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.

With comments due on the proposed LDT rule last week, FDA wasted no time updating the Unified Agenda to indicate that a final rule may be published in April (here).  We take this date with a grain of salt given the frequency with which these dates are missed and given the volume of comments filed. (It is not entirely clear how many comments were actually logged in; on December 7, FDA showed 19,655 comments, and the next day 6,732.)  While some comments were boilerplate, others were comprehensive, detailed critiques of the Proposed Rule.  Under the Administrative Procedure Act, FDA is obligated to address major substantive issues when – and not so much if – it publishes a final rule.  Complying with that requirement between now and April will be a daunting task.  But, FDA has expressed urgency in moving forward with this rule so it is not out of the question that it could happen.

With a possible final rule right around the corner, it made us think – will FDA be ready to actually implement the rule?  FDA must believe it will be, but sound public policy is predicated on accurate and reliable data.  FDA recognizes that “data is at the heart” of the agency’s work as a “science-based Agency.”[1]  Yet FDA’s conclusions about the Agency’s ability to regulate the entire laboratory industry are based on fundamentally flawed assumptions about the number of entities and tests that will be subject to FDA regulation.

FDA estimates that approximately 12,000 CLIA-certified laboratories are currently certified to perform high-complexity testing in the United States.  This is based on FDA’s reported 2018 review of the CLIA database.^[2]  It is unclear how FDA derived this number or why it chose to rely on a review conducted five years ago when the database is—according to FDA—updated monthly. In fact, as of November 2023, the CMS’s Standards and Certification’s (S&C’s) Quality, Certification and Oversight Reports (QCOR) CLIA Laboratory Lookup Database shows 17,206 CLIA-certified laboratories.  This is 50% greater than the 2018 numbers relied upon by FDA in its estimates.[3]

FDA further assumes that these laboratories collectively perform roughly 80,000 LDTs.  But, FDA understates the number of laboratories by roughly one-third.  Using FDA’s per-lab number of tests, the number of LDTs would be well over 100,000.

Even using a lower, out-of-date number of laboratories, FDA anticipates receiving an astounding number of premarket review submissions for LDTs, specifically:

• 32,160 510(k) premarket notifications;
• 4,210 PMAs, PDPs, Panel-Track PMA Supplements; and
• 4,020 de novo[4]

FDA derives these estimates by applying the same metrics applicable to currently‑regulated IVDs: 50% undergo premarket review, and of those 40% are submitted through the 510(k) process, 5% are submitted for de novo classification, and 5% are submitted for premarket approval.[5]  This stratification, though, assumes that LDTs will follow the same pattern as IVDs currently regulated by FDA.  However, this prediction is unfounded, because it assumes that there is an existing classification regulation and/or product code for 90% of currently available LDTs.  Further, it assumes that 80% of LDTs requiring premarket review will be able to identify a “predicate” device and be reviewed under the 510(k) process.  Given that many LDTs introduced are for new indications for which IVDs are not currently available, this assumption is unwarranted. In other words, FDA’s extrapolation from existing IVD submission data ignores some key differences between LDTs and distributed IVDs.

FDA further assumes that half of LDTs will not need to undergo premarket review because they are exempt.  That seems very unlikely to be the case, because exemptions apply only to well-established tests.  In seeking to justify regulation of LDTs, FDA emphasizes that many of these tests are novel.[6]  It is inconsistent to say that LDTs must be regulated as medical devices because of the newness of the tests and then reduce the cost of the proposed regulation by declaring that half of all LDTs will be exempt from premarket review.  FDA’s assumption that 50% of the tests will be exempt is particularly baffling because the laboratories are ones licensed to perform high complexity tests.  By their very nature, these tests are less likely to be exempt from FDA review.

Thus, FDA understates the number of laboratories and almost certainly overstates the number of LDTs that will be exempt.Yet, even assuming the accuracy of these estimates, the predicted volume of submissions would be unprecedented.  FDA’s 5-year average across all of CDRH is 73 PMAs, PDPs, Panel-Track PMA Supplements; 3,877 510(k) premarket notifications; and 66 de novo submissions per year.[7]  This means that OHT7, the Division responsible for reviewing in vitro diagnostic tests, will need to be staffed to review substantially more submissions per year than the entire Center, specifically: 57 times the number of PMAs, PDPs, Panel-Track PMA Supplements; 8 times the number of 510(k) premarket notifications; and 60 times the number of de novo submissions.  This would require a massive increase in staffing and training.[8]  FDA would need to commence a hiring spree at the same time that laboratories would be looking to hire personnel with the same sorts of expertise to be able to navigate the FDA process.  The foreseeable outcome will be a shortage of qualified personnel and significant salary increases.  Regulatory affairs professionals with significant expertise in diagnostics are already in short supply.

Furthermore, given FDA’s proposed 5-Stage, 4-year timeline, these submissions will all arrive within a very narrow window, with PMAs being due 3.5 years after publication of the final rule and all 510(k)s and de novo submissions due a mere six months later (i.e., 4 years after publication of the final rule).  This sudden bolus of submissions will strain FDA’s capacities beyond the breaking point, as happened during the COVID-19 pandemic.

FDA also does not take into account the volume of pre-submissions that laboratories will inevitably need to begin filling almost immediately after issuance of the final rule to ensure that the data they will be presenting to FDA in their premarket submissions is what the Agency will expect.  Unless FDA provides timely responses to pre-submissions, laboratories (and current IVD manufacturers) will not be able to submit applications that address FDA’s expectations.  During COVID-19, however, FDA essentially stopped reviewing pre‑submissions severely limiting feedback to non-COVID test developers.  Under FDA’s own calculations, the number of LDT premarket submissions will far exceed the number of COVID Emergency Use Authorizations (EUAs).  Thus, it is unclear how FDA will have resources to field pre-submissions and the anticipated premarket submissions.

During the October 31, 2023 webinar discussing the proposed rule, stakeholders sought clarity from FDA officials on the Agency’s plan to address the resource gap.  FDA cited two solutions to the resource problem: (1) enhancing the existing third-party 510(k) review program; and (2) resolving resource issues during the next user fee renegotiation process (MDUFA VI).[9]  Neither of these proposed approaches can be expected to adequately address the anticipated volume of submissions.

First, FDA notes that the Agency is “currently working to enhance our Third-Party Review Program, which was reauthorized under MDUFA V.”[10]  While this goal is admirable, the Third-Party Review Program has been available for decades and has long been regarded as a flop.[11]  In fact, in Fiscal Years 2018 – 2022, fewer  than 100 510(k)s went through the Third-Party Review Program annually.[12]  In FY2020, 2021, and 2022, Third-Party Review 510(k)s accounted for 2.6%, 2.6%, and 2.5% of 510(k) decisions, respectively.[13]  Notably, a search of FDA’s 510(k) database shows that zero IVDs were cleared through the Third-Party Review Program between November 1, 2022 and November 1, 2023.[14]  Thus, while the Third-Party Review Program is not well‑utilized generally, it is not utilized at all by the in vitro diagnostic industry.

Furthermore, even if the Third-Party Review Program could gain traction within the IVD industry, it is, per statute, available only to select Class I and II devices.[15]  Even of those IVDs fitting within the statutory criteria, FDA must specify if an IVD type is eligible for third-party review.  Given the innovative nature of LDTs, it is unreasonable to anticipate that many LDTs would be eligible for the program.  Absent legislative change, therefore, the Third-Party Review Program would not be able to review the overwhelming majority of the PMAs, PDPs, Panel-Track PMA Supplements or de novo submissions.  Thus, it is wholly unrealistic for the Third-Party Review Program to provide any meaningful reduction in Agency workload.

Second, FDA assumes that there will be a sufficient number of accredited third-party review organizations available to conduct the reviews.  During the October 31, 2023 webinar, FDA cryptically noted that there are “certain CLIA‑accredited organizations that may be interested in serving in this third-party review role.”[16]  However, the experience of the New York State Department of Health (NYSDOH) should serve as a cautionary tale.  In 2017, FDA announced the addition of NYSDOH as an accredited third-party review organization in the context of the Agency’s clearance of an NGS-based tumor profiling test, explaining that the Agency’s goal in allowing third party review of such tests was “to reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products.”[17]

This initial fanfare culminated in the unheralded disappearance of NYSDOH from FDA’s list of accredited third parties earlier this year.[18] Despite NYSDOH’s expertise in reviewing diagnostic tests, the program was used sparingly.  Notably, NYSDOH was reported as having fewer than five 510(k) submissions in each fiscal year of MDUFA IV (FY18 – FY22).[19]  It is unclear why FDA expects other CLIA-accredited organizations would succeed in this program where the most prominent and “only state that requires test approval for IVDs offered as LDTs” failed.[20]

In short, without both statutory changes and a specific plan to revamp the Third-Party Review Program so that it can have a meaningful effect on the workload related to LDT pre-market review, the reliance on this program to provide critical resources for this massive regulatory undertaking is, at best, wishful thinking.  Without dramatic changes to the Third-Party Review Program, FDA will need to shoulder on its own the unprecedented burden of receiving thousands of applications for novel, complex diagnostics in a very short period of time.

In reality, FDA’s staffing plan relies almost entirely on hiring a significant number of additional reviewers with user fees authorized by Congress under MDUFA VI.  However, while Congress can authorize the funding mechanism, it cannot ensure the availability of qualified personnel.  (Congress could also decide not to authorize the funding mechanism or take other steps that would hamper hiring.)  Even assuming a 3% reduction in the 510(k) workload from the Third-Party Review Program, under FDA’s projections OHT7 will need to be staffed to review nine times the current capacity of the entire Center.[21]  Calling this task impossible may be an understatement.  Indeed, FDA has publicly noted its challenges with hiring under MDUFA IV, explaining that “competition with well-known tech innovation locations, the creation of new scientific and technical professional fields, and fewer candidates with a hybrid of specialties have resulted in hiring delays for the MDUFA program.”[22]  The “competition” for these candidates will inevitably worsen due to the hiring needs of laboratories that must submit tens of thousands of applications. Regulating LDTs as medical devices will mean that neither FDA nor laboratories will be able to recruit, hire, and train enough qualified personnel to meet their respective obligations.

Given the acknowledged and ongoing recruitment and retention challenges, FDA’s reference to MDUFA VI amounts to nothing more than “kicking the can down the road,” rather than a meaningful plan to ensure adequate resources. Meanwhile, given the compressed enforcement discretion phaseout timeline proposed by FDA, upon issuance of a final rule (which could occur while MDUFA V is still in place) laboratories would need to immediately begin compliance efforts, including by filing pre-submissions.  FDA has proposed no plan for how resources, including those needed to review pre-submissions for LDTs or the numerous other questions laboratories will have, will be handled under MDUFA V.  Even if MDUFA VI were to allow the hiring of a significant number of new personnel, implementation of the Proposed Rule would begin before those employees arrive.

OHT-7’s well documented meltdown during the COVID-19 public health emergency should serve as an object lesson.  The massive onslaught of EUA submissions, in part caused by FDA’s decision to not exercise enforcement discretion for LDT-based COVID-19 tests, led FDA to decline most pre-submissions and to delay review of most submissions for non-COVID-19 IVDs for many months.[23]  This significant disruption to the broader IVD industry was triggered by an increase of approximately 1,200 submissions annually.[24]  These submissions all related to a single disease.  FDA’s own estimates would result in an influx of premarket submissions, in a six-month period, that would be 40 times greater than the number of COVID submissions and related to an extraordinarily diverse set of diseases and conditions.

Nor can FDA simply reallocate staff and resources from other, non-IVD product areas, as it did during COVID-19.  The requirements and data specific to in vitro diagnostics are unlike those for other device types.  Further, even if all CDRH review staff were reallocated to OHT7 to support this effort, it would still be insufficient given the vast volume of submissions that are expected.

The bottom line is this: without far better resource planning, this massive regulatory undertaking is going to be a disaster for all stakeholders, including FDA, industry, health care systems, providers and, most importantly, patients.  Certain points are indisputable.  First, under FDA’s own, extremely conservative projections there will be an exponential increase in submissions for diagnostic tests.  Second, based on years of experience, it would be hopelessly optimistic to expect the Third-Party Review Program to provide any meaningful relief.  Third, even with user fee support, it will be extremely challenging for FDA to recruit, hire, train, and manage the staff needed to cope with an unprecedented onslaught of submissions.  Fourth, the inability to manage this influx will harm the diagnostic industry, including manufacturers of distributed IVD products.

Without proper preparation one of two things will happen: (1) the regulatory review of non-LDT premarket submissions will come to a halt, or (2) there will be significant delays in the implementation of the final rule.  We do not expect that the broader IVD  industry will tolerate the first, particularly in light of the MDUFA VI negotiations that would be on-going leading up to the time at which labs will be required to file premarket submissions.  Thus, it is likely that FDA will have to push out the timelines for review of LDT premarket submissions to align with its available resources.  It would be far better for everyone if FDA acknowledged this reality now, and significantly extended the timelines for implementation.

As we explained in our comments (here), FDA should not finalize the proposed regulation.  If it does, instead of requiring submissions and then hoping to obtain resources and the necessary congressional authorizations, FDA should have a clear plan for obtaining the required resources.  The failure to do so is likely to result in chaos for all diagnostic products.

[1] https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/modernizing-fdas-data-strategy-06302020-06302020#:~:text=Data%20is%20at%20the%20heart,making%20and%20public%20health%20mission.

[2] U.S. Food & Drug Administration (FDA), II. Preliminary Regulatory Impact Analysis, Reference 34, Laboratory Developed Tests Proposed Rule, Docket No. FDA-2023-N-2177, at 21 (Oct. 4, 2023) [hereinafter PRIA], https://www.regulations.gov/document/FDA-2023-N-2177-0077. (“Laboratories that meet these requirements are the only laboratories that can perform LDTs under CLIA regulations, because LDTs are considered high complexity tests”)

[3] S&C’s Quality, Certification and Oversight Reports (QCOR), Active CLIA Laboratory Search Database, https://qcor.cms.gov/advanced_find_provider.jsp?which=4&backReport=active_CLIA.jsp.

[4] PRIA at 28.

[5] Id. at 75.

[6] 88 Fed. Reg. 68006, 68012 (Oct. 3. 2023) (hereinafter the “Notice of Proposed Rule Making”).  Notice of Proposed Rule Making Reference 1 “Grand View Research, “Laboratory Developed Tests Market Size, Share & Trends Analysis Report By Technology (Immunoassay, Molecular Diagnostics), By Application (Oncology, Nutritional & Metabolic Disease), By Region, and Segment Forecasts, 2023–2030: Report Summary,” available at https://www.grandviewresearch.com/industryanalysis/

laboratory-developed-tests-market-report (last accessed on Nov. 20, 2023) (“The lack of an equivalent IVD on the market is the primary reason labs develop LDTs.”)

[7] PRIA. at 28.

[8] FDA assumes that user fees will cover much of the increased costs. These fees, however, do not cover all costs. FDA does not discuss the consequences of a shortfall in congressional appropriations, which is a foreseeable risk.

[9] FDA anticipates the beginning of the MDUFA VI user fee cycle aligning with Stage 4 – FDA’s end of its enforcement policy for high-risk LDTs.  FDA, Transcript of CDRH Webinar regarding Proposed Rule: Medical Devices; Laboratory Developed Tests, at 9-10 (Oct. 31, 2023), https://www.fda.gov/media/173623/download?attachment.

[10] Id. at 9.

[11] Jeffrey N. Gibbs, Allyson B. Mullen & Melissa Walker, 510(k) Statistical Patterns, MD+DI (Dec. 2, 2014), https://www.mddionline.com/news/510k-statistical-patterns.

[12] FDA, Third Party Review Organization Performance Report (version 1 of FY2022, Q4), at 38, https://www.fda.gov/media/162658/download?attachment

[13] See id.; FDA, Performance Report to Congress: Medical Device User Fee Amendments FY 2022, at 13-18, https://www.fda.gov/media/167825/download?attachment.

[14] FDA, 510(k) Premarket Notification Search Database (last updated Nov. 13, 2023), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm. Searches were done for all IVD panels: immunology, microbiology, clinical chemistry, pathology, toxicology, hematology, and molecular genetics.

[15] 21 U.S.C. § 360(m)(a)(3).

[16] FDA, Transcript of CDRH Webinar regarding Proposed Rule: Medical Devices; Laboratory Developed Tests, at 9-10 (Oct. 31, 2023), https://www.fda.gov/media/173623/download?attachment.

[17] FDA, News Release, FDA unveils a streamlined path for the authorization of tumor profiling tests alongside its latest product action (Nov. 15, 2017), https://www.fda.gov/news-events/press-announcements/fda-unveils-streamlined-path-authorization-tumor-profiling-tests-alongside-its-latest-product-action.

[18] Compare FDA, Current List of FDA-Recognized 510(k) Third Party Review Organizations (updated July 31, 2023), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfthirdparty/accredit.cfm  [https://web.archive.org/web/20230803134353/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfthirdparty/accredit.cfm], with FDA, Current List of FDA-Recognized 510(k) Third Party Review Organizations (updated Nov. 13, 2023), https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfthirdparty/accredit.cfm?party_key=7.

[19] FDA, Third Party Review Organization Performance Report (version 1 of FY2022, Q4), at 38, https://www.fda.gov/media/162658/download?attachment.

[20] PRIA at 22.

[21] Total number of submissions from PRIA estimates less 3% of 510(k)s divided by the annual number of submissions, given that all of these submissions are slated to be filed within six months of each other under the proposed rule.

[22] FDA, Financial Report to Congress: Medical Device User Fee Amendments of 2017 FY 2022, at 27, https://www.fda.gov/media/165116/download?attachment.

[23] https://www.fda.gov/news-events/fda-voices/year-pandemic-how-fdas-center-devices-and-radiological-health-prioritizing-its-workload-and-looking

[24] “[W]e continue to receive more than 100 IVD pre-EUA and EUA submissions per month.” See Jeff Shuren & William Maisel, Looking Ahead to 2022 as FDA’s Center for Devices and Radiological Health Manages a Sustained Increase in Workload, FDA Voices (Dec. 21, 2021), https://www.fda.gov/news-events/fda-voices/looking-ahead-2022-fdas-center-devices-and-radiological-health-manages-sustained-increase-workload.

The annual Enforcement, Litigation, and Compliance Conference put on by the Food and Drug Law Institute (“FDLI”) took place in Washington this week. There were too many interesting panels and discussions to mention them all, but presentations about DOJ’s and FDA’s coordination deserve some special mention.

In his conference keynote address, Arun Rao—the Deputy Assistant Attorney General for DOJ’s Consumer Protection Branch—provided an overview of DOJ’s year in FDA enforcement. This speech is an annual victory lap for CPB’s enforcement achievements, and this year included much discussion about the Branch’s Voluntary Self Disclosure (VSD) policy. We’ve blogged on VSDs previously here and here, as the application of the VSD for FDA-regulated industry has been vexing. DOJ has provided few bright lines about when conversations and disclosures to FDA may also satisfy its own VSD requirements. Meeting those requirements might, as Rao said, make the difference between facing an indictment and receiving a declination.

At FDLI, Rao clarified that CPB’s policy dictates that “to receive credit for a disclosure, the disclosure must be made directly to the branch.” He also noted that the VSD “does not supplant existing obligations to report to appropriate regulatory agencies, nor is it intended to alter those existing practices and channels of communication.” This amounts to the clearest confirmation we’ve seen that companies in the FDA-regulated space face parallel reporting obligations when they deal with Federal oversight of FDCA violations and hope to short-circuit a potential criminal prosecution.

A panel on Day 1 discussed FDA’s efforts to ramp up domestic and foreign inspections following the COVID-19 slow down. A regulatory consultant on the panel made a recommendation to FDA that it lean more heavily on Remote Interactive Evaluations (“RIEs”) to help alleviate its backlog—of which HPM recently learned the Agency had only conducted 10 in the last 30 months for purposes of drug manufacturing compliance. Given that FDORA recently expanded FDA’s RIE authority to include device facilities, we may see more activity from FDA on this in the near future.

The last panel of Day 1 provided a bookend to the keynote’s clarifications about parallel disclosure. Panelists from CPB, FDA, and the Federal Trade Commission (FTC) all amplified the enduring government policy that they expect companies in the food and drug space have robust and legitimate compliance programs. And not to be left out of the conversation, FTC’s Associate Director on the panel noted twice that the Commission intends to be a player in this game as well and has robust plans to team with DOJ and use its enforcement authority over advertising for health products. The Associate Director highlighted FTC’s recent notice of penalty offenses sent to nearly 700 companies—many of whom may consider FDA to be their primary regulatory body—as a key example of FTC’s renewed activity in this space. She also hinted that such notices may become more common following the 2021 AMG v. FTC Supreme Court decision stripping FTC of its ability to obtain restitution or disgorgement under Section 13(b) of the Federal Trade Commission Act.

On Day 2 of the conference, HPM’s Anne Walsh moderated a fascinating conversation about due diligence investigations relating to FDA-regulated industries. Ms. Walsh is a nationally recognized expert in such matters, and the discussion combined the nuances of complex regulations, the prevailing ethos of both biotech and medtech, and securities law. Also on Day 2, HPM’s John Claud was part of a discussion of some of 2023’s more prominent enforcement resolutions, offering perspective from his vantage point as a former federal prosecutor.

The conference closed with an energized luncheon lecture that featured some amplified opinions that FDA and DOJ need to step up their criminal enforcement of bad actors in the industry, potentially by delegating the criminal enforcement authority currently centralized with OCI to FDA’s field offices. As that may develop, the 2024 edition of this conference will be worth coming back for.

On Monday, Hyman, Phelps & McNamara, P.C. filed comments on behalf of the Coalition to Preserve LDT Access and Innovation in response to FDA’s proposed rule to regulate laboratory developed tests (LDTs) as devices.  Weighing in at nearly 60 pages, the comments detail extensive flaws in the proposed regulation.  We’ve previously written about this proposed rule (see here, here, and here) which would transform the diagnostic market in the United States.

As a threshold matter, FDA lacks the power to regulate tests developed and used in a laboratory.  The Federal Food, Drug, and Cosmetic Act simply did not confer that power upon FDA.  Congress has, on multiple occasions, considered legislation that would have given FDA that authority, but it never did so.  FDA cannot now unilaterally assume power that Congress chose not to confer in the first instance.

FDA tries to justify the proposed rule by claiming that LDTs present significant risks, and that the solution is to regulate them all as medical devices.  The support FDA offers for its proposition – which comes from a mixture of sources, including a few published scientific articles, newspaper stories, FDA’s experience with LDTs with COVID, anecdotes, older case studies, and class action lawsuits – is singularly unconvincing.  For example, one of the primary articles cited by FDA to show poor laboratory performance of LDTs has been the subject of a reanalysis by the College of American Pathologists that found “excellent laboratory performance” of molecular oncology proficiency testing for cancer-associated genetic variants.  Similarly, a newspaper article cited by FDA, which asserted risks from Non-Invasive Prenatal Testing, was rebutted by multiple peer-reviewed studies and is at odds with the conclusion reached by medical professionals, such as the American College of Medical Genetics.  Although the sources cited by FDA differ, there is a common denominator: FDA never acknowledges the existence of contrary evidence.

The proposed rule similarly ignores the benefits of LDTs.  Tests such as genetic testing of prospective parents, prenatal screening, cancer prognosis, and testing for rare diseases play a critical role in the health care system.  Reading the proposed rule, one would never know why LDTs even exist, since there is no reference to their benefits.  Similarly, there is no recognition of the harm that would occur if many of these tests were to vanish because laboratories cannot sustain the significant economic burdens resulting from the new regulatory requirements.

FDA’s assessment of the costs of regulating LDTs as devices is similarly problematic.  The agency’s Preliminary Regulatory Impact Assessment (PRIA) repeatedly either understates the costs of certain tasks or ignores them altogether.  For example, in FDA’s “primary” case, laboratories would be expected to spend eight hours a year on management reviews.  That projection is ludicrously low, and one can only wonder how FDA could expect a compliant company to spend so little time on this function.  The PRIA also omits entire other categories of costs, such compliance with 21 C.F.R. Part 11, the need to hire new laboratory personnel, and engage outside experts such as Contract Research Organizations, biostatisticians, lawyers, and software engineers.

Although the proposed rule cites FDA’s reports of allegedly flawed Emergency Use Authorizations for COVID-19 tests submitted by labs – a complaint that ignores the extraordinary and non-representative circumstances presented by COVID – FDA apparently has developed its own post-COVID brain fog concerning the Agency’s inability to handle the deluge of EUAs during the course of the pandemic.  And yet, under the proposed rule, FDA is expecting a far greater surge, for a longer period of time, of far more complicated submissions.  Based on the COVID experience, this is a recipe for gridlock and chaos. FDA seems unconcerned by this prospect.

In sum, we think the proposed rule is a mistake.  But don’t take our word for it in this summary; read the other 6,731 comments submitted to FDA’s docket.   Speaking of which, given the statements FDA has made to date, we fully expect FDA to issue a final rule; while we cannot predict when, one press report predicted it could happen as soon as May 2024. Although the Administrative Procedure Act requires a federal agency to review and carefully consider all comments, it is inconceivable that FDA could read, let alone reflect on, this volume of comments within that timeframe.  Nevertheless, whenever the final rule is issued, there is very likely to be litigation.  For the reasons laid out in our comments, as well as the many others that objected to FDA’s proposal, the comments filed with FDA will provide plaintiffs with numerous bases for judicial challenge.