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.

FDA, like much of the rest of the world, has been adjusting to the rapid changes in our world these last few years.  For nearly three years following the declaration of the COVID-19 health emergency, there were no in-person meetings held.  Then, in early 2023, CDER and CBER started a slow phase-in of in-person meetings in a hybrid format, with some attendees present only virtually.  The hybrid format was necessary due to limitations in the number of attendees who could be accommodated in-person in the handful of newly revamped meeting rooms.  At first, this option was only available for Type A meetings, Biosimilar Product Development (BPD) Type 1 sessions, and Type X meetings.  In June 2023, the list expanded to include Type B End-of-Phase 2 meetings (which we blogged about here).

And there we stayed for 6 more months, until now.  On Monday, December 18, FDA announced its most recent update for in-person meetings, and it is one we have been eagerly awaiting.  The Agency has completed upgrades to its conference rooms with new technology to enable participation by virtual attendees.  CDER and CBER will expand in-person face-to-face formal meetings to all PDUFA, BsUFA, and OMUFA meeting types.

This will apply to all meeting requests received on January 22, 2024, or later.  Meetings will still be hybrid, with core attendees, those with a primary speaking role, attending in-person, and others joining virtually.  Even after the implementation of this update, there is no guarantee of an in-person meeting; the review division will make the final determination on the format.

Still, we are very glad to see this update.  At this point we all have extensive experience with conversations over Zoom or Teams and the like and have experienced both the convenience and limitations as compared to an in-person conversation.  Most FDA meetings are strictly limited to one hour, and minutes lost to technical issues in virtual meetings are keenly felt by sponsors.  More significantly, virtual meetings seem to result in more limited engagement by FDA staff, and the important ability to “read the room” is significantly impaired. An hour can go by noticeably faster with all of these challenges, and it is crucial to make the most of these limited engagements.

As reported in this recent Pink Sheet article, FDA staff recently noted that a substantial majority of meeting requests for eligible in-person meeting types have not been requested as such.  Here at HPM, we were surprised to hear this, as we find that for most FDA meetings, in-person meetings are preferable, if at all possible.  Simply put, it is hard to overstate the value of an in-person conversation; the in-person meetings we have attended with FDA since the reopening have allowed for collaborative dialogue that is not fully replicated even via Zoom.  An in-person meeting may not be the best choice for all sponsors for all meetings.  However, it is a welcome sight to see that there is now a possibility of one for all PDUFA, BsUFA, and OMUFA meeting types.

As we have blogged about before, “face-to-face” can now mean either in-person face-to-face or virtual face-to-face.  This has been memorialized in draft guidance and is not changed by the recent announcement.  Therefore, sponsors must be specific when requesting in-person meetings and specify whether an in-person or virtual face-to-face meeting is requested.

We hope to see you soon at White Oak!

It has been a few weeks, but we thought it important to do a deeper dive on the two Office of Prescription Drug Promotion (OPDP) Untitled Letters published in November.  The letters, both issued on October 31, 2023 but published in early November, were to Otsuka and Evofem for misleading efficacy claims relating to overstating the efficacy of their respective products in direct-to-consumer (DTC) advertisements. Both letters addressed quantitative efficacy presentations—attacking the numbers as well as the underlying methodology for obtaining those numbers. The letters come on the heels of FDA finalizing its Guidance on Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements.

The Letters

In the letter to Otsuka, FDA called out a DTC television advertisement and web banner for misleadingly claiming that REXULTI® (brexpiprazole), an adjunctive treatment for major depressive disorder (MDD), was proven to “reduce depression symptoms 62% more,” and to provide “a 62% greater reduction in depression symptoms,” than with an antidepressant alone. Instead, OPDP calculated that the 2 mg tablet advertised reduced depression by 11.9%, and even less for other doses. To OPDP, the violative claim was even more concerning given the seriousness of MDD and Rexulti’s multiple serious, potentially life-threatening or irreversible risks. Rexulti carries a boxed warning for increased mortality in some elderly patients and an increased risk of suicidal thoughts and behaviors in young patients.

In the letter to Evofem, FDA focused on a DTC patient brochure claim that a “separate analysis” on PHEXXI® (lactic acid, citric acid, and potassium bitartrate), a contraceptive vaginal gel, showed that “99% of pregnancies were prevented per act of sex (101 pregnancies over 24,289 acts of sex).” FDA argued that the “per act of sex” efficacy claim is not validated. Because of the lack of validation, the claim that 99% of pregnancies were prevented overestimates the effect of Phexxi on pregnancy prevention.  The analysis treats each act of sex as equally likely to cause pregnancy, which is untrue given that conception depends on the timing of intercourse in relation to ovulation.

Digging into the Data

In Rexulti’s case, FDA used the results of Study 1, presented on Table 12 of the drug’s prescribing information (see below and here) to calculate efficacy. This is the placebo-subtracted difference in least-squares (LS) mean change from baseline (difference between 8.4 and 5.2 = 3.2) divided by the average baseline score of 27 to get 11.85%. Otsuka did not provide a citation for the 62% claim but may have used the placebo-subtracted difference in least-squares (LS) mean change from baseline (difference between 8.4 and 5.2 = 3.2) divided by the placebo LS mean change from baseline of 5.2 to get 61.5%. Even though Otsuka may have used the same underlying efficacy data as the FDA, the enforcement letter shows that the agency considered the company’s twist to be misleading to consumers.

OPDP calculated Phexxi’s efficacy using two alternative methods—a Kaplan-Meier life-table analysis, which provided an 86% cumulative pregnancy prevention rate, and the Pearl Index, a measure of pregnancies per 100 women with their first year of typical method use, which corresponded to a 72.5% cumulative pregnancy prevention rate. Both methods were included in Phexxi’s own prescribing information as well as in FDA’s draft 2019 guidance on establishing effectiveness for hormonal contraceptives (note: Phexxi is not a hormonal contraceptive). OPDP noted that both these methods analyzed cumulative failure rates over specific lengths of exposure rather than failure rates based on individual acts of intercourse.

OPDP noted that the “per act of sex” is not a validated measure to demonstrate the efficacy of contraceptive products and using it is misleading to consumers. While “per act of sex” measurements have been used to calculate breakage events for condoms, or the risk of HIV transmission in research, that measure has not traditionally been used to evaluate overall contraceptive rates.

Notably, Evofem provided considerable context around its 99% claim. The brochure (see screenshot below and here) presented the 86% figure from the prescribing information in bold font, albeit in smaller type. The company noted that the 99% claim was from a “separate analysis,” included “[s]ince Phexxi is an on-demand birth control.” Evofem also acknowledged that the data is “not found in the Product Information” and had “not undergone the same rigorous evaluation as other data from the study.” While OPDP noted the additional context around the analysis, it did not acknowledge the presentation of the 86% efficacy figure from the prescribing information and found that the context around the 99% number “[did] not mitigate the misleading overstatement of efficacy created by these claims.”

Some Additional Thoughts

Of the enforcement letters issued in 2023, all five have addressed misleading efficacy presentations with four out of the five letters prioritizing the efficacy presentations as misleading over any allegations regarding presentation of risk.  Earlier in the year, FDA finalized its guidance on Presenting Quantitative Efficacy and Risk Information in [DTC] Promotional Labeling and Advertisements (and updated it this month). In it, FDA explains that consumers are better at recalling and comprehending quantitative descriptions, which increases the importance of quantitative information being accurate and understandable.  This explains the focus in the last two letters on DTC materials with quantitative efficacy statements as well as the first Untitled Letter of the year to Xeris that focused on inaccurate quantitative representations of efficacy on a DTC website.

The August OPDP Warning Letter to AstraZeneca for making false or misleading efficacy claims serves as another  “wake up” call to industry as it grapples with what presentations may be considered “consistent” with FDA-Required labeling as well as the adequacy of underlying substantiation and sufficiency of disclaimers and additional context (see our post on that letter here).  The fact that the promotional piece, itself, was directed to healthcare professionals and not generally considered part of a wide-ranging promotional campaign, yet rose to the level of a Warning Letter, still has us scratching our heads.

In any case, the two new letters serve as yet another two reminders for pharmaceutical companies to ensure that their efficacy claims are adequately substantiated with appropriate data. And while the letters certainly call to mind the newly finalized Guidance on Quantitative Efficacy Presentations, the emphasis on efficacy presentations also signals to these bloggers that 2023 may be the year that FDA begins to dismantle the “shelter” that was once thought to be provided by the CFL guidance.

Last week, in a letter thanking President Joe Biden for his leadership to federally reschedule cannabis, Democratic governors sought to make the case for rescheduling.  Letter to President Joseph R. Biden, Jr., from Governor Jared Polis et al., Dec. 5, 2023.  The governors (of Colorado, Illinois, Louisiana, Maryland, New Jersey and New York) thanked the President for his leadership in directing the Department of Health and Human Services (“HHS”) to reconsider the current scheduling of cannabis and HHS’ August 2023 rescheduling recommendation to the Drug Enforcement Administration (“DEA”).  Quoting a Pew Research poll, the governors expressed their “hope” that DEA reschedules cannabis to schedule III “this year” because 88% of Americans favor legalization for medical or recreational use.

However, anyone reading the letter would take away the impression that rescheduling to schedule III would legalize cannabis for medical and recreational use.  As explained more fully below, that impression would be partially correct, but partially incorrect.

In October 2022 President Biden asked the Secretary of HHS and the Attorney General to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  Statement from President Biden on Marijuana Reform, White House (Oct. 6, 2022).  HHS and DEA officials confirm that HHS recommended rescheduling cannabis from schedule I to schedule III in August.  Riley Griffin et al., US Health Officials Urge Moving Pot to Lower-Risk Tier, Bloomberg News (Aug. 30, 2023).

The governors, acknowledging that while the Food and Drug Administration (“FDA”) based its recommendation “solely on science and medicine,” asserted that rescheduling “also increases public health and safety, is sound public policy, and is a big win for states,” particularly for the 38 states that authorize cannabis for medical or recreational use, or both.  Authorized cannabis activities in those states, the governors wrote, have delivered $15 billion in tax revenue for education, law enforcement and other historically underfunded programs.

Conceding that they may disagree whether legalization of recreational cannabis or cannabis use is a “net positive,” the governors agreed that the cannabis industry is permanent, that states have implemented “strong regulations,” and supporting the state regulated cannabis marketplace “is essential for the safety of the American people.”

Rescheduling cannabis to schedule III, the governors asserted, would protect the public against more dangerous drug use because legal cannabis products sold in states where they are legal “are significantly safer than myriad alternatives, including opioids.”  They contended that access to cannabis is associated with reduced rates of:

• Opioid use and abuse;
• Opioid-related hospitalizations;
• Opioid-related traffic fatalities;
• Opioid-related drug treatment admissions; and
• Opioid-related overdose deaths.

Citing a DEA publication, the governors asserted that “cannabis use killed no one.”  The governors observed that the U.S. needs “real solutions to our addiction epidemic” and while not expressly stating as much, believe cannabis rescheduling is the safer alternative.  Rightly or wrongly, the governors seem to be saying that with the U.S.’ addiction problem, it is preferable to promote state-regulated cannabis products as an alternative to illegal opioid and non-regulated cannabis use.

The governors expressed confidence that rescheduling cannabis will ensure enhanced regulation and oversight of cannabis use while decreasing the use of unregulated cannabis and hemp products, noting that unregulated, untested hemp products are being sold to kids in convenience stores.  They observed that unregulated cannabis products have been found to contain fentanyl, high levels of heavy metals, contaminants, and even high delta-9 tetrahydrocannabinol (“THC”) concentrations.  The governors contended that regulated cannabis is safer than opioids and the unregulated illicit cannabis market and safer than hemp-derived THC products.

As justification, the governors argued that state-regulated cannabis would require age verification, packaging and labeling standards, testing and warning symbols or statements, and allow for tracking products from seed to sale.  The governors noted that the public safety requires protection of the state-regulated marketplace by ensuring regulated companies are able to operate efficiently.

The governors concluded that it is time to act like “the greatest nation on earth” that the United States is by promoting safe products, taking enforcement action against dangerous products and entities that violate state law and focusing on the real problems the states face as a community “with opioid use at the top of the list.”  The governors further asserted that FDA’s and HHS’ recommendation to reschedule cannabis is a “signal” of their faith in state regulators and the regulations they have promulgated to keep their citizens safe.  We believe it is a reach to conclude that FDA’s and HHS’s rescheduling recommendation is a signal of faith in state regulators and regulations.

The governors appear to have the best interests of their constituents, the public and the authorized cannabis industry in their states at heart.  While they sent their letter to President Biden, we note that the rescheduling analysis based on the “eight factors” is in DEA’s court, not the President’s.

Lastly, the governors wrote as if rescheduling cannabis to schedule III will authorize unfettered adult access for medical and recreational use.  It will not.  While rescheduling cannabis to schedule III would more closely align federal law with that of the 38 states that allow for some form of cannabis for medical use (depending upon the state), it would still conflict with the laws of the 23 states that legalize cannabis for recreational use.  Obtaining cannabis as a schedule III substance would require a prescription “issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice.”  21 C.F.R. § 1306.04.  In other words, a prescription written by a DEA-registered, state-licensed practitioner.  In addition, cultivators, manufacturers, distributors and dispensers would have to obtain DEA registrations, create and maintain transaction records, file certain reports and maintain adequate security.  Federally rescheduling cannabis to schedule III would not create the unlimited public access the governors alluded to in their letter.

On December 12, 2023, FDA announced the creation of a new advisory committee specifically for treatments for genetic metabolic diseases, the Genetic Metabolic Diseases Advisory Committee, or “GeMDAC.”  As described by FDA’s press release, genetic metabolic diseases are conditions whereby a genetic mutation, generally one that leads to dysfunction of a key protein or enzyme, disrupts the chemical processes (metabolism) responsible for converting food into energy and eliminating metabolic byproducts and waste from the body.  There are hundreds of known genetic metabolic diseases, most of which are rare and carry significant morbidity.

GeMDAC was established to advise FDA regarding treatments under the purview of CDER’s Division of Rare Diseases and Medical Genetics (DRDMG), within the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine.  Dr. Janet Maynard, Director of this Office, highlighted in the press release that “[g]enetic metabolic diseases include very rare diseases that individually affect a limited number of patients. Drug development for these conditions has unique and complex challenges, therefore few treatments are available to patients.”

GeMDAC’s mandate is to advise the Agency on these complicated issues in this challenging area of medical product development.  The advisory committee’s website notes that membership will be selected not just “from among authorities knowledgeable in the fields of medical genetics, [and] manifestations of inborn errors of metabolism” but also experts in “small population trial design, translational science, pediatrics, epidemiology, or statistics and related specialties” (emphasis added).  Note that FDA is currently soliciting applications to staff this committee.

Here at HP&M, we applaud this announcement and hope that it leads to a greater understanding of the challenges faced by rare disease patients, caregivers, and medical product developers, and, hopefully, to the successful development and approval of treatments for rare and ultra rare disease patients.  However, the challenges faced by these stakeholders are not isolated to products overseen by DRDMG alone.  Given that Dr. Maynard described that a primary focus of the advisory committee is for rare diseases, and its membership will include experts in the science of small trials, FDA’s establishment of GeMDAC creates an opportunity to support all rare disease drug development broadly, that is, not only for genetic metabolic conditions but rare diseases that fall under the purview of any FDA review division.

An Opportunity to Convene this New Advisory Committee for All Rare Disease Therapies

In 2018, HP&M attorneys Frank Sasinowski and James Valentine proposed a Rare Disease Center of Excellence (which we blogged about here).  The proposal outlined how a new Rare Disease Center of Excellence (COE) could leverage the skills of experts experienced in rare diseases to help expedite rare disease drug development across CDER, CBER, and CDRH, as well as other offices across FDA.  Importantly, the proposal also included a call to create a Rare Disease Advisory Committee, which could be called jointly with disease area-specific advisory committees to advise on the review of new products for any rare disease.  Members for this advisory committee would be selected “from among authorities knowledgeable and experienced in rare disease research and development.”

As the Agency fills out GeMDAC’s roster, particularly with those knowledgeable in the fields of small population trial design and other areas related to rare disease medical product development more broadly, it is a significant opportunity for FDA to leverage this expertise beyond products overseen by DRDMG.  The membership of the committee would not need to change beyond what FDA has proposed, nor would its primary mandate of serving DRDMG NDAs and BLAs.  However, there is tremendous potential in such a committee to advance rare disease drug development broadly.  GeMDAC could be used in conjunction with other advisory committees for rare disease products overseen by other divisions as well as CBER and even CDRH, as described in our 2018 proposal.  In addition, the rare disease experts included in GeMDAC’s membership could serve as ad hoc members of other advisory committees.

Volume of Genetic Metabolic Diseases Therapies Suggests Capacity to Serve Whole Agency

DRDMG was formed in 2020 as part of the CDER Office of New Drugs reorganization, so it is a fairly new Division.  However, our research reflects that of the orphan-designated novel drugs approved since 2013 by DRDMG or its predecessor, the Division of Gastroenterology and Inborn Errors Products (DGIEP), only 1 out of 18 went to an advisory committee meeting.  The online records of the Gastrointestinal Drugs Advisory Committee, the advisory committee of choice for DRDMG/DGIEP prior to the establishment of GeMDAC, only list 7 meetings total in these 10 years, likely none of which would have been in DRDMG after the split (e.g., irritable bowel syndrome, primary biliary cholangitis).

Presumably, the Agency foresees greater use of advisory committees in the future for genetic metabolic disease products, but this still leaves significant bandwidth and potential to address rare disease issues more broadly.  Meanwhile, other Divisions have referred a multitude of rare disease drugs to other advisory committees with issues on which the proposed constituency of GeMDAC, with its rare disease expertise, would be well-positioned to provide meaningful advice.

Again, we heartily applaud CDER’s creation of GeMDAC.  It is a significant step forward for rare disease patients whose diseases bring them within the oversight of DRDMG.  In addition, many other rare disease patients could (and we hope WILL) benefit from this committee’s expertise, so long as FDA extends the reach of GeMDAC to benefit all rare disease patients, and not only those with genetic metabolic conditions.

On November 30, FDA’s Center for Veterinary Medicine (CVM) released a draft guidance, “Using Relative Supersaturation to Support ‘Urinary Tract Health’ Claims for Adult Maintenance Cat Food,” to provide recommendations for how pet food companies manufacturers can use relative supersaturation (RSS) methodology to support urinary tract health (UTH) claims for certain adult maintenance cat food.

RSS is a measurement used to estimate the potential for crystal formation and bladder stone (urolith) growth, a common affliction in cats.  In fact, clinical studies estimate that as many as 23% of cats suffer from urolithiasis.  We know what you must be thinking: “With all this crystal formation, why don’t they call them Glitter boxes?”  (Apologies to our readers—word play is FDA Law Blog’s catnip.)

Acknowledging concerns about urolithiasis, pet food manufacturers use a range of formulation strategies to make UTH cat food, which have included limiting the magnesium content or formulating it to produce slightly acidic urine.  However, creating UTH cat food has been quite the cat-and-mouse game: apparently, the historical strategies of limiting the cat food’s magnesium content or formulating it to produce slightly acidic urine are effective in creating a urinary environment that is unfavorable to certain types of urolith growth, yet favorable to others.  Formulating cat food based on RSS methodology is a more recent dietary strategy whose principles apply to all urolith types.

The recommendations in the draft guidance address:

1. The wording of UTH claims based on RSS for use on adult maintenance cat food labeling;
2. The RSS criteria to substantiate those UTH claims; and
3. The study data that CVM recommends to demonstrate the utility and target animal safety of the cat food.

For pet companies that use RSS methodology to substantiate general structure or function claims that an adult maintenance cat food supports UTH, CVM recommends that prior to marketing the product, the company submit the following:

1. Empirical data demonstrating the utility and safety of the product’s mechanism(s) for maintaining UTH (discussed in greater detail below);
2. A complete quantitative ingredient formulation and nutrient composition of the product; and
3. A complete product label, which includes the following FDA recommended claim regarding : “Formulated to promote a healthy mineral content in the urinary tract.”

To demonstrate a UTH cat food’s utility based on RSS methodology, CVM recommends that pet manufacturers submit the results of at least one feeding study demonstrating that cats that consume the food achieve RSS values below the formation products for the two most common types of uroliths found in cats (struvite and CaOx).  CVM explicitly states in the draft guidance that preventing one urolith type while potentially promoting formation of the other is not supportive of a general UTH claim.

To allow for some spread in individual RSS values while still providing an acceptable margin of safety against urolith formation, CVM’s recommended mean RSS and 95% CI limits are:

• Struvite: Mean RSS ≤ 1.8; Upper bound of 95% CI ≤ 2.5
• CaOx: Mean RSS ≤ 6.0; Upper bound of 95% CI ≤ 12

In addition, CVM advises the study to be based on at least four separate RSS measurements on urine collected over at least 24 hours.  To be clear, this minimum measurement requirement is intended to provide evidence that cats consistently produce urine that meets the RSS targets, as demonstrated by at least four consecutive measurements.  Apart from these recommendations, the length of a study and how many RSS measurements are performed are left to the pet food company.

In terms of target animal safety, CVM highlighted potential safety concerns that vary with the method(s) used to formulate the cat food (e.g., the degree to which the cat food acidifies the urine, which could increase the risk of metabolic acidosis, or the nutritional adequacy of the cat food).  CVM recommends that UTH cat food based on RSS methodology meet at least one, and preferably both, of these Association of American Feed Control Officials (AAFCO) methods for substantiation of nutritional adequacy:

1. Formulate the cat food to meet the AAFCO Cat Food Nutrient Profile for Adult Maintenance, and/or
2. Successfully complete and pass an appropriate AAFCO Protocol Feeding Study that demonstrates the cat food to be adequate for maintaining the nutritional status of adult cats.

The draft guidance provides a number of other specific recommendations on study data used to demonstrate target animal safety of the cat food.  Although not all of them are covered in this blog post, do not fur-get:

1. Because CVM recommends conducting both target animal safety and utility studies for a minimum of 40 days, pet food companies may choose to combine safety and utility in one feeding trial to maximize efficiency;
2. Regardless of duration, the study should include:
   • Veterinary physical exams, serum chemistries, hematologies, and urinalyses performed at the beginning and end of the study;
   • Weekly body weight measurements;
   • Daily food consumption measurements;
   • Morbidity and mortality observations;
   • A record of any medical treatment provided and why; and
   • All data generated from individual animals as well as summary statistics for each day of measurement.

You can submit comments on the draft guidance here until February 28, 2024—unless, of course, the cat’s got your tongue.