As we previously discussed, FDA recently held two meetings that, while separate, provided a cohesive discussion of the use of Real World Evidence (RWE) and Artificial Intelligence (AI) in regulatory decision making.  The discussions during the Artificial Intelligence in Drug & Biological Product Development meeting (AI Meeting) are also relevant to device programs and it was noted that FDA leadership is pushing for a coordinated approach to AI across the centers.

The AI Meeting included panels on the current state of AI in development programs; data quality, reliability, representativeness, and access; model performance, explainability, transparency, and interpretability; and navigating the future.  AI was described as a means to allow for reinvention – not just a faster horse, but a car – and pairing of AI with RWE came up frequently across the panels.

In opening remarks, FDA noted that it takes a risk-based approach when considering AI, not just in looking at safety and efficacy, but in promoting innovation, and also highlighted that innovation doesn’t automatically mean increased risk.  CDER discussed its January 2025 draft guidance, Considerations for the Use of Artificial Intelligence to Support Regulatory Decision Making for Drug and Biological Products, and noted that it is processing over 1400 comments from a variety of perspectives.  FDA also recognized the rapidly changing technology and noted internal and external training being provided to ensure that review staff are familiar with new technology when it is used.  FDA also recognized the need for infrastructure to enable better data sharing between sponsors and the Agency.

The panels noted that AI can be used in many ways across the total product lifecycle.  Examples of areas where AI is used now and can be expected in the future included:

• Indication selection
• Portfolio positioning
• Dose finding
• Protocol design
• Comparator arms for standard of care and disease evolution
• Inclusion/exclusion criteria
• Endpoint optimization
• Digital biomarkers
• Recruiting for studies
• Adaptive trial design
• Digital twins (in silico representations of a complex system, which can include an individual person)
• Agentic AI acting as a Clinical Research Associate (CRA) agent for tactical tasks, allowing humans to focus on strategic work
• Maximizing yield in manufacturing
• Personal use of an app utilizing AI to help a patient titrate dose when there are no data and no studies.

Discussion of data recognized four pillars:   data quality (as the saying goes, garbage in garbage out); data reliability (ensuring data are accurate, complete, consistent); data representativeness (to prevent bias and promote fairness); and data access (data can’t be used if siloed).  Foundation models were identified as a means to address many issues seen in narrow AI models that don’t generalize well across diverse populations.

There was also discussion of data sharing, with recognition of challenges due to the competitive nature of industry and intellectual property concerns.  The importance for both RWE and AI to share not only the successes, but also the failures, so that others can learn from them, was also a frequent point of discussion.

Big promise for AI was seen in collaboration and being able to bring together information that is in isolation across many systems today.  Another area of promise was noted to be in rare disease, where AI can have a big advantage since it is an area without a lot of training data, and AI is increasingly good and getting better where disease is not well characterized.  Speakers noted that in order for these promises to be achieved, the use of AI needs to be transparent, interpretable, and explainable.

In addition to the promise, speakers also cautioned against AI hype and noted many hurdles that need to be cleared in its use.  Throughout the sessions, the need for data standardization, especially for RWD, was discussed as a means of improving AI. Establishing guardrails to prevent misinforming the models was also noted as essential for building trustworthy AI.  Several speakers also mentioned establishing ground truth measures for comparison, especially with generative AI, as an area for thoughtful consideration.  Another hurdle is people themselves, with many being cautious to use AI or accept information generated by AI.  While some of the caution is warranted, the field is moving so quickly that in many cases issues that were bigger concerns in the past have been addressed with more recent technology.  For example, speakers noted that rates of hallucinations in AI models are much lower today than they were two years ago.

For FDA, speakers noted that technology is moving much too quickly for the standard process for release of guidance documents and encouraged more interactive collaboration between the Agency and sponsors to ensure up to date information on acceptance of AI models in applications is available.  It was also emphasized that FDA should consider the patient perspective and ensure policies do not penalize RWE.  Speakers encouraged FDA to not expect perfect data, but transparency and early engagement, to move forward.

As one who is cautious with use of AI, this blogger decided to test the waters.  While an initial draft of these posts, based on notes from the RWE Meeting and AI Meeting, was unclear, and none of the AI-generated text was used, the following concluding paragraph didn’t seem too bad:

As FDA continues to embrace the evolving landscape of RWE and AI, the message from both meetings is clear: collaboration, transparency, and adaptability are essential. These tools are not just technical innovations—they are catalysts for smarter, more inclusive, and more responsive regulatory decision making. By fostering early engagement, prioritizing data fitness, and encouraging shared learning across sectors, FDA is laying the groundwork for a future where RWE and AI work hand in hand to deliver better outcomes for patients and more efficient pathways for innovation.

On October 9, 2025, the U.S. Senate voted in favor of including a revised version of the BIOSECURE Act as an amendment to the National Defense Authorization Act (NDAA). The bill was not included in the version of the NDAA passed by the U.S. House of Representatives and will be subject to the reconciliation process. The last version of the BIOSECURE Act narrowly failed to pass during last year’s Congress due in part to fervent opposition by the biopharma industry, which would have seen enormous disruption of development and manufacturing operations if the bill was enacted.

Readers can revisit our blog post from last year for detailed background on the Act, but in short, the Act prohibits the government from procuring or funding, or contracting with entities that perform government contracts through the use of, certain “biotechnology equipment or services” from a “biotechnology company of concern.”

Previously, the companies of concern included a specific list of Chinese companies—BGI (formerly Beijing Genomics Institute), MGI, Complete Genomics, WuXi Apptec, and affiliates—and there was a process for the government to add new companies to the list that met certain criteria having to do with control of those companies by “foreign adversaries” (China, Iran, Cuba, North Korea, and Russia) and associated national security risks. This list of companies was the subject of much of the pushback from industry, most acutely the inclusion of WuXi and affiliates, which provide an outsize volume of CDMO services to U.S. biopharma companies.

The new version of the Act that passed the Senate removes this specific list of companies and instead establishes that any entity included in the annual list published by the U.S. Department of Defense (DoD) as a Chinese military company operating in the United States (known as the “1260H List”) qualifies as a biotechnology company of concern. Although the 1260H List published by DoD on January 7, 2025 includes BGI and MGI, it does not include any WuXi entities at this time. This could be viewed as a limited win for some in the biopharma industry, but a note of caution that in February 2024 a bipartisan group of House and Senate members sent a letter to the Biden administration requesting that WuXi be investigated and potentially added to the 1260H list. Additionally, the revised bill maintains the original process for OMB to designate additional biotechnology companies of concern that meet the criteria under the Act.

Another notable change in the new bill is the narrowing of the “biotechnology equipment or service” that are subject to the Act’s prohibition to include any equipment. While the general definition is still equipment or service “that is designed for use in the research, development, production, or analysis of biological materials,” the updated draft now omits the specific reference to combined mass spectrometry technologies and polymerase chain reaction machines from the prior definition. Carving out these two technologies was a high priority for the biopharma industry due to their ubiquity in product development and manufacturing. For example, in our experience something like 90% of manufacturers use mass spectrometry during the manufacture of small molecule drugs.

The exact effective date of the Act’s prohibitions can vary widely (a few months to a few years) depending on whether the company of concern is currently on the 1260H list, added later to the 1260H list or is added through the OMB process defined in the Act. Additionally, the time can vary depending on how quickly the federal government meets its obligation to issue revised Federal Acquisition Regulations.

We are monitoring whether the BIOSECURE Act makes it through the reconciliation process with the House and any changes to the bill if it is enacted.

FDA’s recent support and presentations at meetings on Regulatory Submissions with Real-World Evidence: Successes, Challenges, and Lessons Learned (RWE Meeting) and Artificial Intelligence in Drug & Biological Product Development (AI Meeting) provided updates on the current status of these initiatives at FDA, while also showing how the long-term benefits of Real World Evidence (RWE) and Artificial Intelligence (AI) may be linked.

The RWE Meeting included updates on PDUFA VII and MDUFA V commitments, along with case studies and a panel discussion.  Representatives from CDER discussed the Advancing RWE Program launched in 2022, which seeks to improve the quality and acceptability of RWE-based approaches, noting that of 26 requests, only five had been accepted, showing that there are still challenges to successful use of RWE, including concerns related to interpretability of data.  Representatives from CDRH discussed ongoing work with the use of Real World Data (RWD) to generate RWE across the total product life cycle, staff training, National Evaluation System for health Technology (NEST) program developments, and RWE guidance documents.

Case studies and panel discussions highlighted areas where RWE has been successful and obstacles to greater use.  Success was seen using RWE to collect natural history data to be used as a historical control.  This was especially useful in rare conditions.  In one example, the collection of natural history RWD was collected before a treatment was available to understand the progression of the condition  with standard of care.  Once there was a treatment available to study, the previously collected RWD was used as a control for comparison against patients receiving the treatment.  Success was also linked to early interaction with FDA, and where sponsors put in a lot of thought into ensuring data were fit for use and that bias was minimized in the study design stage. One challenge identified relates to data accessibility since patient level data are needed for CDER reviews and are hard to obtain from studies conducted outside of the United States.  For medical devices, one of the biggest challenges noted was being able to identify devices by manufacturer and model in RWD sources.  The successful device case study presented, for a spinal implant subject to medical device tracking (21 C.F.R. Part 821), was able to overcome this challenge by pairing its own tracking data with a CMS data set that included outcome measures.

To overcome challenges, several points were discussed.  Panelists suggested published consensus positions on the disease and data collection can help standardize data collection across studies and registries, which can in turn support future approvals.  Sharing additional case studies by FDA or industry in sessions like the RWE Meeting, both what works and does not work, was also noted as an opportunity to develop new solutions.

For the future, FDA noted that it wants to see RWD and RWE as a credible part of evidence to complement randomized controlled trials.  CDRH identified the use of Unique Device Identifiers (UDI) as a means to overcome the lack of device manufacturer and model information in RWD.  Several panelists brought up AI as a key opportunity for the future of RWE, noting that all data collection allows AI to be leveraged, but not all data are reliable for use.  It was also mentioned that AI can be used to annotate data, ultimately improving quality and fit for use.  The end of the RWE Meeting was the perfect transition to the AI Meeting, which will be covered in our next post.

I became a Diversion Investigator with the Drug Enforcement Administration (“DEA”) in 1986, but it only recently dawned on me that my relationship with the agency actually began as a ninth grader about 14 years earlier.  In 1972, DEA’s predecessor, the Bureau of Narcotics and Dangerous Drugs (“BNDD”), produced and distributed a series of public service posters warning against drug misuse and abuse.  The posters featured individual Washington Redskin players.  Each poster provided an antidrug message purportedly made by the player associated with the position they played on the football field.  Pro Football Hall of Fame quarterback Sonny Jurgensen advised “In a drug situation-pass.”  Linebacker Chris Hanburger, also in the Hall of Fame, warned “Don’t get trapped-dodge the drug crowd.”  And Walt Rock, who had the perfect moniker for an offensive lineman, urged “Hold the line against drugs.”

BNDD distributed the posters to intermediate and high school students, and I received a couple of them.  BNDD produced about 20 different posters, all of them featuring Washington Redskins.  The posters featured antidrug messages from Coach George Allen (It takes a team effort to win against drugs”), Hall of Famer Charley Taylor (“Be ready to outrun the drug tackle”), Jerry Smith (“Get your point across without drugs”), and defensive players Ron McDole (“Push drugs aside-they’re for losers”), Brig Owens (Win the race against drugs”), and Pat Fischer (Stand firm-don’t yield to drugs).

Over fifty years later I stumbled upon the complete set of the posters rolled up and stashed in a box.  Finding the posters reminded me of some of the other memorable anti-drug public service ads and campaigns over the years.  Those of a certain age recall First Lady Nancy Reagan’s “Just Say No” to drugs campaign in the 1980s.  And in a 1987 commercial produced by the Partnership for a Drug Free America, an actor asserted “This is your brain.  This is drugs.  This is your brain on drugs.”  The camera panned to eggs frying in a skillet, and then asked “Any questions?”  And a colleague reminded me that the “your brain on drugs” commercial was revived in the ‘90s and hosted by Rachel Leigh Cook.

The BNDD/Washington Redskin posters were among the first antidrug campaigns featuring professional athletes.  BNDD merged and became DEA in July 1973.  Also in 1973 DEA produced and distributed posters featuring several players from each NFL team, and those posters bore the DEA logo and NFL shield.  The Redskins are now the Commanders.  1972 proved to be a good year for the Redskins with the team the NFC champion at season’s end, losing to the perfect Miami Dolphins in Super Bowl VII, 14-7.

And what did my favorite Redskin?  Running back Larry Brown urged “Find the way to your goal without drugs.”

Secretary of Health and Human Services Robert F. Kennedy, Jr., did not hide his disdain for FDA prior to his appointment, stating:

FDA’s war on public health is about to end. This includes its aggressive suppression of psychedelics, peptides, stem cells, raw milk, hyperbaric therapies, chelating compounds, ivermectin, hydroxychloroquine, vitamins, clean foods, sunshine, exercise, nutraceuticals and anything else that advances human health and can’t be patented by Pharma.

Since his appointment, he has indicated his desire to allow individuals to try healing themselves as they see fit, regardless of FDA approval, stating, “We want to make sure that information is out there. But we also want to respect the intelligence of the American people.” At a congressional hearing over the summer he signaled his strong support for wearables and their role in allowing individuals to take control over their health, stating in June, “We think that wearables are a key to the MAHA agenda — Making America Healthy Again. My vision is that every American is wearing a wearable within four years.”

There seems to be a disconnect, however, between Secretary Kennedy’s statements and certain actions by FDA. First, the now famous (infamous?) Warning Letter issued to WHOOP, on which we blogged here, which took a swipe at the extent to which “general wellness” software features on wearables can survive if non-medical claims are “inherently associated” with a disease or condition. Then, on September 16, CDRH issued two safety alerts related to potential risks associated with use of products that have not been authorized by FDA. One of these was focused on devices for measuring blood pressure, stating, “Do not use unauthorized blood pressure devices, including software features on wearables, such as smartwatches and smart rings, that claim to measure blood pressure.”  This seems in stark contrast to Kennedy’s statements supporting wearables and the desire to have all Americans use them to track health metrics. The second safety alert pertained to devices used to monitor vital signs in infants.

For both safety alerts, FDA stated that many of these devices “currently sold over-the-counter (OTC) do not have FDA marketing authorization, meaning the FDA has not evaluated the safety and effectiveness of those devices. The FDA recommends looking for an FDA-authorized device appropriate for your [or your child’s] needs.” In contrast to Kennedy’s statements about giving individuals more control over their own health, these safety alerts indicate FDA’s view that consumers should not have access to these types of general health metrics unless they come from products that FDA has reviewed and authorized.

There can be differences of opinion when it comes to whether FDA authorization is appropriate (or legally required) for certain product types. Much of that turns on the claims being made about the product, as discussed in our post on the WHOOP letter. Because, by statute, FDA does not have authority over general wellness products, if a company makes claims that fall within “wellness,” its product should not be subject to FDA oversight. It is then up to consumers to determine how best to utilize such a product – one which, hopefully, includes an appropriate disclaimer indicating that it is not a medical device, is not intended to diagnose or treat disease, and has not been reviewed by FDA. This would be an example where “the intelligence of the American people” should be relied upon to appropriately make use of an unregulated product for low-risk purposes.

Dr. Marty Makary, FDA Commissioner, seems aligned with Secretary Kennedy’s position to make more products available to Americans, stating at a BIO meeting in June 2025 that FDA would “use gold-standard science and common sense to be able to deliver more cures and meaningful treatments for Americans.” At least with respect to medical devices, this has not been our experience since this administration came into office. To the contrary, we have found review teams to be more risk averse and less inclined to make reasonable risk-benefit decisions, even for products that were previously granted Breakthrough Device Designation (BDD). For products seeking BDD, the data requests have ballooned and are entirely out of line with FDA’s own stated requirements.

In addition to seemingly more stringent pre-market requirements, the Agency has kept up its issuance of Warning Letters despite the reductions in force. Historically, CDRH has taken a risk-based approach to issuing Warning Letters, and low-risk products often would not rise to the level of receiving such a letter.  Recently, however, many Warning Letters from CDRH are focused on consumer use or other low-risk products. For example, in August, FDA sent a Warning Letter to SeniorLife Technologies about the SeniorLife.AI mobile application, stating that its intended uses are different from devices classified as Measuring Exercise Equipment. More specifically, the Letter states that the app is intended to “screen and ‘pre-diagnose’ mobility and cognitive health conditions.” Claims are related to gait and balance, identification of fall risk, and potential early detection of Alzheimer’s. Other than claims related to the early detection of Alzheimer’s, these claims seem innocuous and are consistent with features offered on wearable products (see, e.g., Apple’s Walking Steadiness feature).

Also in August, FDA issued a Warning Letter to The Richline Group about its Ear Care Antiseptic, Ear Care Solution, and Home Ear Piercing Kit. FDA stated that wound washes containing chemicals such as antimicrobials include risks that require premarket review. Notably, the Warning Letter does not indicate that the product has in fact presented any risks to users, and the product in question is intended only for use as an ear antiseptic after use of the home ear piercing kit—it is not intended for wound healing or other clinical uses.

Given the above, consumers may be left to wonder about the role of FDA in ensuring safety and effectiveness of medical products, and the significance of actions being taken that are increasingly related to low-risk consumer products. As long-time readers of this blog are aware, we have our fair share of criticism for Secretary Kennedy’s stated approach to public health – on this, however, we think consumers should follow the Secretary’s direction and rely on their own intelligence when making decisions about product use.  The Center’s failure to find a reasonable path forward to low-risk products and to work with sponsors to remedy minor violations related to low-risk products will only hurt the American public by preventing the availability of such products.

Actually, it is. No sooner had FDA flagged its intent to maybe eventually hammer out a federal definition of ultra-processed foods than California leapfrogged ahead with the Real Food, Healthy Kids Act (a/k/a AB 1264). The Act had strong bipartisan support, so it was no surprise when Governor Newsom signed it into law yesterday. Among other things, the Act will eliminate from the state’s schools “ultra-processed foods of concern” and “restricted school foods.” So what are those?

The answer will be determined by the California State Department of Public Health, but the Act provides a partial answer by defining “ultra-processed foods” (or “UPFs”) as any food or beverage that contains:

1. a substance listed in FDA’s Substances Added to Food database that has any of several technical effects (e.g., stabilizers, propellants, colors, emulsifiers, flavoring agents, and flavor enhancers), with certain exceptions; and
2. (a) high amounts of saturated fat, sodium, or added sugar, as defined in the Act; or (b) a nonnutritive sweetener or certain other sweeteners.

There are exemptions to the definition of UPFs, including for raw agricultural commodities, certain minimally processed prepared foods, Class 1 milk, and infant formula (if exempted by the Department by regulation).

In deciding which UPFs are “of concern” and defining “restricted school foods,” the Department must consider several factors, including whether:

1. “the food has been modified to be high in saturated fat, added sugar, or salt”;
2. Other jurisdictions require a warning label “due to concerns about adverse health consequences”;
3. a substance or group of substances is: a.  banned in other jurisdictions “due to concerns about adverse health consequences” or is linked to such consequences “based on reputable peer-reviewed scientific evidence”; or b.  “may be hyperpalatable, or may contribute to food addiction.”

Once the target foods have been defined, schools will have to start phasing them out by July 1, 2029, such that vendors will be prohibited from offering them by July 1, 2032.

Separately, starting on February 1, 2028, vendors will have to submit annual reports on the total quantity of foods sold to schools and whether they qualify as UPFs, UPFs of concern, or restricted school foods. The Department will in turn submit annual reports to the legislature that include a strategy for reducing consumption of such foods, and recommendations for legislative actions to reduce consumption of restricted school foods and UPFs of concern.

Now for the most interesting question: which state will jump into the pool next?

As part of the review of a BLA, NDA, or ANDA, FDA assesses the manufacturing facilities named in the application to determine whether they can perform the proposed manufacturing operations in conformance with CGMP requirements, and whether the data submitted in the application are accurate and complete.  In some cases, FDA determines that information is needed from a pre-approval inspection (PAI) or pre-licensure inspection (PLI) in order to approve or license the product.

Traditionally, this would mean an in-person inspection, but FDA has other options available, as described in the recently published Guidance for Industry on Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications (Alternative Tools Guidance).  While the document provides some meaningful insights, it is largely a repackaging of three existing alternative tools that we’ve blogged about before, now presented specifically in the context of a PAI or PLI:

1. Remote Regulatory Assessment (RRA)
2. Remote Interactive Evaluation (RIE)
3. Mutual Recognition Agreement (MRA)

The first two tools are discussed in relation to each other, and both RRA and RIE are also covered in standalone guidances.  An RRA is an entirely remote evaluation of a facility, which can include a records request under FD&C Action section 704 (a)(4) (21 USC § 374(a)(4)).  An RRA could potentially obviate the need for an in-person PAI/PLI, or could be used to resolve application-specific deficiencies identified during a prior PAI/PLI.

While record requests under section 704(a)(4) are mandatory, an RRA is not itself considered an “inspection”—meaning that no Form FDA 483 will be issued at its conclusion.  As described in the Alternative Tools Guidance, an RRA can also include an RIE during the application assessment.  An RIE could involve, for example, livestreaming a production area so Agency staff can observe a specific manufacturing process.  Unlike RRAs, participation in an RIE is voluntary and largely depends on the facility’s technological capabilities.

The Alternative Tools Guidance addresses inspections conducted by “trusted foreign regulatory partners” (i.e., foreign nations with which FDA has an MRA).  FDA currently has MRAs in place with the European Union, Switzerland, and the United Kingdom.  These agreements allow FDA to legally recognize inspections conducted by those regulators in their respective countries (21 USC § 384e). MRA recognition applies to both same-country inspections (e.g., a Swissmedic inspection of a facility in Switzerland) and third-country inspections (e.g., a Swissmedic inspection of a facility in China).

Under the Food and Drug Omnibus Reform Act (FDORA), enacted December 2022, FDA is required to report the number of routine surveillance and for-cause MRA inspections it has recognized (21 USC § 360(h)(6)(A)(vii).  In FY2023, FDA recognized 199 MRA surveillance inspections; that number increased slightly in FY2024 to 206 inspections.  However, based on the FY2023 and FY2024 data, FDA has yet to recognize any for-cause MRA inspections.  Additionally, while FDORA gave FDA the authority to recognize MRA inspections “in order to facilitate preapproval”, the Agency acknowledges in the Alternative Tools Guidance that it “has not to date recognized PAIs or PLIs conducted by a foreign regulatory authority” (page 8).

Unfortunately,  FDA is not using the Alternative Tools Guidance to announce any plan to expand recognition of MRA inspections.  However, when a facility lacks sufficient FDA inspection history, the Agency may request inspection reports from an MRA partner and use that information to determine whether a PAI or PLI is necessary.  As a longer-term strategy, FDA is also evaluating remote participation in inspections conducted by foreign regulators.

The final section of the Alternative Tools Guidance describes how FDA subject matter experts (SMEs) may participate virtually in a PAI/PLI.  Anyone who has taken part in an FDA surveillance or for-cause inspection knows that investigators often confer with FDA SMEs located off-site.  The new Guidance now provides a framework for remote FDA SMEs to engage directly with the facility staff during a PAI/PLI.  Interestingly, the facility must agree in writing to the use of a remote SME; a firm may decline this request but, as the Guidance notes, doing so may “prolong a decision on an application” ( page 7).

Practically speaking, FDA’s use of alternative tools will be risk-based and remain at the Agency’s discretion.  As the Guidance states, “FDA does not intend to grant requests from applicants or facilities for FDA to use alternative tools” (page 5).  While RRAs may be used to collect information in advance, facilities with no regulatory inspection history or with unresolved compliance issues from prior inspections should still expect an in-person PAI or PLI.

On October 3, 2025, FDLI published an article analyzing Warning Letters (WLs) issued since January 9, 2020 by Hyman, Phelps & McNamara P.C.’s Véronique Li and Jeff Gibbs.

The in-depth analysis identified posting and issuance patterns, the length of time between milestone activities such as the conclusion of some FDA activity (e.g., inspection or promotional review) and issuance of a WL, volume trends over time, and trends in citations.

Given that WLs are issued on average 124 days after an inspection, companies should not interpret the absence of a WL within 30 working days as meaning that no WL is forthcoming. Rather, they should look to observations in the Form FDA 483 and other WLs to aid in predicting whether they are likely to receive one themselves. While the circumstances will vary for individual companies, knowing these patterns can help companies understand the probabilities of different outcomes.

The authors also determined that close-out letters, issued when a response demonstrates that violations have been corrected, or implementation of corrective actions was adequate, or a follow-up inspection does not reveal other significant violations, are becoming rarer. They caution that the number of WLs that have not received a close-out letter will grow unless FDA changes priorities or resource allocations particularly in light of recent reductions in FDA personnel.

FDA has long permitted ANDA applicants to “carve-out” patent-protected uses from product labeling, resulting in differences between the Reference Listed Drug and the ANDA.  Legal challenges to the carve-out are not new: The GSK v. Teva saga, followed by the Amarin v. Hikma litigation, made clear that Reference Listed Drug sponsors are no fans of the carve-out.  But the recent highly-publicized challenges have originated from patent law, essentially taking the position that ANDA manufacturers induce infringement by promoting their carved-out generics as AB-rated or therapeutically-equivalent to the fully-labeled Reference Listed Drugs (even though such a generic is only AB-rated insofar as it is labeled the same as the brand-name drug).  While we’re still waiting to see if the induced infringement theory renders the carve-out effectively dead (and whether legislation will revive it), the D.C. Circuit recently had the opportunity to take on an Administrative Procedure Act (APA) challenge to the carve-out as one of the first suits challenging FDA’s authority after Loper Bright.

In 2024, Novartis sued FDA in the District Court of D.C. under the APA for approving MSN’s ANDA for a generic version of ENTRESTO (sacubitril/valsartan) with a carve-out of a patent-protected use.  Specifically, MSN carved-out a modified dosing regimen for patients not taking other drugs used to treat heart failure.  The generic label included an indication for chronic heart failure with reduced ejection fraction, which was an indication previously on the ENTRESO labeling before the addition of the modified dosing regimen. The proposed label also stated that the generic drug “contains anionic forms of sacubitril and valsartan, and sodium cations.”  Novartis argued that the carve-out was improper, as it both rendered the product less safe and effective than the Reference Listed Drug and impermissibly added words to the indication statement, rather than simply omitting words as permitted under the statute.  Novartis also argued that the complex active ingredient in the Reference Listed Drug is not the same as the active ingredient in the ANDA.

This lawsuit comes on the heels of a 2019 and repeat 2022 Citizen Petition (Docket No. FDA-2022-P-2228), both filed by Novartis, asking FDA to reject any generic version of ENTRESTO that does not present the active ingredients—sacubitril and valsartan—“in the same chemical structure.”  Novartis also asked that FDA prohibit the carve-out of its patented uses from its label, arguing that carving out the modified dosage would impermissibly render the generic version less safe and effective than the Reference Listed Drug.  Finally, Novartis argued that such a carve-out would require the impermissible addition of words to ENTRESTO’s existing label (i.e., the so-called labeling “carve-in” or “chubby label” approach FDA first took with generic SENSIPAR (cinacalcet) Tablets and then discussed later in a Citizen Petition response (Docket No. FDA-2017-P-3672) concerning generic VELCADE (bortezomib) Injection – see our post here).  FDA denied both petitions in July 2024 and approved the MSN ANDA, and Novartis filed this suit seeking to set aside FDA’s denial of the petitions and approval of the ANDA.  Novartis lost in the District Court and immediately appealed.

In this appeal, Novartis asked the Court to resolve two questions:

1. Did FDA approve labeling for generic ENTRESTO that impermissibly deviates from the ENTRESTO label (i.e., labeling carve-out)?
2. Did FDA unreasonably conclude that the generic drug has the same active ingredients as ENTRESTO?

To address the first question, the Court looked at FDA’s reasoning for approving the language change omitting the modified dosing regimen.  While Novartis argued that the omission rendered the generic “less safe or effective” than ENTRESTO in violation of 21 C.F.R. § 314.127(a)(7), the Court found that FDA’s Citizen Petition “analysis turns squarely on the FDA’s expertise in evaluating the clinical significance of drug studies, which” the Court “will not lightly second-guess.”  Indeed, FDA looked at a study relied upon by Novartis showing that patients not taking concomitant heart drugs “might” have fewer side effects with a modified dosing regimen and determined that 1) the study was not sufficient to prove that the dosing regimen would put patients at any greater risk of adverse reaction, and 2) any adverse reaction could be adequately managed through the warnings included in the generic labeling.

The Court also determined that allowing MSN to omit the modified dosing regimen could be “reconciled with [the Agency’s] approval of the regimen for Entresto itself” even though “[b]oth decisions rested on the same titration study.”  Novartis argued that either the results of that study were robust enough to require inclusion of the modified regimen on both labels or its results were inconclusive enough to foreclose the inclusion on either label.  The Court said that FDA’s reasoning that ENTRESTO is safe and effective with the modified regimen “does not foreclose a later determination that the generic equivalence is not ‘less safe or effective’ without it.”  There thus is no unexplained change in the Agency’s position.

Next, the Court looked at the concerns about a difference in indications. Novartis argued that FDA compared the ANDA labeling to an old version of the ENTRESTO labeling, which had an indication only for patients with a reduced ejection fraction.  The Court found that that allegation was wrong: “FDA plainly compared it to Entresto’s current label.”  And, more importantly, the Court found that the addition of four words to the indication section was not impermissible, as those words were added specifically to omit an indication.  “[T]hat is how this scheme is supposed to work; an ANDA applicant may ‘propose labeling for the generic drug that ‘carves out’ from the brand’s approved label the still-patented methods of use.’”

Finally, Novartis challenged FDA’s finding that ENTRESTO and the ANDA have the same active ingredients.  Novartis claimed that ENTRESTO’s active ingredient is a complex, while the ANDA’s is not a complex.  But the Court found that “longstanding FDA regulations and guidance make clear that drugs can have the same active ingredients even if they have different solid-state physical forms or crystal structures” and that “FDA convincingly applied that principle in rejecting Novartis’s request to require generic drugs to have the same co-crystal structure as Entresto.”

The long-short of the decision is that Novartis gave the Court “no reason to question the FDA’s expert judgment regarding these scientific issues.”  Even after Loper-Bright, the Court is going to continue to defer to FDA on matters of science.

Moreover, the carve-out lives on at FDA, even if a few words are necessary to properly carve-out an indication (and even if it can induce infringement).

On September 30, 2025, FDA released a Request for Public Comment: Measuring and Evaluating Artificial Intelligence-enabled Medical Device Performance in the Real-World. Comments are due to the docket by December 1, 2025.

The request for comments is to obtain feedback about the “current, practical approaches to measuring and evaluating the performance of AI-enabled medical devices in the real-world, including strategies for identifying and managing performance drift, such as detecting changes in input and output.” The driving concern appears to be assessing whether the devices “remain safe and effective throughout their life cycle.”

Specifically, the agency is looking for information on methods that are:

• Currently deployed at scale in real-world clinical environments,
• Supported by real-world evidence, and
• Applied in clinical (patient- or health care worker-facing) settings.

While the request sets forth a number of specific questions for consideration—many of which would appear to require disclosure of potentially confidential or proprietary information—a critical and unanswered question relates to how FDA intends to use the information it receives from this request. One paragraph in particular caught this blogger’s attention:

Currently, many AI-enabled medical devices are evaluated primarily through retrospective testing or static benchmarks. While these methods may help establish a baseline understanding of the medical device performance, they are not designed to predict behavior in dynamic, real-world environments. Ongoing, systematic performance monitoring is increasingly recognized as relevant to maintaining safe and effective AI use by observing how systems actually behave during clinical deployment.

While it may be too early to conclude that this language is cause for concern, it certainly should give manufacturers of AI-enabled devices a reason to take a pause and consider submitting comments.  Even assuming it is true that the data and information provided in a premarket submission are not designed or intended to demonstrate long-term safety and effectiveness, it is not clear how FDA intends to remedy this post-hoc. Would FDA try to impose post-market requirements on currently marketed AI-enabled devices even if those devices were authorized without any such requirements? What would be the legal authority for doing so? There could also be impacts on the pre-market side, for example, if FDA takes learnings from this public comment period to impose additional pre-market requirements moving forward that could potentially impact substantial equivalence determinations.

We agree that is it important to determine how to ensure the ongoing safety and effectiveness of AI-enabled devices, but in doing so it will be important not to impose new or different requirements for this particular device type, as that would require statutory changes. We would encourage manufacturers to submit comments emphasizing that post-market obligations for medical devices are appropriate for all device types, including AI-enabled device types, even if the methods for collecting that information may be different. We would be happy to help you with your submission.

On September 11, 2025, Reps. Diana Harshbarger (R-TN) and Buddy Carter (R-GA)—the only two pharmacists in the U.S. House of Representatives—introduced a new bill, titled “Drug Shortage Compounding Patient Access Act” (H.R. 5316), that would expand the ability of compounding pharmacies and outsourcing facilities to compound products during a drug shortage, while also providing these entities with a greater sense of regulatory certainty while trying to serve patients when the FDA-approved supply chain fails.

What Does the Bill Say?

The legislation would codify FDA policies—similar to the temporary policies implemented during the COVID-19 pandemic—that allowed compounding of medications for urgent hospital needs during particular shortage situations.  Specifically, it would:

• Authorize Section 503A pharmacy compounding during shortages:  Allow state-licensed 503A compounding pharmacies to compound FDA-approved drugs that, among other requirements, are on the shortage list for urgent hospital or clinical use when the hospital or clinic has documented that it is not able to procure the drug from the manufacturer or a Section 503B outsourcing facility.  FDA similarly permitted this Section 503A “office use” compounding for hospitals and clinics during the COVID-19 pandemic and also expanded Section 503B outsourcing facilities’ ability to compound COVID-19 medications in short supply.  See our April 2020 blog posts discussing these temporary FDA policies here and here.
• Provide transition periods:  Require a 60-day transition period for Section 503A pharmacies and a 180-day transition period for Section 503B outsourcing facilities to carry on compounding medications once a shortage has been declared resolved.  This appropriately permits compounders to diminish their supplies of API and finished products after the resolution of the shortage.
• Update compounding lists:  Require FDA to annually update the list of 503B bulk drug substances that can be used in compounding, thereby providing further clarity and regulatory certainty for Section 503B outsourcing facilities in more quickly defining what these facilities can—and cannot—compound.
• Improve drug shortage reporting:  Mandate that FDA-approved drug manufacturers report anticipated supply disruptions, including, for the first time, anticipated surges in demand, and that FDA consider “real-world data” from hospitals and patients when designating shortages.
• Provide clarity around monographed dietary supplements:  Allow compounders to use USP/NF monograph dietary supplements in their compounded drug products.  Notwithstanding Section 503A’s use of the term “USP/NF monograph” when addressing what bulk substances may be used in compounding, FDA has limited that term in its non-binding guidance document to mean compounders can only compound USP/NF monograph substances that are the subject of a “drug” and not a “dietary supplement” monograph.  Specifically, FDA historically has stated that FDA interprets “an applicable USP or NF monograph” to mean an official USP or NF drug substance monograph.  “Accordingly, FDA does not consider USP monographs for dietary supplements to be applicable USP or NF monographs within the meaning of section 503A(b)(1)(A)(i)(I).”  FDA, Guidance for Industry, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act at 3 (2025).
• Modernize outdated statutory terms:  Eliminate the decades old, contentiously litigated (to the compounders’ success), and much maligned interstate distribution Memorandum of Understanding requirement and related provisions in Section 503B(b)(3)(B).

Why It Matters

Drug shortages remain a persistent and growing challenge in the U.S. healthcare system, affecting treatments from cancer therapies to commonly used injectables.  Compounding pharmacies and outsourcing facilities have long acted as a critically needed safety net that provides patients access to lifesaving medications—both during the pandemic and, most recently, in the aftermath of the 2024 Western North Carolina floods.

Hurdles Ahead

Despite broad support from pharmacists and patient advocates, the bill likely will face resistance from brand name drug manufacturers, who often push to limit compounding once FDA declares a shortage resolved.  Legal disputes over compounded versions of high-demand and ubiquitously prescribed drugs, such as semaglutide and tirzepatide, highlight the ongoing tension between ensuring needed access to medications and addressing alleged safety concerns.

However, with shortages continuing to disrupt patient care and bipartisan interest in strengthening the pharmaceutical supply chain, the bill could gain important traction as part of broader efforts to bolster domestic drug availability.

On September 29, 2025, FDA announced that it would be expanding its use of “Early Alert” communications for potentially high-risk device recalls, having determined that the pilot of this program was a success. The pilot program, initiated November 21, 2024, sought to minimize the time between FDA’s initial awareness of and public communication of potentially high-risk medical device recalls. Under the pilot, FDA issued Early Alerts for recalls related to a limited subset of medical devices: cardiovascular, gastrorenal, general hospital, obstetrics and gynecology, and urology. As of this latest announcement, FDA will now issue Early Alerts for all medical device recalls that are likely to be classified as the most serious type.

Although FDA already publishes notifications of high-risk recalls after manufacturers submit formal 806 reports and FDA classifies the recall, this process generally results in notifications published 2-3 months after recall letters are sent to customers. Based on our review of recent early alerts issued under the pilot program, FDA has been able to bring this timing in to around 1-3 weeks after initial customer letters. To do this, FDA is likely relying on voluntary pre-notifications by companies of potential recalls before an 806 report has been submitted (and potentially before some companies have determined that a recall is even reportable to FDA).

FDA publicizes these Early Alerts on its website  for all Class I medical device recalls.  FDA includes the status of whether FDA still is “collecting information” about the recall, whether the recall has been confirmed, and whether there is new information that has been updated since the Early Alert first issued.  The database is easily searchable and can be exported to Excel.  The public also can subscribe to receive instant email notifications for new Early Alerts that are issued.

Overall, we do not expect that FDA’s expansion of this pilot program should materially change a company’s process for evaluating whether to initiate a recall or report it to FDA. But, companies should be prepared for FDA to issue public notice of high-risk recalls earlier in the process than before and potentially before a company submits a formal 806 report.

On September 26, 2025, the Department of Commerce published a notice requesting public comment on “an investigation to determine the effects on the national security of imports of personal protective equipment (PPE), medical consumables, and medical equipment including devices.” 90 Fed. Reg. 46383 (Sept. 26, 2025). The investigation was initiated on September 2, 2025, pursuant to section 232 of the Trade Expansion Act, which “allows the President to impose restrictions on goods imports or enter into negotiations with trading partners if the U.S. Secretary of Commerce determines, following an investigation, that the quantity or other circumstance of those imports ‘threaten to impair’ U.S. national security.”

This section 232 investigation certainly is not the first under the Trump administration and almost certainly will not be the last. Devices now find themselves in the company of copper, timber and lumber, semiconductors, pharmaceuticals, trucks, minerals, commercial aircraft and jet engines, polysilicon, unmanned aircraft systems, and wind turbines. Essentially any product regulated by FDA as a medical device is the subject of this investigation, though the notice breaks them down as follows:

• Personal protective equipment (PPE) such as surgical masks, N95 respirators, gloves, gowns, and related medical parts and components;
• Medical consumables including medical/surgical instruments such as syringes, needles, and infusion pumps, supplies such as IV bags, catheters, bandages, and diagnostic and lab reagents;
• Medical equipment, which refers to items such as carriages and wheelchairs, crutches, and hospital beds; and
• Medical devices generally, which tracks the definition in the FDCA and includes “any instrument, apparatus, or machine used in the diagnosis, monitoring, or treatment of medical conditions.” Examples provided include blood glucose monitors, pacemakers, heart valves, hearing aids, x-ray equipment, and MRI machines.

The notice requests comments and information related to potential national security risks associated with medical devices, including:

• Current and projected demand for devices in the United States;
• The extent to which domestic production of devices can meet the domestic demand;
• The role of foreign supply chains in meeting US demand;
• The concentration of US imports of devices from a small number of suppliers or countries and associated risks;
• The impact of “foreign government subsidies and predatory trade practices on the competitiveness” of medical device manufacturers in the US;
• The “economic impact of artificially suppressed prices” of medical devices “due to foreign unfair trade practices and state-sponsored overproduction”;
• The potential for export restrictions by other countries, “including the ability of foreign nations to weaponize their control over supplies” of medical devices;
• The feasibility of increasing domestic production of devices;
• The impact of current trade policies on domestic production of devices and whether tariffs or quotas “are necessary to protect national security”;
• The potential “for foreign control or exploitation of supply chains” for devices; and
• The “ability of foreign persons to weaponize the capabilities or attributes of foreign-built” devices.

The date by which comments must be submitted to the docket is October 17, a very short turnaround. Medical device manufacturers who import products or components from overseas should strongly consider submitting comments. Since implementation of tariffs or quotas under section 232 relies upon a finding of a threat to national security, those comments should establish a record indicating strength and oversight of the foreign supply chain, the systems in place to identify potential “weaponization” of imported devices, and the likely consequences to Americans of imposing tariffs or quotas on critical medical products.  Because the Section 232 investigation provides an opportunity for notice and comment, it may be more difficult to challenge the government’s imposition of these tariffs after this process has completed.

To date, we are not aware of any reason to believe that medical devices manufactured overseas pose, or have posed, a national security threat. Making this assessment will be a nuanced and challenging responsibility.  But if there is any lesson that can be drawn from the 100% tariffs that will go in effect on October 1 for pharmaceuticals, it is that there is room for many exemptions.  The drug tariffs are not going to impact generic drugs, which account for the vast majority of drugs imported to the U.S., nor will they apply to drug from the European Union, which already is subject to a much smaller 15% tariff.  There also is an exemption for those companies that have a U.S.-based manufacturing plant under construction.

Against this backdrop, it is timely that one of the authors of this post, Anne Walsh, an HPM Director and Co-Chair of the IBA Healthcare and Life Sciences Law Committee, is facilitating a panel titled “National security issues, such as biosecurity and supply chain impacts, related to the life science and healthcare sectors.”   Panelists will include Ravi Bharwani, from FDA’s Office of Global Policy and Strategy; Shannon Humphreys from Canada’s Investment Review Directorate; and in-house and outside counsel representing industry from all over the globe.  It will be an opportune and insightful discussion from the government and industry perspective.  Join Anne at the IBA Annual Conference in Toronto on November 4, 2025!

The legal and regulatory landscape for controlled substances is in flux – telehealth prescribing rules have been extended to December 31, 2025, the new “HALT Fentanyl Act” heads to President Trump’s desk, all while recent opioid settlements signal sharper enforcement.  Against this backdrop, the American Conference Institute’s (ACI’s) 7th Annual Summit on Controlled Substances – Regulation, Litigation, and Enforcement is relaunching and is scheduled to take place from January 26-27, 2026 at the Virgin Hotels New York City in New York, NY.  The summit aims to deliver the essential strategies you need to respond, adapt, and lead in the legal and regulatory landscape for controlled substances.

Why You Can’t Miss It:

Hear firsthand from regulators, in-house counsel, compliance leaders, and enforcement specialists. Walk away from tailored sessions that empower you to:

• Decode shifting DOJ & DEA priorities to reduce legal and regulatory exposure
• Prepare for telehealth’s next chapter under the pending Special Registration rule
• Align your SOM programs with new DEA compliance standards
• Manage supply chain and quota risks through smarter strategies
• Stay ahead of the prosecution curve as federal and state enforcement intensifies

What You’ll Gain:

• Forward-looking insights to shape your 2026 legal, compliance, and operations roadmap
• Proven solutions for telemedicine prescribing, enforcement readiness, and enterprise risk
• Trusted expertise from past and current DEA, FDA, DOJ officials, top law firms, and leading in-house teams
• Cross-functional connections spanning pharma, biotech, telehealth, distributors, retail, and government

Hyman, Phelps & McNamara, P.C.’s Andrew J. Hull (and former Assistant U.S. Attorney, United States Attorneys’ Office) will moderate a discussion with the Hon. John Mulrooney, a former DEA Chief Administrative Law Judge (see our previous posts here and here), in a session titled “Perspectives From the Bench: The Ins and Outs of Trying a Diversion Case and Best Practices for Working With Your Outside Counsel.”

FDA Law Blog is a conference media partner.  As such, we can offer our readers a special 10% discount.  The discount code is: D10-999-FDA26.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference!

In a case involving international horse-doping conspiracies, racetracks, and state horse racing regulators, the Second Circuit expanded the application of the FDC Act’s felony provisions.  There are two forms of criminal penalties for violations of the FDC Act contained in 21 U.S.C. § 333(a): a strict liability misdemeanor and a felony.  Except in cases of repeat convictions, felonies require the government to prove the defendant also acted with “intent to defraud or mislead.”  21 U.S.C. § 333(a)(2).

Despite this specific intent requirement, the FDC Act does not identify who the defendant must intend to defraud or mislead.  Given the FDC Act’s role as a public health and welfare statute, it’s to be expected that the object of the ruse would, at a minimum, be FDA and patients/consumers.  And that’s generally how federal courts have interpreted the intent element.  See, e.g., United States v. Ellis, 326 F.3d 550, 554 (4th Cir. 2003) (upholding a felony conviction where evidence supported that defendant intended to defraud or mislead FDA by failing to register his establishment with the FDA); United States v. Haga, 821 F.2d 1036, 1041 (5th Cir. 1987) (explaining that FDC Act felony prosecutions are ordinarily premised on intent to defraud or mislead “purchasers”).  Over the years, federal prosecutors have sought—and federal courts have granted—an expansion of this element to include intent to defraud or mislead other federal or state regulators tied to consumer food and drug laws or the practice of medicine.  See, e.g., United States v. Kaplan, 836 F.3d 1199, 1214 (9th Cir. 2016) (upholding felony conviction on evidence of intent to defraud or mislead the state medical board); United States v. Mitcheltree, 940 F.2d 1329 (10th Cir. 1991) (holding that the object of the intent to defraud or mislead can be an “identifiable drug regulatory agency involved in consumer protection”).

The Second Circuit’s recent decision in United States v. Fishman, No. 22-cr-1600 (2d Cir. Sept. 22, 2025), interpreted the application of the intent element to apply to additional types of state regulators.  Fishman, a licensed veterinarian, developed performance enhancing drugs (PEDs) that could not be detected in a drug test.  For years, he worked with a racehorse trainer, Navarro, to distribute these PEDs to dope horses entered into races around the world (you can read more about the doping scheme here and here).  Navarro pleaded guilty, but Fishman and his salesperson went to separate trials where they were both convicted of conspiracy to manufacture and distribute misbranded or adulterated drugs with intent to defraud or mislead.

On appeal, the defendants challenged the district court’s jury instructions that felony intent to defraud or mislead could be satisfied by evidence that defendants acted with intent to “defraud state horse racing regulators.”  The defendants argued that the FDC Act’s purpose is not to regulate the competitive integrity of horse racing.  Instead, they contended, the purpose and structure of the FDC Act is to protect consumers and purchasers, leaving only three categories of possible victims: (1) the horse trainers who purchased the PEDs (but they did so knowingly and were not deceived); (2) the horses (defendants argued they were incapable of being defrauded or misled); and (3) the FDA or “other comparable state agencies that regulate drugs, as opposed to governmental entities that regulate racing.”  Id. at 16-17.

Sadly, the Second Circuit did not contemplate the weighty philosophical question of whether a horse can be deceived or misled.  But it did reject the defendants’ argument that only a state agency that regulates drugs could trigger the intent element.  In upholding the defendants’ convictions, the court stated:

[W]e do not agree . . . that the [FDC Act] reaches only fraudulent or misleading conduct directed at certain targets.  What matters under this statute is not the identity of the target of a defendant’s intent to defraud or deceive.  What matters is the connection between the fraudulent intent and the offense of adulteration and misbranding: Was the misbranding undertaken with the intent to deceive?

Id. at 17.  In other words, the object of the fraudulent action is irrelevant for determining the scope of the felony.  Instead, the important issue is whether the violation of the FDC Act is “connected” to the intent to defraud or mislead some government agency.  Because the evidence at trial supported that some state racing regulators prohibit administering unapproved drugs to horses, the court upheld the conviction because the fraudulent intent of defendants was linked to the misbranding of the PEDs.  Id. at 24-25.

Bottom line: by refusing to limit the type of government regulators that can be the object of an intent to defraud or mislead, the Fishman decision provides a broad application of what constitutes a felony under the FDC Act.  While the Second Circuit was careful to talk only about state regulators in its analysis, the decision leaves open the possibility that the government could pursue felony charges where there is evidence of intent to defraud or mislead parties other than government actors or consumers as long as there is a connection between the FDC Act violation and the fraudulent intent.  The court’s reasoning presents a slippery slope with no clear stopping point.  As the Supreme Court noted about a decade ago, the FDC Act’s primary purpose is “to protect the health and safety of the public at large.”  POM Wonderful LLC v. Coca-Cola Co., 573 U.S. 102, 108 (2014).  Recognizing that primary purpose, other courts may rein in such a broad interpretation of the intent element by holding that only evidence of intent to defraud or mislead parties tied to public health and safety—not horse racing or other activities—can satisfy this type of FDC Act felony conviction.