Hyman, Phelps & McNamara PC, (HPM), which will mark its 45th Anniversary on March 17, 2025, is pleased to announce that it is increasing its directors, counsel, and associates as it starts the year.

• Kalie E. Richardson has been promoted to Director.
• Mark Tobolowsky has been promoted to Counsel; and
• Esther Petrikovsky is joining the firm as an Associate.

“While HPM prides itself on being the largest dedicated FDA law firm in the United States, it is small by design, so it is the quality of each of these individuals and what they contribute to the firm that is most exciting,” said HPM managing Director J.P. Ellison.

• Richardson, who focuses her practice on state and federal regulatory strategy and compliance, primarily for pharmaceutical manufacturers and wholesale distributors, has been with the firm 7 years and has proven herself invaluable to colleagues and clients alike. “Kalie is the quintessential HPM lawyer. She puts the firm and clients first and is solution-oriented,” said founder Paul M. Hyman.
• Tobolowsky, who has been with the firm 3 years, focuses on assisting clients with legal and regulatory considerations for the development of new drug and biologic products as well as with post-marketing compliance. Mark’s work often deals with therapies for rare and serious diseases that face unique challenges and, therefore, require unique solutions. “Mark’s promotion to Counsel reflects the value that he brings to the firm and his clients based on expansive and diverse experiences in the drug development arena,” commented HPM Director James Valentine.
• Petrikovsky, a 2022 Georgetown law grad, who was articles editor for the Food and Drug Law Journal in law school, joins HPM from a national law firm. She already has broad-based exposure to a variety of FDA regulated products.  “Esther is a natural fit at HPM given her background. We expect her to hit the ground running,” said Deb Livornese, HPM’s Director responsible for recruiting.

“HPM’s success over the past 45 years is solely a function of the quality of the people at the firm.  It’s gratifying to see such a talented group continuing that tradition,” noted founder Robert A. Dormer.

On January 7, 2025, FDA announced that back on November 12, 2024, the Center for Veterinary Medicine (“CVM”) issued Warning Letters to six online retailers marketing unapproved new animal drug products that purported to treat and control seizures and epilepsy in dogs and cats.  At minimum, this autumnal burst of Warning Letters from CVM is notable because CVM only issued a total of 22 Warning Letters in 2024—at least that have been made public by the Agency.

In each November 2024 Warning Letter, FDA explains that it reviewed the target company’s online promotion from October through November 2024—including Facebook, Amazon, and other third-party webpages—and determined that the six companies were marketing and selling unapproved new animal drug products in violation of the federal Food, Drug, and Cosmetic Act (“FDCA”).  Half of the products were available for purchase on Amazon, indicating that FDA is keeping an eye on Amazon sales.

The six target companies, including their FDA-cited violative products, are:

• Energetic Essences, LLC d/b/a Pet Essences (Seizures formula(s))
• Evolution Pets (SeizureGuard Plus and Life Span Arthritis & Mobility Advanced Enzyme Therapy)
• HD Frenchies, LLC/Bully Baum (HDBully Baum No Seize, Can-B-Gone – Cancer Oil Extract, and Brain & Neurological)
• Intermarket Industries Inc. d/b/a Doc Ackerman’s Pet Products (Doc Ackerman’s – Epilepsy & Seizure Formula)
• Nutrition Strength Ltd. EOOD (Dog Seizure and Epilepsy Supplement and Blood Support for Dogs)
• Vet Select Formula, Inc. (Vet Select Nuroplex Capsules, Vet Select Nuroplex – 2oz Homeopathic Spray, and Vet Select Nuroplex – Full Treatment Pack)

New animal drug products must be approved by FDA via a New Animal Drug Application (link), Abbreviated New Animal Drug Application (link), Conditional Approval (link), or have an index listing (link).  21 U.S.C. §§ 360b, 360ccc, 360ccc-1.  The marketing of a new animal drug product which has not been approved by FDA through one of these three regulatory pathways or included in an index listing renders the product adulterated.  21 U.S.C. § 351(a)(5) (“A drug … shall be deemed to be adulterated … if it is a new animal drug which is unsafe within the meaning of section 360b of” the FDCA.); see also id. § 360b(a) (requiring that, for a new animal drug to be legally marketed, it must have been approved by FDA via one of the aforementioned pathways).  The marketing of an unapproved and therefore unsafe, adulterated new animal drug is a violation of the FDCA.  Id. § 331(a) (listing as a prohibited act “[t]he introduction or delivery for introduction into interstate commerce of any … drug … that is adulterated or misbranded.”).

Here, the companies marketed their products as intended to treat idiopathic seizures or epilepsy in dogs and cats.  FDA found that each of the companies were marketing products that were unapproved new animal drug products because the products at issue were “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and/or “intended to affect the structure or any function of the body of … [an] animal.”  Id. § 321(g)(1), (v).  Notably, FDA has only conditionally approved two animal drugs to treat idiopathic epilepsy in dogs—KBroVet-CA1 and Fidoquel-CA1.  Because FDA established the products at issue were unapproved new animal drugs, the Agency found the products to be unsafe and adulterated and the companies to have committed a prohibited act per the FDCA.

It will be interesting to see whether CVM carries this flurry of activity into 2025, especially as it relates to online retailers, which have quickly become hubs for pet-related products.  We will continue to monitor and report on further developments.

A little over two years ago, the Modernization of Cosmetic Regulation Act (MoCRA) was (at long last) enacted.  The passing of the law which, among other things, amended the Federal Food, Drug, and Cosmetic Act to include requirements for facility registration and product listing, safety substantiation, adverse event reporting, and requirements for FDA to issue several new regulations, brought excitement and anxiety.  Excitement that after about a decade the FDC Act finally was amended giving cosmetics more legitimacy; anxiety because MoCRA seemed a substantial change for many involved in the business of cosmetics. There remains much uncertainty about the practical aspects of the new requirements.

As we previously reported, MoCRA includes various provisions requiring that FDA develop regulations within a specific time frame.  A brief review of FDA actions (or lack thereof) in 2024 shows that FDA failed to meet any of the statutory deadlines set by MoCRA.  FDA’s report card therefore shows a big Incomplete.

MoCRA includes several self-executing requirements, such as registration and product listing, adverse event reporting requirements and labeling for adverse event reporting.  However, MoCRA also requires action by FDA.  Notably, the law requires that FDA develop three major rules within specific time frames.  MoCRA mandates that FDA develop a regulation regarding the testing for asbestos in talc (statutory deadline for proposed rule  Dec. 29, 2023), a regulation for fragrance allergen labeling (statutory deadline for proposed rule June 29, 2024); and good manufacturing practice regulations (statutory deadline for proposed rule Dec. 2024).  FDA has failed to meet all deadlines for these three MoCRA rules.

Just on the cusp of 2024, on Dec. 27, 2024, almost a year after the statutory deadline, FDA published a proposed rule for asbestos testing of talc.

The proposed rule on asbestos testing describes the test methods that, if finalized, manufacturers of talc-containing cosmetic products must use to detect and identify asbestos in these products. FDA proposes to require that manufacturers test a representative sample of each batch or lot of a talc-containing cosmetic product or of each batch or lot of the talc ingredient to be incorporated in the cosmetic product for asbestos using both Polarized Light Microscopy (PLM) (with dispersion staining) and Transmission Electron Microscopy (TEM)/Energy Dispersive Spectroscopy (EDS)/Selected Area Electron Diffraction (SAED). Alternatively, manufacturers may rely on a certificate of analysis for each batch or lot from a qualified talc supplier prior to using the talc in a talc-containing cosmetic.  Not surprisingly, reliance on a supplier is acceptable only if the supplier used both PLM and TEM/EDS/SAED to test the talc.

FDA recognizes that the proposed testing method is different from what most of the industry has used thus far.  According to FDA, the requirement for the use of both PLM and TEM/EDS/SAED is consistent with established scientific opinions recognizing the limitations of PLM which may result in false negative test results.  FDA added the requirement to use TEM/EDS/SAED to ensure sensitivity and specificity.  According to FDA, “combining TEM, which enables detection of smaller fibers, with PLM, which enables testing of larger samples, gives the best chance of detecting asbestos.”

FDA proposes to require that manufacturers keep records of testing for asbestos that show test data, including raw data (including microscopy images, spectra, diffraction patterns and bench sheets), and describe, in detail, how samples were tested.  If the manufacturer chooses to rely on a certificate of analysis from the talc supplier, the records must include any certificate of analysis from the supplier for testing of the talc used to make the finished product, and documentation of how the manufacturer qualified the supplier.  Records written in English (or when requested an English translation) must be made available for inspection and copying to an authorized FDA representative within one business day, upon request.  FDA proposes to require that records must be retained for a period of 3 years after the date such records were created.

Presence of asbestos at any level in a cosmetic product, or in talc used in a cosmetic product, causes that cosmetic product or talc to be adulterated under the FDC Act. In addition, failure to operate in compliance with the testing or recordkeeping requirements would cause the talc containing cosmetic products to be adulterated under the FDC Act.

Comments to the proposed rule must be submitted by March 27, 2025

Target dates for the two other rules that FDA must issue pursuant to MoCRA, have been pushed to January 2025 for the proposed rule for fragrance allergen labeling and to October 2025 for the proposed rulemaking for good manufacturing practices.  If FDA meets those deadlines, 2025 will be a busy year for both FDA and industry.  Hopefully, FDA will also find time to develop guidance for industry answering the many questions that remain about MOCRA’s requirements for adverse event reporting and related labeling requirements, as well as MOCRA’s safety substantiation standard for cosmetics.

On January 6, 2025, FDA released two final guidance documents on food allergens: Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling Requirements of the Federal Food, Drug, and Cosmetic Act (Edition 5), and Evaluating the Public Health Importance of Food Allergens Other Than the Major Food Allergens Listed in the Federal Food, Drug, and Cosmetic Act.

Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling Requirements of the Federal Food, Drug, and Cosmetic Act

This final guidance replaces previous draft and final guidance documents on food allergen labeling that FDA issued in November 2022, which we discussed in a previous post.  Among other changes, the final fifth edition revises and updates questions and answers related to allergen labeling.  The most significant changes from the draft guidance are described below:

• Tree Nuts: FDA clarified that only 12 tree nuts are considered tree nuts for purposes of allergen labeling due to the “robust body of scientific evidence support[ing] their inclusion in the list.” These are listed in Table 1 of the final guidance:

1. 1. Almond
   2. Black walnut
   3. Brazil nut
   4. California walnut
   5. Cashew
   6. Filbert/Hazelnut
   7. Heartnut/Japanese walnut
   8. Macadamia nut/Bush nut
   9. Pecan
   10. Pine nut/Pinon nut
   11. Pistachio
   12. Walnut (English, Persian)

Missing from this list are several tree nuts that FDA had included in the “non-exhaustive” list in that draft guidance.  Notably, coconut is now omitted, meaning it is coco-not considered a tree nut for allergen labeling purposes. This is a significant turnaround from FDA’s historical position, prompting at least one FDA Law Blogger to wonder, “FDA, do think you just fell out a coconut tree? You exist in the context of all that came before you.”  The context here is that, for more than a decade, FDA has held that coconut is an allergen for labeling purposes.  In its previous final guidance document, Questions and Answers Regarding Food Allergens, Including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 4), FDA specifically listed coconuts on its list of tree nuts that are major food allergens.  Failure to list coconut as an allergen has also been mentioned in several warning letters (see, e.g., here) and as the reason for several product recalls, including a recent Class I recall in April 2024 (see also, e.g., Class II recalls in 2018 and 2022 for listing coconut as an ingredient but failing to disclose coconut in the allergen statement).

In addition, FDA walked back its previous position on certain parts of a plant that bears tree nuts.  In its draft guidance document, FDA stated that roots, leaves, stems, bark, or other parts of the same plant that bears tree nuts, but which are distinct from the tree nut portion of plant, are not considered major food allergens.  The final guidance adds more nuance, confirming that an ingredient derived from other parts of the same plant that bears tree nuts (or other sources of major food allergens for that matter) are subject to food allergen labeling requirements only if the ingredient is or contains proteins from a major food allergen.

• Milk and Eggs: FDA has broadened its interpretation of both “milk” and “eggs,” which it historically interpreted as from a domesticated cow and from a domesticated chicken, respectively. For purposes of food allergen labeling, FDA now considers “milk” to include milk from domesticated cows, goats, sheep, or other ruminant animals.  Similarly, FDA now considers “eggs” to include eggs from domesticated chickens, ducks, geese, qual, and other fowl.
• Allergen-Free Claims: FDA addressed “allergen-free” claims, confirming that firms may make voluntary statements on product labeling that certain allergens are absent from the product. Although there are no regulations on the specific conditions to make such a claim, the claim must be truthful and not misleading.  Importantly, although the final guidance makes clear that food allergen labeling requirements do not apply to allergens that may be present unintentionally due to cross-contact (e.g., from the use of shared equipment during the production process), FDA expects that a product with an allergen-free claim contains none of the major food allergen, including unintended allergens due to cross-contact.

Evaluating the Public Health Importance of Food Allergens Other Than the Major Food Allergens Listed in the Federal Food, Drug, and Cosmetic Act

Under Section 201(qq) of the Federal Food, Drug, and Cosmetic Act, “major food allergens” include milk, eggs, peanuts, wheat, soybeans, fish, shellfish, tree nuts, and effective Jan. 1, 2023, sesame.  This final guidance describes FDA’s approach to evaluating food allergens not included in this nine-item list (i.e., non-listed allergens) to inform decisions on potential regulatory requirements for such allergens.

The final guidance largely matches FDA’s draft guidance from 2022, which focuses on immunoglobulin E antibody (IgE)-mediated food allergies.  In the final guidance, however, FDA stated that it also intends to evaluate food allergens acting through other mechanisms that may raise public health concerns.  Consistent with the draft guidance, FDA will continue to evaluate the public health importance of food allergens on a case-by-case basis, taking into account the four following scientific factors:

1. Evidence of IgE-mediated food allergy;
2. Prevalence of an IgE-mediated food allergy in the U.S. population;
3. Severity of IgE0mediated food allergic reactions; and
4. Allergenic potency.

In addition, FDA explained that it generally intends to evaluate additional data and information, including, for example, the prevalence and amounts of the food allergen in food that is not disclosed on the labeling, food product characteristics and production practices, and patient-centered studies or other patient-centered information, when applicable.

Any interested party may submit a citizen petition requesting that FDA evaluate the public health importance of a non-listed food allergen, establish regulatory requirements based on the public health importance of such an allergen, and/or disclose how it generally intends to evaluate the public health importance of such an allergen.

On December 5, 2024, FDA published a new draft guidance on accelerated approval providing a much needed and substantial update to its guidance on the pathway.  FDA’s application and use of accelerated approval has evolved dramatically since it was first developed by the Agency to help address the HIV/AIDS epidemic in the late 1980s.  Since that time, it was formalized in FDA regulations (21 CFR § 314 Subpart H) in 1992, codified in the Food, Drug, & Cosmetic Act by FDAMA (21 USC § 356(c)) in 1997, revised by FDASIA in 2012, and described in guidance, most importantly, in the 2014 Expedited Programs for Serious Conditions – Drugs and Biologics (“2014 Guidance”).  However, it has been recent circumstances, such as, reforms enacted by FDORA in 2022 (as well as FDORA’s requirement to publish new guidance; see HPM’s previous coverage here) and our observations of the evolving ways in which FDA has been applying its accelerated approval authority across a wide-range of areas of drug development that has driven our desire to see FDA provide new guidance on the topic.

The new draft guidance, Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics, is intended to replace much of the 2014 Guidance’s discussion of the topic.  However, the 2014 Guidance cannot be ignored entirely.  FDA’s interpretation of several threshold criteria for eligibility (serious condition, available therapy, unmet medical need) will continue to rely upon the 2014 Guidance.  What will be replaced and is described in more detail in the new guidance is (1) FDA’s overarching view of the pathway’s applicability, (2) interpretation of what constitutes an accelerated approval endpoint, that is, a surrogate or intermediate clinical endpoint, (3) the evidentiary standard for demonstrating that such an endpoint is reasonably like to predict clinical benefit, (4) recommendations and policies regarding confirmatory trials, and (5) the procedures governing the withdrawal of accelerated approval.  Despite including guidance on confirmatory trials and FDA’s authority to require them, the Agency decided to publish an additional guidance focused solely on how it is interpreting the authority to require that such trials “be underway prior to accelerated approval or within a specified time period after the date of accelerated approval.” As such, we will publish a separate blog post focused on confirmatory trials and how FDA is interpreting this key provision of its accelerated approval authority.

Background on Accelerated Approval

The key concept, an ingenuity of FDA itself that has been around since the beginning of accelerated approval, is to allow earlier access to a promising therapy for a serious condition with an unmet medical need based on an endpoint that is reasonably likely to predict clinical benefit.  Accelerated approval endpoints can take one of two forms: (1) a surrogate endpoint that is reasonably likely to predict clinical benefit or (2) a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (i.e., an intermediate clinical endpoint) and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit.  Whether a surrogate or intermediate clinical endpoint (ICE), the endpoint to support accelerated approval is one that can be assessed more rapidly than the ultimate clinical benefit; this is what enables earlier patient access than would be possible while generating the evidence to support a traditional approval, which is typically infeasible.  Such clinical benefit is defined as “a positive therapeutic effect that is clinically meaningful in the context of a given disease,” is supported by a positive benefit-risk profile, and is, generally, a measure of how a patient feels, functions, or survives.

The FDCA requires that FDA also consider the “severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments” when determining whether a program meets criteria for accelerated approval.  It also gives FDA authority to require that the sponsor conduct one or more postapproval studies to verify and describe the predicted effect on clinical benefit, to require pre- and post-approval submission of all promotional materials, and, in certain circumstances, to withdraw approval using expedited procedures for products approved via accelerated approval.

The most recent statutory reforms gave FDA additional authority to set conditions for postapproval studies, such as enrollment targets, the study protocol, and milestones for study conduct and completion, in addition to creating a new obligation for sponsors to submit 180-day progress reports on meeting their postapproval study conditions.  These reforms also gave FDA authority to require that postapproval studies be underway at the time of approval, expanded FDA’s enforcement authority to include failure to comply with the postapproval study conditions and reporting requirements, and laid out the procedures for expedited withdrawal.  Lastly, the reforms enacted by FDORA required that FDA publish guidance on early consultation with FDA to identify novel surrogate or intermediate clinical endpoints, use of novel trials designs for postapproval studies, the expedited withdrawal procedures, and considerations related to the use of surrogate and intermediate clinical endpoints.  FDA’s December 5, 2024 draft guidance on accelerated approvals appears intended to cover each of these topics even if not by dividing them precisely along those lines.

FDA’s Overview of When Accelerated Approval is Appropriate

The new draft guidance explains, that there are two circumstances in which the accelerated approval authority would most clearly apply: (1) when the course of the disease is long or (2) the clinical event that is relevant for demonstrating benefit occurs infrequently.  While these examples could be interpreted to mean that the key consideration is the amount of time needed to accumulate enough evidence of benefit, FDA’s authority does not limit use of accelerated approval only to such circumstances. The new guidance states, for instance, that “accelerated approval may be considered where an effect on a surrogate endpoint could be shown in a smaller number of patients” than would be required to show an effect on a clinical outcome. To us, FDA’s application of accelerated approval in numerous other instances, such as benznidazole for Chagas disease, Oxbryta for sickle cell disease, Qalsody for SOD1 ALS or Kebilidi for AADC deficiency, demonstrate that, while accelerated approval determinations are highly circumstance specific, the authority can apply to a wide-range of development pathways and disease areas.

Moreover, it was also interesting to see how FDA discussed the concept of unmet medical need in the limited fashion that it did in this new guidance. As noted earlier in this post, the new guidance is intended to replace previous guidance in most respects except that FDA’s interpretation of what constitutes a serious condition, available therapy, and an unmet medical need will continue to rely upon the 2014 Guidance. However, while FDA reiterated its interpretation that the statutory requirement to take “into account . . . the availability or lack of alternative therapies” and the regulatory requirement that the drug provides “a meaningful therapeutic benefit over existing treatments” means that accelerated approval is only available to therapies that address an unmet medical need, it chose to highlight one telling example of how a sponsor might satisfy this criteria even when there are available therapies – when the new therapy has similar efficacy but a different mechanism of action compared to the available therapies.

This nod to innovation stands as something of a reminder to sponsors to not ignore disease areas simply because treatments exist and that expedited pathways are still available to those willing to pursue new therapeutic modalities and approaches.  This may also help to derisk parallel product development amongst multiple products for the same condition, where another product in development may gain traditional approval or another product already on the market under accelerated approval may confirm clinical benefit prior to completion of clinical trials to support accelerated approval (e.g., in Duchenne Muscular Dystrophy).  It will be important for FDA to communicate to sponsors its views on whether a product would address an unmet medical need on mechanistic grounds to help ensure greater certainty for investment in the development of therapies for these serious conditions.

On the other hand, sponsors must be aware of several limitations articulated by FDA that may prevent or limit the use of accelerated approval.  First, patients may be exposed to safety risks from a drug that subsequently fails to demonstrate clinical benefit.  Second, given the potential for reliance upon smaller or shorter clinical trials (than would be typical for traditional approval), there may be less information at the time of approval about rare or delayed adverse events.  Third, accelerated approval should not be considered if the completion of an adequate and well-controlled postapproval clinical trial to verify and describe the clinical benefit is infeasible.  Each of these risks and considerations will influence FDA’s decision-making with respect to accelerated approval.  Moreover, the infeasibility of conducting an adequate and well-controlled postapproval clinical trial becomes ever more important because FDA has authority to withdraw an accelerated approval using expedited procedures if the sponsor either fails to conduct the study with due diligence and according the conditions stipulated by FDA, or that study fails to verify the clinical benefit of the product.

FDA’s recommendation to sponsors for how to handle such risks will sound like something of a common refrain (and for good reason) at this point – communicate with the Agency early and often during development.  In particular, the guidance states that sponsors should discuss (1) potential eligibility, (2) proposed surrogate or intermediate clinical endpoints, (3) clinical trial designs, and (4) the planning and conduct of confirmatory trials.  Notably, FDA in this guidance was quite keen to convey their concern that sponsors not overlook the importance of the postapproval confirmatory studies, reemphasizing in a footnote following these recommendations that the “accelerated approval pathway will not be an option for every serious disease with an unmet medical need, particularly when evidence is insufficient to support use of a surrogate endpoint or intermediate clinical endpoint, or when an adequate and well-controlled confirmatory trial would be infeasible” (emphasis added).

Accelerated Approval Endpoints and Evidentiary Criteria to Support Accelerated Approval

As noted above, the endpoints for accelerated approval can fall into one of two categories – a surrogate endpoint or an intermediate clinical endpoint, either of which must be reasonably likely to predict clinical benefit to support an accelerated approval. Moreover, an application (NDA or BLA) based upon a surrogate or intermediate clinical endpoint seeking accelerated approval must still meet the substantial evidence of effectiveness standard and contain sufficient information to demonstrate that the drug is safe for use under the conditions of the proposed labeling. However, as the new guidance helps to explain the additional burden of accelerated approval is to provide “adequate evidence” that the endpoint is reasonably likely to predict clinical benefit and goes on to provide a number of factors for sponsors to consider.

For those somewhat familiar with accelerated approval and surrogate endpoints, you will find that the guidance reiterates a now well-established framework. Surrogates are generally biomarkers, such as laboratory, radiographic, imaging, physical, or other measures that are thought to predict benefit but are not inherently measures of clinical benefit. Surrogates fall into one of three categories in terms the strength of the evidence to support their predictive capacity:

1. validated surrogates (e., one that is known to predict clinical benefit and could support traditional approval);
2. reasonably likely surrogates (e., one that is reasonably likely to predict clinical benefit and could support accelerated approval); and
3. biomarkers that do not qualify as either (e., markers for which there is insufficient evidence to demonstrate is predictive capacity or simply lack predictive capacity based upon the available data).

In contrast, FDA articulated its most detailed guidance to date on the use of; intermediate clinical endpoints (ICE). Beyond reiterating the key criteria, a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) and is reasonably likely to predict an effect on IMM or other clinical benefit, the new guidance states that there is a “threshold” consideration before relying upon an ICE. FDA will consider “whether the demonstrated therapeutic effect on the [ICE] alone would be a basis for traditional approval” because accelerated approvals based on an ICE will be considered “only when it is critical to confirm the effects on IMM or other clinical benefit” (emphasis added). The new guidance provides two examples of when an ICE may be appropriate:

1. following demonstration of “a short-term benefit in a chronic disease [but] a longer duration of effect is necessary to demonstrate a clinically meaningful benefit,” and the short-term benefit is reasonably likely to predict “a longer duration of effect;” and
2. the ICE demonstrates clinical benefit on a “less serious or earlier symptom of serious disease, but the benefit observed is anticipated to predict a favorable disease outcome.”

Notably, the first example provides clarity about a long-standing point of confusion regarding accelerated approval using an ICE – that is, the same clinical measure (captured at two different timepoints) can serve as both the ICE (accelerated approval endpoint) and as the measure of ultimate clinical benefit (traditional approval endpoint). While examples of this approach are uncommon, it stands out to us that FDA included this example in its guidance. Of note, the 2004 accelerated approval of natalizumab (Tysabri) for relapsing-remitting multiple sclerosis was based on the Kurtzke Expanded Disability Status Scale (EDSS) score at one-year; two-year EDSS data were used to verify and describe the clinical benefit for conversion to traditional approval. Further, the recent approval of Kebilidi for AADC is likely to follow this approach, suggesting that FDA may be gaining some comfort with type of ICE-clinical benefit relationship.

Regardless of the type of endpoint, surrogate or ICE, the critical consideration for FDA and sponsors will be whether there is “adequate evidence” that the endpoint is reasonably likely to predict clinical benefit. The new guidance goes on to describe that such determinations will (of course) “be a matter of judgment that will depend on the biological plausibility of the relationship between the disease, the endpoint, and the desired effect, and the empirical evidence to support that relationship.” Such empirical evidence may come from a variety of sources, such as epidemiological, pathophysiological, therapeutic and pharmacologic, but it is not limited to such sources should new innovative methods or tools provide supportive empirical evidence.

The guidance goes on to warn that “pharmacologic activity alone” cannot provide adequate evidence and that clinical data “should be provided.” FDA’s use of “should” here is interesting because the guidance also stated that in the context of certain rare disease development programs (e.g., gene therapies) “where there is (sic) data supporting a relationship between the therapeutic target and the surrogate” clinical data may not be necessary. FDA could, for instance, decide that the “totality of the evidence” (which may include compelling nonclinical data) may be sufficient to determine that a surrogate endpoint is reasonably likely to predict clinical benefit.  This may represent an important difference in the application of accelerated approval between CDER and CBER, as many therapeutic approaches regulated by the drug center have similarly targeted mechanisms to traditional gene therapy but are not mentioned (e.g., antisense oligonucleotides, small interfering RNA).

Irrespective of disease area, FDA will consider “all relevant evidence and may consult external experts” or convene an advisory committee when deciding whether the available evidence supports the relationship between the accelerated approval endpoint and clinical benefit. FDA considers the strongest supportive evidence to be data from interventional studies showing that “the extent of change” in the surrogate correlates with “the extent of improvement” in the measure of clinical benefit. However, the guidance acknowledges that such data may be unavailable in certain settings, such as for rare diseases. For such cases, other sources of information, including nonclinical animal data, epidemiological data, and other clinical data will be considered “to determine if the convergence of evidence supports” the endpoint as reasonably likely to predict clinical benefit.

Finally, FDA provided several factors it considers important to consider:

1. How well understood is the relationship between the pathophysiology of the disease and the surrogate endpoint.
2. How reliable and consistent is the epidemiological evidence supporting the correlation between the surrogate and the clinical outcome.
3. Has the predictive relationship between the surrogate and clinical benefit been demonstrated in an interventional clinical trial previously, and whether the intervention was in the same or a closely related pharmacologic class.
4. Does the relationship between the surrogate and the clinical outcome require achieving a certain magnitude or duration of effect on the surrogate to predict a clinical benefit (or is otherwise necessary to support a favorable benefit-risk assessment).

A Few Concluding Thoughts

As we noted in a few places throughout this post, FDA’s new guidance frequently acknowledges that some flexibility or adjustments to the evidentiary bar may be necessary and warranted in the context of rare diseases. Repeatedly, the guidance stressed that accelerated approval determinations are case-by-case and circumstance-specific. Our experiences and observations of this space further underscore each of these points. However, we were pleased to see FDA acknowledge, explicitly in the context of rare diseases and implicitly in the context of common diseases, that deciding whether the evidence supports a determination that an endpoint is reasonably likely to predict clinical benefit can be based on a totality of evidence approach. In the context of common diseases, FDA may require more and stronger interventional data showing “the extent of change” on the accelerated approval endpoint correlates with “extent of change” in the measure of clinical benefit but nonetheless appears to acknowledge in this new guidance that other information can supplement such data in a meaningful way.

We were also excited to see FDA provide more explicit discussion of ICEs than had been included in previous guidance. That being said, the guidance does leave some ambiguity with respect to what extent FDA’s discussion of the evidentiary criteria applies solely to surrogates or can reasonably be extrapolated to ICEs as well. This portion of the guidance begins by discussing both surrogates and ICEs collectively or simply refers to “an endpoint that is reasonably likely to predict.” However, as the guidance turned to more specific factors and detailed discussion, the focus changed to surrogate endpoints. While we are disappointed by this potential ambiguity, it is our experience that much of FDA’s discussion of the evidentiary criteria can apply to both surrogates and ICEs, with the important caveat that each determination is circumstance-specific.

FDA’s new accelerated approval guidance is a must read. The discussion provides a wide-ranging and much needed update on FDA policies and interpretation of its accelerated approval authorities. Moreover, given its rich and exciting content, it is a topic we expect to return to time and again.

Want to Hear More about Accelerated Approval?

This blog post focused largely on the selection and justification of suitable endpoints for accelerated approval, as well as a discussion of the broader context where accelerated approval would be appropriate.  Undergirding the program is timely initiation and completion of confirmatory studies, which serves to limit the extent of patient exposure to drugs that may not ultimately demonstrate clinical benefit.  FDA intends to use its new statutory authorities under FDORA to set conditions for accelerated approval related to confirmatory studies, including that such studies may be required to be “underway” prior to approval.  Failure to meet these conditions may prevent approval or result in withdrawal of the accelerated approval.  Shortly after publishing the draft guidance that is the subject of this blog post, FDA published a second draft guidance that provides further context to considerations for determining whether a confirmatory trial is “underway” prior to approval, which we will cover in a subsequent blog post.

This is the first in a series of blog posts on tips for successfully handling an FDA inspection.  Using publicly available examples, these “lessons” will illustrate potential pitfalls and strategies for interacting with FDA during and after an inspection.  

Although FDA has long taken the position that it has broad authority in how it conducts its inspections, it was not until 2012 that Congress put some teeth behind FDA’s policy position.  As part of the Food and Drug Administration Safety and Innovation Act (known as FDASIA) and later under the FDA Reauthorization Act of 2017 (known as FDARA), a drug or medical device can be deemed adulterated if a regulated company “delays, denies, or limits an inspection, or refuses to permit an entry or inspection.”  FD&C Act § 501(j).  A foreign food manufacturer that “refuses to permit entry of [FDA inspectors} to inspect such factory, warehouse, or other establishment” can be subject to an import alert under section 807(b) of the FD&C Act.

But what exactly constitutes delaying, denying, limiting or refusing an FDA inspection?  FDA has published Guidance defining examples of circumstances applicable to a drug or medical device company, as well as separate Guidance applicable to foreign food manufacturers.   Much of the debate on this issue centers on whether FDA can take photographs during an inspection (see our previous blog post).  But a recent Warning Letter raises new questions for regulated companies on whether FDA can interview company employees, and if so, how companies should handle these requests during an inspection.

On December 17, 2024, FDA issued a letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection based on the following conduct:

• The Quality Manager “shoving and shouting at our investigators for conducting the inspection without [his] presence”
• Laboratory staff refusing to open a drug stability chamber “based on [the Quality Manager’s] hostile behavior”
• Upon FDA asking questions of the Quality Control Supervisor, the Quality Manager “interrupted and stated that only he can explain and answer the requests”
• While FDA was interviewing an employee regarding mold samples, the Quality Manager “began berating the employee, who then left the room”

Although delaying, denying, limiting or refusing the drug inspection was not the only violation cited in the Warning Letter – it also included several cGMP violations and potential cosmetic violations – the “limiting the inspection” violation was listed first, and thus considered by FDA to be the most significant violation.

Very rarely have we seen a Warning Letter call out the behavior of a single individual, and no less the Quality Manager, who is the public face of the company to FDA during inspections, for being uncooperative and hostile to FDA and the company’s own employees.  Here, the FDA investigators documented several instances in which the Quality Manager appeared directly responsible for preventing company employees from talking with FDA about their responsibilities or responding to direct questions from FDA about areas in which FDA has authority to inspect.  Note that the relevant Guidance document for drug manufacturers (like Brands International) is silent on the issue of employee interviews, but the Guidance applicable to foreign food manufacturers is explicit that FDA considers a company to have refused an inspection if it acted unreasonably in preventing the FDA investigator from talking to pertinent staff to collect evidence.

Examples of where we would generally consider preventing the FDA investigator from fully conducting an inspection include:

. . .

The owner, operator, or agent in charge refuses to allow the FDA investigator to collect evidence to document potential violations (e.g., to take photographs as necessary; to collect samples; talk to pertinent staff; or to collect food labels and labeling).

FDA Guidance, at 8 (emphasis added).  Now, guidances are generally not legally binding, unlike statutes or regulations.  But because this Guidance was specifically authorized by statute, it may carry more weight in a court.

To be clear, FDA cannot coerce employees to testify during an inspection – certainly every Law & Order fan is familiar with the Constitutional right to remain silent – and there is at least some doubt as to the Agency’s legal authority to interview any employee it wants during an inspection.   But it appears FDA will assert that it has a right to question employees, presumably under the statutory provisions cited above, and FDA has the leverage (even if not explicit legal authority) to pressure companies to make their employees available.

How should FDA-regulated companies handle interview requests during an FDA inspection?  As a practical matter, we recognize there are few FDA-regulated firms that are ready and willing to contest the Agency in court over this issue.  (If so, please call us.)  There are tactful ways to accommodate FDA’s request and set appropriate limitations to ensure FDA does not overstep its inspectional mandate.  First, companies should designate the personnel who are authorized to respond to FDA’s questions during an inspection.  Written procedures should clearly state parameters for discussions with FDA, including prohibiting FDA from conducting a private interview with an employee who is not properly designated.  If FDA asks for an interview of a non-designated employee, companies can still be cooperative with the request but insist that designated personnel are present during those interviews and that FDA limit its questions to those that are directly within the employee’s job description and responsibilities.  Wholesale refusal to allow an employee to respond to direct questions from FDA only raises more questions and distrust from the FDA investigator.  Even if not cited in a Warning Letter, the FDA investigators are instructed to document in their Establishment Inspection Report incidents of hostile or uncooperative interviewees (see Investigations Operations Manual, at section 5.3.13), which can be publicly released.   Companies should train (and remind) employees on inspection readiness.

So Lesson #1, companies can control the extent in which FDA talks with personnel, but should do so based on established procedures and a cooperative attitude.

Whether a patent can be listed in the Orange Book is a critical issue for both brand and generic manufacturers, and, of particular interest in the last few years is whether patents claiming just the device constituent of a combination product is eligible for listing.  While mums the word from FDA, the FTC has some strong opinions on the issue.  And both the First Circuit and the District Court for New Jersey have weighed in.  Now, the arbiter of all things patent, the Federal Circuit, has made the most definitive statement yet, holding that:

To list a patent in the Orange Book, that patent must, among other things, claim the drug for which the applicant submitted the application and for which the application was approved. And to claim that drug, the patent must claim at least the active ingredient. Thus, patents claiming just the device components of the product approved in an NDA do not meet the listing requirement of claiming the drug for which the applicant submitted the application.

The background of this case is pretty simple.  Teva is the sponsor of ProAir® HFA, indicated for the “treatment or prevention of bronchospasm with reversible obstructive airway disease in adults and children 12 years of age or older.”  Nine patents are listed in the Orange Book with ProAir HFA.   Amneal filed an ANDA seeking approval to market a generic and filed Paragraph IV certifications for those 9 patents; Teva sued Amneal for infringement of 6 of those patents—later amended to 5—and triggered a 30 month stay.  But because the patents at issue relate to the dose counter of the device constituent, Amneal filed antitrust counterclaims, counterclaims for declaratory judgment of noninfringement and invalidity, and counterclaims seeking an order requiring Teva to delist the five patents that it asserted against Amneal.  Amneal alleged that but for those device patents, only Paragraph I certifications would have been filed and no 30-month stay would have been imposed.   Teva moved to dismiss and Amneal moved for a judgment on the pleadings.  The District Court granted Amneal’s motion and ordered Teva to delist the 5 patents because the patents “are directed to components of a metered inhaler device, but do not claim or even mention albuterol sulfate or the ProAir® HFA.”  Teva appealed to the Federal Circuit, and the Federal Circuit stayed the District Court’s delisting order pending resolution of the case.

On appeal, Teva argued that a patent must be listed in the Orange Book if the claimed invention is found in its product.  Because ProAir HFA contains features claimed by the patent—the dose counter and canister—Teva argued that its patents were properly listed in the Orange Book.  Teva asserted that a patent “claims the drug” as long as the NDA drug product infringes that claim; in other words, “claims” means “infringes”.  Teva also argued that the Federal Food, Drug, and Cosmetic Act’s definition of “drug” includes the device component.  The Court rejected both these arguments “as allowing for the listing of far more patents than Congress has indicated.”

In short, the Court held that a patent does not claim the drug just because it reads on the approved drug product.  Instead, “a patent claims the drug when it particularly points out and distinctly claims the drug as the invention.”  Therefore “to qualify for listing, a patent must claim at least what made the product approvable as a drug in the first place—its active ingredient.”  The fact that a product could infringe a patent does not mean that the patent “claims” the drug.

The Court then moved to Teva’s second argument: that a patent is listable if it claims any part of the combination product.  The Court rejected this argument because, essentially, the device component is not part of the drug.  The Court explained, citing to Genus, that the fact that FDA approved the combination product as a drug does not make the device constituent a drug; that is, a combination product is not a drug, as the drug and device constituents retain their identities as drugs or devices.  “[I]ncluding a drug in a combination product does not transform each and every component of that combination product into a drug.”

In short, “to qualify for listing, a patent must claim at least the active ingredient in the application and the approved drug product.”  Nevertheless, it’s unclear whether this decision, despite its definitiveness, will have the effect of pressuring combination product sponsors to delist their device patents.

Ultimately, this case brings us to the question “what’s in a claim?”  In the context of listing patents in the Orange Book, the Federal Circuit has decided that the answer must be the active ingredient.  We’ll see what FDA and industry does with that.

As promised in the Fall Unified Regulatory Agenda, FDA issued the final rule to establish the pathway to obtain marketing approval of a nonprescription drug product with an additional condition for nonprescription use (ACNU) on December 26, 2024, before the end of the calendar year.  89 Fed. Reg. 105288 (Dec. 26, 2024).  We described the 2022 proposed rule and the ten-plus year history leading up to its issuance in our blog post here.

In response to the proposed rule, approximately 200 comments were submitted to the docket, and a meeting took place among FDA, the White House Office of Management and Budget (OMB) and the Consumer Healthcare Products Association (CHPA).  The changes made in the final rule were minimal and notably did not address two of the biggest subjects of substantive comments to the proposed rule.

Turning first to the four areas in which changes were made, the focus of two of those areas were the requirements for the required labeling statements for a product approved with an ACNU.  The third was the postmarketing requirement for reporting an “ACNU failure.” In discussing these revisions, FDA clarified that an ACNU failure must be reported even if the failure does not cause or lead to inappropriate medication use or consumer harm.  FDA also stated in response to comments that questioned FDA’s authority to require such reports in the absence of an adverse drug experience, that “ACNU failures generally would have a bearing on whether the Agency may consider withdrawal proceedings pursuant to section 505(e) of the FD&C Act.”

Finally, FDA revised language in the final regulation about the circumstances under which a drug product with an ACNU would be misbranded – though it is not clear that the language actually clarifies all that much.  The regulation now reads that a nonprescription drug product with an ACNU is misbranded if it is mislabeled or if the “ACNU is not implemented by the applicant in accordance with the following, as approved by FDA in the application: (i) The key elements [of the NDA or ANDA]; or (ii) The operationalization of the ACNU under [the NDA or ANDA].”  It is not obvious from this language what happens in the case of consumer error or consumer intentional misuse of the ACNU.  In either case, if the consumer wrongly enters their information, e.g., and as a result obtains a drug that had they entered the information correctly, they would not have received, does that make the drug misbranded and the drug manufacturer responsible for distributing a misbranded drug? Further elaboration of FDA’s view would be helpful.

We turn now to the two biggest issues that FDA declined to make changes to address: (1) whether allowing a prescription version and a nonprescription version of the same drug product with the only difference being the nonprescription drug’s having an ACNU violates FDA’s long-held policy against the simultaneous marketing of prescription and nonprescription drug products, and (2) the “fail first” approach to eligibility to submit an ACNU application.

FDA’s policy has prohibited the simultaneous prescription and OTC marketing of the same drug product under the same conditions of use unless there is a clinically meaningful difference between them.  Historically, this has meant a difference in dose, strength, indication, etc. The difference could be as subtle as how long the drug could be used for, e.g., up to 7 days versus chronic use.  FDA’s position expressed in the preamble is that if the only difference is the existence of the ACNU (i.e., all those other conditions are exactly the same), that is enough of a meaningful difference to allow simultaneous marketing.  This is one of the issues on which there were significant comments and was one of the topics of the meeting with OMB.

Interestingly, in the preamble, FDA also said that it would require a separate application rather than a supplement for an OTC switch involving an ACNU because if the ACNU switch of an RLD were approved, then all prescription generics referencing that RLD would be required to submit supplemental applications to switch their products from prescription to nonprescription with ACNU status, potentially removing all prescription products from the market and leavings only drugs that can be accessed via an ACNU on the market. In making this statement, FDA noted that this result would be counter to the purpose of the ACNU program of expanding access because there may be individuals who are not able to access the OTC drug because of their inability to navigate the requirements of the ACNU.  At the same time, if the RLD prescription drug and its generics have gone away, these individuals would not be able to obtain the medication by prescription from their healthcare provider.  This approach by FDA to trying to maintain a prescription option on the market seems to raise some significant issues that we may not have seen the last of.

Commenters, including CHPA, also raised concerns and provided comments on FDA’s “fail first” approach which requires that FDA determine that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, and that the applicant provide adequate data or other information to demonstrate this, before it will accept an application for an OTC drug with ACNU. Numerous comments asked for clarifications or standards which FDA declined to provide, instead advising applicants to meet with FDA to discuss their development plans and recommending a step-wise approach to development which may include an iterative process.  While this is certainly the process undertaken by all nonprescription drug label developers to create a drug facts label that can meet the criteria for being able to provide directions for safe and effective use, proving a negative and testing against no standard poses significant challenges for which there are no precedents.  FDA did not acknowledge this concern speaking instead of the need of “optimizing” the label without more direction on how to determine when optimization is achieved.

Now that the ACNU rule is final, we eagerly await that first approval or first Advisory Committee meeting where we can all learn how FDA will apply some of the vaguer parts of this long-awaited program.

The final rule becomes effective on January 27, 2025.

As we previously reported in 2022, FDA published a proposed rule defining  the nutrient content claim “healthy.”  The proposed revised rule constituted a radical change from the original definition of healthy, which focused on the presence of individual (beneficial) nutrients.  In contrast, the 2022 proposed redefinition focused on food groups recommended by nutrition science and the Dietary Guidelines (DGs), 2020-2025.  Nutrients come into play only where it concerns nutrients to limit (NTL), i.e., added sugars, saturated fat, and sodium.

FDA received more than 400 comments, resulting in a final rule published on December 27, 2024, covering more than 100 pages.

The final rule maintains the concept of the proposed rule.  However, FDA made several changes in the proposed food groups equivalents and NLT criteria; these changes are based on FDA’s review of the marketplace in response to comments.  FDA revised certain criteria providing more flexibility and resulting in additional foods qualifying for “healthy” consistent with nutrition science and the DGs, including:

• Criteria for foods with small reference amounts customarily consumed (RACCs) – Comments had noted that foods with small RACCS were not eligible for the healthy claim even though they were the type of foods recommended by the DGs. FDA revised the rule to provide that the ‘‘healthy’’ criteria apply to individual foods with a RACC of 50 g or less, or 3 Tbsp or less, on a per 50 g basis instead of on a per RACC basis. Consequently, several foods consumed in small amounts recommended for healthy dietary patterns now qualify for the healthy claim.
• Exemption for raw, whole fruits and vegetables – Another issue FDA reconsidered is the exemption for raw whole fruits and vegetables from the NTL criteria.  Under the proposed rule, any raw whole fruits and vegetables could be labeled healthy no matter the level of added sugars, sodium, or saturated fat.  The final rule does not limit this exemption to only raw fruits and vegetables.  Instead, the exemption from the NTL criteria now applies to an individual food, or a mixed product that is comprised of one or more of the foods recommended by the DGs (i.e., vegetables, fruits, whole grains, fat-free and low-fat dairy, lean meat, seafood, eggs, beans, peas, lentils, nuts, and seeds), that contains no added ingredients other than water.
• FGE criteria – FDA also reconsidered the criteria for various food group equivalent (FGE) criteria, e.g., the FGE for dairy was reduced from ¾ cup to 2/3 cup, and for combination foods, each food group must have no less than ¼ FGE (instead of the proposed ½ cup FGE) and the combined amount of two or more FGEs must be at least 1 total FGE, e.g., if the product contains 2 food groups and ¼ FGE of one food group, it must contain at least ¾ FGE of another food group. The increased flexibility for FGE requirements will result in more products being able to meet the FGE requirements for combination foods.
• Nutrients to limit (NTL) – FDA revised the values for NTL for certain food groups because the proposed (lower) limits would disqualify many products recommended by DGs from the healthy definition. Among other things, FDA
  • Increased the limit for sodium in mixed products from 10% DV to 15% DV per RACC;
  • Increased the limit for added sugars for the grain group from 5% DV to 10% DV (FDA did not increase the added sugars limit for dairy products as, based on market review, yogurts and other dairy products containing 5% DV or less added sugars were available and palatable);
  • Excluded the inherent saturated fat in seafood from the saturated fat limit for seafood products and lowered the saturated fat limit for seafood products to 5% DV to provide more flexibility for seafood, which has a fat profile that is predominantly beneficial unsaturated fats but has amounts of naturally occurring saturated fat that can vary across and within different types of seafood; and
  • Streamlined the NTL criteria so that there is one limit each for saturated fat, sodium, and added sugars for mixed products, main dishes, and meals.
• Plain water and plain carbonated water – FDA proposed that plain water and plain carbonated water qualify as healthy. The final rule expands this category to cover all water, tea, and coffee with less than 5 calories per RACC and per labeled serving, including any of these products containing non-caloric ingredients such as flavors, no- or low-calorie sweeteners, vitamins, and minerals.  This category does not include diet sodas, however.
• FDA did not create separate criteria for dietary supplements to qualify as healthy. As discussed in the preamble, several comments asked FDA to exempt dietary supplements from the healthy claim requirements.  FDA refused to do so, referencing the statement in the proposed rule that “good nutrition does not come from intake of individual nutrients (as dietary supplements often provide) but rather from foods with their mix of various nutrients working together in combination.”  The purpose of the healthy claim is to highlight foods that are useful in creating a healthy diet that includes foods from several different food groups.  As discussed in the preamble, FDA recognizes that, although most dietary supplements may not qualify as healthy, some may.
• Important in the context of private litigation in which the issue has come up, FDA acknowledges that the term “healthy” is a nutrient content claim only when the term is used in a nutritional context and not when it is used in a structure/function claim or health claim.

Recognizing that the final rule redefining the term “healthy” is a significant change from FDA’s previous approach (in effect for thirty years), FDA plans to issue guidance documents intended to help industry understand the rule and how to work with FGEs.  FDA also plans to host a stakeholder webinar on the final rule at a later date.  It already published several resources regarding the final rule (e.g., “Updated ‘Healthy’ Claim – Factsheet” and examples of “Products that Now Qualify for Healthy under the Final Rule”).

An important aspect of the new definition of healthy is that for many foods it will be difficult (or impossible?) to determine if the product indeed meets the definition of healthy, as it usually will not involve analysis of the foods.  Therefore, manufacturers must maintain records for foods bearing a “healthy” claim unless it is clear from the food’s mandatory labeling information. Records must be kept for at least two years after the food is introduced or delivered for introduction into interstate commerce.

FDA continues its work on the development of a symbol that manufacturers could use on food labeling to show that a product meets the definition of “healthy.” FDA believes that such a standardized graphic will further support FDA’s goal of helping consumers identify food products that can be the basis of healthy eating patterns consistent with the DGs.

The final rule is effective 60 days from December 27, 2024, i.e., February 25, 2025.  The compliance date is February 25, 2028.

Since the induced infringement finding in GSK v. Teva, the generic industry has feared the death of the skinny label (admittedly stoked by alarmist headlines like my own, see Ding Dong is the Skinny Label (Effectively) Dead?).  This is because, at a minimum, if a skinny-labeled generic is the basis for induced infringement liability, generic manufacturers will certainly think twice about using the skinny label process and still calling themselves AB-rated, which ultimately would lead to less reliance on the skinny label, leaving the statutory skinny label provision to do very little.  Enter Congress.

Senators John Hickenlooper, Tom Cotton, Peter Welch, and Susan Collins recently introduced the bipartisan Skinny Labels, Big Savings Act, which would amend federal patent infringement law so that generic drug manufacturers can:

1. Submit or seek approval of a skinny label for a generic or biosimilar pharmaceutical product;
2. Include labeling, promotional materials, or commercial marketing, consistent with the Federal Food, Drug, and Cosmetic Act regulations, for a drug with skinny labeling approved by the FDA;
3. Describe, consistent with the Federal Food, Drug, and Cosmetic Act, a drug approved via skinny label as a generic of or therapeutic equivalent to the branded drug. .

The sponsors describe it as a “safe harbor” in a one-page explainer on the bill available here.

More specifically, the bill states that these activities “shall not be acts of direct, induced, or contributory infringement of a method of use claim in a patent” listed in the Orange Book.  The safe harbor applies only when the labeling, promotion, or commercial marketing does not reference the condition(s) of use claimed in the patent.  And though induced infringement through skinny label has not yet been an issue with biosimilars and interchangeable biosimilars, the bill seeks to stop any more trouble before it starts.  It applies the same limitation on induced infringement to applications under 351(k) of the Public Health Service Act.  Importantly, the bill applies to conduct that occurs “before, on, of after” enactment of the Act.

This bill would go a long way to alleviating the concerns of the generic industry (AAM has applauded it), but it will clearly have objections from the brand side.  It has a long way to go through the machine that is Congress, but we’ll be watching to see if the skinny label will, in fact, be safe.

The Winter Solstice, signifying the shortest day of the year, was Saturday, December 21.  Although the earliest sunset of the year was actually in early December, this day also marked another premature sunset – the beginning of the end of the rare pediatric disease priority review voucher program.

As we blogged recently, the program has had scheduled sunset dates from its very beginning, which have been repeatedly extended.  The first sunset date is the authority to grant a priority review voucher to a rare pediatric disease product application for a drug that has not been designated as a drug for a rare pediatric disease.  Although such designations are not typically a prerequisite for a voucher, the law is drafted so that once this first sunset date has passed, only designated programs may receive priority review vouchers for rare pediatric diseases until the program sunsets completely.  As we mentioned in our blog post, this first sunset date was originally in September, but was given a brief reprieve until December 20, 2024, as part of a continuing resolution to keep the government funded until that date.

As December 20 approached, there was a need for another continuing resolution to keep the government funded.  Earlier in the week, it was reported that there was a bipartisan agreement on a bill that would have funded the government and extended the first sunset date for the rare pediatric disease priority review voucher program for nearly 5 years, until September 30, 2029.  However, the bill ran into political challenges, and as the minutes ticked away until a potential government shutdown, the bill that was ultimately passed was stripped of many of the provisions that were originally included, such as the extension to the rare pediatric disease priority review voucher program.

This means that, at the current moment, FDA cannot award any priority review vouchers for rare pediatric disease product applications unless it is for a drug that was designated as a drug for a rare pediatric disease not later than December 20, 2024, and such application is approved not later than September 30, 2026.

Although this is a truly regrettable outcome of what seemed like a promising beginning to the week in this regard, this does not mean that all hope is lost.  Congress has since passed several of the bills that were originally stripped out of the continuing resolution, such as the bill that would transfer the land under RFK Stadium in DC to the DC government for the purposes of building a new football stadium (or other potential enumerated purposes).

Therefore, there remains hope that Congress could still act to extend the program.  As we mentioned in our previous blog post, and as stated by many other stakeholders, this program has been crucially important for rare pediatric disease product development, and it does not cost a single government dollar (although we do not wish to minimize the additional resources a priority review application demands).  If the program were to sunset completely, as currently scheduled, the impact on the development of drugs for rare pediatric diseases would be difficult to overstate.  Although FDA cannot currently award rare pediatric disease priority review vouchers to any applications not currently designated as a drug for a rare pediatric disease, there is no provision that prevents FDA from continuing to grant such designations.  We would strongly urge companies to continue to request, and FDA to continue to grant, such designations in the hopes that Congress can accomplish what it seemed ready to do on a bipartisan basis just a few days ago.  In the meantime, we encourage all stakeholders to keep the pressure on to get this done as soon as possible.

FDA recently released 510(k) Third Party Review Program and Third Party Emergency Use Authorization (EUA) Review which finalizes the draft guidance of the same title issued in December 2023.  We previously discussed the Third Party Review Program in a blog post last year when FDA mentioned its expansion as part of its plan to address the resource gap for review of laboratory developed tests (LDTs) under the LDT final rule.  The final guidance appears not to make any meaningful changes that are actually likely to support or incentivize its increased utilization, which is disappointing, although not unsurprising.

The final guidance looks much like the prior draft and is intended to satisfy FDA’s obligation to issue final guidance on consultations with persons under section 565(i) of the FD&C Act and also to provide clarity on use of third party emergency use authorization (EUA) review. The guidance also addresses FDA’s obligation to provide considerations on third party compensation, information sharing, and conflicts of interest.

Discussion of the early interaction (EI) consult policy and details of a third party review memo, which were previously described on the website, are now included within the guidance.  The guidance also clarifies the criteria for re-recognition of third party 510(k) review organizations and the suspension or withdrawal of recognition and discusses how FDA will audit the Third Party 510(k) Review Program as part of ongoing audit plans under the Quality Management and Organizational Excellence (QMOE) Program which are all Medical Device User Fee Amendments (MDUFA) IV and V commitments.

The Third Party Review Program for EUAs looks different compared to the Third Party Review Program for 510(k)s.  Whereas applicants interact directly with third party 510(k) review organizations, for EUAs, FDA will generally contract with the third party review organization and will send submissions it receives to the third party for review.  FDA may, in certain emergency situations, determine that in vitro diagnostic device EUAs may be submitted directly to the third party EUA review organization.  EUAs may only be submitted following a relevant declaration under section 564 of the FD&C Act justifying emergency use authorization of a product and, because such emergencies are not known, FDA will identify and contract with third parties based on expertise and skills needed in anticipation of or at the time of an emergency declaration.

While FDA may utilize third parties to review EUAs to lessen the burden on internal FDA resources during a public health emergency, this might not offer much in the way of advantage or assistance to a new Sponsors or FDA as compared to other programs put in place during the recent COVID-19 public health emergency.  In April 2020, the National Institutes of Health (NIH) launched the Rapid Acceleration of Diagnostics (RADx) to speed innovation in the development, regulatory authorization, commercialization, and implementation of EUA COVID-19 testing.  Sponsors who applied to the program were put through a highly competitive, rapid three-phase selection process to identify the best candidates for at-home (over-the-counter) or point-of-care in vitro diagnostic COVID-19 tests. All proposals underwent an initial technical, clinical, commercial, and regulatory review before receiving funding and in-kind service support.  Sponsors were provided a RADx interdisciplinary consulting team, including a regulatory consultant who worked closely with the FDA to ensure Sponsors were meeting the Agency’s expectations.  This was especially advantageous to Sponsors who had not previously taken a product through the FDA market authorization process.  The purpose of the RADx project team was to help Sponsors quickly accelerate past development hurdles, provide them with close partnerships with other regulatory agencies (e.g., FDA), and to generate data in a format that would streamline FDA’s review. The program led to 18 over-the-counter COVID-19 EUAs, 2 multiplex COVID/Flu EUAs, and supported De Novo and 510(k) submissions for over-the-counter COVID-19 and multiplex COVID/Flu assays.  A similar support program, instead of or in combination with third party review, could be instrumental in assisting manufacturers of LDTs to validate tests and de-risk regulatory authorizations.

As we have previously discussed, the Third Party 510(k) Review Program is not widely used.  We noted in last year’s post that in Fiscal Years 2018 – 2022, fewer than 100 510(k)s went through the Third Party Review Program annually. Fiscal Year 2023 showed similar performance.  The Agency has reportedly been trying to improve the program, as we discussed in 2018 and 2020.  However, the new final guidance does not appear to do anything to enhance the program or change it in a way that would be likely to lead to increased use by industry.  This appears to be yet another failed attempt to remediate a program that has long underperformed its potential.  As the Agency looks towards reviews of LDTs, a program similar to RADx may provide a better approach to assist manufactures and FDA in meeting the challenges to allow for review and authorization of LDTs.

We recently published the first part of our review of FDA’s draft guidance titled “Frequently Asked Questions – Developing Potential Cellular and Gene Therapy Products.” Questions and Answers Guidance (see previous coverage here).  In this post we focus in on the draft guidance document’s chemistry, manufacturing, and controls (“CMC”)-specific content.  In eight pages we get a string of high-level regulatory questions that provide a nice roadmap for CMC product development, which largely align with opportunities to engage with CBER as you progress through the development of cellular and gene therapies (“CGT”).

As you review these questions and answers, nothing that CBER provides in this guidance is “new.”  In fact, nearly all of the CMC comments are directing us to existing guidance documents.  This does not mean that there is no value in this recent publication. What can be gained from this new guidance from a CMC perspective is more nuanced.  The guidance documents that CBER has issued in recent years in the CGT space have been important steps forward.  Each provides high-level considerations for a field that spans a mind-boggling number of indications and therapeutic modalities that CBER is responsible for reviewing.  This is best exemplified by CBER’s description of characterization tests in this guidance:

The appropriate characterization tests depend on the unique features of the product type. For example, characterization testing of a cell-based product may include extended assessment of cell surface phenotypic markers, such as those associated with immune-cell activation, differentiation, and exhaustion. For adeno-associated viral vectors, examples may include characterization of non vector DNA impurities in capsids by next-generation sequencing, vector genome size analysis, and detection of capsid amino acid modifications by mass spectrometry. For tissue-engineered medical products, examples may include biomechanical testing to assess the ability of a vascular graft to tolerate repeat access without leaking, permeability testing to assess the characteristics of a skin graft, or cellular distribution throughout a cell scaffold construct.”

This broad span of products can limit CBER’s ability to give meaningful details or examples in guidance, leaving the Center to make more general recommendations:

• “FDA recommends that sponsors evaluate a number of product characteristics during early clinical development to help identify and understand CQAs”
• “There is no fixed number of lots recommended for PPQ. In general, a greater understanding and knowledge of the product and manufacturing process can reduce the number of PPQ lots that should be sufficient to qualify the performance of the manufacturing process.”

If you make a tissue product you may produce one lot per patient where a gene therapy may only need a handful of lots through Phase 3.  It is harder to execute full testing programs on lots containing one unit.  As a result, how you approach your PPQ will be drastically different.

Key takeaway for CMC:  What makes a successful CMC section for an IND or BLA looks very different for every development program.  In this draft guidance, CBER is walking sponsors through the options available to them to ask program-specific questions as sponsors will only get one shot at some meeting types (INTERACT, Pre-IND, Pre-BLA). It is important that sponsors do not miss an opportunity to engage with CBER on CMC topics. This is even more so in rare disease CGT programs where clinical development can be more streamlined, so CMC product development is expected to happen at a more rapid rate.  This new guidance will help ensure that sponsors get the most out of their interactions with CBER by ensuring they do not have major blind spots.  From there, it is up to sponsors to take every opportunity to ask product-specific CMC questions to CBER.  As this and other CGT guidance documents illustrate, there is no one-size-fits-all approach to CMC.

Administrative Law Judge (“ALJ”) John Mulrooney conducted a prehearing conference hearing on Monday, December 2nd, to kick off the public hearing on the Department of Justice’s (“DOJ’s”) notice of proposed rulemaking (“NPRM”) to reschedule marijuana.  The NPRM seeks to reschedule marijuana from schedule I of the federal Controlled Substances Act (“CSA”) to schedule III.  The DEA Administrator issued a General Notice of Hearing fixing December 2nd as the commencement date for the hearing.

The purpose of the public hearing “is to receive factual evidence and expert opinion testimony” on whether marijuana should be rescheduled to schedule III.  Prehearing Ruling (Dec. 4, 2024), at 1.  Last week’s prehearing conference set the parameters for the hearing on the merits, scheduled to begin January 21, 2025.  Judge Mulrooney’s prehearing ruling establishes the schedule for the parties’ presentations and established hearing guidelines.  Parties will have ninety minutes to present the testimony of their witness.  Counsel may present a two minute opening statement about their witness and the proposed exhibits that will be sponsored through the witness.  The prehearing ruling encourages parties “to consider whether there is merit in consolidation with other participants that have similar (or complimentary) litigation objectives, witnesses, and/or areas of interest.  Id. at 2.  Consolidated parties are allowed to present testimony of up to two witnesses during the hearing, a presentation up to 120 minutes.  Id.

At the conclusion of a party’s presentation, counsel or the designated representative for the party may present either a ten minute closing argument or submit a brief of up to twenty-five pages within five business days of their witness’ presentation.  Id.  Witness cross-examination will be limited to matters covered on direct examination, but if a party submits an affidavit or letter into evidence from a witness who also testifies in person, cross-examination as to matters referenced in the document may be permitted even if the witness does not refer to them during their direct testimony.  Cross-examination will be limited to twenty minutes for each party on the opposing side.  Id. at 3.

The parties have noticed their intentions to offer into evidence documents they identified in their prehearing statements and must serve each other with a copy of the documents noticed in their prehearing statements no later than January 3, 2025.  Parties are required to lay a foundation “for recognition as an expert” and for every proposed exhibit as a condition precedent for inclusion in the record.  Id.  A limited number of affidavits may be received into the record subject to the evidentiary weight adjustment specified in the regulations.  Id. at 3-4.

The court consulted the parties as to availability of their representatives and witnesses.  A party scheduled to present a witness must be physically present in the courtroom even if the witness appears via video teleconference.  A representative seeking to cross-examine an opposing witness must also be physically present.  Id. at 5.  The hearing on the merits commences January 21st with proceedings each Tuesday-Thursday, except for the week of February 10th, through March 6th.

We learned earlier this week that an allision (a runner-up to Merriam-Webster’s 2024 Word of the Year, polarization) may be poised to occur—perhaps within a fortnight (another runner-up to Merriam-Webster’s 2024 Word of the Year thanks to Taylor Swift)—as Congress considers various pieces of healthcare legislation as part of its year-end package.  As part of that package, we understand that discussions on the latest iteration of the “Bringing Low-cost Options and Competition while Keeping Incentives for New Generics Act” (“BLOCKING Act”) (also known as the “Expanding Access to Low-Cost Generics Act”) have resurfaced and could potentially hit the generic industry.  (Unless the legislative ship can be steered away.)

We’ve railed against passage of the BLOCKING Act since February 2018 when it was made as a legislative proposal in the first Trump Administration’s Proposed Fiscal Year 2019 Budget (pages 22 and 51)—including in blog posts (here, here, here, here, and here) and in Congressional testimony—as antithetical to a primary goal of the Hatch-Waxman Amendments: getting high quality, low-cost generic drugs into the hands of consumers—fast.  After all, the BLOCKING Act would significantly alter the ANDA Paragraph IV 180-day exclusivity incentive.  Specifically, it would further dilute the 180-day exclusivity incentive by amending the Paragraph IV 180-day exclusivity statutory provisions at FDC Act § 505(j)(5) to place new conditions on when a subsequent Paragraph IV ANDA can be approved notwithstanding a first applicant’s eligibility for 180-day exclusivity.

In our May 2023 B-B-B-B-Bad to the Bone post, we highlighted some changes to the original version of the BLOCKING Act, restyled as the Expanding Access to Low-Cost Generics Act of 2023, intended to guard against a subsequent Paragraph IV ANDA gutting the 180-day exclusivity incentive and that would somewhat blunt the negative effective of the legislation.  But we’ve made no bones about our take on BLOCKING and its progeny: “That being said, it’s kind of like putting lipstick on a pig.  In the end, the “Expanding Access to Low-Cost Generics Act of 2023” (S. 1114) is still the BLOCKING Act, and it is still bad to the bone.”

Based on what we’ve heard from the talk on Capitol Hill, the latest version of the BLOCKING Act that is poised for introduction in Congress within the next few days is the same language proposed for inclusion in the never-passed “Food and Drug Administration Safety and Landmark Advancements Act of 2022.”  That’s the version we dissected here, and that is available here.

Given that we’ve already covered the version of the BLOCKING Act apparently on tap for congressional consideration, we won’t do so again here.  But we thought a clarion call would be appropriate now.  After all, as we’ve said before—and it bears repeating over and over again—what generic drug companies would be willing to invest millions of dollars in generic drug development and patent challenges for the potential of a hollow exclusivity incentive?  More ANDA approvals does not necessarily translate into more launches.  Over time, a new exclusivity regime for Paragraph IV ANDAs may mean fewer ANDA approvals and launches.  And that ultimately means more drug shortages of critical medicines, fewer choices for consumers, and higher costs to the U.S. healthcare system.