A recent Warning Letter reflects an FDA citation of a company for refusing to permit FDA Investigators to take photographs during an inspection.  We haven’t seen an FDA Warning Letter citing a refusal to permit photographs for years, so, just as FDA is apparently reviving these types of allegations, it is probably time for us to revive blogposts that have discussed this issue for more than a decade now.

The current Warning Letter was issued to a drug manufacturer in China (Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd.) for multiple violations observed during an inspection that occurred eight months ago.  One of the foremost allegations is that the FDA inspection team attempted to take photos of two filling machines that FDA observed to be “dirty and in an apparent state of disrepair, despite the equipment status being identified as clean.”  Management, according to the Warning Letter, “stated that the investigators were not allowed to take photographs of the equipment as part of the inspection.”  FDA reports that it told the company that “failure to allow photography would be documented as a refusal,” and the company “acknowledged the refusal.”

To be clear, as we discussed in a blogpost back in 2013, the Federal Food, Drug, and Cosmetic Act does not explicitly require companies to permit photographs to be taken.  Section 704 of the Federal Food, Drug, and Cosmetic Act (“FDCA”) (21 U.S.C. §374(a)(1)(B)) has required, for years, FDA-regulated industry to allow FDA “officers or employees” to “inspect, at reasonable times and within reasonable limits and in a reasonable manner,” any facility and “all pertinent equipment, finished and unfinished materials, containers, and labeling therein.”  FDA has always claimed that this gives them the authority to take photographs while conducting an inspection, as reflected in its Investigations Operations Manual (at Section 5.3.4.1), provided that “photos are an integral part of an inspection.”  The Manual also advises inspectors, if plant management refuses photographs, to cite two cases that the Manual claims authorize the taking of photographs, but those cases, in the view of critics like me, actually only authorize use of photographs in court when the investigated entity has not refused to permit photographs to be taken.

Then along came the FDA Safety and Innovation Act (“FDASIA”) (our firm’s summary of the law, which was enacted in 2012, is here).  FDASIA authorized FDA, in Section 707(b), to issue a guidance about what constitutes refusing an authorized FDA inspection, which is a crime under Section 301(f) (21 U.S.C. §331(f)).  In addition to the blogpost above, the resulting draft and then finalized Guidance has been the subject of several blogposts on our authoritative blog (authoritative, at least, in our own minds, as to matters of FDA law) and other articles we’ve authored, including here, here, here, here, and here.

Because the Guidance was required to be issued by FDASIA, it may have more compelling effect than most FDA guidances, which explicitly state that they are not binding law.  On the other hand, they may not be any more compelling than other FDA guidances: the U.S. Supreme Court’s Loper Bright decision limits the deference that courts should afford federal agencies in the agency interpretation of what laws mean (see blogposts here, here, and here).

To be sure, this is not the first time that FDA has included the “Limiting Photography” observation in a Warning Letter.  In August 2017, Homeolab USA received a similar observation, although it was the last substantive observation in the letter (in the recently issued Warning Letter, the allegation ranked near the top).  In September 2016, Nippon Fine Chemical received a similar Warning Letter about an attempt to prevent an FDA Investigator from taking photographs.  And for foreign companies, FDA does not even need to go through the formality of issuing a Warning Letter to get its way.  FDA’s standing Import Alert 66-79 includes a long list of companies whose products can be stopped at the border simply because the foreign company tried to limit photography during an FDA inspection, among other things (the Warning Letter that prompted this blogpost included a warning that FDA would “continue” to block imports from the inspected facility for its enumerated violations.  The addition of a company to an import alert is purely administrative, yet it carries an immediate penalty to companies that dare to limit FDA’s inspections.

So, how to proceed?  If you don’t want to face a battle with FDA, keep “quiet on the set,” an obscure reference to a miniseries subtitled “The Dark Side of Kids’ TV,”, and also the phrase directors would supposedly scream after the advent of “talkies.”  Don’t tell Investigators they can’t take pictures.  Ask them why they think they are entitled to take pictures, ensure that what they are photographing is within the scope of their inspection powers, and then take side-by-side photographs so you can demonstrate later if the FDA photos are misleading.

If you want to challenge FDA investigators for being outside of their inspectional authority, prepare to address an observation in a Warning Letter.  Unfortunately, multiple courts have held that Warning Letters are not final agency action, so it may be hard to judicially challenge FDA’s authority to take photographs during an inspection.

Last May the Department of Justice (“DOJ”) and the Drug Enforcement Administration (“DEA”) issued a Notice of Proposed Rulemaking (“NPRM”) to transfer marijuana from schedule I of the Controlled Substances Act (“CSA”) to schedule III.  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 44,597 (May 21, 2024)..  The NPRM was consistent with the Department of Health and Human Services’ finding that marijuana has a currently accepted medical use in the U.S. and its views about abuse potential and physical or psychological dependence.  The CSA requires scheduling actions through formal notice and comment rulemaking on the record after opportunity for a hearing.

If DEA reschedules marijuana to schedule III, regulatory controls applicable to schedule III controlled substances would apply as well as marijuana-specific requirements and any controls that might be implemented to meet U.S. treaty obligations.  Drugs containing any substance within CSA’s definition of “marijuana” would remain subject to the applicable prohibitions in the Federal Food, Drug, and Cosmetic Act.

DEA announced in August after receiving over 43,500 comments in response to the NPRM that it would hold a public hearing regarding the proposed rescheduling.  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 70,148, (Aug. 29, 2024).  The “preliminary hearing,” which will begin Monday, December 2nd at 9:30 a.m. in DEA’s North Courtroom at its headquarters in Arlington, Virginia, will serve to address legal and logistical issues and future dates for the evidentiary hearing on the merits.  No witness testimony will be offered nor received on Monday.  Only designated participants and credentialed media members may attend.  The public may access the hearing virtually at www.DEA.gov/live.

In a Temporary Rule announced on November 19, 2024, DEA with input from HHS again extended current telemedicine flexibilities, which were first initiated on January 31, 2020 at the inception of the COVID-19 pandemic. The federal telemedicine flexibilities (i.e., temporary exceptions from some of the requirements of the Ryan Haight Act of 2008) are extended for an additional year, until December 31, 2025. All DEA-registered practitioners may continue to prescribe via audio-visual telemedicine encounters schedule II-V controlled substances, and schedule III-narcotic controlled substances that are FDA-approved for opioid use disorder management and treatment.  DEA notes in the Federal Register notice that it received over 38,000 comments to its 2023 proposed rules (35,454 for the general telemedicine flexibilities proposed rule and 2,915 for the buprenorphine telemedicine flexibilities proposed rule), and held two days of public listening sessions addressing industry comments.  It cited that feedback as the impetus to once again give DEA time to consider “a new path forward for telemedicine” and to allow for a “smooth transition” for both patients and practitioners that have relied on the availability of telemedicine for prescription of needed controlled substance medications.  While not stated in the Temporary Rule, telemedicine prescribers and pharmacies should ensure that state laws permit telemedicine prescribing, and should ensure they hold necessary licenses in accordance with state law, especially if prescribing or dispensing across state lines.

As a reminder (and as blogged about here), on March 1, 2023, DEA, together HHS, promulgated two notices of proposed rulemaking (NPRMs), one for general telemedicine prescribing of controlled substances and another for telemedicine prescribing of Buprenorphine (“Telemedicine Prescribing of Controlled Substances When the Practitioner and the Patient Have Not Had a Prior In-Person Medical Evaluation,” here, and “Expansion of Induction of Buprenorphine via Telemedicine Encounter,” here).  The proposed rules, while expanding pre-COVID-19 patient access to telemedicine prescriptions for controlled substances, fell well short of the telemedicine flexibilities that existed during the COVID-19 pandemic. More specifically, the proposed rules leave somewhat limited telemedicine options for both medication assisted treatment (i.e., use of buprenorphine) for opioid use disorder, and for Schedule III-V non-narcotic controlled substances unless the patient receives an in-person examination. In addition, the proposed rules leaves no telemedicine options for Schedule II or Schedule III-V narcotic medications, which would require an initial in-person visit before issuing a prescription. The sole exception to this limitation is for a prescription of buprenorphine for treatment of opioid use disorder, where a patient may receive an initial 30-day telemedicine prescription; but the “refill” (or second prescription) still requires an in-person exam.  For schedule III-V non-narcotic prescriptions, patients similarly would be eligible to receive an initial 30-day telemedicine prescription prior to an in-person exam. Any refill, however, would require an in-person exam either by a “referring” provider or dispensing provider.

Thus, while continuing to review industry feedback, DEA is still working on promulgating a more workable final set of telemedicine regulations.  Notably, the draft telemedicine regulatory framework comes 16 years after passage of the Ryan Haight Act of 2008, in which Congress specifically tasked DEA with crafting a framework that included a DEA registration category for telemedicine providers; and some in Congress have voiced concerns with not only telemedicine’s current nebulous status, but also with this lengthy delay.  We cannot predict with any certainty what effect President Trump’s election will have on HHS’s and DEA’s proposed telemedicine framework, especially when one considers the anticipated DOGE (Department of Government Efficiency) activities commencing with President Trump’s January 2025 inauguration. One undertaking of the DOGE, led by Elon Musk and Vivek Ramaswamy, intends to chop away at the broad-sweeping breadth of existing federal regulations. This blogger questions whether any revised proposed telemedicine regulations will successfully dodge DOGE.  Thankfully, we have until December 31, 2025 to ruminate about it.

FDA recently issued a draft guidance, Chemical Analysis for Biocompatibility Assessment of Medical Devices, which describes chemical characterization methods that may be used to demonstrate biocompatibility of a medical device as an alternative to conducting certain biological testing.  Chemical characterization identifies and quantifies chemicals that may be released from the medical device, while a toxicological risk analysis (TRA) evaluates the risks to the patient associated with the chemicals identified.  Data from chemical characterization studies must be evaluated in a separate TRA following ISO 10993-17 guidelines.

For FDA submissions, this strategy can be used to evaluate the biocompatibility endpoints acute, subacute, subchronic, and chronic systemic toxicity, genotoxicity, carcinogenicity, and reproductive/developmental toxicity.  That is, the biocompatibility endpoints cytotoxicity, sensitization, irritation/intracutaneous reactivity, material-mediate pyrogenicity, implantation, and hemocompatibility are not covered by the approach discussed in the new draft guidance.  Chemical characterization can also be useful in evaluating a change to the materials or manufacturing of a device.

Although the draft guidance states that the approach can be used for limited (< 24 hour), prolonged (1-30 days), or long-term (> 30 days) contact devices and “can reduce the time needed to complete biocompatibility testing by evaluating multiple biocompatibility endpoints at once and can reduce animal testing”, it is rarely going to save sponsors time or money to use chemical characterization in place of biological testing for most limited and prolonged contact devices to support FDA premarket submissions.

Using chemical characterization and toxicological risk analysis to support the biocompatibility of a medical device is not new.  Since the first issuance of FDA’s guidance Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” in 2016, sponsors submitting premarket submissions to FDA have had the option of using these techniques to evaluate certain biocompatibility endpoints.  Many sponsors want to reduce animal testing and, therefore, welcome the approach.  However, the experience in practice has been one of frustration as sponsors have struggled to reach agreement with the Agency on acceptable methods and acceptance criteria for these chemical assessments, despite FDA’s  partial recognition of the ISO 10993-18 and -17 standards that describe methods for chemical characterization and TRA, respectively.  Many sponsors have given up and opted to conduct biological studies instead of chemical assessments given the significant uncertainty with the non-animal based approach. FDA also notes variability in the approaches, inconsistent analytical chemistry reports, and deficiencies in review of premarket submissions as a driver for the draft guidance.

The draft guidance provides recommendations for collection and reporting of chemical characterization data and discusses the topics of information gathering, test article extraction, chemical analysis, and data reporting.  The main body of the draft guidance provides high-level recommendations, and four appendices provide detailed recommendations for test design.  Many of the details provide helpful clarity and it is noted that many of the recommendations in the draft guidance follow feedback FDA has provided to sponsors in Pre-Submissions and deficiencies over the last few years; but for others, FDA’s recommendations feel overly burdensome and not tolerable of any uncertainty or risk.  The following topics stood out as being burdensome and likely areas for FDA scrutiny of a sponsor’s chemical characterization data:

• One such area relates to determining a device’s contact duration. The general guidance for biocompatibility references ISO 10993-1 for identification of the nature and duration of contact, including cumulative effects with repeated use.  The standard describes contact duration as the cumulative sum of single, multiple, or repeated duration of contact.  However, Appendix A of the draft guidance contradicts the standard, stating that devices with short duration, but repeated use are categorized according to the total number of days and not the total amount of time.  Watch for a follow-up post on this particular topic.
• One of the most common issues with chemical characterization studies is that the use of harsh non-polar and semi-polar solvents (e.g., hexane and isopropanol) can be incompatible with many devices, including common polymers like silicones. Exhaustive extraction in these solvents can lead to high levels of product degradation or increased levels of extractables found in the chemical data, which is not expected during clinical use, and can often result in a TRA with a negative or inconclusive outcome.  Although FDA suggests in the draft guidance to investigate use of multiple solvents to find a suitable one, this is sometimes not possible even after many rounds of attempted feasibility studies performed by the labs.  In this regard, FDA states if compatible solvents cannot be identified, then chemical characterization data would not be appropriate to support a TRA and biological testing would be needed.  Although the draft guidance suggests that chemical characterization data can reduce time and animal testing requirements for biocompatibility evaluations, this will not be the case for many medical devices, including some long-term contact devices, for these reasons.  Furthermore, because some animal testing to address long-term endpoints is not practical or feasible to perform, sponsors can find themselves in a very difficult position.  FDA suggests that simulated use/leachables studies to simulate the clinical use (i.e., in a more clinically relevant solvent) and release kinetics data can be helpful; we agree with FDA’s thoughts regarding usefulness of these alternative studies especially in the cases where devices are incompatible with non-polar and/or semi-polar solvents and to more accurately estimate clinically relevant exposures.  We would encourage FDA to consider releasing guidances on both of these topics in parallel with the subject guidance.
• Another area that FDA discusses throughout the draft guidance is that chemical identities of extractables must be “confident” or “confirmed” levels to be used in the TRA. However, it is very common to have “tentative” or “unknown” identifications in chemical characterization studies.  In the draft guidance, FDA illustrates the need for additional orthogonal data (i.e., additional primary detection methods) in the sponsor’s methods to help with identification.  FDA also suggests throughout the draft guidance that information gathering on device materials of construction and the manufacturing process, including chemical additives, processing aids, presence of cohort of concern compounds, etc., can be useful in the development of a device-specific chemical characterization plan and analysis of the resulting data.  We agree with FDA on this point, and recognize that a large gap in the industry may be stemming from the fact that a Biological Evaluation Plan/Report (i.e., BEP/BER or Biological Risk Assessment) per ISO 10993-1 is not required for the majority of FDA pre-market submissions.  We have already seen trends in which FDA has started asking for more material, supplier, and manufacturing information in 510(k)s, submissions for which FDA historically did not require this information to be submitted by the sponsor. We have concerns that FDA’s expectations related to chemical identification levels may be unattainable even despite proper information gathering and additional orthogonal data and represent an unwillingness to accept some residual level of uncertainty in their decision-making process.
• In several places in the draft guidance, FDA illustrates that non-targeted chemical analysis is needed for general screening of unspecified device extractables, but that subsequent use of targeted analysis may be necessary to confirm the identity or refine the quantity of certain chemicals, including cohort of concern compounds, or analyze extractables with high concentrations. FDA also states that non-targeted data is insufficient to conclude that a particular substance is absent from the device extracts.  We have seen cases in which devices with claims of “DEHP-free” or “phthalate-free” do in fact contain these chemicals in the device extracts.
• In Appendix A of the draft guidance, FDA provides suggestions on what is and is not considered “worst case” for the test articles used for testing. FDA suggests that test articles represent the worst-case manufacturing process, and provide the examples that the device undergoes the greatest number of sterilization and/or reprocessing cycles.  It is common that sponsors will perform, for example, testing on 2x EO sterilized devices in order to support manufacturing scenarios in which the device needs to be re-sterilized.  However, reprocessing (cleaning and disinfection and/or sterilization) is typically performed by the end user in a healthcare facility rather than part of the manufacturing process.  FDA’s suggestion to test the maximum reprocessing cycles for reusable devices is aligned with the recommendations in clause 4.8 of ISO 10993-1:2018, but is extremely burdensome and not referenced in the related ISO 10993-18.  We have already seen trends for FDA to request biocompatibility and other testing after maximum reprocessing cycles of each separate reprocessing scheme listed in the sponsor’s labeling, including all combinations of detergent and disinfection chemistries, manual vs. automatic washing methods, sterilization modalities, and different sterilizer cycles/parameters for the same sterilization modality.  As many reusable devices can undergo hundreds or even thousands of cycles, the combination of testing the maximum cycles for each of these variables is extremely time-consuming and cost prohibitive, costing many hundreds of thousands or even millions of dollars.  In addition, the recommendation to test the device after maximum reprocessing cycles appears counterintuitive to the other recommendations in the guidance, which focus on the toxicological concern of chemical additives or manufacturing process aids, including cohort of concern compounds, present on the device that can be extracted.  These chemicals would typically have decreased quantities over the lifetime of a reusable device due to being removed by multiple cycles of reprocessing.  Therefore, FDA’s justification for this burdensome approach is not clear.

Given the current frustrations with chemical assessments and desire to reduce animal tests, the release of the draft guidance is a step in the right direction.  However, additional guidance from FDA is necessary in the related areas of simulated use and release kinetics studies.  In order to be more helpful to industry, reasonable recommendations to reduce animal testing in practice (rather than theory) are still needed.  It is recommended to submit a Pre-Submission to the Agency when considering your chemical characterization strategy, especially for any devices/materials with special considerations or use of alternative strategies and solvents.

FDA is extending the comment period on the notice published September 20, 2024 (89 FR 77162). Submit either electronic or written comments on the draft guidance by December 19, 2024, to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.

*KP Medical Device Consulting LLC

Over the past few days, we’ve been blogging about changes that are sure to come to FDA under Trump 2.0. Calls to more generally gut Federal agencies are everywhere, including from Robert F. Kennedy, Jr., the current nominee to lead the department of Health and Human Services. But shedding regulators in sensitive areas like drug manufacturing—even in the era of influencer-driven medicine—can lead to compromises in safety and efficacy, especially when FDA is already facing a massive inspectional backlog. One occurrence where an adulterated drug leads to injury can change a lot of minds about government’s role and the extent of needed FDA oversight.

Americans’ faith in safe drugs is thanks in no small part to the FDA investigators that conduct preapproval, for-cause, and routine inspections. So what does this all mean for FDA’s inspection workforce? Perhaps presciently, the non-partisan Government Accountability Office (“GAO”) issued a report last week imploring FDA to implement strategies to retain its investigators and address a long-simmering shortfall in their ranks.

According to the report, FDA has employed between 200 and 250 investigators in the years since the COVID pandemic. Over that time the number of vacancies has steadily grown, from 25 in 2021 to 73 in 2023. Those vacancies came while FDA was trying to ramp up inspections, after they fell under the first Trump administration and then cratered during the pandemic. The task before these investigators is daunting. According to FDA data, there are over 4,700 registered drug manufacturing facilities globally, more than half overseas. In 2023, FDA conducted 906 domestic and 768 foreign inspections, still well below pre-pandemic levels. According to FDA, and as reported by GAO, the difference was due to lower investigator capacity, due to the departure of several highly experienced investigators and their replacement with largely novice investigators, who can take years to train up.

There is so little capacity because being an FDA investigator requires immense technical knowledge, almost constant travel, and long hours. Unsurprisingly then, GAO has identified turnover as the key problem plaguing FDA inspectional workforce. This is a consistent finding from GAO, which has noted in past reports that investigators face these difficult professional challenges.

Under the Biden administration, FDA has taken some steps to remedy this problem. However, GAO reports that they have been ineffective as “investigator attrition has generally outpaced hiring and has resulted in a large number of relatively inexperienced investigators.” GAO credits FDA for implementing “action plans” to address investigators’ pay and training, but notes that the agency has not yet implemented any remedies for dissatisfaction over travel, workload, and work-life balance. The report also notes that “the continued loss of experienced investigators is already affecting FDA’s ability to meet inspection goals.” Lower numbers of investigators combine with lack of experience to limit the overall number of inspections FDA can conduct. That, in turn, may compromise FDA’s ability to identify lower manufacturing standards and the failure to comply with FDA and cGMP requirements.

The report concludes that FDA stakeholders should continue to collaborate to identify strategies that appropriately address these issues. Of course, making federal jobs more appealing for current and aspiring FDA investigators is not at the top of the incoming administration’s to-do list.

Is the GAO report a Pollyanna assessment of Federal priorities in the face of the current political bent towards proposed massive cuts to Federal jobs and services? We would say certainly not, as it underscores a critical need to ensure drug safety and efficacy. You are forgiven, however, if you’re skeptical that an RFK Jr.-led HHS would ever enact these recommendations. But in the face of the prevalent headwinds, there is also some reason to believe that this part of FDA’s vital role in ensuring public health will not fall entirely by the wayside under the weight of potential cuts. Even small-government members of the Republican-controlled House have long beat the drum of increasing FDA’s foreign inspection capacity. And we can’t help but wonder if the goals of smaller government aren’t outweighed by the political consequences to an administration potentially pock-marked by recalls, shortages, and outbreaks. Those very negative outcomes may be the fate of the American gold standard of drug safety if the incoming administration decides that oversight and inspections are disposable Federal functions.

On Thursday, November 14, President-Elect Trump announced his pick of Robert Kennedy, Jr., for Secretary of Health and Human Services (HHS). Although not altogether surprising, the formality of an official announcement still came as a shock to many of us who work in areas regulated by HHS, as well as to many others in the public health arena.

Kennedy’s tag line is that he and Trump will “Make America Healthy Again.” This seems like a reasonable goal, as most people can probably agree that America is not healthy.  Rates of chronic disease are high, as is obesity. Incentives to motivate better nutritional choices and increase physical fitness would be welcome.

The question, however, is how Kennedy plans to accomplish a generally accepted goal.  Some insights come from an op-ed Kennedy wrote in the Wall Street Journal on September 5, 2024, setting forth some of his plans for a healthier America. The first point he made pertained to reforming the Prescription Drug User Fee Act (PDUFA).  He states, correctly, that PDUFA user fees make up about 75% of the budget for the Center for Drug Evaluation and Research (CDER). Though he did not mention it, there is also a Medical Device User Fee Act (MDUFA), which accounted for approximately 44% of the budget for the Center for Devices and Radiological Health (CDRH) in FY2023. Kennedy stated that payment of these user fees by industry “creates a barrier to entry to smaller firms and puts bureaucrats’ purse strings in the hands of the pharmaceutical industry.”  Kennedy does not say what the alternative to user fees would be given current budget realities.

It seems Kennedy is unaware of the waivers or fee reductions available to small businesses, both for drug and device submissions, precisely to avoid creating a barrier to entry. The second part of Kennedy’s statement expresses concern that because companies are essentially paying the salaries of the review teams, that the teams somehow feel obligated to approve the products.

On this second point, Kennedy elsewhere contradicts his own assertion that user fees lead reviewers to feel beholden to sponsors.   Kennedy has stated that FDA’s recent denial of the psychedelic drug MDMA to treat PTSD constitutes “aggressive suppression of psychedelics” and has listed it as among the regulatory decisions he wants to reverse. If FDA reviewers felt obliged to accommodate the payers of the user fees, it is not clear why this-and many other drugs and devices-would have been rejected. (Based on our own experiences, we can confidently say that FDA reviewers are not rubber-stamping applications because sponsors pay user fees.)  One possible explanation for this apparent contradiction is that in the case of approved drugs that he does not believe should have been approved, they must only have been approved because FDA is in industry’s pocket. On the flip side, in the case of drugs that he believes should have been approved but were not, FDA is waging a “war on public health.”

Belief, anecdote, and opinion seem to be the driving factor behind much of Kennedy’s rhetoric. The New York Post, not known for its Democratic leanings, stated in an article published on November 14 that installing Kennedy as the head of HHS breaks the most important rule of medicine: first, do no harm. Referencing an interview with Kennedy from 2023, the Post says that his views on health “were a head-scratching spaghetti of what we can only call warped conspiracy theories, and not just on vaccines.” They note his position that pesticides, cellphones, and ultrasound “could be driving an upswing in Tourette syndrome and peanut allergies,” and that “all America’s chronic health problems began in one year in the 1980s when a dozen bad things happened.”

The positions he espouses seem to have no grounding in scientific evidence or data. His well-known anti-vaccine stance is in stark contrast to decades of scientific research demonstrating the positive impacts of vaccination globally. Andrew J Shattock et al., Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization, Lancet 2024; 403: 2307-16. He has equated vaccination to the Holocaust and argued that COVID-19 was “ethnically targeted” to spare Ashkenazi Jews and the Chinese. He has stated that ivermectin and hydroxychloroquine are effective COVID treatments, notwithstanding evidence to the contrary. Washington Post, 10 RFK Jr. conspiracy theories and false claims, in his own words, Nov. 15, 2024.

Given the above, the obvious question seems to be: what will be the role of science in an FDA under Kennedy’s leadership? Science is, at its core, a place to ask questions, to challenge norms, and to make new discoveries, and then to subject those discoveries to replication in a controlled manner.  Galen’s belief in the four humors was sincere and deeply held, and also deeply wrong, as evidence-based science eventually showed.  In the meantime, this belief was followed for centuries by doctors, to the detriment of countless patients.

Today, FDA grounds its very existence in the principles of science:

Science—both its quality and integrity—is the touchstone of everything we do at FDA. In conducting our mission to protect, promote, and advance the public health, FDA needs the best scientific and technological information available to make decisions on the products we regulate. Critical to our ability to reach sound decisions and to retain the public’s trust are high-quality data and a scientific review process that is thorough and unbiased.

Kennedy’s pronouncements raise serious concerns as to whether scientific evidence and clinical data will continue to serve as the principles by which FDA makes critical decisions each and every day, or whether his beliefs – or the beliefs of new FDA officials he gets to select –  will drive FDA decisions.

The potential consequences could be severe. CDRH’s long-standing definition of “valid scientific evidence” does not include opinions or beliefs.  21 C.F.R. 860.7(c)(2).  Indeed, it explicitly excludes “random experiences” and “isolated case reports”, which seem to be the kinds of “evidence” that Kennedy is willing to rely upon when making his pronouncements.

Public confidence in the device review process is already fragile.  It relies on the belief that FDA carefully considers the safety and effectiveness of devices.  As noted in an earlier post, the public’s faith in the process is already severely challenged by critics who argue that the process is lax – and whose views are widely reported.  Substantially weakening the data standards would likely cause significant erosion in public trust.  It would also undercut CDRH’s position as being a gold standard for the review process, which benefits US companies seeking to market their devices abroad.  Moreover, Congress has established data standards for device review.  Kennedy could not unilaterally change those congressional criteria; personal beliefs do not qualify as “adequate assurance of safety and effectiveness.”

It is worth noting that the Secretary of HHS is responsible for many tasks and agencies apart from FDA, and generally has very little influence over the day-to-day review decisions.  Thus, while FDA is foremost in our mind, it may not be in his.  Even so, his perspectives on the roles of science and belief could be transmitted to FDA, and have a bearing on who is FDA Commissioner.

The individual tasked with overseeing the agencies responsible for protecting the public’s health should endorse the role of science, not disparage it. Whether a Kennedy regime would base its decisions on science rather than belief remains to be seen, but his words and public pronouncements to date are not encouraging, although his views could possibly shift.  To some degree.  Wise government officials will modulate their views as they learn new facts.  As you consider engaging with FDA under the new administration, we would be happy to help you navigate the potential complexities of an HHS run by Mr. Kennedy in order to continue bringing data-supported, safe, effective, and novel products to market.

The word unprecedented has been used a lot in the past two weeks.  Perhaps appropriately.  Below is some  precedent that’s been on this blogger’s mind recently and that may be relevant in the coming days, weeks, and months:

• Tummino v. Hamburg. Why? The HHS Secretary intervened in an FDA approval decision.  The court ruled the agency’s action was arbitrary and capricious and entered a mandatory injunction ordering FDA to make the drug available.
• Trump v. Hawaii and related cases. Why?  Those litigations discuss the relevance of campaign statements and social media posts in assessing the legality of executive actions.
• Cook v. FDA. Why? The case analyzed when an enforcement obligation was required by statute as opposed to committed to agency discretion.
• FDA v. Alliance for Hippocratic Medicine et al. Why? The Court analyzed constitutional standing requirements, especially in the organizational and associational context.
• Preemption, commerce clause (dormant and otherwise), and related cases, especially those involving state and local government action. Why? Those cases evaluate when state and local governments can act in ways that may be different from the federal government.
• Practice of medicine cases. Why? These cases help inform the jurisdictional bounds of FDA’s authority.
• Cases about the steps the agency must take if it attempts to withdraw an approval. Why? These cases analyze the statutory and regulatory requirements that FDA must follow when considering such actions.
• Cases assessing when FDA has taken final agency action. Why? Those cases analyze when a court will consider a challenge on the merits as opposed to dismissing it on procedural grounds.
• Unreasonable delay cases. Why? Because these cases inform when a party can obtain relief when the agency fails to act.
• Loper Bright. Why? Because it changed the framework that courts will use to resolve statutory ambiguities in the above and other contexts.

Unprecedented or not, we can expect important changes in the coming months.  One thing won’t change, however.  Hyman, Phelps & McNamara, P.C. and the FDA Law Blog will keep our finger on the pulse of developments in the law and our readers informed of how those developments affect them.

“An open foe may prove a curse, but a pretended friend is worse.” When the poet John Gay wrote these words in 1727, the idea of an administrative agency like the FDA was likely the furthest thing from his mind. That he is now being quoted in a blog post to discuss the relationship between medical device companies and their regulatory oversight body shows that some ideas really do have staying power.

There have been many articles (here, here, here, and here) and even some late night TV shows that make it sound like FDA and the device industry are the best of friends, clinical evidence requirements are low, risky devices stay on the market, and FDA cares more about helping industry than protecting the public. In this author’s experience, the opposite is often true: FDA is very risk averse, reviewers do not want to be responsible for approving or clearing a novel device without what essentially amounts to a guarantee of safety, 510(k) substantial equivalence requirements have grown exponentially over the years, and although, as indicated in a prior post, CDRH talks a good game about innovation, that alleged commitment to innovation is overshadowed by fear of being the signature on a submission for a device that causes harm.

So what is the truth? Are industry and FDA friends or foes? As is often the case, the truth is likely somewhere in the middle. Some companies have positive experiences with FDA, and that does not mean getting through the clearance or approval process quickly; it means feeling like the relationship is collaborative rather than adversarial, that FDA appreciates and understands the various shades of gray that are associated with bringing a medical device to market, and that the company understands the importance of protecting the health of the public when it launches its new product. This can, and often is, the outcome, benefitting the company, FDA, and most importantly, the public.

But sometimes, FDA seems to take on the sheen of a pretended friend, and John Gay was right in stating that this persona is far more dangerous than knowing from the start that someone is a foe. With a foe, you consider all the possible outcomes, you expect a challenging conversation, you come prepared for the worst and hope it’s not as bad as you thought it would be. With a pretended friend, you let your guard down. Maybe you talk too much, say things that you shouldn’t. You are not on guard, and you are not prepared. When this happens, it is a virtual guarantee that you will not get what you want.

This is not to say that companies should not pull out all the stops to improve relationships with their review teams and management within CDRH and other areas of the agency. If you have those connections, use them—and if you don’t have them, reach out to us, because we might. It is always helpful for the FDA team to see that the folks on the other side of the table really do share the same goals: for safe, effective, novel devices to get to market to benefit the public health. If you can come to the table seeing eye to eye, it may make getting to the end a lot easier.

If you can establish a positive working relationship with the review team, you may conclude that FDA is a friend. Never forget that looks can be deceiving. You should always assume FDA is a pretended friend, and come prepared.

Among the more interesting developments in the recent election was the emergence of Robert Kennedy as a prominent figure in the MAGA movement – and the collateral emergence of the MAHA movement (Make America Healthy Again). As crisply laid out in short YouTube video, MAHA aims to transform public health by zeroing in on “our nation’s biggest health challenge – chronic disease.”  The first order of business will be to “clean up the public health agencies like CDC, NIH, FDA, and the U.S. Department of Agriculture,” which “have become sock puppets for the industries that they’re supposed to regulate.”

Undoubtedly, the public health and economic toll of chronic disease is staggering. As reported in a recent publication (citations omitted):

An estimated 129 million people in the US have at least 1 major chronic disease (eg, heart disease, cancer, diabetes, obesity, hypertension) as defined by the US Department of Health and Human Services. Five of the top 10 leading causes of death in the US are, or are strongly associated with, preventable and treatable chronic diseases. Over the past 2 decades prevalence has increased steadily, and this trend is expected to continue. An increasing proportion of people in America are dealing with multiple chronic conditions; 42% have 2 or more, and 12% have at least 5. Besides the personal impact, chronic disease has a substantial effect on the US health care system. About 90% of the annual $4.1 trillion health care expenditure is attributed to managing and treating chronic diseases and mental health conditions.

Moreover – and as recognized by FDA’s current commissioner Dr. Califf – several chronic diseases are diet-related. Nonetheless, the medical products sector historically has drawn the lion’s share of attention at FDA, with the agency’s leadership ranks reflecting that priority.

To be sure, there have been nutrition-related initiatives at FDA that target chronic disease. Back near the birth of this century, yours truly sat in on meetings of the agency’s Working Group on Obesity, which ultimately generated a report with a number of recommendations. Whatever the worth of those recommendations may have been, the fact is that the prevalence of obesity has significantly increased in the intervening years. More recently, the agency invested significant efforts in modernizing nutrition labeling requirements and implementing a sodium reduction initiative. However, it’s fair to say that FDA’s food program has focused primarily on implementation of the many mandates in the Food Safety Modernization Act of 2011. With the bulk of that work complete, the program might have more bandwidth for a renewed push at nutrition-related initiatives through the newly established Nutrition Center of Excellence – which brings us back to MAHA.

The Wall Street Journal reports that Mr. Kennedy favors Dr. Casey Means for the role of surgeon general or FDA Commissioner. As a physician trained at Stanford, Dr. Means would fit the mold of a typical FDA commissioner – but the similarities may end there. Dr. Means seems to be laser focused on the root causes of chronic disease, including the role of diet in metabolic health – and she has taken FDA to task for “not adequately protecting us from toxic food.” How much of that critique could be translated into an effective regulatory (or deregulatory) agenda in light of constraints on FDA’s authority and other factors will be the subject of another blog posting, but the power of the bully pulpit should not be underestimated. It also bears mention that much of the MAHA agenda could unfold through USDA, which administers the Supplemental Nutrition Assistance Program (SNAP) and the National School Lunch Program – two food and nutrition assistance programs that directly affect the diets of tens of millions of consumers every day.

Regardless of who ultimately sits in the FDA Commissioner’s seat, MAHA can be expected to have a seat at the table – and those who ignore the emergence of this movement and its priorities may be doing so at their peril.

We recently saw an interesting Instagram post aimed at Swifties disappointed in the election results.  It noted that Tay Tay released four albums during the first Trump administration and only two during the Biden administration, so there’s reason to hope for the next four years if one was despondent over the election.  (One of the undersigned is an avowed metalhead and cannot attest to the accuracy of the statement because he was too lazy to ask his teenaged daughter.).

It got us thinking (dare we saying, having a prophecy?), how would the second Trump administration compare to the Biden administration when it comes to FDA OPDP warning letters and untitled letters for promotional issues?  Our assumption was that using the first Trump administration as a baseline compared to the Biden administration would result in an inverse correlation to the above mentioned Taylor Swift output.  (Thus proving that anything can be made to sound more intelligent when saying “inverse correlation” including a comparison of Taylor Swift albums and FDA letters.)

Much like Ms. Swift, we did something bad in assuming this.  Like most of  Taylor’s dating choices, we were completely wrong.  In fact, the number of letters issued by OPDP (both Warning Letters and Untitled Letters) were almost identical under the first Trump administration and the Biden administration to date.  Under the first Trump administration, FDA issued 16 untitled letters and seven warning letters (almost, but not quite 22).  Under the Biden administration, the numbers were 15 untitled letters and 4 warning letters.

So what does that mean going forward?  We’d like to say that the past is perhaps predictive of the future, but given the potential involvement of Trump whisperers like RFK Jr, who is no fan of Big Pharma (or perhaps any Pharma), we simply don’t know.  While certain aspects of business regulation and other areas of FDA regulatory oversight are likely going to be loosened up under the new administration, companies should remain vigilant about their promotional review processes and should not assume that everything has changed.  We know all too well how delicate this would be treated if this was a movie — all we can say is breathe, we may need to tolerate it but ask, are you ready for it?

On November 8, 2024, FDA issued a proposed order to remove the oral decongestant ingredient phenylephrine (including both phenylephrine hydrochloride and phenylephrine bitartrate) (collectively, PE) from the OTC monograph on the basis of a lack of effectiveness.  FDA also noted that it has concluded that no safety signal was identified for oral PE at doses permitted under the monograph. The action follows the September 2023 meeting of the Nonprescription Drug Advisory Committee (NDAC) at which the NDAC voted unanimously that the current scientific data do not support that the monograph dosage or oral PE is effective as a nasal decongestant and reached a consensus that the data presented did not support that a higher dose would be safe and effective.  As dictated by the process provided for in the 2020 CARES Act,  FDA announced issuance of the proposed order in a Federal Register notice and published the proposed order itself on FDA’s website.

Comments on the proposed order are due May 7, 2025.  Notably, the proposed order provides that the order, if finalized, will become effective one year after the final rule is published.  That means almost certainly no sooner than the second half of 2026.

Along with the proposed order, FDA issued as a supporting document the “Scientific Review Supporting Proposed Administrative Order” in which it describes the scientific data on the efficacy, pharmacology, and safety of oral PE underlying its determination to issue the proposed order. The review included the studies that supported the inclusion of PE in the original tentative final monograph and final monograph, as well as studies that became available after the monograph was finalized.  PE was proposed as Category I in the 1985 tentative final monograph and determined to be generally recognized as safe and effective as an oral decongestant when the final rule (monograph) was adopted in 1994.

Missing from FDA’s POA, generally, or the Background, Regulatory History for Oral Phenylephrine, is any discussion of why PE is so widely used.  As those of us of a certain age remember, prior to 2005/2006, pseudoephedrine was the decongestant of choice for OTC multi-symptom cold medicine. Along with phenylephrine hydrochloride and phenylephrine bitartrate, pseudoephedrine hydrochloride and pseudoephedrine sulfate (collectively, pseudoephedrine) were and are the only GRASE oral nasal decongestants active ingredients.  21 C.F.R. § 341.20(a); OTC Monograph M012: § M012.20.  Then, Congress passed, and the President signed the Combat Methamphetamine Epidemic Act of 2005. As FDA explained, “The act bans over-the-counter sales of cold medicines that contain the ingredient pseudoephedrine, which is commonly used to make methamphetamine.”  Going forward, “The sale of cold medicine containing pseudoephedrine is limited to behind the counter.”  In its response to FAQs, FDA further explained that the law affected combination products and touted that “In response to the issue of misuse of pseudoephedrine-containing products, many companies are voluntarily re-formulating their products . . ..”  That historical context does not change the question of whether PE is effective, but comparisons of the efficacy of PE to pseudoephedrine, see pp. 8, 10, and 14, without noting  the concerns about the misuse of pseudoephedrine that led to the behind the counter requirement does not present the full regulatory history.

Nor does it allow for full consideration of the implications of removing PE from the monograph and leaving pseudoephedrine as the only oral decongestant active ingredient that can be used in an OTC drug marketed under the monograph.  As reflected by the numerous combinations of antihistamine, antitussive, bronchodilator, expectorant, nasal decongestant, and internal analgesic-antipyretic ingredients permitted under the monograph, consumers seeking relief from the symptoms of the common cold are often looking for an OTC drug that can address multiple symptoms.  Although after finalization of the proposed monograph in its current form, these various permissible combinations would remain intact (the proposed order does not propose changes to these sections), the reality is that with the only remaining decongestant ingredients required to be kept behind-the-counter, no products containing an oral decongestant will be available on the shelf available for consideration and purchase by consumers.  Whether those products will be reformulated to include pseudoephedrine and then held behind-the-counter is unknown but seems unlikely as well as unwelcome from the standpoint of pharmacy management. While that may not be a reason to keep PE available, it does bear consideration in decision-making.

Most of the permissible combinations that include an oral decongestant can also be permissibly marketed as a combination without the oral decongestant ingredient. There is at least one permissible combination of four ingredients, however, that is not covered by the monograph except with an oral decongestant. Section M012.40 (n) provides for a permissible combination consisting of an antitussive, an expectorant, an oral nasal decongestant, and an analgesic-antipyretic. There is no permissible combination listed that covers the same product if the oral decongestant is removed.  This may simply be an oversight, but it highlights the unusual potential consequences of this particular proposed change to the monograph.

The U.S. Food and Drug Administration (FDA) plays a pivotal role in fostering the development of treatments for rare diseases through its Orphan Products Grants Program.  Each year, FDA selects a limited number of clinical trials to fund to help sponsors pursue development of medical products for rare diseases and advance their field.  In October, FDA announced seven new clinical trial grants awarded in fiscal year (FY) 2024 – including one for a Phase 3 trial – totaling $17.2 million over the next four years.  FDA also funds natural history studies under the grants program.  The Agency announced the FY2024 funding for the three natural history study grant awardees provides $4.7 million over four years.

While the various expedited programs for serious conditions (Fast Track Designation, Breakthrough Therapy Designation, Accelerated Approval, and Priority Review Designation) are in many cases well understood by companies and academic sponsors developing therapies for rare diseases, the Orphan Products Grants Program represents a lesser known but highly impactful program that importantly can serve to support advancement of novel therapies for rare disease patient populations. This post will highlight the interesting and impactful features of the Orphan Products Grants Program, both financial and non-financial, that we believe could be highly relevant to many audiences within the rare disease ecosystem, including companies with ambitions to develop novel therapies for rare diseases and to investors in rare disease drug development seeking to better understand the Orphan Products Grants Program criteria and potential regulatory insight to be derived related to companies that are awarded these grants.

Background on the Grants Program

Launched as part of the Orphan Drug Act of 1983, this program aims to encourage research and development of drugs, biologics, medical devices, and medical foods for rare diseases, defined as conditions that affect fewer than 200,000 people in the U.S.  While treating rare diseases presents significant challenges due to small patient populations and limited financial incentives, the Orphan Products Grants Program provides crucial financial support to help bridge the gap between early research and successful treatment development. Remarkably, since inception, the FDA Orphan Products Grants Program has funded clinical trials that have facilitated the approval of more than 85 products. This program is administered by the FDA Office of Orphan Products Development (OOPD) within the Office of the Commissioner.

As previously mentioned, the Orphan Products Grants Program includes two key funding opportunities: the Clinical Trials Grants Program and the Natural History Studies Grants Program.  The Clinical Trials Grants Program provides funding for clinical trials that evaluate the safety and efficacy of potential treatments for rare diseases to help move promising treatments through clinical development.  The Natural History Studies Grants Program funds natural history studies that collect gather data on how rare diseases progress over time without treatment.  These studies are crucial because understanding the natural course of a disease helps in designing better clinical trials and defining meaningful endpoints for future drug development.  The rest of this blog will focus on the Clinical Trials Grants Program.

The FDA’s Orphan Products Clinical Trials Grants Program is open to academic institutions, industry sponsors, non-profit organizations, and public or private entities, both within and outside the U.S. who intend to evaluate a drug, biologic, medical device, or food for medical purposes that targets a rare disease in a clinical trial.  Specifically, the clinical trial must aim to obtain data on the safety and/or efficacy of a product for diagnosing or treating a rare disease and, importantly, both randomized controlled trials and other designs, such as single-arm or open-label studies, may qualify, regardless of whether the study is early-stage (Phase 1) or later-stage (Phase 2 and 3).

Applications for Orphan Products Clinical Trials Grants are subject to a rigorous review process and the FDA uses a peer-review system to evaluate grant applications, considering several criteria:

(1) rationale;

(2) study design;

(3) inclusion of patient input;

(4) investigator(s), infrastructure and financial resources; and

(5) ability to advance the current field.

Generally, consultation with the relevant FDA review division occurs during the review process to determine whether the proposed study will provide acceptable data that could contribute to product approval.  A score is assigned to each application based on the scientific/technical review criteria.

The FDA offers substantial financial support for qualified projects, depending on the stage of the trial: Phase 1 clinical trials can receive up to $250,000 per year and Phase 2 and 3 clinical trials can receive up to $500,000 per year.  The duration of funding is typically up to four years, with some trials eligible for extensions under certain circumstances.  For many sponsors in the rare disease space, applying to the Clinical Trials Grants Program could be incredibly helpful because it provides an opportunity not only for direct funding for a clinical trial (which are notoriously expensive endeavors), but the review process generally involves OOPD consulting with the relevant FDA review division.  We would not expect clinical trials to be funded if there was not a meaningful degree of alignment between the FDA review division on the trial design, particularly for later stage trials.  Receiving a Clinical Trials Grant provides insight that the FDA review team likely considered the proposed study as being capable of providing acceptable data that could contribute to product approval.

FY2024 Awardees & Observations

For the FY2024 Orphan Products Clinical Trials Grants Program, FDA received 51 grant applications and awarded only seven new clinical trials a grant, providing more than $17.2 million to clinical researchers over the next four years to advance the development of medical products for rare diseases.  The seven awardees included six early-stage trials (e.g., Phase 1, Phase 1/2, and Phase 2) across rare cancers (n=3) and hematology (n=1), endocrinology (n=1) and ocular (n=1) diseases, and one Phase 3 trial for a rare skin disease.  Interestingly, based on a review of the 709 Orphan Products Clinical Trials Grants awarded since 1983 that are listed in FDA’s public database, as of October 1, 2024, only 48 Phase 3 trials have been granted an award (eight of which were Phase 2/3 trials). These have included clinical trials for rare diseases across metabolic (n=5), oncology (n=5), cardiology (n=3), dermatology (n=3), pulmonary (n=3), hematology (n=2), hepatology (n=2), ocular (n=2), transplant (n=1), gastrointestinal (n=1), immunology (n=1), infectious (n=1), neurology (n=1), orthopedic (n=1), and toxicology (n=1) indications.

Of note, FDA states that this year’s grants include “additional funding to support innovative and efficient trial designs that can be used to advance treatments through product development and as models for future drug development in rare diseases.” We note that the only Phase 3 study funded in the FY2024 announcement is the first-ever late-stage clinical trial for the indication of microcystic lymphatic malformations, a serious, rare genetic skin disease with no FDA-approved therapies.  This study design is both innovative and efficient, leveraging a single-arm, baseline-controlled design.  Relative to other areas of medicine (e.g., metabolism, neurology, oncology), there has not been the same focus by medical product developers on drugs for rare diseases in dermatology.

The FDA’s Orphan Products Grants Program is a cornerstone of the effort to develop treatments for rare diseases.  By providing funding for both clinical trials and natural history studies, the program supports vital research that might otherwise face financial barriers.  With grants available for up to four years and a robust review process to ensure scientific rigor, the program helps drive innovation and bring much-needed treatments to patients affected by rare conditions.

We at Hyman, Phelps & McNamara congratulate the seven FY2024 Clinical Trials Grants Program Awardees, three Natural History Studies Grants Program Awardees, and those past awardees that continue to develop treatments for patients with rare diseases.

In most instances, it is clear if a product will be considered a “device” under the Federal Food, Drug, and Cosmetic Act (FD&C Act).  Sometimes, though, the question of classification defies an easy answer.  When a company is unsure if its product is a device, there are a number of resources that can provide the answer, such as the device regulations at 21 CFR parts 800 – 898; any of the databases that cover product classification; the list of products with 510(k) clearance, premarket approval, and de novo authorization; and/or device guidance documents.

Sometimes, though, there is no clear precedent, and the product’s regulatory status falls into an undiscovered country. One less utilized method (and for good reason) to gain more certitude is the 513(g) Request for Information.

Section 513(g) of the FD&C Act established a mechanism for receiving FDA’s feedback on the classification and regulatory requirements that may be applicable to a device. The provision states:

Within sixty days of the receipt of a written request of any person for information respecting the class in which a device has been classified or the requirements applicable to a device under this Act, the Secretary shall provide such person a written statement of the classification (if any) of such device and the requirements of this Act applicable to the device.

 Upon receipt of the 513(g), FDA will assess whether the product meets the definition of a device under section 201(h) of the FD&C Act. If it does, the letter will also identify the device class, whether a premarket notification or premarket approval is required to market the device, and other pertinent information.

Before FDA can begin its review of a 513(g) Request for Information submission, the applicant must pay the user fee. For fiscal year 2025, which began on October 1 and runs through September 30, 2025, the standard fee is $7,301. If the applicant has been certified as a small business by FDA, the fee is $3,650. (For comparison, a pre-submission is a written request for FDA feedback that is free. One can generally expect to hear back in about 70 days.)

While the FD&C Act gives FDA 60 days in which to review 513(g)s, FDA rarely meets that statutory deadline.  According to the latest MDUFA performance report, only 25% of 513(g)s in fiscal year 2023 met the 60-day statutory time frame.

Table 1 Requests for Information About Classification and Regulatory Requirements Applicable to a Device Type Under 513(g)

This poor performance is both disappointing and frustrating.  As an example, we filed a 513(g) request in December 2023. Three hundred forty-two (342) days later – and counting – we still have not received a response, even though FDA has, in response to our prodding, indicated numerous times that the review was almost finished.

The reality is that FDA simply does not prioritize 513(g) requests. They are not tracked in MDUFA performance reports, and FDA can lose the name of action without consequences. Moreover, unlike with IDE applications, where a missed deadline results in granting the IDE, nothing happens here if FDA misses the 60-day deadline here; the applicant must endure the whips and scorns of time.

Additionally, for unknown reasons, 513(g)s go through more layers of review than most other submissions. While 510(k)s are reviewed through the Office of Health Technology level, 513(g)s also include review from the Office of Regulatory Programs and sometimes even the Regulation, Policy, and Guidance staff. Each of these reviews involve discussions and research with subject matter and policy expertise. This extends the timeline before a sponsor can receive a formal determination from FDA. FDA is aware of the extended timeline and says it has been working through a backlog of submissions, most of which have been on the digital health front. Nevertheless, the drawn out process leaves applicants in a regulatory purgatory. Furthermore, in our experience, because 513(g) decisions tend to err on the conservative side, applicants are prone to suffering the slings and arrows of outrageous fortune.

If a company and/or their regulatory consultant(s)/counsel have evaluated the product and determined it is not a device, the company can decide to proceed to market the product without contacting FDA.  Alternatively, the company can present a justification for not being regulated and receive a free informal determination by sending an email to DeviceDetermination@fda.hhs.gov. Provided that a brief device description, clear intended use, and list or picture of all labeling claims are made, FDA aims to review the information and provide a response generally within 7 days. Of course, FDA reserves the right to recommend a formal submission if the inquiry is complex. And unlike a 513(g) determination, this conclusion is not legally binding.

As shown by the table above, a considerable number of companies do choose to submit 513(g) requests. The primary reason, in our experience, is that companies believe they need a binding, official FDA determination their product is not a device. Yet this method has many drawbacks: cost, time, and uncertainty of a favorable response. Considering these downsides, it is challenging to make the case for submitting a 513(g) when there are other means for determining whether a product is a device. Thus, unless and until FDA changes its approach to 513(g) submissions, the answer to the age-old question should be “Not to 513(g).”

The fight between Jazz, Avadel, and FDA over narcolepsy drug sodium oxybate has been a long and arduous one.  Starting in 2022 with a patent certification requirement, both Jazz and Avadel have sued FDA over this drug, with Jazz most recently bringing suit challenging FDA’s decision that Avadel’s Lumryz (sodium oxybate) is clinically superior to Jazz’s Xywav (sodium oxybate) in 2023.  After more than a year of briefing, the District Court for the District of Columbia finally made its decision, upholding that FDA’s decision that Lumryz and Xywav are not the same drug because Lumryz is clinically superior to Xywav.

As the Court explains, an orphan drug may not be the “same drug” as the same active moiety under the Orphan Drug Act and FDA’s longstanding implementing regulations if one is “clinically superior” than the other by way of greater efficacy, greater safety, or major contribution to patient care (“MC-to-PC”).  In this case, because Lumryz is dosed once-nightly while Xywav requires a second dose in the middle of the night, FDA determined that Lumryz was clinically superior based on an MC-to-PC, as it does not disrupt the sleep cycle.  For that reason, FDA determined that the Orphan Drug Act did not bar it from approving Lumryz during the orphan drug exclusivity period for Xywav, and FDA awarded Lumryz its own period of seven years of orphan drug exclusivity.  This case followed.

Jazz argued that FDA’s determination was a violation of the Administrative Procedure Act on several fronts.  First, Jazz challenged whether FDA has authority to approve Lumryz during Xywav’s unexpired exclusivity period.  Second, Jazz contended that FDA departed from a longstanding agency policy requiring a clinically superior drug to have a “comparable safety” profile to the previously approved drug to obtain approval; because Lumryz has far more sodium and presents a health risk to narcolepsy parties, all parties admitted that Lumryz “presents a greater health risk to all narcolepsy patients.”  Finally, Jazz argued that FDA’s clinical superiority determination was arbitrary and capricious because FDA failed to follow its internal dispute resolution procedures and the Agency’s findings were inconsistent with scientific literature.  Avadel intervened, and both FDA and Avadel refuted these assertions.  As the Court explained, the case effectively boiled down to whether 21 U.S.C. § 360cc(a) “authorize[s] FDA to conclude that two orphan drugs are not the ‘same’ based on the second drug’s ‘clinical superiority’ over the first, even though the two drugs share the same active moiety and are used for the same disease or condition?”  The Court held that it does.

The Court looked to the “statute’s  words, structure, and historical context” and found that they “establish that, when Congress amended the [Orphan Drug Act] in 2017, it ratified and incorporated the existing regulatory definition of ‘same drug’ into the statute.”  Congress was “plainly [ ] aware” of FDA’s definition of “same drug” when it revised the Orphan Drug Act in 2017, which is “evidence that Congress intended to ratify the regulatory definition of ‘same drug’ in § 360cc(a).”  This, explained the Court, is further supported by the history and purpose of the 2017 amendments, which were passed to supersede another case, Depomed v. HHS, and which rejected FDA’s regulations requiring a demonstration of “clinical superiority” to secure orphan drug exclusivity after approval of an orphan-designated drug.  Indeed, said the Court, “Congress’s clear purpose in enacting the 2017 amendments was to supersede Depomed and to codify the agency’s authority to make ‘clinical superiority/ determinations.”  And “it would be an odd result for Congress to have codified only the FDA’s discretion as to exclusivity periods, but not approvals.”  Thus, when FDA determined that Lumryz was not the “same drug” as Xywav because its single-dose formula was clinically superior to Xywav, the Court held that “FDA did not exceed its statutory authority under § 360cc by comparing the clinical benefits of the two drugs in deciding whether to approve Lumryz during Xywav’s unexpired exclusivity period.”

With the statutory question out of the way, the Court looked at Jazz’s three allegations that FDA acted arbitrarily and capriciously when it departed from the “comparable safety” requirement; when it failed to comply with internal dispute resolution policies; and when it acted inconsistently with prior FDA clinical superiority determinations and scientific literature.  The Court found them all unpersuasive.

First, the Court concluded that FDA never had a “comparable safety” policy—neither the Orphan Drug Act, agency regulations, nor precedent require such a showing.  In fact, the Court stated that “there is not a single example of the FDA rejecting a new orphan drug approval based on a major contribution because the drug’s sponsor failed to establish comparable safety to an approved drug.”  Absent such a policy, the court did not deviate from that policy without adequate explanation when approving Lumryz and therefore did not act arbitrarily and capriciously.

Next, while the Review Division initially declined to find that Lumryz was “clinically superior,” the Office of Orphan Product Development (“OOPD”) sought opinion from FDA’s Sleep Team experts (housed in the Center for Devices and Radiological Health) causing the Review Division to change its earlier position.  Though Jazz alleged that the Sleep Team consultation departed from OOPD’s standard operating procedures, the Court found this unsupported by the Administrative Record.  It found that the Review Division’s initial decision was “preliminary.”  Further, the Court explained that “it is always within the discretion of . . . an administrative agency to relax or modify its procedural rules adopted for the orderly transaction of business before it when in a given case the ends of justice require it” (quoting Am. Farm Lines v. Black Ball Freight Serv., 397 U.S. 532, 539 (1970) (cleaned up).

Finally, the Court declined to question FDA on the science, noting that “these are challenges to an ‘area of special expertise’ of the FDA” to which the court “owes the agency the ‘most deferential review.’”  Indeed, FDA found that the benefit of once-nightly dosing outweighs the risk of increased sodium intake because the second dose disrupts sleep and required labeling warnings about the high sodium content.  Accordingly, FDA “provided a rational explanation of the differences between ordinary brief arousals and a prolonged sleep disruption caused by a second dosing of medication.”  And, the Court said, Jazz’s critiques of FDA’s findings do not “rise[] to arbitrary and capricious agency decision-making.”

As of now, FDA’s approval of Lumryz stands, as does its authority to abrogate an orphan exclusivity period when a follow-on product is clinically superior.  But the fight between Jazz and Avadel (and FDA) may not be over.  We’ll have to wait to see if Jazz appeals this decision, so we’ll be watching.  And, as this is only one of a several orphan drug cases pending right now, the fight over orphan drug exclusivity wages on.

Though digital health is not new, it can still often be difficult to determine with precision the regulatory requirements applicable to a particular software product. Sometimes this is because FDA has not opined on a specific set of facts, but more often it is because FDA seems to take different approaches to the same technology offered by different companies. This can be for a variety of reasons, but often comes down to whether the company chooses to ask forgiveness rather than permission.

For example, many large tech companies market software products with heart rate and other vital signs monitors, and do not ask permission beforehand. Smaller companies, however, may have requests from board members and investors to provide confirmation from FDA that their approach to product regulation is correct and in alignment with FDA requirements. The question is how best to go about doing so. Some companies will submit 513(g) requests. Others submit pre-submissions. Both of these options require extensive preparation time and wait time to receive a response. For 513(g)s, FDA has no mandatory response time, so the submitter can, in some cases, wait six months or more for a response, plus there are user fees associated with 513(g)s. For pre-submissions, it is approximately two months before receiving a response from FDA. When a company has a relatively straightforward question, and a board in need of answers, these options may not be viable.

One other option that is used less often is a direct inquiry with FDA’s Digital Health office. If you submit inquiries to DigitalHealth@fda.hhs.gov, the digital health team can provide general feedback about digital health inquiries, such as “how does FDA think about artificial intelligence.” It can also provide feedback about a specific product, if the submitter includes information about the intended use, functionality, and desired marketing claims. The team tries to respond to inquiries within two weeks, and will hold a call with the submitter if requested. This can be an easier, faster option to facilitate important decision-making, particularly during the early stage of product development.

If you have questions about the status of your digital health product-or that of a competitor-please reach out so that we can help you get answers in a timely manner.