If you’re the FDA, you get sued when you enforce violations of the Tobacco Control Act (TCA) for selling e-cigarettes that haven’t received premarket authorization from FDA (see here), and you get sued when you don’t. Or rather, when you put out a Guidance saying you probably won’t enforce for a group of products that make it onto an FDA-maintained list.

That’s what a recently filed case is about, Campaign for Tobacco-Free Kids v. FDA, No. 8:26-cv-2767 (D. Md., filed July 14, 2026). There, Tobacco-Free Kids, along with the American Academy of Pediatrics (AAP) and a slew of other medical and advocacy groups (and a few individuals) are suing to challenge a Guidance FDA issued in May 2026, Enforcement Priorities for Certain New Tobacco Products Without Premarket Authorization.  That Guidance says that FDA “generally does not intend to prioritize enforcement of the premarket authorization requirement, where [an e-cigarette or nicotine pouch] product:

• is subject to an application that is pending, and the application has been accepted and filed or is subject to a supplemental application (sPMTA) that has been accepted and pending for more than 180 days; and
• for nontobacco-flavored ENDS products, if FDA has determined that the application also includes data necessary to evaluate whether such product is appropriate for the protection of the public health.”

Even if you do meet those criteria, FDA said, it may still enforce against you if there are other things of concern about your product, like a special appeal to children, high nicotine content, or large number of adverse events. And in any event, non-enforcement against you still is not “guaranteed.”

Importantly, FDA also said it “will create and maintain a public-facing webpage identifying manufacturers and their associated products that FDA generally does not intend to prioritize enforcement against.” If a manufacturer believes that its product should be listed on that FDA webpage, it should “reach out” to FDA to find out the specific information about the product that FDA wants to consider, which may include “cross-referenc[ing] specific section(s)” of the pending premarket application.  FDA will update this list of products “on a rolling basis,” but FDA did not say when it will publish it. (For lack of a better term, we’ll call this the ‘Whitelist’).

Tobacco-Free Kids charge that this Guidance amounts to “an express and deliberate abdication of FDA’s responsibilities under the [TCA].” In short, the plaintiffs argue that the TCA provides that a product is illegal if it is marketed without FDA’s premarket authorization, and by effectively giving the green light to whole categories of products lacking that authorization, FDA is adopting “an extra-statutory, post-market review system for a significant category of new tobacco products.” The complaint further takes aim at the Whitelist, saying that FDA’s publication of that list will “facilitat[e]” the sale of unlawful products, and “in practice,” give “‘cover’ to the industry.” For this and other reasons, they say, the Guidance is illegal and should be vacated by the court, and FDA should be enjoined from implementing it or its intended Whitelist.

FDA’s Guidance justifies its policy, in short, by saying that those types of products, by virtue of having been “accepted and filed” by FDA and demonstrating that they have other “necessary data”, put them in a separate category from those FDA has refused to accept or file. FDA says by focusing enforcement on those latter products [and those that have not submitted premarket applications at all], FDA can “better allocate its enforcement resources,” which are limited.

Now let’s consider a few deeper questions.

Why the District of Maryland?

In a word, AAP.  In 2018, AAP (and many of the same other plaintiffs here) successfully sued FDA in this district on a different FDA guidance expressing a tobacco non-enforcement policy. In a 2017 Guidance, FDA had announced that for products on the market before a certain date, it would not require those applications to be even submitted for five more years, before FDA would consider enforcement.  FDA attempted to couch that decision as falling within the general legal principle (under the seminal 1985 case Heckler v. Chaney) that agency exercises of “enforcement discretion” are nonreviewable by courts, but Judge Grimm disagreed.  AAP v. FDA, 379 F. Supp. 3d 461 (D. Md. 2019). He ruled that FDA’s policy wasn’t a simple exercise of enforcement discretion, but rather (quoting Chaney) that “the agency had consciously and expressly adopted a general policy that is so extreme as to amount to an abdication of its statutory responsibilities.” So Judge Grimm struck down that Guidance and set a much sooner deadline by which applications had to be submitted to FDA, and another effectively for FDA to act on them.

The Tobacco-Free Kids Plaintiffs make no bones about it: to them, this is just AAP déjà vu all over again, marking an “abdication” of FDA’s statutory responsibilities for the reasons above. And though Judge Grimm’s rulings aren’t binding precedent even in the District of Maryland, the Plaintiffs are likely betting that they’ll get the most serious consideration there.

Indeed, we agree that this case will most likely rise or fall on whether the court decides this Guidance falls on the AAP side of things, or is different enough.

What does DACA have to do with this? Or homeopathy?

After AAP was decided, the Supreme Court weighed in on a different non-enforcement policy: Deferred Action for Childhood Arrivals (DACA), an immigration relief program that allowed certain unauthorized immigrants who arrived in the U.S. as children to apply for a two-year forbearance of removal. In DHS v. Regents of Univ. of Cal., 591 U.S. 1 (2020), The Supreme Court held that both the implementation of that program, and its later attempted rescission, were judicially reviewable. While it reaffirmed the Chaney rule of non-reviewability of “enforcement discretion” decisions, the Court found it did not apply because DACA was not a mere “passive non-enforcement policy; it created a program for conferring affirmative immigration relief,” including establishing a process for individuals to apply for, receive review of, and obtain a formal notice of the two-year forbearance.  The program also provided access to government benefits like Social Security and Medicare.

So here, the Plaintiffs might also argue that the 2026 Guidance is like the DACA program. In particular, they’d likely point to the Whitelist as more than mere passive non-enforcement: FDA apparently plans to solicit application-like information, review it, and then make determinations that are reflected in the published Whitelist.

The government would likely try to distinguish DACA as much as it can: it may argue there are no affirmative “benefits” attendant to making it on the Whitelist, just an indication of likely non-enforcement; and that the Guidance merely says it does not intend to “prioritize” enforcement of products that make it on its list, not offer them a full-on safe harbor, and that it reserves the right to pursue “case-by-case” enforcement.

And the government will likely make similar arguments in attempting to distinguish AAP: for example, while like AAP’s, this Guidance does draw broad categories of products against which FDA doesn’t intend to enforce, it is a more limited and less “across-the-board” set than the 2017 Guidance. It may also point to the distinction it has drawn – applications that have made it at least through FDA’s initial “acceptance” and “filing” reviews (and in the case of flavored ENDS, show other certain indications of public health appropriateness), as showing FDA is attempting to draw reasonable enforcement-priority lines within, rather than wholly abdicating, its TCA duties.

We also have to note that enforcement discretion is a tool FDA reaches for across the products it regulates in a variety of different circumstances — and this case once more presents thorny questions of how far an Agency can go in a formal announcement of a non-enforcement (or enforcement “priority”) policy before it leaves Chaney’s ambit. We won’t get into all of that here, but one can see similar judicial grappling in MediNatura, Inc. v. FDA, 496 F. Supp. 3d 416 (D.D.C. 2020) (finding an enforcement-related policy about homeopathic products reviewable, though not unlawful; decided after Regents).

Of course, all this discussion is mainly just about a threshold legal issue — whether a court can review the 2026 Guidance at all.  FDA possibly could still lose on that, but win on the argument that the Guidance was not arbitrary and capricious or otherwise contrary to law on the various bases Plaintiffs have asserted.  But in our estimation, that’s a relatively less likely outcome here: If a court finds the Guidance reviewable (say, because it abdicated FDA’s duties under the TCA), it wouldn’t be much of a leap for it to strike down the Guidance as violating those same duties.  So the two issues will more likely rise or fall together.

What about standing?

FDA/DOJ often assert procedural defenses wherever they can, and they may have another one up their sleeve here: Article III standing.  The government tried and lost on that issue in AAP, but that was before the Supreme Court’s Alliance for Hippocratic Medicine (2024) decision. In a portion of that ruling that received less outside attention, the Court drew much stricter lines around what is required to establish “organizational standing” — that is, when an organization can show that it has been harmed by a government policy in the requisite sense in order to sue.  Because the lead plaintiffs here are medical and public health advocacy organizations, the government may try to use Alliance to argue they can’t sue in the first place.  Probably for just this reason, the named Plaintiffs here also include two individuals: a pediatrician whose patients do or may vape/use nicotine pouches, and a mother of teenage sons that do or she fears will vape.  For the government to prevail here on a standing argument, it would have to convince the court that neither of those individuals has standing either, on top of whatever standing issues the organizations may have. Time will tell whether the government will give that a try, and if so, how the court will resolve the standing issues.

Where might all this lead?

If FDA wins this case, and proceeds ahead, its Whitelist can be expected to be viewed by many — manufacturers, vendors, retailers, and perhaps state authorities — as an indication of products that may be sold without fear of running afoul of FDA.  (Even though FDA says there are no guarantees and those are only its “priorities” . . . isn’t that reliance the point of the List in the first place?)  If FDA loses, like in AAP, it will still be able to exercise case-by-case enforcement discretion. So a contrary ruling won’t necessarily mean that FDA must enforce against those products, but it would at least mean that FDA cannot have an explicit Guidance, accompanied by a formal Whitelist, saying it (probably) won’t.

And finally, since FDA regularly makes more- and less-formal announcements of exercises of its enforcement discretion, depending on how this case shakes out, it carries the potential for broader implications across FDA’s regulated industries beyond the facts of this case and Guidance.

After being announced in April by FDA and CMS, the Regulatory Alignment for Predictable and Immediate Device (RAPID) Coverage Pathway was released as a proposed procedural notice in the Federal Register on August 11, 2026, and is open for public comment.  Comments may be submitted for 60 days.

This coverage pathway is intended to provide an expedited Medicare national coverage decision (NCD) for new, innovative technologies, which is an important policy objective.  However, it is structured to “leverage existing processes,” specifically the processes for review of Investigational Device Exemption (IDE) studies, and in doing so, creates limitations to the number of devices that will be eligible.

As described in the notice as well as in an accompanying Fact Sheet, only devices that meet the following requirements are eligible for RAPID:

• Presumptive Class II FDA Breakthrough-designated devices participating in TAP [Total Product Life Cycle Advisory Program] planning to submit a De Novo request to FDA; or Class III FDA Breakthrough-designated devices planning to submit a premarket approval application (PMA) regardless of whether they are participating in TAP;
• Devices in the IDE pre-submission stage, and the manufacturer plans to conduct an IDE study that enrolls Medicare beneficiaries and evaluates clinical outcomes that FDA determines are appropriate for the device and that CMS confirms evidence showing that the device achieves those outcomes in the Medicare beneficiary population would demonstrate that the device improves health outcomes for Medicare beneficiaries;
• Based on the information available, there is no evidence that immediately makes clear that the device will not fall under a Medicare benefit category;
• Not already the subject of a controlling Medicare NCD;
• Separately payable devices that can, if approved, be billed to Medicare; and
• Not otherwise excluded from coverage through law or regulation.

The notice further limits eligibility to exclude in vitro diagnostics, including diagnostic laboratory tests, stating that these device types are currently reviewed by specialized Medicare Administrative Contractors (MACs), and should continue through this existing pathway.

As we blogged about previously, the RAPID requirements will significantly limit the devices that are able to take advantage of this pathway.  This Federal Register announcement includes another requirement that was not clear from FDA’s prior announcement—a device need not only be a Class II Breakthrough device in TAP with an IDE study, it must be a device that will go through the de novo authorization process rather than a 510(k), with limited exceptions for 510(k) devices relying on a primary predicate that was recently authorized through the de novo pathway.  Based on our review of FDA’s list of authorized Breakthrough devices, more than 40% came to market through the 510(k) process, but for those meeting the narrow exception for 510(k) devices, these would not have been eligible for RAPID.

Furthermore, the requirement for an IDE will limit eligible devices greatly.  For many, if not most, presumptive Class II devices that might otherwise be eligible, clinical studies will be non-significant risk and will not be required to submit an IDE to FDA.  Devices may also obtain Breakthrough designation by improving accessibility of technology that has already been proven clinically, so there may be instances where new clinical performance data are not needed, but differences introduced to improve accessibility result in the need for a new coverage determination.  Devices that are beyond the IDE pre-submission stage and already have an approved IDE are also currently excluded, although the notice does seek comments on whether a temporary process should be included to allow consideration of these devices.

In our review of RAPID, the need for an IDE was introduced to leverage an existing review process instead of developing a process that can be utilized to achieve the program’s bigger goal.  The Breakthrough Devices Program already includes processes for Data Development Plans and Clinical Protocol Agreements, and the TAP program’s primary goal is to “expedite patient access to innovative medical devices . . . by facilitating engagement with other key parties for developers of devices of public health importance.” It is not clear why the Agencies decided to insert IDE requirements for RAPID eligibility instead of building RAPID on the existing Breakthrough and TAP frameworks.

In its review, CMS needs to assess clinical outcomes (direct measures of how a patient feels, functions, or survives) in Medicare beneficiaries, and there are multiple ways to accomplish this in addition to conducting a clinical study under an approved IDE.  The RAPID coverage pathway has three stages: (1) IDE Pre-submission; (2) Formal IDE Submission to FDA and CMS; and (3) Transition from IDE to Coverage.  Stage 2 provides study design considerations from both FDA and CMS that could seemingly be provided using Breakthrough interactions or TAP amendments for devices that do not require an IDE study.  For those devices that make it through the process, a proposed NCD will be issued the same day as FDA market authorization—with a goal of finalization within 60 to 90 days.

The notice seems to recognize the limited scope of RAPID and devotes significant discussion to other existing coverage pathways that may be utilized for devices that are not eligible for RAPID, including Parallel Review (we note that only two devices have successfully utilized the Parallel Review program, calling into question the extent to which this is truly a viable option).  The notice indicates that CMS also intends to work with FDA to consider updates to the Parallel Review program and other initiatives to align procedures.

RAPID reflects an important effort by FDA and CMS to close the gap between market authorization and Medicare coverage for the small subset of devices that can meet its eligibility criteria.  But manufacturers should not overestimate RAPID’s reach.  The pathway will be unavailable to many Breakthrough devices whose studies are non-significant risk or otherwise do not require an IDE, to devices already past the IDE pre-submission stage, to in vitro diagnostics, to Class II devices that are not in TAP, and Class II devices that will proceed through the 510(k) pathway.  Manufacturers should assess RAPID eligibility, and the tradeoffs of pursuing an IDE study built around Medicare-relevant outcomes, as early as possible in development, ideally in tandem with any Breakthrough Devices Program and TAP interactions.

CDRH’s September 25 public meeting offers a front-row seat to the science shaping the future of medical device review.

Last week, the FDA’s Center for Devices and Radiological Health (CDRH) announced a public meeting titled “Regulatory Science Innovations Catalyzing Medical Device Development,” scheduled for September 25, 2026. For companies developing, manufacturing, or investing in medical devices, this event offers a rare opportunity to hear directly from the agency about the scientific tools and evidence standards that increasingly shape product review and approval decisions.

The day will open with an expert panel session before moving into deep-dive breakout discussions organized around three key focus areas: AI and digital health, emerging device technologies, and evidence generation and advanced testing methods. CDRH leadership and other key stakeholders are expected to participate throughout the day. These tracks signal the agency’s interest in structured industry input on how regulatory science should evolve to keep pace with fast-moving areas—AI/ML-enabled software, novel sensor and wearable technologies, and new approaches to generating clinical and non-clinical evidence—all of which carry direct implications for premarket strategy and submission planning.

The timing is significant. 2026 marks the 50th anniversary of the Medical Device Amendments of 1976—the statutory foundation of modern device regulation. Devices have evolved dramatically over the past half-century, and regulations have often struggled to keep pace. The agency’s current priorities—artificial intelligence, real-world evidence, cybersecurity, and updated quality management system requirements—are reshaping how submissions are prepared and evaluated. For medical device companies and their investors, this meeting presents a unique opportunity to gain insight into CDRH’s thinking on these critical topics and to provide feedback on how the regulatory framework should adapt to ongoing innovation.

We encourage clients to review the official FDA event page for registration details, format, and the full agenda. If you would like help interpreting how these regulatory science developments may affect your product pipeline, submission strategy, or compliance posture, please reach out to our team—we would be glad to assist.

When perusing regulations.gov, as bloggers searching for content are wont to do, we ran across an interesting Citizen Petition from June that grabbed our attention.  Indeed, a June 11, 2026 Petition from Marc R. Matrana, M.D.—System Medical Director of Precision Medicine at the Ochsner MD Anderson Cancer Center in New Orleans and a longtime advocate for precision-oncology legislation in Louisiana—caught our eye because of the novel use of FDC Act § 505(o)(4).  Typically reserved for when the Agency learns of new safety issues from adverse events or publications, FDC Act § 505(o)(4) allows FDA to request that a sponsor update its product labeling when the Agency “becomes aware of new information, including any new safety information or information related to reduced effectiveness, that [FDA] determines should be included in the labeling of the drug.”  In other words, FDC Act § 505(o)(4) instructs FDA to initiate labeling changes once it becomes aware of new safety information, which can include effectiveness (FDA has interpreted the “effectiveness” issue to mean that if a drug’s ineffectiveness leads to death, risk of death, hospitalization, or incapacitation, it can be a basis for a mandated labeling change.).  This Petition uses FDC Act § 505(o)(4) as a lever to force updated scientific information into labeling.  It’s an interesting use of the regulatory procedure.

The Petition asks FDA to direct a labeling change for a group of immunotherapies used to treat NSCLC and adopt a “Limitation of Use” to exclude patients whose tumors carry ROS1 or RET rearrangements so that these patients are redirected to targeted TKIs.  Rather than target a single product, the Petition asks FDA to direct labeling changes across six major immunotherapies (KEYTRUDA, OPDIVO, YERVOY, LIBTAYO, TECENTRIQ, and IMFINZI) simultaneously.  Thus, this Petition asks FDA to use its authority to change labeling for an entire swath of products in one fell swoop, reshaping an entire drug class at once.  If FDA were to grant it, that would demonstrate the statute can be used to make coordinated, class-wide labeling revisions based on evolving evidence—a meaningful precedent for how the agency polices approved oncology labels.

That said, the underlying premise—that oncology labeling can go stale as the evidence base evolves, and that FDA should do something about it—isn’t new to the agency.  FDA’s Oncology Center of Excellence already runs Project Renewal, a standing initiative to revisit older oncology drug labels against current science; it has produced updated labeling for drugs like Xeloda, Temodar, and fludarabine phosphate.  What’s novel here isn’t the idea, but the mechanism: rather than a collaborative FDA-sponsor label update, the Petition asks FDA to use its compulsory §505(o)(4) authority to force the issue across six different sponsors’ products simultaneously.

The Petition itself makes an interesting argument.  It cites recent revisions to NCCN Clinical Practice Guidelines, which no longer recommend immunotherapy as a first-line option for patients with ROS1 or RET fusions, as “new safety information” within the meaning of section 505(o)(4).  The Petition implies that the peer-reviewed data and postmarket observational evidence underlying the NCCN Clinical Practice Guidelines render them a synthesis of newly available scientific information that FDA must consider.  This new evidence, published since the named immunotherapies were approved, shows that using them as first-line therapy in ROS1- and RET-rearranged patients introduces real safety risks, including reduced effectiveness, because immunotherapies do not target the genetic driver of the disease. By failing to warn clinicians that ICIs are inappropriate as first-line therapy for these populations, the Petition contends that the labeling creates a reasonable likelihood that clinicians will initiate a therapy that offers minimal benefit, delays access to effective TKIs, and increases hospitalization risk; the labeling is thus “misleading” absent a Limitation of Use for ROS1 and RET populations.

Underlying all of this is a practical reality: the uptake of biomarker testing is limited, resulting in serious complications for patients.  According to the Petition, roughly half of advanced NSCLC patients who could benefit from personalized treatment do not receive it, and even among patients who are tested and get timely results, a meaningful share still do not receive appropriate targeted therapy.  Because clinicians often rely on drug labeling to guide sequencing decisions, the Petition argues that labeling silence on first-line ICI use in ROS1 and RET patients contributes directly to inappropriate therapy selection.

If FDA acts, it would confirm that section 505(o)(4) can be used to align an entire drug class with updated guidelines and postmarket evidence.  If FDA declines, the response may reveal the statutory threshold for “new safety information.”  Either way, the filing underscores a larger point for anyone tracking precision oncology: keeping drug labeling in step with the science is increasingly a public-health imperative —an imperative FDA has already institutionalized through Project Renewal.

Last week FDA publicly posted the first Quality Management System Regulation (QMSR) Warning Letter and this week it posted the second.  The QMSR went into effect in February of this year.  For months, we have seen the top 483 citations shift in FDA’s inspection database from those under the Quality System Regulation (QSR) to the QMSR.  The most significant change from the QSR to the QMSR is the QMSR’s focus on risk management, as discussed in our prior post (here).  It has, therefore, been of little surprise to see risk-management related 483 citations rise to being the top citation—greater than 20% of all 483 citations—when you combine process and record-related observations under ISO 13485 clause 7.1.

It was perhaps to be expected then that both Warning Letters cited risk management as observations.  Both Warning Letters originated from inspections that occurred almost immediately after the QMSR took effect.  The first Warning Letter FDA posted was issued on May 27, 2026, to the medical device company, Linemaster Switch Corporation (Linemaster).  Among the five violations noted in the letter, FDA cites the company for failure to document one or more processes for risk management in product realization, as required by ISO 13485:2016, Clause 7.1.  More specifically, FDA states:

Your firm’s Risk Management procedure TM-112 does not define how risk management activities are performed and documented, who is responsible for conducting and approving risk management activities, when risk management documentation must be updated, and how post-market feedback data (including complaints, adverse events, and recalls) is incorporated into risk management.

This violation clearly highlights FDA’s focus on risk management and the need for firms to incorporate post-market data in its risk management files.

As noted above, the second Warning Letter, issued to Koven Technologies, Inc., on July 21, 2026, also cites ISO 13485 clause 7.1 for risk management.  In this letter, however, FDA focuses on the risk management documentation.  Specifically, FDA highlights missing potential risks from the company’s risk management files.  This is not the first time that FDA has challenged the substance of a company’s risk management file/methods (see our prior post here).  With the QMSR’s focus on risk, however, we expect there to be a significant focus not just on process but also the substance of a company’s risk files with potential for FDA to challenge the thoroughness of the company’s assessments.

The Koven letter also cites the company for “[f]ailure to document procedures to control design and development changes, and determine the significance of these changes to function, performance, usability, safety and regulatory requirements for the medical device and its intended use, as required by ISO 13485:2016 Clause 7.3.9.”  While this isn’t the first warning letter to reference usability (there are about a dozen or so before this), ISO 13485 does expressly include usability as a requirement, which the QSR did not—it was implicit, much like risk management.

With these new express areas of focus, companies with QSR warning letters could face challenges when the time comes for their reinspection.  FDA, specifically, cautioned several companies, in Warning Letters that were issued after the February 2, 2026 date, but that related to inspections that predated the QMSR effective date.  See letters issued to IsoTis OrthoBiologics, Inc., Longhorn Vaccines and Diagnostics, LLC, and Medline Industries, LP.  These letters allege violations of the QSR and cite directly to 21 CFR Part 820 but also mention the February 2, 2026 Final Rule.  More specifically the letters state that while the inspections were conducted pursuant to the QSR (since the inspections took place prior to February 2, 2026), all corrective actions proposed or implemented must be pursuant to the QMSR.

We will certainly continue to watch these warning letters as they are posted.  We expect there will be more learnings as additional letters become available, and we will share those here.

FDA clinical investigator Warning Letters often involve familiar GCP themes, including protocol deviations, inadequate records, and insufficient oversight. FDA’s recent Warning Letter to a Florida clinical investigator following a Bioresearch Monitoring Program (BIMO) inspection is notable not because it breaks new regulatory ground, but because it demonstrates how routine Good Clinical Practice (GCP) deficiencies can quickly become questions of data integrity.

The July 27, 2026 Warning Letter cites two fundamental investigator responsibilities under 21 C.F.R. § 312.60 (conducting a study according to the investigational plan) and § 312.62(a) (maintaining adequate records of investigational product). While these obligations are well established, FDA’s discussion highlights how failures in either area can undermine confidence in both subject safety and the reliability of study data.

One Subject, Two Clinical Trials

FDA’s first observation involved simultaneous enrollment of a subject in two investigational drug studies. Although one protocol prohibited participation in another clinical investigation, FDA found that the subject was enrolled in a second trial while still participating in the first and received investigational product under both protocols for approximately six overlapping weeks.

Although this may appear to be a straightforward eligibility violation, the consequences extend beyond protocol compliance. Simultaneous enrollment can complicate attribution of adverse events, confound efficacy assessments, and ultimately call into question whether study data are interpretable. As sponsors increasingly rely on centralized monitoring and duplicate-subject detection tools, this Warning Letter serves as a reminder that eligibility is an ongoing responsibility, not merely a screening exercise.

When Drug Accountability Doesn’t Add Up

FDA’s second observation focused on investigational product accountability, demonstrating why FDA views drug accountability as far more than an administrative exercise.

For six subjects, FDA found discrepancies among the subjects’ dosing logs, the site’s investigational product accountability records, and the electronic data capture (EDC) system. Although the investigator explained that subjects self-administered the investigational product at home, FDA emphasized that responsibility for maintaining accurate accountability records remained with the investigator. The discrepancies became even more significant during the sponsor’s remote closeout visit. According to FDA, investigational product kits documented as dispensed and reportedly used by subjects were returned with tamper-evident seals still intact, suggesting the kits had never been opened. At that point, FDA’s concern extended beyond inconsistent paperwork to the reliability of the site’s data.

FDA also found the investigator’s corrective action response inadequate. Although the investigator noted that the study had been closed, the sponsor excluded the site’s data from its analyses, and she did not intend to conduct future clinical research, FDA concluded that the response failed to explain how similar violations would be prevented “if you should change your mind and decide to conduct clinical investigations in the future.” Even when a study has ended, FDA expects investigators to identify root causes and implement meaningful corrective and preventive actions, and a commitment not to conduct regulated research in the future is not an excuse for an inadequate plan.

Takeaways

This Warning Letter underscores several practical lessons for both sponsors and investigators.

For sponsors, eligibility verification should not rely solely on subject self-report. Where protocols prohibit concurrent trial participation, sponsors should consider risk-based approaches to detect duplicate enrollment. Likewise, home-dosing protocols require monitoring plans that reconcile subject diaries, EDC entries, accountability records, and returned investigational product throughout the study, not simply at closeout. When monitors identify discrepancies, particularly physical evidence that contradicts study records, sponsors should treat those findings as potential data integrity issues requiring prompt investigation.

For investigators, the Warning Letter is a reminder that signing the Form FDA 1572 carries responsibility for protocol compliance and investigational product accountability, regardless of where study procedures occur. Accountability records, source documentation, and EDC entries should consistently reflect what actually happened, and returned investigational product should be reconciled against those records on an ongoing basis.

More broadly, the Warning Letter illustrates that FDA evaluates GCP compliance by comparing multiple sources of evidence, not by reviewing any single record in isolation. It also serves as a reminder that corrective actions should go beyond describing what happened. Whether responding on behalf of a sponsor or an investigator, FDA expects a thoughtful root-cause analysis and concrete measures demonstrating how similar deficiencies will be prevented in future studies.

On August 3, 2026, the Health Resources and Services Administration (HRSA) published a Federal Register notice announcing a revised 340B Rebate Model Pilot Program, stating that, for a defined set of drugs, “rebates will be used instead of upfront discounts.” It is HRSA’s second attempt at a rebate pilot in just over a year, and it arrives shortly after the D.C. Circuit’s decision in Novartis v. Kennedy, which held that rebate models are permissible under Section 340B but may not be implemented without approval from the Department of Health and Human Services (HHS). HRSA’s revised Pilot is the agency’s latest effort to exercise the authority the court recognized.

What the Revised Pilot Does

The revised Pilot would require participating manufacturers to provide 340B pricing through rebates rather than upfront discounts for a limited set of drugs selected for the Medicare Drug Price Negotiation Program’s 2026 and 2027 price applicability years. Eligible manufacturers must submit rebate plans to HRSA by August 24, 2026, for an effective date of January 1, 2027. Under the Pilot, covered entities would purchase those drugs at the ordinary purchase price and subsequently submit data to support a rebate request, and manufacturers would have a limited window to pay or deny that request. HRSA has also constrained how those denials may work: a manufacturer generally may not deny a rebate based on suspected patient ineligibility, diversion, or duplicate discounts, issues that remain subject to HRSA’s own audit and dispute-resolution processes rather than a unilateral manufacturer denial.

How We Got Here

The 340B statute requires manufacturers to ensure that eligible covered entities (such as certain safety-net hospitals, health centers, and federally supported clinics) may purchase covered outpatient drugs at no more than a statutory ceiling price, taking into account any rebate or discount “as provided by the Secretary.” Although HRSA historically has administered the program as an upfront discount-based system, manufacturers have long provided 340B pricing through a product-replenishment model, under which eligibility for 340B pricing is generally determined after a drug is dispensed and qualifying volume is replenished at the 340B price.

Beginning in the summer of 2024, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Novartis, and Sanofi proposed moving some or all of their 340B business to rebate-based models. Under those proposals, covered entities would purchase drugs at full price and later seek reimbursement for the difference between that amount and the 340B ceiling price. Manufacturers argued that rebate models would provide greater visibility into claims-level data and help address duplicate-discount concerns. Those concerns became more acute following implementation of the Inflation Reduction Act’s Medicare Drug Price Negotiation Program, which created the possibility that the same drug transaction could receive both a 340B discount and a negotiated Maximum Fair Price. Because manufacturers bear responsibility for preventing that overlap, they argued that additional claims-level visibility was needed.

Litigation Derails the First Pilot

HRSA initially responded to the manufacturers’ proposals with a consistent position: the Secretary had not “provided” for a rebate model, and manufacturers therefore could not implement one on their own. Several manufacturers challenged that position in court, arguing that Section 340B permits rebate models and that HHS lacked authority to require preapproval before such models could be used.

While that litigation was moving forward, HRSA pursued a separate path. In July 2025, the agency launched a voluntary 340B Rebate Model Pilot Program for certain drugs subject to Medicare price negotiation. That effort proved short-lived. In a separate challenge brought by hospital groups in the District of Maine, a federal court vacated the Pilot on Administrative Procedure Act grounds, prompting HRSA to withdraw the notice in February 2026. Importantly, the Maine litigation did not resolve the underlying statutory questions raised by the manufacturers’ lawsuits. Those questions, whether Section 340B permits rebate models and who gets to decide when they may be used, remained unresolved in the D.C. Circuit.

The D.C. Circuit Weighs In

On July 21, 2026, the D.C. Circuit addressed the two questions at the center of the rebate debate: whether Section 340B permits rebate models and, if so, who gets to decide when they may be used. The court first considered whether Section 340B permits rebate models at all. Looking to the statutory text, legislative history, and HRSA’s longstanding recognition of a rebate option for State AIDS Drug Assistance Programs, the court concluded that it does. The statute directs that “the amount required to be paid” not exceed the ceiling price, “taking into account any rebate or discount, as provided by the Secretary.” Reading “rebate” according to its ordinary meaning, the court held that a manufacturer may satisfy the ceiling-price requirement either through an upfront discount or through a later rebate.

The more significant holding concerned who gets to decide when rebate models may be used. Although the court agreed that rebates are permissible, it rejected the manufacturers’ argument that they may implement rebate models unless and until HHS affirmatively disapproves them. Instead, the court concluded that the phrase “as provided by the Secretary” requires HHS to authorize a rebate mechanism before manufacturers may use it. As the court put it, the statute “places the Secretary, not the manufacturers, in the driver’s seat of this important program.”

The court also rejected the notion that HRSA had definitively denied the manufacturers’ proposals. Instead, it emphasized that the Secretary’s consideration of those proposals “remains ongoing” and expressly declined to “address whether the Secretary should ‘provide[]’ for the manufacturers’ proposed rebate models or with what limitations.” The court held only that manufacturers may not implement rebate models without the Secretary’s approval, leaving open whether, when, and on what terms that approval should come.

HRSA’s Rationale for Rebates

HRSA’s rationale for the revised Pilot is rooted largely in the Program’s growth. The agency points to the increasing size and complexity of the 340B Program, coupled with new nonduplication requirements under the Medicare Drug Price Negotiation Program, as justification for moving toward a claims-based rebate framework. The Congressional Research Service has reported that total 340B program sales reached approximately $44 billion in 2021, an increase of almost 15% over 2020, and that 340B hospital participation roughly tripled from before the Affordable Care Act’s 2010 expansion of covered entity categories, with registered 340B sites nearly doubling between 2014 and the CRS report’s issuance. HRSA’s own notice states that the Program has since grown further still, reaching more than $100 billion in purchases at discounted 340B pricing in 2025, with 15,249 covered entities and 49,214 associated sites as of April 2026. HRSA contends that this growth, combined with the nonduplication requirements introduced by the Medicare Drug Price Negotiation Program, has outpaced the upfront-discount model’s ability to prevent duplicate discounts, and that a claims-based rebate mechanism gives the agency and manufacturers better visibility into individual transactions before a discount is paid.

Reaction and What’s Next

Reaction to the revised Pilot has followed familiar lines. The American Hospital Association argues that the model will impose significant compliance, operational, and cash-flow burdens on covered entities. PhRMA had earlier called a rebate model “a commonsense, workable solution to longstanding program integrity failures that have worsened as the 340B program has grown,” urging HRSA to adopt one when it commented on the agency’s request for information in April 2026.

Congress, meanwhile, continues to consider competing approaches of its own. As discussed in our recent post on congressional 340B reform proposals, Senate HELP Committee Chairman Bill Cassidy’s discussion draft, released in June 2026, would permit manufacturers to provide 340B pricing through discounts, rebates, or a claims-repository model; it has not yet been formally introduced as a bill and remains open for stakeholder comment through August 28. Two other proposals have gone further and been formally referred to committee. The House’s bipartisan SECURE 340B Act, introduced July 6, 2026, would impose a multi-year pause on rebates and has been referred to committee, though it has not yet received a hearing. The Senate 340B Bipartisan Working Group’s SUSTAIN 340B Act, introduced August 5, 2026, has likewise been referred to committee and would take a still different approach, affirmatively declaring it the sense of Congress that the 340B program is meant to provide point-of-purchase discounts rather than rebates, and requiring HHS to wind down the Rebate Pilot (or any substantially similar program) within one year of enactment and transition to a data clearinghouse instead.

Whether the revised Pilot survives judicial review, how broadly it is implemented, and whether Congress ultimately supplants it with legislation remains to be seen. But after Novartis, one point is considerably clearer: manufacturers may not implement rebate models unless HHS first authorizes them. HRSA’s revised Pilot represents the agency’s latest effort to do so.

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The day after CBER’s Cellular, Tissue, and Gene Therapies Advisory Committee meeting on Capricor Inc.’s Deramiocel for the treatment of cardiomyopathy in DMD, the Advisory Committee met on July 30, 2026, to discuss Replimune’s BLA resubmission seeking accelerated approval of RP1 (vusolimogene oderparepvec) in combination with nivolumab for advanced melanoma after progression on anti-PD-1 therapy.

Replimune submitted a BLA on November 22, 2024, based on a single-arm Phase 2 IGNYTE study.  FDA issued a CRL on July 21, 2025, concluding that the application lacked substantial evidence of effectiveness.  Replimune resubmitted the BLA, but FDA issued a second CRL in April 2026, reiterating the same concerns. At issue in the advisory committee meeting was Replimune’s second BLA resubmission.

The FDA found that because all patients received RP1 plus nivolumab, without a nivolumab-alone control arm, it could not determine whether the observed responses were attributable to RP1, nivolumab, or the combination.  Where FDA’s review of Capricor’s application centered on data analysis issues, review of Replimune’s hinged on study design issues which the agency stated challenged interpretation, e.g.:

• Because all lesions were treated with RP1 instead of leaving a portion of lesions untreated, evaluating systemic effect in a single-arm trial may have been confounded.
• Using histopathology to reclassify disease progression, where lesions originally classified as having progressed were permitted to have been reclassified, may have inflated the objective response rate (ORR) or duration of response (DOR).
• Re-injecting lesions following disease progression and conducting additional procedures like excising lesions, may also have affected progression analysis and inflated the ORR or DOR.
• Using RECIST v1.1 response assessments to determine RP1’s contribution to systemic activity was questioned, given RP1’s intratumoral mechanism of action and the potential limitations of conventional tumor burden assessments like RECIST here.

Similar to Capricor’s situation, given the issues the agency identified, FDA conducted a more conservative sensitivity analysis and found a much lower ORR and DOR (15.7% and 14.1 months, respectively) than Replimune (who reported an ORR and DOR of 33.6% and 24.8 months, respectively).  The question for the advisory committee thus centered on whether this lower ORR and DOR were clinical meaningful.  By a vote of 10 to 3, the committee found in favor of the drug.  Their decision was largely swayed by the unmet need, the devastating nature of the disease (communicated heartbreakingly by the patients and caregivers during the open public portion of the meeting), and the fact that the confirmatory randomized controlled trial was well underway.

On August 6, 2026, four days after Replimune’s August 2, 2026 PDUFA date, FDA granted accelerated approval to RP1 (TUDRIQEV, vusolimogene oderparepvec-wtpg) in  combination with nivolumab for the treatment of adult patients with unresectable advanced cutaneous melanoma who experienced disease progression with a PD-1-blocking antibody-based regimen based on ORR and DOR of 24.2% and 14.1 months, respectively.

So what are key lessons to take away from this process?

• Proceed with caution when conducting single-arm arm studies. FDA maintains that a very large treatment effect is necessary to demonstrate efficacy when an outcome may be impacted by bias; however, how large that effect needs to be is subject to wide discretion.  FDA’s bar as expressed during the meeting was quite high, and certainly higher than the advisory committee’s.  While acknowledging the challenges identified by the agency, the advisory committee nevertheless found the bar to have been met when taking the unmet need, devastating nature of the disease, and patient perspective into account.  The patient voice proved to be particularly persuasive here.
• Remember that when FDA evaluates single-arm studies, they preserve the right to conduct sensitivity analyses taking a more conservative approach when study design issues are identified and can base their decision on such analyses. For this reason, when feasible, sponsors should consider erring on the side of making more conservative study conduct and design related decisions from the outset when conducting single-arm studies.  Alternatively, sponsors should seek more explicit alignment with the agency when planning these design features to ensure alignment with planned approaches.

Baseline-controlled studies remain an important tool in the arsenal of serious diseases with significant unmet medical need, often rare, however FDA’s review is a good reminder to design with intent to overcome FDA concerns of bias and interpretability challenges (see our previous coverage of successful single arm programs here and here).

Ultimately the advisory committee’s perspective, coupled with the patient voice, appeared to have swayed the agency to not only approve Replimune’s therapy, but to cite a higher ORR and DOR in the prescribing information than they presented at the meeting.

Overall, last week’s advisory committee meetings brought back much needed transparency into the agency’s thinking.  Limitations raised by the agency in reviewing both Capricor’s and Replimune’s BLA resubmissions have, by and large, been validated by the advisory committees, but the committee seemed more willing to exercise flexibility in the final analysis.  At least in Replimune’s case, the agency was persuaded to do the same.

After more than a year with nary an adcomm (just 2 drug approval-related meetings in the Makary era), CBER’s Cellular, Tissue, and Gene Therapies Advisory Committee meetings came back with a vengeance last week with back-to-back meetings to discuss two seemingly controversial cell and gene therapies that received complete response letters (CRLs) and are now under review following BLA resubmissions: Capricor’s Deramiocel for DMD and Replimune’s RP1 for advanced melanoma.

Covered in Part 1 of this FDA Law Blog series is the July 29, 2026 meeting on Capricor Inc.’s Deramiocel for the treatment of cardiomyopathy in patients in Duchenne muscular dystrophy (DMD).  Capricor previously submitted a BLA on December 31, 2024, based on results from a Phase 2 randomized trial (HOPE-2) and open label extension (HOPE-2-OLE).  FDA granted priority review but ultimately issued a CRL on July 9, 2025, finding a lack of substantial evidence of effectiveness.  At issue in the recent adcomm was Capricor’s BLA resubmission, and whether the data from its Phase 3 randomized, double-blind, placebo-controlled HOPE-3 study provided substantial evidence of effectiveness. A 9 to 3 vote by the advisory committee opined that it did not, at least for the cardiomyopathy indication (versus the broader impact on skeletal muscle which was not asked directly).  The PDUFA date for Capricor’s BLA resubmission is set for August 22, 2026.

The FDA’s review principally focused on data analysis and the statistical analysis plan (SAP).  They highlighted that decisions made on imputation, exclusion of certain patient data, and changing the primary endpoint from an absolute change to percent change, with key changes in primary endpoint and methodology made after the last subject visit.  FDA further noted the potential for functional unblinding from the AE profile and cross-over into the open-label extension.

Because of these concerns, in its briefing book and presentation, FDA relied on version 1.1 of the SAP, prior to when substantial data collection began (i.e., first subject, first visit), to analyze the data and found a lack of statistical significance.  While shifting to version 1.1 of the SAP seems to be a draconian and overly conservative analysis of the data, particularly in a rare and devastating disease like DMD where unmet needs are substantial and regulatory flexibility is warranted, the advisory committee members appeared concerned by these issues.  In their discussion, the committee members noted that whether statistical significance was reached appeared to hinge on the inclusion or exclusion of certain data or imputations from just a few patients – leading to what the committee members dubbed as data “fragility.”

Without opining on the merits of FDA’s assertions about Capricor’s program, the critiques the agency raised provide important insights for sponsors:

• Focus on the SAP from the get-go. Now this may seem obvious, but for many small companies with limited resources, most of the time and attention is spent on the clinical trial protocol – debating the sample size, single-arm vs. randomized, open-label vs. blinded, which controls to use, and what endpoints to measure.  The statistical analysis plan at this stage is mainly focused on ensuring the trial is adequately powered.  It’s often not until later, much (MUCH) later, when many of the important details for the SAP are hashed out.  Questions like how to handle missing data, what imputations (if any) should be made, and when it may be appropriate to exclude data, should all be considered carefully and pre-specified in the SAP, ideally before the start of the trial, but at least as early as is feasible.  Of course, not all issues can be forecasted but as issues arise during the conduct of the study, the SAP should be evaluated and updated in much the same way as the protocol.
• Avoid major changes to the SAP once the trial is underway, if at all possible. If major changes are unavoidable, ensure there is a very strong scientific justification for making the change and have that documented with the agency (in addition to the change itself).  Prior to submitting the BLA, sponsors should consider running the analysis prior to the SAP changes as an internal exercise to prepare for what the agency may do during a BLA review and prepare in advance for questions that may arise.
• Consider getting FDA alignment on the SAP – especially if major changes are made – or at least try to. While FDA does not need to approve the SAP, it may nevertheless be in a company’s best interest to actively seek alignment, particularly if there are aspects of the SAP the company predicts may raise questions.  As noted by Capricor, versions of the SAP were submitted to its IND and the agency did not provide comments objecting to the changes at the time, however this didn’t preclude the agency from later rejecting the changes. Seeking FDA feedback requires time, as FDA has taken 6+ months to return comments on a SAP submitted to an IND.

The reality is that we learn about rare diseases as we study them, and medical science advances at a rapid pace in parallel.  However, incorporating these learnings in analysis plans in real time needs to be weighed against the real risk that became apparent on July 29: that FDA may void those changes outright.

On July 20, 2026, FDA posted a funding opportunity for sponsors putting digital health technologies (DHTs) to work in clinical trials. RFA-FD-26-012 is a U01 cooperative agreement with a $1.1 million award ceiling, two expected awards, and no cost-sharing requirement (Assistance Listing 93.103). Applications close August 20, 2026.

The subject is DHTs, including actigraphy, photography, and contactless sensors, used for remote data acquisition in clinical investigations that support drug and biological product development. FDA lists four areas of interest (but notes the scope is non-exhaustive):

• Comparing digital measurements to traditional measurements in clinical trials evaluating drugs;
• Developing and evaluating novel endpoints using DHTs, such as contactless room sensors that capture apnea in pediatric patients;
• Comparing metrics to evaluate continuous measurements, such as maximum activity and stamina; and
• Capturing early manifestations of chronic disease, such as non-memory related signs of dementia detected through tests of balance or slowed reaction time.

The Clinical Trials Optional designation in the announcement title widens the applicant pool. Under NIH policy, that designation permits an applicant to propose a clinical trial without requiring one, so a sponsor running a measurement comparison or endpoint development project with no trial underway remains eligible.

FDA asked the public about this subject four months ago. Its March 2026 Request for Information sought comment on advancing DHT use in clinical investigations for drugs and biological products, with comments closing June 1. The Agency is now funding the work directly, consistent with CDER and CBER commitments under PDUFA VII to support DHT use in drug and biological product development.

Eligibility is broad: small businesses, other for-profit organizations, public and private institutions of higher education, nonprofits, and a range of state, local, and tribal government entities all qualify, which opens the door to sponsor-academic collaborations. The cooperative agreement structure carries an obligation a grant would not. A federal agency uses that instrument when substantial involvement is expected between the agency and the recipient in carrying out the funded activity. 31 U.S.C. § 6305(2). For a sponsor seeking early FDA alignment on measurement strategy, that involvement is the attraction. For a sponsor guarding a proprietary algorithm and a fixed development timeline, it is a cost. Two anticipated awards make the competition demanding either way.

Sponsors weighing an application before August 20 should do two things now. First, confirm federal registrations. Submission through Grants.gov requires an active SAM.gov entity registration, and HHS opportunities issued through the NIH Guide also require an eRA Commons account. NIH recommends starting that process six weeks before a deadline, which exceeds the time remaining for an organization beginning from zero. Second, determine whether the DHT meets the definition of a device, since the answer shapes the application and everything downstream of it.

The device answer changes what the application must contain. If the DHT is a device, its use in the proposed investigation becomes a regulated activity for which the protocol has to account: a significant risk determination sets which requirements attach, and a sponsor relying on another company’s DHT may need a right of reference to the manufacturer’s device master file to describe the technology. If the DHT is not a device, none of that applies, and the proposal advances on the drug or biologic pathway alone. Answering the question before drafting keeps a sponsor from building a budget and timeline around the wrong pathway.

FDA’s December 2023 final guidance, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, tells a sponsor what to do once its DHT is a device: when an investigational device exemption applies, and when information already in an IND suffices. It does not tell the sponsor whether the DHT is a device. The guidance puts that question, whether a DHT meets the definition in FDC Act § 201(h) (21 U.S.C. § 321(h)), expressly outside its scope. The FDA Law Blog covered the guidance when it issued.

The 21st Century Cures Act excluded five categories of software function from the device definition at FDC Act § 520(o)(1) (21 U.S.C. § 360j(o)(1)), and § 520(o)(2) governs products that combine device and non-device functions. FDA moved that line twice in January 2026, revising both the Clinical Decision Support Software guidance, which interprets § 520(o)(1)(E), and the General Wellness: Policy for Low Risk Devices guidance, which now extends enforcement discretion to noninvasive wearables that sense or estimate physiologic parameters where the claims stay within wellness. Because the exclusions depend on function rather than product, one DHT can split: a regulated sensor paired with an unregulated app, or an unregulated sensor feeding software that analyzes the signal and becomes a regulated device. A sponsor should classify each function separately. Under § 520(o)(2), FDA does not regulate an excluded software function as a device merely because it is packaged with a device function, though in reviewing the device function FDA may assess the non-device function’s impact on that function’s safety and effectiveness.

On August 27, 2026, FDA and the Duke-Margolis Institute for Health Policy will host a free virtual public workshop on statistical considerations for digitally derived endpoints in clinical trials for drug and biological products, including updates on FDA efforts under PDUFA VII. Registration is through Duke-Margolis.

Subject matter experts at Hyman, Phelps & McNamara, P.C. are available to evaluate whether a given DHT is a device and to position a DHT program for both the grant and the eventual submission.

Keeping with the 2026 pace of issuing at least two letters a month, the Office of Prescription Drug Promotion (OPDP) has issued letters 20 and 21 this July, and it’s pretty clear to these bloggers that these summer letters are the “filler” to keep up with whatever internal quotas FDA may have regarding prescription drug ad/promo enforcement letters.    This month’s letters take issue with medication convenience claims and an allegation of broadening the indication for a drug to healthcare professionals (HCPs).

With regard to convenience claims, OPDP issued a letter July 13 to Viatris over statements in a video advertisement about its cystic fibrosis drug, the TOBI® PODHALER® (tobramycin inhalation powder), for oral inhalation use.  There, a voice over suggests that the TOBI Podhaler can be used “in the car” or “anywhere,” which OPDP objects to given that the FDA-approved Instructions For Use for the TOBI Podhaler “includes several detailed steps requiring adequate lighting and stable conditions to properly complete the preparation and administration of the product.”  Though the video includes “some information pertaining to the use of the TOBI Podhaler,” OPDP determined that inclusion of this more detailed use information “does not mitigate the misleading impression.”

On July 15, 2026, OPDP issued an Untitled Letter to Sanofi Vaccines US about BEYFORTUS (nirsevimab-alip) injection, alleging that emails intended for HCPs are false and misleading because they create a misleading impression about the approved indication for the product.  Specifically, the emails referred to treating “RSV disease” with Beyfortus, which, according to FDA, suggests the use of Beyfortus for the general prevention of RSV, when Beyfortus is approved for prevention of RSV lower respiratory tract disease.  OPDP alleged, “the emails create a misleading impression about the drug’s FDA-approved indication” despite noting that the full FDA-approved indication is presented in the email in addition to the claims.

These two letters are striking examples (to these bloggers) of OPDP’s efforts to churn out letters whether or not the underlying communications are truly creating any confusion that may, in turn, create a public health risk.  In both cases, FDA acknowledged there was additional context in the communications, but the information was dismissed as “not mitigating the misleading impression.”  And in both cases, the communications at issue are unlikely to be relied upon solely for the administration or prescribing.  Further, in the case of the TOBI Podhaler video, the marketing identifier number referenced in the letter suggests the video has been in use since 2022 (TOBI-2022-0131) – also indicating that OPDP may be actively seeking out opportunities to issue letters.

OPDP is clearly interpreting claims very literally and narrowly, and additional context elsewhere in communications may not be sufficient to overcome any language imprecision.  As OPDP continues issuing Untitled Letters at a rapid pace, one has to wonder whether they are having the intended effect of changing pharma behavior regarding promotional materials or whether the deluge of letters has watered down their impact.  Given FDA’s announcement that it will be issuing a proposed rule that will effectively prohibit DTC TV ads, sponsors should continue to keep their guards up.

Well, don’t say we didn’t tell you what was coming.

Day 2 of the Pharmacy Compounding Advisory Committee (PCAC or the Panel) Meeting (mostly) followed in the footsteps and at the pace of Day 1 (see our prior coverage of Day 1).  Over the course of the day, the Panel worked through three more nominated peptides for possible inclusion on the Section 503A bulk drug substances list, ultimately recommending two—Epitalon and Semax—for inclusion, while declining to recommend Emideltide (the delta sleep-inducing peptide, aka “DSIP”). Was the DSIP “no-vote” the sacrificial lamb here?  As on Day 1, the real drama was less in the vote counts than in the recurring, and still-unresolved, question that FDA pressed from the outset: When a prescriber writes a prescription for one of these peptides, does anyone actually know what the patient is receiving?

FDA: “A Volvo with NASCAR Specs”

FDA opened by reprising its Day 1 themes and answering questions the Panel had raised the day before. The Agency reminded the Panel that none of these substances is an FDA-approved drug, that any clinical investigation would require an IND, and that 503A compounders are not required to submit adverse event reports, so the Agency simply does not receive that information.  FDA asked the Panel to weigh the absence of information as its own data point.

FDA’s Russ Wesdyk leaned into an analogy, likening the exercise to picking a car that is safe for your teenager: The manufacturer makes the nomination, but you may end up with “a Volvo with NASCAR racecar specs,” the same nameplate over a different amino acid count and molecular weight.  The name is fixed; the numbers under it are not.  Turning to “characterization,” FDA noted that “TB500,” a substance discussed on Day 1, typically refers to a 17-amino-acid fragment, but exact sequences and molecular weights vary between vendors, prompting the pointed question, “When you write a script for TB500, what form do you think your patients are receiving?  Does anyone know?”  The Agency stressed that it lacks the authority to define what TB500 is, drawing a comparison to the possibility that the most widely used form of a peptide might not even be the form its inventor discovered or patented (if even a patent were to exist).

“Process” v. “Substances” v. “Application” – What are we doing here?

Panel members quickly zeroed in on the “mechanics” of a peptide.  Panel member Kevin Zacharoff, a Clinical Assistant Professor and Course Director of Pain and Addiction at the Renaissance School of Medicine at Stony Brook University, asked whether the Panel was being asked to evaluate the process for making a peptide or specific compounds within it, noting uncertainty over whether a vote concerned one substance or many forms of a substance sharing a common name.  FDA acknowledged the difficulty: because these are “common name” substances with many possible forms, the open question from Dr. Zacharoff persists, “What form exactly do you want me to put on the list?”  When asked who regulates that question, Russ Wesdyk’scandid answer for the Agency was that one “would need to ask a lawyer.”  Well, being lawyers here, the answer is somewhat unclear; but we can take a good guess.

Panel members also underscored the limits of the record before them.  FDA explained that there is no drug “application” here; there’s only a public nomination, reviewed based on whatever information is submitted (often less than ideal), supplemented by what the Agency can find in the public domain.  As Panel member and patient representative Joshua Mailman, observed, because there is no common dosing schedule, route of administration, or tracking of drug interactions, none of the data generated in the 503A context could support a conventional FDA drug approval process.  FDA’s Office of New Drugs agreed that such information might be supportive of an IND or NDA but could not supplant the clinical evidence of safety and efficacy that approval requires.

Emideltide (DSIP): Not Today

The Panel’s discussion of Emideltide drew sharp opposition—but we note so did the Panel’s discussion of many of the nominated peptides.  Public Citizen’s Mary Ezren strongly supported FDA’s assessment against inclusion, flagging that the common name covers different active molecules, that there are immunogenicity concerns tied to incomplete impurity data, and that the efficacy data are flawed (i.e., small trials, with nothing more recent than 1992).  Dr. John Hertig, Chairman of the Board for the Collaborative for Evidence-Based Medicines, echoed that the sole supporting study is over 30 years old, and warned that once a substance is on the list, the Panel “loses control” over what is ultimately for them a binary choice.

Proponents offered a mix of history and anecdote—one speaker recounted the peptide’s 1977 discovery in the cerebral venous blood of rabbits and its role in regulating sleep architecture without inducing sleep, and others emphasized longevity and circadian applications.  Former Puerto Rico Governor Ricardo Rosselló cautioned that “waiting for perfect certainty” is itself a consequential policy choice.  Rosselló made this point for each substance discussed on Day 2.

The vote on Emideltide (free base and acetate) failed, 6 in favor to 7 against, with 1 abstention.  Dissenting members cited low-quality efficacy evidence, poor characterization, the existence of approved therapies, and the complexity/uncertainty of the dosing regimen.

Epitalon: A Relatively Narrower “Yes”

Epitalon fared better.  Opponents pressed on carcinogenicity—noting a proposed mechanism theoretically linked to cancer via telomere signaling, a concern amplified by chronic dosing—and on the regulatory patchwork that would result from leaving the substance to the states.  There was also a pointed exchange over whether Epitalon is registered in Russia as a dietary supplement, which FDA said it would look into.

The vote on Epitalon passed, 7 in favor to 4 against, with 1 abstention.  Several members in the majority stressed that they were applying 503A criteria—not Phase I or general NDA standards—and would defer to the physician and pharmacist to guide individualized care.

Semax: The (Relatively) Clearest Track Record

Semax drew perhaps the most developed proponent case, anchored by its purported three decades of international use, its mechanistic story (upregulation of neural growth factor BDNF and its receptor TrkB), and study data around neuroprotection and cerebral ischemia.  FDA countered that the available literature—much of it in Russian—often lacked the routes of administration, dosing, and study details needed to verify the study’s claims/outcomes.  In addition, Brian Serumaga, Acting PCAC Chairperson and USP representative, flagged a health literacy risk: the common name could easily be confused with Semaxanib, a distinct compound.

The vote on Semax passed, 8 in favor to 5 against, with 1 abstention.  Members in the majority framed their votes as recognizing a decision “patients are already making” and bringing it into a regulated framework of licensed pharmacies and testing.  Dissenters pointed to weak preclinical evidence, characterization concerns, and the risk of steering patients away from evidence-based therapies for serious conditions.

FDA: Creating—NOT Restoring—Access

Threaded through the day was a recurring correction from FDA.  As FDA’s Matthew Lash, Acting Director of the Office of Compounding Quality and Compliance, explained, Section 503A, enacted in 1997, permits compounding of a bulk substance only through one of three pathways—when a substance is a component of an approved drug, subject to a USP monograph, or included on the bulks list—and these peptides fall outside the first two.  FDA pushed back on the framing that adding them would “restore” post-2023 access, characterizing it instead as the “first time creating legal access,” with uncertain consequences for the scale of availability.  The Agency also emphasized that the withdrawal of the underlying nominations (specifically, all industry nominations had been withdrawn in the months prior to the PCAC meeting) was not a factor in its evaluation, and urged members not to weigh it in their votes.

Takeaways for Industry

Day 2 concluded leaving compounders, prescribers, and manufacturers with a predictable set of open questions.  Two more peptides advanced toward the 503A bulks list Category 1, bringing the total from this PCAC meeting to six; but the votes were relatively close and the Panel’s own members repeatedly acknowledged the tension between individualized patient access and the significant evidentiary and characterization gaps FDA identified.  With FDA confirming that this is a notice-and-comment rulemaking in which it will analyze the full record—including materials submitted after its June 2026 evaluations—the proposed rule, not the Panel’s recommendations, will be where these debates are ultimately resolved.  And with FDA signaling that additional peptides are already queued for a future PCAC meeting, this is just the beginning.

But What’s Next Here?

The compounding and peptide industry is chomping at the bit concerning who can make it across the finish line fastest.  We need FDA to determine—quickly—any needed next steps.  If not, the “gray/black market” production and distribution will continue.  And one of the reasons the PCAC meeting occurred—as addressed through multiple comments over two days—is to rein in the gray/black market and create some guardrails for use.  One option would be placing these “approved” peptides on FDA’s interim Category 1 list (along with all other API awaiting rulemaking) and, as a condition to FDA’s grant of enforcement discretion, put some clear procedures in place at least on a temporary basis.  Some thoughts include (for these peptides only) but are not limited to requiring adverse event reporting, and appropriate, sourcing, grading, identification, and release testing of the bulk substances.

See what we did there?

Well, readers, some big things have taken place.  “Big things” have happened: we previewed these for you in our two-part FDA’s Pep(tide) Rally! What Compounders and Industry Need to Know blog posts (Part I, Part II).

Yesterday, on Day 1 of FDA’s Pharmacy Compounding Advisory Committee (PCAC or Panel) Meeting, the assembled Panel voted to approve for inclusion on the list of bulk drug substances that may be used in compounding under section 503A of the FDC Act (the so-called Category 1 list) the first four of seven bulk drug substances to be considered during this two-day meeting.

With no exaggeration, this is a “sea change” and the “moment” for peptides; it’s just hard to imagine FDA would reverse course given the current administration’s MAHA agenda and HHS Secretary Robert F. Kennedy Jr.’s open support for wider access to peptides (see, for example, his noteworthy appearance on the Joe Rogan podcast, where important drug policy is now announced….).

The PCAC recommended inclusion of four of the most talked-about peptides on the market—BPC-157, KPV, TB500, and MOTS-c.  For BPC-157, KPV, and TB500, the Panel split 8 to 6, with one abstention, reaching that same 8-6-1 result separately for both the free base and the acetate forms.  MOTS-c cleared by a narrower 7-5-2 margin.  The votes are “advisory,” but they are notable because they run flatly against the recommendation of FDA’s own scientific review team.  You can access information about the PCAC, including FDA’s briefing documents, here.

By way of background, the nominations for all of the substances to be considered for inclusion had actually been withdrawn by their nominators at the eleventh hour, with no accompanying explanation; however, the Agency elected to evaluate each substance on its “own initiative,” prioritizing them for consideration given the level of public interest.  We believe that sponsors withdrew the nominations so that their use(s) would not be arguably or otherwise limited to the nominated “indications” should they be added to Category 1.  A multidisciplinary team drawn from the Office of Compounding Quality and Compliance (OCQC), Office of Pharmaceutical Quality (OPQ), and Office of New Drugs (OND)—including OND’s Office of Specialty Medicine (OSM) and Division of Rare Diseases, Pediatrics, Urologic, and Reproductive Medicine/Specialty Medicine (DPT-RPURM/SM)—assessed each substance against FDA’s review criteria and, balancing safety in the context of the proposed use, recommended against their inclusion on the 503A list.

Running through all of the FDA presentations was a foundational concern: identity and characterization of the substance.  As FDA put it, you cannot build meaningful quality standards until you can answer the deceptively simple question of “what is BPC-157?”  FDA repeatedly stated that these are substances described in the literature with a variable number of amino acids and no settled salt, ester, or free base form.  Because different salts and esters of the same active moiety can carry very different physicochemical, toxicological, and PK/PD properties, the Agency stressed that identity and characterization are not technicalities but prerequisites to any compounding standard(s).

The public hearing captured the broader fault line between FDA and non-Panel speakers/Panel members.  Clinicians, telehealth prescribers, and suppliers largely urged a “yes with guardrails” approach, including an FDA-evaluated “greenlist” of FDA-registered API suppliers (NOTE: API suppliers are not, and never can be, “FDA-approved” as many speakers repeatedly referred to them).  The pro-peptide participants also advocated a need for legitimate prescriber-patient relationships, mandatory MedWatch adverse event reporting (NOTE: FDA lacks this congressionally delegated statutory authority to require 503A ADE reporting), and enhanced disclosure that the preparation is compounded—effectively arguing that a blanket prohibition simply pushes patients to an international and research-use-only grey market.  On the other side, public health voices, including but not limited to CSPI’s Peter Lurie and Public Citizen’s Nina Zeldes, opposed inclusion, pointing to inconsistency with FDA’s own compounding standards, safety risks (six of the seven nominated peptides were nominated at least in part for injection, which raises a host of safety concerns), the availability of approved alternatives, and the risk that 503A “listing” would be misunderstood by patients as an FDA “approval.”  Public health speakers also warned that any Category 1-type listing would set a precedent for bypassing approval and strip the incentive to develop these substances under the IND framework.  Pressed on this, FDA invoked its integrity and cautioned that erosion of trust in the Agency’s safety and effectiveness determinations would, itself, endanger public health.

The two remaining substances taken up on Day 1 drew their own distinct debates.  The peptide TB500 was promoted largely for wound healing, tendon and ligament repair, and recovery.  Supporters, including clinicians who described it as part of the so-called “wolverine stack” taken alongside BPC-157, again urged a regulated 503A pathway over the grey market.  FDA and several panelists focused on a potential cancer signal, although FDA acknowledged there are no studies on TB500 itself (… Did we just write that?  No studies?).  Nonetheless, the Panel voted 8-6-1 to recommend inclusion of both the free base and acetate forms, with dissenters citing the paucity of efficacy data, concerns about overlap with tumor progression, and the substance’s proposed use as an injectable.

MOTS-c, a mitochondrial-derived peptide, closed out Day 1.  Opponents—including the Partnership for Safe Medicines, Public Citizen, and the Collaborative for Evidence-Based Medicine—argued that the substance lacks scientific backing, is not well characterized, and that listing would amount to a large, uncontrolled human trial without necessary adverse event reporting.  The Partnership for Safe Medicines’ Shabbir Imber Safdar framed the proponents’ case as a set of myths: that listing gives patients quality-made peptides, that patients will choose licensed dispensers when licensed options exist, and that FDA can permit measured access with guardrails.  On the last point, he said FDA lacks the resources to enforce the guardrails supporters proposed.  Georgetown University’s Adrienne Fugh-Berman was blunter still, calling MOTS-c not merely a harmless supplement but a poorly characterized experimental drug, and arguing that market interest is a reason to study a substance, not to legalize it.  In the closest vote of the day—which, in these authors’ opinions, didn’t feel all that close in the moment—the Panel recommended inclusion of the free base and acetate forms by a 7-5-2 margin, with two members abstaining.  As with all votes taken, victory cheers rang from the audience when PCAC read out the results.

A few points worth keeping in mind as this plays out.  First, the vote is advisory and one input among many; FDA has said it will continue reviewing the comments and data submitted through the docket and will announce any final decision through notice-and-comment rulemaking, not at the PCAC Meeting.  Second, while PCAC recommendations usually track FDA’s ultimate decision, the Agency has gone the other way at least once before, according to Matthew J. Lash, Acting Director, OCQC.  For now, the Committee has SPOKEN, and these four substances appear slated for inevitable inclusion on the 503A list—although timing is still a major question for industry stakeholders.  One question that likely merits a rather immediate answer is whether FDA will place these substances immediately on its interim Category 1 list—as it has with all of the other substances it has reviewed with much less fanfare.  And will it exercise enforcement discretion if compounders start compounding them immediately, like it has with all other substances the PCAC and FDA placed on the Category 1 list?  We bloggers hope FDA’s decision on these gating issues comes promptly as we are sure that the compounding pharmacies are fully primed to the opportunities these decisions present; and they welcome guardrails.

We believe Day 1’s results portend further good news for the peptide industry and consumer market today—stay tuned for our post covering Day 2!

Hyman, Phelps & McNamara, P.C. (HPM) is pleased to announce that Abdie Santiago has joined the firm as an Associate.

Mr. Santiago advises healthcare and life sciences clients on a broad range of healthcare regulatory and compliance matters, including fraud and abuse issues, federal drug pricing and  government healthcare programs, and healthcare transactions.

Prior to joining HPM, Mr. Santiago counseled life sciences and healthcare clients at two AmLaw 100 firms, where he advised on matters involving Medicaid, Medicare Parts B and D, and the 340B Drug Pricing Program. His experience includes counseling clients on drug pricing and reimbursement strategy, negotiating commercial agreements, supporting healthcare and life sciences transactions, and advising on government investigations, audits, enforcement matters, and federal healthcare compliance.

Jeffrey Wasserstein, co-head of the healthcare practice, said “We’re thrilled to have a lawyer of Abdie’s caliber and experience join HPM and expand and support our healthcare fraud and abuse and drug pricing practice.”

Mr. Santiago earned his J.D. from Stanford Law School and his Master of Public Policy from Stanford University. He received his A.B., cum laude, from Princeton University. He is admitted to practice in the District of Columbia and Tennessee.