While Covid is in the rear view for most of us, FDA has had a tough time shaking off the effects of the pandemic on its inspection output. Inspections went down—way down—during the pandemic. In March 2020, FDA temporarily postponed all foreign and domestic and routine surveillance facility inspections. Many have noted that FDA has been slow to recover

We’ve blogged before on FDA’s post-pandemic inspection work, writing about the resumption of both good manufacturing practice (GMP) and bioresearch monitoring (BIMO) inspections. And a look at FDA’s Data Dashboard for Inspections reveals that the Agency is returning to pre-pandemic numbers. But gaps still remain. In 2022, the Government Accountability Office reported that FDA needed to improve its foreign inspection program. That report prompted a hearing on Capitol Hill in February of this year where HPM Counsel John Claud offered testimony.

More recently, GAO has published a new report on FDA inspections entitled “FDA Should Evaluate Its Efforts to Recruit and Retain Its Inspection Workforce.” According to GAO, FDA is facing challenges with clinical research inspections to ensure that the sites that oversee the research that lead to drug approvals meet the necessary standards. These are BIMO inspections of hospitals, clinical research organizations (CROs), and other similar facilities where clinical trial work is performed. The vast majority are for drugs.

GAO reports that BIMO inspections peaked in 2017 when FDA was able to complete over 970 visits. Complete numbers for 2023 and 2024 are not available, but it appears that FDA was only able to complete 537 BIMO inspections in 2022. In other words, the inspectional output was inversely proportional to the importance of clinical research.

The Agency told GAO that the root of the problem was not having enough investigators. These positions suffer from high turnover due to low pay and frequent travel. But of course, a happy inspectional workforce is vital to this foundational part of FDA’s approval mission.

Thus, the findings from GAO that FDA needs to nurture and maintain is clinical inspection force are significant. And the problems identified—salary and travel—are entirely predictable and mirror issues plaguing the entire inspection force. GAO concludes that FDA need to monitor this personnel situation, noting it has cited workforce retention and satisfaction “as a concern across multiple FDA programs and sustained attention in this area will be critical.”

The report comes at a time when FDA is trying to map out how it wants to exercise the authority it has over clinical trials. In December, Commissioner Robert Califf wrote about the importance of transparency in trials, noting the FDA takes a risk-based approach to compliance and enforcement. He also said that notices alerting firms of noncompliance were, in the Agency’s view, highly effective in correcting clinical sites’ practices.

The stakes remain high, though. The Department of Justice has obtained several convictions for fraud in clinical trials, and drug approval sponsors face mighty obstacles if they do not conduct and maintain the appropriate due diligence on CRO’s and clinical sites. We see the risks when we conduct due diligence for clients and ignoring them only serves to put drug sponsors seeking approval at the top of FDA’s list when it’s looking for ways to prioritize its inspection choices.

The FTC appears to be on a mission to cleanse the Orange Book of patents it deems improperly listed.  For the second time in recent years, the FTC has filed an Amicus Brief explaining exactly which patents should not be in the Orange Book.  Last time, back in 2022, the FTC took on REMS patents, explaining in litigation between Jazz and Avadel that the listing of REMS patents in the Orange Book is anticompetitive; this time, the FTC is going after device patents.  Late last week, the FTC submitted an Amicus Brief in recent Hatch-Waxman patent litigation in the District Court of New Jersey between Reference Listed Drug holder Teva Branded Pharmaceutical Products R&D Inc. and ANDA applicant Amneal Pharmaceuticals explaining that patents that claim the device constituent of a combination product but do not expressly claim the relevant drug substance should not be listed in the Orange Book.

In a seemingly run of the mill patent suit, Teva sued Amneal for infringement of 5 patents arising from the submission of Amneal’s ANDA referencing Teva’s combination product ProAir HFA NDA in fall 2023.  Those 5 patents, however, all covered the combination product’s device constituent, a Metered Dose Inhaler, rather than the drug constituent, albuterol sulfate.  In accordance with the Hatch-Waxman Amendments, Teva received a routine 30-month stay precluding FDA from approving Amneal’s ANDA for 30 months so that the patent litigation can proceed.  But this litigation coincided with FTC’s recent intervention into antitrust issues in the Orange Book during which the FTC asked 10 sponsors in November 2023, including both Teva and Amneal, to delist device patents.  Seizing on some opportune timing, Amneal, filed a counterclaim against Teva seeking a declaratory judgment of non-infringement and invalidity of all 5 patents, removal of those patents from the Orange Book, and relief from allegedly anticompetitive conduct in violation of state and federal antitrust laws.

On the heels of its pursuit of the eradication of the “improperly listed” patents in the Orange Book—where notably Teva refused to delist its device patents while Amneal complied—the FTC filed an Amicus Brief in the Teva and Amneal litigation.  The Amicus Brief explains that only drug substance, drug product, and method of use patents are to be listed in the Orange Book yet “Teva has triggered a 30-month stay based on inhaler and dose counter device patents that, on their face, are not specific to any FDA-approved drug” (noting that one patent has been listed with 21 different drug products).  Very clearly, the brief states “In the FTC’s view, device patents that do not mention any drug in their claims do not meet the statutory criteria for Orange Book listing, and a device patent that is improperly listed in the Orange Book must be delisted” (emphasis added).  This is plain as day for FTC, which is interesting considering that FDA—the entity responsible for maintaining the Orange Book—has refused to say a word on the subject, which, presumably, is the entire reason FTC has felt the need to intervene in the first place.

In reading this Amicus Brief, it is clear that FTC is not happy with Teva following Teva’s refusal to delist its device patents in response to the FTC’s Fall 2023 “warning letter” (called that by FTC in the Amicus Brief).  Though Teva listed the asserted patents as “drug product” patents, FTC explains that “none of the [patents in suit] mention any drug in their claims, much less the active ingredient in ProAir HFA, albuterol sulfate.”  (FTC also notes that the last expiring patents covering albuterol sulfate expired in 1989.)  Because a “drug product” is defined by regulation as a “Finished dosage form . . . that contains a drug substance,” FTC explains that “only those [patents] that claim the finished dosage form containing the drug substance of the relevant NDA” can be listed.  Teva’s patents do not meet that criterion.  FTC compares Teva’s listed patents to those at issue in the 2020 First Circuit decision in In re Lantus Direct purchaser Antitrust Litigation, where the Court held that device component patents that do not explicitly claim the drug product cannot be listed in the Orange Book.

Unsurprisingly, the brief takes a trip through antitrust laws as well, explaining FTC’s position why such listings are anticompetitive, and, as part of that analysis addresses head-on FDA’s “ministerial role” with respect to the Orange Book.  Indeed, there has been a lot of criticism of FDA for not intervening in Orange Book device patent-listing disputes, but the FTC excuses that because it is not the FDA’s mission to “resolve economic disputes about the coverage of patent claims.”  While that’s not exactly what industry has asked of FDA, framing it that way provides FDA coverage behind its claims that it “’lack[s] the resources, authority, or expertise to police patent claims’ that delay the entry of generic drugs.”  This lets FDA off the hook pretty easily considering that industry has been asking FDA explicitly whether device patents can be listed in the Orange Book for more than 20 years.  Hearing nothing, industry proceeded to list.

Nevertheless, if FDA is not going to get involved—and it appears that it will continue not to—at least FTC is providing industry with the clear guidelines it has been asking for.  And it doesn’t look like FTC is planning to stop policing the Orange Book any time soon.  It would not be surprising if we see more Amicus Briefs from the FTC in Hatch-Waxman patent suits or if FTC starts to take its own enforcement action beyond the request to delist.  FTC’s resolve here—and its clear assertion of its antitrust authority in this space—should serve as a warning to sponsors of combination products to review their Orange Book patent listings.

On March 21st, FDA announced the approval of the first nonsteroidal therapy for the treatment of Duchenne Muscular Dystrophy (DMD) (FDA press release available here). Duvyzat (givinostat), a histone deacetylase (HDAC) inhibitor developed by Italfarmaco, S.p.A., represents a new class of therapeutics to slow progression of DMD and adds significantly to the armamentarium available to treat this relentlessly progressive and devastating condition.  Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski, James Valentine and Charles Raver are honored to have aided Italfarmaco in the development and approval of this new drug, and to be part of the effort to expand treatment options for the young men and boys living with Duchenne, and the families of those affected by Duchenne.

Even with a growing list of therapies for DMD, this disease continues to cut short the lives of those with Duchenne and rob these young men and boys of the full functions of their bodies and autonomy that many of us take for granted. Several of the approved DMD therapies are available only to those with specific genetic variants, representing small portions of the overall population of people affected, and were approved and made available via Accelerated Approval while studies to confirm clinical benefit are ongoing. As Dr. Emily Freilich, Director of the Division of Neurology 1 in the Office of Neuroscience in CDER noted in FDA’s press release, Duvyzat is the first nonsteroidal DMD therapy approved regardless of genetic mutation.

Beyond the unmet medical needs that Duvyzat helps to address, we see this approval to be notable from a drug development and regulatory perspective. The primary basis for approval, like other drugs for DMD, was based on a single placebo-controlled randomized trial. However, it was the first of a nonsteroidal treatment of any product class to ever demonstrate an effect on a functional primary endpoint, here, the four-stair climb test (4SC). In addition, Duvyzat’s labeling also reports a nominal statistically significant effect on the North Star Ambulatory Assessment (NSAA), a secondary endpoint in the trial and is regarded by many in the field as the most widely accepted instrument for gauging the magnitude of benefit of a DMD therapy. It was also the first trial to be run with a placebo control over 18 months, whereas other DMD therapies have been tested in pivotal trials of 1 year or less.

The evidence reviewed by the FDA’s Office of Neuroscience and Division of Neurology 1 to support the approval of Duvyzat, however, goes beyond these traditional DMD functional endpoints. The underlying pathophysiological hallmarks of DMD are loss of muscle and its replacement with fibrotic and fatty tissue. While the mechanism by which Duvyzat and HDAC inhibition treats DMD likely involves multifaceted effects on the inflammatory and other pathophysiology processes set in motion by mutations in the dystrophin gene, Duvyzat showed an effect on muscle loss, the key pathogenic hallmark of DMD. Treatment with Duvyzat over 18 months resulted in a 30% reduction in fat fraction of major muscle groups in the thigh as measured by magnetic resonance spectroscopy.

Finally, each of the effects of Duvyzat were demonstrated on top of standard of care treatment with corticosteroids. All patients in the pivotal trial were required to be on a stable dose of corticosteroids for 6 months prior to enrollment and continued on corticosteroids throughout the study. While demonstrating an effect on top of an already effective therapy is impressive from a study design standpoint, it is most meaningful in that Duvyzat is not merely an alternative treatment option but it can be used on top of existing corticosteroid therapies to meaningfully delay disease progression for those with Duchenne.

We authors eagerly await the publication of FDA’s Summary Basis for Approval for the Duvyzat NDA so that we can better understand the basis for the Agency’s finding of substantial evidence of effectiveness, particularly in light of recent FDA guidance on the topic of single study approvals with confirmatory evidence, available here.

All the data described above can be found in Sections 12 and 14 of the FDA-approved prescribing information (see here). Additional data from studies of Duvyzat are available in the published literature (see e.g., Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X).

As drug manufacturers battle the Health Resources and Services Administration (“HRSA”) in federal courts over the role of 340B contract pharmacies, an Eighth Circuit decision to uphold a 2021 Arkansas law may render those cases inconsequential in that state.

The 340B contract pharmacy dispute involves several manufacturers who are refusing to provide 340B discounts to covered entities if they requested 340B drugs to be delivered to, and dispensed from, a network of contract pharmacies. The drug manufacturers claim that their statutory obligation to offer 340B discounts to covered entities does not require them to deliver the 340B drugs to an unlimited number of contract pharmacies. They argue that the 340B statute had never intended to give contract pharmacies such an outsized role in the program, in part because their proliferation stretched HRSA’s enforcement capacity and resulted in widespread noncompliance. HRSA disagrees, arguing that manufacturers are violating their duty to provide covered entities access to 340B prices based solely on the delivery location. HRSA also argues that Congress’ silence regarding pharmacies and delivery rendered the statute ambiguous, and dictates deference to the agency’s position. In 2021, HRSA threatened to impose penalties and the drug manufacturers sued to enjoin the agency.

The Arkansas Law

Against this backdrop, in May 2021, Arkansas enacted a law prohibiting manufacturers from interfering in a covered entity’s agreement with a contract pharmacy. Under this law, manufacturers may not deny contract pharmacies access to a covered entity’s 340B drugs, or deny 340B drug pricing to covered entities who use contract pharmacies for distribution. See Ark. Code Ann. § 23-92-604(c)(1), (2) (Act 1103). The Pharmaceutical Research and Manufacturers Association (“PhRMA”) immediately challenged the law at the agency level, and in September of that year, sued Arkansas on the theory that the law was preempted by the federal 340B statute and the Federal Food, Drug, and Cosmetic Act (FDCA), and was unconstitutional under the dormant commerce clause because of its effect of regulating commerce occurring wholly outside that state’s borders. Two 340B covered entities joined the litigation as intervenors arguing to uphold the law.

The Eastern District Court of Arkansas reviewed PhRMA’s arguments for field preemption, obstacle preemption and impossibility preemption (the parties asked the court to stay the dormant clause question pending the outcome of the preemption issue). On December 12, 2022, the district court granted intervenors’ motion for summary judgment, holding that federal law did not preempt the Arkansas statute under any theory. On March 12, 2024, a three-judge panel of the Eighth Circuit affirmed.

The 340B Statute Does Not Preempt the Field

PhRMA first argued that the 340B Program preempts Act 1103 through field preemption. Field preemption applies when federal regulation occupies the regulated area so pervasively that it leaves no room for states to supplement it, even if the state law is consistent with the federal law. PhRMA argued that Congress established the 340B drug discount program, imposed ceilings on prices drugmakers may charge certain healthcare facilities, specified what those facilities are, and provided compliance and enforcement mechanisms for manufacturers and covered entities.

However, the court found that the 340B Program is not so pervasive that it left no room for states to supplement it. Pharm. Rsch. & Mfrs. of Am. v. McClain, No. 22-3675, 2024 U.S. App. LEXIS 5840 (8th Cir. 2024) at 13 (“Decision”). The 340B statute is silent about delivery and distribution of pharmaceuticals by pharmacies to patients even though pharmacies are essential and a legally required part of the drug distribution chain. Decision at 8-9. This silence contrasts with 340B’s provisions that directly address distribution by another third-party—wholesalers. Id. at 12. The court held that Congress’s decision not to legislate the issue of pharmacy distribution indicates that Section 340B is not intended to preempt the field, and the state’s traditional police powers should prevail. See id. at 5, 12.

The court also noted that the practice of pharmacy is an area traditionally left to state regulation. The federal government has long maintained that state law offers an additional, and important, layer of consumer protection that complements federal regulation. Id. at 12-13. Further, the court believed Congress was aware of the role of pharmacies and state pharmacy law when it enacted the 340B Program, and its decision to still stay silent indicated that it did not intend to preempt the field.

PhRMA also argued that Act 1103 impermissibly interfered with 340B’s “closed system” by adding pharmacies to the enumerated list of covered entities eligible to receive 340B-discounted drugs. However, the court noted that contract pharmacies neither purchase 340B drugs, nor receive the 340B price.  They merely dispense 340B drug to the patients of covered entities, while covered entities purchase and maintain title to the drugs. PhRMA next argued that the oversight and enforcement mechanism of Act 1103 contravenes HHS’s exclusive jurisdiction to implement and enforce the program. Again, the court clarified that HHS and Arkansas would have jurisdiction over different disputes: the federal government addresses pricing, overcharging, refunds, and diversion of 340B drugs, while the state law would act only if a manufacturer denied 340B drugs to covered entities’ contract pharmacies.

Act 1103 Does Not Conflict with the 340B Statute’s Purpose

PhRMA also argued that the 340B Program preempts the Arkansas statute through obstacle preemption. The court examined whether the operation of Act 1103 would frustrate the 340B statute’s purpose and intended effects in its chosen field. The court held that the Arkansas statute does not create an obstacle for manufacturers to comply with 340B.  On the contrary, it assists in fulfilling the purpose of 340B. Id. at 15-16. The court explained that Act 1103 does not require manufacturers to provide discounts to contract pharmacies, so the delivery of covered entities’ drugs to contract pharmacies for dispensing should create no obstacle to fulfilling the 340B statute’s purposes. Additionally, Act 1103’s penalties are aimed at activities that fall outside the purview of 340B; the state law is simply deterring manufacturers from interfering with a covered entity’s contract pharmacy arrangements. Id. at 16.

Act 1103 Does Not Make it Impossible for Drugmakers to Comply with the FDCA

PhRMA also argued that Act 1103 is preempted by the Federal Food, Drug, and Cosmetic Act through impossibility preemption. Impossibility preemption exists when it is physically impossible for a private party to comply with both state and federal law. Id. at 17. According to PhRMA, Act 1103 will make it impossible for manufacturers of drugs subject to Risk Evaluation and Mitigation Strategies (REMS) to comply with the restrictive distribution requirement the REMS program imposes—for example, that only certain pharmacies may qualify to receive and dispense REMS drugs.

The court disagreed that Act 1103 would make it impossible for manufacturers to comply with a REMS program. Id. at 17-18. The covered entity would bear the responsibility of seeking out and contracting with a pharmacy that meets the REMS requirements. According to the court, “[j]ust because a medication is subject to multiple legal requirements does not make it impossible to comply with Act 1103. PhRMA alleges no circumstances where a covered entity’s contract pharmacy arrangement has made simultaneous compliance with state and federal law impossible.” Id. at 18. As such, the court held that FDCA does not preempt Act 1103.

The Road Ahead for the 340B Contract Pharmacy Dispute

In January 2023, the Third Circuit handed the manufacturers a victory in one of their lawsuits against HRSA challenging covered entities’ unrestricted use of contract pharmacies.  Other decisions are expected at the D.C. and the Seventh Circuit Courts, and if there is a circuit split, we may see the question reach the Supreme Court. However, the Eight Circuit decision upholding the Arkansas law may encourage 340B entities to lobby state legislatures to adopt similar laws, and potentially circumvent those decisions altogether.

The American Conference Institute’s 11th Annual Legal, Regulatory, and Compliance Forum on Cosmetics & Personal Care Products took place this week in New York, and featured a full house of folks talking about the Modernization of Cosmetics Regulation Act (MoCRA), the legal considerations around making environmental, sustainable, and green (ESG) claims, and the impact of state laws. As readers of our blog know, MoCRA was a significant change to regulation of cosmetics. Now in the second year of implementation, companies have started noticing the consequences as FDA implements the new requirements and develops regulations and guidance. As the new law unfolds—and as state laws regarding ingredients and packaging, as well as laws regarding environmental claims continue to affect the cosmetics and personal care industries—the topics covered at the conference have never been more relevant.

The first panel of the conference discussed upcoming relevant MoCRA deadlines as well as how FDA might develop its monitoring and enforcement system, especially as it relates to safety substantiation. The MoCRA rollout, though, does not preclude that FDA may practice some regulation by enforcement if it deems such action necessary. The Agency’s plans to do so may be affected by FDA’s recent re-organization of its Office of Regulatory Affairs, in addition to the move—for now—of MoCRA oversight from the Center for Food Safety and Nutritional under the Office of Chief Scientist. Such organizational shifts are often motivated by a quest for greater efficiency, but initially the move may be disruptive due to the upheaval of the change.

Panelists also concluded that, in these early days of MoCRA registration and issuance of guidance, organization and preparation are key tools to handling requirements for adverse events (AEs) and recalls. Although much remains to be decided and industry is waiting for guidance from FDA related to some of these issues such as serious adverse event reporting, conference discussions all embraced the development of an appropriate internal company infrastructure to handle new requirements as part of a good faith display of compliance.

In addition to MoCRA, several panels touched on state statutes that regulate chemicals in cosmetics, such as the per- and polyfluoroalkyl substances, known as PFAS. MoCRA requires that FDA issue a report on PFAS in cosmetics by the end of 2025, but one takeaway from these discussions was that several states laws create a patchwork of relevant laws, further complicated by a plaintiffs’ bar that is aggressively pursuing class action lawsuits.

An interesting notice from the conference discussion on PFAS is that, to date, very few if any PFAS class action suits have alleged actual, realized harm from the chemicals. Instead, many of these actions are essentially claim breach of warranty, in which consumers allege that they would not have purchased products at issue if the presence of PFAS had been more clearly noticed. Litigation might include avoiding marketing claims that may trigger suits such as “clean,” “healthy,” “natural,” or “environmentally friendly,” as might be applicable to a particular product. Those claims are often triggers for plaintiff’s litigation if used with products that contain PFAS.

The second day of the conference included a panel that included speakers the Federal Trade Commission and the National Advertising Division of the National Better Business Bureau. That panel reviewed several of the guidelines relating to advertising and marketing practices. Not surprisingly, key takeaways from the panelists echoed guidance from FTC and several recent cases and matters; i.e., provide clear guidance to paid influencers, advise paid influencers to disclose material connections and sponsorships, and clarify when “reviews” are, in fact, marketing. Furthermore, as part of their internal communications about marketing practices, companies are advised that employees who review their own company’s products must disclose their employment.

Thriving in the cosmetics and personal care space requires attention to litigation avoidance strategies and regulatory compliance in addition to more traditional business concerns. Truly, these are complex considerations.

Hyman, Phelps & McNamara, P.C. (HP&M), the largest dedicated food and drug law firm in the U.S., is pleased to announce that Director Allyson Mullen has been appointed to the Board of Directors of the Association of Medical Diagnostic Manufacturers (AMDM). This prestigious appointment recognizes Ms. Mullen’s extensive experience and contributions to the field of in vitro diagnostic (IVD) regulation.  Ms. Mullen brings to the AMDM board a wealth of knowledge and expertise gained from her years of providing counsel to medical device and IVD manufacturers.

AMDM facilitates educational resources within the in vitro diagnostic industry.  AMDM is known for serving as a “connector” for FDA and other regulatory bodies to share information and exchange ideas with industry.

Speaking about her appointment, Ms. Mullen expressed her enthusiasm: “I am honored to join the AMDM Board of Directors. This opportunity allows me to contribute more broadly to an organization that was crucial in my own education when I first joined the in vitro diagnostic industry. I look forward to working with the Board and the members of AMDM to navigate the evolving regulatory landscape and to support the association’s educational mission.”

Fellow HPM Director Jeff Gibbs to Speak at the 2024 AMDM Annual IVD Regulatory Meeting

HP&M Director Jeff Gibbs will present at the 2024 AMDM Annual IVD Regulatory Meeting held in Bethesda, MD on April 24-25, 2024, at the Bethesda North Marriott.  Mr. Gibbs’ presentation, entitled “U.S. IVD Overview and Update,” will cover recent developments in IVDs, including the proposed LDT regulation.  More information on the Annual Meeting can be found here.

FDA recently issued a draft guidance, Evaluation of Thermal Effects of Medical Devices that Produce Tissue Heating and/or Cooling (link), which describes information to include in a marketing application to support the evaluation of thermal effects of medical devices that produce local, regional, and/or systemic changes in tissue temperature due to their use, either by heating or cooling.

The draft guidance applies to medical devices that heat or cool tissue as an intended or unintended consequence of device use.  Examples of such devices include devices that deliver forms of electromagnetic energy; devices that deliver ultrasound; electroporation devices; devices that produce temperature changes by contact; and devices with components such as batteries, generators, chargers, leads, and electrode contacts that can potentially heat surrounding tissue during use.

To evaluate the thermal effects of a device, the draft guidance recommends that bench testing precede evaluation of thermal effects.  Bench testing should be conducted first to verify the device meets its specifications and to demonstrate that the subsequent data generated are representative of the final finished device’s performance.

An evaluation of thermal effects should include an assessment of tissue effects (e.g., thermal damage, tissue appearance, tissue/organ function) and related spread of thermal energy in the tissue.  These assessments may be performed experimentally (i.e., using phantoms, ex vivo animal tissue models, and/or in vivo animal testing), computationally, and/or clinically.  To determine which type of tissue evaluation is appropriate, the draft guidance recommends the magnitude and distribution of the heating and/or cooling provided by the device be considered in addition to the availability of the appropriate experimental model, noting that use of a phantom model or ex vivo animal tissue model may be appropriate for devices with local tissue temperature changes, but may not be suitable for devices with regional or systemic effects, where impact of blood flow on the development of tissue effects needs to be accounted for.

For ex vivo tissue or in vivo animal testing, the guidance includes discussion of the selection of tissue and test methods, noting that testing should be performed such that the tissue is exposed to the minimum, average, and worst-case temperature-time history.  The draft guidance discusses selection of tissues, tissue test methods, and methods for assessing the thermally affected tissue region(s), including thermal energy spread.  For measuring the thermally affected tissue region(s), the draft guidance recommends use of histological methods or methods evaluating changes in properties, such as electrical, mechanical, and optical properties or properties related to imaging.  For measuring thermal energy spread, the draft guidance discusses probe-based and image-based thermometry.

When in vivo animal testing is needed, tests should follow good laboratory practices and the animal model should be representative of the intended clinical application.  For example, aesthetic devices intended to create fractional effects, where the technical parameters of the subject device are significantly different from the comparator device, should be tested using an animal model.  Notably, this same example is used for a situation in which data from a study in humans may be needed.  The draft guidance notes that histological data from use of the device in tissues of interest in humans or an appropriate animal model should be provided.  While histological data is common in studies of animal models, it is not clear how human histological data should be obtained in a study of an aesthetic device and the draft guidance provides no discussion of this point.

The draft guidance also discusses use of computational evaluation of tissue effects and thermal energy spread, recommending that such evaluations should use computational models of relevant tissues, impose clinically relevant boundary conditions, and be validated to predict tissue effects and thermal energy spread in the intended tissue of interest for the full range of spatio-temporal temperature distribution.

Given the complexity of these studies and the lack of detail regarding the applicability of the guidance to specific devices, seeking a pre-submission may be beneficial to sponsors.  The draft guidance recommends seeking guidance through the pre-submission process to address questions of:

• The use of phantoms, ex vivo tissue, or in vivo animal models.
• Selection of appropriate model parameters for the intended clinical application.
• The induced spatial temperature distribution over time (i.e., “temperature-time history”) needed to support a claimed tissue effect.
• Design of clinical studies, when needed, to support the device’s indications for use.
• Scenarios where the recommendations in the guidance may not apply.
• Evaluation of devices that induce reversible or irreversible electroporation effects, as electroporation-based ablation has been associated with induction of cardiac arrhythmias.

The draft guidance notes that the recommendations reflect current review practices.  While companies that already market devices that produce tissue heating and/or cooling may already be familiar with FDA’s expectations, availability of the guidance should help those with new devices avoid surprises during review of their marketing applications.

After waiting with bated breath for more than a week since posting spicy Part 1 and Part 2 of our three-part series on recent U.S. Patent and Trademark Office (“PTO”) Patent Term Extension (“PTE”) decisions under 35 U.S.C. § 156 for certain FDA-regulated products, we know what you were thinking . . . .  Men in Black from the PTO’s PTE branch might have gotten to us.  Not yet!  (Though we keep looking over our shoulder.)

Part 1 focused on both the PTO’s historical and current (180-degree and unsupported change in position) on multiple PTEs.  Part 2 (“Part Deux”) investigated 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 Accelerated Approval provisions (and otherwise).  Today, we move on to Part 3 concerning a group of PTO decisions that left us floored!  And we even throw in Part 3½ in homage to the 1992 comedy “The Naked Gun 2½: The Smell of Fear” starring Leslie Nielson as bumbling Police Lt. Frank Drebin of Police Squad (who also starred in the 1980 movie “Airplane!” referenced in Part 1 of our series, and who made the “Hapsburg” quip in Part 2 of this series).

Part 3:  Who’s Buried in Grant’s Tomb? 

This blogger’s 11th grade math teacher, Mr. Neilitz, used to tell a riddle that he associated with an easy-to-answer math problem: “Who’s buried in Grant’s Tomb?”  The answer he was looking for was simply “Grant” (and not a numerical figure), although the full correct answer would be Ulysses S. Grant and his widow Julia Dent Grant.  (And, in truth, the Grants are not really “buried,” they’re “entombed” above ground in matching sarcophagi.)  The point here for our purposes, however, is that “Grant” includes both Ulysses S. Grant and his widow Julia Dent Grant.  Do you really have to identify both “Grants” to be correct?  How, pray tell, does this relate to PTEs you ask?

The PTE statute at 35 U.S.C. § 156(d)(l)(D) requires that a PTE application contain “a brief description of the activities undertaken by the applicant during the applicable regulatory review period with respect to the approved product and the significant dates applicable to such activities”  In addition, 35 U.S.C. § 156(d)(2)(B)(i) specifies the PTO must “determine if the applicant acted with due diligence during the applicable regulatory review period.”  The lack of due diligence by the applicant during the regulatory review period may be taken into account in calculating the PTE period.

Given these statutory requirements, the PTO has held that in order to be PTE-eligible, the patent owner or its agent must have undertaken the activities that led to the regulatory approval.  If a patent owner has not been involved in the regulatory process—directly or indirectly—then that patent owner has not lost any patent life.  After all, it never invested the time and resources necessary to obtain approval for commercial marketing or use. That was the case in the PTO’s April 3, 1995 decision denying a PTE as to U.S. Patent No. 4,631,286, where the PTO considered “whether Hoechst-Roussel is eligible to file an application for [PTE] based on a regulatory review conducted by its competitor, the marketing applicant Warner-Lambert, wherein Hoechst-Roussel was not associated with the regulatory review that led to FDA approval for commercial marketing of the approved product.”  The PTO said no: “the application does not set forth any activities undertaken by the ‘applicant’ — the patent owner or its agent, as required by the statute. . . .” (see also Hoechst-Roussel Pharms., Inc. v. Lehman, No. 95-650-A (E.D. Va. Oct. 27, 1995); aff’d, 109 F.3d 756, 759, 42 U.S.P.Q.2d 1220, 1223 (Fed. Cir. 1997).

Section 2752 of the PTO’s Manual of Patent Examining Procedure further clarifies 35 U.S.C. § 156(d) (and the PTO’s PTE regulations at 21 C.F.R. § 1.740), stating that:

If the applicant for patent term extension was not the marketing applicant before the regulatory agency, then there must be an agency relationship between the patent owner and the marketing applicant during the regulatory review period. To show that such an applicant is authorized to rely upon the activities of the marketing applicant before the Food and Drug Administration or the Department of Agriculture, it is advisable for the applicant for patent term extension to obtain a letter from the marketing applicant specifically authorizing such reliance. [(Emphasis in original)]

This brings us to a spate of recent letters from the PTO to PTE applicants we’ve seen titled “REQUIREMENT FOR INFORMATION PURSUANT TO 37 C.F.R. 1.750”.  They all as for the same type of information:

U.S. Patent No. 10,544,220 (October 24, 2023)

Pursuant to 37 C.F.R. 1.750, applicant is required to submit the following to the USPTO:

Evidence that Genmab A/S is expressly authorized to rely upon the regulatory review activities by Genmab US, Inc., the marketing applicant before the Food and Drug Administration to support the application for patent term extension of U.S. 10,544,220 (the ‘220 patent). . . .

The PTE application paragraph (C) on page 4 indicates that EPKINLY® (epcoritamab-bysp) received approval for commercial marketing or use on May 19, 2023. According to the PTE application, however, the “Marking Applicant for EPKINL Y® ( epcoritamab-bysp) is Genmab US, Inc., Exhibit 3. Genmab A/Sis thus relying upon the premarket activities ofGenmab US, Inc., PTE application paragraph A (page 4), to support application for patent term extension. The Office now requires Genmab A/S to provide evidence, as set forth above, of its eligibility to apply for extension of the term of the ‘220 patent under 35 U.S.C. § 156. Namely, Genmab A/S must demonstrate its agency relationship with the BLA holder (Genmab US, Inc.) as it relates to the approved product and provide evidence of its express authorization to rely upon the regulatory activities by Genmab US, Inc.

U.S. Patent No. 10,968,453 (November 29, 2023)

Pursuant to 37 C.F.R. § 1.750, applicant is required to submit the following to the USPTO:

Evidence that Biogen MA Inc. is expressly authorized to rely upon the regulatory review activities by Biogen, Inc., the marketing applicant before the Food and Drug Administration to support the application for patent term extension of U.S. 10,968,453 (the’ 453 patent). . . .

The PTE application paragraph (3) on page 5 indicates that QALSODY® (tofersen) received approval for commercial marketing or use on April 25, 2023. According to the PTE application, however, the “Marking Applicant for QALSODY® (tofersen) is Biogen, Inc., Appendix D. Biogen MA Inc. is thus relying upon the premarket activities of Biogen, Inc. to support application for patent term extension. The Office now requires Biogen MA Inc. to provide evidence, as set forth above, of its eligibility to apply for extension of the term of the ‘453 patent under 35 U.S.C. § 156. Namely, Biogen MA Inc. must demonstrate its agency relationship with the NDA holder (Biogen, Inc.) as it relates to the approved product and provide evidence of its express authorization to rely upon the regulatory activities by Biogen, Inc.

U.S. Patent No. 6,929,639 (December 6, 2023)

[Boston Scientific Scimed, Inc. (BSSI)] is required to provide evidence of authorization for its reliance on marketing applicant Boston Scientific Corporation’s activities before the FDA. . . .

The last sentence of the paragraph bridging pages 1-2 of the PTE application states, “BSSI is a whollyowned subsidiary of Boston Scientific Corporation.” Even if BSSI is a wholly-owned subsidiary of Boston Scientific Corporation as stated, it is not clear on the record of this PTE application that BSSI is entitled to rely on the activities of Boston Scientific Corporation before the FDA in connection with the filing of the PTE application for U.S. Patent No. 6,929,639.

PTE applicant BSSI is required, pursuant to 3 7 CFR 1. 7 5 0, to establish on the record of this PTE application that it is entitled to rely on marketing applicant Boston Scientific Corporation’s activities before the FDA. An authorization letter from an appropriate representative of Boston Scientific Corporation would satisfy this Requirement for Information.

U.S. Patent No. 7,553,941 (November 28, 2023)

Pursuant to 37 C.F.R. § 1.750, applicant is required to submit the following to the Office:

Evidence that Opko Biologics Ltd. is expressly authorized to rely upon the regulatory review activities by Pfizer Ireland Pharmaceuticals (Pfizer), the marketing applicant before the Food and Drug Administration to support the application for patent term extension of U.S. Patent No. 7,553,941. . . .

The PTE application states “[u]nder the terms of the AMENDED AND RESTATED DEVELOPMENT AND COMMERCIALIZATION LICENSE AGREEMENT between Pfizer Inc. and OPKO Ireland Ltd. (effective May 12, 2020), Patent Term Extension Applicant OPKO Biologics Ltd., through OPKO Ireland Ltd., exclusively licensed U.S. Patent No. 7,553,941 to Pfizer Inc. for purposes of obtaining marketing authorization for NGENLA™ (Somatrogonghla). Accordingly, OPKO Biologics Ltd. is authorized to rely upon the activities of Pfizer Inc. for the purposes of this application for patent term extension of U.S. Patent No. 7,553,941.” PTE Application at 5. However, an exclusive license is not an authorization to rely on the activities of the marketing applicant for a PTE application. Because Opko is relying on the premarket activities of Pfizer to support the application for patent term extension, the USPTO is requiring Opko to provide evidence, as set forth above, of its eligibility to apply for extension of the term of U.S. 7,553,941 under 35 U.S.C. § 156. In particular, Opko must demonstrate its agency relationship with the BLA holder (Pfizer) as it relates to the approved product and its receipt of express authorization to rely upon Pfizer’s regulatory activities.

Although there are several more examples, we’ll stop here (or here, actually).  But we hope you get our drift: the answer is “Grant; yes, both of them; isn’t that obvious?!”

Why is it necessary for the PTO to ask someone to confirm the obvious—to “triple stamp a double stamp!”, as Harry from “Dumb and Dumber” might say?  After all, if the registered practitioner submits a PTE application on behalf and alleges reliance on the a PTE regulatory review period of another and there is no conflicting PTE filed and the marketing applicant has not objected, then why can’t the PTO rely on the statements made under the practitioner’s ethical duty pursuant to 37 C.F.R. § 11.18(b).  That regulation is pretty clear.  It states, in part:

(b) By presenting to the Office or hearing officer in a disciplinary proceeding (whether by signing, filing, submitting, or later advocating) any paper, the party presenting such paper, whether a practitioner or non-practitioner, is certifying that—

(1) All statements made therein of the party’s own knowledge are true, all statements made therein on information and belief are believed to be true, and all statements made therein are made with the knowledge that whoever, in any matter within the jurisdiction of the Office, knowingly and willfully falsifies, conceals, or covers up by any trick, scheme, or device a material fact, or knowingly and willfully makes any false, fictitious, or fraudulent statements or representations, or knowingly and willfully makes or uses any false writing or document knowing the same to contain any false, fictitious, or fraudulent statement or entry, shall be subject to the penalties set forth under 18 U.S.C. 1001 and any other applicable criminal statute, and violations of the provisions of this section may jeopardize the probative value of the paper. . . .

Of course, PTE applicants respond to the PTO’s information requests, but it takes time and money to do so.  And the PTO is not alone in putting form over function; FDA is increasingly doing so as well!  Take, for example, a recent instance this blogger faced when submitting generic drug Controlled Correspondence to FDA on behalf of a prospective generic drug applicant.  The Letter of Authorization that needed to be submitted was on company letterhead identifying “COMPANY NAME, INC.”, and the signature block identified the signatory as coming from “COMPANY NAME USA, INC.”  That Controlled Correspondence—actually, five of them, because a separate Control needs to be submitted for each approved strength—was bounced and needed to be resubmitted, resulting in a waste of time snd resources.

That segues us nicely into a bonus piece . . .

Part 3½:  Seriously? 

On April 29, 2022, FDA approved Tap Pharmaceuticals, AG’s (“Tap’s”) NDA 215809 for EMERZA (levothyroxine sodium) Oral Solution.  A PTE application (Docket No. FDA-2023-E-2391) was subsequently submitted to the PTO seeking an extension of U.S. Patent No. 9,345,772.

On November 4, 2022, the PTO sent a REQUIREMENT FOR INFORMATION PURSUANT TO 37 CFR 1.750 stating, among other things, the following:

There is a discrepancy in the patent term extension (PTE) application regarding the name of the approved product. The FDA approval letter attached to the PTE application as Exhibit A indicates that the approved product of NDA 215809, referenced in the PTE application, is ERMEZA® (levothyroxine sodium). Thus, our letter to the FDA dated the same day as this Requirement for Information presumes that the PTE application concerns ERMEZA® (levothyroxine sodium).

However, the second full paragraph of the PTE application is as follows:

The approved product of NDA 215809 is ERMEZA® (levothyroxine sodium) oral solution (EMERZA® or the Approved Product). EMERZA® was approved for commercial marketing under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA). (See pages 1 and 35 of the NDA APPROVAL Letter from the FDA, provided as Exhibit A) And the ‘772 patent contains claims that cover EMERZA®.

We note that the paragraph reproduced above includes one reference to “ERMEZA®” and three references to “EMERZA®.” It would appear that “ERMEZA®” was intended, because that tradename is associated with NDA 215809. Nevertheless, for the sake of clarity, Tap is required to confirm the tradename of the approved product.

The PTO letter further requests that “Tap is required to provide evidence of authorization for its reliance on marketing applicant Mylan’s activities before the FDA,” and that “Tap is required to provide support for the submission and approval dates of NDA 215809.”

It appears that Tap never responded to the PTO.  As such, on August 7, 2023—nearly two months after the response deadline—the PTO sent a letter saying that the PTE application for EMERZA had been withdrawn.  Wow!  That’s pretty draconian for a typo (as well as the other issues noted).  And I’ll bet you didn’t even notice that we used “EMERZA” above twice instead of “ERMEZA”!

***

Well, there you have it folks.  We hope that it has been an informative—and hopefully an entertaining—ride.  But you may be asking yourself: “Kurt, why invest so much time and effort in calling out all of these PTO actions?”  It’s a fair question.

First, as folks know, this blogger loves this stuff.  Anything Hatch-Waxman is of interest to me, and is something that I believe deserves the light of day.  The continued integrity of the Hatch-Waxman Amendments—and FDA and PTO interpretations of it—is something in which I am personally invested.

Second, while I realize there are pressures on PTO (and FDA) to “do something” about drug procing and patent concerns, there’s a right way to go about doing that and a wrong way.  Unjustified position reversals, new interpretations, elevating form over function, and denying patent term because of a spelling error is probably not the best way to go about change.  The controversies and battles they often lead to are expensive—in both private and government time and resources.  Those resources might be better used to explore substantive and meaningful changes to the law that—consistent with the intent of Congress in passing the Hatch-Waxman Amendments—“help ensure the intended balance between encouraging innovation in drug development and accelerating the availability to the public of lower cost alternatives to innovator drugs is maintained.”

After years of silence from FDA on whether certain patents could be listed in the Orange Book, some manufacturers of drug and device combination products have had a rude awakening lately.  As we explained in September 2023, then again in November 2023, the FTC has intervened in the matter and asked 10 drug companies (really 8 given common ownerships of some of the relevant companies) to delist about 100 patents from the Orange Book that mainly cover the device constituent of a drug/device combination product.  On the heels of those FTC letters, Senator Warren and Representative Jayapal sent letters to the CEOs of those 8 companies urging them to remove the “sham patent claims improperly included” in the Orange Book, claiming that these companies have been “taking advantage of a loophole that delays generic competition.”

These companies have clapped back.  In their responses, each company emphasized that none of the patents listed were “sham patents” and that FTC never challenged the legitimacy of the patents.  While the letter from Congress suggested nefarious motives for listing these patents, each company pointed out that it was required to list all relevant patents and that FDA repeatedly had refused respond to questions about the proper listing of these types of patents. As Abbvie wrote: “While your letter refers to ‘sham’ patents and concerns about ‘abusing the patent system,’ the FTC’s letter makes no assertions that these patents were ill-gotten or are otherwise illegitimate.  Rather, the FTC questioned whether these patents meet the statutory and regulatory criteria for listing in the Orange Book.  In fact, federal law and regulation appear to require AbbVie to list these patents.”  No matter how Congress and FTC frame it, it is FDA that’s to blame for the listing confusion when it has had more than 20 years to respond to questions about whether these types of patents should have been listable in the first place.  And FDA still hasn’t said a thing!

Despite the continued lack of clarity about the propriety of listing device component patents in the Orange Book, 3 companies agreed to remove the patents cited by FTC while 5 others refused to delist.   Amneal delisted the requested patents, as well as two other patents, but pointed out that all of these patents were listed “[i]n a good faith effort to comply with the statutory requirement [to list relevant patents] given the regulatory guidance at the time . . . .”  Kaleo also delisted, but not without noting that “the decision to list each of these patents was proper, consistent, and required by the applicable statutes, regulations, and FDA’s guidance available at the time of listing.”  GSK and Glaxo Group, while defending their decision to list the relevant patents, delisted, citing to the “recent shift in policy, and the existence of potentially applicable case law in recent years, regarding the application of Orange Book listing criteria to patents covering drug-device combinations.”

Taking the opposite approach, AstraZeneca, Boehringer Ingelheim, Abbvie, Mylan/Viatris, and Teva all refused to delist the patents referenced by FTC and Congress.  Each made similar points as the 3 that did delist: patents that claim the finished dosage form must be listed in the Orange Book, and the referenced patents claim the finished dosage form.  Several even try to rewrite the anticompetitive narrative that Congress is painting by reminding Congress that the Orange Book listing of patents is intended to benefit both the brand and the generic by providing notice of such patents and providing an opportunity to address the patents prior to launch (at which point treble damages could be awarded).  Failing to list the patents, as AstraZeneca points out, “may expose the reference drug sponsor to legal risks,” as “at least one generic applicant has argued that a failure to do so constitutes a violation of the antitrust laws by depriving the applicant of information that would have affected its decision whether to develop a generic product.”

Both Congress and FTC seem to have spun this tale that the named drug companies have been intentionally abusing the Orange Book patent listing requirements by including device patents in the Orange Book, but it’s really important to note that until FTC took the unusual step of requesting delisting in Fall 2023, FDA not only had provided no guidance on whether device patents are listable but also refused to address the question when asked by industry on several occasions.  And, in fact, FDA muddied the waters itself when it stated in the 2003 implementing regulation preamble that “patents claiming devices or containers that are ‘integral’ to a drug product or require prior FDA approval should be submitted and listed” and noting that patents claiming a finished dosage form of a product, which include “metered aerosols, capsules, metered sprays, gels, and pre-filled drug delivery systems,” should be listed.  It’s difficult to conclude from these statements, as FTC and Congress appear to have, that device patents categorically shouldn’t be listed in the Orange Book.

FTC’s and Congress’s activities seem to have triggered litigation.  On March 6, 2024, the first antitrust suit arising from these letters was filed by the Massachusetts Laborers’ Health and Welfare Fund in the District Court of Massachusetts against Boehringer Ingelheim.  That Complaint alleges that “Boehringer improperly submitted 23 device patents to the Orange Book as claiming Combivent Respimat” and another 16 “as claiming Spiriva Respimat” citing specifically to FTC’s and Congress’s inquiries.  We expect that this is just the first of many antitrust cases to come—with AstraZeneca, Abbvie, Mylan/Viatris, and Teva all likely to be on the front lines.

On February 20, 2024, FDA issued a letter to the medical device industry (link) warning medical device firms of recent FDA concerns related to fraudulent and unreliable laboratory testing data in premarket submissions.  Unfortunately, the letter provides little new information to guide industry conduct.  While the title of the letter refers to “fraudulent” data, the rest of the letter provides no explanation of the nature of the allegedly fraudulent activities that could assist industry in identifying bad labs.

It is challenging for device firms of all sizes to maintain the facilities, equipment, and deep subject matter expertise necessary to perform in-house testing necessary to satisfy all requirements for their device type, which may include testing related to sterility, microbiology, biocompatibility, electrical safety, electromagnetic compatibility, software, cybersecurity, human factors, and performance (which includes bench, animal, and clinical tests).  Given this, it is common for firms to contract with independent labs (“third-party test labs”) to generate data for premarket submissions.

For many firms, these third-party test labs are qualified according to the firms’ procedures for purchasing controls (21 C.F.R. § 820.50) prior to the start of testing.  These procedures often define a process to review the qualifications of the lab based on experience, accreditations, policies, and procedures.  For firms developing their first device, these purchasing procedures may not yet be established at the time selection of labs is being performed.  Even so, firms typically evaluate a prospective lab based on its experience, in addition to business considerations such as availability, turnaround time, and cost.

The letter to industry states that FDA has observed testing data from third-party labs that are “fabricated, duplicated from other device submissions, or otherwise unreliable,” that such unreliable data has been generated by “numerous such facilities based in China and India,” and that submission of unreliable data “calls into question the data integrity of the entire file.”  While we suspect that we know why FDA is not naming names—presumably because of ongoing investigation and enforcement activities—the lack of transparency is unfortunate on several levels.  First, it raises the specter of guilt by association for reputable labs in China and India.  While we imagine that FDA is providing specific labs an opportunity to respond to specific allegations, announcements such as this have real world consequences for reliable labs that happen to be based in those countries.  Second, while not dispositive, it likely would be relevant to regulated industry for FDA to identify those labs it believes are generating fraudulent and unreliable data.

In addition to providing limited notice of these issues, the letter also provides general recommendations to the device industry, noting that it is “incumbent on device firms to take proactive steps to qualify third-party test labs and to closely scrutinize all testing data that a firm does not perform itself, especially relating to biocompatibility and other performance testing.”  FDA acknowledges that it may be difficult to detect if data have been copied but expects “device firms to identify testing results that are improbable or impossible on their face or do not seem consistent with known information about the device.”  FDA’s letter further notes that even if the lab is accredited under FDA’s own Accreditation Scheme for Conformity Assessment, that such accreditation “does not substitute for conducting an independent assessment of all third-party data.”

As noted above, while it is typical for device firms to do some level of vetting of third-party test labs, one reason such firms often use a third-party lab in the first place is because they do not have in-house expertise.  Catching obvious errors may be possible during review by a non-subject matter expert, but it is highly unlikely that these reviewers will be able to detect results that are “improbable or impossible.”  Engaging another third-party subject matter expert to review data provided by a third-party lab would significantly increase the burden to device firms.  And if bad actors intend to provide fraudulent data in their reports, these data may appear realistic for the type of device and near impossible to detect, making any efforts to scrutinize data an added burden that provides no value.  Thus, at the end of the day, with no detail from FDA as to which labs to avoid, industry is left with no actionable information.

The letter also provides no information as to how FDA will handle the identification of unreliable data in a premarket submission that is currently pending.  Will the Agency notify the applicant of the issue so that it can seek to have new testing conducted?

Further, this issue is not just affecting new submissions.  FDA appears to be reviewing at least some previously cleared 510(k) submissions if there is a suspicion of fraudulent data.  FDA has gone so far as to rescinded at least one 510(k) based on its determination that allegedly unreliable data have been submitted, even in the case where discrepancies in the data were obvious and not caught during FDA’s own review of the submission and subsequently explained as a simple mistake (Stay of Action Petition from Hyman, Phelps & McNamara, P.C. On behalf of Nautilus Gloves LLC (Nautilus), link).

The Agency’s action to rescind this 510(k) is based on questionable legal authority.  See our prior post of the Agency’s ability to rescind a 510(k) submission here.  FDA has the regulatory authority to withdraw a clearance if unreliable clinical data are submitted in a 510(k).  21 C.F.R. § 812.119(e).  The labs that FDA is referring to in this letter, however, are not conducting clinical studies.  They are conducting non‑clinical testing, including, for example, biocompatibility testing.  FDA does not have the same regulatory or legal authority to rescind a 510(k) for unreliable non-clinical data unless such data is the result of misconduct.  FDA’s letter provides information on what FDA would view as misconduct in the case of a lab deceiving the sponsor by submitting fraudulent/fabricated data.

FDA’s letter to industry is an important step in communicating this issue, but putting the resolution of the issue all back on individual firms to address is not the best solution.  While FDA has guidance related to data integrity for the drug industry (link), such guidance has not been established for the device industry itself.  Given FDA awareness of the issue, practical guidance to help firms establish and maintain data integrity across the total product lifecycle would be more valuable as a long-term solution.  It is also critical for FDA to be transparent with industry as to how this issue will be handled for pending and cleared submissions. The sponsors are almost always victims that had no intention to deceive the Agency.  Unless or until FDA can provide actionable guidance on how to avoid being deceived and/or how to manage the issue, if it is uncovered, we urge FDA to give sponsors the benefit of the doubt and work with them to resolve the issue.

In 2009—15 years ago— the National Organization for Rare Disorders (NORD) announced the first U.S. recognition of Rare Disease Day.  NORD’s announcement followed in the footsteps of European rare disease patient organization, Eurodis, who had celebrated the first Rare Disease Day the year before.  Time flies when your goal is to support the thirty million Americans with rare diseases.  The global rare disease community did not just celebrate Rare Disease Day, but Rare Disease Week, the entire last week of February!

In 2009 I served as Chair of NORD and through the hard work of countless colleagues we inaugurated the first Rare Disease Day.  The idea that year was simple and straightforward—every four years there is a rare day, February 29, so what better day to choose to honor those with rare conditions.  In non-leap years we celebrate on February 28 or March 1.

What started as a day has—due to its popularity and the persistent efforts of patients and industry—evolved into a week-long event.  I was honored to be invited to speak at the plenary session of FDA’s inaugural Rare Disease Day gathering several years ago.  And my support and pride continue since we now see a host of programs and events the last week of February playing out around the world.

This year the Everylife Foundation for Rare Diseases held a week of activities in which more than 800 rare disease patients—from all 50 states, DC, and the Cherokee Nation—advocated in Washington DC.  I currently serve as Vice Chair of the Board of the Everylife Foundation.  I’m proud to share with you that Everylife’s “patient army” held more than 330 meetings with members of Congress last week.  Led by Annie Kennedy, Everylife’s VP of Government Affairs and Policy, we worked the halls of Congress to educate lawmakers on the pressing needs of the rare disease community.

On February 28th, the White House hosted its first ever rare disease event.  It’s astounding that it took this long for any administration—Republican or Democrat—to recognize the thirty million strong rare disease community in our country.  Annie Kennedy chaired a panel discussion and the NIH Director and the NCATS Director spoke passionately of the ways in which the federal government is supporting and planning to expand its work on rare diseases.

Among the forty or so individuals invited to this White House event were long-time rare disease advocates like recently retired FDA Principal Deputy Commissioner Janet Woodcock, Christina Hochul of Alexion and Paul Melmeyer of Muscular Dystrophy Association.  It was a highlight of my career to also be invited to this historic event.

Given the energy and progress accomplished each year at this special time, anyone want to second a motion that the entire month of February become dedicated to the support of rare diseases?  Onward!

Photo from February 28, 2024, White House Rare Disease event (from left to right: Frank Sasinowski, Christina Hochul, Paul Melmeyer)

Last August the Food and Drug Administration (“FDA”)/Health and Human Services (“HHS”) recommended that the Drug Enforcement Administration (“DEA”) reschedule cannabis from schedule I under the federal Controlled Substances Act (“CSA”) to schedule III.  By doing so, FDA/HHS believe that cannabis no longer meets schedule I criteria but does not meet schedule II criteria either.

Hyman, Phelps & McNamara Director Larry Houck will participate as a panelist focusing on this timely topic at the Food and Drug Law Institute’s (“FDLI’s”) Legal and Practical Issues in Cannabis Regulation Conference next month.  Mr. Houck will participate in a session entitled “Marijuana Rescheduling: Exploring FDA’s Recommendation, Stakeholder Impact, and Broader Implications.”  Likely discussion topics during the session will address what has changed since 2016 when FDA/HHS and DEA concluded that cannabis remain in schedule I, why DEA may be required under U.S. treaty obligations to reschedule cannabis in schedule II, and rescheduling implications on federal CSA requirements and in the states that authorize cannabis for medical and recreational use.

Additional sessions planned for FDLI’s conference include: “Surveying the State of Cannabis Research,” “Navigating the Evolving Cannabis and Cannabis-Derived Products Marketplace,” “Notable Decisions and Emerging Trends in Cannabis Litigation,” and “Global Perspectives on Cannabis Regulation.”

The conference, held in Washington, D.C., April 4th and 5th, is an in-person and virtual event.  Additional information, including a preliminary agenda, is available at the conference webpage here.

Our last post on small business certification requests described how small medical device manufacturers, defined as those with gross receipts of less than $100 million in gross receipts and sales for the most recent tax year, are eligible for a reduced fee on those medical device submissions that require a user fee. Now, FDA is granting a waiver of annual registration fees, per the draft guidance for Select Updates for the Medical Device User Fee Small Business Qualification and Certification Guidance.  The catch: the company has to be small and bankrupt.

Section 3309 of the Food and Drug Omnibus Reform Act (FDORA), signed into law on December 29, 2022, amended section 738(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) by adding clause (ii) “Small business fee waiver.” This gives FDA discretion “to waive the establishment registration fee for device establishments that are small businesses, if FDA determines that paying such fee represents a financial hardship,” starting on October 1, 2024. FDA considers a “clear and objective standard” of financial hardship to be when a small business is in active bankruptcy. While this standard has the benefit of being “clear and objective,” it also essentially guts the waiver provision.

Applying for a Small Business Registration Fee Waiver

Per the draft guidance, FDA proposes to combine forms FDA-3602 and FDA-3602A into a single form. The forms are currently used for businesses headquartered in the US and OUS, respectively, to request a small business certification. FDA also proposes to add to the new combined form, a “Registration & Listing Fee Waiver” section, which asks if businesses have registered in the past.

To be considered for the registration fee waiver, a small business in the US or OUS has to demonstrate “financial hardship”. If a business is applying for a small business registration fee waiver, it is recommended that the following be provided to FDA:

1. Income tax return(s) showing $1 million or less in gross receipts or sales (including affiliates);
2. Evidence that the establishment for which a waiver is being sought has previously registered and paid the associated fees under the owner/operator ID with FDA; and
3. Evidence that the establishment if in the US, filed a petition for bankruptcy or if OUS, filed the jurisdiction’s equivalent of a US bankruptcy action.

For those without a National Taxing Authority (NTA), requests for a small business registration fee waiver are considered on a case-by-case basis pending review of gross sales and receipts that demonstrate the establishment falls below the $1 million threshold to qualify. FDA does not squarely address whether those who operate in jurisdictions without an NTA must also have filed the equivalent of a US bankruptcy action through their jurisdiction’s court systems. FDA explains that it chose bankruptcy as a criterion because it satisfies “a clear, objective standard, the meeting of which is a matter of public record.” FDA does not explain why it chose the extremely low sales threshold of $1 million.

Considerations

A sponsor is granted a small business designation for each fiscal year it submits a request and is able to provide evidence that its gross receipts and sales are less than $100 million for the most recent tax year. While FDA does not address an annual expectation for a request for a registration fee waiver in the draft guidance, we expect FDA to be consistent with the Small Business Certification and require an annual application for the registration fee waiver, if applicable.

Sections 738(d)(2)(A) and (e)(2)(A) of the FD&C Act define a “small business” as an entity that reported $100 million or less of gross receipts or sales in its most recent income tax return. FDA uses that definition to designate small businesses eligible for a reduced user fee. FDA goes 100 times further to designate those businesses eligible for a registration fee waiver. Specifically, any business that reported $1 million or less in gross receipts in its most recent tax filing can be considered small.  We consider it micro. Nevertheless, FDA does not offer any insight on why they chose $1 million as the threshold for businesses to obtain a registration fee waiver. This limit – combined with the requirement that the company has filed for bankruptcy — makes it such that very few businesses would benefit.

The draft guidance does not change the existing policy of no reduced fees for registration. That is, a small business either qualifies for the registration fee waiver or does not.

Newly established businesses are unlikely to qualify for the registration fee waiver because they will not be able to meet the second criterion above.

There is no transferability provision that allows one small business to transfer the fee waiver or user fee reduction to another entity. As an example, FDA points to a device establishment certified by FDA as a small business that is then acquired by another entity. The entity is responsible for the full fees unless it obtains its own small business determination. This is consistent with current FDA expectations.

Finally, in the Federal Register notice, FDA estimates 4,500 requests for a Small Business Certification. Our review of the 4^th Quarter 2023 MDUFA V Performance Report shows that just 2,283 applications were eligible for a reduced user fee.  While it is possible that each application is tied directly to a single small business request, suggesting that 2,283 applicants benefitted from a small business designation, this is unlikely to be the case as some businesses may submit multiple submissions within the fiscal year.

We expect few, if any, businesses will meet all three elements for an exemption:  sales under $1 million, previously paid and registered with FDA, and bankrupt. On top of that, the need to provide evidence of bankruptcy and micro sales to FDA at a time when a business is already under financial duress may prove too much for a small device manufacturer to tack on their to-do list.   In essence, FDA has taken the exception created by Congress and made it available only to device companies that are already in extremis.

Comments to the draft guidance must be submitted by April 22, 2024.

The trio of CDER, CBER, and CDRH released a new draft guidance titled “Use of Data Monitoring Committees in Clinical Trials” that revises the 2006 guidance “Establishment and Operation of Clinical Trial Data Monitoring Committees” and, when final, will replace the 2006 guidance.  The new draft guidance was published in recognition by FDA that Data Monitoring Committees (DMC) (aka Data and Safety Monitoring Boards (DSMB), Data and Safety Monitoring Committees (DSMC), or Independent Data Monitoring Committees (IDMC)) are increasingly being utilized by sponsors to implement adaptive trial designs, to review aggregate data for safety reporting, and to oversee an entire clinical development program rather than a single trial.  Moreover, DMCs are being used in trials of modest size and in the context of increased globalization of medical product development.  DMC charters have also grown longer and more detailed.  The new draft guidance is generally reflective of these developments, and we wanted to highlight several of the changes in this blog post.

One notable change in the new draft guidance is the language regarding when a DMC is recommended, reflecting the much broader adoption of DMCs since 2006.  In 2006, FDA stated that DMCs were not recommended “for most clinical studies,” particularly those in early product development, short-term studies, or studies addressing less severe outcomes.  Instead, FDA recommended that sponsors “limit the use of a DMC” to clinical studies in which safety concerns may be unusually high, such as studies that compare rates of mortality or major morbidity or involving a potentially fragile or high-risk population, or large, multi-center studies of long duration.  The new draft guidance maintains some of these recommendations (that is, a DMC is warranted when subjects in the study are at risk of serious morbidity or mortality, the study enrolls vulnerable populations, and for longer-term studies), but also highlights factors that might suggest the value of DMCs in new roles, such as where causation of adverse events may be difficult to assess without a review of unblinded data or where there is limited experience in a therapeutic area.  Along those lines, the new draft guidance does not contain any language regarding DMCs not being appropriate for early phase studies.

Other Oversight Groups

Both documents described the role of other oversight groups, in addition to DMCs, that may be involved in a clinical trial in similar, sometimes overlapping, roles such as IRBs, trial steering committees, and site monitors.  In another update, the recent draft guidance added “entities reviewing safety data” and adaptation committees.  FDA notes that the distinctions between responsibilities for these groups and DMCs should be clearly defined, particularly with respect to access to unblinded information.  For example, an entity reviewing safety data may need to review unblinded safety data to recommend whether or not the sponsor should submit a report to FDA.  However, in contrast to DMCs, such an entity should remain blinded to efficacy data.  FDA acknowledges that the threshold for a DMC to recommend termination or significant modification based on safety concerns may be higher than the threshold for reporting potential serious risks to FDA; this is reflective of the fact that there may be situations where oversight groups observe a serious risk and recommend that the sponsor report it to FDA, but the DMC may still recommend the trial continue based on its overall assessment of unblinded safety and efficacy data.  In such cases, the draft guidance illustrates how employing a DMC may allow a sponsor to proceed with a trial where it might otherwise have been terminated.

Both guidances note that the most common purpose of a DMC is to monitor clinical trials for safety, usually by conducting unblinded interim analysis of data from an ongoing clinical trial.  The new draft guidance acknowledges that an interim analysis may be appropriate in other circumstances, particularly when “[i]mplementing a predefined adaptive feature” in a study, such as to increase trial size or to introduce prognostic enrichment.  Adaptive study designs are becoming increasingly prevalent, and sponsors often use adaptation committees to perform such interim analyses. If the adaptations are to be done on the basis of unblinded data, the new draft guidance emphasizes the importance of prespecification and preservation of trial integrity.  The new draft guidance states that while a DMC could be assigned the role of recommending to the sponsor that a specific adaptive design element be implemented (if specified in the DMC charter), that might best be reserved for relatively straightforward adaptive designs with simple adaptation algorithms.  Use of a separate adaptation committee might enable the inclusion of more relevant expertise and allow the DMC to focus on its primary responsibilities – subject safety and trial integrity.

DMC Composition

Regarding the membership of the DMC, the new draft guidance is largely similar, but substantially less specific on its recommendations.  Both documents discuss how membership should include individuals without conflicts of interest and with expertise in trial conduct, relevant clinical specialties, a qualified biostatistician, and a medical ethicist (in studies with greater risk).  They also both stressed the value of previous DMC experience.  However, notably absent from the new draft guidance are some specific recommendations from the 2006 guidance regarding number of members, types of scientists, and representatives of the relevant patient population and from different gender and ethnic groups.  Another update in the new draft guidance is a recommendation that for the DMC chair, in addition to previous DMC experience (which was in the 2006 guidance), familiarity with FDA regulatory requirements is “typically critical.”

Increased Connections Between a DMC and FDA?

Both documents note that FDA may request that the sponsor submit the DMC charter to FDA for review before the performance of any interim analyses, and ideally before the initiation of the trial. Both documents also note that FDA may request copies of the DMC meeting records when the study is completed, and access to the electronic data sets used for each set of interim analysis.

However, the new guidance suggests that FDA may be recommending, or perhaps acknowledging, a greater degree of its involvement with DMCs.  For example, the new draft guidance recommends that the DMC should have “procedures for adding or removing members when appropriate or for disbanding the DMC, including procedures for informing FDA and disclosing to FDA the rationale for these changes.”  As another example, both documents note the possibility that if FDA has safety information relevant to an ongoing study, it may request that the sponsor confirm that the DMC is aware of that safety data and is taking it into consideration, or “request that the sponsor arrange for FDA to communicate with, or even meet with, the DMC.”  The 2006 guidance noted that these would be “rare cases” limited to “specific issues of urgent concern.”  FDA has dropped such restrictive language in the new draft guidance, and instead intends to refer “relevant and important” information.  As a final example, current regulations require a sponsor of an investigational medical device to report to FDA (and others) “unanticipated” adverse events, which are defined in part as “serious,” and sponsors of investigational drugs to report to FDA serious and unexpected suspected adverse reactions.  The new draft guidance maintains a recommendation from the 2006 guidance that “sponsors inform FDA about all DMC recommendations related to the safety of the investigational product, whether or not the adverse events that led to the recommendation meet the definition of serious.”  The draft guidance therefore continues to “recommend” sponsors go beyond what is required in its regulations in its communications to FDA based on DMC recommendations, highlighting the tension between what FDA needs and what it wants.  Taken together, such changes suggest that FDA may intend to play a larger role in its interactions with the DMC, either directly, or through the study sponsor.

Safety Monitoring

Regarding DMC responsibilities, the two guidance documents are fairly similar on safety monitoring.  In addition to any identified adverse events of particular concern, the 2006 guidance stated that the DMC should be provided with interim summaries of adverse events by treatment arm; the new draft guidance limits this to interim summaries of serious adverse events.  Similarly, the 2006 guidance stated that DMCs will not usually review in detail every adverse event reported, or even every serious adverse event; the new draft guidance is more agnostic on whether all serious adverse events should be reviewed (“the committee may elect to review all or just certain serious adverse events”).  The new draft guidance notes the practicalities of a DMC for short-term trials are not as well established as those for long-term trials.  It cautions that sponsors who consider DMCs for safety monitoring of short-term trials should ensure processes are in place to allow for timely DMC evaluations or oversight on data and safety.  Sponsors of short-term trials, such as those where enrollment is expected to be completed quickly or with short follow up, may find that establishing DMCs to review interim data/analysis may be “impractical and of little value.”

Effectiveness

Both guidances acknowledge that DMCs should have access to unblinded interim data and analyses, including analyses of effectiveness, and emphasize procedures to ensure that the sponsor and investigators in the study remain blinded.  The new guidance specifically recommends that the independent statistician performing those analyses for the DMC should be “clearly firewalled and have no role in modifications of the trial conduct.”  The 2006 guidance also contained an admonition that prematurely terminating studies of less serious outcomes based on effectiveness is “rarely appropriate;” this is absent in the new draft guidance.  Although the sponsor must keep in mind the impact of an early termination, this change appears to be reflective of an acknowledgement that it is perhaps more than just “rarely appropriate” for DMCs to recommend early termination for effectiveness when data are compelling and a false positive risk is acceptably low, even where outcomes are less serious.

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Sponsors considering the use of DMCs (or DSMBs, DSMCs, IDMCs) should carefully consider the recommendations and advice provided in this draft guidance, even prior to its finalization. As reflected in the changes from the 2006 guidance, the new draft guidance describes how DMCs are increasingly used for a variety of critical functions as an independent body with access to unblinded data from the ongoing trial.  It is also reflective of evolving FDA perspectives, in addition to evolving regulatory science.  In addition to adjusting its recommendations in acknowledgement of expanding DMC roles, the new draft guidance is also more focused on the potential utility of DMCs, with most of the language removed describing where they should not be employed (early phase trials, etc.).  This blog post focuses on a few of the specific changes from the 2006 guidance to highlight some changing perspectives, but sponsors should review the new draft in detail to fully understand FDA’s recommendations.

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