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  • FDA Considers Changing Its Nitrosamine Targets as Global Focus Continues

    We need to talk about nitrosamines.  Recent industry comments submitted to FDA and new, international efforts against these nefarious, potentially carcinogenic organic compounds have the shifting state of regulation here back in the news.

    What are nitrosamines?

    Nitrosamines are chemicals that can form during drug manufacturing, known by their scientific names as N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).  N-nitrosamine drug substance-related impurities (NDSRIs) are a pernicious form of nitrosamines that possess structural similarity to active pharmaceutical ingredients (API).

    In addition to human drugs, processed foods that contain nitrates and nitrites such as cured meats and alcoholic beverages may contain nitrosamines.  OTC products are also susceptible; testing has revealed nitrosamines in heartburn remedies containing ranitidine.

    The evolving upswing in NDSRI regulation is due to their link to cancer.  According to several studies, nitrosamines are a potentially potent carcinogen, depending on the length and depth of exposure.

    What is FDA doing about NDRSIs?

    The canary in the coal mine for nitrosamines was their 2018 appearance in blood pressure medications called sartans.  That discovery set off a global response, that included a series of recalls, a number of FDA-issued guidances, public advisements, mitigation strategies, and warnings, and generally created the current regulatory focus that CDER Director Patricia Cavazzoni has recently called a priority for CDER.

    Aside from its publications, FDA is continuing to investigate the presence of NDSRIs in drug products, which may lead to more inspections or, at least, heightened expectations for industry.  The Agency is trying to meet manufacturers a point where testing standards on how to identify and control NDSRIs become more standardized.  Yet, currently, how the Agency plans to handle nitrosamines is unclear, which has led to the delay in approval of many drugs with no path forward for many of these companies.

    As FDA and industry continue to grow their respective understandings about NDSRIs, more of them are turning up.  In May, FDA published a Federal Register request for “collaborative efforts to develop NDSRI data,” and said that as companies are implementing risk assessments recommended in FDA’s 2020 Nitrosamine Guidance, the Agency has unsurprisingly “received an increasing number of reports of NDSRIs that had formed in drug products across multiple drug classes.”  And FDA has had numerous with meetings with individual stakeholders seeking a better understanding of their approach to nitrosamines.  Seek, and ye shall find, so FDA hopes.

    Upcoming Deadlines and New International Guidances

    Responses to the May 2023 request for comments were due to FDA in early July, as FDA originally hoped that industry would collectively detail its best practices by October 1, 2023.  However, discovering NDSRI-producing gaps in manufacture is so tricky, FDA is considering giving industry an extension on its homework project.  When asked in the Federal Register Notice if a one-year extension would be useful, the response was a resounding “yes!”  Respondents also asked FDA to align its standards to the emerging new guidances and ongoing global efforts to root out NDSRIs.  In addition to the FDA’s efforts, agencies in the E.U., Canada, Australia, and Malaysia have also recently updated their policies and recommendations.

    The global search for nitrosamines is rapidly becoming a complex game of Three-Dimensional Chess, as international regulators try to work together to find solutions, walking hand-in-hand with the industry they must all oversee.  Meanwhile, manufacturers are on the hunt to find their quarry before their customers do it for them.  We’ll report back as this complex regulatory structure continues to take shape.

    No Sleep ‘Til District Court: Jazz Sues FDA Over Sodium Oxybate Clinical Superiority Determination

    Neither Jazz Pharmaceuticals nor Avadel CNS Pharmaceuticals has taken the battle of sodium oxybate—a drug approved to treat narcolepsy—lying down.  After suing each other in patent litigation and Avadel’s suit against FDA challenging the Agency’s authority to compel patent certifications, it’s Jazz’s turn to sue FDA.  This time, rather than use codes and patent certifications, the fight is over orphan drug exclusivity (“ODE”), with Jazz challenging FDA’s clinical superiority decision concerning sodium oxybate in the treatment of narcolepsy.  Specifically, FDA determined that Avadel’s Lumryz can “break” Jazz’s ODE because it is “clinically superior” based on Lumryz’s “major contribution to patient care,” rendering it not “the same drug” under the Orphan Drug Act.  With that decision, Jazz lost its ODE, allowing Avadel’s sodium oxybate product to compete with Jazz’s long before the expiration of the ODE covering Jazz’s most recent product, Xywav, in 2027.

    Approximately six weeks after FDA approved Lumryz and issued its clinical superiority decision, Jazz filed a Complaint against FDA in the District Court of D.C. asking the Court to set aside FDA’s approval of Lumryz, alleging that FDA did not have statutory authority to use clinical superiority to break ODE and that FDA’s approval of Lumryz was arbitrary and capricious.  Like in the multitude of Orphan Drug Act cases preceding this one, Jazz alleges that FDA’s authority under the Orphan Drug Act was limited by the statutory language.  Its main argument is that Congress included only two exceptions to FDA’s restriction barring FDA from granting new approvals during the ODE period: the inability to provide sufficient quantities of a drug and consent from the ODE holder.  Though the Orphan Drug Act (now) includes a clinical superiority clause, Jazz argues that it is not a third exception to ODE.  Jazz also argues that, notwithstanding the language that instructs FDA to promulgate regulations implementing the clinical superiority provisions at 21 U.S.C. § 360cc(c), the statute does not permit FDA to promulgate regulations to use clinical superiority to break ODE.

    Taking another stab at the plain language of the statute, Jazz argues that FDA does not have the authority to interpret the term “same drug” in its implementing regulations, as the term is not ambiguous.  Specifically, Jazz notes that the clinical superiority provisions in the Orphan Drug Act “does not authorize FDA to use a determination of clinical superiority as a basis to find that two drugs are not ‘the same drug’ for purposes of [ODE].”   In other words, Jazz states, the “‘different drug’ fiction is the linchpin of OOPD’s [ODE] analysis,” but the distinction between “same drug” based on clinical superiority is “inconsistent with the statute. . . .”

    More specific to the facts of this case than the governing statute, Jazz argues that OOPD’s determination that Lumryz is clinically superior to Xywav is inconsistent with FDA’s regulations.  Essentially, Jazz argues that FDA’s determination is based on “greater efficacy,” which is not supported by the types of evidence FDA requires for such a determination—namely, head-to-head comparative studies.  Though FDA framed its clinical superiority decision as a Major Contribution to Patient Care (“MC-to-PC”) superiority finding, Jazz believes that it is actually a greater efficacy argument in disguise.  Because the premise of FDA’s determination—that not needing to awaken to take a second dose will provide medical benefits to narcolepsy patients by improving their sleep architecture and reducing disrupted or fragmented sleep—it must be a comparative effectiveness finding.  And, because comparative effectiveness claims must be supported by substantial evidence—one or more adequate and well-controlled clinical trials—FDA’s decision cannot stand as Avadel never conducted a comparative clinical trial of Xywav and Lumryz.  Thus, Jazz argues, there is no evidence that Lumryz is more effective than Xywav.

    Perhaps the most notable assertion is that FDA deviated from Agency policy with respect to clinical superiority in determining that a drug need not be comparable in safety to break ODE on efficacy or MC-to-PC grounds.  In the ODE determination, FDA explained that “one drug can demonstrate a [MC-to-PC] over a previously approved drug even if the drug is not as effective or safe in every respect as the previously approved drug.”  Jazz believes that FDA precedent precludes that position and thus FDA departed from established policy, which FDA denied ever existed.  Jazz, however, cites to the preamble to the 2011 revised implementing regulations for the Orphan Drug Act, which states that MC-to-PC is a narrow category that is applicable and “meaningful only when the subsequent drug [product] provides safety or effectiveness comparable to the approved drug.”  Thus, Jazz contends that FDA has had a longstanding policy that comparable safety is necessary for an MC-to-PC clinical superiority finding.  Jazz points to several other examples of such a requirement, including Procysbi (the brief states that OOPD “observed that an ‘[i]nherent’ part of a major contribution to patient care finding was a threshold requirement that the new drug ‘would maintain a similar or improved adverse event profile and similar efficacy’”) and Ravicti (which, the brief states, FDA rejected the MC-to-PC request “because there was ‘a lack of objective evidence to support [the sponsor’s] claim that [Ravicti] would have comparable safety and effectiveness profiles as those of [the existing phenylbutyrate products].’”

    Jazz also asserts that FDA failed to disclose or explain three prior memos in the Lumryz administrative record that found that Lumryz does not provide a MC-to-PC.  In rejecting Avadel’s argument for Priority Review, Jazz explains that FDA must have determined that Lumryz did not represent a “significant improvement” over existing therapies, including Xywav, and thus the clinical superiority determination conflicts with the Priority Review determination.  Jazz argues, essentially, that the change in position was the product of a pressure campaign within the Agency.  But rather than disclose these conflicting analyses, Jazz contends that FDA “conceal[ed] the existence” of these prior determinations.

    Finally, Jazz argues that the ODE determination was arbitrary and capricious and an abuse of discretion because FDA ignored relevant scientific considerations.  FDA did not seek input from Jazz or Avadel, and neither had an opportunity to “comment on FDA’s thinking because FDA did not share it.”  Consequently, FDA made its determination without informed comments from the affected stakeholder, which Jazz says is “an indispensable feature of well-reasoned agency decisionmaking.”  The record also does not reflect consultation with the requisite experts, and FDA ignored some of the risks associated with elevated sodium intake, which is precisely the benefit provided by Xywav.  Additionally, Jazz says, FDA exaggerated the importance of once-nightly dosing because the idea that Lumryz allows narcolepsy patients to achieve “normal” sleep is scientifically baseless and unsupported.

    Avadel has intervened as a Defendant, and neither FDA nor Avadel has yet to respond to the Complaint.  Our best guess is that FDA will argue that it has broad authority to interpret the provisions of the Orphan Drug Act and interpret “clinical superiority” and “same drug” as it sees fit.  Though FDA has a losing streak when it comes to the Orphan Drug Act, this case is a bit of an uphill battle for Jazz because Congress did include a clinical superiority provision in the Orphan Drug Act as of 2017, and FDA has broad discretion to categorize the basis of its clinical superiority decisions (i.e. greater efficacy, greater safety, or MC-to-PC), and even wider discretion to make MC-to-PC determinations, “which are evaluated on a case-by-case basis for each drug product.”  Such discretion is typically carte blanche for FDA in these types of cases, but again FDA’s track record with the Orphan Drug Act is pretty bleak.  We will keep on watching, as this case is one that might keep us up at night.

    ACI’s 3rd Annual Passport to Proficiency on the Essentials of Hatch-Waxman and BPCIA – October 10-26, 2023 (Virtual)

    Gain a comprehensive understanding of Hatch-Waxman and BPCIA essentials AND a critical competency for legal and business professionals in the biopharmaceutical arena AT THE American Conference Institute’s (ACI’s) 3rd Annual Passport to Proficiency on the Essentials of Hatch-Waxman and BPCIA!

    Attend ACI’s Hatch-Waxman and BPCIA Proficiency Series from October 10-26, a virtual three-week program designed to provide new lawyers and executives for the life sciences industry with a solid foundation for understanding the essentials as well as the intricacies of Hatch-Waxman and BPCIA litigation and regulation. This year’s co-chairs include Li Feng, Ph.D. (Finnegan) and Rachel Pernic Waldron (RMSS Legal).

    This series will provide an in-depth review of Hatch-Waxman and the BPCIA along with other IP basics relative to small molecules and biologics. This program will also lay the necessary foundation to understand the dynamics of the applicable patent life cycles for biopharmaceutical products and business development plans.

    To learn more visit here, or email at customerservice@americanconference.comSave 10% with the FDA Law Blog promo code: D10-999-FDA24.

    OPQ’s 2022 Report Shows the Global Task of Ensuring Quality

    The Office of Pharmaceutical Quality (OPQ), located within FDA’s Center for Drug Evaluation and Research (CDER), uses global inspection, surveillance, policy, and research activities to set quality standards for drugs.  Among its top priorities, OPQ’s Director Mike Kopcha has recently said that OPQ is focused on quality problems that contribute to drug shortages.

    Consistent with that initiative, OPQ recently issued its 2022 Annual Report on the State of Pharmaceutical Quality.  The report reiterated a commitment to maintain the supply chain and provides more context about how OPQ—and FDA, more generally—are approaching quality and enforcement as we continue to hurtle past the COVID-19 public health emergency (PHE).

    Here’s a breakdown of some of the more interesting highlights, statistics and graphics from the FY 2022 report.

    Geography of Manufacturing Sites

    OPQ reports that as of October 2022, CDER’s manufacturing site catalog listed 4,814 facilities, a 12% increase over 2018.  Forty percent of those sites are in what CDER terms the “No Application” sector, meaning that those sites make over the counter (OTC) products, unapproved drugs, and homeopathic products, all sold without premarket approvals.  That leaves 60% that manufacture at least one application product.  Those include biological products licensed under Biologics License Applications (BLAs), approved drugs under New Drug Applications (NDAs), and generic products under approved Abbreviated New Drug Applications (ANDAs).

    As one might expect, the lion’s share of the registered facilities—over 2,000 of the total—are located here in the U.S.  But the Report helps emphasize the global challenges FDA faces trying to ensure quality.  After the U.S., the most prominent site for facilities was India, with over 600 sites.  China was third with over 430 sites, and after that, several countries in Europe and in Asia each had over a hundred catalog sites, including Germany, Canada, Italy, France, Japan, the U.K., and South Korea.

    Table: Inventory Shift Over FY2018-FY2022 for Countries (Greater Than 50 Sites)

    Drug Products

    In addition to a catalog of manufacturing sites, OPQ reports that CDER also keeps a drug product catalog that contains over 140,000 entries.  Of those, a whopping 123,000 are non-application products that have a unique national drug code number, leaving around 17,000 products covered under BLAs, NDAs, and ANDAs.  For these covered products, voluntary reports to MedWatch increased by seven percent for 2022, but other monitoring such as Field Alert Reports, Consumer Complaints, and Biological Product Deviation Reports showed declines in reporting.  OPQ attributes that in part to the decrease in the use of injectable products as the PHE waned.  The PHE also had a dramatic effect on import alerts.  FDA issued 28 quality-related import alerts in 2022, and most of those 28 alerts were for hand sanitizers that contained impurities or had other defects.


    Recalls hit a five-year peak in 2022.  OPQ reported that 166 catalog sites generated 912 recalls.  Four specific kinds of events comprised over a third of the 900+ recalls.  Temperature problems were the primary leaders, as the leading event was temperature abuse at 130 recalls, followed by 100 recalls related to products held outside appropriate storage temperature conditions.  CGMP deviations caused 56 recalls, and excipient manufacturers performed 51 recalls due to contamination.

    Warning Letters

    Non-sterile, non-application products received most warning letters issued in 2022, according to OPQ.  FDA issued 72 CGMP-related warning letters to pharmaceutical manufacturing sites, and over two-thirds of those went to makers of non-application products.  That number is notable because those sites comprised only 30% of inspections.  Again, the effects of the PHE lingered in this area, as FDA targeted hand sanitizer manufacturers with 31 of those 72 letters.  The top-five CGMP issues in 2022 were related to 1) quality control units, 2) production record review/investigations, 3) written procedures/deviations, 4) equipment cleaning and maintenance, and 5) testing and release procedures.


    While the 2022 Report does not specify what specific circumstances might prompt FDA to take samples for testing, of those that FDA collected, 892 of 1,552 samples—57%–tested at FDA laboratories were out of specification or non-compliant.  FDA’s PHE-focused testing found more troubles with sanitizers, as all the non-compliant COVID tests came from hand sanitizer products that were either subpotent or contaminated with impurities. 2022 marked the fifth straight year that FDA labs found an increasing level of noncompliance.

    Table: Laboratory Sample Compliance Rates by Fiscal Year


    OPQ faces increasingly global challenges as it seeks to protect the drug supply chain.  Rest assured that 2023 will see FDA continue to direct resources away from the PHE and into other quality initiatives on an international scale.

    The Active Ingredient Stands Alone

    One of the most important questions FDA has to answer is whether a given product is appropriately characterized as a drug, biologic, device, food, cosmetic, or something entirely different.  As we have explained before, that distinction is critical to assigning a particular product to the appropriate regulatory scheme.  While it is exceedingly obvious that some products, like eyeshadow for example, are cosmetics, or a pacemaker is a device, it can get thorny where the distinction is based on a very fine line—like the number of amino acids in a given active ingredient.  That line becomes even more blurred where it’s not entirely obvious what constitutes the active ingredient.  And, like it has before, the District Court of D.C. recently grappled with this very question in Ipsen v. Becerra.

    To set the stage for this case, we need to go back to March 2020, when a new definition of “biological product” threw the world of protein products into a tizzy.  As a result of the Biologics Price Competition and Innovation Act (BPCIA) passed in 2010, the definition of a “biological product” expanded to include “proteins.”  FDA further defined the term “protein” so that it includes any peptide product that has an amino acid sequence greater than 40 amino acids.  FDA also published a list of products anticipated to “transition” from a drug approved under an NDA (FDCA § 505) to a biological product deemed approved under a BLA (PHS Act § 351), and, in March 2020, products meeting the definition of “protein” officially transitioned to BLAs.

    But, as is inevitable, there were some disputes about whether certain products should have transitioned, including several that resulted in litigation against FDA for continuing to regulate given products as drugs rather than biologics.  In one such lawsuit, Ipsen sued FDA arguing that the Agency’s decision to regulate its Somatuline Depot (lanreotide acetate) product as a drug rather than a biological product was “arbitrary, capricious, an abuse of discretion, and contrary to law.”  More specifically, Ipsen argued that Somatuline Depot is a “protein,” and therefore, pursuant to the March 2020 transition, should be regulated a biologic rather than a small molecule drug.

    Approved in 2007 for the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy, with several indications added in the subsequent years, Somatuline Depot is a synthetic octapeptide available as ready-to-use prefilled syringes for deep subcutaneous injection.  Importantly, as an octapeptide, Somatuiline Depot is a “protein” but consists of only eight amino acids linked in a polypeptide chain.  However, Ipsen argued, Somatuline still meets FDA’s definition of a protein—more than 40 amino acids—because it contains multiple copies of its active ingredient that are linked together “in a manner that occurs in nature” to form a “nanotube” greater than 40 amino acids long.  Should the nanotube not constitute a biologic, Ipsen also argued that Somatuline Depot is at least “analogous” to a protein under the statute.   Thus, Ipsen asked the Court to direct FDA to transition the NDA to a deemed BLA.

    FDA, on the other hand, argued that the finished product form—i.e., the nanotube—is irrelevant, as it is the “active ingredient” that matters for purposes of classifying the product as a drug or biologic.  Thus, FDA’s position is that a drug is a “protein” only if its “active ingredient” is composed of at least 40 amino acids.  That is not Somatuline Depot, which has only eight amino acids, and thus Somatuline Depot is not a biologic.  FDA also took the position that Somatuline Depot is not “analogous” to a protein because “it would not be appropriate to interpret the statutory term . . . in a way that would include amino acid polymers that are specifically excluded by the interpretation of the term ‘protein’ set forth in FDA’s Biological Product Definition Final Rule.”

    As in most cases, the Court first addressed standing.  In one of the most plainly stated declarations we’ve seen in an FDA APA case, the Court clearly stated the principle of competitor standing.  In other words, the Court found that “Ipsen has sufficiently shown that it suffered a competitive injury because the FDA’s decision to regulate Somatuline Depot as a drug, rather than a biologic, allowed InvaGen to compete with Ipsen using the Drug Act’s § 505(b)(2) pathway. That option would not have been available to InvaGen had the FDA instead determined that Somatuline Depot and InvaGen’s product were biological products.”  Because FDA’s refusal to regulate Somatuline Depot as a biologic was the “but-for” cause of Ipsen’s competitive injury, and because “that injury flowed directly and inextricably from the FDA’s decision to regulate Ipsen under the [FDCA],” the Court found a causal nexus between FDA’s action and Ipsen’s competitive injury.  Thus, the threat of competition is enough to confer standing.

    While Ipsen had standing, however, the Court pretty clearly found that FDA’s determination that Somatuline Depot is not a biologic was consistent with the regulation’s plain language and reflects rational decision making.  Though Ipsen argued that FDA should look at the finished drug product—the nanotube with far more than 40 amino acids—rather than the substance with only eight amino acids to assess whether the product is a drug or a biologic, the Court explained that “[n]either the statute nor the regulatory definition of a ‘protein’ requires the FDA to consider the size of the active ingredient as it appears in the final drug product, rather than standing alone” (emphasis in the original).  Instead, FDA’s decision to discern the active ingredient based on what “confers [its] pharmacologic activity” and thus FDA’s decision to analyze just the lanreotide acetate rather than the nanotubes “was unambiguously correct”—and even if it weren’t, the Court stated it would “defer to the FDA’s interpretation as reasonable” because it falls within FDA’s area of special expertise.   Ipsen’s alternative argument—that Somatuline Depot is “analogous” to a protein—was also rejected by the Court.  Thus, as expected the Court deferred to FDA, and left the determination as to whether a product is a drug or a protein to the active ingredient rather than the finished drug product.

    Ipsen recently appealed this decision to the D.C. Circuit.  No briefs have been filed yet, with the initial submissions due the end of July.  The D.C. Circuit has previously addressed questions of drug versus device, finding against the Agency based on the plain language of the statute, so this is not entirely unfamiliar territory.  We’ll be watching to see what happens next.

    Mastering Responses to FDA 510(k) AI Letters: A Strategic Approach

    It takes a significant amount of time, cost, and effort to prepare a premarket notification 510(k) submission.  But that is only the beginning.  After a firm submits a 510(k) to FDA, FDA will request still more information after a first-pass review.  According to the 2nd Quarter FY2023 MDUFA V Performance Report, FDA issued a request for additional information (AI request) on the first FDA review cycle for 63% to 68% of 510(k)s submitted in FY2018 to FY2022.  In this blog post, we will first briefly outline the procedural steps in the 510(k) review process for medical devices.  We will then present an effective strategy to address FDA’s AI request in a timely manner.

    Understanding the Traditional 510(k) Review Timeline

    There are three types of Premarket Notification 510(k)s: TraditionalSpecial, and Abbreviated.  The most common type is the Traditional 510(k), therefore this section summarizes the timeline of the FDA review process for a Traditional 510(k).  However, the strategy of addressing the AI request presented in the next section of this blog post applies to all three types of 510(k)s.  Table 1 below shows the 510(k) submission process based on the MDUFA III Performance Goals.

    FDA Day (in calendar days)FDA Actions
    Day 1FDA receives 510(k) submission.
    By Day 7FDA sends Acknowledgment Letter.


    FDA sends Hold Letter if unresolved issues with User Fee and/or eCopy.

    By Day 15FDA conducts Acceptance Review.

    FDA informs submitter if 510(k) is accepted for Substantive Review or placed on RTA Hold.

    By Day 60FDA conducts Substantive Review.

    FDA communicates via a Substantive Interaction to inform the submitter either that FDA will proceed with Interactive Review or that the 510(k) will be placed on hold until FDA receives a complete response to an Additional Information request.

    By Day 90FDA sends final MDUFA Decision on 510(k).
    By Day 100If MDUFA Decision is not reached by Day 100, FDA provides Missed MDUFA Decision Communication that identifies outstanding review issues.

    Table 1. Traditional 510(k) Submission Process.

    FDA aims to make the MDUFA Decision (i.e., SE or NSE decision) for 95% of 510(k)s by FDA Day 90 to achieve the performance goals under MDUFA V.  A best-case scenario for a firm would be that FDA does not place the submission on hold and clears it within 90 total calendar days (or less) to reach the SE decision.  However, the reality is usually different.  The 2nd Quarter FY2023 MDUFA V Performance Report shows that 63% to 68% of 510(k)s submitted over the past five years received an AI request.  As demonstrated by the statistics over the past five years (Table 2), the average number of Total Days (FDA Days + Industry Days) ranged from 127 to 159 calendar days.

    Performance MetricFY 2018FY 2019FY 2020FY 2021FY 2022
    Average Number of FDA Days to MDUFA IV Decision72.6273.5579.3383.4077.38
    Average Number of Industry Days to MDUFA IV Decision54.6960.4070.3475.8252.17
    Average Number of Total Days to MDUFA IV Decision127.31133.95149.67159.22129.55

    Table 2. 510(k) Time to MDUFA IV Decision. Note that days are in calendar days.

    When a firm submits a Traditional 510(k), FDA first performs the acceptance review to determine whether a submission is administratively complete, or passes the technical screening for an electronic submission submitted using the eSTAR.  If the submission passes the acceptance review, the firm will receive the first good news from FDA via email that the submission has been accepted for substantive review.  In this case, the FDA clock start date is determined as the date of receiving the submission by the Document Control Center (DCC).  Note that the FDA clock uses calendar days.

    FDA then conducts a substantive review.  To achieve the 510(k) performance goals under MDUFA V, FDA aims to make the Substantive Interaction (SI) decision by Day 60 for 95% of 510(k) submissions.  The SI communication could be great news for the firm if FDA notifies that it will continue to resolve any outstanding deficiencies via Interactive Review.  In this case, the FDA’s clock continues to forward without placing the submission on hold.  FDA may issue “real-time” requests by sending an email to the firm with a list of relatively minor questions to resolve.  In such email correspondence(s), FDA may indicate the response due date (usually very tight timelines) and the firm may provide its response by sending an email to the FDA lead reviewer by the indicated response due date.

    If FDA issues an AI letter, it could be stressful news for the firm and a very different scenario will play out.  In this case, FDA’s email includes a PDF attachment that lists deficiencies that FDA identified in the submission.  There are two types of deficiencies: major and minor.  If major deficiencies are not adequately resolved, they may preclude a favorable decision on the 510(k).  Minor deficiencies can be resolved in a straightforward manner, but they need to be addressed to meet regulatory requirements or to prevent potential misbranding or adulteration.  When FDA issues an AI request, it places the submission on hold and the FDA clock stops.  The firm has a maximum of 180 calendar days to respond.  The CDRH Portal will highlight the response due date.

    The stakes are high.  The firm has a maximum of 180 calendar days to respond, or FDA will treat the 510(k) as terminated.  That deadline seems generous, but it can come quickly if the firm needs to engage with FDA to further clarify the deficiencies, receive feedback on the plan to address the deficiencies, or the firm needs to perform additional testing to adequately respond.  All of these activities must be completed within the 180-day timeframe.  Worse, the firm only has one bite of the apple.  The AI response package must respond completely to all parts of the deficiencies and include all information needed to address the deficiencies; in other words, a firm cannot submit a partially completed response package and plan to submit another AI response package at a later date to address remaining deficiencies.

    If the response to an AI request does not successfully address all deficiencies, FDA will issue an order declaring a device not substantially equivalent (NSE) to a legally marketed predicate device (NSE letter).  At this point, if the firm wishes to pursue clearance for its device, it has two options: it may either request supervisory review (i.e., an administrative appeal) under 21 CFR 10.75 or submit a new 510(k) application, which will be reviewed within a new 90-day timeframe.  It is crucial, therefore, to develop a comprehensive response strategy as soon as possible after receiving an AI request.  In the next section of this blog post, we will explore effective approaches to addressing 510(k) AI request to optimize the chances of success.

    Comprehensive Analysis of FDA Deficiencies

    What is FDA’s guiding principle for generating deficiencies?  The Least Burdensome Provisions, amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) and the 21st Century Cures Act, provide the following principle of generating deficiencies: “Whenever the Secretary requests information to demonstrate that devices with differing technological characteristics are substantially equivalent, the Secretary shall only request information that is necessary to making substantial equivalence determinations. In making such request, the Secretary shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly.” Federal Food, Drug, and Cosmetic Act, Section 513(i)(1)(D)(i).

    Per FDA’s guidance documents, Developing and Responding to Deficiencies in Accordance with the Least Burdensome Provisions, each FDA deficiency should include the following four elements: (1) what was submitted, (2) identification of a specific issue or concern, (3) statement of basis for the deficiency, and (4) explicit request for the additional information needed.  We suggest a firm thoroughly review and analyze the AI letter to understand the FDA’s rationale behind the deficiencies and the FDA’s “ask.”

    These AI requests often address complicated scientific scenarios in which a submitter has already provided some information, but FDA is not completely satisfied.  Under the guidance, the AI request must summarize the state of play based on the information submitted so far, and then define what would be necessary to resolve the issue.  It is not as easy to formulate this type of request as the firm might think, and as a result, FDA’s AI requests can sometimes seem convoluted.  Not infrequently, a request is lengthy, with multiple subparts.  So the first task is to thoroughly understand each deficiency and map out what will be needed to address it.  This process can require a great deal of time and collaboration as further described below.

    Collaborative Planning and Execution

    In the AI letter, deficiencies are arranged according to review areas, such as administrative information, 510(k) summary, performance data, engineering performance, biocompatibility, sterilization, software validation, clinical data, and labeling.  An AI letter typically begins with the most significant deficiencies.  There is a wide range of the number of deficiencies−it could be just one major deficiency about one of these review areas.  The AI letter could also present 20 major deficiencies covering multiple review areas and another 30 minor deficiencies.  There is no limit to the number of deficiencies that FDA may generate and include in the AI letter.

    Upon receiving the AI letter, appoint a lead person and disseminate the letter among team members for review.  This approach would be particularly helpful if the AI letter covers a wide range of subject matter expertise.  It is typical that a regulatory expert would take the lead.  A spreadsheet may be helpful to track deficiencies, response strategies (e.g., if additional testing is required or justification would suffice), responsible individuals, proposed timelines, and any clarifying questions for FDA.  Team meetings with subject matter experts can be scheduled to discuss response strategies for deficiencies that require extensive clinical, scientific, or engineering input.  If necessary, the firm may engage with third-party laboratories early on to address deficiencies about, for example, but not limited to, biocompatibility, electromagnetic compatibility, or electrical safety and determine timelines for conducting and completing the testing.  When contacting third-party testing laboratories, we suggest discussing the FDA deficiencies with the laboratory personnel so that they understand FDA’s concerns and can generate the data required to address the deficiency as efficiently as possible.  Working with third-party testing laboratories will be effective only if the corresponding deficiency is clearly understood.  If any deficiency is confusing to the firm, we suggest the firm correspond with FDA first to clarify it before planning or conducting any additional testing.

    Effective FDA Correspondence Strategy

    After a thorough review of the AI letter, the team should consider whether each deficiency is fully understood.  When in doubt, take advantage of FDA’s standard offer of a 10-day call to clarify one or more of the deficiencies.  A list of questions should be prepared and sent to the FDA lead reviewer 48 hours prior to the call.  As this is a 30-minute call, questions should be prioritized in the order of importance to ensure there is time for discussion of key issues.  The 10-day call is intended only to clarify the deficiencies and not to receive FDA’s confirmation on the adequacy of a firm’s plan to address the deficiencies.  It is our experience, however, that some FDA review teams generously offer a quick response to confirm the firm is on the right track in addressing certain deficiencies.  While formal meeting minutes are not mandatory for a 10-day call, it is beneficial to draft minutes and include them in the AI response.

    If the scope of the questions submitted for the 10-day call is extensive or if discussion of plans to address the deficiencies is needed, a Submission Issue Request (SIR) pre-submission can be used to seek FDA feedback on proposed approaches to address deficiencies.  If a SIR pre-submission is submitted within 60 days of the AI letter, FDA targets providing meeting or written feedback in 21 days from a request, to the extent resources permit.

    Thus, it is beneficial to determine early whether a SIR is needed and to submit as soon as possible within the first 60 days.  If the 60-day mark is missed, FDA may provide meeting or written feedback from a request in 70 days as resources permit.  Note that the method of feedback for a SIR is meeting or written feedback, not both.  However, in our experience, there are some occasions that FDA has offered both written feedback and a meeting for a SIR, and FDA is generally able to respond to follow-up questions interactively via e-mail once the meeting has been held or written feedback provided.  Whether a firm used the 10-day call and/or an SIR, it should include any prior feedback from those interactions with FDA in the AI response and describe how and where in the AI response package the prior feedback was addressed.

    Streamlining the AI Response Preparation

    The Guidance recommends a response format which entails restating the identified issue and providing one of the following: (1) the requested information or data, (2) an explanation of why the issue does not impact the marketing authorization decision, or (3) alternative information that adequately addresses the issue.

    To ensure a comprehensive and timely response within the given 180-day timeframe, it is a good idea to begin drafting responses early on.  This approach not only allows the response to be submitted promptly upon receipt of the last reports or other information, but can also be helpful to identify any gaps in the planned approach and to ensure the team is addressing all aspects of the response.  If the AI response becomes extensive, it can be organized with a table of contents, list of attached files, list of figures, and/or list of tables to facilitate ease of review.  In each response, a firm should include a clear explanation as to how the response addresses the FDA’s concerns.

    Tips for Facilitating FDA Review

    When providing new test data, a firm should provide a clear narrative description of the goals, protocols, and how the data address FDA’s concerns.  Avoid simply referencing attachments without additional context or descriptions and letting FDA “figure out” the data.  Such responses may lead to reviewer confusion and delay.

    When referencing documents within the AI response, cite location within the 510(k) supplement (e.g., Attachment number) and document name or description as appropriate.  When discussing specific information within a referenced document, also include the page number where the specific information may be found.  For labeling documents and the 510(k) summary, FDA often requests both clean and redlined versions.  If a firm provides an editable version of the 510(k) summary to FDA, it may be helpful to facilitate editing and finalizing the 510(k) Summary with FDA.  In the AI response package, hyperlinks can be used to help the reviewer get to the referenced information quickly.  If a response to one deficiency addresses other deficiencies, it is best to refer back to the previous response and avoid redundancy or the potential for inconsistency.

    During the recent Regulatory Education for Industry (REdI) Annual Conference, June 6-10, 2022, FDA presented “Tips from a Lead Reviewer” for the presentation titled “Detangling the 510(k) Process.”  In this presentation, FDA suggested the following tips.

    Tip #1: Keep in mind that your file will be reviewed by a human

    • Keep your file organized
    • Must be submitted in English

    Tip #2: Check your email often

    • Work to get you a decision as soon as possible, within MDUFA deadlines
    • Sometimes, this makes it necessary to issue communications during non-business hours
    • Don’t forget about your spam folder!

    Final Remarks

    An FDA AI letter can be lengthy – it is not unusual for AI letters to exceed 10 pages – and therefore challenging to address.  Take a deep breath and address them one by one.  We have had many successful experiences addressing challenging AI requests with the strategic approach discussed here and hope this approach may help your next 510(k) clearance.

    Categories: Medical Devices

    Finalizing the Quality Management System Regulation – A High Priority for End of 2023

    Earlier this year, neither the Quality System Regulation (QSR) nor the Quality Management System Regulation (QMSR) were referenced in the semiannual regulatory agenda.

    We now see that the proposed rule to “harmonize and modernize” the QSR with ISO13485:2016, creating the new QMSR, is on the Spring 2023 Unified Agenda (see here). According to the Unified Agenda, the proposed rule is in the final rule stage.

    The final rule’s publication is a “high priority”, according to Dr. Jeff Shuren, director of FDA’s Center for Devices and Radiological Health (CDRH), during his remarks at the annual Food Drug and Law Institute (FDLI) conference in May 2023. In fact, the priority designation for the final rule is labeled as “economically significant.” Dr. Shuren further elaborated that he hopes the final rule will be “out by the end of this year.” This would align with the timeline in the Unified Agenda which identifies December 2023 as the expected publication date for the final rule.

    We remain cautiously optimistic of the timeline given the extensive and competing priorities CDRH has in front of them, including:

    Even if the teams are different for each of these activities, freeing up resources to finalize the rule, it is still a significant undertaking in the next six months.  While the proposed rule contemplates a transition period of one year to allow for this, commenters to the proposed rule think two to three years is more appropriate. We will not know the official transition period until the final rule has been published.  However, two to three years seems far more appropriate even from FDA’s perspective.

    Once the final rule is published there will still be significant work to be done by FDA.  For example, during the transition period, FDA would need to address the effect of the new regulation to the existing inspection process and staff would need time for training to effectuate execution and enforcement.  Finally, CDRH would need to ensure alignment on existing guidance documents and regulations that refer to the QSR or 21 C.F.R. Part 820.

    Time will tell if the rule can be finalized by year’s end and how much time both FDA and industry will have to prepare for its effect.  Those in industry who are already ISO 13485 and QSR compliant and participating in FDA’s Medical Device Single Audit Program are likely the most well prepared and will feel the least impact by the change.

    Categories: Medical Devices

    The Wholesaling Prohibition (Potentially) Demystified? FDA’s Take on Supply Chains for Section 503B Outsourcing Facilities

    Last week FDA published a long-awaited Draft Guidance for outsourcing facilities addressing the Prohibition on Wholesaling Under Section 503B of the Federal Food, Drug, and Cosmetic Act (Draft Guidance).  As a reminder, in Title I of the 2013 Drug Quality and Security Act (DQSA) (the Compounding Quality Act), Congress created the “outsourcing facility” FDA registration category, and set forth statutory parameters for their operation in new section 503B of the FDCA.  Under section 503B, drugs compounded by an FDA-registered outsourcing facility under the supervision of a licensed pharmacist can qualify for exemptions from FDA approval, labeling with adequate directions for use, and certain drug supply chain security requirements, subject to specific conditions.  See 21 U.S.C. § 353b(a).  On an annual basis, outsourcing facilities must register with FDA, pay the facility establishment fee, and submit biannual drug reporting to the Agency, among other requirements.  Outsourcing facilities are not exempt from FDA’s cGMP for drug manufacturers (as lightly tweaked via cGMP Guidance for outsourcing facilities) or adverse event reporting requirements, and are subject to regular inspection by FDA.

    This Draft Guidance pertains to the prohibition on wholesaling or transfers—a two sentence provision in section 503B that states that a drug compounded by an outsourcing facility “will not be sold or transferred by an entity other than the outsourcing facility that compounded such drug. This paragraph does not prohibit administration of a drug in a health care setting or dispensing a drug pursuant to a prescription.”  21 U.S.C. § 353b(a)(8).

    As explained in the Draft Guidance, the prohibition on wholesaling “preserves important distinctions between outsourcing facilities, which are intended to compound drugs for patients whose medical needs cannot be met by approved drugs, from conventional manufacturers, which generally engage in mass manufacturing of FDA-approved drug products.”  Section II at 2.  While section 503B expressly does not require a patient-specific prescription, FDA clarifies that Congress evidently did contemplate a “connection” (our words…) between an outsourcing facility and the prescriber; the more attenuated that relationship, the more an outsourcing facility starts to resemble a conventional drug manufacturer.  Essentially—in contrast with a conventionally manufactured drug that may be sold and resold several times before it reaches a patient (and is subject to Drug Supply Chain Security Act requirements)—FDA believes the supply chain for a drug compounded by a 503B outsourcing facility should be less attenuated and easily traceable.

    FDA clarifies that the “sold or transferred” statutory language makes it clear that the prohibition applies to the physical movement of the product, regardless of whether or not money has changed hands.  Many of the examples provided in the Draft Guidance concerning the application of the wholesaling prohibition seem somewhat consistent with industry’s understanding in the nearly 10 years since the enactment of the DQSA.  For example, FDA does not intend to apply the prohibition to transfers of product that do not affect the integrity of the drug approval process or supply chain, which product movement is typically conducted for public health reasons, such as a transfer as part of a recall or return, or to a laboratory for testing.  Additionally, sales by an outsourcing facility to a wholesale distributor, repackager, or relabeler that, in turn, sells or transfers the drug are clearly prohibited because the drug is being sold by an entity other than the outsourcing facility that compounded it (i.e., the wholesale distributor, repackager, relabeler).

    Concerning what FDA finds “Not Prohibited” under the Draft Guidance, we applaud FDA for what we consider its most significant clarification in the Draft Guidance.  Specifically, the Agency recognizes that that an outsourcing facility may distribute a drug it compounded to a “state licensed pharmacy, federal facility, or licensed physician, which subsequently dispenses the drug pursuant to a prescription.”  Draft Guidance III.B.2(e) at 9.  Outsourcing facilities may also distribute a compounded drug to a hospital or health system,  clinic, or physician’s office where it is used as “office stock” to dispense to patients pursuant to prescriptions. Draft Guidance III.B.2(d) at 9.

    An area of clarification that we believe will be appreciated by industry concerns sales to a group purchasing organization (GPO).  Under the Draft Guidance, the distribution by an outsourcing facility of a drug it compounded to an entity that provides healthcare services (e.g., a hospital or health system, health clinic, or physician’s office) based on pricing agreements the outsourcing facility negotiated with a GPO acting on behalf of the healthcare services entity, is not prohibited wholesaling.  Because a GPO “does not own drugs, ship drugs, warehouse drugs, handle drugs, or hold drugs” and “does not purchase, or decide to purchase, drugs,” the GPO has not “sold” or “transferred” the drug compounded by the outsourcing facility.  Draft Guidance III.B.2(f) at 9-10.  The outsourcing facility transferred the drug to the healthcare services entity; the GPO is merely the “negotiator.”

    One truly surprising inclusion in the “Activities Prohibited” section of the Draft Guidance, however,  addresses FDA’s interpretation of a non-traditional type of wholesaling or transfer (if one could even call it wholesaling or transferring in the first instance) where a third party actually does not take possession of the drug product.  More specifically, the prohibition includes when a “third party (e.g., a marketing firm or operator or a website that is not a pharmacy ) sells a drug compounded by an outsourcing facility even though the third party does not take physical possession of the drug, by providing services (e.g., training, billing, advertising) to physicians that prescribe the drug and bundling the cost of those services with the costs for obtaining the drug.”  Draft Guidance III.B.1.(e) at 7-8.  Here, FDA may be concerned that the outsourcing facility “does not recoup the cost of the compounded drug product directly from the prescribing physician,” rather than the physical movement of the product, which is still from the outsourcing facility to the provider.

    FDA presents an arguably strained reading of the practice of wholesaling (whether via a marketer, third party website or otherwise).  The contemplated activities here would not in any event affect the “quality” of the compounded formulation.  And compounding “Quality” is indeed at the heart of the “Compounding Quality Act” under any interpretation.  This seems targeted, more or less, at the advertising and promotion by third parties of drugs compounded by outsourcing facilities that are made available to prescribers for dispensing to patients, rather than the “quality” of the compounded formulation itself.  This prohibition also seems wholly inconsistent with FDA’s statements concerning “essentially copies,” where the “price” of the compounded drug cannot be a consideration when compounding what may be essentially a copy of a commercially available drug product. But in this prohibition provision, it seems that charging a higher “price” for the drug—notwithstanding part of a bundled service—is exactly what FDA is trying to prevent.

    There are two somewhat related examples for which further clarification may be needed:

    1. Intracompany transfers: The prohibition does not apply to “intracompany transfers during shipment” to the customer, “including when an outsourcing facility sends drugs it compounded to a warehouse it owns or leases that is not located in the outsourcing facility that compounded the drugs for shipment to the outsourcing facility’s customers.” Draft Guidance III.A.1 at 5.

    For example, if an outsourcing facility located on in one state ships drugs to its warehouse several states away so that the product can then be shipped to customers in a different part of the country that is closer to the warehouse than the outsourcing facility, this would not be a prohibited transfer.  This is a much-needed clarification for industry.

    However, Section III.B.2(a) suggests a more limited view of an “intracompany transfer,” which would apply only to the movement of a compounded drug to another location that is “part of the same outsourcing facility (i.e., at the same address or geographic location) for subsequent distribution.”  Under this narrower provision, the transfer of product from an outsourcing facility in one state to a warehouse in another, which then ships it to an end customer in another part of the country would seemingly be prohibited because the outsourcing facility and warehouse are not at the same address or geographic location.  But such a transfer is plainly permissible in the scenario FDA describes in Section III.A.1—so long as it is an intracompany transfer during shipment to a customer.

    1. Outsourcing facility-to-outsourcing facility transfers: The concept in this example is not dissimilar to an intracompany transfer. FDA’s Guidance example states that the transfer of drugs compounded by outsourcing facility A to outsourcing facility B for subsequent distribution is prohibited wholesaling.  However, the Draft Guidance specifies that A and B are “are owned by different entities and registered with FDA as separate outsourcing facilities.”  Section III.B.1(b).  But what if A and B are owned by the same entity, but are registered with FDA as separate outsourcing facilities because they’re in different geographic locations?  Is this a prohibited transfer, or is it a permissible intracompany transfer?  And, what if instead of only handling the “subsequent distribution” or shipment, outsourcing facility B is further compounding the product it receives from outsourcing facility A?  We believe that, because the outsourcing facilities are “owned” by the same entity, the transfer between facility A and facility B would be permissible under the Draft Guidance.

    Our main takeaway from this Draft Guidance is that even this short supply chain can get surprisingly tangled.  Let us know if you have questions!

    3 in 1 Guidance Issued by FDA Covering Formal Dispute Resolution, Administrative Hearings and Consolidated Proceedings for OTC Monograph Drugs

    On June 23, 2023, FDA issued a draft guidance for industry – Formal Dispute Resolution and Administrative Hearings of Final Administrative Orders Under Section 505G of the Food, Drug, and Cosmetic Act (the Monograph FDR Guidance) – to fulfill another commitment agreed to in support of the 2020 Coronavirus Aid, Relief, and Economic Security Act (CARES Act)(see our blog posts here, here and here about the CARES Act and OTC monograph reform).   Under the OTC Monograph User Fee Program commitment letter, FDA committed to modify existing guidance on formal dispute resolution (FDR) process and to issue guidance on consolidated proceedings for appeals.  Rather than modify the existing FDR guidance and issue separate guidance on consolidated proceedings, FDA has issued a single draft guidance covering both topics. The CARES Act also provides for an administrative hearing process that may be utilized under certain conditions following the formal dispute resolution process.  This is the third topic included in the new draft guidance.

    Formal Dispute Resolution

    The draft guidance draws from the existing CDER and CBER guidance on formal dispute resolution (Existing FDR Guidance) with some significant differences.  After FDA issues a final order under Section 505G of the Food, Drug, and Cosmetic Act, requestors who will be subject to the final order and sponsors of OTC monograph drugs that will be subject to the final order are eligible to request formal dispute resolution.  The draft Monograph FDR Guidance clarifies that FDR is appropriate only when there is a scientific and/or medical dispute related to a final order.  A proposed order or an interim order is not an appropriate subject for an FDR.  Additionally, meeting minutes and other communications of advice that are not final orders are not appropriate subjects of an FDR because those materials typically make recommendations or give advice to which the sponsor or requestor is not bound (even though they may in some cases justifiably feel that not following the recommendation would be unlikely to lead to success).  Like the Existing FDR Guidance, the new draft guidance also clarifies that an FDR for an OTC final order must be based only on the same information that was relied upon to make the original decision and that new information or new analyses of previously reviewed data should not be included in the FDR.

    Unlike the Existing FDR Guidance, however, the new draft guidance does not provide that a meeting with the decision maker can be requested, though it appears that FDA may decide on its own to have such a meeting.  This significant opportunity under the Existing FDR Guidance is not offered for monograph FDRs.  Another difference that may prove challenging for those seeking an FDR is that the new draft guidance includes quite short deadlines for submission of the FDR:  within 45 days of issuance of the final order for the first level of appeal and within 30 days of a prior decision for the next level of appeal.  While FDA provides a list of the information that needs to be included in the FDR, and this information can easily be put together in that time frame, 45 or 30 days does not allow much time for those seeking FDR to fully digest the decision being appealed and develop a meaningful analysis in response – a critical element of any effective FDR request under the Existing FDR Guidance.

    The timelines for FDA’s response to an FDR follow those in the Existing FDR Guidance.  Ordinarily, the decision will be issued within 30 days from receipt of the request.  If, however, the deciding official requires additional information from the party submitting the request or from internal or external experts, or decides that a meeting with the requesting party is needed, an interim response will be issued within 30 days from receipt of the request, and the decision will then be issued within 30 days of FDA’s receipt of the needed information or the meeting.

    The Monograph FDR Guidance also explains that, except to the extent public disclosure of information submitted to FDA is prohibited, the Agency generally intends to make information submitted to FDA in the context of FDR available to the public. This could include the FDR request and information submitted to FDA in support thereof.  Information submitted in connection with an FDR will remain confidential if (1) the information pertains to pharmaceutical quality information, unless the information is necessary to establish standards under which a drug is generally recognized as safe and effective or GRASE, or (2) the information is of the type contained in raw datasets.

    Administrative Hearings

    If the FDR process up to the Director of CDER is completed, eligible requestors and sponsors that participated in each stage of the FDR may request an administrative hearing not later than 30 days after the final FDR decision is issued.

    FDA will not provide an opportunity for a hearing if the final order relates to certain drugs that were classified in Category III for safety or effectiveness in the preamble to the proposed rule that established the most recent tentative final monograph (TFM) if no human or nonhuman studies on the safety or effectiveness of the drug have been submitted to the administrative record since the most recent TFM was issued.

    FDA may deny a request for a hearing if the request does not identify the existence of a “genuine and substantial question of material fact.”  In making its determination, FDA may consider only information and data that are based on “relevant and reliable scientific principles and methodologies”.

    A hearing for a final order is not a formal, trial-type, evidentiary hearing.  The hearing will generally be public, but FDA may close all or part of the hearing to prevent disclosure of information FDA has held as confidential in the administrative record.  The presiding officer will not be an employee of CDER or have been previously involved in the development of the administrative order at issue.

    Consolidated Proceedings

    One of the challenges unique to the monograph system that the CARES provisions applicable to dispute resolution sought to address is the potential for a decision on a final order to affect multiple parties.  Consequently, proceedings may be consolidated on FDA’s initiative or upon request.

    If more than one request for an FDR or hearing is submitted concerning the same final order, FDA may consolidate the requests and direct that a single proceeding be conducted.  Although all consolidated parties may participate in the FDR or hearing, the number of individuals from each party able to attend the consolidated proceedings in person may be limited because of facility and space limitations. FDA will determine the total number of individuals who can attend the consolidated proceedings in person.

    Additionally, eligible requestors or sponsors may submit a joint request for an FDR or hearing with respect to the same final order.  In that case, a single point of contact must be designated by those requesting consolidation.  If a participant in a consolidated proceeding decides they no longer want to participate, they may withdraw and the proceeding may continue with the remaining eligible requestors or sponsors.

    It may be a while before anyone seeks to utilize the processes covered by the draft guidance, but it is another commitment under OTC monograph reform checked off FDA’s to-do list.

    DEA Fine-Tunes the Theft and Significant Loss Reporting Two-Step

    Like the celebrated Texas dance of the same name, reporting controlled substance thefts and significant losses to the Drug Enforcement Administration (“DEA”) requires just that: two steps.  For the first time in eighteen years, DEA has revised its controlled substance theft and significant loss reporting regulations.  Since 1995, at least 28 registrants, primarily hospitals and pharmacies, have paid significant civil penalties ranging from $10,000 to $5,000,000 to settle allegations that they wholly or in part failed to report, or failed to report in a timely manner, controlled substance thefts or significant losses to DEA.  We thought it appropriate to take this opportunity to not only explain DEA’s revised regulations but also how registrants must now report controlled substance thefts and significant losses.

    Step 2: DEA-106 Submission

    DEA just published a final rule amending its theft and loss reporting regulations to require registrants to submit a “Report of Theft or Loss of Controlled Substances,” DEA Form 106 (“DEA-106”), electronically to the agency within 45 days of discovery of a theft or significant loss.  Reporting Theft or Significant Loss of Controlled Substances, 88 Fed. Reg. 40707, 40708 (June 22, 2023) (to be codified at 21 C.F.R. §§ 1301.74(c) and .76(b)). Attached here.

    The rule now requires registrants to first report a theft or significant loss in writing within one business day of discovery (step 1), followed literally by a DEA-106 filed through the agency’s secure network application “within 45 calendar days” (for non-practitioners) and “within 45 days” (for practitioners) after discovery (step 2).  Id. at 40712.  DEA will no longer accept hardcopy DEA-106s as of July 24, 2023.  Id. at 40708.

    DEA’s notice of proposed rulemaking would have required registrants to electronically file a DEA-106 within 15 calendar days after discovery, the original intent to align the shorter DEA-106 submission with the time required for submission of a “Report of Theft or Loss of Listed Chemicals,” DEA Form 107, for listed chemicals.  Id.  DEA expanded the proposed rule to allow 45 days, reasoning “that adequate time is needed in order to complete an accurate and thorough investigation” to submit a DEA-106.  Id. at 40709.  The 45-day timeframe within which to complete the second step allows registrants time to adequately investigate and make a final determination about the incident.  Id.  DEA justified requiring electronic submission of DEA-106s rather than a paper copy because it “will allow all report submissions to be received more quickly and stored in a central database, as well as allow for analysis.”  Id. at 40710.

    Step 1: Initial Notification

    The final rule does not revise the requirement that registrants must initially notify the DEA field division office in their area in writing within one business day of discovery of a theft or significant loss.  21 C.F.R. §§ 1301.74(c) and .76(b).  Notification by email or facsimile work; a telephone call does not.  Written notification eliminates misunderstanding that can arise with oral communication.  It documents what information was provided, when, and to whom.  Registrants should provide as much information about the incident as possible, including controlled substance quantity and the circumstances if known.  Reporting within one day of discovery allows the agency to know promptly about a theft or significant loss and to investigate immediately or undertake other appropriate actions.  88 Fed. Reg. 40707, 40709.


    Registrants must report all controlled substance thefts but only those losses that are “significant.”  The agency does not clarify what constitutes a “theft,” an intentional taking or diversion, while non-theft losses can include miscounting, dispensing an incorrect quantity, or misplacing or accidentally disposing of controlled substances.  In addition, registrants should also report thefts to local law enforcement.

    Significant Loss

    While DEA regulations require registrants to report all thefts, they must report only controlled substance losses that are “significant.”  21 C.F.R. §§ 1301.74(c) and .76(b).  Registrants have long wrestled with whether a particular loss they have experienced is significant and therefore reportable.  Over the years industry has requested DEA to define what constitutes a “significant loss.”  As with its 2005 revision of the regulations, the agency has again punted on defining “significant loss,” reasoning that what constitutes a significant loss for a manufacturer experiencing continuous losses in the manufacturing process may not be deemed significant by that registrant (but would need to be recorded in batch records).  88 Fed. Reg. 40707, 40709.  For non-manufacturer registrants, the loss of small quantities over time “may indicate a significant aggregate significant loss that must be reported to DEA, even though the individual quantity of each occurrence is not significant.”  Id.  DEA concluded once again that registrants are in the best position to determine whether their loss is significant, requiring reporting.

    While not defining what constitutes a significant loss, DEA has again provided a list of factors that registrants should consider in determining whether a loss is significant.  Factors include:

    1. The actual quantity of controlled substances lost in relation to the type of business;
    2. The specific controlled substances lost (schedule IIs as opposed to schedule IIIs, IVs and Vs);
    3. Whether the loss can be associated with access by specific individuals or attributed to unique activities that may take place involving the controlled substances;
    4. A pattern of losses over a specific time period, whether the losses appear to be random, and the results of efforts taken to resolve the losses, and, if known;
    5. Whether the controlled substances are likely candidates for diversion; and
    6. Local trends and other indicators of diversion potential of the missing controlled substances. 21 C.F.R. §§ 1301.74(c) and .76(b).

    Because DEA has abdicated defining whether a loss is significant, the agency should only seek enforcement for failure to report a significant loss in the most egregious cases.


    Registrants must report a theft or significant loss in writing within one business day of discovery, followed by a DEA-106 filed electronically within 45 days after discovery.  In 2005, DEA acknowledged that discovery can occur incrementally.  Reports by Registrants of Theft or Significant Loss of Controlled Substances, 79 Fed. Reg. 47094, 47095 (Aug. 12, 2005).  The agency has again declined to define discovery in the current final rule, but plans “on addressing the definition of Discovery in a future rulemaking.”  88 Fed. Reg. 40707, 40709.

    DEA Field Division Office

    The regulations require registrants to notify the DEA field division office in their area of thefts and significant losses.  Field division offices are the largest offices within a DEA field division where diversion program managers, diversion investigators, program analysts, and registration assistants are assigned, while resident and district offices are smaller offices, only some of which may be staffed by diversion investigators.  Strict adherence to the regulation requires reporting to the larger field division office despite geographic proximity or a relationship with a particular diversion group or investigator.

    In-Transit Losses

    Suppliers must report all in-transit controlled substance losses, not just those that are thefts or significant.  The agency also does not define “in-transit,” but uses the term in connection with use of a common or contract carrier.  21 C.F.R. § 1301.74(c).  So, suppliers must report any controlled substance lost while en route via common or contract carrier.  Purchasers must report any loss after they have signed for and taken custody of controlled substances.  DEA, Pharmacist’s Manual: An Informational Outline of the Controlled Substances Act (Rev. 2022), at 63.

    Breaks and Spills

    Breaks, spills, and other witnessed controlled substance losses do not require reporting to DEA.  DEA has reasoned that they are not actually lost “because they can be accounted for.”  Reports by Registrants by Registrants of Theft or Significant Loss of Controlled Substances, 70 Fed. Reg. 40576, 40578 (July 8, 2003).

    Miscounts and Inventory Adjustments

    Neither controlled substance miscounts nor inventory adjustments involving clerical errors should be reported.

    ARCOS Reporting

    Thefts and losses must be reported to DEA’s Automation of Reports and Consolidated Orders System (“ARCOS”).  Registrants should report thefts via ARCOS as “thefts” using the appropriate transaction code and report losses as “losses.”  Reporting to ARCOS is in addition to initial notification and electronic submission of a DEA-106.


    A one and a two…

    Is ASCA worth it? FDA’s Accreditation Scheme for Conformity Assessment

    The Center for Devices and Radiological Health’s (CDRH) Standards and Conformity Assessment Program (S-CAP) encourages medical device sponsors to use FDA-recognized voluntary consensus standards in their product submissions.  Use of voluntary consensus standards can reduce regulatory burden, streamline conformity assessment, harmonize requirements globally, and enhance the quality and safety of a device. As part of that effort, Accreditation Scheme for Conformity Assessment (ASCA) is designed to reduce FDA review time, reduce and/or remove Sponsor guesswork on documentation to provide in a premarket submission, and improve the quality of testing conducted.

    ASCA was authorized under section 514(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In accordance with amendments made to section 514 by the FDA Reauthorization Act of 2017 (FDARA), and as part of the enactment of the Medical Device User Fee Amendments of 2017 (MDUFA IV), FDA was directed to issue guidance regarding the goals and implementation of the ASCA Pilot. The MDUFA V reauthorization converts the ASCA Pilot to a permanent program.

    If a device manufacturer chooses to use an ASCA-accredited testing laboratory to conduct testing for premarket submissions to the FDA, the device manufacturer includes an ASCA declaration of conformity, an ASCA Summary Test Report and a cover letter that indicates that the submission contains ASCA testing as part of their premarket submission. For testing conducted under ASCA, the FDA will have confidence in the testing laboratories’ test methods and results and does not intend to request additional information regarding testing methodologies.

    ASCA includes FDA-recognized consensus standards and related test methods across two scopes: biocompatibility and basic safety and essential performance. FDA selected these categories of standards because they are used for the majority of devices and are frequently associated with FDA requests for additional information.  For the nine most common biocompatibility test methods, there are nine ASCA Summary Test Report templates that are used to document results.  There is one ASCA Summary Test Report template available to document results for basic safety and essential performance.

    2022 Device Submissions with ASCA Testing

    According to the ASCA 2022 Annual Report, the “FDA received five submissions that contain ASCA testing: four with basic safety and essential performance testing and one with biocompatibility testing. The following conclusions were drawn from these submissions:

    • The ASCA Summary Test Reports used the format provided in the ASCA standards-specific guidance documents and the declarations of conformity and Summary Test Reports included all critical data and testing conditions.
    • FDA reviewers had greater confidence in the ASCA testing results, and because the ASCA Summary Test Reports were complete and because the internal FDA review checklists use a similar format, reviewers were able to conduct the conformity assessment elements of the device reviews efficiently.
    • In one submission, a device sponsor used ASCA testing for one test (60601-1) and non-ASCA testing for another, similar test (60601-1-2). The results showed that the ASCA test review found zero deficiencies and the length of the report was one-tenth the length of a typical complete test report. The non-ASCA testing found four deficiencies (one major) and the report was approximately five times the length of the report with ASCA testing.”

    Using an ASCA-accredited testing laboratory to produces test results using the ASCA template may reduce the need for a lead reviewer to request consultations on a submission and reduce the size of the report submitted, thereby saving time on during the premarket review.  FDA recently shared some statistics on the impact of ASCA during the FDA Small Business Regulatory Education for Industry (REdI) Annual Conference held on June 5-9, 2023.  Using an infusion pump as an example, the review time for six biocompatibility tests and electrical safety/EMC testing would go from approximately 21 hours to 3 hours, with no need for an additional consultation.

    As industry is always looking for ways to improve speed to market and create more predictable timelines for regulatory submission, ASCA may provide that advantage, at least when it comes to biocompatibility and basic safety and essential performance. We look forward to reviewing the 2023 Annual Report when published to see if there are more statistics on submissions using ASCA.

    Categories: Medical Devices

    Zootechnical Animal Food Substances; a New Category of Animal Food Additives Proposed

    On June 8, 2023, bipartisan legislation creating a new category of animal feed ingredients, named zootechnical animal food substances, was introduced.  This legislation, named the Innovative Feed Enhancement and Economic Development Act (Innovative FEED Act), is an effort to create an approval process for ingredients with environmental or food safety claims as food additives rather than as animal drugs. On June 15, 2023, an amendment modeled after the Innovative FEED Act, was proposed as an amendment to S.1844 – Animal Drug and Animal Generic Drug User Fee Amendments of 2023.

    The proposed legislation appears to be an effort to resolve issues created by FDA’s Center for Veterinary Medicine’s (CVM) interpretation of the Federal Food, Drug, and Cosmetic Act (FDC Act) definition of food.

    In September 1998, CVM published Policy and Procedures Manual (PPM) 1240.3605, Regulating Animal Foods With Drug Claims, which provides guidance on how CVM regulates substances for animals.  Under CVM’s PPM, nutritional ingredients or products with claims of an intended effect on the structure or function (structure/function claims) of an animal’s body would usually be regulated as animal feed or food (“regulated-as-foods”).  Nutritional ingredients or products with production claims and non-nutritive ingredients or products with structure/function claims would be regulated as animal drugs (“regulated-as-drugs”).  CVM’s interpretation, as expressed in the PPM, has severely limited development of animal feed ingredients with benefits for the environment and other benefits.

    On October 18, 2022, CVM held a virtual listening session on the regulation of animal foods with certain types of claims. CVM invited the public and stakeholders to comment on FDA’s regulation of animal foods with certain types of claims, including claims of environmental benefits (e.g., reduced greenhouse gas emissions from animal digestive processes), enhanced animal health, and productivity, as well as claims about an effect on the animal microbiomes.  According to CVM, these claims would constitute drug claims and, therefore, animal foods with these types of claims would be regulated as animal drugs subject to a time-consuming and expensive premarket approval process. CVM held this listening session to get feedback on how it could modernize or improve PPM 1240.3605, what challenges the current approach presents, and what additional types of claims or ingredients should be considered.  CVM maintained that, without new legislation, it does not have the authority to regulate products with these types of claims as feed ingredients.

    The proposed amendments to the FDC Act would provide CVM with the needed authority.  They establish a new category of substances, called zootechnical animal food substances, which act in the animal’s gut to provide health benefits, reduce emissions, or address human food safety concerns.  New FDC Act § 201(tt) would define zootechnical animal food substance, in relevant part, as a substance intended to:

    (i) affect the byproducts of the digestive process of an animal;

    (ii) reduce the presence of foodborne pathogens of human health significance in an animal intended to be used for food; or

    (iii) affect the structure or function of the body of the animal, other than by providing nutritive value, by altering the animal’s gastrointestinal microbiome.

    The category is limited to substances that achieve their “intended effect by acting solely within the gastrointestinal tract of the animal,” and does not include substances intended to diagnose, cure, mitigate, treat, or prevent a disease, hormones, and ionophores.  The proposed definition also specifically excludes substances approved as a drug under FDC Act § 512, conditionally approved under FDC Act § 571, indexed under FDC Act § 572, or for which “substantial clinical investigations have been instituted and for which the existence of such investigations has been made public.”

    These zootechnical animal food substances will be deemed food additives (under FDC Act § 201(s)) subject to approval  under amended FDC Act § 409.  In addition to information about safety, the petition for approval of a zootechnical animal food substance would need to  include data to support the claimed effect of the zootechnical animal food substance.  Furthermore, the label for the zootechnical animal food substance would need to include the statement: “Not for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in animal.”

    The creation of the new category of animal food additives is intended to provide a route to market for zootechnical animal food substances that is faster than the animal drug approval route and has broad support by industry and trade associations.  Although the FDC Act describes a timeline for FDA’s review of food additive petitions, this timeline often has not been met without repercussions for FDA.

    We will be monitoring further developments related to this legislation, as well as other developments concerning the issues brought up during the listening session in 2022.

    Helping FDA Help Itself: Voluntary Submissions of Allegations of Regulatory Misconduct

    Last fall, we blogged about the process FDA uses to review allegations of regulatory misconduct against device manufacturers, suggesting greater transparency on the FDA process was needed (see here).  FDA now seeks comments on this very program to support its continued collection of information as required under the Paperwork Reduction Act.  On June 12, 2023, FDA issued a public notice to solicit comments on the information collection related to the voluntary submission of allegations of regulatory misconduct to CDRH.  Specifically, FDA invited comments on:

    1. Whether the proposed collection of information is necessary for the proper performance of FDA’s functions, including whether the information will have practical utility;
    2. The accuracy of FDA’s estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used;
    3. Ways to enhance the quality, utility, and clarity of the information to be collected; and
    4. Ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

    Any comments to the public notice must be submitted by August 11, 2023.

    FDA’s Collection of Information

    As noted in our prior blog post, FDA requests that the following information be submitted with each complaint to help the Agency assess an allegation:

    • Name of the company;
    • Address and telephone number of the company;
    • Name of the device and model;
    • Lot/serial/part numbers;
    • Unique Device Identifier (UDI); and/or
    • Recall numbers.

    FDA also requests a “detailed description of the allegation with any available supporting documentation.”  In our experience, the more detailed the documentation that accompanies the submission, the more likely FDA will follow-up on the submission.  We have seen companies submit screenshots of social media sites making misleading promotional claims, pictures of violative product labeling, and evidence of damaged or uncalibrated manufacturing equipment.

    Supporting information is critical to illustrate the specific points of regulatory misconduct.  Companies typically already have this information collected internally, well before contemplating a voluntary submission to FDA, so it is not overly burdensome to collect the information.  More importantly, the proposed collection is necessary for FDA to identify the offending manufacturer and confirm its regulatory misconduct.

    Estimate of Burden

    In the public notice, FDA estimates that it receives 2,500 voluntary submissions a year, and that it takes FDA an average of 15 minutes to respond to each submission.  This statistic is quite disheartening.  Companies labor over the initial decision of whether to submit an allegation to FDA, and even after deciding to take action, dedicate significant resources to prepare a thoughtful submission, with supporting documentation, for FDA consideration.  FDA’s template responses appear to be generated automatically to simply acknowledge receipt and assign a document number (hardly a 15 minute endeavor).

    We understand that 15 minutes is simply an estimate of the average time it takes FDA to review each submission, but it suggests nothing more than a cursory glance, if at all, on those submissions that allege, with supporting documentation, very serious offenses akin to those that have been cited in warning letters and 483s.  Further, it is hard to reconcile the 15 minute per response estimate with FDA’s recommendation to check on the status six months after an allegation has been submitted to FDA.

    We can only conclude that the estimate of burden is grossly under-representative of efforts FDA should be taking to consider the information submitted to FDA under this program.

    Ways to Enhance Information

    There is little transparency in how FDA prioritizes and reviews the information submitted to it.  We understand that FDA prioritizes review based on the level of potential risks, as assessed by the allegation type and completeness of information.  FDA does not define, however, when information submitted is deemed to be “complete.”

    To provide transparency to industry, and to assist FDA prioritize and conduct its review, FDA should bolster its website to include specific examples of appropriate information to include in voluntary submissions.  FDA could present this information in a Frequently Asked Questions (FAQ) section, like it uses on other webpages describing its programs.  Not only would this streamline the collection process, but it would enhance the quality, utility, and clarity of the information that is submitted to FDA to support allegations of misconduct.

    Companies may decide to hold-off on private litigation against a non-compliant competitor to allow FDA to first address areas of public health concern.  Without any transparency on the process, however, companies do not know whether FDA has taken action, intends to take action, or does not deem the allegation meritorious.  Disclosure of this information, even in a redacted format, would further FDA’s public health mission and keep industry aware of, and compliant with, areas of urgent concern.  Under the current process, FDA recommends waiting six months after submitting the allegation(s) to submit a Freedom of Information Act (FOIA) request for related records.  As we discussed in our prior blog post, there needs to be a better way to understand the outcome of FDA’s review.  Those who submit an allegation should be notified directly, not asked to go through a laborious (and sometimes unfruitful) process of submitting a FOIA request to only receive redacted pages.

    Ways to Minimize Burden of Information Collection

    FDA currently accepts voluntary submission of allegations of regulatory misconduct through electronic form, email, or regular mail. There are drawbacks to the current communication channels: 1.) The electronic form does not allow for attachments; it requests that you separately email any attachments; 2.) We have usually received a same day acknowledgment to our email submission and no substantive follow-up; and 3.) It is not known how long it would take FDA to respond to allegations via regular mail.

    For these shortcomings, we suggest the adoption of the CDRH Customer Collaboration Portal in its efforts to receive, track, and provide updates on the status of any voluntarily submitted allegation(s). In our experience, the portal has the ability to accept supporting documentation in the form of PDF attachments, no larger than 1 GB. That would create a central location for all documents and information regarding the allegation. Unlike the current state, which is to submit a FOIA request and receive redacted information six months (at the earliest), the CDRH Customer Collaboration Portal would allow a submitter to track FDA’s progress. We hope the status is more than just an “Under Review” label. Finally, a submitter would receive the potential benefit of more tangible information.

    In conclusion, there is merit in FDA’s collection of information involving allegations of regulatory misconduct, but it can be improved. We recommend companies submit comments to FDA on the areas FDA can change to improve the user (submitter) experience and provide greater transparency on the outcomes of the information collected. Without improvements, companies may decide that this program is not a useful pathway for addressing regulatory misconduct, and the quality of information FDA receives will only decline.

    HP&M Attorneys Receive Accolades: Top Lawyer Under 40 and WWL: Life Sciences 2023 Global Elite Thought Leader

    HP&M’s James E. Valentine Named Top Lawyer Under 40; Only Food and Drug Lawyer Selected

    Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce that Law360 has recognized one of our firm’s Directors, James E. Valentine, as a 2023 Rising Star.  The honor was bestowed on only 183 attorneys, which is awarded to “top attorneys under 40 whose legal accomplishments belie their age.”  James was only one of five life sciences attorneys selected and the only food and drug lawyer to make the list.

    Amongst his accomplishments, Law360 considered the role James has played in leveraging little-used pathways to FDA approval for often first-ever drugs to treat rare diseases (e.g., Duchenne, Friederichs’s Ataxia, Sickle Cell Disease, Chagas, ALS).  This includes both forging the application of the FDAMA 115 “single study plus confirmatory evidence” standard as well as expanding the use of accelerated approval for products in conditions outside of cancer.

    James’s status as a 15-year champion for bringing patient voices to the table with FDA and industry decision-makers was also considered.  James is recognized as helping fundamentally shift the culture to consider the patient voice as an integral part of drug development.  He is proud to have helped establish the Patient-Focused Drug Development initiative while working at FDA and has since gone on to help organize nearly three-quarters of the 76 externally-led PFDD meetings to date.

    We are proud as a firm of this honor and would also like to extend congratulations to all of this year’s Law360 Rising Stars!

    HP&M’s Kurt R. Karst Awarded WWL: Life Sciences 2023 Global Elite Thought Leader

    HP&M Director Kurt R. Karst was named by Who’s Who Legal: Life Sciences 2023 as one of only 14 “Global Elite Thought Leaders.”  This is an achievement that only around 5% of WWL-listed practitioners were accorded in 2023.  Mr. Karst, a co-author of the FDA Law Blog, provides regulatory counsel to pharmaceutical manufacturers on Hatch-Waxman patent and exclusivity, drug development, pediatric testing, and orphan drugs. He helps clients develop strategies for product lifecycle management, obtaining approval, managing post-marketing issues, and defining periods of exclusivity.

    In addition to Mr. Karst, ten other HP&M Directors were tagged as “Recommended” by WWL: Life Sciences 2023:

    Congratulations to all of the WWL: Life Sciences 2023 awardees!

    Categories: Miscellaneous

    Inflation Reduction Act Faces More Legal Challenges, including long-expected PhRMA lawsuit

    As we and others closely following drug pricing have predicted, multiple additional lawsuits have followed in the wake of Merck’s challenge to the Inflation Reduction Act (IRA) price negotiation provisions in the D.C. federal district court on June 6 (see our post here).  Since then, complaints have been filed in federal court in Ohio by the U.S. Chamber of Commerce (complaint here), in New Jersey by Bristol Myers Squibb (complaint here), and in Texas by Pharmaceutical Research and Manufacturers of America (PhRMA) and others (complaint here).

    Both Merck (maker of Januvia, Janumet, and Keytruda) and BMS (maker of Eliquis and Opdivo) argue that the IRA is unconstitutional under the First Amendment because it compels speech and under the Fifth Amendment because it represents an uncompensated taking. PhRMA’s lawsuit makes a similar Fifth Amendment argument, but adds an Eighth Amendment excessive fines argument based on the exorbitant excise tax penalty, and a “separation of powers” argument—i.e., that Congress may not delegate to an agency the authority to arbitrarily set pricing while “barring judicial review of many decisions critical to pricing determinations under the Act.” PhRMA Complaint at 54.  The U.S. Chamber of Commerce makes all the arguments that the other plaintiffs have made, and also alleges that Congress has no power to levy the excise tax because it “compels” commerce.

    September 1, 2023 will be the selection date for the 10 drugs that will be subject to “maximum fair price” ceilings under Medicare Part D starting in 2026.  After that date, we may see lawsuits brought by additional manufacturers whose drugs are on the list and who will then be able to demonstrate the requisite actual or imminent injury to achieve standing.