Eric Idle, as a body collector, immortalized the phrase, “Bring out your dead,” in the 1975 comedy classic, Monty Python and the Holy Grail.  The Drug Enforcement Administration (“DEA”) could voice a modern variation, “Bring out your meds,” as the agency and its law enforcement partners host local drop-off locations nationwide for safe disposal of unneeded medication on Saturday, April 22, 2023, from 10:00 a.m. to 2:00 p.m. local time.

Stockpiles of old, unwanted and expired controlled prescription medication in medicine cabinets are susceptible to theft, misuse and abuse.

DEA hosts National Prescription Drug Take Back Days each spring and autumn.  DEA’s Take Back Day last October collected almost 650,000 pounds of unneeded medication at about 5,000 collection sites.  DEA’s bi-annual Take Back Days have collected nearly 17 million pounds of medication since 2010.  More information about DEA’s National Prescription Drug Take Back Day, including disposal locations, can be found at: https://www.deadiversion.usdoj.gov/drug_disposal/takeback/index.html.  That DEA website also lists permanent, year-round disposal locations.

So, bring out your meds!  Bring out your meds!

On Thursday, April 20, from 1:30-3:00pm, John Claud of Hyman, Phelps & McNamara, P.C. will present a webinar entitled “Medical Device Enforcement: Latest Developments from the FDA, DOJ and FTC.”

John will provide participants with a greater understanding of new guidance implications, as well as recent guidance on delaying, denying, limiting, or refusing an inspection, and the DOJ’s revised Corporate Enforcement Policy, which altered the way the agency reviews corporate criminal prosecution decisions.

Other key takeaways will include: a  comprehensive understanding of how FDA, DOJ, and FTC coordinate their priorities and resources for enforcement actions of medical devices; a review of recent FTC enforcement cases, with a focus on the perils of promoting claims that aren’t supported by science; an explanation of the FTC’s health products compliance guidance and other rules; key updates from the FDA’s guidances on medical device-related cybersecurity; and, tips for navigating DOJ’s new Corporate Enforcement Policy.

Register here!

Drugs and substances classified within schedule I of the federal Controlled Substances Act (“CSA”) by definition have a high potential for abuse, no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision.  21 U.S.C. § 812(b)(1).  Last month bipartisan legislation, S. 689 and H. 1393 introduced in the Senate and the House, would facilitate removing barriers to research and compassionate use for schedule I controlled substances including the psychedelics psilocybin and 3,4-methylenedioxymethamphetamine (“MDMA”).

Senator Cory Booker (D-NJ), a co-sponsor of the Breakthrough Therapies Act in the Senate with Senator Rand Paul (R-KY), stated that MDMA and psilocybin “have shown exceptional promise in treating an array of mental health conditions, including treatment-resistant suicidal depression, anxiety, PTSD, and substance use disorders.”  Booker, Paul, Mace, Dean Introduce Bipartisan Legislation to Promote Research and Access to Potential Life Saving Drugs, Mar. 8, 2023.  Booker opined that the Act would expedite rescheduling schedule I substances that receive breakthrough therapy designation to schedule II that “with DEA oversight-will enable patient access and reduce the burden on further clinical investigation.”  Id.

On the House side, Representative Nancy Mace (R-SC), a cosponsor of the companion House bill with Madeleine Dean (D-PA), noted that MDMA and psilocybin research “has been so promising” that the Food and Drug Administration (“FDA”) designated them as “Breakthrough Therapies,” meaning that “they demonstrate substantial improvement over any currently available treatments with a clear demonstration of efficacy.”  Rep. Mace & Dean with Sen. Booker & Paul introduce the Breakthrough Therapies Act for Veterans and Patients, Mar. 7, 2023.

Mace cited recent research in the U.S. and United Kingdom demonstrating “significant medical benefits” of MDMA and psilocybin, noting that The New England Journal of Medicine published Phase 2b clinical trial results showing that a small dose of psilocybin caused remission of treatment-resistant depression in about 30% of patients.  Id.  Likewise, a 2020 National Center for PTSD study of MDMA use by military veterans led to significant reductions in suicidal thoughts, PTSD, depression, and anxiety.  Id.

The Breakthrough Therapies Act would facilitate access research with schedule I substances like MDMA and psilocybin by amending the CSA’s “currently accepted medical use with severe restrictions” criteria.  Id.  The Act would revise criteria to include the active ingredients of therapies that receive FDA Breakthrough Therapy Designation or Expanded Access approval “to treat patients with serious or life-threatening diseases for which no comparable or satisfactory therapies are available.”  S. 689, § 1 (to be codified at 21 U.S.C. § 802(a) (7)(A)).  With this definition, DEA would begin making findings necessary to transfer breakthrough therapies involving schedule I substances to schedule II for limited research and compassionate medical use.  Schedule II regulatory requirements for research are less restrictive than schedule I requirements, which require schedule I researchers to submit and receive approval of a research protocol with detailed information depending upon whether their research involves human or animal subjects.

The legislation, while loosening requirements for necessary MDMA, psilocybin, and other research, presents no increased risk of diversion of those substances from legitimate channels.  The Act would create an expedited process for DEA to transfer an Expanded Access drug from schedule II back to schedule I if the drug is placed on clinical hold.  Id.

If enacted, the Act would facilitate research, access to, and potential roll-out of promising psychedelic and other potentially lifesaving therapies via compassionate use pilot programs.

The bills were introduced in their respective chambers on March 7th, then referred to the Senate and House Committee on the Judiciary, and to the House Committee on Energy and Commerce.

The text of the bill can be found here.

South Korea has made significant achievements over the years in the biohealth industry, establishing the world’s second-largest biopharmaceutical manufacturing capacity. South Korea continues to drive the effort in the biohealth industry, which will lead to more Korean players in the U.S. market.

The South Korean government has recently announced its plan to provide support for the growth of the nation’s biohealth industry, aiming to establish it as a significant and strategic sector in the nation, similar to the semiconductor industry. South Korean President Yoon Suk Yeol plans to provide full support to create a Korean version of the Boston Biotech Cluster. President Yoon also urged lawmakers to pass the digital healthcare bill that would protect personal data while boosting the industry’s competitiveness through data usage.

In line with President Yoon’s orders for biohealth and digital healthcare development, the Ministry of Health and Welfare proposed new strategies with the following five core tasks to achieve the objectives of making new digital markets and activating biohealth exports.

1. “Innovation of data-driven medical, health, and care services;
2. Activation of exports of the bio-health industry;
3. Ramp up of R&D in advanced convergence technologies;
4. Development of advanced bio-health experts and increase of startup support;
5. Establishment of laws, frameworks, and infrastructure.”

The Ministry of Health and Welfare also announced that it will pursue regulatory innovation in the following seven core areas of the biohealth industry for protecting public health and promoting innovation by the private sector.

1. “Innovative medical devices;
2. Innovative and essential pharmaceuticals;
3. Digital health care;
4. Advanced regenerative medicine and advanced bio-pharmaceuticals;
5. DNA tests;
6. Brain-machine interface;
7. Infrastructure”

We are excited to hear that South Korea is investing in the growth of the biohealth industry and promoting digital healthcare. This effort shows a strong commitment to the development of its biohealth industry and, if implemented effectively, could potentially position South Korea as a significant player in the industry globally. As this blogger is originally from South Korea, we look forward to working with many Korean companies to bring their innovative products to the U.S. market.

On March 31, the Federal District Court for the District of Maryland upheld CMS’s definition of a “new formulation” under the Medicaid Drug Rebate Program (MDRP).  Vanda Pharmaceuticals, Inc. v. CMS, Civ. No. MJM-22-977 (Dist. Md. 2023).  By way of background, manufacturers are subject to an additional per-unit Medicaid rebate if they increase their prices greater than the rate of inflation.  The amount of the additional rebate is the excess (if any) of a drug’s current Average Manufacturer Price (AMP) over the inflation-adjusted AMP for a statutorily specified baseline quarter.  In 2010, concerned that manufacturers were making minor changes to a drug merely so that it could be characterized as new covered outpatient drug with an updated baseline AMP, Congress added to the statute an alternative rebate for line extensions of oral dosage form innovator (i.e., NDA or BLA) drugs.  Under that provision, a manufacturer that introduces a line extension with a new baseline AMP must pay the greater of the rebate calculated in the ordinary manner, or an alternative rebate calculated in a manner that is tied to the inflation rebate of the predicate drug (and therefore indirectly to the predicate drug’s baseline AMP).  Under the statute, a line extension is a ‘new formulation” that is not an abuse-deterrent formulation.

Over ten years after this statutory amendment, on December 31, 2020, CMS finalized a broad definition of “new formulation” as “any change to the drug, provided that the new formulation contains at least one active ingredient in common with the initial brand name listed drug.”  Examples in the regulation include extended-release formulations, new strengths, dosage forms, routes of administration, ingredients, and combinations.  See our memo summarizing CMS’s regulation here.

In 2014 Vanda introduced Hetlioz (tasimelteon) capsules to treat a rare sleep disorder.  In 2020, Vanda obtained approval of an NDA to market Hetlioz LQ, an oral suspension of tasimelteon, to treat children with Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder that causes sleep disturbances (among other things), and Vanda also obtained approval of an sNDA to expand the indication of Hetlioz capsules to include adults with SMS.  Vanda is also conducting clinical studies of a long-acting injectable form of its marketed drug Fanapt tablets, an anti-seizure drug.  All of these products are line extensions under CMS’s definition.  Vanda therefore filed a complaint in the Maryland Federal District Court in April 2022 to challenge CMS’s definition on Administrative Procedure Act grounds.  The essentials of Vanda’s complaint were that (1) a drug approved under a new NDA cannot be a line extension; (2) a line extension, like its predicate drug, must be an oral solid dosage form; (3) CMS’s definition exceeds the plain meaning of “line extension”; and (4) Congress intended to target only slight alterations of a drug, as evidenced by the sole example in the statute of “an extended-release formulation”.

The court rejected all of these objections, either citing the plain meaning of the statute or applying Chevron deference to CMS’s interpretations of ambiguities.  As to Vanda’s argument that a drug approved under a full NDA cannot be a line extension, the Court reasoned that the line extension provision applies to single source drugs or innovator multiple source drugs, both of which are defined, in part, as a drug approved under an NDA.  Accordingly, the Court concluded that a line extension can be a new drug product approved under an NDA.

The court next dismissed Vanda’s claim that, in order for the alternative rebate to apply, the line extension (in addition to the predicate drug) must be an oral solid dosage form.  (Neither Vanda’s Hetlioz LQ nor Fanapt injectable is an oral solid dosage form.)  The alternative rebate provision applies to “a line extension of a single source drug or an innovator multiple source drug that is an oral solid dosage form,” leaving a question as to whether the underscored text qualifies “line extension,” “single source drug”, and innovator multiple source drug” or merely the latter two.  In an extended grammar lesson explaining the “rule of the last antecedent,” the Court held that CMS could permissibly construe “oral solid dosage form” to refer only to the latter two terms, so that the line extension does not have to be an oral solid dosage form.  The Court also rejected Vanda’s attempt to define “line extension” by reference to the dictionary definitions of each word.

Finally, the court addressed Vanda’s claim that CMS’s definition of line extension was overly broad, exceeding Congress’ intent to capture only slight alterations to existing drugs.  This objection echoed a criticism that had been expressed by industry ever since CMS’s proposed rule in 2012.  After all, the statute gives only the example of “an extended-release formulation,” and from that CMS has fabricated a broad net that captures everything from new strengths to new ingredients to new combinations and indications.  Nevertheless, the Court found that a narrow interpretation would be inconsistent with Congress’ intent to reduce Medicaid drug costs.  Somewhat more convincingly, the court also reasoned that Congress recently used the identical statutory language in the August 2022 Inflation Reduction Act (more on this below), and declined to further define “new formulation” despite its presumed knowledge of CMS’s previous Medicaid interpretation.

Absent a successful appeal by Vanda, this decision will have implications going beyond the MDRP.  Beginning this fiscal year (October 1, 2022 through September 30, 2023), the Inflation Reduction Act (IRA) imposes inflation rebates for Medicare Part D drugs whose price increases exceed the rate of inflation. See our summary of the IRA drug provisions here.  The IRA directs CMS to establish a formula for determining the inflation rebate for line extensions consistent with the formula under the MDRP, and defines “line extension” in a manner substantially identical to the MDRP definition.  In a guidance issued on February 9, CMS did as instructed, tying the inflation rebate for a line extension drug to that of initial drug, as under the MDRP.  Given that drug spending under Medicare Part D is over 2.5 times that of Medicaid ($98 billion and $38.1 billion, respectively, in FY 2021), the impact on drug manufacturer rebates of CMS’s line extension definition, and the Court’s failure to overturn it, will be that much magnified.

Perhaps you obtain controlled substance quotas or submit ARCOS reports?  Maybe you identify and report suspicious orders or thefts/losses.  Or you obtain import or export permits, submit import or export declarations or listed chemical DEA-486s.  Do you want to learn more?  You have your chance.

DEA’s Diversion Control Division is hosting a Supply Chain Conference for registered manufacturers, distributors, importers and exporters on controlled substance and listed chemical requirements in Houston on May 2-4, 2023.  The first day is dedicated to manufacturers, while Days 2 and 3 are for regulatory compliance personnel and mid-level to senior managers.  DEA will offer virtual accessibility to those who cannot attend in person.  Relevant information and links follow.

Click here to VIEW AGENDA.

Click here for In-Person Registration or Live Stream Registration

Refer questions to VDAT@dea.gov with subject line “Supply Chain Conference.”

Early on March 29, 2023, FDA announced the landmark approval of Narcan (naloxone hydrochloride) Nasal Spray for use as a nonprescription opioid overdose reversal agent.  I previously blogged on the February 15, 2023 Joint Meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) which unanimously agreed that the benefit-risk profile of Narcan Nasal Spray (NNS) is “supportive of its use as a nonprescription opioid overdose reversal agent.”  FDA Commissioner Robert M. Califf, M.D. announced that “Today’s approval of OTC naloxone nasal spray will help improve access to naloxone, increase the number of locations where it’s available and help reduce opioid overdose deaths throughout the country.”  Both harm reduction experts and FDA have long agreed that the prescription status for naloxone posed a barrier to wider access to this safe and life-saving drug.  While many states have had standing orders that allow for the dispensing of naloxone without an individual prescription, “harm reduction programs” that provide products and services to at-risk individuals still faced logistical difficulties in acquiring naloxone due to its prescription-only status which I discussed in this October 2022 blog post.

Now what?

When OTC NNS will become commercially available is ultimately determined by the sponsor of the drug—Emergent BioSolutions.  Emergent will need time to manufacture and distribute NNS with the new OTC labeling, so the public should not expect to be able to walk into their local pharmacy and grab a box off the shelf in the coming days.

NNS (N208411) is the reference listed drug (RLD) which applicants have relied on for approval of generic versions of naloxone nasal spray.  The sponsors of the currently approved 4 mg generic naloxone nasal spray products that rely on Narcan as the RLD will need to submit supplements to their applications (A209522, A211951) to also switch their drugs to OTC status.  However, additional naloxone products will remain prescription drugs.  The OTC approval of NNS will not change the prescription status of the 21 injectable naloxone products listed in the Orange Book.  Additionally, 8 mg naloxone nasal spray (N212045) is also still a prescription drug.

Today’s OTC naloxone approval is limited to NNS specifically, but we are aware of other OTC naloxone applications currently being reviewed by FDA.  I previously blogged on the cancellation of the Joint Meeting scheduled on March 20 to discuss the direct-to-OTC application for 3 mg naloxone nasal spray submitted by Harm Reduction Therapeutics under the trade name RiVive.  Last week Harm Reduction Therapeutics announced that it has entered into a commercial supply agreement with Catalent which will manufacture RiVive—if approved—at its facility in Morrisville, North Carolina.  According to this announcement, FDA approval of RiVive is anticipated in July 2023 and the U.S. launch would be in early 2024.

How “accessible” will OTC naloxone really be?

In announcing the approval, Commissioner Califf encouraged the manufacturer to make OTC NNS available “at an affordable price,” but FDA does not ultimately have control over Emergent’s pricing.  Prescription naloxone has generally been covered by private health insurance, Medicaid, and Medicare Part D meaning that it has been available to many people for free or at a low price through their insurers.  However, many insurance plans do not cover OTC drugs so there are concerns that the out-of-pocket price for OTC NNS could potentially increase for those accessing the drug through their health insurance.  In addition to price, physical barriers such as placing NNS in a locked box or behind-the-counter in the pharmacy would also impede accessibility.  While accessibility is an open and important question, approval of OTC NNS is nevertheless a crucial and life-saving step in combatting the ongoing opioid crisis.

The Unique Device Identification (UDI) System final rule requires all medical devices to bear a unique numeric or alphanumeric code in easily readable plain-text and machine-readable form. Such codes need to be placed on device labels and packages to allow devices to be easily identified and tracked throughout their lifecycle, except where the rule provided for an exception or alternative. In addition, the final rule requires the submission of product information to the Global Unique Device Identification Data (GUDID).

FDA has been implementing the UDI system with different compliance dates for different types of medical devices to ensure a smooth implementation. The compliance dates were first published in 2013, and subsequently updated in various guidance documents and regulations published by FDA. Most of the compliance dates have been passed. So, what is special about September 24, 2023?

The Transition from the Use of Legacy Identifiers on Device Labels to UDI

The September 24, 2023, date is specific to the enforcement policy described in the May 2021 FDA Guidance, which applies to the requirement that legacy FDA identification numbers should no longer be used on a device label or device package. Legacy FDA identification numbers refer to both National Health Related Item Code (NHRIC) and National Drug Code (NDC) numbers created using labeler codes previously assigned to device manufacturers by FDA. Once the device is required to bear a UDI, any NHRIC and NDC codes will no longer be permitted on the device label or device packaging. Firms can continue to include catalog numbers, inventory numbers, ordering numbers or other identification numbers on device labels and packaging. This transition does not apply to Class I devices that had a Universal Product Code (UPC). For Class I device, the UPC can serve as the UDI required by 21 CFR 801.20.  See 21 CFR 801.40(d).

The Expiration Date of FDA UDI Alternatives: UDI-A160001 and UDI-A160002

The FDA has granted a variety of time-limited alternative requests since the publication of the UDI Rule. For the stakeholders who use UPC as their device identifier, UDI alternatives UDI-A160001 and UDI-A16002 will expire on September 24, 2023. Check out here and here to see if a device is classified with product codes included for these two alternatives. Devices can have both a UPC code and a UDI on their label and package.

Once UDI-A160001 and UDI-A16002 expire, devices previously using these alternatives must comply with applicable requirements of the UDI Rule, including placing a UDI to device labels and packages and submitting updated device information to the GUDID. FDA notes the following: “The FDA does not object to the continued use of the alternative for finished devices that are manufactured and labeled prior to September 24, 2023. Devices that are manufactured and/or labeled on or after September 24, 2023, cannot use this alternative.” (Emphasis added.)

Planning Now is a Good Idea

If a firm needs to remove NHRIC and NDC legacy identifiers or currently relies on UDI-A160001 and UDI-A160002, it would be wise to plan for the transition.  It is not far off! If not already started, firms need to start soon to implement the UDI requirements. When a firm develops requirements for UDI, an important step is to determine if the products can utilize any of the existing general exceptions from the requirement per 21 CFR 801.30. Use the FDA’s resources to determine the best UDI implementation strategy.

The single-use device exception under 21 CFR 801.30(a)(3) and the convenience kit exception 21 CFR 801.30(a)(11) (see UDI Convenience Kits Guidance) may be useful in some cases.  We recommend working with the issuing agency to determine if the NHRIC or NDC number may be used as part of a UDI code. In planning for UDI compliance, remember to determine if the product must bear a permanent marking per 21 CFR 801.45 (see UDI Direct Marking of Devices Guidance).

While the final UDI Rule allowed labelers to request an alternative to UDI compliance, the Agency emphasized that the time for extensions is over:  “… the FDA does not intend to grant additional extensions to alternatives UDI-A160001 and UDI‑A160002 beyond September 24, 2023.”

Finally, as a general matter, every firm needs to make sure its supply chain stakeholders (e.g., retail stores, pharmacies, and payors) are ready for the UDI transition by September 24, 2023.

Thank you to those who registered for and attended Hyman, Phelps & McNamara’s March 23, 2023 lunchtime webinar addressing the “End of the COVID-19 Emergency and the Ryan Haight Act: Telemedicine and Next Steps.”  Our in-house team brought together many talented HPM attorneys, including Karla Palmer, John Gilbert, Jeff Wasserstein, John Claud, and Kalie Richardson, who gave not only a broad overview of timely and relevant legal, regulatory, and enforcement considerations, but also discussed some interesting, more detailed matters involving the use of telemedicine and telehealth in a post-pandemic environment, and various important DEA and Controlled Substances Act considerations.  As promised during the 90-minute program, we provide our slides here, and a recording of the program, here (passcode.   Our attorneys are happy to respond to questions you may have, and look forward to hearing from you.

On April 18, the Supreme Court will hear oral argument in two consolidated cases that present the question of whether a defendant can “knowingly” submit a false claim under the Federal False Claims Act when the alleged falsity is based on an objectively reasonable legal interpretation of an ambiguous provision of law and no authoritative guidance from the government warned the defendant away from its interpretation.

The defendants in the cases recently submitted their brief arguing that the answer to that question should be “no.”  On the other side of the issue are the whistleblowers/relators in the case and the DOJ, which the Court has granted leave to participate in the argument. Much has already been written on this issue and more is sure to come as the tea leaves from the argument are read, and a decision is ultimately issued.   We will continue to follow the developments, but for today’s blog, focus on what’s at stake—in short, massive amounts of damages and penalties.

When an ambiguous law or regulation is presented to a court, it is the court’s job to decide what it means, no matter how ambiguous or inartful the provision may be.  The upshot is that a court, for the first time in a False Claims Act case may be called upon to decide what a law means, and therefore whether a claim submitted well before the issue reached the court is a “false” claim.

Unlike the FDC Act, the FCA is not a strict liability statute, however. So, even if the court resolves the ambiguity and determines that a claim was “false” there is no FCA liability unless, among other elements, the defendant acted “knowingly.”  Under an objective reasonableness standard for “knowingly,” if the court finds that when the defendant was engaged in the allegedly violative conduct, the provision was ambiguous and the defendant’s interpretation objectively reasonable, the case can be dismissed at the pleading stage or summary judgment avoiding trial.

Much of the objection to an objective reasonableness standard suggests that creative lawyers using post-hoc rationalizations could allow defendants who subjectively “knew” to “get away” with something. That commentary does not typically focus on the stakes for a defendant that believes it was right, goes to trial and loses.  A recent case before the Minnesota District Court shows how high those stakes are.  In a recent trial, a jury verdict finding $43M in single damages has, according to the government, resulted in $490M in statutorily mandated liability.  The sheer size of that type of exposure gives the government and relators an outsized hammer in negotiating with a putative or actual defendant.  Even defendants that ultimately prevail can spend years defending their actions.  We recently blogged about a qui tam suit that was dismissed despite an en banc review at the 4th Circuit, but not before spending nearly a decade defending its reasonable interpretation of an ambiguous best price statute.

Given the already stacked scales of justice in these FCA cases, we are hopeful that the Court will adopt the objective reasonableness standard, but regardless we will be following the issue closely and keep you apprised of the latest developments.

Hyman, Phelps & McNamara, P.C.’s Mark Tobolowsky co-authored the peer-reviewed article “Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials” in the recently published edition of Human Gene Therapy.  The article arose out of work conducted by the Pathway Development Consortium, a partnership between stakeholders in the AAV gene therapy space.

The article describes the challenges facing development of AAV gene therapy treatments for Duchenne Muscular Dystrophy, a serious and life-threatening condition.  In particular, as the gene encoding the full-length dystrophin protein is too large to fit inside a single AAV vector used to deliver genes to human cells, development has focused on designing shortened versions of the dystrophin gene, known as microdystrophins, that can fit inside the AAV vector and retain the primary functionality of the full-length dystrophin protein.  The article describes the evidence supporting microdystrophin expression as a reasonably likely predictor of clinical benefit from AAV DMD gene therapy treatment and advocates for the use of accelerated approval for such therapies, as appropriate.

On March 8th FDA granted Quidel’s De Novo for the Sofia 2 SARS Antigen+ FIA and Sofia 2 SARS Antigen+ FIA Control Swab Set.  This announcement is the first traditional marketing authorization for a non-PCR based test to detect SARS-CoV-2.  The authorization of this De Novo, with a formal classification of Class II, now opens the door for follow-up 510(k) submissions that declare this product as their predicate.

This device is indicated for the following use:

for the rapid, qualitative detection of SARS-CoV-2 nucleocapsid protein antigens directly in anterior nasal swab specimens from individuals with signs and symptoms of upper respiratory infection (i.e., symptomatic) when testing is started within 6 days of symptom onset. The test is intended for use as an aid in the diagnosis of SARS-CoV-2 infections (COVID-19) in symptomatic individuals when tested at least twice over three days with at least 48 hours between tests.

The inclusion of a requirement to test twice over three days with at least 48 hours between tests is consistent with study findings from the National Institute of Health published in 2022 (LINK); however, it is not clear if this proposed use case is practical for “point-of-care” outside of an in-patient setting.  While serial testing may be required to meet FDA’s performance bar, one can likely rely on working Americans not returning to their doctor’s office after 48 hours for the serial test.

The new regulation is listed as 21 CFR 866.3982: “Simple point-of-care device to directly detect SARS-CoV-2 viral targets from clinical specimens in near-patient settings.”

We note the unique use of the word “simple” to define a point-of-care device.  We are not aware of any other microbiological in vitro diagnostic test that contains the word “simple” in the regulation.

Fortunately, “simple point-of-care” is defined in the reclassification order:

A simple point-of-care device to detect SARS-CoV-2 viral targets directly from clinical specimens in near-patient settings is an in vitro diagnostic device for the direct detection of SARS-CoV-2 in clinical specimens and is intended as an aid in the diagnosis of SARS-CoV-2 infections COVID-19. The device is simple to use and does not involve sample manipulation, transportation of the sample to another functional area (e.g., a central laboratory or other specialized area), or measurement of reagents or analytes that could be affected by conditions such as sample turbidity or cell lysis. The design and procedures of the device are appropriate for use by healthcare professionals in near-patient settings outside a centralized laboratory.

Thus, ironically the definition of “simple” is anything but and is almost certain to lead to debates about what, exactly, is simple.  Moreover, it appears that the specificity of the regulation coupled with the definition of simple may limit the devices that can claim this product as a predicate to Point-of-Care antigen tests with similar workflows.  However, FDA has shown considerable flexibility in expanding the scope of de novo classifications, so it remains to be seen whether this class will, in fact, be narrowly circumscribed.

We also note that this review took place over nine (9) months and was originally submitted to FDA as a 510(k) that was given a “Not Substantially Equivalent” decision and then converted to a “De Novo.”  We are aware through public statements that companies have been pursuing traditional marketing authorizations since at least late 2021.  We take the pace and timing of this first through-the-gate submission to be a reaffirmation of the persistent stress and workload that has plagued OHT-7 and more specifically the OHT-7 COVID Team for over three years.

What does this de novo say about FDA’s expectations for data to support 510(k)s?  A lot.  In the best tradition of teasers, keep reading our blog.  HPM will provide an analysis of the special controls and decision summary in follow-up posts.

Earlier this month, FDA published a final rule to update the mammography regulations, issued under the Mammography Quality Standards Act of 1992 (MQSA) and the Federal Food, Drug, and Cosmetic Act (FD&C Act). The MQSA was passed to ensure, among other things, that nationwide, patients have access to quality mammography services. It authorized FDA oversight over mammography facilities. This oversight encompasses facility accreditation and certification as well as annual inspections and enforcement of standards.

Mammograms

A type of medical imaging, mammography uses x-rays to create images (mammograms) of the internal structures of breasts. It can help detect breast cancer in its earliest, most treatable stages, when it is too small to be felt or detected by an alternative method.  See ACS, “Can Breast Cancer Be Found Early?.”  However, it can also be among the most difficult images to interpret.  See Government Accountability Office, “GAO-06-724 Mammography: Current Nationwide Capacity Is Adequate, but Access Problems May Exist in Certain Locations” (July 2006).  A reader may miss a cancerous lesion if the image quality is poor, resulting in a false negative diagnosis, which could delay treatment and result in an avoidable death. Conversely, a diagnosis could be a false positive, which can occur when an otherwise normal tissue is erroneously read as abnormal. In turn, this could create unwarranted anxiety for the patient and result in additional testing (and costs).

Mammograms can also detect breast tissue density. Approximately half of women over the age of 40 in the United States have dense breast tissue. Dense breast tissue can make cancers difficult to detect on a mammogram and have been identified as a risk factor for developing breast cancer.

Updates

Most of the requirements in the mammography regulations are over 20 years old. Current regulations do not require breast density notification to be part of the healthcare provider report or the lay summary to the patient.

One key update to the regulation will require that facilities provide information to patients regarding the density of their breasts. Although thirty-eight states require notification of breast density, the requirements vary from state to state. By updating the mammography regulations, FDA sets a minimum standard that patients be informed of whether they have dense or non-dense breast issue and the significance of breast density and suggest that patients consult their doctors about the need for additional tests. The notification to patients will depend on the breast density:

1. For the non-dense breast notification: “Breast tissue can be either dense or not dense. Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer. Your breast tissue is not dense. Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation.”
2. For the dense breast notification: “Breast tissue can be either dense or not dense. Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer. Your breast cancer is dense. In some people with dense tissue, other imaging tests in addition to a mammogram may help find cancers. Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation.”

The amendments also require that the written report of the mammographic examination provided to the healthcare provider include an overall assessment of breast density, classified in one of the following categories:

1. “The breasts are almost entirely fatty.”
2. “There are scattered areas of fibroglandular density.”
3. “The breasts are heterogeneously dense, which may obscure small masses.”
4. “The breasts are extremely dense, which lowers the sensitivity of mammography.”

Other updates include ensuring the availability of qualified mammography personnel and standards for mammography reports, quality assurance testing, and clinical image quality.

The final rule will be effective on September 10, 2024.

Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal will be moderating a panel on “The Use of Bioactive Substances in Food and Dietary Supplements” during the Food and Drug Law Institute (FDLI) Food and Dietary Supplement Safety and Regulation Conference. The conference will be held live in Washington DC on March 23-24, but virtual registration is an option. The conference brings together leading regulators, attorneys, scientists, industry representatives, academics, consumer advocates, and consultants to discuss current issues and the latest trends. Topics will include FDA and USDA regulatory compliance and enforcement, inspections, recalls, food safety technology, and emerging and growing product categories such as cell-cultured meat and Cannabis ingredient-infused products. This is a must-attend event for attorneys, advocates, and regulatory affairs professionals whose work focuses on conventional foods and dietary supplements.

Like EF Hutton television commercials of the 1970s and ‘80s, when Attorney General Merrick Garland talks, people listen.  With Hutton it was about investing, for the Attorney General it is cannabis.  AG Garland most recently talked cannabis during a Senate Judiciary Committee hearing last week when Senator Cory Booker (D-NJ) asked about the Department of Justice’s (“DOJ’s”) review of cannabis and when we might expect policy changes.  Readers will recall that President Joe Biden directed the Attorney General and Health and Human Services (“HHS”) Secretary Xavier Becerra in October to begin the administrative process of reviewing current federal marijuana scheduling.  AG Garland replied that “HHS is working on the question of scientific analysis of marijuana” while DOJ is “still working on a marijuana policy.”  AG Garland concluded that he anticipates DOJ’s cannabis policy will be consistent with what he said during his confirmation in that “it will be very close” to the Cole Memorandum.  Merrick Garland, Testimony Before the Senate Judiciary Committee, Mar. 1, 2023 (02:38:46).

AG Garland opined during his confirmation that he did not think it the best use of DOJ’s limited resources to prosecute those who are complying with the laws in those states that have legalized marijuana and are effectively regulating it.  Merrick Garland, Responses to Questions for the Record to Judge Merrick Garland, Nominee to be United States Attorney General, 24.  Deputy Attorney General James Cole advised U.S. Attorneys in August 2013 that DOJ was unlikely to take enforcement action against marijuana-related businesses operating in compliance with state law unless the businesses implicated any one of eight enforcement priorities.  James M. Cole, Deputy Attorney General, Memorandum for All United States Attorneys (Aug. 29, 2013), 3. (Attorney General Jeff Sessions rescinded the Cole Memorandum and all prior DOJ guidance on marijuana enforcement in January 2018.)

Earlier in the week before the Senate Judiciary Committee hearing Representative Earl Blumenauer (D-OR) began circulating a letter for signature among House colleagues pushing AG Garland and HHS Secretary Becerra “to make available for public review and comment any evidence cited to demonstrate marijuana is more prone to drug abuse than descheduled substances already regulated at the state level.”  Rep. Blumenauer to AG Garland and Secretary Becerra, quoted in Marijuana Moment, Feb. 28, 2023.  Rep. Blumenauer, founder and co-chair of the Congressional Cannabis Caucus, concluded that marijuana should be decontrolled altogether, given its medical potential, state regulatory frameworks and “reduced harm and abuse” compared to non-controlled stimulants and depressants.  Id.

AG Garland and Rep. Blumenauer appear to have their sights set on two different end goals for cannabis.  President Biden asked AG Garland (and Secretary Becerra) to conduct an administrative review of cannabis scheduling with an eye towards rescheduling or descheduling.  AG Garland spoke of a policy consistent with the Cole Memorandum which would fall short of rescheduling or descheduling cannabis.  Any action short of total decontrol will disappoint Rep. Blumenauer and cannabis proponents.