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.”

****

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.’”

As an end of the year gift, FDA finalized its guidance document, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, in late December. We previously blogged on the draft guidance (here) and on FDA’s broader framework for Digital Health Technologies (DHT) (here and here).  A DHT is a system that uses computing platforms, connectivity, software, and/or sensors, for health care and related uses. The guidance addresses the use of DHTs in clinical investigations of drugs, biologics, and medical devices.

Overall, the final guidance provides many editorial clarifications as well as some noteworthy updates, including discussions on DHTs that meet the definition of a device, selection of a DHT and rationale for use in a clinical investigation, retention and protection of data collected by DHTs, and DHT updates.

The final guidance provides additional discussion with respect to DHTs that meet the definition of a device. Just like other devices used in a clinical investigation are exempt from most regulatory requirements, the same goes for DHTs. The table below, consistent with FDA’s DHT Guidance, illustrates what regulatory requirements apply to medical device DHTs used in clinical investigations, whether the DHTs are the object of the investigation (i.e., investigational device as defined in 21 C.F.R. § 812.3(g)), or simply used to collect data as part of a clinical investigation of a drug, biologic, or different medical device. It is interesting to note that even when the DHT is not the subject of the investigation and therefore not an investigational device as defined in 21 C.F.R. Part 812, the requirements under 21 C.F.R. Part 812 are applied for the use of the DHT in the clinical study.

Another noteworthy update in the final version of the guidance relates to the selection of a DHT or other technologies (e.g., smartphones and tablets) for remote data acquisition in a clinical investigation. For these devices that do not have market authorization and are only used for remote data collection in a clinical investigation, if the sponsor conducts verification and validation activities consistent with the guidance to demonstrate the DHT is “fit-for-purpose,” FDA does not intend to assess sponsors’ compliance with design controls. Drug or biologic sponsors should engage with manufacturers of DHTs to ensure appropriate evidence has been established for the DHTs before use in a clinical study. Whereas if the DHT meets the device definition and is used outside of a clinical investigation, full compliance with design controls requirements is applicable.

The final guidance also revised sections on verification, validation, and usability evaluation of DHTs, clarifying that verification and validation should be addressed regardless of whether the DHT meets the definition of a device and should consider all relevant functions of the DHT in the context of use in the clinical investigation. An important footnote is added stating that when DHTs include device software functions that sponsors should address the documentation recommendations in the FDA’s guidance on Content of Premarket Submissions for Device Software Functions.  Considerations for design of usability evaluation are provided as well as a statement that the principles in the FDA’s guidance on Applying Human Factors and Usability Engineering to Medical Devices may be helpful in designing appropriate usability evaluations for DHTs.

The final guidance also expands the discussion of analysis of data collected from DHTs which should be defined in a clinical study’s statistical analysis plan. New content in this section relates to late phase trials and reduction and handling of missing data. Use of automated data monitoring and alerts, participant reminders, a “run-in” period for participants, and investigator outreach are provided as examples that may reduce missing data.

With respect to DHT record protection and retention, the final guidance clarifies how DHT data will be reviewed in an inspection, noting that data may be requested in various formats and that data must be maintained according to sponsor or investigator’s record retention requirements and should be in human readable form. However, in general, FDA does not intend to request machine or raw data that require electronic processing to be understood in an inspection. This section of the guidance further clarifies that source data are considered the first durable electronic data repository which the data are transferred to, and that FDA does not intend to inspect individual DHTs for source data.

With respect to DHT updates and other changes during clinical investigations, the final guidance notes significant changes in the measurement after updates may invalidate the results from a clinical investigation. As such, careful evaluation of changes and validation of changes where measurements may be affected by a change are important. If changes to the measurement have occurred after the update, sponsors should compare data from DHTs before and after the update, conducting sensitivity analyses as necessary, and taking steps to mitigate any resulting differences.

If a sponsor is considering the use of a DHT in a clinical investigation, this guidance will help ensure they have the required documentation to demonstrate the DHT is “fit-for-purpose” to include in a final submission. The sponsor should be able to describe the DHT design and technological characteristics, data output provided, and how the DHT measures the event of interest. Details such as this might be publicly available or provided by the DHT manufacturer to the sponsor or, depending on the technology, could require the DHT manufacturer to provide the sponsor a right to reference to the DHT master file. If sponsors are considering the use of DHT to capture novel endpoints, rather than simply using the DHT to replace manual capture of established endpoints, sponsors should be prepared to provide additional justifications regarding the use of the DHT, its impact on the participants, effect on interventions, how it relates to other endpoints, the reliability of the data, and how the positive control can be detected using the novel endpoint.

Any sponsor considering the use of DHT in a clinical investigation will benefit from careful consideration of the recommendations contained in the guidance to facilitate a successful future marketing authorization submission to the FDA.

Last week, DEA and DOJ announced a $59 million civil penalty settlement with eBay related to the failure to comply with Controlled Substances Act (CSA) requirements for identifying purchasers, maintaining records, and filing reports of individuals selling/purchasing pill presses and encapsulating machines.  As stated in the press release, this was the fourth largest civil penalty settlement under the CSA and, ironically, did not involve the sale or distribution of any controlled substance.  It also was the first CSA settlement with an e-commerce company on violations of the CSA but, given the environment on diversion and counterfeits, may not be the last.

The CSA and regulations promulgated by DEA regulate the sale, import, and export of tableting machines the same as they regulate List I chemicals.  21 U.S.C. § 830.  While a DEA registration is not required to sell these products, by definition, any person selling these products is a “regulated person” and all sales of these products are considered “regulated transactions.” 21 U.S.C. §§ 802(38), (39)(B).  Thus, such persons are subject to identification, recordkeeping, and reporting requirements.  In brief, in regard to proof of identity, the seller must obtain sufficient information to identify and document the identity of the purchaser.  21 C.F.R. § 1310.07.  The regulations also require detailed information about each transaction involving a tableting machine, including the date, name and address, quantity, method of transfer, etc.  21 C.F.R. § 1310.06.  Also, pursuant to 21 U.S.C. § 830(b) and 21 C.F.R. § 1310.05(b)(2), each regulated person must orally report “any domestic regulated transaction in a tableting machine or an encapsulating machine . . . when the order is placed with the seller.”  Also, a DEA Form 452 report must be electronically filed within 15 days after the order is shipped.

According to the eBay settlement agreement, the government contends that from October 2015 to the present, eBay did not comply with any of “the CSA’s reporting and recordkeeping obligations” involving thousands of transactions.  In addition to the tableting machines, the government alleged that eBay sold pill presses and counterfeit dies to hundreds of buyers.  Also, DEA and DOJ contend, eBay did not verify purchaser’s identification as required by the regulations.

The settlement agreement states that the government took into account eBay’s compliance investments, implying that eBay was given some credit that may have reduced the amount of the fine.  eBay also agreed to a policy of “Corporate Compliance Program and Reporting Requirements” which includes:

• continued prohibition on listing on the website any pill press, tableting machine, or encapsulating machine;
• continuing to maintain a Prohibited, Restricted, and Counterfeit Items Committee;
• within 90 days, providing a report identifying any listing with sales that were removed or purchased items in violation of eBays policy within the prior year; and
• quarterly reports of any listings with completed sales that are identified as violating eBay’s policies and whose accounts eBays suspended.

Given the recent reports of counterfeit drugs, especially fentanyl, we would expect DEA and DOJ to continue strict enforcement of these requirements.  See, e.g., DEA’s Fake Pills Fact Sheet.  This matter also raises anew the applicability and scope of laws and regulations to e-commerce platforms that, while not directly the seller or purchaser, is involved in facilitating such transactions.  Of note, in August 2020, DEA announced a “proactive collaboration with online e-commerce companies” to inform and educate e-commerce companies about the requirements and importance of safeguarding these products and ensuring they do not get diverted.  DEA reported that Amazon had already agreed to ban sales of tableting, encapsulating, and pill punch machines for its platform.  It is unclear whether DEA had any conversations with eBay at that time.

The House Committee on Energy and Commerce Subcommittee on Oversight and Investigations invited Hyman, Phelps & McNamara, P.C. Counsel John Claud to testify yesterday about FDA’s foreign inspection program. Mr. Claud frequently counsels foreign and domestic clients on issues relating to inspections and cGMP remediations.

We’ve blogged previously on the troubles FDA has faced ramping up its foreign inspections program after the pandemic. Yesterday, Mr. Claud went to Capitol Hill to participate in a hearing called “Protecting American Health Security: Oversight of Shortcomings in the FDA’s Foreign Drug Inspection Program.”

Mr. Claud was joined in his testimony by Mary Denigan-Macauley, a Director for Health Care at the Government Accountability Office (GAO) and Dinesh Thakur. Mr. Thakur is a public health advocate and a former executive at Ranbaxy Laboratories in India. FDA was invited to attend but did not.

GAO wrote a thorough 2022 report that assessed relative lack of foreign inspections for drug making facilities, and dissected the complex problems that make foreign inspections difficult for FDA. The Subcommittee majority has held prior hearings and written letters about these problems, as the issue has vexed FDA in recent years. In fairness, we’d note that FDA reports that inspections are on the rise—but definitely not back to pre-pandemic levels.

In its 2022 report, GAO recommended that FDA initiate pilot programs that assess unannounced international inspections. At the hearing yesterday, several Subcommittee members expressed dismay that FDA announces international inspections, an Agency policy due in part to the logistical burden of getting inspectors to foreign sites. The Chair of the Subcommittee, Morgan Griffith (R-VA), noted that “It’s alarming that—given this advanced warning—the FDA still found deficiencies during 66 percent of foreign inspections, including serious deficiencies in 16 percent of those inspections.”

The hearing also featured discussion about high turnover in FDA’s inspector employment ranks. GAO found that “vacancies among investigators available to conduct foreign inspections represent another challenge” for FDA, and that in some cases FDA relied on translators supplied by the inspected facilities. The Subcommittee members discussed how the Agency might make those jobs less apt to turnover. Several minority members called for flexible appropriations so that international inspectors could be fairly compensated.

In his remarks, Mr. Claud noted that FDA might make more efforts to gather evidence using technology. Teleconferences, document review, and other remote tools may not be a full inspectional cure for a bad actor, he said, but using remote inspections to “contribute to FDA’s risk assessment” might allow the Agency to divert resources to other, more dire inspectional priorities that require an in-person presence.

He also noted the outsized impact that the foreign inspection issue has on the generic industry, which faces stiff competition from many foreign manufacturers for already thin profit margins. Finally, Mr. Claud noted that FDA should also rely on its like-minded foreign counterparts and its cadre of mutual recognition agreements to ease the foreign inspection burden.

The Members of the Subcommittee and the witnesses all acknowledged that these are complex issues, and the Chairman went out of his way to say that “The FDA . . . is trying to do the best they can. We just need to figure out how to make them a little quicker and more agile.” Mr. Claud closed his testimony echoing that sentiment. He said that resolving the obstacles to successful international inspections that FDA faces “are vitally important challenges in a global marketplace.”

Last week FDA issued a new draft guidance titled Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products.  As we described in our blog post here, the Food and Drug Omnibus Reform Act (FDORA) enacted at the end of 2022 adds new statutory obligations related to the development of diversity action plans by sponsors of certain device and drug clinical trials, and requires FDA to issue guidance.  FDA specifically notes that the Draft Guidance does not address diversity action plans or the appropriate population for a clinical study, while also reminding readers that sponsors should enroll participants who reflect the population that will use the medical product if approved.  Nevertheless, the Draft Guidance represents another step forward in the journey toward increasing diversity in clinical trials and representation of the real world populations who will use the products in studies.

The new Draft Guidance focuses on standardizing the approach and terminology used in gathering information about race and ethnicity to ensure that information is collected and reported consistently in submissions to FDA.  In keeping with the goal of standardization, the Draft Guidance is issued by a long list of agency level offices (including the Offices of the Commissioner, Minority Health and Health Equity, and Women’s Health, among others) and all three human medical product centers (CDER, CBER and CDRH), as well as the Oncology Center of Excellence.

Specifically, the Draft Guidance recommends that the minimum choices offered for ethnicity include “Hispanic or Latino” and “Not Hispanic or Latino.”  Similarly, for race, the Draft Guidance recommends the following minimum choices with direction to the reader to select one or more:

• American Indian or Alaska Native
• Asian
• Black or African American
• Native Hawaiian or Other Pacific Islander
• White

FDA states that it recognizes that the categories were developed in the United States and may not be adequate to describe racial and ethnic groups in other countries. If expanded choices are desirable, FDA recommends following the standards from the 2011 HHS Implementation Guidance on Data Collection Standards for Race, Ethnicity, Sex, Primary Language, and Disability Status and provides more detailed categories from that guidance.

The Draft Guidance emphasizes that study team should not answer the questions based on observation or even on existing medical records. Instead, the information should be self-reported or, if that is not possible, provided by a first-degree relative or knowledgeable representative.

Notably, FDA recognizes that Office of Management and Budget (OMB) Policy Directive 15 (issued in 1997 and currently being reviewed for update) which provides a minimum standard for collecting and presenting data on race and ethnicity by Federal agencies states that recommended race and ethnicity categories “were not anthropologically or scientifically based designations, but . . . describe the sociocultural construct of our society.”  FDA states, however, that collecting data on race and ethnicity is critical to identifying population-specific signals, noting that differences in response to medical products while uncommon may be attributable to intrinsic factors (e.g., genetics, metabolism, skin pigmentation) or extrinsic factors (e.g., diet, socioeconomic status, culture).

FDA states that the term clinical studies refers in the Draft Guidance to both interventional studies and observational studies though some recommendations are relevant only to interventional studies.

When finalized, the Draft Guidance will take the place of the 2016 guidance Collection of Race and Ethnicity Data in Clinical Trials.  The comment period ends on April 29, 2024.

HP&M has been helping clients navigate the challenges of state licensing regulations for drugs, biologics, medical devices, OTCs, 503B outsourcing facilities, 503A pharmacies, foods, dietary supplements, cannabis, and wholesalers/distributors for many years. With regulations varying significantly from one state to another, companies in these sectors often find themselves immersed in a labyrinth of compliance requirements.

Some of the services HP&M offers include:

• comprehensive regulatory assessments
• pre-launch licensing support
• license gap analysis
• support for new product/company acquisitions, regulatory diligences
• DEA registrations and state-controlled substance licenses

With the complexities of licensure, Sara M. Keup has joined the firm to assist attorneys Karla L. Palmer, Larry K. Houck, and Kalie E. Richardson with navigating this ever-changing regulatory environment.  It is critical for companies to stay abreast of current laws and regulations to avoid costly penalties and business disruptions.

Having previously worked at HP&M, Sara recently rejoined the firm to assist clients with regulatory licensing services.  Her expertise includes preparation and maintenance of licensing documentation, communications with state boards and government agencies, conducting research, and the preparation of associated licensing documentation and applications. She also provides consulting services for state licenses, as well as regulatory due diligence concerning licensing requirements, primarily for pharmaceutical manufacturers, wholesale distributers, and pharmacies. Sara is conveniently able to be a client’s one-stop point of contact for licensing needs.

If you’re concerned about regulatory gaps, facing licensing issues, or looking for a more efficient way to manage your state licensing program, HP&M is here to help. Our state licensing team is dedicated to providing the expertise you need to navigate the state licensing maze with ease.

On January 18, 2024, the director of FDA’s Center for Devices and Radiological Health and the chief medical officer and acting director of CMS’ Center for Clinical Standards and Quality issued a joint press release supporting FDA’s recent proposed rule regulating Laboratory Developed Tests (LDTs). That CMS teamed up with its sister agency to support FDA’s proposed rule is itself unusual.  More surprising still is CMS’ unabashed declaration of its own lack of “expertise to assure that tests work,” given CMS has for decades been responsible for implementation of the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and, according to CMS’s own 2006 CLIA fact sheet, “has primary responsibility under CLIA for regulating laboratories.”

Indeed, as the fact sheet explains, Congress enacted CLIA following reports of inaccurate Pap smear results intended to detect cervical cancer precisely to ensure the “accuracy and reliability of all laboratory testing.”  Under this paradigm, only laboratories certified by CMS (or a deemed accrediting body) may perform clinical testing services.  To obtain certification, laboratories must comply with regulatory requirements relating to personnel qualification and training, record keeping, quality control, and proficiency testing, and must maintain a quality assurance and quality control program adequate to ensure the validity and reliability of the laboratory examinations. CLIA-certified laboratories are subject to inspections by CMS (or a CMS-approved accreditation organization) to confirm that the testing complies with CLIA regulations, including that there is adequate validation of the tests, supervision by the laboratory director and quality procedures in place.

The joint press release largely repeats, and has CMS endorse, the arguments FDA has previously made in support of its proposed rule, which we rebut in the detailed comments we filed on behalf of a coalition of laboratories. The two agencies are similarly aligned in their opposition to suggestions that “concerns with LDTs should be addressed through expansion of CLIA.” Many have read this as a deliberate swipe at an alternative, legislative pathway for CLIA modernization proposed by the Association for Molecular Pathology and supported by a diverse group of stakeholders.  The joint press release counters that “this is not the answer,” and alleges that “establishing a duplicative system for the oversight of tests by expanding CLIA would create more government bureaucracy and inconsistencies.”

There is great irony in the agencies’ professed concern for increasing bureaucracy.  In a case of the pot calling the kettle black, FDA has no stated plan of how it will address its exponentially increasing workload should it finalize its proposed LDT rule. FDA estimates that the proposed rule would increase the volume of device premarket submissions it receives up to twenty-fold in a single year and that the volume would, on an ongoing basis, be at levels at least twice as high as FDA currently manages. FDA will need to hire (and train) significant volumes of new personnel to manage these new submissions just as CMS may need to hire (and train) additional personnel if its authority is significantly expanded. And while FDA suggests in the proposed rule that review of LDT applications could be outsourced to third-party reviewers (which is entirely unrealistic given the program’s history), the suggestion of needing outside help simply underscores that FDA does not believe that it currently has the personnel it needs to regulate LDTs.

The press release also fails to consider other pathways to address the agencies’ concerns about LDTs. Some states, like New York, require separate licensure of laboratories and premarket review of certain tests, including review of clinical validation data, to perform LDTs on specimens from the state. We are unaware of FDA having expressed that New York State’s validation requirements are inadequate, and New York State approval is not accompanied by the myriad other FDA requirements for medical devices that FDA’s proposed rule would impose on labs (e.g., Medical Device Reporting, Quality System Regulation compliance, and reporting of corrections and removals).

The joint press release provides support for the adage that “opposites attract”; FDA claims broad authority to regulate LDTs notwithstanding its lack of statutory authority under the Federal Food, Drug, and Cosmetic Act, while CMS disavows the clear authority over clinical laboratory testing with which it has long been imbued under CLIA.

On January 31, 2024, FDA announced its intent to initiate the reclassification process for most in vitro diagnostic (IVD) products that are currently class III (high risk) into class II (moderate risk). Most of these reclassified tests will supposedly be infectious disease and companion diagnostic IVDs. Reclassification would allow developers to seek clearance for substantially equivalent tests through the 510(k) pathway rather than the more costly and time-consuming premarket approval (PMA) pathway.

The announcement also states that FDA expects most future companion diagnostic and infectious disease IVDs would be regulated as class II devices, even if they are novel and require de novo classification.

One can’t help but read this announcement as an effort by FDA to prepare for (or at least give the appearance of preparing for) the deluge of IVD premarket submissions the agency expects it will receive following (the presumed) finalization of its proposed rule regulating LDTs. As we outlined in a previous blog, by FDA’s own (artificially low) estimate, the agency anticipates in will receive, in a single year:

• 32,160 510(k) premarket notifications;
• 4,210 PMAs, PDPs, Panel-Track PMA Supplements; and
• 4,020 de novo

This is 10 times the number of submissions the agency currently receives in a year across all device types. These numbers look even worse when you consider that most of these LDTs would be high risk or novel and, therefore, result in 57 times more PMAs and 61 times more de novo submissions than the FDA normally receives in a year.

This is to say nothing of the expected doubling of annual device submissions FDA expects it will then receive on an ongoing basis. And as we note in that earlier blog, there is good reason to believe all of the above numbers are gross underestimates.

Perhaps this is why FDA is trying to preemptively reclassify most of the high-risk tests currently on the market and signaling that it expects most future companion diagnostic and infectious disease IVDs would be regulated as class II devices going forward. But there are reasons why this move will not lessen FDA’s workload nearly as much as it might seem at first blush.

First, all this would do is move the premarket submission from one bucket to another. LDTs that can demonstrate substantial equivalence to a reclassified predicate device will still have to submit a 510(k) premarket notification. More novel LDTs will need to pursue de novo classification, which in many cases requires extensive clinical data to support authorization. Either way, FDA will need to review each of these applications and within shorter MDUFA timelines to boot.

Second, the lower cost to developers to assemble, and user fee to file for, a 510(k) or de novo submission compared to a PMA could increase the overall number of applications FDA receives, as developers that might have been deterred by the high cost of a PMA decide that a 510(k) or de novo submission is more manageable.

Finally, the vast majority of these submissions, whether for 510(k) clearance, de novo classification or PMA are likely to be accompanied by pre-submission requests to ensure the data the laboratories will be presenting to FDA in their submission is what the agency will expect.

FDA simply does not have the resources to handle the apocalyptic volume of premarket submissions it will have to review if it finalizes the LDT rule. We have yet to see the agency put forth a plan that would meaningfully change this calculation (see e.g., our view of FDA’s farcical reference to its third-party review program). This reclassification announcement is no different.

While we commend FDA for taking a critical look at the regulatory burdens placed on current high-risk tests, it is no substitute for creating a meaningful plan for how it will address the resources needed should the agency finalize the proposed LDT rule.  We hope that the next announcement for FDA includes such a plan.

In a new publication in the Washington Legal Foundation’s (WLF) Legal Backgrounder, we argue that FDA’s recent proposed rule regulating Laboratory Developed Tests (LDTs) is vulnerable to legal challenge, once finalized. FDA’s proposed rule has every hallmark of a case subject to the “major questions doctrine,” according to which agency action must be support by clear congressional authorization.  FDA points to a nearly 50-year-old statute, the Medical Device Amendments (MDA), as the source of its supposed authority to regulate LDTs as medical devices—authority which it apparently chose to not enforce until now. But, as we detail in the WLF publication: “the MDA supplies no such clear [congressional authorization]. Instead its text and structure affirmatively undermine the Proposed Rule’s core claims.”

This is to say nothing of the Administrative Procedure Act (APA) challenges the final rule may be vulnerable to, including whether the Agency manages to meet its obligations to fully respond to the more than 6,000 comments it received on the proposed rule by the breakneck April timeline the Agency is pursuing for publication of the final rule.

FDA’s proposed rule, and the industry fervor it has sparked, may supply Congress with a renewed sense of urgency and purpose to pass legislation that expressly addresses how LDTs should be regulated—industry groups have, for example, proposed legislation that would modernize the CLIA regulations that currently govern laboratories. In the absence of new legislation, litigation over the rule is virtually inevitable.