The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp”—now in its 42nd iteration—is scheduled to take place from March 13-14, 2024, at the SpringHill Suites NY Manhattan Times Square South, New York. The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

For nearly 20 years, ACI’s FDA Boot Camp has been the training grounds for life sciences attorneys and executives to master the fundamentals of FDA law and regulation.  Join our co-chairs Kurt R. Karst (Director, Hyman, Phelps & McNamara, P.C.) and Stacy Cline Amin (Partner, Morrison & Foerster (Former Chief Counsel, U.S. FDA)) as they lead an all-star faculty in providing you and your team with the working knowledge of core essentials of FDA law and regulation, including the new amendments under the Food and Drug Omnibus Reform Act (“FDORA”).  This in-depth training will include practical real-world examples that will help you to excel in your everyday practices.  Join the “Who’s Who” of the FDA Bar and don’t miss your opportunity to join their ranks!

FDA Law Blog is a conference media partner.  As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA24.  You can access the conference brochure and sign up for the event here (or by emailing customerservice@americanconference.com or by calling 1-888-224-2480).  We look forward to seeing you at the conference.

The Office of Compliance (OC) at FDA’s Center for Drug Evaluation and Research (CDER) had a role in many of the major public health enforcement matters you may have read about last year. OCs recent 2023 Annual Report—covering the fiscal year from October ’22 to September ’23—puts some meat on the bones of those issues and describes how OC touches almost every area of enforcement that CDER undertakes. One of 12 offices at CDER, a look at its annual report tells us a great deal about CDER’s enforcement priorities.

Led by former federal prosecutor Jill Furman, OC is charged with shielding consumers “from poor quality, unsafe, and ineffective drugs through compliance strategies and risk-based enforcement actions.” The tools it uses to accomplish that mission include those designed to help regulated entities that want to follow best public health practices, like guidances, public notifications, and requests for information. OC also has input into FDA’s more forceful enforcement measures, like warning letters, import alerts, and consent decrees.

Of course, CDER is a massive organization and OC doesn’t do its work alone. But its Annual Report is a helpful tool to highlight CDER’s post-pandemic public health enforcement priorities. Some takeaways on those efforts that we gleaned from the report:

Compounding. OC devoted a lot of resources to its compliance efforts directed at human drug compounding. OC and CDER continue to use a carrot-and-stick approach with compounders, noting both the creation of the Compounding Quality Center of Excellence and its collaboration with the industry, but also the eleven warning letters FDA sent to drug compounders last year.

Drug Supply Chain. Recalls, warning letters to online pharmacies, and drug-related import alerts were key tools for OC’s efforts to safeguard the drug supply chain from adulterated products over the prior fiscal year. Communication in this area included on-line videos, webinars, summits, conferences, and international outreach. This is another area in which FDA works with industry to try to ensure voluntary compliance from regulated entities.

Guidances. OC had a major hand in drafting some key guidances this year, including the recent draft guidance on Post-Warning Letter Meetings Under GDUFA, a potentially important enforcement guide for generic drug makers that we blogged on back in September.

Quality. According to the report, the most common FY23 CGMP citations from warning letters involved citations of quality units under 21 CFR 211.22, “Responsibilities of quality control unit.” In practice, this means that in addition to observations about specific quality deviations, FDA is intent to cite entire quality units for overall dereliction of duty. This is important information for every drug maker and its quality teams.

Clinical Trials. We’ve recently discussed FDA’s clinical trial oversight, and OC didn’t miss the chance to emphasize that it has a role in developing policy about how FDA-regulated research should be conducted. OC boasted of over 600 bioresearch monitoring inspections, 128 clinical inspection summaries, and 11 warning letters in the clinical trial space, among its other efforts.

FDA components aren’t always forthcoming with initiatives and statistics that provide insight into policy priorities. Additionally, annual reports can often be a collection of stylized, glossed-over stats masking bureaucratic shuffling. But at an agency where so many different offices are charged with working together across numerous missions, we were impressed with OC’s 2023 accomplishments. We also appreciate any glimpse we can get into the Agency’s compliance priorities.

Select Graphics and Charts from Office of Compliance 2023 Annual Report (here and here)

In August 2023 the Food and Drug Administration (“FDA”) and Health and Human Services (“HHS”) recommended that the Drug Enforcement Administration (“DEA”) reschedule marijuana from schedule I under the federal Controlled Substances Act (“CSA”) to schedule III.  By doing so, FDA determined that marijuana not only no longer meets schedule I criteria, but by leapfrogging to schedule III, concluded that it does not meet schedule II criteria either.

FDA conducted the eight-factor scheduling analysis required by the CSA in 2016 and found that marijuana continued to meet the scheduling criteria for remaining in schedule I.  Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).  FDA found that marijuana continued to have a high potential for abuse, lacked accepted safety for use under medical supervision and had no currently accepted medical use in treatment in the United States.  Id.  DEA also made specific findings relative to the eight factors, but without FDA finding that marijuana had a currently accepted medical use in treatment, DEA had to deny rescheduling petitions to move marijuana from schedule I.

For FDA to recommend rescheduling marijuana from schedule I in 2023 means that it has been determined that unlike in 2016, marijuana now has a currently accepted medical use in treatment in the U.S.

The mostly redacted, then publicly available letter accompanying the basis for the recommendation stated that FDA was making a recommendation about marijuana, referring to botanical cannabis (Cannabis sativa L.) within the CSA’s definition of “marihuana” or “marijuana” based on FDA’s eight factor analysis.  Rachel L. Levine, Assistant Secretary for Health, HHS, to Anne Milgram, Administrator, DEA (Aug. 29, 2023).  The letter noted that the National Institute on Drug Abuse (“NIDA”) concurred with FDA’s recommendation.

Scheduling under the CSA

The CSA classifies controlled substances into one of five schedules depending upon their potential for abuse.  Schedule I drugs have a high potential for abuse and no currently accepted medical use in treatment in the U.S.  Controlled substances that have an accepted medical use are classified in schedules II-V based on their relative potential for abuse and physical and psychological dependence.  Among the drugs with accepted medical uses, those in schedule II have the greatest potential for abuse and those in schedule V the least.

The CSA requires analysis of eight statutory factors for scheduling, rescheduling or descheduling substances of abuse.  Those factors are:

1. The drug’s actual or relative potential for abuse.
2. The scientific evidence of the drug’s pharmacological effect, if known.
3. The state of current scientific knowledge regarding the drug.
4. The drug’s history and current pattern of abuse.
5. The drug’s scope, duration, and significance of abuse.
6. The risk to public health.
7. The drug’s psychic or physiological dependence liability.
8. Whether the drug is an immediate precursor of substance already controlled.  21 U.S.C. § 811(c).

In addition to the eight-factor analysis, for scheduling purposes FDA and DEA make three additional findings to determine scheduling placement.  Those findings are:

1. The drug’s relative abuse potential to other drugs;
2. Whether the drug has a currently accepted medical use in treatment in the U.S. or a currently accepted medical use with severe restrictions; and
3. The drug’s relative safety or ability to produce physical dependence compared to other drugs.

FDA’s Center for Drug Evaluation and Research Controlled Substances Staff conducts the scheduling analysis and makes recommendations.  HHS forwards FDA’s analysis and recommendation to DEA.  DEA completes its own eight-factor analysis and scheduling determination.  If FDA recommends a substance not be controlled, DEA cannot control it.  FDA’s recommendation as to “scientific and medical matters” is binding on DEA.  21 U.S.C. § 811(b).

Rescheduling Analyses, 2016

DEA noted in 2016 that a drug had a currently accepted medical use for purposes of the CSA if it was the subject of an approved new drug application (“NDA”) under the Federal Food, Drug and Cosmetic Act.  FDA had not approved any drug product for marketing containing marijuana so DEA applied a five-part test it had established when denying marijuana rescheduling in 1994.  Under that test, a drug was considered to have a currently accepted medical use only if it met all five elements.  The elements were:

1. The drug’s chemistry is known and reproducible;
2. There are adequate safety studies;
3. There are adequate and well-controlled studies proving efficacy;
4. The drug is accepted by qualified experts; and
5. The scientific evidence is widely available. 81 Fed. Reg. at 53,700; 81 Fed. Reg. at 53,779.

DEA found in 2016 that marijuana met none of the of elements and therefore did not have a currently accepted medical use in treatment in the U.S.

Rescheduling Recommendation, 2024

FDA’s 2023 analysis and recommendation finally came to light when Texas attorney Matt Zorn posted it on his website a week ago.  The basis for FDA’s recommendation explains how it now considers marijuana to have a currently accepted medical use in treatment seven years after recommending against rescheduling for lack of a currently accepted use.

“Marijuana,” subject to the rescheduling recommendation, means all parts of the plant Cannabis sativa L., whether growing or not; its seeds; resin extracted from any part; and every compound, manufacture, salt, derivative, mixture, or preparation of the plant, its seeds or resin.  21 U.S.C. § 802(16)(A).  “Marijuana” outside of the CSA definition, including hemp, mature stalks, fiber from the mature stalks, oil or cake made from seeds, and sterilized seeds incapable of germination are not controlled and not subject to the recommendation.  21 U.S.C. § 802(16)(B).

FDA has not approved an NDA for a drug containing botanical marijuana but notes that two drug products containing delta-9-tetrahydrocannabinol (“delta-9-THC”) (as dronabinol), the primary compound in marijuana have received FDA approval: Marinol and Syndros.  FDA, Basis for the Recommendation to Reschedule Marijuana Into Schedule III of the Controlled Substances Act, 3.  Dronabinol is a schedule I substance unless contained in FDA-approved Marinol (schedule III) or Syndros (schedule II).  Id. at 4.

FDA’s 2023 analysis focused on whether marijuana has a currently accepted medical use and on new epidemiological data related to abuse of marijuana since its last analysis.  Id. at 5.  FDA conducted epidemiological analyses regarding marijuana abuse and associated harms by comparing with heroin (schedule I); fentanyl, oxycodone, hydrocodone, cocaine (schedule II); ketamine (schedule III); benzodiazepines, zolpidem, tramadol (schedule IV); and alcohol. Id.

FDA concluded based on analysis of the eight factors that marijuana should be rescheduled to schedule III.  Id.  FDA also found that marijuana meets the following three criteria for placing a substance in Schedule III under 21 U.S.C. 812(b)(3):

1.  Marijuana has a Potential for Abuse Less than for Schedule I and II Drugs.

FDA explained that delta-9-THC is the substance in marijuana with psychoactive properties that produces euphoria or a “high” and is responsible for the drug’s abuse potential.  Marijuana is the most frequently abused illicit drug in the U.S. among illicit comparator drugs and FDA found that even with the high prevalence of nonmedical use, epidemiological indicators suggest that marijuana does not produce outcomes as serious as those compared to schedule I or II drugs.  The data demonstrate that marijuana produces fewer negative outcomes than drugs in schedules I or II.  Id. at 62.

When compared with the selected comparator drugs for various epidemiological measures, marijuana was at the lowest ranking for poison control abuse, likelihood its use would lead to a poison control call, accidental poisoning, unintentional exposure, emergency department visits and hospitalizations, likelihood of substance use disorder diagnosis, deaths reported to poison control centers, and overdose deaths.  Comparators drugs heroin (schedule I), oxycodone and cocaine (schedule II) were in the highest rankings.   Id.  FDA evaluated available data and concluded that “while marijuana is associated with a high prevalence of abuse,” serious outcomes related to that abuse led FDA to conclude that marijuana is most appropriately controlled in schedule III.  Id. at 63.

2.  Marijuana has a Currently Accepted Medical Use in Treatment in the U.S.

HHS conducted a two-part test to determine whether marijuana has a currently accepted medical use in the U.S.  The Office of the Assistant Secretary for Health (“OASH”) found that more than 30,000 healthcare professionals “are authorized to recommend the use of marijuana for more than six million registered patients, constituting widespread clinical experience associated with various medical conditions recognized by a substantial number of jurisdictions across the United States.”  Id. at 24.  Thirty-eight states currently authorize marijuana in different dosage formulations for specific qualifying medical conditions.  OASH concluded that “there is widespread current experience with medical use of marijuana in the United States” by the licensed healthcare providers for which “such medical use is recognized by entities that regulate the practice of medicine” in these states.  Id. at 63.  OASH concluded that Part 1 findings warranted assessment by FDA under the test’s Part 2 to determine if credible scientific evidence supports at least one of the medical conditions satisfied in Part 1.

FDA conducted Part 2 based on reviews of studies investigating the safety and efficacy/effectiveness of marijuana, relevant professional societies’ position statements, data from state medical marijuana programs and national surveys, and labeling of FDA-approved products relevant to the analysis.  Id.  FDA analyzed the following indications: anorexia related to a medical condition, anxiety, epilepsy, inflammatory bowel disease, nausea and vomiting (e.g., chemotherapy-induced), pain, and post-traumatic stress disorder.  FDA and HHS concluded that “there exists some credible scientific support for the medical use” in the U.S. of marijuana for the treatment of anorexia related to a medical condition, nausea and vomiting (e.g., chemotherapy-induced), and pain.  Id. at 63-64.  The conclusions do not imply the safety and effectiveness for FDA approval of marijuana for any particular indication.

FDA also noted that one of the criterion for schedule I control is the lack of accepted safety for use of the drug under medical supervision.  FDA concluded that there is accepted safety for the use of marijuana under medical supervision for the treatment of anorexia related to a medical condition, nausea and vomiting (e.g., chemotherapy-induced), and pain.  Apart from the findings made for recommending rescheduling marijuana in schedule III, marijuana does not meet the schedule I criteria.  Id. at 64.

3.  Marijuana Abuse May Lead to Moderate or Low Physical Dependence or High Psychological Dependence.

FDA noted that clinical studies demonstrate that marijuana produces physical and psychological dependence, and abuse may lead to moderate or low physical dependence depending on frequency and degree of marijuana exposure.  While exposure can produce psychic dependence, FDA noted that the likelihood of serious outcomes is low.  Id. at 64-65.

International Treaty Obligations

While FDA made its case for recommending that marijuana be rescheduled to schedule III under the CSA, DEA asserted as a threshold matter in 2016 that the only schedule it could have rescheduled marijuana to was schedule II in order for the U.S. to comply with its international treaty obligations.  The CSA requires the Attorney General, and by delegation the DEA Administrator, to carry out treaty obligations without regard to the required scheduling findings or procedures.  21 U.S.C. § 811(d)(1).  The U.S. is a signatory to the Single Convention on Narcotic Drugs, 1961, and marijuana is a schedule I substance under that treaty.  The DEA Administrator has to control marijuana in the schedule she deems most appropriate to fulfill U.S. obligations under the Single Convention.  Prior rescheduling proceedings established that marijuana could not be scheduled in any less restrictive schedule than schedule II.

A new lawsuit against FDA is the latest happening in the veterinary drugs space and, by extension, FDA’s Center for Veterinary Medicine (CVM). We blogged about CVM last week and explained the increasing attention to animal health products due to the expansion of the animal and pet product market. Phibro Animal Health Corp. has filed suit in the D.C. District Court challenging FDA’s plan to remove their products from the market.

Specifically, FDA is looking to remove a drug called carbadox from the market. Used for over 50 years, carbadox is an antimicrobial drug used to treat gastrointestinal disease in pigs. Last November, FDA published a notice of a proposal to withdraw approval of the three carbadox New Animal Drug Applications (“NADAs”) under 21 U.S.C. 360b(d)(1)(I). That section of the FDCA allows the Agency to issue an order refusing to approve a drug if substantial evidence shows it to be carcinogenic. But did FDA pig out?

FDA says that since the approval of carbadox, new evidence about residue from the drug remaining in pork products has come to light. That evidence now leads FDA to believe that old testing methods used for approval are inadequate to measure the cancer risk that the drug poses. According to FDA, the more recent evidence shows that carbadox residues stick around in processed pork longer than was previously understood. In light of this new data and improved science, FDA has determined that carbadox must come off the market.

Phibro holds the three NADAs at issue here, and the company, unsurprisingly, vehemently disagrees with FDA. In its whopping 70-page complaint. Phibro is asking for judicial review of FDA’s decision, claiming that the Agency skirted its responsibilities under the Administrative Procedures Act (“APA”). Phibro alleges that once FDA determined internally that carbadox was a danger to the pork-eating public, it “took shortcuts by issuing its orders without conducting an evidentiary hearing mandated by statute.”

Indeed, according to the company, FDA’s revocation of the regulatory method of testing that landed the carbadox approval is all a pretext to remove the drug from the market without an evidentiary hearing that Phibro claims would reinforce the drug’s safety. The company asserts that carbadox residues fall below dangerous levels before the products hit consumers’ plates, and that the Agency’s anti-carbadox bias and failure to follow the mandated regulatory procedures violated the “the FDCA, FDA’s regulations, the APA, and due process.”

Carbadox has had a tortured approval history. FDA has expressed concerns about risks to consumers since the drug was approved. At that time, the Agency allowed it to stay on the market under a program that tested edible portions of pigs, a method FDA now claims is not sufficient. The EU prohibited it in 1999, almost immediately after FDA approved the testing methods at issue here, and Canada banned it in 2006. In 2016, FDA again threatened to remove it, but ultimately took no action for reasons that remain unclear.

FDA now says that this long prologue put Phibro on notice that its bacon was close to the fire. In its public website message about carbadox, FDA notes that “[b]ecause the FDA first made public its concern regarding the adequacy of the 1998-approved [testing] method with regard to carbadox in 2016, the swine industry has had the opportunity to consider and mitigate potential impacts of this action for several years.”

We will see how FDA responds to the suit, but we also note that Phibro’s complaint prominently uses internal communications from FDA, obtained via FOIA, to make its case that the Agency’s bias prompted the alleged shortcuts in administrative procedure. Included in those messages are staff assertions that further consideration of this issue is a “waste of time” given the current state of the evidence, as well as an unfortunate allegation that during a public meeting, Agency officials “exchanged Internet memes lampooning Phibro’s representative while she presented the company’s evidence and legal arguments.” One image was of a small violin with the caption “Aww, you poor thing” sarcastically emblazoned below it.

While these may be distractions from the real question—whether the Agency followed APA requirements in withdrawing Phibro’s NADAs—they certainly aren’t a good look for the Agency. FDA has not responded to the suit yet, but its litigators from the Department of Justice are going to need to figure out if they want to respond to the allegations of bias as viewed through this window into how the FDA policy sausage is made.

You know a court decision is going to be worth reading when the judges compare FDA’s regulatory governance of flavored e-cigarettes to a Shakespearean gaslighting.  To quote the Fifth Circuit: “It was the regulatory equivalent of Romeo sending Mercutio on a wild goose chase—and then admitting there never was a goose while denying he even suggested the chase.”  With such an opening, you can just imagine the tenor of the opinion the Fifth Circuit released a few days ago in response to a lawsuit filed by a manufacturer of bottles of flavored nicotine liquid used to refill e-cigarette products or tank systems after the Agency denied plaintiff’s marketing applications, along with 55,000 other flavored e-cigarette applications.  Let’s just say, the smackdown—er, decision—eviscerates FDA’s approach to regulating flavored e-cigarettes.

In Wages and White Lion Investments (DBA Triton Distribution) v. FDA, Petitioners, a liquid nicotine manufacturer, sued FDA arguing that the Agency was arbitrary and capricious in rejecting the Petitioner’s Premarket Tobacco Application (“PMTA”) in violation of the Administrative Procedure Act (“APA”).  If you made it through the first 2 pages of the opinion, this Court’s answer is clear: FDA flagrantly violated the APA in denying those flavored e-cigarette applications due to the Agency’s utter failure to provide comprehensible instructions and consistent policies.

This story goes back to the 2009 Family Smoking Prevention and Tobacco Control Act, which prohibits manufacturers from selling any “new tobacco product” without authorization from FDA.  In 2016, FDA determined that e-cigarettes and their component parts fell under the term “new tobacco products,” requiring manufacturers of such products to submit PMTAs for FDA review before the Agency would issue a marketing order permitting the legal sale of the product.  FDA extended PMTA compliance deadlines for years so it could figure out appropriate application instructions and so that manufacturers could figure out how to comply. FDA originally set the PMTA deadline as August 8, 2022, but a district court in Maryland ordered FDA to shorten it. FDA complied with that order, later extended the deadline because of COVID, and eventually settled on a PMTA deadline of September 9, 2020. Before that deadline, as the Fifth Circuit Court explained, FDA provided PMTA instructions on at least five relevant occasions:

1. At an October 2018 Public Meeting, FDA said in a formal presentation that “No specific studies are required for a PMTA” and that PMTA could be supported without conducting new nonclinical or clinical sources given other data. Youth behavioral data was not specifically required but FDA encouraged such information.
2. FDA published a June 2019 guidance, which stated that manufacturers would not need to perform long-term studies or submit long-term data in PMTAs. FDA said randomized clinical trials could be used, but so could observational studies with respect to cessation data.  FDA also directed manufacturers to produce detailed marketing plans.
3. At an October 2019 Meeting, FDA explained the application process and provided assurances that decisions would be made on each specific product in a submission—not the submission in its entirety.
4. In September 2019, FDA issued a proposed rule reiterating that it did not expect long-term studies to be necessary, but that marketing plans were critical to success of a PMTA.
5. Finally, FDA issued another guidance in January 2020 (and revised in April) that stated that after the PMTA deadline set for September 2020, the Agency would prioritize “flavored, cartridge-based” e-cigarettes over than tobacco or menthol-flavored. FDA explained that “cartridge-based” products are more attractive to youth than “open tank systems,” which are bigger, harder to conceal, more complicated, and require refilling.

Importantly, the Court emphasized, “Never in this long, winding, and byzantine regulatory process of meetings, PowerPoint decks, proposed rules, comment periods, guidance documents, and enforcement priorities did FDA ever say that it was contemplating an across-the-board ban on flavored products.”  Nor did FDA give notice that favored product manufactures had to submit robust scientific studies on flavored cigarette products.  Yet…

Petitioners filed PMTAs for their flavored nicotine liquids, which included marketing and sales access restriction plans, with FDA before the deadline.  They also submitted long-term, controlled, and peer-reviewed studies to show that e-cigarettes generally cause smokers to switch to vaping.  They also included observational studies.  But they did not submit information specific to flavored products.

In August 2021, FDA issued a press release announcing the denial of 55,000 flavored e-cigarette applications en masse.  FDA proceeded to deny 946,000 flavored product applications in just over two weeks. In the August 2021 press release, the Agency announced for the first time that a randomized controlled study or other comparably robust and reliable study is required in a PMTA for a flavored e-cigarette product.  Petitioners asked for more time to amend their PMTAs to include the newly-required studies, but, as the Court explained, FDA went ahead and issued Marketing Denial Orders due to the absence of the “once-optional-but-now-required scientific studies.”  The Court also took umbrage with FDA’s plain statement that it “refused to even read petitioners’ marketing plans” that the Agency emphasized so heavily in guidance.  Petitioners moved to stay their Marketing Denial Orders pending review in Court.  Though a Fifth Circuit merits panel refused, the Court granted rehearing.

In a 10-5 en banc decision, the Fifth Circuit Court found that “FDA acted arbitrarily and capriciously in rejecting petitioners’ PMTAs.”  Going through “[f]our well-established and longstanding principles of administrative law,” the Court explained how any one of such principles “independently require that result.”  Specifically, the Court explained that:

• Any agency cannot invent post hoc justifications for its decision in court and outside the administrative record;
• An agency must provide fair notice before it deprives a citizen of property;
• When an agency chances its position, it must display awareness of the change and explain it; and
• Even if an agency acknowledges and explains a change in its position, it cannot fault a regulated entity for relying in good faith the on the previous one.

FDA failed on each count.  FDA said no new clinical data would be necessary then denied Petitioners’ and many other PMTAs for flavored e-cigarette products because those applications contained no randomized controlled trial and/or longitudinal cohort study.  And FDA deemed irrelevant robust scientific studies showing e-cigarettes induce adults to switch from smoking because it did not show that flavored e-cigarettes promote switching more than unflavored ones.  And, the Court stated, FDA failed to even read the marketing plans it stressed as necessary.

FDA did justify its position—using arguments that apparently have worked in other circuits—by citing to several ambiguous sentences in its June 2019 guidance insinuating that randomized data might be required.  FDA claimed that these sentences provided fair notice, but the Court disagreed, noting that FDA had repeatedly stated in no uncertain terms that such studies would not be mandatory in PMTAs.  Indeed, FDA received over one million PMTAs for flavored e-cigarette products “and not a single one of them contained the scientific studies that FDA now requires . . . .”  Says the Court: “It is perhaps possible that FDA did its part to give the regulated community clear guidance and that one million out of one million not only got it wrong but got it unreasonably wrong. But administrative law does not turn on such infinitesimal possibilities.”

While FDA did try to suggest that these studies were not a requirement, the Court cited a PMTA checklist in FDA’s Decisions Document that included a requirement for a randomized controlled trial or a longitudinal cohort study.  According to the Court, “[t]hat sure looks like a requirement that petitioners perform long-term scientific studies on their e-cigarette products.” Further, FDA “created a new, after-the-fact, categorical ban on using scientific data from unflavored products to support flavored PMTAs.”  The Court stated that FDA essentially “imposed an across-the-board ban on all flavored products, regardless of device type.”  All of this, the Fifth Circuit stated, is a clear demonstration that FDA added requirements without fair notice and without acknowledging any change in its position.   “All that matters here,” said the Court, “is that the agency unquestionably changed its position and then pretended otherwise.”

FDA’s argument in the alternative—that any “error was harmless”—was shut down by the Court as the Agency’s “misunderstand[ing] of how harmless error review works under the APA.”  The harmless error doctrine arises from the administrative law principle than agency errors result in a remand back to the Agency—not in a court substituting a more adequate or proper remedy.  The Fifth Circuit Court reasoned that the harmless error doctrine would have applied only if FDA were required to deny the Petitioner’s applications; but it did not apply just because FDA “will deny [the Petitioner’s applications] on remand even if we send the case back . . . .” The harmless-error rule, in other words, does not apply to discretionary administrative decisions.

We note that the Fifth Circuit is not the first circuit to have addressed the issue.  The Eleventh Circuit came to the same conclusion as the Fifth—that FDA acted arbitrarily and capriciously—but five other circuits have sided with FDA.  FDA clearly made that point in this case, arguing to the Fifth Circuit that it must look to its “sister circuits,” but the Court flatly rejected that line of reasoning noting that “law is not a nose-counting exercise” and then explaining why it disagreed with each of its “sister circuits.”  With this circuit split and the literal millions of rejected PMTA e-cigarette applicants, and several other circuits left to opine, this is not the last we’ll hear of this issue.  We just hope that all future decisions are as engagingly written as the Fifth Circuit’s.  Give it a read—you’ll enjoy it.

Two Hyman, Phelps & McNamara, P.C. (HPM) Directors, Karla Palmer and Dara Levy, will present at the Puerto Rico Pharmaceutical Summit 2024, February 6, 2024, at the La Concha Renaissance San Juan Resort in San Juan, Puerto Rico.  This day-long (FREE) seminar is a must-attend event for anyone in the pharmaceutical sector interested in understanding the “ins and outs” of doing business in the Territory, as well as an opportunity to interact with those who already have a keen understanding of doing business in Puerto Rico.  As a bonus, you can spend a day or two away from the cold US weather.

Given the significant growth and development opportunities available in Puerto Rico, Karla and Dara will discuss the FDA’s prescription drug approval process, and more importantly the “exportation” of prescription pharmaceuticals — including controlled substances — from Puerto Rico into the United States.

Some of the other (but not all…) topics of interest at this day-long conference presented by US and Puerto Rico industry thought leaders include:

1. Experiences and Challenges of Puerto Rico State Licensing
2. Internal Investigations: Monitoring, Compliance, Enforcement Actions
3. The State of the Pharmaceutical Industry in Puerto Rico
4. Navigating Global Turbulence: Drop Your Anchor in Puerto Rico

Puerto Rico continues to attract and retain the best and brightest in pharmaceuticals across the globe. Boasting a highly skilled workforce, state-of-the-art facilities, and a supportive business environment, it’s no surprise that Puerto Rico has become a hub for industry pioneers in biopharma, research, supply chain management and technology.

HPM is a co-sponsor of the event.  The event is hosted by by Porzio, Bromberg & Newman. Advance registration is required, and capacity is limited.  To register, please use this link.

Back in late September 2023 (and corrected in October), FDA issued its first interchangeable exclusivity determination pursuant to the Biologics Price Competition and Innovation Act (“BPCIA”).  As has been explained, the BPCIA provided an abbreviated pathway to market for follow-on biologics—biosimilars and interchangeable biosimilars—and with that pathway came two types of exclusivity periods: one for the “Reference Product” to encourage continued innovation and one for the “First Interchangeable” biosimilar to encourage the development of biosimilars that could be substituted for the brand product without health care provider intervention.  Relevant here, “First Interchangeable Exclusivity” (referred to by FDA as “FIE”) provides that FDA may not license a second interchangeable biosimilar until the earlier of:

• 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;
• 18 months after­:
  • a final court decision on all patents in a BPCIA suit against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
  • dismissal with or without prejudice of a such an action;
• 42 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has been sued under the BPCIA and the litigation is still ongoing within such 42-month period; or
• 18 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has not been sued under the BPCIA.

The FIE determination released in fall 2023 involves the Reference Product AbbVie’s Humira (adalimumab) and two interchangeable biosimilars—first approved is Cyltezo (adalimumab-adbm), filed by Boehringer Ingelheim Pharmaceuticals, Inc, which was followed by Abrilada (adalimumab-afzb), filed by Pfizer.  Important to note here is that each interchangeable biosimilar was first approved as a biosimilar and each biosimilar manufacturer had been sued under the so-called “patent dance” procedure prior to seeking licensure of the biosimilar products as interchangeable.  The question at issue for FDA was therefore: When is the expiration date of FIE for the first approved interchangeable adalimumab, Boehringer’s Cyltezo, and whether that exclusivity has expired?  In other words, FDA needed to determine whether the initial biosimilar litigation—pre-interchangeable supplemental approval—counts towards the FIE expiration date calculation.

FDA provided each Boehringer and Pfizer the opportunity to present its interpretation of FIE expiration provisions, but FDA ultimately “decline[d] to adopt either Pfizer’s or BI’s proposed interpretation.”  Congress, FDA explained, did not seem to have accounted for staggered licensure of biosimilars in which interchangeable status would be sought as a supplement and that litigation might happen between initial licensure and supplemental licensure, leaving the statutory text relatively ambiguous.  Whoops.

With the ambiguity of the statutory text, FDA looked at the plain language, context, and the structure and purpose of the statute—including both parties’ positions on those points.  Notably, the purpose of the statute seemed to govern much of FDA’s interpretation.  The Agency writes in its determination “[w]e were thus mindful of Congress’s desire to both provide a meaningful opportunity for a period of exclusivity for the first interchangeable product, without allowing the applicant of such product to have unilateral control of the start and end date for that period of exclusivity,” but cautioned against “[a]dopting an interpretation that would allow a first interchangeable product’s applicant plenary control over the entry of competing interchangeable products could enable manipulation and distortion of the market, which would undo the incentives for competition that Congress sought to put in place.”

FDA chose to read the FIE expiration period relevant to patent litigation to apply only where such litigation involved the submitted interchangeable products—litigation over the original biosimilar that later may be determined interchangeable is not relevant to the FIE expiry calculus.  Here, because the relevant patent litigation (resulting in settlements) “commenced and concluded” before Boehringer submitted its interchangeability supplement, the litigation is not relevant to Cyltezo’s FIE period.  Instead, FDA explained, “the term ‘action instituted under [PHS Act § 351(l)(6)]’ must be linked to ‘the application for the first approved interchangeable biosimilar biological product,” which means the application seeking a determination of interchangeability.  And FDA also is clear that any action that triggers the potential FIE expiration “must at the very least be limited to . . . litigation involving the same reference product as in the interchangeability application.”

FDA explained the public health benefits of this interpretation: it encourages applicants to submit aBLAs as soon as practical to increase competition and access.  If the expirations clock starts ticking before the application for the interchangeable product has been submitted, “applicants may choose to either delay submitting their BLA until they have a data package that can support licensure of their proposed product as an interchangeable, or they may submit an application for biosimilarity only, and may not seek licensure as interchangeable at all because their biological product will likely not have a chance to benefit from FIE.”  Thus, FIE expiration is triggered only upon infringement suit arising from the submission of the first interchangeable product application; this interpretation applies to both the litigation trigger and the absence of litigation trigger.

Indeed, if it were possible for neither the litigation triggers nor the absence of litigation trigger to apply to start the clock running for FIE expiry, the only possible trigger would be one year after first commercial marketing.  FDA raises concern that such an interpretation could lead to anti-competitive behavior, for example, where the applicant enters into an agreement with the reference product applicant not to start marketing its interchangeable product as part of settling the patent infringement action, which could have the result of blocking all other interchangeable products indefinitely.  Thus, the fact litigation was filed regarding the biosimilar and no litigation was filed against the interchangeable would trigger the 18-month forfeiture of FIE under FDA’s interpretation.

Because AbbVie filed no patent infringement against Boehringer for the interchangeable biosimilar (presumably because it was covered in the settlement for the previous non-interchangeable biosimilar), FDA used the date of approval to calculate FIE expiration.  Boehringer’s interchangeable Cyltezo in 40 mg/0.8 mL and 20 mg/0.4 mL for subcutaneous injection was approved on October 15, 2021; the supplement for 10 mg/0.2 mL was approved on March 18, 2022.  Thus, 18 months from approval would result in expiration of FIE on April 15, 2023, and on September 18, 2023 respectively.  The first commercial marketing of each, according to the biosimilar patent settlement agreement, was July 1, 2023, which would render the FIE expiration date July 1, 2024.  But because the statute sets FIE expiration at the earlier of the relevant conditions, the April 15, 2023 and September 28, 2023 dates were the FIE expiration dates.

This all sounds complicated, I know.  But the main takeaway from this FIE expiration determination is that it’s only interchangeable approval and litigation that count towards the FIE expiration calculations.

The law permitting the importation of cheaper prescription drugs from Canada—Section 804 of the Federal Food, Drug, and Cosmetic Act (FDC Act)—has been on the books for decades.  After its enactment in 2003, successive administrations thwarted its implementation by declining to certify to Congress that importation will pose no additional risk to public health and safety and will result in a significant reduction in cost to American consumers, as the statute requires.  The waning months of the Trump administration saw a flurry of activity to implement Section 804, with an Executive Order, a final rule, and the required certification issued in quick succession. The final rule permitted FDA to solicit Section 804 Importation Programs (SIPs) from States and Tribes to import prescription drugs from Canada. So far, the Agency has received SIPs from at least five states.

The final rule met quick opposition from the pharmaceutical industry. In late 2020, industry groups challenged the final rule in federal court, but the case was dismissed for lack of standing.  The following year, the same groups submitted a citizen petition to FDA arguing that the rule violates the constitution and the FDC Act.  Last week, FDA denied the citizen petition and authorized its first SIP, which had been submitted by Florida. A statement issued by Florida’s governor Ron DeSantis claimed that the authorization was the result of Florida’s lawsuit accusing the Biden administration for unreasonable delay.

FDA’s authorization letter to Florida’s Agency for Health Care Administration confirmed that the SIP complies with section 804 of FDC Act, in that it will result in significant cost savings to consumers without posing additional risk to the public’s health and safety. The authorization is valid for two years from the date the state files for entry of its first shipment of drugs, and may be extended for subsequent two-year periods. See 21 C.F.R. § 251.6. But the state still needs to pull together several stakeholders and expend additional effort before it can import any drugs.

More Steps Ahead

As the SIP sponsor, Florida will be responsible for implementing the program. However, before the state can start importing drugs, it must first submit for FDA approval a pre-import request for each eligible prescription drug it plans to import into the United States. See 21 C.F.R. § 251.5; § 251.6(c). This request must provide details about, among other things:

1. The foreign seller that will purchase the prescription drug directly from its manufacturer, along with invoices, batch, and lot/control numbers to verify the sale and the units sold. This must be a Health Canada-licensed wholesaler that is registered with FDA as a foreign seller.
2. The importer that will purchase the prescription drug directly from the foreign seller, along with invoices, batch, and lot/control numbers to verify the sale and the units sold. This must be a U.S.-based entity licensed as a wholesale distributor or a pharmacist that will import the drugs.
3. A description of each eligible drug covered by the pre-import request. This includes the name and identity of the Health Canada-approved drug; information about the API manufacturer; and information about the manufacturer of the eligible prescription drug.
4. The FDA-approved counterpart drug and NDA or ANDA number, and an attestation and information statement from the manufacturer that the drugs meet the conditions in the FDA-approved NDA or ANDA (including cGMP compliance).
5. A plan to test the drugs, as required by section 804(e), including for authenticity, degradation, and to ensure compliance with the established specifications and standards.
6. Proposed relabeling and proposed NDC numbers for the drugs to be imported.
7. Information about the facility where the relabeling and/or repackaging will occur for the eligible prescription drug.
8. Information related to the importation (e.g., date, location, warehouse).

Florida has 12 months to submit a pre-import request. FDA would need at least 30 days to review each pre-import request. The government would require at least another 30 days to examine the shipment at the U.S. Customs and Border Protection (CBP) port of entry.

Major Barriers Persist

The state plans to start by importing medications for chronic conditions like HIV/AIDS, mental illness, prostate cancer, and urea cycle disorder for patients under the care of its state agencies before expanding the program to Medicaid patients. If FDA grants Florida’s pre-import request for these drugs, Florida will be required to ensure supply chain integrity, monitor and submit adverse event reports, comply with drug recall procedures, and send quarterly reports to the FDA about the imported drug, cost savings, and potential safety or quality issues. FDA may suspend or revoke a SIP at any time if the SIP sponsor can no longer demonstrate that the SIP complies with section 804, or for any of the other reasons listed under 21 C.F.R. § 251.7.

Once fully implemented, the state estimates the SIP will save its taxpayers up to $183 million per year. But it is too early to tell whether this or any other SIP that FDA authorizes will succeed in reducing the price of the imported drugs. Major barriers still persist. For example, the Canadian government reiterated its commitment to safeguard Canada’s domestic drug supply and has issued regulations to prohibit bulk exports to the United States that will cause or worsen drug shortages in Canada. Additionally, industry stakeholders remain convinced that the SIPs will impact drug quality and patient safety, and they may bring further lawsuits against these programs.

As the calendar turned to 2024, we came across the usual end-of year looks back and projections ahead. Our feed saw a number of rosy forecasts for mergers and acquisitions in FDA-regulated industries. Interest rates may be on the way down, which in turn may mean that more capital will free up and thus more deals may be in the offing. If this all holds true, it will follow the upward trend of the 2023 year in deals.

In a “hot” deal market, it’s worthwhile reiterating the fundamentals of regulatory due diligence that don’t change, no matter how attractive the deal or how short the window is to seize the opportunity. We’ve previously posted on the importance of regulatory diligence generally and DOJ’s recent Safe Harbor Policy for Voluntary Self-Disclosures of Criminal Conduct made in connection with M & A transactions. We won’t repeat ourselves, but we will summarize—regulatory due diligence and an understanding of historical regulatory compliance issues is a critical component of assessing whether a deal is what it seems to be.

Having the right diligence team is critical because proper risk assessment of regulatory risk requires a broad range of expertise. Assessing risks in regulated industry requires the appropriate depth and breadth of regulatory expertise. Diligence related to FDA-regulated industries often involves not only FDC Act review, but also federal and state False Claims Acts, and Anti-Kickback Statutes, along with other state and local laws and regulations. Moreover, it requires not only an understanding of what the laws say, but what the government would be expected to do in the future based on the regulatory compliance history.

Proper risk assessment requires the expertise to ask the right questions and understand the answers.  While there may be a diligence “template,” no two diligences are the same. Your diligence team should understand the nature and scope of the transaction to determine how to efficiently conduct the diligence to identify the critical issues that determine whether your interests are protected.

Your regulatory diligence team should be able to solve problems, not just identify them. Not every diligence issue is a dealbreaker. Your regulatory diligence team should understand the difference between a minor issue, a potentially concerning trend, and a red flag. Moreover, it should be able to offer you guidance on mitigating risk in the face of future uncertainty, including, when appropriate, self-disclosure.

Deals in FDA regulated space are among the most complicated of any industry, and diligence adds cost. But the cost of rooting out potential regulatory problems and assessing liabilities before the deal closes is almost always money well spent.

New Year’s is often associated with baby New Year and with resolutions, which in a convoluted way got us thinking about post-approval pregnancy studies.  Lots of us start the new year with a resolution.  Is it a commitment, or a requirement, and does the difference matter?  For post-approval pregnancy studies, it most certainly does.

A review of FDA’s Postmarketing Requirements and Commitments database reveals that one of the most common reasons FDA requires postmarketing studies is to assess the impact of a drug on maternal and fetal outcomes when taken by pregnant women.  These studies typically take the form of a pregnancy “registry,” which passively tracks outcomes in pregnancies followed through the registry, and prospective outcomes studies, which actively recruit and enroll pregnant women exposed to a drug.  For many drugs, both a registry and an outcomes study are required.

Post-approval studies can be classified by FDA as a postmarketing requirement (PMR) or a postmarketing commitment (PMC).  What distinguishes a PMR from a PMC?  A PMR is a study “that sponsors are required to conduct under one or more statutes or regulations,” whereas a PMC is a study “that a sponsor has agreed to conduct, but that are not required by a statute or regulation” (see FDA Webpage, Postmarketing Requirements and Commitments: Introduction).  As a result, failure to conduct a PMR would be a violation of the Federal Food, Drug, and Cosmetic Act (FDCA) and/or implementing regulations, subject to enforcement action.  Potential enforcement actions can include an FDA Warning Letter, charges under section 505(o)(1) of the FDCA, misbranding charges under section 502(z), or civil monetary penalties.  In contrast, failure to conduct a PMC would not be a violation of the FDCA or regulations, and therefore not subject to enforcement action.

To better understand FDA’s approach in classifying postmarketing pregnancy studies as PMRs or PMCs, we reviewed all postmarketing requirements (PMRs) and postmarketing commitments (PMCs) related to maternal and fetal outcomes in FDA’s PMR/PMC database for drugs approved in the ten-year period from January 2014 through December 2023.  This review was limited to drugs with approved New Drug Applications (NDAs); biologics and vaccines were excluded.  Additionally, this review excluded pharmacokinetic and animal studies.

In that ten-year period, there were 67 drugs approved with a requirement to conduct a postmarketing pregnancy study, and 99 studies.  As noted above, many drugs were approved with the requirement to both establish a pregnancy registry and conduct a prospective pregnancy outcomes study, which is why there are more studies than drugs.

Notably, of the 99 postmarketing pregnancy studies in the 10-year period, all but one were PMRs.  The only example of a pregnancy PMC is for Paxlovid, for treatment of COVID-19, which is a distinguishable example because the sponsor committed to this study while the drug was still under an Emergency Use Authorization (EUA), not an NDA.

Under Section 505(o) of the FDCA, FDA may only require a PMR for one of the following reasons:

1. “To assess a knownserious risk related to the use of the drug involved.”
2. “To assess signals of serious risk related to the use of the drug.”
3. “To identify an unexpected serious risk when available data indicates the potential for a serious risk.”

(Emphasis added.)  PMRs can also be required for confirmatory studies for accelerated approval, deferred pediatric studies, and studies for products approved under the Animal Efficacy Rule, but those categories of PMRs are not relevant here.

In all three bases for a PMR listed above, there must be information indicative of a serious risk or the potential for a serious risk, because that serious risk is “known,” there are “signals” suggesting the serious risk, or “available data” indicating a potential serious risk.  Without data or information indicative of a serious risk, FDA does not have authority to require a PMR.  FDA’s Draft Guidance on Postapproval Pregnancy Safety Studies states that “pregnancy registries may be required to assess potential serious risks to the pregnancy that may affect the health of the fetus or the woman due to drug or biological product use during pregnancy.”  However, the language in the Draft Guidance omits the requirement in Section 505(o) that “available data” must indicate the potential for a serious risk.

It is notable that all but one postmarketing pregnancy study for drugs in this 10-year review were PMRs, and not PMCs, because for the studies to be PMRs, FDA must have identified a basis for the study under the statutory language, requiring data or information indicative of a serious risk.  It is difficult to believe that all 99 studies fell within this category, and not one (except perhaps Paxlovid) fell short of the statutory basis for a PMR, instead requiring categorization as a PMC.

In fact, the publicly available review documents for Zavzpret (zavegepant hydrochloride), Sotyktu (deucravacitinib), and Quviviq (daridorexant) do not identify any data (e.g., animal data or pregnancy exposure data from clinical trials) indicating a known or potential serious risk associated with drug exposure during pregnancy.  The Quviviq Integrated Review states explicitly: “Animal studies do not suggest an increased risk for embryofetal toxicity.”  At least for these few examples, FDA’s basis for requiring a post-approval pregnancy study as a PMR is unclear.

FDA often presents PMRs to applicants as a required condition of drug approval.  As a result, applicants often feel compelled to agree to perform the PMR.  Given the statutory limitations to FDA’s authority to require a PMR in Section 505(o) of the FDCA, we would encourage applicants faced with the prospect of a pregnancy PMR, where there are no data suggesting a serious risk, to assess whether FDA’s position is justified and whether a PMC is more appropriate.

The American Conference Institute (“ACI”) will be hosting the go-to forum for critical updates on OTC regulation and enforcement, monograph reform, ACNU and advertising essentials… and FDA Law Blog readers can get a discount.

This unique forum, designed for in-house counsel and executives, as well as private practice attorneys working for the OTC drug industry will provide invaluable insights on FDA’s most recent directives and compliance standards governing OTC drug production, marketing and distribution.

HPM is ably represented by seasoned drug product development and authorization attorney—and former FDA counsel—Deborah Livornese.  Deb assists pharmaceutical drug companies of all sizes on regulatory requirements and strategies related to obtaining FDA approval and other paths to market, as well as on post-marketing regulatory requirements.  Prior to joining HPM as a Director, Deb spent seven years in the Office of Regulatory Policy in FDA’s Center for Drug Evaluation and Research. As a Senior Regulatory Counsel at FDA, she was involved in a wide variety of policy issues in the areas of drug approvals and withdrawals, the regulation of unapproved and over-the-counter drugs, and development of the OTC monograph reform.

Deb along with fellow panelists Kyle Y. Faget, Partner, Foley & Lardner LLP and Amy Replogle, Director, Rx-to-OTC Switch, Bayer will present a must-attend panel focusing on:  FDA’s recent efforts to enhance accessibility to OTC drug products that has set the stage for a wave of approved switches in the industry — a development being warmly embraced by non-prescription drug companies. This panel will analyze the recent high-profile switches shaping the OTC industry landscape, including:

• Opill
• Naloxone
• Explore what FDA has considered in approving the latest switches and hurdles industry may face in obtaining future switches
• Assessing the significance of the Opill switch and its implications on new opportunities for RX-OTC switches, particularly in the area of women’s health

Make your plans today to meet and benchmark with present and former FDA and FTC enforcers, NAD representatives and leading OTC industry stakeholders.  Attend and walk away with an enhanced understanding of how to navigate the current OTC legal and regulatory environment.

This year’s Keynote Speaker will be Dan Brum, PharmD, MBA, BCPS, Chief of Project Management, Office of Nonprescription Drugs, Food and Drug Administration (FDA).  Also on the federal side is Jennifer Santos, Attorney, National Advertising Division (NAD).

To obtain a copy of the conference brochure and to register for the event, please visit ACI’s website – here.

FDA Law Blog is a conference media partner for this event.  As such, we can offer our readers a special 10% discount off the current price tier for the event.  The discount code is:  S10-826-826L24.S.  We look forward to seeing you at this important conference.

Most of us love our furry friends, and with the boom in pet ownership during the pandemic, it is no surprise that the market for pet products has become enormous.  With the growth in pet ownership, the pet health product market has also exploded; a Bloomberg article from March 2023 noting that the growth in the pet industry market “is driven by an increase in spending on pet-related healthcare—including veterinary care, diagnostics, and pharmaceuticals—that has created longer pet lifespans that require more expensive elderly care.”  So, much like humans, pets are living longer and facing the ailments so common to old age.  Enter the FDA’s Center for Veterinary Medicine (“CVM”).

A longstanding component of the FDA and its predecessor, CVM, in its initial form as part of the Department of Health, Education, and Welfare, was established in 1965 and evolved in CVM by 1984.  Responsible for “Protecting Human and Animal Health,” CVM makes sure that the drugs, devices, and food we provide for our pets are safe and effective.  Specifically, CVM ensures that animal drugs are safe and effective, properly made, and adequately labeled and packaged; food-producing animals only take drugs that would be safe for humans to consume; pet foods and additives are safe; and educates the public, monitors the market, and encourages development of new animal health products.  CVM does not regulate the practice of veterinary medicine (that’s a state licensing board) or vaccines for animal diseases (that’s USDA).

To carry out its mission, CVM has the same enforcement tools that the rest of FDA, like CDER and CDRH, have, including the authority to conduct inspections, issue warning letters, seize products, add manufacturers to import alerts, and impose penalties on bad actors.  And CVM certainly exercises that authority.  In late2023, CVM issued nine Warning Letters to distributors of veterinary products for use in aquarium fish and birds.  In all of these letters, CVM alleges that the distributors who “take orders” are selling unapproved drug products—typically for infection control—for use in fish and, in some cases birds.  The unapproved drug claims are not, in and of themselves, notable, but it is always interesting when FDA takes a stand against such a large swath of manufacturers and distributors at the same time.  The way FDA has explained the risks, which is presumably the reason CVM is taking action at this point, is also interesting: the drugs marketed contain antimicrobials used to treat human disease, and given the development of resistance to antimicrobials in human medicines, FDA has decided “to promote more judicious use of animal drugs containing medically important antimicrobials, including working toward ensuring that these drugs can be used in animals only under the supervision of a licensed veterinarian.”  If the drug were legally marketed, the considerations may be different, and therefore CVM recommends that these sponsors “obtain an index listing, approval, or conditional approval.”

CVM may not be the flashiest part of FDA, but it’s important to stay abreast of the trends in animal drug enforcement, which are, as evidenced by the language quoted above, related strongly to the use of similar drugs in human patients.  Those of you with pandemic pups (or other pets) should be aware that FDA—specifically CVM—is working hard to keep your furry (or scaly or feathery) friends safe.

Primacy and recency are recognized psychological phenomena: people tend to remember the first thing they hear, and the last.   It’s why litigators concentrate on their opening statement to a jury, and their closing argument.

Maybe that’s also why FDA last week publicized the highest number of important Warning Letters of the year (compared with prior releases in 2023).  Perhaps FDA wanted us to remember 2023 as the year FDA succeeded in uncovering critical defects in drug and device manufacturing, and in clinical trials.  If FDA wanted to create that impression, it likely succeeded.

Warning Letters, generally made public in a batch each Tuesday, are FDA’s public sanction that is most widely used to bring pressure on manufacturers and clinical trial investigators.  They have great impact on most companies that receive them.  Excluding rashes of Warning Letters for things like hand sanitizer manufacturers not checking their ingredients properly, there are only a few each week, at most, that address drug or device manufacturing issues, and rarely is there a Warning Letter addressed to investigators in clinical trials.  In fact, a statistical analysis of such Warning Letters issued over 2023 shows that there were only an average of about 3 per week.  Last week, 11 such letters were posted in the Tuesday batch of posted Warning Letters.  Four of the letters addressed failure to comply with drug Current Good Manufacturing Practice regulations, four more stated that the recipients were distributing unapproved drug products, two alleged violations of the Quality System Regulation by medical device manufacturers, and one was addressed to a clinical investigator.

Summaries of the most striking recently released Warning Letters are included below.  We are unable to determine whether the number of such Warning Letters issued during the entire year represents a significant increase over 2022.  The FDA compliance data, sorted by category, shows there were 159 Warning Letters issued to drug manufacturers or sponsors during 2023, with 161 issued in calendar year 2022.  Overall, in 2023, about 30 of the Warning Letters were issued to manufacturers of hand sanitizer, and we are not sure how many of the letters issued in 2022 were addressed to manufacturers of hand sanitizer.

Here, then, are the critical findings in the recent raft of letters:

• Omeza LLC, an Over-the-Counter drug manufacturer in Sarasota, Florida, was advised in a Warning Letter to hire an independent expert on good manufacturing practices because FDA said it “observed mold-like substance on an air conditioning unit sleeve” located in a drug product manufacturing area and “insects both alive and dead, and other animal waste” in areas used to store bulk drug products and samples. The letter also stated that the company’s response to the inspection report was “inadequate because it did not include a review of environmental monitoring data in your manufacturing areas, an adequate risk analysis of previously manufactured drug product, or testing of reserve samples from impacted batches.”
• Dextrum Laboratories Inc. of Miami, Florida, a contract manufacturer of over-the-counter (OTC) drug products, including oral cough and cold drug products marketed for both adults and children, was also advised in a Warning Letter to retain an independent expert on good manufacturing practices. FDA stated that the firm failed to adequately test each shipment of glycerin for diethylene glycol (DEG) or ethylene glycol (EG) contamination, failed to adequately validate production and process controls, and failed to conduct a retrospective review to ensure materials previously used were suitable for their intended use.
• Patcos Cosmetics Pvt. Ltd. of Mumbai, India, was criticized for many of the same issues. According to FDA, the company failed to show that there was adequate testing for DEG and EG, and failed to have an efficient and adequate quality unit.
• Colonial Dames Company, Ltd. of Commerce, California, received a Warning Letter because FDA alleged that it failed to establish Standard Operating Procedures for production and process control to ensure its products met appropriate standards of identity, strength, quality, and purity; failed to appropriately clean, maintain cleaning records, and to sterilize equipment; failed to have an adequate and efficient quality unit; and failed to have adequate stability data.
• Four drug manufacturing companies received Warning Letters for manufacturing or distributing products that FDA said were unapproved drugs, including East Fork Cultivars of Takilma, Oregon (cannabidiol products; Warning Letter; Hua Da Trading, Inc. of Brooklyn, NY (sildenafil in a product marketed as a dietary supplement; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hua-da-trading-inc-664359-12202023); Botanical Be of El Paso, Texas (“Kuka Flex Forte” and “Reumo Flex,” marketed as dietary supplements, contain diclofenac; Warning Letter; and com, Inc., of Seattle, Washington (selling products marketed as “energy enhancing supplements or food” that contained sildenafil, tadalafil, or other drug active pharmaceutical ingredients; Warning Letter.
• Two device manufacturers received Warning Letters for QSR violations (QSR is FDA’s label for cGMP requirements applicable to medical device manufacturers). Terragene S.A., an Argentinian company that makes and sells Biological and Chemical Sterilization Process Indicator Systems, allegedly failed to show adequate procedures to handle complaints. FDA stated that the firm received 96 U.S. market complaints in 2021 through 2023 but could not provide documentation to demonstrate how the complaints were reviewed or evaluated.  FDA said that the firm also did not have an adequate procedure to determine whether Medical Device Reports (MDRs) needed to be filed with FDA, and was distributing a product that was required to be cleared in a new 510(k) submission, but had not been.  Swedish company Sonesta Medical AB was accused of several violations of medical device design requirements, failure to exercise appropriate control over contractors, and failure to adequately review complaints and determine whether MDRs needed to be filed with FDA.
• Finally, FDA said in a Warning Letter that a Clinical Investigator, Anish S. Shah, M.D., of Siyan Clinical Research in Santa Rosa, California, performed study-defined efficacy endpoints without being properly blinded as to blinded to certain safety assessments (“for example, clinical laboratory evaluations, vital signs, physical examinations, and adverse event assessments”).

*Legal Assistant

What do Gene Autry’s Rudolph the Red-Nosed Reindeer and FDLI have in common?  Both are celebrating their 75th anniversaries in 2024.  While “The Singing Cowboy” Gene Autry was busy in Los Angeles recording Rudolph the Red-Nosed Reindeer, The Food and Drug Law Institute (FDLI) founders were hard at work in Washington forming the association that still serves as the platform for discussing complex legal and regulatory issues associated with food, drugs, cosmetics, medical devices, and other health-related products.

2024 brings a host of HPMers who have important roles at FDLI as part of recently announced Committee positions:

• Ricardo Carvajal, Director, Board of Directors and the Audit Committee (Chair)
• Jeffrey Gibbs, Director, Finance Committee
• Karla Palmer, Director, FDLI at the Forefront (formerly Webinar Programs)
• Anne Walsh, Director, 75th Anniversary Advisory Committee and FDLI at the Forefront (formerly Webinar Programs)
• James Valentine, Director, Patient Organization Committee
• Sara Wexler Koblitz, Director, Advertising and Promotion for Medical Products Committee
• John Claud, Counsel, Enforcement, Litigation, and Compliance Conference Planning Committee
• Mark Tobolowsky, Associate, Food and Drug Law Journal Advisory Board
• Philip Won, Associate, New to Food and Drug Law and Regulation Committee
• Sophia Gaulkin, Associate, Austern Writing Awards Committee

FDLI’s President & CEO Christine Simmon noted, “HPM has long been a critical partner in the work of FDLI – generous with expertise from the HPM team as well as sponsorship support of our mission. We are enriched by the service of Ricardo Carvajal on our Board of Directors and Anne Walsh’s contributions to our 75th Anniversary Advisory Committee as just two of several examples. FDLI looks forward to this continued partnership for many more years to come.”

In other exciting news — in 2024 FDLI will be getting a make-over!

Those who attended their annual Enforcement, Litigation, and Compliance Conference holiday reception earlier this month got a sneak peek at this new branding effort with the unveiling of the association’s new logo (here).

The new logo — and a host of other new association branding — will be rolling out throughout 2024.  Simmon and the Board of Directors felt strongly that the 75th anniversary was the right time to unveil their “new look” while continuing the mission to lead the FDA bar and associated members into the future.

Gone is the familiar burgundy triangle surrounding FDLI.  But FDLI leadership and board members did not want it forgotten.  So, the new logo features a triangle in the F, as part of the ampersand and a nod within negative space in the right-hand corner. Plus, the burgundy was kicked up a notch to a cherry red.  In an interview with the Blog, FDLI wants to recognize the efforts of Chris Perkins, Gabe Lindman and Emma Dardis of Washington, DC-based marketing agency Model B, for their amazing work.

News flash — FDLI will also be extending this exciting branding to include a new website in 2024.  Additionally, there will be smaller touches that often go overlooked like podium branding, event signage, publication cover art and more.

But FDLI is also thinking beyond logos and websites—2024 will be filled with events to mark FDLI’s 75th anniversary. In an e-mail interview with the Blog, Simmon was excited to describe a series of “quarterly events that will start by spotlighting past accomplishments, and then consider the future as we close out the year.”  The highlight will be a “festive celebration dinner, to be held the evening prior to our 2024 Annual Conference on May 14th.  This dinner—at the Waldorf Astoria in DC—will commemorate FDLI’s role during key eras in food and drug law and will have fun surprises as well!”  Mark your calendars now.

When asked what excites FDLI the most about 2024 and the 75th anniversary, Simmon was quick to say, “FDLI has a front-row seat to the ever-changing and intriguing legal and regulatory developments impacting FDA-regulated products. Whether its new legislation, court decisions, agency regulations, or science-based innovations like AI that no one could have dreamed of 75 years ago, FDLI is excited to bring together industry leaders, experts, and government agencies in a neutral forum for conversations that inform and advance public health and safety.”

Little known holiday fact: The story of Rudolph was originally written in 1939 by Robert May as a booklet for Montgomery Ward, a department store. May’s brother-in-law, songwriter Johnny Marks, later adapted the story into the famous song.  May penned the story of Rudolph as a way to comfort his daughter after her mother (May’s wife) died of cancer.  The story of Rudolph overcoming obstacles resonated with May’s personal struggles during that time.

Here’s to the enduring tradition of Rudolph, the enduring fight to cure cancer and other diseases, the enduring legacy of FDLI and best wishes from all of us at HPM.

In October 2022 President Joseph Biden directed the Secretary of Health and Human Services (“HHS”) and the Attorney General to begin the administrative process of reviewing expeditiously how cannabis is scheduled under federal law.  HHS recommended that the Drug Enforcement Administration (“DEA”) reschedule cannabis from schedule I to schedule III in August.  In making such recommendation, HHS concluded that cannabis no longer meets neither schedule I nor schedule II criteria.

Hyman, Phelps & McNamara, P.C., Director Larry Houck will present a webinar on HHS’ cannabis rescheduling recommendation hosted by the National Association of State Controlled Substance Authorities (“NASCSA”) scheduled for Tuesday, January 9, 2024 at 3:00 pm (Eastern).  The webinar will examine rescheduling ramifications and focus on:

• HHS’ 2023 recommendation vs. HHS’ 2016 findings;
• What’s next with DEA and its eight-factor scheduling analysis;
• Implications of cannabis as a schedule III substance;
• The current regulatory landscape of cannabis and related products including hemp and CBD; and
• The state of the states.

Information, including how to register, can be found here.