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 This guidance finalizes a draft guidance issued in February 2023.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.

Eric Idle, as a body collector, immortalized the phrase, “Bring out your dead!  Bring out your dead!” in the 1975 comedy classic, Monty Python and the Holy Grail.  The Drug Enforcement Administration (“DEA”) would do well to update that phrase as “Bring out your meds!  Bring out your meds!” to call attention to the 26th National Prescription Take Back Day.

Unwanted and expired controlled prescription medication languishing in medicine cabinets are susceptible to theft, misuse and abuse.  DEA and its law enforcement partners will once again host local drop-off locations nationwide for safe disposal of unneeded medication on Saturday, October 26, 2024, from 10:00 a.m. to 2:00 p.m. local time.

DEA holds the popular take back event each spring and autumn.  Last April’s Take Back Day collected over 670,000 pounds of unneeded medication at 4,900 collection sites nationwide.  DEA has collected over 18.5 million pounds of medication since 2010.  More information about National Prescription Drug Take Back Day, including disposal locations, can be found here.  DEA’s Diversion website also lists permanent year-round disposal locations and other information about drug disposal.

So, in imagined updated Monty Pythonian phrase: “Bring out your meds!  Bring out your meds!”

Further talks of the Skinny Label’s demise may be premature, as demonstrated by a new decision from the District Court for the District of Columbia upholding FDA’s interpretation of the “same labeling” provisions of the Hatch-Waxman Amendments.  That is not to say that concerns about the induced infringement theory at issue in GSK v. Teva and Amarin v. Hikma are no longer relevant—they very much are—but the newest theory posed in Novartis v. FDA, arguing that labeling modifications are impermissible, has been squarely rejected.  There, as we explained back in July, Novartis argued that FDA’s approval of a generic ENTRESTO with indication information modified rather than simply omitted “represents a sharp departure from FDA’s statutory and regulatory mandate to require that a generic drug be the ‘same’ as its reference listed drug.” Novartis additionally alleged that FDA unlawfully permitted the carve-out of critical safety information of a modified dosing regimen and unlawfully approved an active ingredient that was not the “same” as the Reference Listed Drug (“RLD”).  In a redacted opinion published October 15, 2024, the DDC granted FDA and intervenor MSN’s Motion for Summary Judgment, rejecting all of Novartis’s allegations and holding that FDA’s approval of MSN’s product did not violate the Administrative Procedure Act or the FDC Act.

In brief, ENTRESTO was once approved “to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction” but its labeling was subsequently amended to reflect that the product is approved to treat all patients with chronic heart failure, and to add a new dosing regimen for specific patients. While denying a Citizen Petition from Novartis asking FDA to refuse to approve any ANDA that omits the new dosing regimen or changes the indication, FDA approved MSN’s ANDA on July 24, 2024.  FDA, in its Citizen Petition Denial, stated that it retains the authority to approve generic labeling that modifies an approved indication and that it could lawfully approve generic labeling that omits the modified dosing regimen in ENTRESTO’s labeling.  To that end, FDA approved the MSN ANDA without the modified dosing regimen and with the indication “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. Left ventricular ejection fraction (LVEF) is a variable measure, so use clinical judgment in deciding whom to treat.”  The labels differed as such: (here)

Novartis sued FDA arguing that the FDC Act requires generic labeling to match the current labeling for the reference listed drug—not the discontinued labeling—and that the new MSN labeling violates the statutory requirement that the indications for a generic be “the same” as its RLD.  Novartis noted that FDA’s regulations permit only the “omission of an indication”—not the modification of the product’s currently approved indication—and asserted that FDA failed to explain “how a full cloth rewriting of the reference drug’s labeling is consistent with the rest of the ENTRESTO labeling” and that the modified labeling, especially considering the omission of the modified dosing regimen, “renders [the MSN product] both less safe and less effective.”  Novartis also argued that FDA’s approval of the active ingredients in the MSN product violate active ingredient sameness requirements, as ENTRESTO is a contiguous valsartan-sacubitril-sodium complex while the generic is a physical mixture of individual sodium salts.

Noting the change in review standard from Chevron deference to Loper Bright, the DDC nonetheless found that “MSN’s generic drug is consistent with FDA regulatory and statutory requirements that require a generic drug to have the same label and active ingredients as the reference drug.” Citing to “[b]inding Circuit law” in Bristol-Myers Squibb v. Shalala, the Court explained that the law “permits changes to generic’s label to account for patient-protected indications.”  The Court noted that the D.C. Circuit interpreted the relevant statutory provisions itself—it did not defer to FDA’s interpretation­—and thus Bristol-Myers remains good law even in light of Loper Bright.  Additionally, the Court found no support in the record for Novartis’s claim that FDA reverted back to original labeling rather than comparing the MSN labeling to the most recently approved ENTRESTO labeling.  The Court further “agree[d] with FDA that an ‘omission’ under the regulation must turn on the ‘substance of the information that is omitted—not whether that substantive omission is accomplished by adding words or deleting them.’”  Thus, Novartis’s position, “that a generic drug label may only omit patented uses by deleting words rather than adding them—puts form over substance.”  Adding words, said the Court, is consistent with FDA precedent.

The Court also found that FDA did not act arbitrarily by excluding the patent-protected dosing regimen from MSN’s labeling. The Court deferred to FDA’s determinations about the categorization of chronic heart failure patients and about the carve-out of the dosing regimen, as both issues are in FDA’s “area of technical expertise.”  Novartis failed to demonstrate that the modified labeling affects the drug’s safety and efficacy and FDA thoroughly explained its rationale in its Citizen Petition response.  Finally, the Court reviewed FDA’s scientific determinations about active ingredient sameness for reasonableness and consistency with the evidence in the record and deferred to FDA’s determination that the two products contain the same active ingredients.  The Court stated that “FDA’s determination on chemical identity sameness reflects its reasoned ‘scientific analysis,’ which deserves ‘a high level of deference,’” as it is “pure scientific judgment.”  FDA’s determination that the products contain the same active ingredients was “rational, carefully explained, and consistent with the record evidence;” thus, the Court will not “unduly second-guess” FDA’s judgment.

By leaving intact Bristol-Myers Squibb, notwithstanding the argument that Loper Bright nullifies it, the Court preserved an important avenue for generic drug manufacturers.  The skinny label—whether utilizing omission or labeling modification—can continue to exist, allowing generic manufacturers to come to market earlier for non-protected uses of RLDs.  We note, however, that this is unlikely to be the last affront to the skinny-label, which clearly remains a target for RLD sponsors.

On September 27, 2024, in U.S. v. California Stem Cell Treatment Center, Inc., a Ninth Circuit panel unanimously held that a stem cell clinic’s Stromal Vascular Fraction (SVF) procedure constitutes a “drug” under the Food, Drug and Cosmetic Act (FDCA) and does not meet the “same surgical procedure” (SSP) exception to FDA’s regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) contained in 21 C.F.R. Part 1271. The District Court in this case, which came to the opposite conclusion and is now reversed, was a notable outlier in a string of cases in other circuits upholding FDA’s authority to regulate stem cell clinics on similar grounds as the Ninth Circuit did here. See U.S. v. Regenerative Sciences, LLC, 741 F.3d 1314 (D.C. Cir. 2014); U.S. v. U.S. Stem Cell Clinic, LLC, 998 F.3d 1302 (11th Cir. 2021). The case was remanded to the District Court for further proceedings, which could include consideration of whether Defendants’ SVF procedure is eligible for lighter-touch regulation under section 361 of the Public Health Service Act (PHSA) or, instead, Defendants must obtain approval of a Biological License Application (BLA) for the SVF prior to its marketing and use. Defendants may also seek en banc review of the decision from the full Ninth Circuit.

Facts

Defendants in this case are two licensed physicians and the stem cell clinics they founded. At the clinics, Defendants offer treatments that consist of extracting fat tissue from patients and, through a multi-step process, turning that tissue into a liquefied mixture of stem cells, other cells and cell debris known as Stromal Vascular Fraction (SVF). The resulting SVF is then administered to the same patient by injection, intravenous drip, or inhalation. There are two varieties of the procedure: one where the fat tissue extraction and reimplantation of SVF is completed on the same day and another where the tissue is sent to a cell bank for processing and cell expansion for later use by the patient.  (Note we do not discuss the cell expansion variety of this treatment further in this blog as the court quickly dispensed of it as obviously not subject to the SSP exception.)  These procedures are offered to treat a variety of conditions, including Alzheimer’s, arthritis, asthma, cancer, etc., no doubt with varying degrees of scientific support for their safety and efficacy in treating these conditions.

Regulatory Background

FDA regulates and generally requires premarket approval of all new drugs, which are defined as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,” or “intended to affect the structure or any function of the body.” 21 U.S.C. § 321(g)(1). FDA also regulates HCT/Ps, defined as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient,” including bone, ligament, skin, cornea, stem cells derived from blood, and reproductive tissue. See 21 C.F.R. § 1271.3(d).

FDA has a tiered, risk-based approach to regulating HCT/Ps, with three levels of oversight depending on the category of HCT/P. The lowest risk category, which is not subject to any oversight by FDA, includes HCT/Ps removed from an individual that are implanted into the same individual during the “same surgical procedure.” 21 C.F.R. § 1271.15(b). HCT/Ps that meet the four criteria under 21 CFR 1271.10(a), such as being “minimally manipulated,” and that do not meet the SSP exception fall in the middle of the hierarchy and are regulated solely under section 361 of the PHSA, aimed at preventing the spread of infectious disease. The highest risk category of HCT/P are those that do not meet the criteria under 21 CFR 1271.10(a) or the SSP exception. HTC/Ps in this last category are regulated as drugs or medical devices under the FDCA, or biological products under section 351 of the PHSA, which typically require premarket approval and compliance with the full panoply of FDA regulation.

Court Opinion

One of Defendant’s primary arguments was that its SVF treatments constituted the practice of medicine, not the manufacture and administration of a “drug” and were, therefore, not subject to FDA regulation. The Court rejected this argument, finding instead that the SVF mixture itself was a drug (favorably citing the prior Regenerative Sciences case).

The Court also found that the SVF treatment did not meet the SSP exception and was, therefore, not wholly exempt from FDA regulation on that basis. The SSP exception requires that the HCT/P implanted into the patient be the same “such HCT/P” that was originally removed from the patient. The Court interpreted this provision to mean that the HCT/P removed from the patient had to be viewed as a whole (not its constituent parts), before any significant processing. Although the cells in the SVF mixture were present in the fat tissue originally removed from the patient, the Court found that the relevant HCT/P for purposes of the SSP exception was the fat tissue itself and, therefore, the significantly processed SVF was not the same “such HCT/P”.

Although the holding was unanimous, one judge concurred with respect to the SSP exception analysis. The concurrence found the language of the SSP exception genuinely ambiguous, but would have reached the same conclusion as the majority because FDA was owed Auer deference on its interpretation of the regulation (citing Auer v. Robbins, 519 U.S. 452 (1997); see also Kisor v. Wilkie, 588 U.S. 588, 566 (2019)).

Conclusion

The Court did not consider the question whether the SVF treatment required an NDA/BLA or, instead, met the criteria under 21 C.F.R. 1271.10 to be regulated solely under section 361 of the PHSA. This could be the subject of further proceedings at the District Court level on remand. Additionally, Defendants may also seek en banc review of the decision from the full Ninth Circuit. In the meantime, FDA now has three different circuit courts that have upheld its authority to regulate stem cell clinics performing the sort of procedures at issue in these cases.

The Rare Pediatric Disease Priority Review Voucher program has had a bit of a tumultuous history in its 12 short years of existence.  Designed to incentivize the development of drugs for pediatric rare diseases where such development may not otherwise have occurred, vouchers may be granted for drugs for serious or life-threatening rare diseases where the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years.  Once granted, the vouchers may be used by the recipient or sold to another company for use with an application that may not otherwise qualify for priority review.  A very important aspect of the program is that it costs FDA, and the government, no additional dollars, though we do not wish to minimize the additional resources a priority review demands over the standard review that such an application might otherwise receive.  The value to industry for receiving a speedier review depends on the specific circumstances of the application, but it is clear that they are valued highly.  The dollar prices of the vouchers themselves have fluctuated, recent sales have been in the neighborhood of $100 million.

Over 50 rare pediatric disease priority review vouchers have been awarded to date.  We have heard over and over again how the potential for a priority review voucher has allowed small companies with limited resources to invest in the development of drugs for rare pediatric diseases.  Although the program has not been without its critics (including as documented in two GAO reports from 2016 and 2020), there is ample evidence that the program has been successful at accomplishing its goals, which has become more evident with time.  A recent analysis from NORD showed that among the 39 rare pediatric diseases for which vouchers were awarded, only three had any FDA-approved products on the market before the program’s enactment.  Even FDA officials, who have historically been hesitant, at best, to support the program (this opposition was documented in the GAO reports), have recently issued statements of support.  This also appears to be the administration’s position at this time, as it was included in the government’s “anomalies” list for purposes of inclusion in a continuing resolution.

The program, however, has always had a scheduled sunset date.  Notably, it was reauthorized in 2016 (until 2020) and in 2020 (until 2024).  We watched as the days ticked away as we crept closer to the first scheduled sunset date in the amended law, September 30, 2024.  After this date, without action by Congress, FDA’s authority to grant rare pediatric disease designations would expire, and no vouchers could be granted unless previously granted such a designation.  No rare pediatric disease vouchers could be awarded even to designated applications after September 30, 2026.

We heard and felt the anxiety from many of our clients about the uncertainty this caused.  It is extremely difficult, if not impossible, to do the long-term planning and substantial fundraising required for drug development without knowing whether such an important and valuable incentive will be there.  After all, this is what incentives are for.  While the dates have been written in the law, the previous extensions provided a reasonable hope that the program would continue.

Nearly at the last minute, Congress acted to kick the can down the road just a little bit.  On September 26, as part of a continuing resolution to keep the government funded, the President signed an extension into law that allows rare pediatric disease designations to be granted until December 20.

That brings us to today, where we are halfway through October without a longer-term fix.  After coming so close to the brink, we were relieved to see the last-second short-term extension.  However, this is only a brief reprieve, leaving substantial uncertainty for stakeholders as to what might happen in the coming months.  Adding to the difficulty is that Congress is not scheduled back in session until mid-November, following Election Day.

However, there has been movement.  A few days before the continuing resolution, on September 23, 2024, the House of Representatives passed H.R. 3433, the Give Kids a Chance Act of 2024.  It was shortly thereafter introduced in the Senate and referred to the Committee on Health Education, Labor, and Pensions, where it remains.  This bill would extend the designation deadline until September 30, 2029, a five-year extension (and would require yet another GAO report).

While we were heartened to see this movement, finally, we remain in an uncertain position, watching as the days tick away until December this time.  With so much support from stakeholders, we are hopeful that Congress will recognize the immense value of this program, primarily for pediatric rare disease patients, the ultimate beneficiaries of the program, and authorize an extension.  Hopefully, this can be accomplished without coming quite so close to the brink this time.

It took only 3 months.  In June, the Supreme Court ruled that the SEC cannot use its administrative authority to impose civil penalties for securities fraud on the ground that these penalties violate the U.S. Constitution’s Seventh Amendment right to a jury trial.  See SEC v Jarkesy, 144 S. Ct. 2117 (2024).  The Court reasoned that the SEC’s civil penalties “are designed to punish and deter, not compensate,” and that they are a remedy “that could only be enforced in courts of law.”  At the time we posted about the Jarkesy decision, we predicted that it would impact FDA-regulated industry:

The impact on FDA matters could be significant.  FDA has civil money penalty authority relating to clinical trials, devices, foods, drugs, and tobacco; although with the exception of tobacco, FDA has not recently exercised that authority with regularity.  If FDA is prohibited from pursuing the relatively small dollar value tobacco penalty cases administratively, it could affect enforcement.  Bringing an administrative claim is typically much less demanding in time and resources than litigating a jury trial.

Sure enough, the first challenge to FDA’s civil money penalty authority was filed last week in the Central District of California.  In Huff and Puffers v. U.S. Food and Drug Administration, No. 8:24-cfv-02110 (C.D. Cal. filed Sept. 27, 2024), the plaintiff H&P challenged an FDA administrative complaint assessing a civil money penalty of $20,678 for H&P sale of an electronic cigarette without FDA authorization.  In its administrative complaint, FDA alleged that H&P sold unauthorized tobacco products through its online website despite FDA notification through a Warning Letter that H&P’s tobacco products are adulterated and misbranded.  FDA alleged that H&P shipped an unauthorized tobacco product from California and Virginia, in violation of the law, and thus sought an order assessing a civil money penalty against H&P.   Under the Federal Food, Drug & Cosmetic Act (FD&C Act), retailers who violate a requirement of the Act related to tobacco products shall be liable for a civil money penalty up to $20,678 for each such violation, not to exceed $1,378,541 for all violations adjudicated in a single proceeding. 21 U.S.C. § 333(f)(9)(A); 21 C.F.R. § 17.2.   H&P timely responded to the administrative complaint with several defenses, and specifically stated that it did not waive its Seventh Amendment right to a jury trial.

True to its word, H&P filed a Complaint in the District Court for the Central District of California seeking declaratory and injunctive relief on the ground that the FDA’s civil money penalty proceeding against it violates the U.S. Constitution.  H&P specifically relies on the Supreme Court decision in Jarkesy, as well as the 2023 Supreme Court decision in Axon Enterprise, Inc. v. FTC, 598 U.S. 175 (2023) (holding that district courts have jurisdiction to hear constitutional challenges to agency authority to adjudicate enforcement actions).  H&P seeks a declaration that the FD&C Act’s statutory provisions allowing FDA to impose civil money penalties violate the Seventh Amendment, a declaration that the administrative proceeding against H&P violates the Seventh Amendment, an order requiring FDA to dismiss the administrative complaint against H&P, an order prohibiting FDA from adjudicating civil money penalties generally and against H&P specifically, and an order awarding fees and expenses.

The case could provide greater clarity on whether and to what extent the “public rights” exception continues to permit the adjudication of certain administrative issues.  The majority and dissenting Jarkesy opinions discuss and debate the history of the adjudication of certain “public rights” without a jury.   Whether a civil penalty for violation of the FDC Act is sufficiently different from an SEC fraud penalty to be a “public right” remains to be seen.

Another potentially interesting aspect of this case appears only in the caption, which is styled as an action “SEEKING STATEWIDE OR NATIONWIDE RELIEF.” The propriety of nationwide injunctions has been discussed by legal scholars, judges and Justices in recent years.  Even more limited statewide injunctive relief would be a departure from the normal rule that non-mutual collateral estoppel does not prevent the federal government from re-litigating an issue that it has lost, especially at the district court level.

In sum, this case raises some interesting unresolved legal issues, so we’ll be following it. Note that we also predicted that “[t]he impact on USDA and DEA could be similarly significant.“  Stay tuned.

A recent draft guidance on predetermined change control plans (PCCP) for medical devices continues FDA’s effort to implement Section 515C of the Food and Drug Omnibus Reform Act of 2022 (FDORA),   which Congress enacted to make it easier for manufacturers to make post-market device changes by avoiding the need for additional FDA authorization (see our prior summary of FDORA here). A draft guidance issued last year focused on PCCPs for devices incorporating artificial intelligence and machine learning (AI/ML), which we blogged about here; this guidance has not yet been finalized.  In contrast, the new draft guidance,  Predetermined Change Control Plans for Medical Devices (Draft Guidance), addresses all device types, and describes the types of modifications that the agency “believes generally may be appropriate for inclusion in a PCCP, and the information that should be included in a PCCP in a marketing submission for any device type.” Draft Guidance at 4.

As a reminder, a PCCP is a document submitted in a marketing application that describes future modifications to a device that would typically require submission of a subsequent application and a description of how the sponsor will verify and validate the modified device.

FDORA gives wide latitude to FDA with respect to the types of changes that may be made to a device with an approved or cleared PCCP.  The statute states that FDA may approve a PCCP for a PMA device for any change that would otherwise require a supplemental application as long as the device remains safe and effective without any change.  For 510(k) devices, FDA may authorize a PCCP as long as the changes would not affect the device’s substantial equivalence to the predicate device and the change is not necessary to maintain the device’s safety and effectiveness without any change.

The Draft Guidance takes a narrower approach.  For 510(k) devices, PCCPs can be considered for modifications that “significantly modify an existing risk”, but generally not for those that “introduce a new risk.”  Id. at 20.    Longstanding guidance on evaluating postmarket device changes, Deciding When to Submit a 510(k) for a Change to an Existing Device (Change Guidance), states that a change “could significantly affect the safety or effectiveness of the device”—and requires a new 510(k)—if it either introduces a new risk or significantly modifies an existing risk. Change Guidance at 8.  Given that this prior FDA guidance treats both types of changes—modifications to existing risk and introduction of new risks—as significant and likely to require a 510(k) submission, logic dictates that, in determining PCCP eligibility, FDA should apply it to both categories of change since the purpose of a PCCP is to avoid the need for a new marketing submission.  In fact, FDORA does not preclude PCCPs for changes that introduce a new risk, as long as the device remains safe and effective without any change and remains substantially equivalent to the predicate.  Nevertheless, the Draft Guidance would preclude the use of PCCPs for such changes, even if the modified device would remain substantially equivalent to the predicate device.  Likewise, for PMA devices, the Draft Guidance would preclude use of a PCCP for changes that are considered major or that modify the intended use of the device.  As both these categories of changes are currently permitted via a PMA supplement, and the goal of FDORA is to provide an alternative to the need for such supplements, we would expect major changes and modifications to intended use to be permissible via a PCCP as long as the device remains safe and effective without any change.

The Draft Guidance includes examples of changes that would be eligible for PCCPs, as well as those that would continue to require new submissions.  These examples further demonstrate that FDA is narrowing the scope of PCCP-eligible changes contemplated under FDORA.  For instance, the Draft Guidance states that a PCCP would be appropriate to add a device to a product with different dimensions that are within the range of dimensions of those currently authorized.  Under the Change Guidance, such change would likely be classified as non-significant, meaning that no additional submission would be necessary even without a PCCP, so it is unclear how this example furthers the goal of FDORA.  On the other hand, the Draft Guidance states that a significant change to the design of a printed circuit board (PCB) in a multi-parameter physiological patient monitor, with arrhythmia detection alarms for use in a hospital environment, would not be appropriate for inclusion in a PCCP. Draft Guidance at 34. As described, this change would not appear likely to introduce a new risk, making it unclear why it could not be implemented via a PCCP.

The Draft Guidance also provides detail regarding the content of a PCCP, stating that the sponsor should include:

• a description of the modification, including specific changes to the device characteristics and performance;
• a modification protocol, including performance evaluation methods and update procedures;
• traceability between the description of the modifications section and the modification protocol section; and
• an impact assessment. Id. VII.

FDA recommends a PCCP include “only a limited number of modifications that are specific, and that can be verified and validated.” Id. at 26.  Practically speaking, we agree that limiting the number of modifications in a PCCP will be most efficient for sponsors to achieve timely submission and authorization, but again, FDORA does not impose this limitation.  If a sponsor is able to provide a detailed description of multiple changes with appropriate performance evaluation methods for each, we hope the Agency will be willing to consider them under a single PCCP.

Finally, the Draft Guidance indicates that a PCCP may be included with most application types.  For PMA devices, a PCCP may be included with an original application, modular application, or any of the pre-approval supplement types (panel-track, real-time, 180-day, 135-day).  A PCCP may also be submitted as part of a De Novo application.  For 510(k) devices, a PCCP may be submitted only with a traditional or abbreviated application.  We find it surprising that a PCCP may not be submitted with a Special 510(k), given a Special 510(k) may be used to modify an existing device where well-established methods are available to evaluate the change. FDA, Guidance for Industry,  The Special 510(k) Program (2019).  Given the limitations in the Draft Guidance for types of changes that may be made using a PCCP, it seems that changes eligible to be made via a Special 510(k) may be well suited for being made via a PCCP.  The Draft Guidance states that Special 510(k)s may be an appropriate submission type if the Sponsor wishes to modify a previously cleared PCCP for their own device and the PCCP methods are well-established. Given FDA appears prepared to permit modification of an existing PCCP via a Special 510(k), it remains unclear why one could not implement a PCCP via the Special 510(k) pathway in the first instance.

While the description of the content that should be included in a PCCP is generally helpful, the Draft Guidance leaves much uncertainty—and uneasiness—about the types of changes FDA will ultimately allow manufacturers to make via the PCCP process.

Comments on the Draft Guidance may be submitted until November 20, 2024.

If you monitor Regulations.gov dockets and litigation dockets on PACER like we do, then you know that one company name—more than any other over the past several years—pops up: Vanda Pharmaceuticals, Inc.  But unlike the fictitious Vandelay Industries of Seinfeld that George Costanza claims to have been interviewed for as a latex salesman, Vanda Pharmaceuticals, Inc.—and the issues the company raises—are very, very real.

Not only that, but they are often novel issues!  Consider, for example, a Complaint filed just recently in the U.S. District Court for the District of Columbia (“DDC”) against FDA alleging that the Agency’s structure of NDA review is unconstitutional (by our count the 31st Vanda litigation against FDA or another government entity in the last five years, including appeals).

Or consider Vanda’s challenge that FDA’s approval of a generic version of one of the company’s drugs violated the Appointments Clause of the Constitution (U.S. Const. art. II, § 2, cl. 2) because the FDA employees who approved the application were not “Officers of the United States.”  In that case, the DDC recently said:

[T]he Court has lingering concerns about whether [Dr. Iilun C. Murphy, Director of the Office of Generic Drugs’] ratification cured any Appointments Clause deficiency because it is unclear whether any statute properly authorized her appointment.  Given this uncertainty, as well as the maze of procedural barriers that may prevent the Court from even considering the matter, the Court will allow the FDA one more chance to put the matter to bed for good (should it so choose) before the Court renders a final decision on it.

Or consider Vanda’s lawsuit filed in the U.S. Court of Federal Claims alleging that FDA improperly disclosed Vanda’s trade secrets by offering certain recommendations to various generic competitors, and thus that FDA breached its duty of confidentiality.  Specifically, Vanda alleges that FDA communications to certain generic competitors regarding dissolution rates, impurities, and micronization revealed Vanda’s confidential manufacturing information and caused economic injury to the company. To that end, Vanda asserts a Fifth Amendment takings claim based upon a government official’s alleged disclosure—intentional or inadvertent—of claimed trade secrets and confidential commercial information.  In January 2024, the U.S. Court of Federal Claims allowed Vanda’s Fifth Amendment takings claim to move forward in litigation.

The ramifications of the Federal Claims case and some of the other lawsuits brought by Vanda could be significant to regulated industry and to the food and drug bar.

Given all of the Vanda lawsuits flying around, some of which are based on FDA Citizen Petition decisions or other FDA decisions, we thought it would be helpful to pull them all together in a couple of tables.  To that end, below is a list of the cases Vanda has filed over the past five years or so against FDA or another government agency or entity, as well as a list of FDA Citizen Petitions and appeals.

Table 1. Litigation filed by Vanda Pharmaceuticals against FDA (and the Federal Government) Since 2019

Table 2. Citizen Petitions and Appeals Filed by Vanda Pharmaceuticals Against FDA Since 2019

In May 2023, we posted about a CMS proposed regulation that sought to make a wide variety of changes to the Medicaid Drug Rebate Program (MDRP), including a new “price verification survey,” and a controversial proposal to require “stacking” of discounts to different customers when determining best price.  Fortunately, in the final regulation, which was published in the Federal Register on Thursday, September 26, CMS decided not to finalize some of the more objectionable proposals – a good illustration of the usefulness of submitting comments on proposed regulations.

CMS did not finalize the price verification survey, which would have required manufacturers of 10 costly drugs selected annually to provide clinical information as well as information on production, distribution, research, and marketing costs, revenue and profit, and ex-U.S. pricing, among other things.  CMS also decided to forego its best price stacking proposal, which has been the subject of litigation, though CMS is instead going to pursue a “collection of additional information from manufacturers related to best price stacking methodologies to inform future rulemaking.”  In addition, CMS is not going to finalize an “all-in” definition of “manufacturer,” which would have required that a manufacturer and all of its affiliates, subsidiaries, business segments, and entities under common corporate ownership or control each maintain a National Drug Rebate Agreement (NDRA), with the threat of termination of all of the manufacturer’s agreements if this requirement were violated.  Another rejected proposal was a definition of “vaccine” (vaccines are exempt from Medicaid rebates), which would have limited this term to a product that is administered prophylactically – i.e., to prevent rather than treat a disease. Yet another rejection was a proposal requiring a diagnosis on Medicaid prescriptions as a condition for claims payment.

Despite the removal of some of the most controversial proposals, the final rule still contains a variety of significant changes, which become effective on November 19, 2024.  The most noteworthy are the following:

1.  Penalties for “Misclassification”

The Medicaid Services Investment and Accountability Act of 2019 added new penalties to the Medicaid rebate statute for knowingly misclassifying a covered outpatient drug.  See 42 U.S.C. § 1396r-8(b)(3)(C)(iii).  CMS’ final regulation expansively defines a “misclassification” to include not only misclassifying the drug category (e.g., misclassifying a single source drug or innovator multiple source drug as a non-innovator multiple source drug), but also reporting other “drug product information . . . that is not supported by the statute and applicable regulations.”  The term “drug product information” is now defined to include NDC, drug name, units per package size (UPPS), drug category (S, I, or N), unit type (e.g., TAB, CAP, ML, EA), drug type (prescription or OTC), base date AMP, therapeutic equivalent code, line extension indicator, 5i indicator, 5i route of administration (if applicable), FDA approval date, FDA application number or OTC monograph citation (if applicable), market date, and covered outpatient drug status.  In response to comments, the catch-all phrase “any other information CMS deems necessary” was deleted from this list.  A misclassification also includes correctly reporting drug product information, but paying rebates at a level not corresponding with that classification.  A misclassification can occur even if it was not a knowing error.

The regulation sets forth a process under which CMS may notify a manufacturer in writing about a misclassification, after which the manufacturer must (1) report and certify corrected product information in the Medicaid Drug Programs (MDP) system within 30 calendar days after the CMS notice; and (2) pay any underpaid rebates to states and provide documentation to CMS that such payments were made, both withing 60 calendar days after the CMS notice.  Remarkably, manufacturers may not dispute a CMS notification.  CMS specifically declined to provide a dispute resolution process, inconsistently explaining on one hand that the statute does not provide for such a process, but on the other hand stating that CMS will consider a dispute process for future rulemaking.  The preamble notes that the corrections required by a CMS notice may extend back to periods beyond the 10-year recordkeeping requirement under the MDRP.  If a manufacturer no longer has records required to make corrections, it may make “reasonable assumptions.”

With regard to the 30-day deadline for corrections, many manufacturers who have corrected drug product information know that it frequently takes longer than 30 days to investigate and correct information such as base date AMP, market date, or unit type, and revise the other drug data and prices that follow from such corrections – especially if numerous NDCs are involved.  However, CMS rejected requests to extend the 30-day timeframe.  The preamble (but not the rule) does state that a manufacturer may request an informal extension of the 30- and 60-day deadlines if there are extenuating circumstances.

The 60-day deadline for adjusting rebates to the states means that these adjustments will take place outside of the usual quarterly cycle in which rebate adjustments have traditionally been made with the states.

If a manufacturer fails to make corrections or pay rebates within the respective deadlines, CMS may do any or all of the following:

• Unilaterally correct the drug product information, which the manufacturer must certify in MDP within 30 days;
• Suspend the drug in question from the MDRP and deny federal financial participation (FFP; i.e., funding) to states if the drug is dispensed to Medicaid beneficiaries;
• Impose a civil monetary penalty not to exceed 23.1% of the AMP for each unit paid for by Medicaid during the period of misclassification.

If these actions were not enough, a manufacturer’s rebate agreement may be suspended if the information required in a CMS notice is not reported within 90 calendar days, as further explained in section 2, below.

CMS will also post annually on a public web site all of the drugs that were identified as misclassified during the previous year, and any of the above actions taken by CMS.

2.  Rebate Agreement Suspension

The final rule for the first time provides for suspensions of rebate agreements in two circumstances.  The first is where a manufacturer receives a notice of a misclassification described in section 1, above, and fails to correct the drug product information within 90 calendar days.  Second, if a manufacturer fails to submit timely quarterly pricing reports, CMS will notify the manufacturer of the failure.  If the manufacturer fails to submit the required pricing reports within 90 calendar days after the notice, the manufacturer’s rebate agreement will be suspended for all of the manufacturer’s covered outpatient drugs furnished after the end of the 90-day period, and will remain suspended until the pricing information is reported in full to CMS and certified, and CMS reviews it for completeness, but may not be suspended for less than 30 calendar days.  Continued suspension of the rebate agreement may result in termination for cause.  The suspension of a rebate agreement will not affect the status of the manufacturer’s covered outpatient drugs under the 340B Drug Discount Program or under Medicare Part B.

3.  Restatements Pursuant to Internal Investigations

Under the MDRP, manufacturers must restate incorrect AMPs and best prices and may do so without CMS involvement going back three years from the current quarter.  Periods before the three-year window may only be restated pursuant to a request to CMS citing one of the grounds specified in the regulations.  One of the specified grounds for such a request is to address specific rebate adjustments as required “under an internal investigation.”  CMS proposed to define an “internal investigation” as a manufacturer’s investigation of its AMP, best price, customary prompt pay discounts, or nominal prices previously certified to CMS “that results in a finding of fraud, abuse, or a violation of law or regulation.”  In response to manufacturer objections, CMS inserted the word “possible” before “fraud, abuse, or a violation of law or regulation” so that manufacturers would not have to concede legal fault in order to make a restatement beyond three years. However, a restatement request will still concede a “possible” violation of law – even if the error caused an overpayment of rebates to the government’s benefit.  (CMS has previously stated that a restatement may result from an internal investigation that discovered an underpayment or an overpayment of rebates.)  The manufacturer must also “make data available to CMS to support its finding” of a possible violation.  CMS has not typically required manufacturers to submit data supporting a restatement beyond the three-year window, other than submission of change request templates and an estimate of the financial impact (i.e., how much money will be owed to the states or to the manufacturer).  It remains to be seen what additional information CMS will be requesting to support a manufacturer’s finding of possible fraud, abuse, or violation of law.

4.  Other Changes

The final rule contains an assortment of other changes to the MDRP, which include the following:

• “Direct reimbursement” definition: Under the statute, covered outpatient drugs do not include drugs that are used incident to other services (e.g., physicians services or inpatient hospitals services) and for which Medicaid payment may be made as part of payment for the service “and not as direct reimbursement for the drug.”  42 U.S.C. § 1396r-8(k)(3).  Under the final rule, “direct reimbursement for the drug” would not be limited to separate payment for the drug.  It would also occur when there is an all-inclusive payment for the drug and the service, but the drug, the charge for the drug, and the units are specified on the claim, and the inclusive payment includes an amount directly attributable to the drug based on a reimbursement methodology described in the state’s Medicaid state plan.
• Market Date definition: Market Date, which determines the baseline quarter, is defined in the final rule to be “the date on which the covered outpatient drug was first sold by any manufacturer.”  The preamble explains that manufacturers may use reasonable assumptions as to when a sale takes place (e.g., date of payment, date of shipment, date of invoice, etc.).  The preamble also explains that the definition is prospective only, so that manufacturers that determined Market Date in accordance with earlier program instructions that Market Date was the earliest date the drug was available for sale will not be required to change the Market Date to the earliest date sold.
• Three-Year Limit on Disputes: The final rule establishes a three-year limit for manufacturers to dispute, audit, or request a hearing on state utilization data.  The three years runs from the last day of the quarter from the state invoice postmark date.  Commenters had advocated a similar restriction on states seeking to submit rebate utilization, citing certain states that have sent invoices for decades-old utilization.  CMS declined to impose any similar time limit on states, explaining that states have an incentive to resolve disputes promptly because federal law prohibits them from receiving FFP for adjustments beyond two years after a claim for FFP is first filed.  CMS failed to mention that states may request a waiver of the two-year deadline for good cause.  The final rule contains no provision for good-cause waivers of the new three-year limit on disputes.
• PBM Spread Reporting: Pharmacy Benefit Managers (PBMs) have been criticized in recent years for their practice of spread pricing, and Congress has been debating legislation that would prohibit it.  Spread pricing refers to PBMs’ practice of charging their health plan clients a higher price for a unit of dispensed drug than the PBM pays the pharmacy for the unit.  The so-called spread, or margin, is not disclosed by the PBM to their clients, patients, or anyone else.  The final rule, while not prohibiting spread pricing, takes a step toward discouraging it through a new transparency reporting requirement.  Medicaid managed care plans must contractually require their PBMs to separately report to them payments made to providers — such as drug reimbursement, dispensing fees, drug administration fees, and payments for other patient services — and expenses of the PBM itself —  such as administrative costs, fees, and other expenses.
• Codification of URA cap sunset: Under the American Rescue Plan Act of 2021, a provision that capped the Unit Rebate Amount to 100% if the average manufacturer price (AMP) was sunsetted effective December 31, 2023.  The final rule makes conforming changes to the MDRP regulations.  In the preamble, CMS foreclosed any possibility of waiver of inflation rebates for drugs in shortage (similar to waivers provided for under the Medicare Inflation Rebate Programs), explaining that CMS has no such authority under the Medicaid statute.

We can all acknowledge that the title of this post is not that funny-at least, not to anyone other than medical device regulatory nerds, such as the author of this post. What no one should find funny is how CDRH seems to be approaching Breakthrough devices of late, setting clinical study expectations so high that these innovative, novel, life-saving products may never get to the other side of the door, regardless of how much they knock.

CDRH takes great pride in stating that it is committed to innovation. In fact, it has a whole page dedicated to “CDRH Innovation,” which states that CDRH “is committed to advancing public health by helping to bring innovative technologies to market.” In particular, CDRH touts its Breakthrough Devices Program, which it advertises as a “program for certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. Manufacturers can expect increased interaction with the review team and prioritized review of the marketing submission.”

The reality, however, is quite different. The Breakthrough program started in 2015. Since that time, CDRH has granted 921 Breakthrough devices, and CBER has granted 12. This graph shows the number of granted Breakthrough Device designations by fiscal year.

Of the 933 devices granted Breakthrough status, a whopping total of 95 have received marketing authorization (91 CDRH devices and four CBER devices). That is just barely over 10% in almost a decade. While there can be any number of reasons why so few have received authorization, if this were truly a program to benefit innovative products, it would stand to reason that more would have been successful in getting to market, especially given the volume granted designation in 2020-2021.

In advising clients who have received Breakthrough designation, one theme seems to be emerging, which we expect is responsible for at least some of the missing authorizations-CDRH’s clinical trial expectations, especially for low-prevalence conditions, can almost guarantee that most of these Breakthrough devices never see the light of day. CDRH seems unwilling to move away from a theoretical world in which money and time are abundant and enriching studies is a simple task. For certain indications or populations, a prospective study is simply infeasible-even a well-funded, large company is unlikely to enroll tens of thousands of study participants to properly power a study for a low-prevalence disease. Even for higher-prevalence conditions, CDRH’s recent feedback in pre-submission meetings shows just how far apart the review teams are from the reality of what it takes to run a robust clinical trial.

For many companies, start-ups in particular, a request for Breakthrough designation may be their first interaction with FDA. These requests are often based upon promising data from early feasibility studies, and the indication requested stems from the results of those small studies without considering what the requirements might be for a pivotal study to support the same indication.

If a company is successful in obtaining Breakthrough status, when it goes back to the FDA with a proposed pivotal study design, it may not like what it hears-that a study to support the Breakthrough indication will need to be larger and more complex than the company likely anticipated or is able to support. This then puts the company in the unenviable position of deciding whether to abandon its Breakthrough status to design a more palatable study for a different indication, or to negotiate study design with the Agency to support the Breakthrough indication. And while FDA repeatedly states that it does not design studies, the sponsors do, the hard truth is that only FDA can ultimately deem a study adequate to open the door to allow the Breakthrough device to cross the threshold into the marketplace.

So what can be done? There is no reason for the Breakthrough to be the first interaction-it only has to be submitted to the Agency before submitting the marketing application. Therefore, while there is no guaranteed path to success, one suggestion is that before going to FDA with a Breakthrough designation request, companies should submit a standard pre-submission with proposed indications and clinical trial design. If a company takes this approach before submitting a Breakthrough request, the company can gain alignment with FDA on what its expectations will be for a study to support the indication desired by the company, before getting a Breakthrough indication only to learn that FDA’s clinical trial expectations are impractical.

CDRH should take a close look at the Breakthrough designations granted to date, how many sponsors with Breakthrough devices submitted marketing applications that were not ultimately granted, and how many came in with pre-submissions with requests for feedback on clinical trial design that ultimately never submitted a marketing application. If CDRH truly wants to be a hub of innovation, it needs to find ways to work with companies to facilitate market access, rather than slamming the door in their face.

In the Hatch-Waxman Community there are certain folks who are viewed as “the Founders” or pioneers of the law.  There are, of course, the names Representative Henry Waxman and Senator Orrin Hatch, but there were several other Founders.  One of them—who was said to have been an honorary Member of Congress leading up to the September 24, 1984 enactment of the Hatch-Waxman Amendments—is Alfred B. Engelberg.

These days, Al (as we have come to know him) is a Trustee for The Engelberg Foundation, a private foundation that supports the Icahn School of Medicine at Mt. Sinai.  But forty years ago, Al was the generic drug industry’s patent counsel during the negotiations that led to the Hatch-Waxman Amendments.  He originated the idea of patent certifications, new drug exclusivity, and the Bolar exemption.  (And by the by, Al, a patent attorney, also brought the earliest successful Paragraph IV patent challenge in the 1980s – see here).

Throughout his illustrious career, Al has been engaged with Hatch-Waxman, even authoring one of the earliest papers providing an account of the law: “Special Patent Provisions for Pharmaceuticals: Have They Outlived Their Usefulness?”  In his new book, “Breaking the Medicine Monopolies: Reflections of a Generic Drug Pioneer,” which will be released in January 2025 by Post Hill Press and is available now for pre-order on Amazon, Al provides a first-hand account of the events that led to the enactment of the Hatch-Waxman Amendments and of the many others who have shaped brand-name and generic drug competition over the last fifty years.

From Chapter 1 (My First Generic Drug Client), through Chapter 4 (The Hatch-Waxman Act), to Chapter 12 (My Prescription for the Future), the 208-page “Breaking the Medicine Monopolies: Reflections of a Generic Drug Pioneer” is definitely worth a read!  It provides a perspective on Hatch-Waxman that only a few folks out there (and dwindling) can provide.

FDA issued a Federal Register notice on September 13, 2024, seeking feedback on the Integrated Review format that the Center for Drug Evaluation and Research (CDER) began using as part of its New Drugs Regulatory Program (NDRP) modernization effort several years ago.

The NDRP focused on six strategic objectives one of which was the implementation of the Integrated Assessment which per CDER was designed to “critically, collaboratively, and consistently assess whether information in drug approval applications meets legal and regulatory requirements.”  These efforts included the adoption of a new review template for the assessment and documentation to be used in reviewing NDAs and BLAs with an overall goal of having a more collaborative inter-disciplinary approach to the process.  While much of the effect may have been on the internal processes of the review division and other disciplines tasked with evaluating the approvability of applications submitted to CDER, a significant change also occurred in how CDER conveys information about the internal review process and conclusions that lead to an application approval.  Specifically, CDER moved from sharing the reviews of the individual disciplines in the documents available to the public to sharing an Integrated Review which shares the conclusions but much less of the detail of each review.

Before FDA even asked, we had been considering an HPM FDA Law Blog post on this subject.  The appeal of distilling down the extensive process that goes into the decision to approve an application into a single package is easy to see, and some may be interested in only the ultimate distillation – an approval is issued or not. As frequent consumers of both the old-style Summary Basis of Approval (SBA) that includes the individual detailed discipline reviews and the newer leaner Integrated Assessments, however, we have found the more summary nature of the Integrated Assessments to be lacking information that can be critically important in identifying and understanding how resolution was reached on issues identified in the review.

For example, one cannot always discern the opinions of individual reviewers in an Integrated Review.  Those of us seeking to learn how FDA may approach a similar issue in another context want to understand what the differences of opinion were.  The Additional Analyses and Information section of the Integrated Review includes only the separate reviews of reviewers who “disagree with significant elements of the Executive Summary and Interdisciplinary Assessment sections or the decision of the Signatory Authority.”  89 FR 74966 at 74968 (Sept. 13, 2024).  Differences of opinion that were resolved before the action was taken would not be included.

Another potential problem with an Integrated Review is that we can never know what information was eliminated from the individual reviews.  For example, perhaps the Integrated Review simply agrees with some conclusion in an individual review but does not include the “why” rationale that the individual reviewer found persuasive.  Fully understanding FDA’s thought process and the basis of its conclusions (i.e., the “why”) is of particular import to those who seek to understand how FDA may view the issue in other situations.

We also have encountered instances where there was a mathematical or other objective error in the underlying review.  The Integrated Review includes the conclusions or results of various analyses, but there is no “show your work” feature.  Consequently, it can be difficult to follow how FDA came to its conclusion.

Some of the goals of the Integrated Review (including making information available to lay people) may be well-served by the more concise document.  Consolidation into a single review by its nature, however, will leave details of the individual review process on the cutting room floor.  There are those who are willing to read through the more extensive package consisting of all the reviews.  These individual reviews already exist and could be posted in addition to the Integrated Review or an even more concise version of the Integrated Review.

We look forward to seeing what others have found useful or frustrating about the Integrated Review, including in comments that provide responses to these specific questions FDA asks in the Federal Register notice:

1. We are interested in preserving for stakeholders what they find most useful in FDA reviews.
2. Comparing the Integrated Review to previous review documentation, is there any information you are having difficulty locating?
3. Are you able to use the Integrated Review for the same purpose that you used previous reviews? If not, please provide specific examples.
4. We are interested in specific recommendations about any areas of the Integrated Review documentation of the Integrated Assessment that can be improved to meet the needs of stakeholders.
5. We are interested in stakeholders’ views regarding the advantages and disadvantages of an interdisciplinary assessment presentation of key review issues and the resultant integration of the assessments of multiple disciplines into a single Integrated Review document.
6. We would like to know whether the new format of the Integrated Review documentation for the Integrated Assessment provides clarity of benefit-risk assessments and informs your knowledge of FDA’s basis for making decisions.
7. Based on the integrated review, were the issues that concerned the review team clear and understandable? If so, what helped achieve this? If not, what can be improved?

Comments are due by December 12, 2024.

Forty years ago today—on a sunny Monday, September 24, 1984 at approximately 3:30 PM Eastern Time in the Rose Garden at the White House—President Ronald Reagan signed into law Public Law 98-417, the Drug Price Competition and Patent Term Restoration Act of 1984, stating that “[t]he legislation will speed up the process of Federal approval of inexpensive generic versions of many brand name drugs, make the generic versions more widely available to consumers, and grant pharmaceutical firms added incentives to develop new drugs.”  (Thanks to the Ronald Reagan Presidential Library & Museum and its White House Photo Collection Contact Sheets, you can see some of the enactment pictures here and here with President Reagan, Margaret Heckler, Strom Thurmond, Orrin Hatch, Henry Waxman, James (Jimmy) Quillen, and Ralph Regula.)  Some would initially refer to the new law as Waxman-Hatch, but during the 1990s it became known as Hatch-Waxman.  And that name has stuck for many of us.

There have already been (with more coming) a slew of 40th anniversary celebration papers, analyses, and events in 2024, including:

• The Brookings Institution’s Hatch-Waxman at 40
• The Association for Accessible Medicines’ Hatch-Waxman turns 40. Is it over the hill? (Or is the Hill over Hatch-Waxman…)
• The Engelberg Center on Innovation Law & Policy at NYU School of Law’s Health Care at Reasonable Cost: The Hatch-Waxman Act at 40 and Beyond
• The Food & Drug Law Institute’s Hatch–Waxman at 40: A Critical Examination of its Past and Future
• The American Academy of Neurology’s Happy Birthday, Hatch-Waxman: What 40 Years of Generic Drug Access Has Done for Neurology
• The Orrin G. Hatch Foundation’s For cheap generic drug prices, you can thank 40 years of Hatch-Waxman
• We Work For Health’s Hatch-Waxman Act: Celebrating 40 Years of a Balanced and Innovative Drug Ecosystem
• Tradeoffs’ Race to the Bottom Series
• FDA CDER Conversations – 40th Anniversary of the Generic Drug Approval Pathway
• The U.S. Patent and Trademark Office’s Drug Patent and Exclusivity Study

Over the years we’ve celebrated various Hatch-Waxman milestones.  For the 25th and 30th anniversaries, we held trivia contests (here and here).  For the 40th anniversary of the Orange Book (and the quasi-35th anniversary of Hatch-Waxman), we put together a public Orange Book Archive (and it has become one of the more popular stops on the FDA Law Blog).

So what should we do here on the FDA Law Blog to celebrate the 40th anniversary of Hatch-Waxman?  We thought about an interview with Rep. Waxman (sadly, Sen. Hatch passed away in April 2022), but Eli Mazour’s Clause8 podcast from October 2018 already covered that ground: see Henry Waxman – The Hatch-Waxman Act and a Life In Congress.  We wanted something different . . . something useful to Hatch-Waxman practitioners.  We thought long and hard, and then it came to us.  We’ve done our best over the years to collect each Paragraph IV Certifications List FDA has published.  (And, as you’ll see, sometimes we’ve captured multiple versions on the same day as FDA furiously changed some things around.)  How about an archive of what is, next to the Orange Book, perhaps the second most relied on and viewed list associated with the Hatch-Waxman Amendments—FDA’s ANDA Paragraph IV Certifications List?!?  That stuck with us, so we went ahead and created the ANDA Paragraph IV Patent Certifications List Archive.

The “PIV List” started out in the early 2000s as a pilot program FDA initiated in response to a July 27, 1999 Citizen Petition submitted by Biovail Corporation International (FDA Legacy Docket No. 1999P-2778) requesting that “FDA disclose to the public through its Web site (1) the name of the innovator drug and approved dosage strengths, (2) the date the first Paragraph IV-containing ANDA is submitted, and (3) the dosage strengths included in that ANDA.”  On October 4, 2000, a second Citizen Petition (FDA Legacy Docket No. 2000P-1556) was submitted by Hyman, Phelps & McNamara, P.C., requesting, among other things, “that FDA disclose to the public through its Web site (1) the date on which the first Paragraph IV-containing ANDA was received by FDA, and (2) the patents to which ANDA applicants have made Paragraph IV certifications and the date of the first such certification for each patent.”  FDA responded to the Citizen Petitions on February 27, 2004, and issued a Press Release on March 2, 2004 (yeah, we saved that as well) concerning the PIV List.

The Paragraph IV Certifications List began as a web-based list on FDA’s website, and eventually transformed into a PDF downloadable list.  The most recent facelift to the PIV List occurred in June 2019 when FDA announced various enhancements (see our previous post here).  Unfortunately, FDA’s PIV List does not track changes to each of the entries (except for a change in 180-day exclusivity status).  And, as we recently noted, those entries can quietly change.  So, our new ANDA Paragraph IV Patent Certifications List Archive (which we will add a link to on the FDA Law Blog homepage) will serve to preserve more Hatch-Waxman history.

Thank you Senator Orrin Hatch and Representative Henry Waxman!  Your leadership and grit brought disparate parties together to benefit the public good (and has led to countless careers, including this blogger’s career)!

Oh, and what is this blogger’s memory of September 24, 1984?  It was uneventful.  I had just started 6th grade at Franklin Elementary School in Manitowoc, Wisconsin.  Here’s the class picture for proof.  You’ll have to find me in it . . . .  Thank Gawd there’s some safety in numbers!