tuesday and Thursday afternoons on ACI’s interactive platform, will provide an in-depth review of Hatch-Waxman and the BPCIA, as well as other intellectual property basics related to small molecules and biologics. This program lays the groundwork for understanding the patent life cycles of biopharmaceutical products and business development plans.

To learn more about the program and to view the agenda, see here.  FDA Law Blog readers receive a 10% discount (use FDA Law Blog promo code: D10-999-FDA25).

Who says nothing happens in Washington, D.C., in August?  The Drug Enforcement Administration (“DEA”) will announce Thursday in the Federal Register that it will hold a hearing on the proposed rescheduling of marijuana to schedule III at DEA Headquarters in Arlington, Virginia on December 2, 2024.  DEA received over 43,500 public comments in response to the agency’s Notice of Proposed Rulemaking in the Federal Register on May 21, 2024.

“Interested persons,” that is “any person adversely affected or aggrieved by any rule or proposed rule issuable” under the Controlled Substances Act wishing to participate in the hearing must file a written notice of their intention to participate, which DEA will review.

Each notice of intention to participate must:

1. State with particularity the interest of the person in the proceeding;
2. State with particularity the objections or issues concerning which the person desires to be heard; and
3. State briefly the position of the person regarding the objection or issues.

Interested persons can file electronically as a PDF attachment via email to the Drug Enforcement Administration, Attn: Administrator at nprm@dea.gov or in writing to the Drug Enforcement Administration, Attn: Administrator, 8701 Morrissette Drive, Springfield, VA 22152 within 30 days after publication in the Federal Register.

As we said in our earlier post when DEA announced initiation of the rescheduling proposal in May, “buckle up!”

In 1997, Congress wisely amended the Federal Food, Drug, and Cosmetic Act (FDCA) by adding Section 513(f)(2) to establish the De Novo process.  The De Novo process provides a regulatory pathway to classify novel devices for which general controls alone or general and special controls provide reasonable assurance of safety and effectiveness for the intended use.  This amendment allowed sponsors with low or moderate risk devices to proactively employ the De Novo process.

In 2012, the FDCA was modified to allow the submission of a De Novo request without the need for a prior 510(k), and set a target review time by FDA of 120 days.  Before then, to use the De Novo process a sponsor had to submit a 510(k) premarket notification, receive a decision of “not substantially equivalent” due to lack of a predicate device, and then submit a De Novo request for the device.  There was no time limit for De Novos, which meant some requests languished for prolonged periods.  For the first fifteen years after the De Novo program was established, it was basically a failure.

These legislative changes helped.  The average annual number of De Novos granted leapt. (This is a good example of Congress fixing a problem.  Of course, Congress had created the problem in the first instance.)  The average annual number of De Novos granted increased from 5 to approximately 29.

De Novos now play an important role in product advancement.  For example, FDA granted seven De Novos for COVID-19 related indications for use.  Each of these De Novos can represent a clinical advance.  Equally important, once these De Novos are authorized, they can serve as predicate devices in the 510(k) process.  In other words, De Novos serve as springboards for other new devices.

When FDA grants a De Novo, it is supposed to issue a decision summary and classification order.  Sponsors of a new 510(k) device can use the decision summary and classification order affiliated with the De Novo to learn what the De Novo applicant submitted and build the case for substantial equivalence to the De Novo device.  In effect, these documents serve as road signs helping to direct new market entrants.

These summaries can be invaluable to companies that want to get their own clearance, providing the details that can be the key to understanding what the recipient of the De Novo did.  Since 2010, FDA has posted classification orders and decision summaries for devices classified through the De Novo classification process.  The classification order identifies the special controls and therefore is extremely important.  However, the special controls tend to be high level, such as “Electromagnetic compatibility (EMC) and electrical safety testing must be performed for any electrical components” and “Software verification, validation, and hazard analysis must be performed for any software components of the device.”  This high level statement leaves many questions about details.

However, far too often, potential 510(k) applicants get to a fork in the regulatory road and find that no road signs have been posted, metaphorically speaking.  According to the Medical Device Databases webpage, the De Novo database is to be updated weekly.  When we reviewed the De Novos that were granted between CY 2022 and 2024, we saw that only 28% had decision summaries posted:

Dishearteningly, the trend is in the wrong direction.

Breaking this down further, we found that the rate of decision summaries posted varied by offices:

What’s more astonishing is the number of years that have lapsed between De Novos being granted and their decision summaries posted:

For 2024, some De Novos were recently granted and therefore do not reflect badly on FDA—yet.  The same cannot be said for De Novos from January or February.

We further identified the ten De Novos with the greatest number of days elapsed between when they were granted and the lack of a decision summary.  These numbers are accurate as of August 16, 2024:

FDA has not publicly explained why the decision summaries for De Novos are not posted in a timely manner.  FDA has said that these summaries need to go through multiple levels of review, but that cannot excuse delays of 500 days or more.  The agency has done far better in posting 510(k) summaries, which are similar types of documents.  FDA delaying the De Novo decision summary postings is contrary to their promotion of timely access to information, and hinders companies that are trying to get new 510(k)s.  We have had multiple clients who have had to guess what to submit because the De Novo summary was not available, even though the De Novo had been granted long before.

It is important that FDA posts the decision summaries in a timely fashion.  Delays unnecessarily hamper the ability for other companies to efficiently move through the 510(k) process, which also makes the review process less efficient for FDA itself.  Without the decision summaries, companies are left to guess at the study design to satisfy special controls and/or engage with FDA through the pre-submission process to obtain feedback.  FDA’s failure to post decision summaries for 70% of De Novos granted in the last 2.5 calendar years is both inexplicable and deprives patients and clinicians of options.  By taking the simple step of making summaries available faster, FDA can facilitate the clearance of new products, and make life easier for its own reviewers.

Enacted in 2022, the Inflation Reduction Act (IRA) amended the Medicare provisions of the Social Security Act to impose several discount requirements on pharmaceutical manufacturers.  In addition to the widely publicized drug price negotiation program, the IRA established inflation rebate programs under Medicare Part B and Part D.  Since 1991, the Centers for Medicare and Medicaid Services (CMS) has administered inflation rebates in the Medicaid Drug Rebate Program (MDRP), but the IRA brings inflation rebates to Medicare.

The two inflation rebate programs share many features in common, with key differences.  These programs require manufacturers to pay rebates to Medicare if they raise their prices for certain Part B and Part D drugs faster than the rate of inflation.  The programs do not impose additional price reporting requirements on manufacturers; instead, CMS will determine rebates based on prices currently reported under the MDRP and Medicare Part B.  CMS will develop a new online portal for manufacturers to review their reports, submit Suggestions of Error, and make rebate payments.  CMS will provide all manufacturers of Part B and Part D rebatable drugs the respective reports, even if their rebate amount due for an applicable period is $0.  The Part B program applies to calendar quarters beginning with the first quarter of 2023, and the Part D program applies to 12-month periods beginning on October 1, 2022.  Because of the limited time between enactment and the effective dates of the inflation rebate programs, Congress directed CMS to implement these two programs initially through program guidances.  Accordingly, CMS issued first a preliminary guidance on each program, then, after a 30-day comment period, issued revised guidances on December 14, 2023.  On July 31, 2024, CMS published a proposed rule to codify its guidances, with some changes. We have drafted a memorandum that summarizes the main provisions of this proposed rule and notes where the regulation differs from the guidances.

Among other topics, the memorandum summarizes CMS’s proposed regulations for both these Part B and Part D inflation rebate programs, including:

• Key definitions;
• The drugs to which the rebates apply;
• Methods of calculating and applying rebates;
• Processes for reporting, reconciling, and paying rebates; and
• Penalties and enforcement.

We will be watching the development of these inflation rebate programs and will provide an update as the rule progresses.

In the world of patent term extensions, every day considered part of the regulatory review period is important, as that day—either in whole or in part—gets added back to the patent upon approval of the product.  In the veterinary world, where rolling applications are common, the testing phase is usually particularly important because the review phase, which starts only when the last component of the rolling New Animal Drug Application (NADA)—called the Administrative NADA—is submitted, is short, typically around 60 days.  So to maximize patent term restoration, the earlier the start of the testing phase, the better.

As background, under the PTE statute at 35 U.S.C. § 156(g), certain patents covering animal drugs are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  As with other FDA-regulated products, such as human drugs and medical devices, the “regulatory review period” is composed of a “testing phase” and a “review phase.”  For animal drugs approved under FDC Act § 512, the “testing phase” begins on the earlier of the effective date of an Investigation New Animal Drug (“INAD”) exemption or the date a major health or environmental effects test on the drug was initiated and ends on the date a NADA is “initially submitted” to FDA under FDC Act § 512(b).  The “review phase” is the period between the initial submission and approval of the NADA.  FDA’s PTE regulations at 21 C.F.R. § 60.22(f) clarify that a marketing application “is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application.”  FDA guidance has been clear that that point for rolling submissions is when the last component has been submitted.

Since 1991, FDA has taken the position that the testing phase starts when the sponsor submits a request to Center for Veterinary Medicine to establish an INAD file and ends when an NADA is submitted.  In February 2018, however, FDA issued a PTE decision determining that the testing phase for a NADA starts only once a Notice of Claimed Investigational Exemption (“NCIE”)—a written notification to FDA under an INAD of the sponsor’s intent to ship an investigational new animal drug—has been submitted.  In that PTE decision, this made a difference of over a year (which could result in an additional 6 months added back onto the patent).  The NADA applicant requested reconsideration, but FDA refused to set the testing phase at the INAD opening and instead used the date that a major health or environmental effects test on the drug was initiated.

In response,  Nissan Chemical Corporation, Intervet, and Merck Sharp & Dohme collectively sued FDA in June 2022 under the Administrative Procedure Act alleging that FDA’s determination of the regulatory review period for its approved NADA for BRAVECTO was arbitrary and capricious and violated due process principles because FDA changed its methodology for determining a drug’s regulatory review period without acknowledging the change or providing fair notice.  In February 2010, an oral formulation of BRAVECTO, a medication to treat and prevent fleas and tick infestation in dogs, was the subject of an INAD submitted to the Agency.  Plaintiffs performed the necessary studies on BRAVECTO and filed an NADA on April 8, 2014; FDA approved the NADA on May 15, 2014.  As required by law, Plaintiffs submitted a request for PTE within 60 days of approval, claiming that the regulatory testing phase began on February 19, 2010, the date in which the INAD was assigned number 11-903 for the investigation of the oral formulation of BRAVECTO.  When the U.S. Patent and Trademark Office consulted with FDA on the appropriate timelines, FDA claimed that the INAD, and thereby the testing phase, was not effective until August 4, 2011 because no NCIE was submitted until then.  After a Request for Reconsideration, FDA determined that the study actually began on June 28, 2011, but rejected the February 2010 date stating that “an INAD file was established when we received the first NCIE” and that the opening of the INAD file on February 19, 2010 was merely a “housekeeping matter” and thus the testing phase did not begin in February 2010.  While Nissan et al. sued FDA, at FDA’s request, the Court remanded the decision back to the Agency, but it came to the same conclusion.  Nissan thus filed an Amended Complaint and each party filed Motions for Summary Judgment.

The District Court for the District of Columbia determined that “the key question at issue in this case” is the appropriate start of the testing phase: February 2010 or June 2011.  The Court pretty quickly determined that “FDA acted arbitrarily and capriciously when applying [the PTE statute] to BRAVECTO because the FDA did not provide fair notice or an adequate explanation of its shift in methodology.”  FDA, since 1991, had publicly signaled that the opening of an INAD file starts the testing phase for a new animal drug.  FDA explicitly said as much in the 1991 preamble accompanying proposed patent restoration regulations.  FDA also consistently interpreted it that way between 1990 and 2007. While FDA had acknowledged this approach, in its 2022 remand decision FDA said that such approach was an “improper application” of the regulation and that the Agency started differentiating the opening of the INAD file from submission of an NCIE in 2009.  Thus, the Agency concluded, the June 2011 date should stand.

On August 8, 2024, the Court granted Nissan et al.’s Motion for Summary Judgment finding that FDA failed to provide fair notice to plaintiffs of the need to submit an NCIE rather than an INAD to trigger the start of the testing phase.  The Court explained that “FDA never publicly acknowledged that it was changing course.”  “It was not until the FDA’s 2022 remand decision that the agency publicly acknowledged these past mistakes and clarified its methodology for determining the testing phase start date.”  FDA was required to provide fair notice that it would no longer use the INAD date to start the testing phase.  The appropriate inquiry was “whether, as of February 2010, plaintiffs would have been ‘able to identify, with ‘ascertainable certainty,’ the standards with which the agency expect[ed] parties to conform’ in order to trigger the start of the testing phase for BRAVECTO.”  Because the Agency did not repudiate its prior contradictory statements and precedents until 2022, “FDA’s regulations, decisions, and statements did not provide fair notice to plaintiffs of the actions they were required to take in order to trigger the start of the testing phase for BRAVECTO, and the FDA’s actions therefore violated the APA.”

With this decision, the testing phase for BRAVECTO began on February 19, 2010, giving Plaintiffs an additional year to be included in its testing phase calculations.  It’s a clean win for the Plaintiffs and yet another hit to FDA’s court losses.  More important for industry, however, is that the case affirmatively puts every NADA filer on notice: the NCIE is now what triggers the start of the testing phase—not opening the INAD.

FDA’s Office of Prescription Drug Promotion (OPDP) has issued two new Untitled Letters this summer after 5 months without any letter activity. The letters are vastly different from one another in subject matter, but together they make a cruel summer of OPDP enforcement against industry. [Editorial note – the Gen X’er included that link first – for the arguably more popular reference, read on.]

The first Untitled Letter was issued to kaleo, Inc. on July 17, 2024 for a social media post published by Instagram influencer Brittany Mahomes (who has 2 million Instagram followers) about AUVI-Q (epinephrine injection, USP) that “entirely omit[ed] all risk information” about the drug. Mahomes, spouse to Kansas City Chiefs quarterback, Patrick Mahomes, is the mother of 2 young children with severe food allergies. Presenting only information about the benefits or efficacy of a prescription drug, like AUVI-Q, without any risk information is considered a false or misleading presentation under the Federal Food, Drug and Cosmetic Act (FDCA), and is considered misbranding of the product.

AUVI-Q is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects… biting insects… allergen immunotherapy, foods, drugs, diagnostic testing substances… and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The approved labeling for AUVI-Q includes warnings and precautions regarding emergency treatment, injection-related complications, serious infections at the injection site, allergic reactions associated with sulfite, and disease interactions.

The Instagram post contained both a video portion and text portion, neither of which mentioned or included any risk information. Instead, the post focused solely on the benefits and efficacy of AUVI-Q, with statements otherwise consistent with AUVI-Q’s approved labeling, such as “Auvi-Q is the only epinephrine autoinjector out there for infants and toddlers” and “AUVI-q® (epinephrine injection, USP) is for life-threatening allergic emergencies.”  The FDA acknowledged that although the post included the statement, “For Important Safety Information, visit @auviq_IS[,]” this “does not mitigate the misleading impression created by the omission of risk information,” (emphasis added). FDA’s stated concern from a public health perspective is that the omission of risk information “fails to provide material information about the consequences that may result from the use of Auvi-Q and creates a misleading impression about the drug’s safety.”  In other words, individuals may not be as vigilant about avoiding allergens if they only hear the benefits of AUVI-Q without understanding there may be safety consequences as well.

Honestly, we are pretty shocked that this social media post slipped through the review committee.  Haven’t we all learned that celebrity endorsements for prescription drugs still need to meet traditional promotional requirements? Thank you, Kim, for paving the way here.

Moral of the story – simply referring consumers (or followers) to a drug’s website for safety information is not enough  – even if you are TSwift’s bestie.

August 2024 Untitled Letter to Mirati Therapeutics Inc.

The second Untitled Letter was issued to Mirati Therapeutics Inc. (Mirati), a Bristol Myers Squibb company, on August 1, 2024 for content on a healthcare provider branded website for its product, KRAZATI (adagrasib), which was approved under FDA’s accelerated approval pathway for patients with certain types of non-small cell lung cancer based on objective response rate (ORR) and duration of response (DOR). The FDA’s accelerated approval pathway can allow for earlier approval of drugs intended to treat serious conditions and fill an unmet medical need where approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit and the predicted clinical benefit is subsequently verified in a post-approval confirmatory trial(s). FDA notes in its letter that it received multiple complaints about the website under its Bad Ad Program.

The letter states the website makes false or misleading claims and representations about the benefits and efficacy of KRAZATI, thus misbranding the product. The website makes numerous clinical efficacy claims for the drug, including claims relating to “depth of response,” “disease control rate” (DCR), and rates of “stable disease” (SD), “partial response” (PR), “complete response” (CR), and “progressive disease” (PD) from Mirati’s KRYSTAL-1 study which was the basis for FDA’s accelerated approval of KRAZATI. However, as FDA points out in its letter, KRYSTAL-1 was a multicenter, single-arm, open-label expansion cohort study that evaluated the effect of KRAZATI on ORR and DOR and thus did not establish that the SD observed in the study was attributable to the effect of the drug; such an assessment would need to be based on the results of a randomized controlled trial. FDA noted similar findings for the website’s presentation of DCR, overall survival (OS) and progression free survival (PFS) results since the KRYSTAL-1 study design was not capable of producing interpretable results on these endpoints. The website also included claims from “data on file” that were based on “pooled DOR” information. FDA stated “[p]ooling data poses analytical problems as differences among studies and study populations can affect the validity and interpretability of such pooled analyses,” and, because the FDA could not verify the presented results, requested Mirati provide data to support its claim for FDA’s review. Additionally, Mirati included disclaimers that the data presented on the website were based on descriptive and post-hoc analyses, which FDA stated is not sufficient to mitigate the overall misleading impression created by the inclusion of the data.

The Mirati letter deals with much more nuanced issues than the letter to kaleo. When dealing with a drug that is approved via the accelerated approval pathway, can efficacy data be presented as consistent with the FDA-required labeling (CFL) and be subject to the “scientifically appropriate and statistically sound” (SASS) standard, generally thought to be a lesser substantiation standard than the traditional regulatory requirements of “substantial evidence” and “substantial clinical experience?”  Even in a CFL world, these presentations likely fall short of the SASS standard where the communication “relies on a study that is inadequate to support the representations or suggestions it presents [and] disclosure of the material limitations of that study does not correct the misleading message conveyed by the communication.”

What these bloggers find interesting about this letter (beyond the CFL analysis) is that because KRAZATI was approved under the accelerated approval pathway, Mirati would have been required to submit all promotional materials for the drug thirty (30) days in advance of the material being used. As FDA did not object to the timing of the submission in the letter, it seems that FDA (likely) received a copy of this website for review, FDA did not comment, and Mirati moved forward with publishing – only to receive an Untitled Letter months later.  Years ago, FDA had much more robust communications about promotional materials with sponsors of accelerated approval products. This Draft Guidance, withdrawn in 2015, outlines FDA’s historical intent to review submissions and provide comments in a timely manner, “usually within 15 working days of the day the materials are received by FDA.” While it is likely not reasonable to maintain this expectation given the volume of materials submitted, it begs the question:  if OPDP cannot review materials and/or provide comments within the thirty (30) day window for accelerated approval products, why bother requiring sponsors to submit their materials in advance in the first place? Just some food for thought.

States better get ready,
Rescheduling may be coming,
You may need to make changes,
You may need to do more,
Than just get on board.
(With apologies to Curtis Mayfield)

By the close of the public comment period for the Drug Enforcement Administration’s (“DEA’s”) proposal to reschedule marijuana two weeks ago, the agency had received over 43,500 comments.  Governors, state cannabis regulators, law enforcement groups and local governments weighed in, as did marijuana advocates and opponents, marijuana industry associations, Members of Congress, federal law enforcement groups, healthcare and human rights groups, unions and trade associations, and private individuals.  Comments ranged from single sentence declarations to lengthy, cogent treatises, expounding on whether to reschedule marijuana from schedule I to schedule III or another schedule under the federal Controlled Substances Act (“CSA”), to leave marijuana in schedule I, or to deschedule altogether.  Regardless of whether DEA holds a public hearing, the issue will not be resolved for some time.

Rescheduling or descheduling from the most stringent schedule under the CSA, should one of those actions occur, would loosen federal manufacturing, import/export, distribution, and security requirements.  Rescheduling out of schedule I would allow for the medical use of FDA-approved prescription drugs dispensed by DEA-registered, state licensed pharmacies pursuant to prescriptions issued by similarly DEA-registered, state licensed practitioners.

While DEA is the primary federal authority that enforces the CSA and its regulations, the states, commonwealths, and territories also regulate marijuana and other controlled substances within their borders.  What has been overlooked is how rescheduling or descheduling may impact how the states and the District of Columbia might have to regulate marijuana.

Every state has enacted its own controlled substances statutes and regulations, many of which mirror the federal CSA and DEA regulations.  While states regulate most controlled substances similarly to regulation at the federal level, DEA and the states often diverge with marijuana.  Marijuana has been in schedule I of the CSA, the most stringent schedule for substances of abuse, since 1970.  21 U.S.C. § 812(c)(c)(10).  Schedule I substances have a high potential for abuse, no currently accepted medical use in treatment in the U.S., and lack accepted safety for use under medical supervision.  21 U.S.C. § 812 (b)(1).  In the most recent eight factor analyses prior to August 2023, in 2016 HHS and DEA concluded that marijuana continued to meet criteria for remaining in schedule I.  Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).

The states, through their own controlled substance authorities, pharmacy boards, departments of health or legislatures schedule and impose regulatory requirements on substances of abuse and the legitimate entities that handle them.  Some states have authorities that regulate marijuana exclusively.  To date thirty-eight states authorize marijuana in different dosage formulations for specific qualifying medical conditions and twenty-four states authorize adult recreational use of marijuana.  Marijuana use remains illegal in a handful of states.

Depending upon the state, substances of abuse are scheduled, rescheduled or descheduled if, as under the federal CSA, they meet certain criteria.  State scheduling criteria, though differing by state, are also generally consistent with CSA criteria.  About half the states require the same eight factor scheduling analysis as the CSA, and while some states require analysis of additional factors, others require analysis of fewer factors.

States’ controlled substances acts generally mirror the federal CSA.  This internal mandate may conflict with the state’s current allowance of marijuana for medical or recreational uses.  Federal scheduling actions may automatically trigger a number of states to control the substance consistent with the federal CSA.  In some states the regulatory authority is required to take action within a certain period of time, say thirty or sixty days following the final scheduling notice appearing in the Federal Register, or the federal action becomes effective in the state.  Some of those states require a public hearing, after which the state publishes its decision to follow or not follow the federal scheduling action.  States required to automatically schedule, reschedule or deschedule based on what DEA does may lack the authority to schedule marijuana more independently.  A number of states have discretional scheduling authority not tied to federal scheduling.

The federal CSA does not preempt state law unless there is positive conflict between one of its provisions and state law such that they cannot stand together.  21 U.S.C. § 903.  DEA has historically taken the position that in conflicts between the CSA and state law, the stricter governs.

DEA rescheduling marijuana in either schedules II or III may not represent a big change for states that already authorize marijuana for medical use.  However, for states that allow for recreational use of marijuana, even federal rescheduling from schedule I to a less restrictive schedule may trigger a sea change and potential culture shift.

At least half of the states currently regulate marijuana as a schedule I substance under their controlled substances act.  Other states variously control marijuana as a schedule III (Minnesota), schedule VI (Arkansas, Massachusetts, North Carolina and Tennessee), schedule VIA (Alaska), or schedule Z (Maine).  There are some states that do not control marijuana, or they regulate it outside of their controlled substances act.

Were DEA to reschedule marijuana to schedule II or III, or leave it in schedule I, and the states regulate it in a less restrictive schedule or allow continued recreational use, how will the U.S. Department of Justice (“DOJ”) and DEA respond?  Will DOJ and DEA continue to exercise the enforcement discretion generally shown since the Cole Memo was issued in August 2013?  Merrick Garland may not be Attorney General if DEA takes scheduling action on marijuana, but if he is, he may have provided a clue during his confirmation.  He said at that time that it was not the best use of DOJ’s limited resources to prosecute those complying with laws in states that have legalized marijuana and are “effectively regulating marijuana.”  Merrick Garland, Responses to Questions for the Record to Judge Merrick Garland, Nominee to be United States Attorney General 24 (Feb. 28, 2021).  We wonder if the Cole Memo was a holding pattern of sorts until DOJ and DEA resolved the federal/state marijuana divide and having done so, determine that states are not “effectively regulating marijuana” if they regulate marijuana less restrictively.

Rescheduling or descheduling, should either occur, will likely not become effective anytime soon.  In the meantime, authorities should take stock of potential federal rescheduling ramifications by assessing and understanding how it may impact how they regulate marijuana their state.