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.

As we reported back in January, Phibro Animal Health Corporation challenged FDA’s decision to remove a drug called carbadox—used as an antimicrobial drug to treat gastrointestinal disease in food-producing pigs—from the market.  More specifically, FDA rescinded approval of a “regulatory method” that Phibro used to establish that carbadox is safe and effective. Under that method, the company’s testing demonstrated that no residue of the drug can be found in an edible portion of the animal after slaughter or in any food derived from the living animal.  But because FDA must withdraw approval of a drug after it withdraws approval of the related regulatory method that warranted approval in the first place, FDA subsequently proposed to take away approval of carbadox entirely after it torpedoed the “regulatory method.”  As a sponsor of three NADAs for carbadox, Phibro repeatedly tried to fight this decision, but to no avail.  Ultimately, Phibro filed this lawsuit alleging that FDA’s withdrawal of the carbadox NADA approvals violated the Administrative Procedure Act (APA).

As background, the Center for Veterinary Medicine (CVM) had approved a regulatory method for carbadox in 1998 but changed its position in 2011. At that time, CVM informed Phibro that the company needed to submit data demonstrating that the product posed no health risk and, in 2016, issued a Notice of Opportunity for a Hearing proposing to withdraw approval for all carbadox NADAs.  Phibro requested a hearing, and though the then-CVM Director recommended granting the hearing, FDA never did.  Instead, CVM issued a notice withdrawing the 2016 Notice of Opportunity for Hearing in July 2020 and published a new proposed declaratory order, which, if finalized, would revoke the approved carbadox regulatory method.

Once the revocation of the carbadox regulatory method was finalized, CVM said it would publish a new Notice of Opportunity for Hearing proposing to withdraw all carbadox NADAs based on the lack of approved regulatory method. Phibro filed a comment to the proposed order presenting data supporting use of the 1998 regulatory method or alternative existing regulatory methods, as well as a Citizen Petition requesting that “FDA refrain from finalizing, and withdraw, the 2020 Proposed Order.”  In November 2023, FDA denied Phibro’s Citizen Petition and issued a final order revoking the 1998 carbadox regulatory method, explaining that while the FDCA “requires an opportunity for a hearing prior to withdrawing an animal drug approval,” a hearing on the regulatory method revocation itself was not required because it was only an “interlocutory revocation of an approved method.”

Simultaneously with the Revocation Order, CVM issued a Notice of Opportunity for a Hearing on its proposal to withdraw approval of the carbadox NADAs.  Phibro objected to the proposed withdrawal of the carbadox NADAs and requested a hearing before the FDA Commissioner.  CVM issued a response recommending that Phibro’s request for a hearing be denied and that the carbadox NADAs approvals be withdrawn but took no final action.  Phibro filed the instant lawsuit.

In this lawsuit, filed on  January 5, 2024, Phibro alleged that the carbadox orders violate the Administrative Procedure Act by depriving it of a hearing, by arbitrarily and capriciously departing from FDA practice, and by acting inconsistently with record evidence.  FDA moved to dismiss under the ripeness doctrine, arguing that the carbadox orders were not final.  The Court therefore looked to both constitutional ripeness and prudential ripeness, explaining that even if the case is constitutionally ripe, as all parties agreed, it may not be prudentially ripe, meaning that it may be premature for the Court to get involved at this time, as stated in the attached Memorandum Opinion and Order.  In assessing prudential ripeness, the court evaluated the “fitness of the issues for judicial decision” and the “hardship to the parties of withholding court consideration.”

First, the Court looked to the “fitness of the issue for judicial decision.”  Though the parties disagreed that the agency actions at issue were final, the Court held that that point was irrelevant, as “even a final agency action can be ‘unripe for judicial review’ if further proceedings affecting the agency action will take place or judicial consideration of the issue would benefit greatly from more certainty.”  Here, because CVM had not actually denied Phibro’s request for a hearing, the Court held that the issue was not yet fit for judicial decision.  Thus, “[u]nless and until FDA denies Phibro’s request for a hearing on some level, the Court agrees with FDA that Phibro’s claims are not yet fit for judicial review….”  With respect to the “hardship prong,” the Court found that Phibro has not shown that enforcement—and actual liability—is imminent, as CVM advised Phibro that it can continue to market carbadox until the NADA is withdrawn.  In other words, the actual hardship does not arise until FDA actually withdraws the NADAs.  Nor has Phibro provided concrete evidence of reputational harm.

In sum, the Court dismissed Phibro’s case because its claims do not meet the standard for ripeness under the prudential ripeness doctrine. Additionally, the District Court said the suit was in the wrong place, writing in a footnote that  “counseling against this Court exercising jurisdiction over Phibro’s claims is the fact that Congress gave exclusive jurisdiction over appeals ‘from an order . . . refusing or withdrawing approval of an application’ to the federal courts of appeals,”  citing 21 U.S.C. §§ 360b(h) and  355(h).   Thus, in the event FDA ultimately withdraws the carbadox NADAs, the Court noted that Phibro “would be required to challenge the withdrawal in a court of appeals—not a district court.”  Any ruling on Phibro’s claim now could result in a ruling over issues which the Court of  Appeals—not the District Court—has jurisdiction.

Back in July, the United States Supreme Court turned the world of administrative law on its head, adding new layers of judicial oversight to what might have previously been thought of as fairly non-descript Federal agency functions. One of those cases was Loper Bright v. Raimondo, which formally overruled the 40-year precedent under Chevron, under which courts gave agencies deference when interpreting statutory ambiguity.

The early scorecard indicates that rulings that consider Loper Bright may not prove to be a complete death knell to FDA’s statutory interpretations. For example, a recent decision in the D.C. District Court denied Novartis its attempt to block a generic version of its heart failure drug Entresto from the U.S. market. The opinion cited a central holding from Loper Bright, that “courts need not and under the APA may not defer to an agency interpretation of the law simply because a statute is ambiguous.” However, the court decided that FDA did not overstep its authority in approving the generic and refused to substitute its own opinion where the agency had reasonably applied its technical expertise.

As that case seems likely to hit the Circuit Court of Appeals’ docket, another example out of D.C. may very well add to the workload there. We have previously blogged about Jazz Pharmaceuticals’ challenge to FDA’s clinical superiority decision concerning sodium oxybate in the treatment of narcolepsy. The D.C. District Court recently rejected FDA’s argument that it is entitled to deference for its reasonable reading of the FDCA, touching on Loper Bright. However, the court still denied Jazz’s request for summary judgment, finding that the agency’s decision-making was reasoned and rational. More on this case coming to the Blog soon.

Other recent complaints filed against FDA are attempting to mix Loper Bright into their pleadings. In one, Eli Lilly has challenged FDA’s decision to classify its anti-obesity product Retatrutide as drug instead of a biological. It’s asking the Southern District of Indiana to weigh in on the definition of the word “protein” under the judicial authority Loper Bright grants. In another case in the Northern District of Texas, the Outsourcing Facilities Association (OFA) recently sued FDA regarding the agency’s sudden removal of obesity drug Tirzepatide from the federal drug shortage list without also providing required notice. The OFA cites Loper Bright as authority that the court should interpret the relevant parts of the FDCA without deference to the Agency. And we blogged last week about a suit against FDA over provisions of the 2020 CARES Act, where the Alliance for National Health USA invokes Loper Bright and asks the D.D.C. to deprive FDA of judicial deference for its pronouncement that homeopathic cures must obtain new drug approvals or exist in the uncertain realm of FDA’s exercise of enforcement discretion.

Of course, Loper Bright wasn’t the only blockbuster admin law case this year. SEC v. Jarksey held that if agencies want to levy civil monetary penalties, they can only do so after first winning a jury trial. Ohio v. EPA promises to apply downward pressure on agencies to closely scrutinize and more fully respond to comments made during the rule-making process. Corner Post v. Board of Governors of the Federal Reserve extended the statute of limitations for challenges to agency rules. The pace at which these different rulings will evolve and impact FDA will differ. We wrote recently that it took all of three months for the first challenge to FDA’s civil money penalty authority under Jarksey, in a case over the sale of an electronic cigarette without FDA authorization. Given the time that a case under Ohio v. EPA or Corner Post might take to ripen, effective litigation strategies under those rulings—either for or against FDA—might take longer to mature.

Somewhere in the middle on this timeline, though, is Loper Bright. Disputing FDA’s deference is fast becoming de riguere, and we’ll be back with more as these cases develop.

The neonatal period is a unique and complex period of rapid growth and development throughout the body, thus creating unique and complex challenges in medical product development for this population. These changes may affect the safety of a product used in this population in ways that are not reflected in studies of the same product in other populations. Additionally, short term studies have not always been sufficient to identify important adverse effects in this population, as there may be latent effects that are not immediately apparent.

To this end, FDA recently announced the publication of a guidance titled “Considerations for Long-Term Clinical Neurodevelopmental Safety Studies in Neonatal Product Development,” (the “Guidance”). This guidance finalizes a draft guidance issued in February 2023.

For the purposes of this Guidance, the definition of “neonates” is adopted from the relevant ICH guideline as meaning day of birth plus 27 days for term and post-term infants and, for preterm infants, as meaning day of birth through expected age of delivery plus 27 days.

The Guidance is formatted to address three questions at issue:

• Is there a need for a long-term neurodevelopmental safety evaluation for neonates enrolled in clinical studies?
• What factors should be considered when developing a long-term safety study plan?
• What to measure, when, and for how long?

Is there a need for a neurodevelopmental follow-up evaluation?

To determine whether a long-term neurodevelopmental safety study is necessary, the Guidance describes general considerations, patient and population-specific considerations, and product-specific considerations that should be considered.

General considerations for this assessment include the degree of central nervous system (“CNS”) exposure; the timing of exposure relative to a particularly vulnerable stage of organ and tissue development; and the duration of exposure, as products involving repeated dosing, prolonged exposure, or with persistent effects may be associated with higher risk for long-term consequences. However, even products with single doses may require long-term safety assessments based on other considerations.

Patient and population-specific considerations include an understanding of the background rates of specific long-term neurodevelopmental outcomes in the population of interest, and disease-specific characteristics that may increase the risk for adverse neurodevelopmental outcomes.

Product-specific considerations include results from nonclinical studies conducted specifically to evaluate potential adverse effects on the developing CNS of neonates and young infants. The Guidance notes that extrapolation of data across species is challenging; however, in accord with Agency pronouncements elsewhere on this topic, the Guidance describes FDA’s limited experience with alternative assays to characterize neurodevelopmental toxicity while expressing a theoretical openness to such methods when feasible. Additional product-specific considerations include clinical pharmacology considerations, such as whether the product is thought to penetrate the CNS; clinical experience with the product in other populations; the route of administration (such as the impact of pain from repeated injections on neurodevelopment); and the nature of product components, including the active pharmaceutical ingredient, excipients, and impurities.

What factors should be considered when developing a long-term safety study plan?

If the determination is made that a long-term neurodevelopmental safety evaluation should be conducted, FDA recommends a controlled study design when feasible.  Beyond that, the Guidance again describes general considerations, patient/population-specific considerations, and product-specific considerations.

General considerations include a standardization of evaluations to ensure reliability; a plan for community acceptance and inclusivity; engagement of key stakeholders to identify clinically meaningful outcomes and to assess the acceptability and feasibility of the study design; planning to keep families engaged and to maintain contact to encourage retention; and minimization of barriers to study enrollment and burdens of participation. The protocol should also include a plan for clinical referral and support services if any developmental problems are identified during the follow-up.

Patient/population-specific considerations include the timing and frequency of assessments.  Neurodevelopmental safety outcomes should be evaluated up to at least 2 years of age, adjusted for prematurity. The duration and frequency of follow-up assessments depends on the nature of the outcome(s) being evaluated and the ages at which they can be reasonably measured. Sponsors should also collect relevant covariate data when other factors may influence interpretability of results in the population of interest. In most cases, a general assessment of all key neurodevelopmental domains is recommended, but if specific domains of vulnerability are known or suspected, sponsors should identify validated, age-appropriate tools to measure relevant outcomes within those domains. Additionally, the Guidance states that sponsors should provide study plans for FDA review.

Product-specific considerations include whether the product has effects on organ systems that may impact neurodevelopment and whether the product’s target changes in distribution or function throughout maturation.

What to measure, when, and for how long?

Comprehensive neurodevelopmental outcomes should be evaluated at a minimum of 2 years of age, adjusted for prematurity, though earlier and/or later evaluations of certain outcomes may also be warranted. Some evaluations can be reliably performed during the first 2 years, but others, such as subtle cognitive, language, and behavioral outcomes, may require follow-up until later in childhood even if there are no neurodevelopmental concerns observed at the initial 2-year assessment.

These evaluations should be based on well-defined and reliable clinical outcome assessments (“COAs”) that assess clearly defined concepts of interest with appropriate justification to support their use in neonatal long-term safety evaluations. Key considerations include minimizing participant burden; accounting for potential confounding factors; carefully considering the type of score to use, as some COAs may generate multiple types of scores (e.g., raw scores, standardized norm-referenced scores), some of which might present floor or ceiling effects; and ensuring that selected COAs have demonstrated reliability across demographic groups.

When a comprehensive neurodevelopmental evaluation is needed, it should include an evaluation of physical, mental, and social health. The Guidance provides a listing of domains for such assessment as pertains to general concerns (e.g., quality of life, physical health) and neurodevelopmental concerns (e.g., sensory, motor, cognition, communication).

The Guidance notes that adjunctive assessments and biomarker measures may not provide as meaningful information as long-term functional outcomes assessments and thus may not substitute for such, but they still may be useful as supportive information. This is more likely to be the case when following a known signal of concern from nonclinical studies, studies in a different population, or known effects of medical products from a similar class.

What does it all mean?

The Guidance is written carefully to communicate that these determinations are all very case-specific. It also describes all the relevant considerations as being on a sliding scale where some level of potential risk will trigger the need for and inform the design of long-term studies. Although this lack of specificity could make long-term planning challenging, we expect and hope the Agency will take an active role in answering these questions early in development.

The Guidance does not describe the proposed timing or mechanism for these studies in the context of development programs. It states that the evaluations “could be useful to support a determination of safety” for use in neonates; however, a determination of safety to support an approval is made at the time of approval.

This Guidance explicitly excludes gene therapies (a change from the draft guidance), but instead makes reference to a separate guidance that has been in place since 2020 titled Considerations for Long-Term Clinical Neurodevelopmental Safety Studies in Neonatal Product Development. In this gene therapy guidance, FDA states that: “the recommended [long-term follow-up] . . . will often not elapse for all subjects who received an investigational [gene therapy] product in the pre-marketing program before the product is licensed. Considering that, the safety data generated during clinical trials may not capture all possible delayed adverse events.” As such, FDA’s recommendations for long-term follow-up for gene therapy products include a pharmacovigilance plan in addition to the long-term follow-up study. The long-term follow-up study could be a component of the pharmacovigilance plan. It is unclear if FDA intends to treat non-gene therapy products requiring long-term follow-up similarly, but it is a reasonable assumption in the absence of information to the contrary.

FDA’s authority to require studies to support a determination of safety would be either pre-approval, as a condition for approval, or as a post-marketing requirement. Under PREA, for qualifying non-orphan designated applications, sponsors and FDA must negotiate an agreed initial pediatric study plan (iPSP) during development to be included in the application describing the sponsor’s development plans (or waiver requests) for the drug in all pediatric age groups. If the agreed iPSP is not included in the application, FDA has the authority to refuse to file (RTF) it. These requirements have generally been directed toward safety and efficacy in the relatively short term, to our knowledge. However, it seems reasonable to assume that in addition to studies typically required under PREA, sponsors will need to commit to conducting these long-term neurodevelopmental safety studies in neonates as reflected in an agreed iPSP at risk of an RTF. This highlights the importance of discussing with pediatric study plans with FDA well in advance of submitting a marketing application.

Assuming FDA intends to treat other products requiring long-term follow-up similarly to gene therapies, the long-term follow-up will not need to elapse for all subjects prior to approval. As such, the long-term follow-up would involve post-approval follow-up, perhaps in the form of a post-marketing requirement, which could be a component of pharmacovigilance. A question left unanswered is the extent of required follow-up pre-approval as a condition for approval. The answer likely is, as with most things in this Guidance, case-specific. As such, sponsors developing drugs for the neonatal population should be prepared to discuss long-term follow-up plans with FDA as early as possible to have the best understanding of regulatory requirements for approval.

On October 21, 2024, the Alliance for Natural Health USA (“ANH”), and Meditrend Inc., a homeopathic drug company, filed a complaint on behalf of the homeopathic drug industry against FDA in the District Court for the District of Columbia (“D.D.C.”). This lawsuit presents an interesting reading of the statute at issue, one that is diametrically opposed to that of FDA.

The genesis of this lawsuit is a disagreement over regulatory language and, more significantly perhaps, statutory interpretation. Sometimes two people can look at the same thing but have entirely different understandings of it. Maybe you recall the viral blue dress/yellow dress internet sensation. Or maybe in high school English class you discussed whether The Turn of the Screw was a ghost story or a cautionary tale about mental illness. It’s a dessert topping; no, it’s a floor wax.

This lawsuit has FDA and the homeopathic health community looking at the same provisions of the 2020 CARES Act from vastly different perspectives. The plaintiffs are suing FDA over its December 2022 final guidance, “Homeopathic Drug Products,” which we discussed here. In the final guidance, FDA pronounces that homeopathic cures must obtain new drug approvals or exist in the uncertain realm of FDA’s exercise of enforcement discretion.

The recent suit has its origins in FDA’s re-evaluation of its homeopathic enforcement policies, which began at the Agency in 2015 in light of the growth of the industry. In 2017, FDA issued a draft guidance describing how it would apply its standard “risk-based” assessments to enforcement and regulatory actions in this space, which we also discussed in a previous post. FDA’s issuance of the draft guidance marked a shift in its decades-long policies that largely permitted the marketing of over-the-counter (“OTC”) homeopathic products. The next step in this shift of policy was FDA’s withdrawal in late 2019 of its 1998 Compliance Policy Guide (“CPG”) 400.400, discussed here. The withdrawal of this CPG immediately drew ire from the homeopathic industry, which believes the CPG was and is a far superior regulatory policy than enforcement discretion.

In 2020, the CARES Act reformed and modernized the OTC drug review process. Before enactment of the CARES Act, FDA issued regulations to add, remove, or make changes to OTC monographs based on whether they were generally recognized as safe and effective (“GRASE”). After enactment of the CARES Act, FDA began using administrative orders to accomplish the same task. However, the CARES Act specifically excluded homeopathic products from the OTC drug review. § 3853 CARES Act. From this exclusion the conflict arises.

Industry saw FDA’s issuance of the final guidance as an escalation of the Agency’s prior, arguably lenient approach to the continued marketing of unapproved homeopathic drugs. FDA has never assessed any homeopathic drugs under the OTC drug review, and thus has never made any GRASE determinations about any of them. This exclusion was in response to a request from the homeopathy industry when the OTC drug review was first adopted in 1972. Then, FDA stated that it “decided to exclude homeopathic drugs from this OTC drug review and to review them as a separate category at a later time after the present OTC drug review is complete.” 37 Fed. Reg. at 9466 (May 11, 1972). FDA had had little knowledge how long the OTC drug review would take to complete, as of course, that day remains in the future. But based on its current position, the Agency reads the CARES Act exclusion to mean that to be on the market, homeopathic drug makers continue to need to have either an approved drug application (NDA or ANDA) or operate at their own peril under FDA’s risk-based enforcement framework.

The homeopathic community has a completely different take on the CARES Act exclusion and does not see it as a continuation of the status quo vis-à-vis homeopathic drugs. It believes that Congress excluded their products with the intention of easing the path of homeopathic drugs to market, not to make that process harder—perhaps impossibly so—under the rigor and expense of an NDA. Thus, in their suit, the plaintiffs argue that by “concluding in the [2022] Final Guidance that all homeopathic drugs are subject to premarket drug approval requirements, the FDA has foreclosed practical channels to market OTC homeopathic drugs.”

Invoking Loper Bright, the plaintiffs ask the D.D.C. to deprive FDA of judicial deference and make the decision. The suit also asks for several forms of relief that judges were loath to provide in similar cases pre-Loper Bright. Here, plaintiffs are also asking for judicial declarations that drugs marketed under a unique homeopathic monograph are not new drugs, that OTC homeopathic drugs are excluded from pre-market approval requirements, and that the 2022 final guidance violates the Due Process Clause. Lastly, the plaintiffs want an injunction against FDA to prevent it from taking enforcement action against OTC homeopathic products.

The plaintiffs and FDA are both looking at the same language in the CARES Act and are seeing  diametrically opposite meanings. As this Jamesian controversy plays out in the Courts, we’ll provide updates in future posts.

A recent blog post focused on the potentially negative implications of the proposed Patent Eligibility Restoration Act (PERA) for manufacturers of generic drugs and biosimilar products.   The concerns raised by PERA are not limited to these industries, however.  Rather, developers of diagnostic tests      and, indeed of any product that relies on free access to gene sequence and other biomarker information, should pay also close attention, as PERA would overturn longstanding judicial precedent.

Under federal patent law, 35 USC § 101, an invention must fall within one of four categories to be considered eligible for a patent: process; machine; manufacture; or composition of matter. Courts have interpreted the statutory categories to exclude, inter alia, natural phenomena, including products of nature.  When it became possible to isolate the sequence of an individual gene from the genome, the Patent Office began issuing patents for them as compositions of matter.  By 2010, about 2000 isolated human genes had been patented in the U.S.  Critics of gene patenting argued, however, that it violated the statutory prohibition on patenting “products of nature,” restricted the conduct of basic research, and hindered innovation.

In 2010, the Association for Molecular Pathology (AMP), among other organizations, brought suit against Myriad Genetics, challenging the validity of the company’s patents on the BRCA 1/2 genes.  Mutations in these genes vastly increase the risk of breast and ovarian cancer in women who carry them, and the isolation of BRCA 1/2 allowed clinical laboratories to develop tests enabling the identification of women at heightened risk.  When laboratories other than Myriad began offering such testing and researchers attempted to study the genes, Myriad claimed infringement on their gene patents.  In a landmark 2013 decision, a unanimous Supreme Court held that a naturally occurring DNA segment, even when isolated, is a product of nature and therefore does not meet the subject matter eligibility requirement for patentability.  Although the controversy under review involved BRCA 1/2, the conclusion that isolated naturally occurring genes are not patent eligible subject matter was broad enough and has been understood to include isolated naturally occurring non-human (e.g., animal, viral, bacterial) DNA and RNA sequences.

Supporters of AMP v. Myriad have credited it—and the earlier unanimous Supreme Court decision Mayo v. Prometheus that narrowed the scope of patent claims for laboratory methods—for helping to precipitate an explosion in the availability of new genetic tests and laboratories and the concomitant decrease in the cost of such testing. As was noted by Dr. Bob Cook-Deegan et al. in a recent issue of the Journal of Law and the Biosciences, the impact of these Supreme Court decisions in molecular diagnostics “was especially pronounced, given the elimination of an entire category of claims on DNA molecules and related methods.”

Since Myriad and Mayo were decided, numerous other judicial decisions have addressed—with often inconsistent interpretations—the scope of subject matter eligibility under Section 101.  This has led to calls to amend Section 101, and in response, Senators Thom Tillis (R-NC) and Chris Coons (D-DE) introduced PERA, which would eliminate all judicially created exceptions to subject matter eligibility under Section 101 and instead establish five narrow categories of inventions ineligible for patent protection. Of relevance here, PERA would – and pardon the double negative – exclude as unpatentable “an unmodified human gene, as that gene exists in the body” (emphasis added). However, the bill also includes a condition that effectively nullifies this exclusion by stating that isolated genes “shall not be considered to be unmodified” (or, more plainly, will be considered to be modified).  This presumptively would mean that examination of genetic material by a research or clinical laboratory would involve a patentable modification under PERA, since such examination necessarily requires isolation of DNA from the sample. The Manager’s Amendment expected to be offered in an upcoming Senate Judiciary Committee markup is even more explicit; it includes a rule of construction listing the Myriad decision as one of the cases abrogated by the legislation.

While two former Directors of the Patent and Trademark Office testified in support of the legislation, Richard Blaylock, testifying on behalf of the biotechnology company Invitae (testimony here), disagreed, arguing that PERA “as introduced, will unintentionally stifle innovation and harm patient care in the fields of diagnostic genetic testing and precision medicine.”  Blaylock noted the importance of new knowledge gained from biomarker discovery to advances in personalized medicine and the harms that would result from the privatization of such information.  Invitae’s concerns are echoed by AMP as well as the College of American Pathologists (CAP), and nearly 100 other patient and provider organizations and industry.  (HPM is currently representing AMP in unrelated litigation.)

Proponents of PERA also invoked the COVID-19 pandemic, asserting (incorrectly in our view) that the shortage of COVID-19 tests at the height of the pandemic was the result of  the Supreme Court’s patentable subject matter decisions. They argued that the legislation was necessary to spur innovation of new vaccines and therapies in response to emerging health threats. Conversely, CAP President Emily Volk cited the importance of free, unfettered access to the full sequence of the SARS-Cov-2 genome early in the pandemic as critical to clinical laboratories’ ability to develop innovative COVID-19 tests:

Imagine if the genetic sequence for SARS-CoV-2 had been patented, and if laboratories were forced to pay fees to develop these critical tests . . . . Under the current patent framework — where natural phenomena, rules of nature and abstract concepts are judicially exempted from patent eligibility — pathologists and laboratories were able to directly develop and deploy tests to meet the capacity needs in communities across America.

Others have questioned whether a return to the pre-Myriad and Mayo status quo ante would in fact promote innovation in molecular diagnostics. Cook-Deegan et al. challenge the notion that there is an “innovation deficit for molecular diagnostics that would be addressed” by PERA and question whether “expanding patent-eligibility” would improve innovation in the field.  Whether it would do so is a topic that deserves careful thought.

To be sure, the issue of subject matter eligibility under Section 101 is complex, and we are cognizant that molecular diagnostics is only one aspect; we leave to others an assessment of how PERA’s proposed changes to Section 101 may affect innovation of other technologies. We are also aware that Section 101 is not the only statutory provision relating to patentability.  It is also hard to argue, in principle, with the desire for greater judicial certainty and predictability, although one can question whether the legislation will accomplish that goal, and whether that quest will cause unintended adverse consequences, e.g., the need for one laboratory to obtain multiple licenses from multiple companies just to run one novel multigene assay.   Returning to a time where merely isolating a naturally occurring DNA sequence was sufficient for patentability seems a problematic and unnecessary step backwards, in light of the ever-increasing importance of molecular diagnostics to clinical care.  Given the explosion in diagnostic tests and genetic research, it is difficult to see how patenting sequences would stimulate innovation.  We hope Congress will take seriously the concerns raised about PERA’s impact on continued innovation in this extremely important field.