As readers of this blog know, there is a lot of contention about the naming of alternative protein products (APPs), including both plant-based and cell-cultured alternatives for (traditional) animal products.  The animal product industry, particularly the beef industry and the dairy industry, has challenged naming of APPs using what they consider to be traditional meat terminology.

Many individual states have pursued some type of legislation to restrict the use of traditional meat terminology for the labeling of APPs.  Last November, Florida went further by introducing a bill to prohibit the manufacture, sale, and distribution of cell-cultured meat entirely.  Arizona’s House of Representatives passed a similar bill on February 22 of this year, which is now pending review by the State Senate. Many states have proposed but failed to enact legislation regulating the labeling of APPs, in some cases due to concerns of potential legal challenges based on federal preemption claims.  Language in both the Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA) explicitly states that requirements for marking, labeling, and ingredients in addition to or different from those required under the Acts may not be imposed by any state or territory.  Federal legislation that amends the FMIA and PPIA could sidestep many of the issues hampering state-level efforts in this arena.  On January 30, the U.S. Senate and House of Representatives introduced the Fair and Accurate Ingredient Representation (FAIR) on Labels Act of 2024, a bipartisan bill that would establish new labeling requirements for alternative meat and protein products and prohibit the use of certain meat-related terminology and imagery for such products.  For the traditional meat industry, APP industry, and consumers, one of the few points of agreement may perhaps be a preference to avoid a messy patchwork of potentially inconsistent state laws.  This particular federal legislative effort, however, continues the debate.

If enacted, the legislation would amend the FMIA and PPIA to establish definitions for “imitation” and “cell-cultured” meat and poultry products, and revise the definitions of “meat” and “poultry” to exclude such products.  We’ve previously blogged about this ongoing battle here, here, here, and here.  Spoiler alert: the FAIR on Labels Act brings the traditional and alternative protein industries no closer to “meating” in the middle.

Imitation Meat and Poultry

More specifically, the bill would define “imitation meat” and “imitation poultry” as any food that does not contain meat, meat food product, or meat byproduct ingredients (or poultry or poultry product), and:

1. uses a market name, descriptors, or iconography for, or is otherwise represented as, meat or meat food product (or poultry or poultry product);
2. is manufactured to appear as a meat or meat food product (or poultry or poultry product); or
3. approximates the aesthetic qualities (primarily texture, flavor, and appearance) or chemical characteristics of specific types of meat or meat food product (or poultry or poultry product).

The bill would require the labeling of any “imitation meat” or “imitation poultry” to (1) include “a disclaimer that clearly indicates that the imitation meat [or poultry] product is not derived from, or does not contain” meat or poultry, as applicable, and (2) display, in a prominent and conspicuous manner, in the same size and prominence as and immediately adjacent to the market name:

1. the word “imitation”; and
2. a statement that “the imitation meat [or poultry] is derived from sources other than meat [or poultry].”

The bill also includes a provision that bars the Secretary of Health and Human Services, the agency overseeing USDA and FDA, from providing for any exceptions to these requirements.

Cell-Cultured Meat and Poultry Products

The FAIR on Labels Act would define “cell-cultured meat product” and “cell-cultured poultry product” as “any product capable of use as human food that:

1. is made wholly or in part from any cell culture or the DNA of an amenable species [or live bird]; and
2. is grown or cultivated outside of the live animal [or live bird] from which the cell culture or DNA was acquired.”

The labeling of any cell-cultured meat and poultry products would be required to display the words “cell-cultured” or “lab-grown” in uniform type size and prominence as, and immediately adjacent to, the name of the food.

Who Gets to Bring Home the Bacon (and Other Terms)?

What’s in a name?  According to some, the terminology used to describe a product—particularly a novel product like cell-cultured meat—is critical to framing consumers’ perceptions of the product and, in turn, its success in the market.   It’s not surprising, then, that the FAIR on Labels Act has been most strongly supported by the traditional meat industry, from the National Cattlemen’s Beef Association—which petitioned USDA to restrict the use of meat and meat-related terminology to that which has been “harvested in the traditional manner”—to the National Chicken Council, the National Pork Producers Council, the American Sheep Industry, and other livestock trade groups.

Preventing consumer confusion is one of the chief arguments that the animal product industry uses in support of the bill.  We’ve certainly heard this line of reasoning before in litigation over APP labeling, but the relatively few examples of consumer litigation on the basis of deceptive or misleading labeling have rarely been successful.  Instead, the majority of such litigation have involved First Amendment challenges to state laws that restrict APPs’ access to traditional meat nomenclature.  In these cases, plaintiffs claimed, with varying degrees of success, that the use of traditional meat nomenclature (e.g., tofu burger) was not misleading.  Some plaintiffs also have successfully argued that the challenged state laws created confusion where none existed before.  APP proponents’ other arguments are captured in the Good Food Institute’s 2017 Citizen Petition to FDA, which requested regulations to clarify how foods may be named by reference to the names of other “traditional” foods (we previously blogged about this).

We will continue to monitor this bill and the legislative, administrative, and judicial developments with respect to this rapidly evolving issue.

Last Friday, the Delaware District Court rejected AstraZeneca’s lawsuit against the Medicare Drug Price Negotiation Program enacted under the Inflation Reduction Act (IRA) and CMS’s guidance implementing it. AstraZeneca, whose drug Farxiga was selected last September for negotiations for price applicability year 2026, claimed that the IRA violated AstraZeneca’s Fifth Amendment right to due process because it deprived the company of its investment-backed patent rights and common-law right to sell its products at market prices free from governmental constraints. AstraZeneca also claimed that CMS’s revised guidance on the Negotiation Program for Price Applicability Year 2026 (“Guidance”) interpreted the IRA in two very faulty ways, which violated the Administrative Procedure Act (APA) and harmed and will continue to harm the company.

In granting the Government’s summary judgment motion, the court held that AstraZeneca did not have the requisite standing for the APA arguments because it failed to identify a cognizable injury-in-fact that could be redressed by vacatur of the Guidance. The court also found that the company could not win on its Fifth Amendment argument because it did not have a protected property interest.

AstraZeneca’s APA Arguments on CMS’s Guidance

The majority of the court’s analysis revolved around AstraZeneca’s two APA claims. First, AstraZeneca alleged that CMS improperly defined a “qualifying single source drug” to include all dosage forms and strengths of the drug marketed by the manufacturer with the same active moiety or ingredient—even if those different forms and strengths were approved under different NDAs. Opinion at 17. According to AstraZeneca, the statute defines a qualifying single source drug by reference to its individual “approval,” and “any other reading . . . contradicts the plain text of the statute and therefore must be set aside.” Id.; see also 42 U.S.C. § 1320f-1(e)(1)(A). Second, AstraZeneca alleged that CMS’s requirement that a generic drug must be marketed in a bona fide way to be “marketed” under § 1320f-1(e)(1)(A)(iii) “impermissibly expanded the requirements” for a drug to be deemed to have generic competition in order to avoid selection and negotiation. Id. at 17-18. According to AstraZeneca, “the ordinary and accepted meaning of ‘marketing’ is ‘exposure for sale in a market,’ and if a generic drug is exposed for sale in any way or quantity, the reference brand drug cannot be a selected drug for negotiation under the Program.” Id. at 18.

But AstraZeneca did not, and could not, allege harm due to CMS’s selection of Farxiga: indeed, neither argument related to Farxiga, which is approved only under one NDA and has no generic versions marketed in any manner or quantity. Id. at 19-20. Instead, AstraZeneca alleged harm in four other ways. The court reviewed each argument in turn and in each case, found AstraZeneca unable to allege cognizable injury that could be redressed by vacatur of the Guidance. As a result, the court found that AstraZeneca did not have standing to assert its APA claims.

First, AstraZeneca claimed that CMS’s interpretation of a qualifying single source drug will decrease the company’s incentives to investigate additional uses of Farxiga’s single-ingredient active moiety. The court dismissed this argument holding that a loss or diminishment of an incentive to do something is not a concrete injury, and even if it was a sufficiently concrete injury, it was not “actual or imminent,” but only an allegation of possible future injury. Id. at 21-23. Moreover, the court found that the record showed a very low likelihood that AstraZeneca could get approval for a new indication with the same active moiety or ingredient and that it was not actively investigating drugs with only that active moiety. Even if the company did obtain approval, such approval would likely be after generic competition for Farxiga enters the market, in which case the definition of a qualifying single source drug would no longer apply to Farxiga.

Second, AstraZeneca claimed that the Guidance’s bona fide marketing test will cause it imminent injury in the form of simultaneous generic competition and mandatory pricing “for months” after generic versions of Farxiga enter the market. AstraZeneca argued that CMS’s bona fide marketing test, which is based on claims data, moves “at glacial pace” and can be delayed by numerous months. The court found numerous flaws with this argument. First, the Act has no requirement for CMS to “release” a selected drug from negotiations from the 2026 price simply because a generic is approved and marketed before or during 2026, so CMS’s bona fide marketing requirement could not have created an injury. Rather, the IRA requires a selected drug to remain selected for “each subsequent year beginning before the first year that begins at least 9 months after the date on which . . . at least one drug” has been approved and marketed. See id. at 28. Also, the IRA would subject Farxiga to the negotiated maximum fair price for the entirety of 2026 if no generic version entered the market before August 1, 2024, even if a generic drug later enters the market before or during 2026. Id. at 28-29. Because the alleged harm arises from the Act, not from the Guidance, the court found that AstraZeneca did not meet the causation or redressability elements of standing under this argument. To the extent that AstraZeneca alleged that CMS would cause it this type of harm in 2027, the court found that allegation to be too speculative. In any case, AstraZeneca did not address whether CMS’s “totality-of-the-circumstances” test (which involves more than just the claims data) would suffer from the same delays, and whether those delays will be greater than those under AstraZeneca’s proposed definition of “marketed.”

Third, AstraZeneca argued that its current decision-making about other drugs has been and will continue to be negatively affected by CMS’s Guidance. AstraZeneca argued it would very likely have products in future lists of drugs selected for negotiations. The court dismissed this alleged harm as too vague to establish a cognizable injury, and the argument as irrelevant given the fact that the allegedly violative Guidance only applies to the 2026 price applicability year.

Fourth, AstraZeneca argued that CMS’s erroneous interpretation of the statute has made it very difficult for the company to understand the real value of their product under CMS’s guidance and impaired its ability to make a counteroffer to the Government’s price offer. The court disagreed: AstraZeneca clearly understood how CMS’s guidance impacted the value of its product because it based its entire complaint on that impact. The court agreed that AstraZeneca faced uncertainty due to the instant lawsuit, but explained that the lawsuit cannot, by itself, be used to create standing.

Constitutional Challenge

AstraZeneca also alleged that the Negotiation Program violated the Constitution’s Fifth Amendment prohibition against depriving a person of property without due process of law. AstraZeneca claimed that the IRA deprived it of its “common law right to sell its products at market prices free from arbitrary and inadequately disclosed governmental constraints” by “directing [CMS] to fix prices at the ‘lowest’ level, without affording adequate procedural safeguards.” Id. at 42. AstraZeneca also alleged that the Program deprived the company of its property interest in “undefined ‘patent rights’ . . . and the revenue it derives therefrom . . . by compelling sales of its products at well-below market prices.” Id. at 42-43.

The court found that AstraZeneca did not have any protected property interest of which the IRA allegedly deprived it. According to the court, AstraZeneca’s “desire” or even “expectation” to sell its drugs to the Government at the higher prices it once enjoyed does not create a protected property interest.” Id. at 45. The court reasoned that no one is entitled to sell to the Government at prices the Government will not agree to pay. According to the court, because AstraZeneca has no legitimate claim of entitlement to sell its drugs to the Government at any price other than what the Government is willing to pay, the due process claim must fail as a matter of law. Id. The court also reiterated that neither the IRA nor any federal law requires AstraZeneca to sell its drugs to Medicare beneficiaries. “On the contrary, participation in the Medicare program is a voluntary undertaking.” Id. at 44.

The Road Ahead for the Negotiation

AstraZeneca is the first case to be decided among at least nine federal lawsuits brought by the pharmaceutical industry against the Negotiation Program (a tenth lawsuit brought by Astellas was withdrawn last fall; see list of cases in the chart below). In another case, the Southern District Court of Ohio denied a motion for preliminary injunction, but a decision on the merits is still pending. We expect decisions in the remaining cases in the upcoming weeks, and certainly before the maximum fair prices are published in September 2024.

On February 6, 2024, FDA issued a draft guidance titled Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act. The draft guidance provides recommendations for applicants and manufacturers about the requirements for notifications about production changes of certain finished drugs and biological products and certain active pharmaceutical ingredients (API), and outlines information FDA would like to receive in addition to the requirements.

Why?

Given the disruptions in supply that have continued to occur even beyond the end of the pandemic crisis, it is not surprising that FDA has issued a draft guidance on this subject. Early notification can play a role in decreasing the impact and duration of such supply disruptions and product shortages. Since the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, manufacturers have been required to notify FDA of product changes affecting certain finished drugs and biological products. In 2020, the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) expanded the notification requirement to include reasons contributing to the discontinuance or interruption (e.g., API and its source and any alternative sources; associated medical devices), and expected duration of the interruption.

Who?

The notification requirements under section 506C apply to:

• Applicants with approved new drug applications (NDAs) or approved abbreviated new drug applications (ANDAs) for certain finished drug products (see below for description of covered products);
• Applicants with approved biologics license applications (BLAs) for certain finished biological products other than blood or blood components;
• Applicants with approved BLAs for blood or blood components for transfusion that manufacture a significant percentage of the U.S. blood supply; and,
• Manufacturers of certain finished drug products marketed without an approved NDA or ANDA.

Others involved in the drug supply chain, such as third-party API manufacturers and suppliers, are not required to submit such notifications.

The notification requirements apply to each individual manufacturer regardless of market share, the number of competitors making therapeutically equivalent products, or the amount of product in distribution. FDA stresses, however, that the relevant analysis is whether a change in production is likely to lead to reduction in supply of a product by that manufacturer. The assessment is to be based solely on the reporting manufacturer’s capacity and supply without regard to other manufacturers’ capacity or market demand.

For purposes of these notification requirements, finished products are prescription drugs and biological products that are (1) life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, and (2) not radiopharmaceutical drug products or any other products specifically designated by FDA.

FDA considers a permanent discontinuance to be a manufacturer’s decision to stop manufacturing and distributing its product indefinitely. Interruptions are those where a production change is likely to lead to a meaningful disruption in the supply of the product or API such that it impacts the manufacturer’s ability to fill orders or meet demand.

When?

Applicants and manufacturers are required to notify FDA at least six months in advance of a permanent discontinuance of certain finished drugs or API for such products or an interruption in manufacturing that may cause a disruption in the supply of the drug or API.  If it is not possible to provide advanced notice, notification must be provided as soon as practicable.

For a permanent discontinuance or interruption in manufacturing of a covered finished product, the notification must be submitted no later than five business days after such production change in manufacturing occurs.

In all cases, FDA should be notified by manufacturers before their own supply of a finished product or API for those products is meaningfully disrupted (e.g., interrupted).

Manufacturers are urged to notify FDA even if the manufacturer is unsure whether manufacturing interruption could lead to a meaningful disruption in order to allow FDA to monitor the market and help or prevent any resulting shortage.

FDA stresses in the draft guidance that other notifications to the agency such as a field alert report or report of marketing status do not substitute for notifications of discontinuance or disruption.

It is worth noting that although not a requirement, FDA requests that manufacturers contact the Agency in instances when supply cannot meet demand for covered finished products. Doing so creates a signal to FDA about a potential shortage and allows the Agency to mitigate against the potential shortage.

A separate notification for each permanent discontinuance or interruption in manufacturing is expected. The initial notification may include a list of all affected covered finished products or API. Subsequent updates should not include a newly affected product (e.g., a new strength). A separate notification should be submitted to ensure that the newly affected product is tracked appropriately.

What?

Covered Finished Products

At a minimum, a notification for a permanent discontinuance or interruption in the manufacturing of a covered finished product must identify:

• Product name;
• Applicant name;
• Whether it is a permanent discontinuance of the product or an interruption in the manufacturing;
• Reason for the discontinuation or interruption;
• Estimated duration of the interruption;
• Whether an API is a reason for, or risk factor in, the discontinuation or interruption, and, if so, the API source and any alternatives; and,
• Whether a device used for preparation or administration is a reason for, or risk factor in, the discontinuation or interruption.

APIs

At a minimum, a notification for a permanent discontinuance or interruption in the manufacturing of an API must identify the reason for the discontinuation or interruption, API source and alternatives, and expected duration of the interruption.

For both covered finished products and APIs, FDA recommends including a laundry list of additional information, most of which many manufacturers will not object to sharing with FDA.

What if?

Failure to provide notification of a discontinuance or interruption to FDA potentially could, among other things, land a manufacturer on the Drug Shortages: Non-Compliance With Notification Requirement website.

FDA will send a letter to the manufacturer noting that the applicable notification requirement was not met (a noncompliance letter). The draft guidance states that if FDA determines that an applicant could not have reasonably expected a reportable interruption six months in advance but failed to notify FDA “as soon as practicable,” a noncompliance letter will be issued. The manufacturer has an opportunity to respond, and both the noncompliance letter and response letter(s) will be posted on the website unless FDA determines it was issued in error or determines the manufacturer had a reasonable basis for not meeting the notification requirement.

We note there have been seven instances where FDA has posted the noncompliance letter and response letter over the last eight years, suggesting that manufacturers have mostly self-reported any production changes in manufacturing of finished products or APIs, or this was not a priority for FDA.

Where to look

FDA communicates shortage information about drugs and biological products through public, daily updated lists (e.g., CDER shortages and CBER shortages).

A product is added to a list only after FDA has determined it to be in shortage. Conversely, if a shortage is resolved based on FDA’s market assessment, which considers whether all backorders have been filled and supply is either meeting or exceeding demand, affected market share, alternative manufacturers to cover demand, and confirmed market stabilization, the affected product is removed from the list.

FDA informs the public of both shortages and extended use dates to assist with drug shortages. By actively updating the information related to shortages, FDA intends to allow the public and prescribers to develop alternative treatment plans before learning a prescription cannot be filled at the pharmacy when there is a supply issue.

Hyman, Phelps & McNamara, P.C. (HP&M), is pleased to announce that Director Anne Walsh will be speaking at the DIA Advertising and Promotion Regulatory Affairs Conference. This essential event for regulatory professionals in the biopharmaceutical and medical device industries will take place March 12-13, 2024, in Arlington, VA. Ms. Walsh will contribute her extensive expertise in FDA regulatory matters to a session titled “Global Ad Promo and Enforcement Insights,” addressing the complex landscape of advertising and promotion compliance on a global scale.

Ms. Walsh, with over 26 years of experience in providing counsel to the pharmaceutical and medical device industries, will provide invaluable insights into global advertising and promotion regulations. Her deep understanding of FDA administrative actions alongside her proactive approach in helping companies prevent or respond to government investigations, makes her a pivotal voice in discussions on regulatory compliance. Before joining HP&M, Ms. Walsh served as an Associate Chief Counsel with the FDA’s Office of Chief Counsel, where she was recognized with several awards for her significant contributions.

The “Global Ad Promo and Enforcement Insights” session promises to highlight Ms. Walsh’s unique perspectives on navigating the challenges and opportunities presented by advertising and promotion regulations worldwide. Attendees can expect to gain practical strategies for compliance and enforcement, drawn from Ms. Walsh’s varied experience with global entities operating in this space and her proactive approach to regulatory affairs.

The DIA Advertising and Promotion Regulatory Affairs Conference is an unparalleled platform for professionals at all career stages, offering insights into regulatory policies, professional development strategies, and the latest trends in medical product advertising. Participants also will have the opportunity to network with key thought leaders from the FDA, industry, and other regulatory agencies, fostering a deeper understanding of the advertising and promotion regulatory framework.

FDA Law Blog readers can use the discount code 24SPKR150 for reduced registration fees.  For complete information on the conference, click here.

FDA’s proposed rule to regulate laboratory developed tests (LDTs) as devices took one more step towards publication as a final rule – and to a likely judicial showdown.  On March 1, the Office of Management and Budget (OMB) received the draft final LDT rule for review (here).

The LDT rule has moved forward with astonishing speed, advancing from the release of the proposed rule on October 3, 2023 to OMB in less than five months.  This stands in marked contrast to FDA’s prior efforts to regulate LDTs (see posts here, here, and here), and to the agency’s more typical, deliberate pace for rulemaking.  For comparison, it took FDA nearly two years from issuance to finalization of the proposed rule to harmonize the Quality System Regulation with international standards.

This extreme rapidity has been attributed to FDA’s desire to avoid having the rule being overturned by Congress under the Congressional Review Act.  Of course, if a new administration takes over next year, the rule’s future would be questionable, even without congressional action.

The speed of the LDT rule is even more astonishing in light of the nearly 7,000 comments that were submitted in response to the proposed rule. Under the Administrative Procedure Act (APA), the FDA is obligated to address all major substantive comments.  While some comments were duplicative or brief, others pointed out major flaws.  See for example our firm’s comments on the proposed rule (here). For  FDA to review and respond in a matter of months to comments that raised substantial issues about a major rule that would transform the laboratory industry is nothing short of breathtaking.  It seems unlikely that FDA would have made significant revisions and meaningfully addressed these concerns..  It remains to be seen whether FDA’s hasty review of these comments will provide additional fodder under the Administrative Procedure Act for failing to have adequately addressed major substantive comments.

With the release of the final rule by the Department of Health and Human Services to OMB, litigation is now virtually inevitable.  There had been some speculation that the release of the proposed rule would spur Congress to take action.  That hasn’t happened yet.  Given that Congress struggles to keep the government funded, it is far-fetched now to expect Congress to enact this complex legislation – especially since it has repeatedly failed to do so.  Congress has engaged in multiple attempts to pass the VALID Act (see posts here and here).

Barring unexpected action by OMB, we would expect the final rule to be published in the next few months.  And at that point, given the large number of laboratories and clinicians that will be adversely affected, it would be very surprising if FDA were not sued by one or more plaintiffs.  As we have previously noted, there are plenty of grounds for challenging any final rule that is released.  See our prior post here.

For years, lawyers have debated what the courts would do if FDA sought to regulate LDTs via a regulation.  It now appears that we will not have long to wait to find out.

The most recent version of  the BIOSECURE Act (the “Act”) was introduced in the U.S. House of Representatives (H.B. 7085) and Senate (S.B. 3558) on January 25, 2024. This proposed legislation should be of interest to any biotechnology companies that want to do business with the federal government in the future.

Background

Section 2 of the House Bill outlines some of the historical background that spurred Congressional action here, including national security risks highlighted by U.S. Departments of Defense (DoD) and Commerce actions against several specific Chinese biotechnology companies. An earlier version of the BIOSECURE Act was included in the House version of the FY24 National Defense Authorization Act (NDAA) but did not become law. Instead, the final NDAA directed the DoD to determine whether Chinese biotechnology companies should be identified as Chinese military companies operating in the United States.

On January 31, the DoD issued an updated list of Chinese military companies operating in the U.S., which did not include some of the Chinese companies specifically identified by Congress in prior and current versions of the BIOSECURE Act. On February 12, a bipartisan group of Senators and Representatives sent a letter to the Secretaries of Commerce, Defense, and Treasury, asking the Secretaries to consider adding WuXi-affiliates to various national security lists maintained by each of the agencies, including the DoD’s Chinese military list.  The Act is intended to address national security concerns by prohibiting certain conduct by regulated industry.

The Act

The Act would prohibit federal agencies from

(a) procuring or obtaining (or loaning or granting funds to procure or obtain) “biotechnology equipment or services” from any “biotechnology company of concern”;

(b) entering into a contract or extending or renewing a contract (or loaning or granting funds to do the same) with any entity that either

(i) uses biotechnology equipment or services from a biotechnology company of concern acquired after the effective date of the Act to perform the federal contract, or

(ii) enters into a contract with a third party that will require the direct use of biotechnology equipment or services from a biotechnology company of concern acquired after the effective date of the Act to perform the federal contract.

To state the inverse, the Act does not apply in cases where federal contractors do not use “biotechnology equipment or services” acquired from a “biotechnology company of concern” to perform the services under the contract—as each term is defined in the Act.

Biotechnology equipment includes genetic sequencers, mass spectrometers, polymerase chain reaction machines or any other equipment, components or accessories designed for the research, development, product, or analysis of biological materials as well as any software, firmware, or other digital components.

Biotechnology services include advising or consulting services related to the use of the above equipment, disease detection, or genealogical information, or any other service for the research, development production, analysis, detection, or provision of information including data storage and transmission related to biological materials.

The U.S. Office of Management and Budget (OMB) can also specify other equipment or services to be subject to the Act’s prohibitions.

Biotechnology companies of concern include BGI (formerly Beijing Genomics Institute), MGI, Complete Genomics, WuXi Apptec, and any subsidiary, parent, affiliate, or successor of such entities. Additionally, the OMB is directed to publish a list of additional biotechnology companies of concern within 120 days of enactment, which may include companies from “foreign adversaries” (i.e., China, Russia, Iran or North Korea).

Although the Act only applies to such equipment or services if they were acquired by the contracting entity after the “effective date” of the Act, which can differ depending on the source company of those equipment and services, it’s worth taking note of these potential provisions now. The planned prohibitions are effective for biotechnology equipment or services acquired from BGI, MGI, Complete Genomics, WuXi Apptec, and related entities 60 days after OMB issues guidance required under the Act (itself within 120 days of enactment of the Act). The prohibitions are effective for biotechnology equipment or services acquired from entities later added by OMB, 180 days after issuance of the above OMB guidance.

This guidance will be critical because the Act leaves open a number of key questions that would be important to compliance and changes to the FAR are not required until a year after the guidance—and therefore after the effective date.  The legislation may be revised, and the below is not an exhaustive list of our questions and concerns, but at present we have several observations and questions about how the Act may be implemented and potential consequences.

1. Scope Part 1—though the Act’s restrictions are seemingly limited to equipment and services that perform activities in relation to “biological materials”—a term that is not defined in the Act—the restrictions may still impact manufacturers of small molecule drugs or API that contract with third-parties using covered products or services as part of, e.g., various non-clinical testing in the development or manufacturing process.
2. Effect on FDA approvals—In cases where a biological product or drug needs to change aspects of its manufacturing processes to avoid using a covered equipment or service, will it need to file supplements with FDA for the CMC update?
3. Scope Part 2—Is reimbursement under Medicaid a grant of funds by the federal government, such that they are governed by the Act? In this regard we note that Medicaid is described in federal regulations as “Federal grants to States for medical assistance.”  See, e.g., 42 CFR § 430.0.

Conclusion

Although the BIOSECURE Act has not been passed by Congress (or signed by the President), its sponsors are expected to push for its inclusion in the FY25 NDAA or as part of other omnibus legislative packages that arise this year. Given the bipartisan attention that Chinese national security risks have garnered in recent years, biotech companies would be well advised to consider the potential impact this legislation could have on existing and future federal contracts. HPM will continue to monitor developments related to the Act.

Earlier this week, we posted Part 1 of our three-part series on U.S. Patent and Trademark Office (“PTO”) Patent Term Extension (“PTE”) decisions under 35 U.S.C. § 156, as added by the 1984 Hatch-Waxman Amendments, for certain FDA-regulated products.  Part 1 focused on both the PTO’s historical and current (180-degree and unsupported change in position) on multiple PTEs.

Today, we move on to Part 2 (or “Part Deux” in homage to the 1993 comedy “Hot Shots! Part Deux,” which starred Lloyd Bridges, who also starred in the 1980 movie “Airplane!” referenced in Part 1 of our series) concerning the PTO’s position and recent decisions on PTE applications for patents covering products approved—and then withdrawn years later—under the Federal Food, Drug, and Cosmetic Act’s (“FDC Act’s”) Accelerated Approval provisions (as well as the Agency’s corresponding regulations, which actually preceded the statutory provisions).  As FDA explains on its website (which includes lists—here and here—of the more than 300 Accelerated Approvals (and withdrawals)):

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint.  A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.

Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.  If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

The statutory Accelerated Approval provisions were amended in 2023 as part of the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) to, among other things, give FDA greater authority to expedite the withdrawal of approval of an Accelerated Approval product if clinical benefit is not confirmed post-NDA or -BLA approval.  For more on those amended provisions, see our FDORA Summary here.

Part 2:  Accelerated Approval Withdrawals and the End of the PTE Road

Last week, FDA announced that, for the first time, the Agency flexed its new FDORA-enhanced Accelerated Approval muscle when issuing a final decision to withdraw the approval of Oncopeptides AB’s  (“Oncopeptides’s”) PEPAXTO (melphalan flufenamide) for Injection.  FDA approved PEPAXTO on February 26, 2021 under NDA 214383 for use in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.

As part of the Accelerated Approval, Oncopeptides was required to conduct “further adequate and well-controlled clinical trials to verify and describe clinical benefit.”  That did not happen.  FDA’s February 23, 2024 decision says that “the grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use.

We note all of this FDA law in the context of a patent-related PTE post because FDA’s withdrawal decision has ramifications beyond the FDA world.  You see, Oncopeptides has has pending at the PTO since March 2021 a PTE application for U.S. Patent No. 6,992,207 covering PEPAXTO (Docket No. FDA-2022-E-3124).  And given recent PTO PTE decisions, it may be the end of the road for this PTE application.

Although we don’t know for sure how far back this apparently new effort goes (the precedents we know of are all from 2023), the PTO has—as quiet as a mouse peeing on cotton, as my mother might say—taken the position that once FDA withdraws approval of an NDA or BLA under the Accelerated Approval program (or otherwise!), that action nullifies any pending PTE application.  (Whether withdrawal also nullifies any already-granted PTE is a separate question folks can ponder.)  Consider, for example, the following four PTO decisions we unearthed.

On April 14, 2023, the PTO issued an ORDER TO SHOW CAUSE to Eli Lilly and Company (“Lilly”) “based on the apparent ineligibility of U.S. Patent No. 8,128,929 [] for [PTE] request under 35 U.S.C. § 156.”  The PTE application for U.S. Patent No. 8,128,929 was submitted on December 8, 2016 (Docket No. FDA-2017-E-5106), and concerns FDA’s October 19, 2016 Accelerated Approval of BLA 761038 for LARTRUVO (olaratumab).  The PTO’s ORDER TO SHOW CAUSE points out that:

According to the published Federal Register Notice of July 17, 2020, Lilly requested withdrawal “(revocation)” of its BLA for the human biological product LARTRUVO® (olaratumab).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Lilly waived its opportunity for a hearing.

From there, the PTO notes that a PTE “determination is made based on the representations contained in the PTE application,” and that “35 U.S.C. § 156(c) provides ‘[t]he term of a patent eligible for extension under subsection (a) shall be extended by the time equal to the regulatory review period for the approved product which period occurs after the date the patent is issued.’” (Emphasis in original).  Then comes the PTO’s requirement to show cause:

Since there is no longer an approved product, Lilly is required to show cause with regard to its PTE application for LAR TRUVO® ( olaratumab) and establish: (1) why the USPTO should not terminate the PTE application based on the plain language of 35 U.S.C. § 156(c); and (2) why the PTE application for the ‘929 patent should remain under consideration despite Lilly’s express written request of withdrawal (revocation) of BLA-761038 and waiver of the opportunity for a hearing.  In responding to the show cause request, Lilly should identify statutory language in 35 U.S.C. § 156 or case law that would support extension of the ‘929 patent that claims the product despite revocation of the biologics license application. Moreover, Lilly should explain how a PTE application for a withdrawn “revoked” biologics license application is in compliance with requirements of 37 C.F.R. § 1.740.

According to documents in the PTO’s Patent Center, Lilly has not yet filed a response.

Our second example follows the same pattern as the first example above.  On April 20, 2023, the PTO issued an ORDER TO SHOW CAUSE to Glaxo Group Limited (“Glaxo”) “based on the apparent ineligibility of U.S. Patent No. 9,273,141 [] for [PTE] request under 35 U.S.C. § 156.”  The PTE application for U.S. Patent No. 9,273,141 was submitted on September 18, 2020 (Docket No. FDA-2020-E-2275), and concerns FDA’s August 5, 2020 Accelerated Approval of BLA 761158 for BLENREP (belantamab mafodotin-blmf).  The PTO’s ORDER TO SHOW CAUSE points out that:

According to the published Federal Register Notice of March 30, 2023, Glaxo requested withdrawal “(revocation)” of its BLA for the human biological product BLENREP® (belantamab mafodotin-blmf).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Glaxo waived its opportunity for a hearing.

From there, the PTO conveys the same message to Glaxo as it did with Lilly above.  But in this case, there’s a response on file from Glaxo pushing back on the PTO’s position and taking the position that a PTE in this case “is mandatory and not discretionary.”

Our third example also follows the same pattern as the first two examples above.  In addition, it’s playing double duty for us because it’s also one of the pending multiple PTE cases we identified in Part 1 of this series.  On June 27, 2023, the PTO issued two ORDER TO SHOW CAUSE letters (here and here) to Gilead Sciences Inc.  (“Gilead”) “based on the apparent ineligibility of U.S. Patent No. RE 44,599 [and U.S. Patent No. RE 44,638] for [PTE] request under 35 U.S.C. § 156.”  The four PTE applications for U.S. Patent Nos. RE 44,599 and RE 44,638 were submitted nearly ten years ago (a point not lost on Gilead as noted below), on September 17, 2014 (Docket Nos. FDA-2015-E-2602, FDA-2015-E-2604, FDA-2015-E-2619, and FDA-2015-E-2615), and concern FDA’s July 23, 2014 Accelerated Approval of NDA 205858 and NDA 206545 for ZYDELIG (idelalisib) Tablets for different uses.  The PTO’s ORDER TO SHOW CAUSE letters point out that:

According to the published Federal Register Notice of May 26, 2022, Gilead requested withdrawal “(revocation)” of its active ingredient ZYDELIG® (idelalisib).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Gilead waived its opportunity for a hearing.

From there, the PTO conveys the same message to Gilead as it did to Glaxo and Lilly above.  But in this case, as with Lilly, there are responses (here and here) on file from Gilead with respect to each ORDER TO SHOW CAUSE letter.  And Gilead takes the PTO to town(!):

As described below, Applicant believes that the Order rests on a basic factual error regarding the approval status of ZYDELIG (idelalisib) oral tablets (100 and 150 mg). In particular, the Order incorrectly states that [FDA] withdrew approval of ZYDELIG (idelalisib) in May 2022.  In fact, FDA withdrew approval of two of the three indications for which ZYDELIG (idelalisib) had initially been approved. ZYDELIG (idelalisib) remains approved for use “in combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.”  On this basis, the pending applications for [PTE] should not be terminated, and Applicant respectfully requests that the USPTO promptly issue a final determination on the pending applications.

In addition, Applicant would like to take this opportunity to address several issues raised by the Order.  First, the Order repeatedly characterizes the Accelerated Approval pathway as “conditional” or otherwise short of final approval.  This characterization represents an incorrect interpretation of the eligibility requirements for patent term extension under 35 USC 156.

Finally, Applicant respectfully requests that the USPTO promptly issue a final determination on the pending PTE applications related to ZYDELIG (idelalisib).  These applications have been pending for more than nine years. There is no apparent justification for such delay, particularly where the USPTO has granted dozens of patent term extensions based on products approved – and PTE applications submitted- more recently than ZYDELIG (idelalisib).

Ouch!  Since then, there’s no record of the PTO responding.  As Lt. Frank Drebin of Police Squad once said: “The truth hurts, doesn’t it, Hapsburg?  Oh sure, maybe not as much as landing on a bicycle with the seat missing, but it hurts!”

Our fourth example ties in our Part 1 post and the references to BELVIQ (lorcaserin HCl) Tablets (NDA 022529; approved on June 27, 2012) and the Improving Regulatory Transparency for New Medical Therapies Act (“IRTNMTA”), with the PTO’s December 21, 2023 ORDER TO SHOW CAUSE “based on the apparent ineligibility of U.S. Patent No. 6,953,787 [] for [PTE] request under 35 U.S.C. § 156.”  That PTE application was submitted to the PTO on July 26, 2012.  While that’s quite a while ago, the file was complicated by a fight over the IRTNMTA (see our previous post here).

In any case, the PTO’s December 21, 2023 ORDER TO SHOW CAUSE, unlike the two cases above, goes outside of the Accelerated Approval withdrawal context.  It follows a February 13, 2020 request from the sponsor of BELVIQ that FDA withdraw approval of BELVIQ, a September 17, 2020 FDA Federal Register Notice withdrawing approval of BELVIQ (effective September 17, 2020), and a March 4, 2021 Federal Register Notice in which FDA determined that BELVIQ was withdrawn from sale for safety or effectiveness reasons.  According to the PTO:

Since there is no longer an approved product, Eisai as authorized entity acting on behalf of the PTE Applicant, Arena, is required to show cause with regard to its PTE application for BELVIQ® (lorcaserin hydrochloride) and establish: (1) why the USPTO should not terminate the PTE application based on the plain language of 35 U.S.C. § 156(c); and (2) why the PTE application for the ’787 patent should remain under consideration despite the express written request of withdrawal (revocation) of the active ingredient BELVIQ® (lorcaserin hydrochloride) and waiver of the opportunity for a hearing. In responding to the show cause request, Eisai should identify statutory language in 35 U.S.C. § 156 or case law that would support extension of the ’787 patent that claims the product despite revocation of the active ingredient. Moreover, Eisai should explain how PTE application for a withdrawn “revoked” of active ingredient BELVIQ® (lorcaserin hydrochloride) is in compliance with requirements of 37 C.F.R. § 1.740.

In a February 16, 2024 response to the PTO’s ORDER TO SHOW CAUSE, “Applicant submits that the PTE statute (35 U.S.C. § 156) does not condition the right to an extension on the continued approval of a drug product during pendency of a PTE application,” and that the “patent should remain under consideration for PTE, and Applicant’s second interim extension request should be granted, despite the fact that FDA’s approval for BELVIQ has been withdrawn.”

Based on the above documents, the PTO is in for a fight on negating PTE for products withdrawn under the Accelerated Approval withdrawal procedures, and where FDA determines that a product is withdrawn for safety or effectiveness reasons.  But one must wonder whether or not the PTO—absent failing in its current efforts—will go one step farther and seek to negate PTE applications when approval of a product is withdrawn outside of the Accelerated Approval or safety/effective circumstances above.  That is, when the application holder voluntarily requests withdrawal of approval for no particular reason.  After all, as Mama Karst is fond of saying: “Why do a job half-assed when you can do it whole-assed?”  To that end, one can almost picture someone at the PTO sitting back in his/her office poring over FDA Federal Register notices withdrawing application approvals and comparing them to long-pending PTE application files.  And with the unbelievable lag-time from PTE application submission to PTE grant, there may be a lot of candidates to choose from.

On Friday, February 23, 2024, FDA announced its final decision to withdraw the approval of Pepaxto (melphalan flufenamide), which was approved in February 2021 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.  This is the third withdrawal of an accelerated approval FDA has performed, following Avastin in 2011 and Makena in 2023.  Notably, this decision marks the first use of the new expedited procedures for withdrawal of an accelerated approval that were enacted in the Food and Drug Omnibus Reform Act of 2022 (FDORA).  Prior to FDORA’s enactment, the statute did not provide details on the withdrawal procedures other than offering an opportunity for an informal hearing.

Without commenting on the merits of the decision, it is an interesting window into how FDA may use these new procedures in practice.  All in all, the new expedited procedures took about 7 months from proposal to withdrawal.  In contrast, the two previous withdrawals, Makena in 2023 and Avastin in 2011, took 30 months and 11 months, respectively.

The Pepaxto NDA, which was submitted by Oncopeptides AB (Oncopeptides), was approved based on overall response rate (ORR) and duration of response (DOR) in a subpopulation of subjects with RRMM who had received 4 prior lines of therapy and whose disease was refractory to one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody (reflective of the approved population) in a single-arm Phase 2 study.  As the approval was granted using the accelerated approval pathway, the approval was subject to a postmarketing requirement to verify and describe the clinical benefit of the drug in a Phase 3 trial.  The confirmatory trial was to have a primary endpoint of progression-free survival (PFS) and secondary endpoints including ORR and overall survival (OS).

Oncopeptides subsequently conducted a randomized, controlled Phase 3 trial comparing Pepaxto and dexamethasone to pomalidomide and dexamethasone.  This trial did not meet its primary endpoint of improvement in PFS using the pre-specified analysis and appeared to show a detrimental effect on OS.  In September 2022, CDER convened a meeting of the Oncology Drugs Advisory Council (ODAC), which voted 14-2 that the benefit-risk profile of Pepaxto was not favorable for the indicated population.

In December 2022, FDORA was enacted.  Among other things, it revised the provisions relating to accelerated approval at 21 U.S.C. § 356(c) to describe specific expedited procedures to withdraw an accelerated approval if certain conditions are met, including where a required confirmatory study fails to verify and describe the predicted clinical benefit or where evidence demonstrates the product is not shown to be safe or effective under the conditions of use.  The new procedures include the provision of due notice and an explanation for a proposed withdrawal, an opportunity for a meeting with the Commissioner or the Commissioner’s designee, an opportunity for a written appeal, an opportunity for public comment, and the convening of an advisory committee if requested and no such committee had previously advised FDA on the relevant issues.  However, the timelines for these procedures were not specified by the law.  FDORA also directed FDA to issue draft guidance on the topic of the new expedited procedures for withdrawal of accelerated approval not later than 18 months following enactment and a final guidance 1 year after the close of the public comment period on the draft guidance.  FDA has not yet published draft guidance; however, the statutory deadline to do so is June 2024.

On July 7, 2023, armed with these new procedures, CDER notified Oncopeptides that it proposed expedited withdrawal of Pepaxto because the postapproval study failed to verify clinical benefit and because Pepaxto was not shown to be safe or effective under its conditions of use (the documents discussed herein are published in the docket here).  As dictated by FDORA, the notice offered the opportunity for a meeting and/or written appeal, which the notice stated should be submitted within 30 days.  The notice explained that if Oncopeptides decided to appeal the proposal to withdraw, there would be an opportunity for public comment.  It also stated that, since the ODAC had already met to discuss the relevant issues, Oncopeptides was not entitled to another advisory committee meeting.  If Oncopeptides decided not to appeal, the notice encouraged the company to request a voluntary withdrawal of approval and to waive the procedural options in the new statutory language.  Moreover, if Oncopeptides did not respond within 15 business days either requesting voluntary withdrawal of approval or notifying FDA of its intent to submit a written appeal, FDA would deem Oncopeptides to have waived the new procedures.  The notice was accompanied by a detailed explanation of the justification for CDER’s determination, as required by FDORA, drafted by the review division to the CDER Director, Dr. Patrizia Cavazzoni.

Before the 15-business day window expired, Oncopeptides submitted a notification to FDA of its intent to file a written appeal within 30 days of receipt of the original notification.  Additionally, Oncopeptides requested a meeting with the Commissioner or the Commissioner’s designee.  In response, Commissioner Dr. Robert Califf designated CBER Director, Dr. Peter Marks, to serve as the Commissioner’s designee for both the appeal and the opportunity for a meeting.

On August 4, 2023, Oncopeptides submitted its appeal.  In an August 9, 2023, letter, Dr. Marks notified both CDER and Oncopeptides of the documents, including CDER’s notice and explanation and Oncopeptides’s appeal document, that would be submitted to the to-be-opened docket with the required notice for public comment on the proposed withdrawal.  Dr. Marks also requested that CDER submit a response to Oncopeptides’s appeal by September 8, 2023, and stated that his team would work to coordinate a meeting with the parties following this response.

On September 8, 2023, CDER submitted its response.  The next document in the docket is a letter from Dr. Marks referring to an upcoming October 2, 2023, joint (virtual) meeting with CDER and Oncopeptides.  The letter described the mechanics and timing of the meeting, laying out a 2-hour agenda, with 50 minutes dedicated to a presentation by Oncopeptides.  The parties submitted additional arguments prior to the meeting that were posted in the docket.  Additionally, the docket contains the slides that were used by CDER and Oncopeptides during the meeting.  The docket also contains a brief summary of the meeting.

On February 23, 2024, Dr. Marks issued his final decision, which concluded that the grounds for withdrawing approval were met.  The justification for his decision was that the confirmatory study did not confirm clinical benefit, and the available evidence demonstrated that Pepaxto was not shown to be safe or effective under its conditions of use.  Either of these conditions would be sufficient grounds for withdrawal of the approval.  A section of the final decision letter addressed a proposal made by Oncopeptides that Pepaxto remain on the market, potentially with a narrower indication, while further studies were conducted.  Dr. Marks’s letter cited the previous experience with Avastin’s withdrawal in determining that this was contrary to legislative intent.  Moreover, the letter noted that whether Pepaxto was safe and effective for a narrower indication was outside the scope of the statutory basis for withdrawing accelerated approval; the question was whether it should remain on the market as currently approved and labeled.

With FDORA in place and designed to provide a structured and expedited process for withdrawal of an accelerated approval, it is a safe bet that this is not the last we will see of this process.  However, FDORA left a lot to FDA interpretation, and with the deadline for the draft guidance several months away, this case may provide a window into FDA’s thinking.  For example, in deciding this appeal, Dr. Marks ultimately combined the meeting and the written appeal into a single process.  In theory, a company may request one or the other, but it appears reasonable that we would see this in the future.  The table below may also provide a guide for timing for a future appeal.  Of note, the fact that Oncopeptides was not eligible for an additional advisory committee meeting likely made this process faster than it might otherwise have been.

Timeline of Key Events

*FDA’s deadline was 15 business days

**FDA’s deadline was 30 days

It’s been a while since we last blogged on Patent Term Extension (“PTE”) issues of interest.  And with 2024 (September 24th) being the 40th anniversary of the enactment of the 1984 Hatch-Waxman Amendments—the statute that amended Title 35 of the United States Code to create PTEs for certain FDA-regulated products—and a recent spate of PTE-related items posted on regulations.gov, we thought we would peruse some decisions to see what’s up at the Patent and Trademark Office (“PTO”) PTE-wise.  Well, we found much more than we thought we would.  And some of our finds left us asking if the PTO has taken on the role of Dr. Rumack (Leslie Nielsen) in the 1980 movie “Airplane!”.  But all kidding aside, some of the recent decisions we found are rather distressing.

Our last two PTE-related posts concerned the issues of: (1) multiple PTEs—a topic we blogged on in 2020, but that we have been following since the very early days of the FDA Law Blog in 2008 and 2009 (see our previous posts here, here, and here)—and (2) the Improving Regulatory Transparency for New Medical Therapies Act (“IRTNMTA”)—a topic we blogged on in 2022, and that was enacted to, among other things, address controlled substance scheduling issues that arose with BELVIQ (lorcaserin HCl) Tablets (NDA 022529; approved on June 27, 2012) (see our previous posts here and here) and that ended up raising some PTE issues.

We will start this post—Part 1 of a three-part series over the next several days—with one of the PTE topics we last posted on (i.e., Multiple PTEs), then move on to the second topic (which involves BELVIQ, among other drug products, and that we’ll call “Accelerated Approval Withdrawals and the End of the PTE Road”), and end with a third topic that will surely (or is that Shirley?) leave you scratching your head (we’ll call it “Who’s Buried in Grant’s Tomb?”).

Part 1:  Multiple PTEs

Under the PTE statute at 35 U.S.C. § 156, a patent may be extended only once (even if it would be eligible for extension on more than one occasion because it applies to several FDA-approved products), and only one patent may be extended for each regulatory review period.  To that end, 35 U.S.C. § 156(c)(4) states that “in no event shall more than one patent be extended under subsection (e)(1) for the same regulatory review period for any product” (emphasis added).  This led one commentator—Federal Circuit Judge Alan David Lourie—to speculate shortly after enactment of the Hatch-Waxman Amendments that a second patent could be extended for a second regulatory review period for the same product. See Lourie, Patent Term Restoration: History, Summary, and Appraisal, 40 Food, Drug, and Cosm. L.J. 351, 355-56 (1985).

For years after the enactment of the Hatch-Waxman Amendments the PTO interpreted the PTE statute to permit multiple PTEs, provided there are separate, but not necessarily different, regulatory review periods.  This means that there multiple same-day FDA NDA approvals for the same drug.  For example, the PTO has granted multiple PTEs with respect to pregabalin (LYRICA) (U.S. Patent No. 6,001,876 with respect to NDA 021446 and U.S. Patent No. 6,197,819 with respect to NDA 021723); cefdinir (OMNICEF) (U.S. Patent No. 4,559,334 with respect to NDA 050739 and U.S. Patent No. 4,935,507 with respect to NDA No. 050749); brentuximab vedotin (ADCETRIS) (U.S. Patent No. 7,829,531 with respect to BLA 125399 and U.S. Patent No. 7,090,843 with respect to BLA 125388), and alogliptin (U.S. Patent No. 6,329,404 with respect to NDA 022426 for OSENI (alogliptin and pioglitazone) Tablets, U.S. Patent No. 8,288,539 with respect to NDA 203414 for KAZANO (alogliptin and metformin HCl) Tablets, and U.S. Patent No. 8,173,663 with respect to NDA 022271 for NESINA (alogliptin) Tablets – see our previous post here).

FDA also approved two NDAs on the same first day for micafungin (MYCAMINE)—NDA 021506 for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation, and NDA 021754 for the treatment of esophageal candidiasis.  In that case, the NDA sponsor applied for two PTEs based on these approvals—one for either U.S. Patent Nos. 5,376,634, 6,265,536, or 6,107,458 for NDA  021506, and one for either of these same patents for NDA 021754—but ultimately decided not to elect a second PTE.  A similar decision was made with respect to lacosamide (VIMPAT).  In that case, the NDA sponsor applied for two PTEs based on the same-day approvals of NDA 022253 and NDA 022254 and with respect to U.S. Patent No. RE 38,551 and U.S. Patent No. 5,654,301.  The sponsor ultimately decided not to elect a second PTE. (As an aside, the PTO has also granted multiple interim PTEs under 35 U.S.C. § 156(e)(2), but has denied multiple interim PTEs under 35 U.S.C. § 156(d)(5) (see our prior post here.)

Despite a rather long history of granting multiple PTEs, in 2020, in an about-face, the PTO took the position that multiple PTEs are no longer supported by the statute.  In several letters to applicants, each styled as a REQUIREMENT FOR INFORMATION PURSUANT TO 37 C.F.R. § 1.750, the PTO takes the position that “Section 156 does not allow for multiple extensions of patents beyond the one patent per one approved product.”  See, e.g., Letter from PTO to FDA CDER, Docket No. FDA-2020-E-1840 (July 13, 2020).  These determinations were finalized in 2021.  See, e.g., Letter from PTO  to FDA CDER, Docket No. FDA-2020-E-1840 (Mar. 25, 2021) (“[U]nder the plain statutory language of 35 U.S.C. § 156 and interpretive case law, if an applicant for patent term extension has multiple NDA approvals of a product, PTE applicant can only rely on ‘a’ (single) regulatory review period for a first permitted commercial marketing or use of a product to establish the requirements for patent term extension.  That is, pursuant to § 156, there cannot be more than one ‘first permitted commercial marketing or use’ of the product.”).

The PTO’s not-even-specious-argument, citing what certainly appears to us to be absolutely irrelevant case law, such as Novartis AG v. Ezra Ventures LLC, 909 F.3d 1367 (Fed. Cir. 2018), Arnold Partnership v. Rogan, 246 F. Supp. 2d 460 (E.D. Va. 2003), and Biogen lnt’l v. Banner Life Sciences LLC, 956 F.3d 1351 (Fed. Cir. 2020), has not yet—and to our surprise—ended up in court.  But there are still a couple of possibilities lurking out there!

The first multiple PTE case up-to-bat concerns Gilead Sciences Inc.’s idelalisib (ZYDELIG) tablets, which FDA approved on July 23, 2014 under NDA 205858 (for relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies) and under NDA 206545 (for relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities).  In September 2014—nearly ten years ago!—PTE applications were submitted to FDA for each of U.S. Patent No. RE 44,599 and U.S. Patent No. RE 44,638 and with respect to each NDA approval,  See FDA Docket Nos. FDA-2015-E-2602, FDA-2015-E-2604, FDA-2015-E-2619, and FDA-2015-E-2615.

Earlier this month, the PTO issued a REQUIREMENT FOR INFORMATION PURSUANT TO 37 C.F.R. § 1.750 with respect to the multiple PTE applications for each of U.S. Patent No. RE 44,599 and U.S. Patent No. RE 44,638 (here and here).  The issue, of course, is the legitimacy of multiple PTEs.  Thus, the PTO states:

The issue is whether 3 5 U.S.C. § 156 permits a patent owner who owns more than one patent to obtain more than one patent term extension for the same FDA approved product.  Applicant has filed multiple PTE applications directed to the same product (idelalisib ).  If applicant contends that more than one patent may be extended based on the approval of idelalisib, then applicant is required to provide legal support pursuant to 35 U.S.C. § 156, expressly demonstrating that the statute permits multiple term extensions based on the same product.  Absent a convincing showing, the Office after considering all of Applicant’s argument plans to issue only one PTE directed to ZYDELIG® (idelalisib).

Despite the PTO’s request, the Office makes its position clear later on in the letter, citing to the same cases identified above (and with a footnote addressing past precedent):

Section 156 does not allow for multiple extension of patents beyond the one patent per one approved product. The regulatory review period of ZYDELIG® (idelalisib) can be used as a basis for extension of only one patent.  See 3 5 U.S.C. § l 56(c)(4) and 37  C.F.R. § 1.785(b).  Therefore, the Office plans to limit applicant to extending only one patent for the approved product (idelalisib).

The Office acknowledges that in the past it has permitted more than one extension when multiple forms of administration of the same drug product were applied for and approved by the FDA on the same day. However, the Office believes that the proper interpretation of the statute, especially in light of recent court decisions discussed in this requirement for information mandates that only a single patent be extended for any given drug product, regardless of the number of forms of administration approved by the FDA.

We’ll be keeping out eye out for the applicant’s response to the PTO’s request.

The second multiple PTE case brewing concerns FoldRx’s (a wholly owned subsidiary of Pfizer, Inc.) tafamidis, which FDA approved on May 3, 2019 as VYNDAMAX (tafamidis) Capsules under NDA 212161, and as VYNDAQEL (tafamidis meglumine) Capsules under NDA 211996—both approved for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. Two PTE applications were submitted to FDA (See FDA Docket Nos. FDA-2022-E-3123 and FDA-2022-E-3120) with respect to U.S. Patent Nos. 7,214,695 and 7,214,696.

On February 8, 2024—the same day the PTO requested information with respect to the multiple PTE applications for idelalisib—the FDA sent a letter to the PTO in response to the PTE applications for U.S. Patent Nos. 7,214,695 and 7,214,696 and a PTO request for information as to the first permitted commercial marketing prong of the PTE statute.  According to FDA:

USPTO has requested information about whether the FDA first approved VYNDAMAX (NDA 212161, tafamidis) or VYNDAQEL (NDA 211996, tafamidis meglumine).  Our records indicate that the two NDAs were received for review at the same time and were approved concurrently in the same approval action.  Consequently, because both applications were approved at the same time, both applications represent the first permitted commercial marketing or use of the product or the individual active ingredients, as outlined under 35 U.S.C. sections l56(a)(5) and 156(f)(1).

NDA 212161 and NDA 211996 were approved concurrently on May 3, 2019, at 6:13 pm, which makes the submission of the patent term extension applications on June 27, 2019, timely within the meaning of 35 U.S.C l56(d)(1).

Oh-oh!  Another case of same-day (and same-time) FDA approvals!  It’s another possible set-up to challenge the PTOs 180-degree position change on multiple PTEs.  But before the multiple PTE issue can be addressed, there’s another interesting issue lurking here that needs to be resolved first.

The PTE statute defines the term “product” to mean “drug product,” and the term “drug product” is defined to mean “a new drug, antibiotic drug, or human biological product (as those terms are used in the [FDC Act] and the Public Health Service Act). . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.”  35 U.S.C. § 156(f)(2).  For several years, the PTO interpreted the term “product” to mean “active moiety” rather than “active ingredient” (i.e., the ion or molecule, excluding salts, esters, etc., responsible for the pharmacological action of a drug, instead of the ion or molecule including salts, esters and other derivatives).  In PhotoCure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010), however, the U.S. Court of Appeals for the Federal Circuit interpreted the term “product” in the PTE statute to mean active ingredient rather than active moiety.  Post-Photocure, the PTO has framed PTE eligibility as a three-part inquiry: (1) Has the active ingredient been previously approved?; (2) Has a salt of the active ingredient been approved?; and (3) Has an ester of the active ingredient been approved?  A “yes” to any of these questions means that permission does not meet the first permitted commercial marketing prong of the statute.

VYNDAQEL (NDA 211996) contains tafamidis meglumine, an organoammonium salt obtained by combining tafamidis with one molar equivalent of 1-deoxy-1-(methylamino)-D-glucitol, whereas VYNDAMAX (NDA 212161) contains the tafamidis base.  Which approval came first (if any)—a bit of a “Which came first, the chicken or the egg?” issue—could affect PTE eligibility as a foundational issue.  While FDA has confirmed date and time stamps in the past for PTE purposes (for example in the 2020 case of U.S. Patent No. 8,327,844 for XHANCE (fluticasone propionate) (here)), we’ve never seen such determinations come down to seconds on the clock.

. . . . Part 2 (Accelerated Approval Withdrawals and the End of the PTE Road) coming soon . . . .

Hyman, Phelps & McNamara, P.C. (HP&M) proudly announces that Director Anne Walsh will be a featured panelist at the highly anticipated 2024 Women’s White Collar Defense Association (WWCDA®) Leadership Retreat and Annual Attorney Meeting. The event is set to take place from March 4-6, 2024, in San Francisco, California. This annual gathering, renowned for its influential speakers and dynamic networking opportunities, will see Ms. Walsh among an elite panel discussing “Around the World Hot Topics” – a session dedicated to exploring recent enforcement trends, regulator expectations, and best practices in white-collar crime law.

With over 26 years of dedicated service to the pharmaceutical and medical device industries, Ms. Walsh brings to the table an unparalleled depth of FDA regulatory expertise. Her career is distinguished by her commitment to guiding clients through the complexities of FDA administrative actions, including inspections, warning letters, and recalls. More notably, Ms. Walsh has garnered acclaim for her passionate efforts in assisting companies with preventing or responding to government investigations, conducting internal investigations to ensure compliance, and defending against DOJ prosecutions.  Prior to her tenure at Hyman, Phelps & McNamara, Ms. Walsh’s excellence was recognized through multiple awards from the FDA, DOJ, and other prestigious institutions, a testament to her impactful contributions to the field.

The WWCDA Leadership Retreat and Annual Meeting is a cornerstone event for women in white-collar defense law, offering unparalleled opportunities for learning, networking, and advancing the role of women in the legal profession. From its inception as a modest assembly to its current status as a flagship event attracting hundreds of female attorneys globally, the WWCDA Annual Meeting exemplifies the spirit of connection, collaboration, and advancement among women in the law.

For additional information on the WWCDA, please click here.

While the Biologics Price Competition and Innovation Act (“BPCIA”) is inherently distinct from the Hatch-Waxman Act, many of the fundamental concepts FDA adopted as it enacted the Hatch-Waxman Act made their way into FDA’s implementation of the BPCIA.  This of course, make sense—after decades of experience implementing the Hatch-Waxman, Congress and FDA had learned a few new tricks by 2009/2010.  Amongst other things, FDA co-opted many of the same definitions for key terms for implementation of the BPCIA.  Relevant here, FDA interpreted in Guidance that a proposed injectable biosimilar must “demonstrate that its product has the same strength as the reference product by demonstrating that both products have the same total content of drug substance (in mass or units of activity) and the same concentration of drug substance.”  FDA borrowed this definition from 21 C.F.R. § 314.3, codified in 2016, which defines strength as the “total quantity of drug substance in mass or units of activity in a dosage unit or container closure” and/or “the concentration of the drug substance.”  But in 2020, a Citizen Petition came along looking to upend FDA’s approach to strength.

Boehringer Ingelheim submitted a Citizen Petition in December 2020 encouraging FDA to interpret the term “strength” under the BPCIA differently than the Agency does under the Hatch-Waxman Act.  Specifically, Boehringer asked FDA to interpret “strength” for biosimilars to mean “total drug content” to the exclusion of “concentration.”  The Petition alleged that “such action is necessary to:

(1) ensure the Food and Drug Administration’s (“FDA’s” or “the Agency’s”) interpretation is consistent with the clear meaning of the Biologics Price Competition and Innovation Act (“BPCIA”);

(2) prevent abusive “evergreening” tactics from stifling competition of affordable biosimilar and interchangeable biological products; and

(3) maintain fair and consistent treatment of all similarly situated parenteral biological products.

As FDA explains, Boehringer’s request would allow its “Cyltezo (adalimumab-adbm) injection, which contains the same total content of drug substance and same concentration as Original Concentration Humira (e.g., 40 mg/0.8 mL), to be biosimilar to or interchangeable with High Concentration Humira (e.g., 40 mg/0.4 mL) in addition to Original Concentration Humira.”

On February 23—the same day that the Agency licensed SIMLANDI (adalimumab-ryvk) Injection, the first interchangeable high-concentration, citrate-free biosimilar to HUMIRA, and that qualifies for First Interchangeable Exclusivity (“FIE”)—FDA denied the Boehringer Petition.  FDA responded to each of Boehringer’s arguments in turn.  To Boehringer’s first and most significant argument, that Congress intended the terms “strength” to match FDA’s interpretation in 2009—prior to the codification of the definition in 21 C.F.R. § 314.3—FDA replied that its definition of strength including concentration was clear even in 2009.  Notwithstanding some language in the Orange Book Preface that may be ambiguous, FDA stated that “FDA’s interpretation of ‘strength’ as applied to liquid parenteral drug products is reflected in nearly forty years of implementation of the statutory requirement that an ANDA contain information to show, among other things, that the “strength” of the proposed generic drug product is the same as that of the RLD…”  (emphasis added).  Even more definitively, FDA wrote:

Thus, when the BPCI Act was passed by Congress in 2009 and signed into law on March 23, 2010, the statutory term “strength” in section 505(j)(2)(A)(iii) of the FD&C Act had an existing, well-established administrative meaning that reflected both the total drug content (e.g., mg) and the concentration (e.g., mg/mL) for liquid parenteral drug products.

FDA provided detailed support, going through almost every instance that Boehringer cites as evidence that FDA interpreted “strength” differently in 2009, to show that FDA has consistently applied the same definition of “strength” since the enactment of the Hatch-Waxman Act.

Boehringer’s regulatory argument got no further traction.  FDA explained that its bioequivalence regulations at 21 C.F.R. § 320.22 do not help Boehringer’s case.  Those regulations break “concentration” out from strength but only in certain contexts.  Here, FDA breaks our concentration from strength in the context of self-evident bioequivalence that would allow FDA to grant a biowaiver (requiring inactive ingredients to be present in the same concentration as the Reference Listed Drug), which is only narrowly applicable.  In contrast, a different part of that regulation uses the term “different strength” without reference to “concentration,” but that is because the term “different strength,” in that context, is drug product and dosage form dependent; thus, there is no reference to “concentration” because it would be inapplicable to most dosage forms.  FDA concluded, its “use of the terms ‘strength’ and ‘concentration’ in different places in its BE regulations reflects the Agency’s view that ‘concentration’ is an element of strength for certain products (e.g., parenteral solutions) but is not typically broken out for others (e.g., solid oral dosage forms),” which, FDA posits, suggests “that the terms have overlapping meanings.”

Citing multiple Suitability Petitions in the small molecule context in which FDA has addressed changes to strengths by way of concentration, FDA also concluded: that “the Agency’s longstanding interpretation of the ‘strength’ of a liquid parenteral drug product to include both the total drug content and the concentration of the drug product is scientifically justified and provides a consistent and predictable approach for the development and approval of generic drug products.”  FDA then explains that scientific justification for its approach by raising significant safety and scientific concerns about Boehringer’s proposal.

With respect to safety, FDA raised concerns that differences in the either the concentration or total drug content of a parenteral product can introduce risk for medication errors, like dosing errors from difficulty in switching from the Reference Product.  Differences in drug substance concentration may also affect the quality profile of a drug product.  While the risks may not be present for all parenteral products, the Agency noted that its “definition of strength for liquid parenteral drug products accounts for its use in all scenarios, not just in the lowest risk scenarios…”  But even if those potential risks can be mitigated, FDA raises concerns that differences in concentration can affect product quality attributes in biosimilars, which directly impact safety and effectiveness.  FDA thus disagrees that such differences are not clinically meaningful.

FDA next addressed Boehringer’s allegations that FDA’s interpretation of “strength” violates the Administrative Procedure Act because there is no safety or effectiveness reason to consider concentration as relevant to a parenteral product but not a lyophilized powder for injection or other product “for injection” that ultimately become parenteral.  FDA rejects the argument because, inherently, the products Boehringer cites are not liquids at approval—they are solids that are reconstituted to become liquids.  Thus, FDA explained that “injection” and “for injection” dosage forms need not be treated the same, as “it is scientifically appropriate for the strength of a ‘for injection’ dosage form to be determined based on the total content of drug substance in the container closure because the concept of concentration (mass per volume) used for a liquid does not apply to a solid.”

Finally, FDA dismantled Boehringer’s argument about “evergreening” stifling competition.  Countering the evergreening concerns and Boehringer’s assertions that there are no countervailing interests that support its proposed omission of concentration from the “strength” definition, FDA recited its concerns of proliferation of biosimilar products with different concentrations from the reference product particularly where products evolve over their lifecycle.  More to the evergreening point though, FDA raises the point that Boehringer’s interpretation “may result in broader exclusivity that blocks a wider range of products from being licensed as interchangeable….”  In other words, because each strength is a different reference product, each is associated with its own period of interchangeable exclusivity; under Boehringer’s interpretation, FIE for one concentration would block FDA approval of another interchangeable with a different concentration but with the same total drug content.

It was not too long ago that FDA punted on BI’s petition.  In a memorandum issued last Fall concerning FIE for certain interchangeable adalimumab products (see our previous post here), the Agency recited that “[Boehringer] argues that because the original and high concentrations of Humira should be considered to have the same strength under [Boehringer’s] interpretation, Cyltezo’s exclusivity ‘covers all 10 mg, 20 mg and 40 mg adalimumab products, regardless of presentation or concentration.’”  In addressing this assertion, FDA noted that it “is not consistent with the agency’s interpretation of ‘strength’ for biosimilar and interchangeable products as articulated in [2021 Guidance].  The Agency also commented, however, that “[w]e do not need to address that pending citizen petition for the purposes of determining the expiration dates for Cyltezo 40 mg/0.8 mL, 20 mg/0.4 mL, and 10 mg/0.2 mL, in part because Pfizer is seeking licensure of Abrilada as interchangeable in those same concentrations.”  FDA’s licensure of IMLANDI (adalimumab-ryvk), and in a 40 mg/0.4 mL concentration presentation, appears to have forced FDA’s hand on the issue.

More than five years after FDA first announced its plan to harmonize 21 CFR Part 820 with ISO 13485, on February 2, 2024, FDA finally issued the Quality Management System Regulation (QMSR) Final Rule. The final rule emphasizes risk management activities and risk-based decision making. It is intended to reduce regulatory burdens on medical device manufacturers and importers by enhancing global harmonization in device regulation.

The long-awaited final rule, which we last discussed in a July 2023 blog post and have tracked in our March 2023 and March 2022 posts, aims to harmonize quality management system requirements for medical devices with requirements set forth by other regulatory authorities around the world. It does this by chiefly amending Part 820 to incorporate by reference quality management systems requirements of the 2016 version of ISO 13485 and Clause 3 of ISO 9000:2015(E), Quality management systems – Fundamentals and vocabulary, which FDA describes as “generally consistent with the overall intent and purposes” behind FDA’s regulation of quality management system requirements. Both ISO 13485 and ISO 9000 contain terms and definitions that are referenced within Part 820.

This amendment marks the first significant revision of Part 820 since 1996, which established the Quality System (QS) regulation and “included requirements related to the methods used in, and the facilities and controls used for, designing, manufacturing, packaging, labeling, storing, installing, and servicing of devices intended for human use.” Notably, Part 820 will look different. As described in more detail below, instead of Subparts A – O, the QMSR retains Subpart A – General Provisions, and renames Subpart B – Supplemental Provisions. Subparts C – O have been removed and reserved. (Reserved is a term used as a placeholder within the Code of Regulations to fill in gaps in CFR numbering and signals that an agency may add regulatory information in the future). The final rule closely resembles the proposed rule issued on February 23, 2022. One of the major changes is the extension of the transition period from one to two years, with FDA now planning to enforce the QMSR requirements upon the effective date of the final rule on February 2, 2026.

Subpart A – General Provisions

Subpart A – General Provisions, incorporates by reference ISO 13485:2016 and Clause 3 of ISO 9000:2015 (new § 820.7), and requirements for a quality management system (new § 820.10). The new § 820.10 includes considerations with respect to documentation, applicable regulatory requirements, design and development, and enforcement. The scope of the QMSR is “unchanged” from the QS Regulations, which applies to finished devices and human cells, tissues, and cellular and tissue-based products (HCT/Ps) regulated as devices.

Revised § 820.3 maintains definitions for certain terms not found in ISO 13485 or in Clause 3 of ISO 9000 but deemed essential by FDA to ensure alignment with the Federal Food, Drug, and Cosmetic Act (FD&C Act), such as the definitions for “component,” “finished device,” and “remanufacturer” (amended § 820.3(a)). FDA further retained some definitions in the QSMR. Certain definitions in ISO 13485 cannot be adopted by the FDA due to conflicts or discrepancies with definitions established in the FD&C Act or its implementing regulations in other sections of Title 21 of the CFR, such as “device,” “labeling,” “implantable medical device,” “manufacturer,” “rework,” and “safety and performance” (amended § 820.3(b)). Certain definitions are also removed from § 820.3, such as definitions for the terms “customer,” “design validation,” “nonconformity,” “process validation,” and “verification.”

Subpart B – Supplemental Provisions

Subpart B – Supplemental Provisions, adds requirements related to control of records (new § 820.35) and device labeling and packaging controls (new § 820.45). This subpart clarifies expectations for record keeping for complaint handling and includes requirements to capture information, as required by Part 803, Medical Device Reporting, on certain records of complaints and service activities. It also specifies that manufacturers document the Unique Device Identifier (UDI) for each medical device or batch of medical devices in accordance with Part 830, Unique Device Identification. In the proposed rule, FDA had proposed requiring manufacturers to “obtain the signature for each individual who approved or re-approved the record” (proposed § 820.35). However, FDA agreed with the comments to the proposed rule that this requirement went beyond those in either ISO 13485 or the former QS Regulation and removed the signature requirements from the final rule. As a result, the term “approved” under ISO 13485 is now adopted, which refers to “an approved document, or certain record of a type that requires approval by ISO 13485, has a signature and date.”

Under § 820.45, FDA also requires manufacturers to inspect labeling and packaging for accuracy. FDA believes ISO 13485 does not specifically address “the inspection of labeling by the manufacturer” and that many device recalls are related to labeling and packaging. Based on FDA’s experience, automated readers have not caught label errors and, at a minimum, human examination of a representative sampling of all labels is needed. Subpart B reserves §§ 820.20 – 820.30, 820.40.

One other notable change is the removal of the exception in the QS Regulation related to management review, quality audits, and supplier audit reports, which are not carried over in this final rule (which was also absent in the proposed rule). The final rule now allows FDA to consider these records during an inspection. FDA states this exception is not included in the QMSR to further move closer towards global harmonization and alignment, and that such exceptions are not available to firms inspected by other regulators or audited by other entities. The removal of these exceptions could fundamentally change how manufacturers document internally identified and discussed quality metrics and issues.

FDA plans to develop a new inspection process to align with the requirements of the QMSR in time to implement when the rule takes effect on February 2, 2026.

FDA clarifies in the preamble to the final rule that it plans to continue to participate as a regulatory authority in the Medical Device Single Audit Program (MDSAP) and, similar to the QS Regulations, it “may accept” MDSAP certification, in lieu of conducting FDA routine surveillance inspections. Although both MDSAP and ISO 13485 audits cover the QMSR requirements, FDA notes that it cannot ensure other applicable device requirements – such as those outlined in Parts 803, 806, 821, and 830 – are audited during ISO 13485 audits. Therefore, for companies not participating in MDSAP, such establishments should not expect FDA to rely solely on ISO 13485 certificates during routine inspections. FDA will continue to use the audit reports from MDSAP audits, rather than the certificate, as a supplementary tool for FDA regulatory oversight of audited manufacturers.

The rule also amends the title of the regulation (21 CFR Part 820) from the QS Regulation to now the QMSR. FDA concurrently makes conforming edits to 21 CFR Part 4 to clarify the Quality Management System requirements for combination products, and states that “[t]hese edits do not impact the [current good manufacturing practice] requirements for combination products.”

Similar to the QS Regulation, manufacturers of components and parts of finished devices are not subject to the QMSR requirements. FDA encourages parties to require compliance with such requirements through contractual agreements between manufacturers. Nonetheless, FDA explicitly states it has “the legal authority to inspect component manufacturers,” if necessary. While this may be true, in our experience, FDA rarely exercises this authority and there is nothing in the proposed rule that suggested the frequency of the Agency exercising this authority will change.

In the preamble, FDA acknowledges the potential for future updates to ISO 13485. However, FDA plans to assess any such future revisions and implement any necessary amendments to the QMSR through rulemaking.

The two-year transition period reflects a compromise between FDA’s original intent to implement within a year of the final rule’s publication and industry suggestions of an effective date two to three years after the Federal Register publication. We think the extended transition period makes sense, given the need to ensure FDA staff (and device manufacturers) are familiarized with the QMSR requirements.

Despite the availability of a two-year transition period, it is imperative for device manufacturers, including manufacturers of combination products, to review and revise their quality management system procedures and develop a transition plan, as appropriate, to ensure timely compliance.

On Feb. 2, 2024, FDA’s Center for Veterinary Medicine (CVM) announced that it will withdraw its Program Policy and Procedures Manual Guide 1240.3605 (PPM). As readers of this blog may recall, this PPM dates from 1998.  It reflects CVM’s narrow interpretation of what constitutes a permissible structure function claim for an animal food.  The PPM has severely limited development of new animal feed ingredients, including ingredients that promote growth, productivity claims, and ingredients with benefits for the environment.

By now, more than a year ago, on October 18, 2022, CVM held a virtual listening session on the regulation of animal foods with certain types of claims. CVM invited the public and stakeholders to comment on FDA’s regulation of animal foods with certain types of claims, that under the now withdrawn PPM, would be considered drug claims.

So what is the consequence of the withdrawal of the PPM?  That remains to be seen.  In its announcement of the withdrawal, CVM recommends that companies that are developing (or planning to develop) products with substantiated claims related to animal production, well-being, food safety, environmental and other benefits consult the agency early in the development process to ensure that products are appropriately reviewed through the right pathways.  In the absence of the policy, there seems a chance that CVM will recognize that certain claims such as production claims are not drug claims.  However, for certain ingredients, including ingredients that work via the gut microbiome, the withdrawal likely will have little to no effect.   As we reported previously, CVM believes that it does not have the authority (under the FDC Act) to regulate as feed ingredients, substances that work within the animal’s gastrointestinal tract with claims that affect the microbiome of the animal, byproducts of the digestive process or human food safety.  According to CVM, before it can consider substances with such claims as food ingredients, an amendment of the FDC Act granting the Agency authority to treat such products as food (ingredients) rather than as drugs is required.  As reported previously, the Innovative Feed Enhancement and Economic Development Act (H.R.6687 and S. 1842) (Innovative FEED Act), introduced in 2023, would amend the FDC Act to provide CVM with the required authority. Unfortunately, despite support bipartisan support and support from industry, this Act has not yet been passed.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Ana Loloei has joined the firm as Counsel. Ms. Loloei is a 14-year veteran of the FDA, where most recently she served as a Senior Regulatory Counsel in the Office of Policy at CDRH. While at FDA, Ms. Loloei also served as a Senior Policy Advisor in CDRH and as a Special Advisor in the Office of the Commissioner.

During her FDA tenure, Ms. Loloei tackled legal matters related to various aspects of the regulation of medical devices, in vitro diagnostics, and combination products including regulatory and compliance issues, dispute resolutions between the FDA and sponsors, and FDA enforcement actions.  She also worked closely with Congress, the Department of Health and Human Services, the National Institutes of Health (NIH), and the Centers for Medicare & Medicaid Services (CMS) on the development of numerous guidances, rulemakings, and policy and legislative initiatives.

Ms. Loloei will focus on guiding clients through complex premarket and postmarket regulatory requirements and assisting with the management of total product life-cycle matters.  Ms. Loloei’s deep knowledge includes the requirements for advertising and promotion of FDA-regulated products, and she advises clients on matters regarding product marketing, labeling, promotion, and advertising.

Prior to entering the legal field, she served as a biomedical/electrical engineer at an engineering firm involved in the design and development of radio frequency (RF) distribution systems from initial market and data preparation through testing and troubleshooting of these products.

“I am thrilled to be joining HPM to collaborate with an experienced and dedicated team.  It was a true honor and privilege to collaborate with so many fantastic coworkers and partners for nearly 14 incredible years at FDA.  The journey has been filled with great memories,” said Loloei. “Now, I’m eager to contribute my experience to our shared mission of working towards protecting the public health with this talented team.”

“I am very excited to have Ana join HP&M.  Her extensive knowledge of, and insights into, some of the most important device regulatory and legal issues, such as digital health technologies, in vitro diagnostic products and labeling/advertising will be of immense value to device manufacturers.  We look forward to working with Ana as she further enhances HP&M’s capacity to assist companies with regulatory strategy, marketing applications, product promotion, and post-market issues,” notes Jeffrey N. Gibbs, HP&M Director.

Ms. Loloei graduated magna cum laude, with a degree in Biomedical Engineering with a concentration in Electrical Engineering from The George Washington University.  She then went on to receive her J.D. from the University of Maryland School of Law.

With apologies to David Letterman, who introduced the first Top Ten List on Late Night with David Letterman on September 18, 1985, we present “Marijuana: Top Ten Reasons for Descheduling, Rescheduling or Not.”*

The wide range of assertions supporting or opposing Health and Human Services’ (“HHS’”) recommendation that the Drug Enforcement Administration (“DEA”) reschedule cannabis federally from schedule I to schedule III would lead an outsider to conclude that commenters are referring to different substances.  We thought that it would be educational and entertaining to list the Top Ten reasons presented in letters from three high profile stakeholder groups to Attorney General Merrick Garland and/or DEA Administrator Anne Milgram on how to handle the scheduling recommendation.  We present the Top Ten Reasons in chronological order of the letters and in order of their appearance in those letters.

Letter 1 is signed by former DEA administrators and Directors of National Drug Policy.  Letter 2 is from twelve Democratic state attorneys general.  Twelve Democratic senators signed the most recent letter.  The three letters together provide the range of actions DEA may take: no rescheduling from schedule I (former drug officials), rescheduling to schedule III (Democratic state attorneys general), or descheduling altogether (Democratic senators).  (We blogged on the December 5, 2023, letter from six Democratic governors to President Biden).

Letter 1: Top Ten Reasons for Not Rescheduling Cannabis from Schedule I

From: Former DEA Administrators and Directors of National Drug Policy
Date: October 2023

Former federal drug officials who served in Republican and Democratic administrations open by expressing their grave concern about rescheduling.  Letter to U.S. Attorney Merrick Garland and DEA Administrator Anne Milgram, from Michele Leonhart, et al., (Oct. 2023).  The letter is signed by six former DEA administrators and five former Directors of National Drug Policy.  The earliest tenured is John Bartels, who served as Administrator from 1973 to 1975.  Not surprisingly, then-presidential candidate Asa Hutchinson, DEA Administrator from 2001 to 2003, did not sign the letter.  The former officials implore following the science demonstrating marijuana’s high addictive potential, its lack of accepted medical use, and the rescheduling impact on prosecuting drug trafficking organizations.  In other words, no rescheduling.

1. There has been no evidence that marijuana’s schedule should change since the last rescheduling review in 2016.
2. FDA has not approved marijuana for medical use because no double-blind, published studies show safety and efficacy for raw marijuana.
3. Marijuana is more addictive than ever, with increasingly potent marijuana becoming the norm.
4. There have been no changes to assert any new conclusions since HHS concluded that marijuana has a high potential for abuse, no accepted medical use in the U.S., and lacks an acceptable level of safety for use even under medical supervision.
5. Three in ten people who use marijuana become addicted and the rate is even higher for those who begin using before age 18.
6. Potency has increased since the last scheduling review, with the average tetrahydrocannabinol (“THC”) potency of marijuana seized by DEA spiking from 3.96% in 1995 to 15.34% in 2021.
7. Few would oppose FDA-approved marijuana-derived medications if marijuana compounds are found to have medical value; the National Institute of Health should continue to fund research on any potential medical value of marijuana and on the harms of highly potent products.
8. The illicit marijuana market remains strong despite state laws legalizing marijuana.
9. Rescheduling marijuana, thereby reducing criminal penalties for marijuana trafficking, removes a key tool of federal agents to prosecute cartels.
10. Rescheduling marijuana to schedule III would supersize the cannabis industry by allowing evasion of IRS Section 280E and deducting business expenses for advertising to youth, sale of kid-friendly gummies, and dramatically increasing the industry’s commercial ability.

Letter 2: Top Ten Reasons for Rescheduling Cannabis to Schedule III

From: Democratic State Attorneys General
Date: January 12, 2024

Twelve state attorneys general representing “state-regulated cannabis marketplaces” are encouraged about HHS’ recommendation to reschedule cannabis to schedule III “in the interest of public health and safety” and “encourage” rescheduling to schedule III based on FDA’s “scientific and medical conclusions.”  Letter to DEA Administrator Anne Milgram, from Phil Weiser, et al., (Jan. 12, 2024). The authors view such rescheduling “as a public safety imperative and write in support of this policy change.”

1. As state attorneys general, they are concerned about the illicit market, unregulated intoxicating hemp-derived cannabinoids, and the proliferation of dangerous opioids.
2. With thirty-eight states having legalized medical use of cannabis and twenty-four states and the District of Columbia allowing for adult recreational use, states have developed robust regulatory frameworks to protect consumers from health risks in the unregulated market while accounting for recognized risks of marijuana use, especially among youth.
3. A state-regulated cannabis industry better protects consumers than the illicit market or the unregulated intoxicating hemp-derived marketplace.
4. Rescheduling to schedule III will allow the state-cannabis industry to continue setting the standard for legal products and working to eliminate the illicit market and unregulated intoxicating hemp products operating in interstate commerce.
5. Demand for cannabis products will continue, and meeting that demand only in a regulated, legal marketplace better protects consumers.
6. Rescheduling increases the ability to research cannabis to determine the physical and mental impacts of cannabis use.
7. The regulated cannabis marketplace brings in billions of dollars in revenue into state and federal governments, with predictions that cannabis sales will exceed $53 billion by 2027.
8. Rescheduling would eliminate a tax burden on cannabis companies, allowing licensed companies to expand investments into state programs and focus on public health in collaboration with law enforcement efforts.
9. States’ regulatory regimes have sought to balance a safe framework with the health and safety risks, especially among youth.
10. There is a public health and safety mandate to protect the state-regulated industry by rescheduling cannabis to schedule III.

Letter 3: Top Ten Reasons for Descheduling Cannabis Altogether

From: Democratic Senators
Date: January 29, 2024

Twelve Democratic senators signed Letter 3.  Five of the senators (Elizabeth Warren, Cory Booker, Bernie Sanders, Kristen Gillibrand, and Ron Wyden) wrote to the Attorney General, President Joe Biden, and HHS Secretary Xavier Becerra in July 2022, urging cannabis descheduling and pardons for those convicted of non-violent cannabis-related offenses.  Letter to President Joseph Biden, et al. from Senator Elizabeth Warren, et al. (July 6, 2022).  The senators “write to urge” DEA to “swiftly deschedule marijuana” and, while rescheduling to schedule III “would mark a significant step forward, it would not resolve the worst harms of the current system” for marijuana as a controlled substance, which “has had a devastating impact on our communities and is increasingly out of step with state law and public opinion.”  Letter to Attorney General Merrick Garland and Administrator Anne Milgram, from Elizabeth Warren, et al. (January 29, 2024).  They note that, descheduled, marijuana could still be subject to public health regulations.

1. Marijuana as a schedule I substance is in the same schedule as heroin and in a more dangerous schedule than fentanyl or cocaine, even though it is consistently found to be less dangerous than those substances, and less dangerous than alcohol.
2. HHS’ recommendation noted that marijuana “does not produce serious outcomes compared to drugs in Schedules I or II” and “the vast majority of individuals who use marijuana are doing so in a manner that does not lead to dangerous outcomes to themselves or others.”
3. To support its 2016 rescheduling denials, DEA pointed to lack of scientific evidence supporting medical use of marijuana, which created a catch-22 because, as a schedule I substance, marijuana is subject to DEA’s arduous research approval process and restrictions on federal research funding, stymieing researchers’ ability to rigorously study its medical uses.
4. Today, experts generally agree that marijuana has currently accepted medical uses for several indications, including managing pain, spasms, and nausea in patients undergoing chemotherapy and stimulating appetite in patients with weight loss from AIDS.
5. Studies have found that marijuana access has public health benefits by reducing the rates of opioid use and opioid deaths.
6. Thousands of doctors in the 38 states that permit the medical use of cannabis recommend marijuana to their patients and millions of patients consume medical marijuana under healthcare professionals’ guidance each year.
7. The relevant international treaties respect the legal frameworks of signatories and allow for sufficient flexibility for states parties to design and implement national drug policies in light of their priorities and needs.
8. HHS’ recommendation analysis could support descheduling, particularly as marijuana has less adverse outcomes, including less potential for an overdose, and less abuse potential than non-scheduled substances like alcohol or those scheduled lower than schedule III like benzodiazepines.
9. Many criminal penalties for marijuana will continue as long as marijuana remains federally controlled because those penalties are based on the quantity of marijuana involved, not the drug’s schedule status.
10. Without descheduling marijuana, “criminal penalties (including prison sentences, fines, and asset forfeiture) for recreational marijuana use, and for medical use of marijuana products that lack federal approval, would still exist, disproportionately penalizing Black and Brown communities.”

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We presented Top Ten Reasons from three recent letters to the Attorney General and/or DEA Administrator on cannabis rescheduling.  We encourage you to read the letters in their entirety.

*Late Night’s first Top Ten List was “The Top Ten Words That Almost Rhyme with ‘Peas.’”