Since the U.S. Food and Drug Administration (FDA) launched the Over-the-Counter Monograph User Fee Program (OMUFA) in 2020, the Agency has been pushing for modernization and self-funding of its regulatory oversight for over-the-counter (OTC) products.  But five years in, the Agency’s OMUFA Facility Arrears List paints a concerning picture:  nearly 1,400 businesses—foreign and domestic—appear to have either ignored or fallen behind on their facility registration payments.

As the character Winston Bishop from the sitcom New Girl would say, “Shame shame I know your name.” (link – start from around the 28-second mark).  In this case, we all know the delinquent companies’ names.  What we don’t know is whether each of those companies ought to be on the list.

Importantly for industry, under the federal Food, Drug, and Cosmetic Act (FDCA), failure to pay OMUFA fees and inclusion on the public arrears name-and-shame list render all products from that site as misbranded.  FDCA § 502(ff).  This applies to all “[d]rugs manufactured, prepared, propagated, compounded, or processed in facilities for which fees have not been paid.”  Id.

OMUFA: A Quick Refresher

OMUFA was established under the Coronavirus Aid, Relief, and Economic Security (CARES) Act as a way to streamline the approval and oversight of OTC monograph drugs.  As we described in a prior blog post (here), the program introduced two major fee categories:

• Facility Fees:  Charged annually to manufacturers and contract manufacturing organizations (CMOs).
• OTC Monograph Order Request (OMOR) Fees:  Paid when companies request changes to drug monographs, like adding a new ingredient or indication.

These fees are critical for funding FDA’s ability to review monographs, inspect facilities, and enforce compliance.

Arrears List 2025: A Red Flag for Industry Compliance

In June 2025, FDA’s Division of User Fee Management published a 70-page OMUFA Facility Arrears List covering fiscal years 2021 through 2025.  The report identifies 1,377 entries—well above the Agency’s 1,134 estimate of entities expected to pay OMUFA fees in FY2025.

This discrepancy likely highlights a systemic issue:  many firms are still listed despite no longer manufacturing OTC products or having failed to formally cancel their registration.  Among them are companies that ramped up production of hand sanitizers during the COVID-19 pandemic but exited the market once demand normalized.  At least some other small OTC manufacturers exited the market following the imposition of fees.

Who’s Not Paying

The arrears list includes:

• 956 foreign and 421 domestic facilities
• Well-known and -established firms with long histories of regulatory expertise and experience
• Defunct firms
• Startups and small-scale manufacturers who may have limited regulatory expertise or are still unaware of the OMUFA requirements

The Numbers

For FY2025, facility fees rose to:

• $37,556 for OTC monograph drug manufacturers (up $3,390 from FY2024)
• $25,037 for contract manufacturing organizations (up $2,260 from FY2024)

OMOR fees are even steeper:

• $559,777 for Tier 1 requests (e.g., adding new ingredients or indications)
• $111,955 for Tier 2 changes (e.g., altering drug facts labels)

Late payment triggers penalties, interest accrual, and regulatory consequences, including being barred from submitting OMORs or meeting with FDA on monograph issues.

Public Shaming as a Compliance Tool

Publication of the arrears list isn’t just administrative—it’s strategic.  Under Section 744M(e) of the federal FDCA, listing a facility in arrears publicly flags and renders all products from that site as misbranded.  FDCA § 502(ff).  This means these products cannot legally be marketed in the United States, and any submitted OMORs will be automatically rejected.

On its webpage Other OMUFA Fee-Related Questions, FDA makes clear that failure or refusal to pay OMUFA fees can have significant ramifications including the issuance of Warning Letters and use of “various enforcement tools with respect to marketing of products deemed misbranded for failure to pay fees.”  It is unclear what the latter category of “enforcement tools” encompasses.  The webpage further explains that the U.S. government will treat any outstanding fee that is not paid within 30 calendar days of its due date as a claim subject to federal collection activity.

To date, we have not seen any Warning Letters specifically based on a failure to pay OMUFA fees.  However, not only FDA but online retailers may be reviewing and relying on this list because the Agency can issue and has issued Warning Letters for introducing or delivering for introduction a misbranded OTC drug into interstate commerce.  FDCA § 301(a).  Some online retailers may use the list to decide whether to carry certain products and manage their own risk of FDA enforcement.

What’s to come?

The OMUFA program expires at the end of FY2025 (expiring on September 30, 2025), and reauthorization is not guaranteed.  In its proposed commitment letter for FY2026–2030, FDA vows to strengthen fee collection, more aggressively update and monitor its registration data, and continue publishing non-compliance lists.  HPM is available to assist companies who find themselves on this list and believe they don’t belong there and to help others who require assistance determining whether they do belong and, if so, how to register.

Hyman, Phelps & McNamara, P.C. (HP&M) seeks to add an experienced regulatory expert to our strong and busy team of non-attorney regulatory experts.  Our team assists clients with a wide variety of quality and manufacturing regulatory topics for drugs and biologics.  Types of matters include:

• Developing regulatory strategy for manufacturing and related issues that arise in product development programs. Specifically, manufacturing/testing procedures and compliance with cGMPs.
• Reviewing test protocols and reports for small molecule or biologic drug programs.
• Meeting with FDA on behalf of clients or assisting clients seeking marketing authorization in preparing to meet with FDA and in other interactions with the Agency.
• Conducting internal investigations and audits of manufacturing facilities for compliance with 21 CFR 211/600.
• Preparing for and responding to government inspections and other compliance matters.
• Conducting due diligence on manufacturing facilities and products related to transactions and securities offerings

A background in chemistry, biochemistry, engineering, or biomedical engineering is preferred.  Strong verbal and writing skills are required.  Experience working at FDA in CDER or CBER for at least 2 years as a scientific reviewer or a consumer safety officer, with experience conducting inspections is strongly preferred.

The boutique, collaborative nature of this firm provides regulatory experts unique opportunities to work directly with clients and to contribute in substantive ways to sophisticated, high-end matters.

Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.  Please send your curriculum vitae and transcript to Deborah Livornese (dlivornese@hpm.com).

A memorable Florida Orange Growers’ television ad campaign in the late 1970s proclaimed that “Orange juice from Florida isn’t just for breakfast anymore.” The Federal Controlled Substances Act (“CSA”) and its regulations require Drug Enforcement Administration (“DEA”) registrants to submit certain reports related to narcotic drug transactions, thefts and significant losses, and suspicious orders. However, some DEA registrants may not realize that they may also have to submit the same or similar reports to their state professional boards or controlled substance authorities. They do not know that controlled substance reporting isn’t just for DEA anymore.

DEA registrants include manufacturers, distributors, importers, exporters, practitioners, pharmacies, hospitals, and narcotic treatment centers who handle federally-controlled substances. State-controlled substance requirements generally mirror federal requirements, but there are some subtle and not so subtle differences. Let’s take a short stroll through a few federal and state controlled substance reporting requirements. Note that we are not focusing on listed chemicals here.

A. Transactions

1. DEA

Manufacturers and distributors must report all schedule I and II, schedule III narcotic, and GHB transactions, quarterly via DEA’s Automated Reports and Consolidated Ordering System (“ARCOS”). Manufacturers must also report selected schedule III and IV psychotropic drugs quarterly. 21 U.S.C. § 827(d)(1); 21 C.F.R. § 1304.33.

2. The States

About a dozen states require reporting controlled substance transactions to the responsible state authority. New York, for example, requires electronic reporting of all controlled substances to the state’s Bureau of Narcotic Enforcement. N.Y. Codes R. Regs., tit. 10, § 80.23(f). Texas requires reports of all controlled substance distributions in an ARCOS format. Tex. Health & Safety Code Ann. § 481.0766. Florida requires reporting all controlled substance receipts and distributions monthly also in ARCOS format, and zero transaction reports if no transactions occur in a calendar month. Fla. Stat. Ann. § 499.0121(14). Ohio also requires monthly controlled substance transaction reports, including zero reports, to the Ohio Automated Rx Reporting System. Oh. Admin. Code 4729:8-3-04. Several states, including California and Georgia require transaction reporting when requested by the California Board of Pharmacy and the Georgia Drugs and Narcotics Agency. Cal. Code Regs., tit. 16, § 1782; Ga. Code Ann. § 26-4-115(b)(11).

B. Thefts/Significant Losses

1. DEA

Registrants must notify the DEA Field Division Office in writing of the theft or significant loss of any controlled substance within one 1 business day of discovery. They must also submit a Report of Theft or Loss of Controlled Substances, a DEA Form 106, through DEA’s secure network application within 45 calendar days after discovery. 21 C.F.R. § 1301.74(c) and .76(b).

2. The States

The vast majority of states likewise require reporting controlled substance thefts and significant losses. Consistent with federal requirements, a number of states, such as Arizona, Colorado, and Delaware require submitting the DEA-106 that they submit to DEA. Ariz. Admin. Code § R4-23-1003(A)(2); 3 Colo. Code Regs. § 719-1:7.00.10; Del. Code Regs. 24 § 7.3.1-.2. Some states require reporting immediately or within 1 business day of discovery. Others have different timing requirements: Connecticut (72 hours); New Mexico (5 days); Nevada (10 days); Mississippi (15 days), and Colorado (30 days). Conn. Agencies Regs. § 21a-262-3(b); N.M. Code R. § 16.19.20.36B; Nev. Rev. Stat. § 453.568; 30-030 Miss. Code R. § 3001, Art. XXXII.4; 3 Colo. Code Regs. § 719-1:15.05.13.

Ohio requires reporting thefts or significant losses of any prescription drug, including controlled and non-controlled substances upon discovery, followed by a DEA-106 within 30 days. Oh. Admin. Code 4729:6-3-02. California, Kentucky, and New Hampshire require pharmacies to report. Cal. Code Regs. tit. 16, § 1715.6; Ky. Rev. Stat. § 315.335(1); N.H. Admin. Code § Ph 702.03(a). A few states require that registrants include and adhere to theft and loss reporting in their policies and procedures.

C. Suspicious Orders

1. DEA

Manufacturers and distributors must design and operate a system to identify suspicious orders of controlled substances, and inform the DEA Field Division in their area of suspicious orders or a series of orders when discovered. A suspicious order may include, but is not limited to:

1. Orders of unusual size;
2. Orders deviating substantially from a normal pattern; and
3. Orders of unusual frequency. 21 U.S.C. §§ 802(57), 832; 21 C.F.R. § 1301.74(b).

2. The States

For about half of the states, suspicious order criteria mirror DEA’s criteria and require registrants to identify and report suspicious orders. Several states, like Maryland, allow registrants to satisfy their reporting requirement by submitting the reports that they provide to DEA. Md. Code Ann., Crim. Law § 5-303(e). Georgia requires reports of excessive controlled substance purchases using DEA’s suspicious order criteria to the Georgia Drugs and Narcotics Agency. Ga. Code Ann. § 26-4-115(b)(2). Ohio and Washington require a report indicating that no suspicious orders were identified in a calendar month. Oh. Admin. Code 4729:6-3-05(F); Wash. Admin. Code § 246-945-585(1). Virginia requires registrants who cease distributing controlled substances because of suspicious orders to report to the Board of Pharmacy within 5 days. Va. Code Ann. § 54.1-3435.01(b). Idaho requires processes to be in place for monitoring customers’ purchase activity and suspicious ordering patterns. Idaho Code r. 24.36.01.250.02.

****

So, registrants, the next time you submit a required federal report, remember the states because “controlled substance reporting isn’t just for DEA anymore.” (In some states reporting may never have been just for DEA.)

The Federal Food, Drug, and Cosmetic Act (FD&C Act) has very different regulatory regimes for pharmaceutical products than devices. Knowing how a product will be regulated is essential to companies. The means to gaining that knowledge for combination products or single entity products where the regulatory classification is unclear is the Request for Designation (RFD). A sponsor may submit an RFD, not to exceed 15 pages, to the Office of Combination Products (OCP) to obtain the product classification (i.e., drug, device, biologic, or combination product) and/or review/lead Center (i.e., CDER, CDRH, CBER). In the 15 allotted pages, amongst other things, the submitter:

• Identifies “any component of the product that already has received premarket approval, is marketed as not being subject to premarket approval, or has received an investigational exemption,”
• Describes the “chemical, physical, or biological composition,” and
• Provides a “description of all known modes of action, the sponsor’s identification of the single mode of action that provides the most important therapeutic action of the product, and the basis for that determination.” (21 CFR 3.7 (c)(2)(iv), (v), (ix)).

The sponsor is also expected to provide their “recommendation as to which agency component should have primary jurisdiction based on the mode of action that provides the most important therapeutic action of the combination product.” (21 CFR 3.7 (c)(3)).

OCP then makes the binding determination within 60 calendar days of filing the RFD by determining the primary mode of action (PMOA). If OCP does not issue a decision within the statutory timeline, the sponsor’s recommendation for the classification or assignment of the product is the designation. (21 CFR 3.8 (b)).

FDA also offers sponsors the opportunity to submit a Pre-RFD (which we have blogged about here) and obtain FDA’s preliminary, nonbinding assessment of the product classification and/or review Center.  Unlike an RFD, the Pre-RFD does not have a page limit. Companies can use that feedback in deciding whether to submit an RFD, and if they decide to submit, how best to frame it. OCP’s goal is to provide feedback within 60 calendar days. While the content of Pre-RFD and RFD is different, in part because one allows for unlimited text and the other is confined to 15 pages, FDA would conduct the same PMOA analysis in both the Pre-RFD and RFD process.

In 2016, we said that “OCP has earned a reputation for designating products as drugs rather than devices.” (This was demonstrated in the decision to regulate PREVOR’s Diphoterine® Skin Wash product as a drug, which a District Court vacated after finding that FDA failed to provide a reasoned basis for its classification decision, which we summarized here. The District Court then vacated FDA’s classification decision to regulate the product as a drug a second time (see our previous post here).) Recently, we reviewed the most recently available data, which is the FY 2023 OCP Performance Report. This raises a separate question: where is the FY 2024 report, given that we are more than halfway through FY 2025? This is not the first time FDA has been delinquent in releasing information (see our De Novo post) that allows stakeholders to be more informed.  (In that vein, FDA just released the formal classification regulation for a device that had received De Novo authorization eight years ago.

The data from this report provide some interesting insights.  As shown below, when it comes to combination products CDER was identified as the presumptive review Center in 74% (23 of 31) of the assessments.  Those determinations were relatively swift, with 57% were issued within 60 days. In contrast, of the six presumptively assigned to CDRH, only two (33%) were decided within 60 days. For non-combination products, 75% of decisions (6 of 8), when assigned to CDRH, were made within 60 days; in contrast, only 15% (2 of 13) had a decision in 60 days when OCP determined the product to be non-combination with CDER as the review Center.  In all comparisons except for the non-combination products assigned to CDRH, OCP performed worse in 2023 than in 2022.   The tailing off for non-combination products assigned to CDER was particularly pronounced, with only 15% being issued in 60 days.  Given that the FY 2024 OCP report has not been released, we don’t know if these patterns have persisted, worsened, or improved.

Perhaps more important, our 2016 comment about drug determinations being more common is still valid. The table above clearly shows that 74% (25 of 31) of combination products were found to have a chemical PMOA. The proclivity for finding chemical PMOA in FY 2023 was not an anomaly. In FY 2022 a chemical PMOA was also more common, albeit by a less lopsided margin (63% (19 of 30))     Since most companies that submit Pre-RFDs want to be designated as devices and believe that device classification is appropriate, presumably  the majority of submitters are disappointed by the outcome.

The FY 2023 report also acknowledged 66 RFD submissions. Of those 66, only seven RFDs (11%) had a decision issued, 54 (82%) had insufficient information for filing, three (4%) were withdrawn, and two (3%) were still under review at the close of FY 2023 (these were later determined to lack sufficient information for filing). Similarly, the FY 2022 report stated that OCP received 41 RFD submissions. Of those, four (10%) had a decision issued, 35 (85%) had insufficient information for filing, one (2%) was withdrawn, and one (2%) was within the 60-day review period at the close of FY 2022. A process which results in so few decisions obviously needs revamping.

This raises the question of why so many of these RFDs were deemed insufficient. We had proposed changes in 2018 to remove the 15-page limit such that there be a “free exchange of relevant information about a proposed product.” This limitation is burdensome in light of the heavy expectations for submitters. In our experience, if anything, OCP is demanding even more details now than it did before. And while one can argue that removing the page limit does not necessarily ensure sufficient information is included, it can’t hurt. As the administration looks at ways to reduce the regulatory burden, eliminating the 15-page limit would be a good candidate. While ordinarily one would expect shorter submissions to be less burdensome, that is not the case here; squeezing complex technical arguments into 15 pages is highly challenging.

Of the eight RFD determinations (one was received in FY 2022 and completed in 2023) made in FY 2023 (all of which were issued by the statutorily mandated 60-day deadline), half were classified as combination products; the other half were classified as non-combination products. More specifically:

Notably all eight RFD assessments which reached a decision were completed on time. As noted above, that was not the case for Pre-RFDs. These data show that by imposing mandatory deadlines coupled with consequences, Congress can ensure prompt action by FDA.  If FDA will not itself make improvements to the RFD program, perhaps Congress will.

Earlier this month, the Association for Accessible Medicines and its Biosimilars Council (“AAM”) announced (here and here) the release of a report, titled “Assessment of the Impact of Settlements,” examining the effects of patent litigation settlements on patient savings and access to generic drugs and biosimilar biological products.  The report, based on research and analysis undertaken by the IQVIA Institute for AAM, concludes “that patent settlements between brand and generic/biosimilar medicine manufacturers accelerated patient access to generic and biosimilar medicines to market by, on average, more than five years before patent expiration,” and that there were significant healthcare system savings.

That the IQVIA Institute concluded that patent settlement agreements are a good thing is not news to this blogger.  That’s pretty much the message this blogger has been saying in posts on this blog for years (here): If you limit a generic drug manufacturer’s ability to settle cases, that manufacturer does not settle fewer cases, it submits fewer Paragraph IV ANDAs; fewer ANDAs means less, not more, generic drug competition.  And now we have a pretty comprehensive data set from the IQVIA Institute to show the positive effects of patent settlement agreements.

As detailed in the report, the IQVIA Institute assessed 288 molecules for settlement information, 84 of which involved patent settlements and early or timely generic/biosimilar entry.  And of that cohort, the IQVIA Institute found that product launches averaged 64 months (more than 5 years!) before patent expiry (with 17% of the cases accelerating generic or biosimilar entry by more than a decade prior to patent expiry).  We all know that time is money.  The IQVIA Institute report shows just how much money: “Savings to the healthcare system from patent settlements since the FTC v. Actavis decision in 2013 total $423 billion, and the average savings to the healthcare system per molecule are $5 billion.”

The report was published just a week before the Federal Trade Commission and the Department of Justice announced a series of “listening sessions” intended to implement, in part, Executive Order No. 14273, Lowering Drug Prices by Once Again Putting Americans First.  According to a recent description of the listening sessions, one panel will look at “recent trends in pharmaceutical patent settlements.”  Given the FTC’s long history of opposition to patent litigation settlement agreements in general, we suspect there may be a renewed effort to fan the flames and push for the passage of legislation (see our earlier post here) that we think would ultimately chill procompetitive patent settlement agreements.  But maybe the data from the IQVIA Institute detailed in AAM’s new report can put a wet blanket on those efforts.

On June 5, 2025, FDA announced two proposed monograph orders: 1) Proposed order OTC000038 proposes to make it easier to make (minor) changes to solid oral dosage forms not currently permitted under the specific order, and 2) proposed order OTC000037 proposes to require that certain oral dosage forms, namely orally disintegrating tablets (“ODTs”) and film dosage forms, be packaged in single unit or unit dose containers.

FDA’s proposed order OTC000038, “Over-the-Counter Monograph Procedure for Minor Changes C001: Minor Changes to Solid Oral Dosage Forms for Certain Over-the-Counter Monograph Drugs,” when finalized, will permit manufacturers to make minor changes in the dosage form of certain over-the-counter (“OTC”) monograph drugs, from tablets and capsules to chewable tablets, ODTs, and films, without requesting a separate order, i.e., companies making such dosage form changes need not submit a request for amendment of the applicable OTC monograph order. (To be clear, the minor changes are permitted only for OTC monograph drug products that are included in deemed final orders, and not for OTC monograph products that may remain on the market pending FDA monograph orders allowing or prohibiting such products.)  The proposed order is intended to significantly simplify the development of new dosage forms for oral monograph order drugs that, at this time, may be marketed only in tablets or capsules.

A “requestor” (defined in proposed order OTC000038 as “[a]ny person or group of persons marketing, manufacturing, processing, or developing a drug”) of an OTC monograph order drug making changes to dosage forms subject to the order may manufacture and market that new dosage form, provided the requestor maintains information necessary to demonstrate that the change 1) will not affect the safety or effectiveness of the drug, and 2) will not materially affect the extent of absorption or other exposure to the active ingredient(s) in comparison to a suitable reference product. The suitable reference product must be a capsule or tablet that is swallowed. FDA issued a companion draft guidance, which provides recommended procedures for companies to meet these requirements.

Although this order would provide more flexibility, it does come with a price as, in a companion order, FDA proposes to require that the packaging of drugs in ODT and film dosage form must be consistent with the requirements described in monograph proposed order OTC000037, “Over-the-Counter Monograph Condition B001: Single-Unit or Unit-Dose Containers for Over-the-Counter Monograph Drugs in Orally Disintegrating Tablet and Film Dosage Forms.”  That proposed order, if finalized as proposed, will require that OTC monograph drugs in an ODT or film dosage form and subject to OTC monograph orders be packaged in single-unit or unit-dose containers.

FDA notes that it has, in the past, required single-unit or unit-dose containers for approved new drugs in ODT and film dosage form due to concerns about such products being more palatable than capsules or tablets. Moreover, they are designed to dissolve rapidly and, for products in film dosage form, there is a concern of films sticking together.  FDA asserts that the single-unit or unit-dose containers help ensure safe and effective use of OTC monograph order drugs in ODT and film dosage forms.

The requirement for the single-unit or unit-dose containers is not a substitute for special packaging, i.e., child resistant packaging required for certain products under the Poison Prevention Packaging Act and implementing regulations.  See 16 C.F.R. part 1700.  The proposed order describes the scope of the order to apply to all orally administered monograph order drug products in ODTs and film dosage form, even those that currently already may be marketed in such dosage form.  As readers of this blog may know, the requirement for child resistant packaging applies only to OTC oral drug products containing certain specific active ingredients.

Comments to proposed order OTC0000037 must be submitted by August 4, 2025, and comments to proposed order OTC0000038 and the accompanying draft guidance must be submitted by October 3, 2025.

Last Friday, the Supreme Court delivered a trio of decisions making it easier to litigate against the federal government.  The facts and law in each case matter, and as is often the case when the Supreme Court “decides” an issue, much remains to be seen.  That said, it’s hard to see how the score on Friday wasn’t 3 for regulated industry and 0 for the federal government.

In a pair of 7-2 decisions authored by Justice Kavanaugh, the Court took the more expansive view of who can sue the government.

• In FDA v. R. J. Reynolds Vapor Co., the Court held that the Tobacco Control Act’s language permitting “any person adversely affected” by a denial order permitted not just the applicant, but retailers and an association of retailers to seek judicial review of the order.  While in the present case, the manufacturer, retailer, and trade association were all part of the same lawsuit, nothing in the Court’s decision requires that the applicant be a party to such a challenge.  Nor does the analysis limit the statute’s scope to retailers.  The right of consumers to bring such a statutory action is not addressed, although consumers are much discussed in analyzing prior precedent, but it is hard to see from the Court’s analysis why a consumer disappointed by a denial order would not be able to sue where they resided.
• In Diamond Alternative Energy, LLC v. EPA, the Court held that producers of automobile fuels had Article III standing to challenge EPA’s approval of state regulations requiring automobile manufacturers to manufacture more electric and fewer gasoline powered vehicles. While the legal issue and analysis was different than in FDA v. RJ Reynolds, the outcome was the same, additional parties had the right to challenge government regulation.

Finally, in McLaughlin Chiropractic Associates, Inc. v. McKesson Corp., a 6-3 majority held that notwithstanding statutory language providing “exclusive jurisdiction” in the courts of appeals to set aside final orders of the FCC, a party could challenge the validity of an agency’s interpretation in the district court. In sum, the Court concluded that pre-enforcement review in the courts of appeals was optional but not mandatory, and a party could wait to litigate the issue in an enforcement proceeding.  While this case interpreted the Hobbs Act, the FDC Act, CSA, and other statutes that more directly affect blog readers also contain similar exclusive jurisdiction provisions for certain agency orders. The Court’s analysis preserving the right to contest agency interpretations in district court enforcement proceedings logically extends to those statutes as well.

We’ll be watching to see how these cases play out in the lower courts as parties in litigation with the federal government test their limits.

After teasing a new rapid review pilot program for the past few weeks, on June 17, 2025, FDA officially announced the Commissioner’s National Priority Voucher (“CNPV”) program to expedite new drug and biologic (but not device or drug-device combination product) reviews.  As described in the press release and accompanying FAQ, the CNPV program is designed to reduce review time to 1-2 months following final drug application submission.  This would be substantially shorter than PDUFA goal timelines (including for priority review as it is currently known), which range from 6 months to 12 months from submission.  The CNPV program will begin in 2025, and FDA will give a limited number of vouchers during a first-year pilot phase.  This pilot phase may be followed by an increase in the number of CNPVs issued.

The press release describes the CNPV process as a “team-based review rather than using the standard review system of a drug application being sent to numerous FDA offices.”  This multidisciplinary team will “pre-review” the submitted information and convene for a “1-day ‘tumor board style’ meeting,” drawing on Commissioner Makary’s experience as a surgical oncologist.  As defined by the National Cancer Institute, tumor board meetings convene multidisciplinary specialists to decide on the best treatment plan for new and complex cancer cases.

FDA plans to issue a limited number of vouchers, without specifying an exact number as of yet.  The vouchers will be issued to “companies aligned with U.S. national priorities.”  According to the press release, which uses slightly different language than the FAQ, the Commissioner will establish these national priorities, which may include, but are not limited to:

• Addressing a health crisis in the U.S.
• Delivering more innovative cures for the American people.
• Addressing unmet public health needs.
• Increasing domestic drug manufacturing as a national security issue.

The Commissioner will use “specific criteria” to award the vouchers, and information will be provided in the near future on how companies can apply for a CNPV and “indicate their alignment with the FDA Commissioner’s criteria to meet national priorities.”  Although many of the initial criteria are broadly applicable, and FDA has not indicated that any single criterion is more important than any other, manufacturing in the U.S. may turn out to be a significant differentiator, particularly while numbers of CNPVs are more limited.

According to the press release, “[v]ouchers can be directed by the FDA towards a specific investigational new drug of a company or be granted to a company as an undesignated voucher, allowing a company to use the voucher for a new drug at the company’s discretion and consistent with the program’s objectives.”  As suggested by this language and made clear in the FAQ, there will be “product designated” and “product undesignated” CNPV vouchers.  We look forward to additional information about the scope of each type of voucher and, in particular, the criteria and limitations for product undesignated vouchers.  With the available information, a product undesignated voucher would seem to provide the most flexibility and allow companies to pivot from one program to another in the event of unforeseen circumstances, such as ambiguous clinical trial results or problems with a manufacturing facility.

If a company receives a voucher, it must meet certain requirements to qualify for expedited review: an applicant must submit the CMC portion of its application and draft labeling at least 60 days prior to the final application submission and be available for “ongoing communication with prompt responses to FDA inquiries.”  Commissioner Makary stated that this new program “will allow companies to submit the lion’s share of the drug application before a clinical trial is complete.”  While an interesting idea, it is not clear how that timing would ultimately work in practice and whether this refers to more than the CMC section and labeling being submitted 60 days early.

If a company will not yet know if its clinical trial will be successful when it begins submission of the application, it might result in a situation where “the lion’s share” of an application has been submitted to FDA, and a review initiated, for an application that may never be fully submitted due to disappointing results.  The risk of cashing in a voucher in such a situation would be magnified in the case of a product undesignated voucher that could have been better used on a different program.  This assumes that the early submission would be considered a “use” of the voucher, though it is not clear that this is the intent.  Even if a company decides to wait until it has topline results in hand to decide to use a voucher, the potential for a 1-2 month review could be very valuable.  We also note that the agency has given itself some latitude to extend the review window if the data or application components are insufficient or incomplete, if pivotal trial results are ambiguous, or if the review is particularly complex.

The benefits of the CNPV are not limited to FDA review of marketing applications.  The FAQ states that the CNPV can be applied to a product “at any stage in development.”  Such benefits during the IND phase include “enhanced communication” and “prompt responses.”  Among the questions we have are whether the voucher award criteria will differ for a product in development as compared to at the application submission stage and whether a voucher that is used for enhanced communication benefits during development can carry over to the subsequent review of an application.

Although there are some conceptual similarities with other FDA priority review voucher programs, CNPVs are non-transferrable.  However, they remain valid through changes in company ownership, suggesting they are transferrable through mergers and acquisitions.  Vouchers must also be used within two years following receipt or the voucher will expire, so companies should consider their application submission timelines when applying for the CNPV. Time will tell if this leads to some creative corporate mergers and acquisitions.

The CNPV program appears to share some aspects in common with the Real-Time Oncology Review (“RTOR”) program for cancer drugs and the Split Real Time Application Review (“STAR”) pilot program.  While we await additional details for the CNPV program, these programs might provide a reference for some of the details not yet provided.

The RTOR program also involves the earlier submission of certain information, initially top-line efficacy and safety data to determine eligibility, and, if accepted, a maximum of three presubmissions and a final submission.  As described in guidance, the eligibility criteria for RTOR are as follows:

• Clinical evidence from adequate and well-controlled investigation(s) indicates that the drug may demonstrate substantial improvement on a clinically relevant endpoint(s) over available therapies.
• Easily interpreted clinical trial endpoints (e.g., overall survival, response rates), as determined by the review division and the Oncology Center of Excellence.
• No aspect of the submission is likely to require a longer review time (e.g., requirement for new REMS, advisory committee, etc.).

As described in a 2022 FDA analysis, the median time-to-approval from submission for RTOR applications was 3.3 months, ranging from 0.4 months to 5.9.  As an extreme example, FDA approved a supplement for Adcetris (brentuximab vedotin) for a new indication 11 days following application submission.

Similarly, the STAR pilot program “aims to shorten the time from the date of complete submission to the action date” leveraging an earlier submission of much of the application prior to a final submission. However, there is not much public information about the success of the STAR program, perhaps due to low participation (in November 2024, FDA said that there had been no applications in the STAR program to date).

Unsurprisingly, the criteria for the RTOR and STAR program are relatively similar.  They require clear and robust evidence of efficacy without any aspects that would otherwise delay a review.  The RTOR program has shown that FDA is capable of meeting ambitious review time goals under the right circumstances.  However, given that the CNPV program anticipates allowing the “lion’s share” of the application to be submitted before a trial is complete, there may not be efficacy data available at the time of this submission.  This raises questions about the extent to which the use of the CNPV will depend on evidence of efficacy and how that might affect the ability of a review to be completed in the target timeframe.

We applaud FDA in its efforts to set, and hopefully meet, ambitious goals to approve safe and effective drugs in an expedited fashion.  However, at a time when non-expedited FDA approval decisions are delayed due to heavy workloads, we wonder whether such goals can be regularly met and whether they might come at a cost to non-participating programs.  We will be monitoring this program closely to see how it is implemented.

Special Surveillance List of Chemicals, Products, Materials and Equipment Updated

A “laboratory supply” is any List I or List II chemical, or any chemical, substance, or other item on a special surveillance list published by the Attorney General (delegated to the Drug Enforcement Administration (“DEA”)) of chemicals, products, materials, or equipment used in the illicit manufacture of controlled substances and listed chemicals.  21 U.S.C. § 842(a).  DEA publishes the Special Surveillance List to inform about potential illicit uses of a laboratory supply and reminds that civil penalties may be imposed on businesses that distribute a laboratory supply with reckless disregard for the illegal uses to which it will be put.  21 U.S.C. § 842(a)(11).

There is a rebuttable presumption of reckless disregard if DEA notifies a firm in writing that a laboratory supply it sold has been used by a customer, or distributed further by a customer, “for the unlawful production of controlled substances or listed chemicals a firm distributes and 2 weeks or more after the notification the notified firm distributes a laboratory supply to the [same] customer.”  21 U.S.C. § 842(a).  Distribution of a laboratory supply with reckless disregard subjects the seller of distributor to a civil penalty of not more than $250,000, now $470,640 with inflation.  21 U.S.C. § 842(c)(2)(C).

DEA issued a notice on June 4th effective immediately updating the Special Surveillance List for the second time in less than two years.  Special Surveillance List of Chemicals, Products, Materials and Equipment Used in the Manufacture of Controlled Substances and Listed Chemicals, 90 Fed. Reg. 23,711 (June 4, 2025). DEA published the original Special Surveillance in May 1999.  The agency revised the list in October 2023 when it added twenty-eight chemicals, removed two List I chemicals automatically included as a laboratory supply and added “tableting machines, including punches and dies.”

The newly updated Surveillance List includes chemicals, materials and equipment used in the manufacture, production and distribution of currently abused synthetic drugs like fentanyl, amphetamine, methamphetamine, PCP, LSD, ketamine and others.  Id. at 23,712.  Updating the list, DEA consulted law enforcement officials, forensic laboratory authorities, intelligence groups, drug signature and profiling programs, and international organizations.  Id.  The agency examined clandestine laboratory seizure reports, drug signature and profiling reports, intelligence reports, and scientific literature regarding:

1. Illicit controlled substance and listed chemical production methods;
2. Chemicals, materials, and equipment used in the clandestine production; and
3. Their role and importance in the synthesis of controlled substances and listed chemicals.  Id.

DEA added fourteen additional chemicals to the Surveillance List, updated the listing of a chemical on the list to include its other esters, and removed a List I chemical that is automatically a laboratory supply.  In addition, DEA added binding, disintegrating, filling, flowing, and lubricating agents that are excipients, specifically including products containing:

• Dicalcium phosphate,
• Magnesium stearate,
• Microcrystalline cellulose,
• Silicon dioxide, and
• Stearic acid.  Id.

The Surveillance List continues to include hydrogenators, “tableting machines, including punches and dies,” encapsulating machines and twenty-two liter heating mantels.  Id. at 23,713.

DEA did not touch the Special Surveillance List for over twenty years, and has revised it twice within the past two years.  We think that the agency will revise and update the list more frequently as clandestine manufacturing trends require.

Propionyl Chloride, A Proposed List I Chemical

DEA issued a notice of proposed rulemaking on June 3rd, following its October 12, 2023, advanced notice of proposed rulemaking (“ANPRM”) to regulate propionyl chloride as a List I chemical.  Designation of Propionyl Chloride as a List I Chemical, 90 Fed. Reg. 23,483 (June 3, 2025).  DEA found that propionyl chloride is being used and is important in the illicit manufacture of fentanyl, fentanyl analogues and fentanyl-related substances.  DEA found that propionyl chloride is a replacement for other List I and precursor chemicals in several illicit fentanyl manufacturing methods.  Id. at 23,485, 23,486.  DEA states that without regulations, propionyl chloride is readily available from 43 chemical suppliers.  Id. at 23,486.

Six respondents submitted comments to DEA’s ANPRM: three in support of controlling propionic chloride as a List I chemical, and three opposed.  Three commenters noted that propionyl chloride has legitimate potential use as a reagent for chemical synthesis processes  including in the natural product syntheses of N-deoxymilitarinone A and torrubiellone B, potential pharmaceutical development, resin/materials development, and agricultural chemicals.  One commenter, without providing details, asserted that the chemical may have uses in the medical field.  Id. at 23,486.

DEA does not propose to establish a regulated transaction threshold for propionyl chloride, therefore all transactions would be regulated and subject to DEA registration, recordkeeping, reporting and security requirements.  DEA also does not propose to exempt chemical mixtures containing concentrations of propionyl chloride, though manufacturers may submit an application for exemption from control of their specific product.  Id. at 23,483.  DEA explained that an exemption can be granted if the agency determines that the mixture is formulated such that “it cannot be easily used in the illicit production of a controlled substance and the listed chemical cannot be readily recovered.”  Id. at 23,486.

The proposed placing of propionyl chloride in List I is not subject to Executive Order 14192 requiring the elimination of ten regulations for each new regulation.  Public comments must be submitted electronically or postmarked on or before July 3, 2025.

4-Fluoroamphetamine, A Proposed Schedule I Substance

On June 3rd DEA also issued a notice of proposed rulemaking to control 4-fluoroamphetamine (“4-FA;” 1-(4-fluorophenyl)propan-2-amine), including it salts, isomers, and salts of isomers, in schedule I.  Schedules of Controlled Substances: Placement of 4-Fluoroamphetamine in Schedule I, 90 Fed. Reg. 23,477 (June 3, 2025).

4-FA is a central nervous system stimulant sharing structural and pharmacological similarities with the schedule II stimulants amphetamine and methamphetamine, and the schedule I stimulant 3,4-methylenedioxymethamphetamine, “MDMA”.  In March 2018 the Commission on Narcotic Drugs voted to add 4-FA to schedule II of the 1971 Convention on Psychotropic Substances, requiring signatories including the U.S. to schedule the substance to meet minimum requirements of the treaty.  The treaty requires signatories to implement licensing (registration) requirements to manufacture, distribute, import and export 4-FA, impose 4-FA importing and exporting requirements, and submit reports on 4-FA quantities manufactured, exported and imported as well as stocks to the International Narcotics Control Board.  Scheduling 4-FA in schedule I will enable the U.S. to fulfill its treaty obligations.  Id. at 23,478-79.

In response to a September 2019 DEA request to the Assistant Secretary for Health and Human Services (“HHS”) to conduct a scientific and medical evaluation of 4-FA, HHS recommended that it be placed in schedule I.  Id. at 23,479.  DEA conducted its own eight-factor analysis of 4-FA and found “that the facts and all relevant data constitute substantial evidence of the potential of abuse of 4-FA…[a]s such, DEA hereby proposes to permanently schedule 4-FA as a schedule I controlled substance.”  Id. at 23,481.  DEA also found that 4-FA has a high potential for abuse, no currently accepted medical use in treatment in the U.S. and lacks accepted safety for use under medical supervision, the criteria for schedule I placement.  Id. at 23,482.

Similar to DEA’s ANPRM for propionyl chloride, comments on DEA’s proposed scheduling of 4-FA must be submitted electronically or postmarked on or before July 3, 2025.  And, DEA scheduling actions are not subject to Executive Order 14192.

Thirty two years ago today, on June 10, 1993, Congress passed the landmark National Institutes of Health (NIH) Revitalization Act to remedy historical exclusion of women and minorities from research participation.  The law directed the NIH Director to ensure the inclusion of women and minorities as research subjects in NIH conducted or supported research unless doing so was “inappropriate” with respect to their health.  The law also required such research to be designed to enable a “valid analysis of whether the variables being studied in the trial affect women or members of minority groups, as the case may be, differently than other subjects in the trial.”

Contemporaneous with the NIH Revitalization Act, the Food and Drug Administration (FDA) reversed longstanding guidance categorically excluding non-pregnant women of childbearing potential from phase I and early phase II clinical trials in favor of encouraging women’s participation, requiring gender-based safety and efficacy analyses, and instituting contraception or abstinence stipulations for women of childbearing potential in early trials.

These events marked a turning point in expanding representation in clinical studies and opening the door to more personalized medical care.  Today it is widely accepted that both sex and race may be meaningfully correlated with physiological and pathological functions and that increasing trial representativeness may produce new biologic insights, improve the generalizability of research findings, and yield targeted therapeutic strategies with improved safety and effectiveness. Advancing the frontier of scientific knowledge has been an important rationale for diversifying trials.

Since 1993, Congress has continued to direct the federal government, and in particular FDA, to take steps to close the gap in clinical research representation.  For example:

• The Food and Drug Modernization Act of 1997 (FDAMA) directed FDA to develop guidance on the inclusion of women and minorities in research.
• The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law in 2012, directed FDA to investigate how well demographic subgroups (sex, age, race and ethnicity) were included in clinical trials to support approval of applications for medical products and whether subgroup-specific safety and effectiveness data were available.
• The FDA Reauthorization Act of 2017 (FDARA) directed FDA to develop guidance to enhance diversity in clinical trials.
• The Food and Drug Omnibus Reform Act of 2022 (FDORA) required sponsors of certain clinical trials for drugs, biologics and devices to submit Diversity Action Plans (DAPs) to improve enrollment of underrepresented populations and to ensure that participants in pivotal clinical trials reflect the demographic diversity of the population that will ultimately use the medical product, if approved. FDORA further directed FDA to issue guidance on the format and content of DAPs.

These legislative mandates in turn resulted in new initiatives by FDA to expand diversity and inclusivity in clinical trials.  In 2016—dubbed the “Year of Clinical Trials Diversity”  by FDA—the agency published two guidance documents in furtherance of FDASIA related to the standardized collection and reporting of race and ethnicity data in submissions of drug and device clinical trials (see our previous blog post on the device guidance here). In 2020, as required by FDARA,  FDA published guidance to enhance diversity in clinical trials that makes recommendations regarding (1) broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials; (2) developing eligibility criteria and improving trial recruitment so the enrolled population better reflects the population most likely to use the drug, if approved; and (3) applying the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.

In 2024, FDA issued its long overdue draft guidance on DAPs as required by FDORA (which we blogged about here). Under this guidance, sponsors must submit a DAP to the FDA for a Phase 3 or other pivotal study that describes the sponsor’s enrollment goals for the study disaggregated or tabulated by race, ethnicity, sex, and age group of the clinically relevant population, the sponsor’s rationale for its goals, and an explanation of how the sponsor intends to meet those goals. The draft guidance also encourages sponsors to consider additional factors that may affect clinical outcomes when developing DAP goals (e.g., demographic, socioeconomic, presence of co-morbidities).

FDORA directed FDA to finalize the draft DAP guidance no later than 9 months after closing the comment period, which will be June 26, 2025.

Recent developments give reason for concern about whether FDA will meet this deadline and, more broadly, about whether FDA will continue to implement Congress’ mandates for clinical trial diversity and inclusion.  In January 2025, FDA removed three draft and final guidance documents from its website: the 2024 draft guidance on DAPs; a 2025 draft guidance on sex- and gender-based differences in device development; and a 2020 final guidance on enhancing diversity in clinical trials.  FDA gave no public notice and offered no explanation for its actions.  Following a February 11, 2025 temporary restraining order issued by the U.S. District Court for the District of Columbia the documents were restored with a disclaimer stating: “Any information on this page promoting gender ideology is extremely inaccurate and disconnected from the immutable biological reality that there are two sexes, male and female,” (see 2/15/25 archive of FDA’s draft DAP guidance). As of the date of this blog, the 2024 draft guidance on DAPs and 2020 final guidance on enhancing clinical trial diversity appear to have been removed again (see here and here, respectively).

Ensuring diversity and inclusion in clinical trials is a scientific and public health imperative.  Lack of representation has serious and wide-ranging adverse consequences that include compromising generalizability of clinical research findings, hindering medical innovation, increasing healthcare costs, exacerbating disparities in healthcare, and undermining trust in the research enterprise.

Consistent with its mission to protect and promote public health, FDA has for decades been at the forefront of efforts to expand clinical trial diversity and inclusion.  Although political priorities may shift, continued commitment to its mission—as well as to implementation of Congress’ directives– requires FDA to continue the forward momentum toward greater representation in clinical research.  We hope FDA will issue the final DAP guidance by June 26, as required by Congress, and thereby signal its continued commitment to advancing this goal.

It was about a year and a half ago that we first proclaimed mass hysteria when FTC crossed streams into FDA territory, but perhaps our cries were premature.  As we mentioned last year, a large number of the drug companies targeted by FTC in its Orange Book delisting campaign refused to delist their device patents from the Orange Book.  The FTC took another swing in the courts with an amicus brief in Teva v. Amneal, in which the Court ultimately held that “to qualify for listing, a patent must claim at least what made the product approvable as a drug in the first place—its active ingredient,” but that case didn’t have the effect of causing mass delisting (according to an FTC press release, only about 22 of the 100 patents identified were delisted).  So, as of now, many of the device component patents to which FTC objected remained listed in the Orange Book.

Well, the FTC is back at it—again without the help of FDA.

Armed with the Federal Circuit opinion in Teva v. Amneal, the FTC sent another spate of “warning letters” on May 21, 2025 to Novartis, Amphastar Pharmaceuticals, Mylan Specialty, Covis Pharma, and three Teva entities.  It also notified FDA that it disputes the appropriateness of more than 200 patent listings, most of which FTC “previously disputed” but remain in the Orange Book.  The FTC is again taking the position that “[t]hese patents do not meet the statutory criteria for listing in the Orange Book, as confirmed by a recent ruling in the U.S. Court of Appeals for the Federal Circuit.”

The warning letters and delisting requests are not, in and of themselves, groundbreaking.  They’re mainly a continuation of FTC’s activities from 2023 and 2024.  But what makes them noteworthy is the elephant in the room: the change in administration.  The Press Release makes clear that this is not just a Democrat-led initiative.  The Republican-led FTC is continuing to move the ball forward:

‘The American people voted for transparent, competitive, and fair healthcare markets and President Trump is taking action. The FTC is doing its part,’ said FTC Chairman Andrew N. Ferguson. ‘When firms use improper methods to limit competition in the market, it’s everyday Americans who are harmed by higher prices and less access. The FTC will continue to vigorously pursue firms using practices that harm competition.’

It seems that this FTC isn’t willing to let this go.

Yet mum is the word from FDA.  There was some hope that, with pressure from the FTC, FDA would issue a guidance on whether device patents can be listed in the Orange Book since, after all, the Orange Book is plainly an FDA issue.  But FDA has been radio-silent.  So, the FTC continues on alone.  Down the only road its ever known.  Because, like a drifter, it was born to walk alone.

We have written many posts (here, here, here, and more) about the impact of the reductions in force (RIFs) on various activities across FDA. One area where the RIFs are beginning to have an impact is with respect to Small Business Determination (SBD) requests submitted to CDRH. The Office of Management, which was eliminated in the April 1 RIF, was responsible for processing these requests, and generally did so within 60 days of receipt. It is unclear which group is now reviewing and processing these requests, and the time it will take to do so. (We note that the webpage for the Office of Management is still functional, but has not been updated since January 2024.)

On June 4, CDRH sent out an email stating that it would be updating the CDRH Portal to add new functionality to the SBD feature to allow communications between CDRH and industry in the portal rather than via email. This indicates that CDRH is still reviewing SBDs and looking for ways to facilitate communications. It does not, however, help industry understand how long they can expect to wait for a response.

The SBDs are critically important for many medical device manufacturers. A “small business” is defined as a business, including its affiliates, whose gross receipts and sales are less than $100 million for the most recent tax year. Being granted an SBD provides discounted user fee rates for 510(k)s, de novos, and PMAs, among other submission types. The table below highlights the standard fee versus the small business fee for FY2025 for product authorization submissions.

There are many small start-up companies developing novel, innovative devices that will go through the de novo process. For these entities, the difference between the standard fee and the small business fee is not trivial. Indeed, for companies for whom every dollar is hard earned and every investor is closely watching the spend, a difference of over $120,000 for a de novo submission is significant.

If a small business submits an SBD request relying on the 60-day turnaround in advance of submitting an application to CDRH, and the SBD is delayed, the company may be forced to choose between paying the standard user fee payment or waiting for the granting of the SBD. To make this decision the company will likely need to weigh, among other matters, the strength and complexity of the submission, available funds, and timelines promised to investors and/or Boards of Directors. Companies would also likely need to consider the certainty of starting the review clock, with an eye to having a commercially viable product and being better positioned financially down the road, versus saving money on the submission now but potentially delaying commercial availability. (We acknowledge, of course, that a later submission does not necessarily delay commercial availability-this takes us back to the strength and complexity of the submission.)

We recognize that these decisions are unique to each company and would be happy to help weigh options to determine the best path forward.

Among other things, EO 14212 established the Make America Healthy Again (MAHA) Commission (with HHS Secretary Kennedy as its Chair) and tasked it with a tall order: submission to the President of an Assessment that tackled 10(!) complex public health issues within 100(!) days. Perhaps it was inevitable that the Commission would turn to AI for help, as seems to have been the case in light of media reports that the Assessment as originally published included references that don’t exist. We lawyers have seen that show before.

The process through which the Assessment was developed remains a mystery. Ordinarily, a public health initiative of such magnitude would have been governed by a transparent multi-step process featuring public meetings and drawing on external scientific expertise. In this instance, the Assessment appears to have been developed behind closed doors, and evidently did not undergo an internal or external review thorough enough to capture these errors.

Nevertheless, pursuant to EO 14212, the Commission now has less than 80(!) days to submit to the President a Strategy based on the findings of the Assessment. The Strategy must “address appropriately restructuring the Federal Government’s response to the childhood chronic disease crisis, including by ending Federal practices that exacerbate the health crisis or unsuccessfully attempt to address it, and by adding powerful new solutions that will end childhood chronic disease.” In other words, as you read this, the Assessment’s findings and recommendations are getting baked into federal government policy, for better or worse.

What might that look like for the drug sector? As stated, the primary focus of the Assessment is on chronic diseases, encompassing both their causes and their treatments. The Assessment uses a significant amount of real estate to discuss prescribing practices, alleging that current practices amount to overprescribing. The Assessment highlights various trends related to chronic disease diagnoses (such as increasing rates of autism spectrum disorder and attention deficit hyperactivity disorder) with associated trends in prescribing practices.

This overprescribing relates to a lack of long-term data for either safety (particularly neurodevelopmental) and efficacy for drugs which are nevertheless often prescribed long-term. There are also drugs the Assessment identifies as being used off-label without high-quality evidence or for uses that are approved but without rigorous “true placebo”-controlled trials (namely vaccines) and/or with known safety concerns. Some specific examples cited in the Assessment are the increased use of stimulants to treat ADHD despite evidence they did not improve long-term outcomes, higher rates of antidepressant prescribing despite evidence that psychotherapy is as effective in the short-term and potentially more effective long-term, increased prescribing of antipsychotic medication with many prescribed for off-label conditions in children, and unnecessary antibiotic use that is associated with higher rates of certain chronic conditions. The Assessment states that this prescribing is tantamount to doing direct harm, given the known and unknown risks and benefits of drugs in these contexts of use.

This Assessment does not itself prescribe specific remedies for the ills it diagnoses; those are supposedly coming in the future Strategy document. That leaves us to speculate what the implications of this Assessment will be. Notably, many of the issues regarding drugs are typically considered the practice of medicine, which FDA does not regulate.

However, that does not mean FDA is has no tools to address what the Assessment refers to as the “Overmedicalization of Our Kids.” Therapies for chronic diseases, even in pediatrics, are not approved based on decades-long studies, and this is not likely to change. Indications for chronic diseases do not generally reflect the length of the clinical trial; FDA determines that clinical trials supporting such approvals are of sufficient duration and makes an approval determination. If there are no known or anticipated safety or efficacy concerns from continued use, FDA draft guidance states that the description of the duration of use from the clinical trials should be discussed in the Clinical Studies section of labeling, not in the Indications and Usage section, as it is generally not necessary to limit duration of use in the indication unless it is essential to ensure the safe and effective use of the drug. Likewise, contraindications describe situations in which the drug should not be used because the risk of use clearly outweighs any possible therapeutic benefit; however, this should include only known hazards, and not theoretical possibilities. The Assessment suggests that FDA may be viewing indication claims with greater scrutiny moving forward, either at the time of approval or after, when such information may be available.

Known clinically relevant safety and effectiveness information is generally included in the label under current practices. However, as the Assessment notes, “[t]here are…many possible adverse events for which there is inadequate evidence to accept or reject a causal relationship,” which may otherwise lead manufacturers to opt not to include them in the labeling. This Assessment suggests causation may be viewed using a different standard moving forward, leading to the inclusion of additional information in the Warnings and Precautions or Adverse Reactions sections of drug labeling, or other potential consequences.

FDA also has other tools, such as Risk Evaluation and Mitigation Strategies (REMS), which are implemented to ensure that the benefits of a drug outweigh the risks. However, the most burdensome REMS restrictions, Elements to Assure Safe Use, are intended for situations only where specific serious risks are identified.

Similarly, FDA can use post-marketing requirements (PMRs). PMRs are implemented to assess possible serious risks associated with drugs, which can include assessing known serious risks, assessing signals of serious risks, or identifying an unexpected serious risk when available data indicate the potential for a serious risk. This can resemble enhanced post-marketing surveillance, and it is not difficult to see how the MAHA Assessment may support an increase in their usage where the qualifying criteria are met.

The Assessment does not focus solely on safety. For example, it describes a “replication crisis,” which it suggests should be addressed by government agencies to confirm both safety and efficacy findings from industry-funded research. Such efforts are intended to “improve trust and reliability in basic science and interventions in childhood chronic disease” and may have implications for labeling or continued approvals.

As described here in brief, FDA has a variety of tools that are already in use to address the issues raised in the MAHA Assessment. For example, the Assessment notes that SSRIs carry a Boxed Warning describing the risk of suicidal thinking and behavior in adolescents to facilitate safe prescribing practices. However, if FDA determines that these tools are not sufficient to address the issues described in the Assessment, we may see their use enhanced. Ultimately, FDA has the authority to decide whether benefits of a drug outweigh the risks, either in only limited circumstances, only with appropriate warnings, or in no circumstances, and approvals may be limited or withdrawn. Approvals may also not be made at all or may require more evidence, as we may also see increased pre-approval requirements such as true placebo-controlled trial requirements for vaccines. We will continue to monitor these developments as they come.

We appreciate receiving feedback on our blog posts.  We received a response to our post on the prescribing red flags indicating the likelihood of certain prescriptions filled by Walgreens pharmacies “were invalid because they lacked a legitimate medical purpose or were not issued in the usual course of professional practice.”  Press Release, Walgreens Agrees To Pay Up to $350M for Illegally Filling Unlawful Opioid Prescriptions and Submitting False Claims, U.S. Attorney’s Office, Northern District of Illinois, April 21, 2025, quoted here.

We noted that the Drug Enforcement Administration (“DEA”) had explained in its 2021 Gulf Med Pharmacy decision that prescribing red flags do not prohibit pharmacies from filling a prescription but are potential signs of diversion or risks to patient harm that pharmacists must resolve before filling.  Gulf Med Pharmacy; Decision and Order, 86 Fed. Reg. 72,694, 72,703 (Dec. 22, 2021).  Our reader informed us of two additional prescribing/dispensing red flags that DEA has alleged are “unresolvable” that he wanted to share with the pharmacy community.

The first “unresolvable” red flag is the continued prescribing and dispensing of immediate-release/short-acting opioids after two or three months.  Immediate-release/short-acting opioids act faster than extended-release/long-acting opioids.  DEA alleged that the pharmacy at issue dispensed oxycodone 30 mg., oxycodone/acetaminophen 10/325, hydromorphone 8 mg., and tramadol 50 mg. tablets to patients over the course of many months.  DEA specifically alleged that the pharmacy dispensed immediate-release opioids over a significant period of time, often at the highest strength available and in combination with other immediate-release opioids.

While prescribing immediate-release/short-acting opioids as a red flag is not new, that it is considered “unresolvable” is.  DEA’s position is contrary to statements made in the agency’s 2024 Coconut Grove decision when its expert opined at the hearing that filling immediate-release opioids prescribed and dispensed over a period of one and a half to two years “presented red flags and [the pharmacy] needed to properly resolve these red flags before dispensing.”  Coconut Grove Pharmacy; Decision and Order, 89 Fed. Reg. 50,372, 50,375, (June 13, 2024).  That decision includes a footnote stating that the expert “did not testify as to a specific time period that would cause concern, but made clear that a patient taking immediate-release opioids for ‘30, 60 days maximum’ would be acceptable and that over two years would be ‘very concerning.’”  Id. at 50,374-75 n.18.

The assertion that prescribing immediate-release opioids longer than two or three months is a red flag may have originated with the Center for Disease Control and Prevention (“CDC”) 2022 Clinical Practice Guideline for Prescribing Opioids for Pain.  The Guideline recommends that when clinicians begin opioid therapy for acute pain (of less than one month), subacute pain (of between one to three months) and chronic pain (longer than three months), they should prescribe immediate-release opioids instead of extended release-long-acting opioids.  Deborah Dowell et al., CDC Clinical Practice Guideline for Prescribing Opioids for Pain – United States, 2022, 71 MMWR Recomm. Rep. 1, Recommendation 3.  The Guideline also recommends when diagnosis and severity of acute pain warrant the use of opioids, clinicians should prescribe immediate-release opioids instead of extended-release and long-acting opioids at the lowest effective doses and for no longer than the expected duration of pain severe enough to require opioids to minimize the initiation of long-term opioid use.  Id., Recommendation 1.  However, the 2022 Clinical Practice Guideline, which updated the CDC’s 2016 Guideline, notes that its “recommendations are voluntary and intended to be flexible to support, not supplant, individualized, patient-centered care.”  Id. at Background.

The second “unresolvable” red flag alleged by DEA and shared by our reader was patients continuing to pay cash after the pharmacy filled their second prescription.  While certain circumstances surrounding a patient paying cash for controlled medication may be a prescribing/dispensing red flag, we cannot help but think that there are many legitimate reasons for patients paying cash for it to be patently “unresolvable” after their second fill.

At midnight on Friday, May 30, 2025, the government’s deadline to notice an appeal from the U.S. District Court for the Eastern District of Texas’s decision vacating the LDT Rule lapsed without the government doing so. This means the District Court decision stands, with no further right of appeal, and the LDT Rule remains vacated in its entirety.  As HPM argued in both the groundbreaking citizen petition Jeffrey Gibbs filed thirty-two years ago and the papers we filed on behalf of our clients, Dr. Michael Laposata and the Association for Molecular Pathology in the recent LDT litigation, the Federal, Food, Drug, and Cosmetic Act does not authorize FDA to regulate LDTs as medical devices. Those in the lab industry – and the physicians and patients who rely upon LDTs – are sure to be breathing a well-deserved sigh of relief over this development.

Just before this decisive event, though, FDA released a relatively rare Warning Letter to a manufacturer of research use only (RUO) reagents.  RUO-labeled reagents and materials are often used in LDTs in clinical laboratories.  The letter, which FDA issued on March 31, 2025 (but only posted on its website last week), was only one of two that FDA has sent in the last five years and only one of five that FDA has issued since finalizing its RUO Guidance in November 2013 (see guidance here).

The Warning Letter to DRG Instruments GmbH states that FDA determined the Company’s RUO‑labeled assay was intended for clinical diagnostic use, citing statements on the company’s website and labeling, as well as records that showed distribution to clinical laboratories that did not perform any research. Some of the claims that FDA cited as being for diagnostic use included “Simple and patient-friendly measurement of hormone profiles,” “Provides accurate, low level detection,” and “Can be performed also by patients.”

A striking detail in this Warning Letter was that FDA found it did not matter that the company had certification letters on record that showed at least some of their customers were aware that the products should only be used for research purposes, because FDA’s own “review of these customers’ websites strongly suggests that these customers are engaged in clinical diagnostic testing.”  RUO certification programs were something that FDA had, at one time, recommended.  In the current RUO Guidance, FDA notes that the existence of an RUO certification program would only be viewed as a factor when assessing the intended use of an RUO product.  Indeed, FDA states, “the existence of a certification program alone would not relieve manufacturers from their responsibilities to ensure that their labeling and distribution practices for RUO/IUO products are consistent with the product’s RUO/IUO label.”  The Warning Letter seems to echo this point.  Importantly, FDA did not say that sales to customers who are doing exclusively clinical diagnostics, alone, formed the basis of the agency’s letter.  These, along with the promotional claims formed FDA’s basis for concluding the products were intended for diagnostic use.

Because LDTs for clinical diagnostic use can sometimes include RUO labeled components, FDA may look to increase its scrutiny of these components as a means of tightening its control of the inputs to LDTs. We do not see the release of this Warning Letter as directly related to the LDT litigation, however.  The DRG Warning Letter cited information gathered in a November 2024 inspection and the warning letter itself was issued the same day as Judge Jordan’s decision in the LDT case.  Therefore, the events surrounding this particular Warning Letter preceded the LDT decision.

That being said, we have no doubt that as the door to regulating LDTs directly has closed, absent new legislation, FDA is likely to look for a new door to open.  Greater scrutiny of RUO products and those companies that manufacture them could be one of those doors.  HPM is keeping a watchful eye on the various indirect means by which FDA may try to regulate LDTs. In a follow-up post, we’ll discuss the different avenues FDA could seek to try to regulate LDTs (or components thereof) without new legislation.  Stay tuned.