FDA’s Office of Prescription Drug Promotion (OPDP) has issued two new Untitled Letters this summer after 5 months without any letter activity. The letters are vastly different from one another in subject matter, but together they make a cruel summer of OPDP enforcement against industry. [Editorial note – the Gen X’er included that link first – for the arguably more popular reference, read on.]

The first Untitled Letter was issued to kaleo, Inc. on July 17, 2024 for a social media post published by Instagram influencer Brittany Mahomes (who has 2 million Instagram followers) about AUVI-Q (epinephrine injection, USP) that “entirely omit[ed] all risk information” about the drug. Mahomes, spouse to Kansas City Chiefs quarterback, Patrick Mahomes, is the mother of 2 young children with severe food allergies. Presenting only information about the benefits or efficacy of a prescription drug, like AUVI-Q, without any risk information is considered a false or misleading presentation under the Federal Food, Drug and Cosmetic Act (FDCA), and is considered misbranding of the product.

AUVI-Q is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects… biting insects… allergen immunotherapy, foods, drugs, diagnostic testing substances… and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The approved labeling for AUVI-Q includes warnings and precautions regarding emergency treatment, injection-related complications, serious infections at the injection site, allergic reactions associated with sulfite, and disease interactions.

The Instagram post contained both a video portion and text portion, neither of which mentioned or included any risk information. Instead, the post focused solely on the benefits and efficacy of AUVI-Q, with statements otherwise consistent with AUVI-Q’s approved labeling, such as “Auvi-Q is the only epinephrine autoinjector out there for infants and toddlers” and “AUVI-q® (epinephrine injection, USP) is for life-threatening allergic emergencies.”  The FDA acknowledged that although the post included the statement, “For Important Safety Information, visit @auviq_IS[,]” this “does not mitigate the misleading impression created by the omission of risk information,” (emphasis added). FDA’s stated concern from a public health perspective is that the omission of risk information “fails to provide material information about the consequences that may result from the use of Auvi-Q and creates a misleading impression about the drug’s safety.”  In other words, individuals may not be as vigilant about avoiding allergens if they only hear the benefits of AUVI-Q without understanding there may be safety consequences as well.

Honestly, we are pretty shocked that this social media post slipped through the review committee.  Haven’t we all learned that celebrity endorsements for prescription drugs still need to meet traditional promotional requirements? Thank you, Kim, for paving the way here.

Moral of the story – simply referring consumers (or followers) to a drug’s website for safety information is not enough  – even if you are TSwift’s bestie.

August 2024 Untitled Letter to Mirati Therapeutics Inc.

The second Untitled Letter was issued to Mirati Therapeutics Inc. (Mirati), a Bristol Myers Squibb company, on August 1, 2024 for content on a healthcare provider branded website for its product, KRAZATI (adagrasib), which was approved under FDA’s accelerated approval pathway for patients with certain types of non-small cell lung cancer based on objective response rate (ORR) and duration of response (DOR). The FDA’s accelerated approval pathway can allow for earlier approval of drugs intended to treat serious conditions and fill an unmet medical need where approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit and the predicted clinical benefit is subsequently verified in a post-approval confirmatory trial(s). FDA notes in its letter that it received multiple complaints about the website under its Bad Ad Program.

The letter states the website makes false or misleading claims and representations about the benefits and efficacy of KRAZATI, thus misbranding the product. The website makes numerous clinical efficacy claims for the drug, including claims relating to “depth of response,” “disease control rate” (DCR), and rates of “stable disease” (SD), “partial response” (PR), “complete response” (CR), and “progressive disease” (PD) from Mirati’s KRYSTAL-1 study which was the basis for FDA’s accelerated approval of KRAZATI. However, as FDA points out in its letter, KRYSTAL-1 was a multicenter, single-arm, open-label expansion cohort study that evaluated the effect of KRAZATI on ORR and DOR and thus did not establish that the SD observed in the study was attributable to the effect of the drug; such an assessment would need to be based on the results of a randomized controlled trial. FDA noted similar findings for the website’s presentation of DCR, overall survival (OS) and progression free survival (PFS) results since the KRYSTAL-1 study design was not capable of producing interpretable results on these endpoints. The website also included claims from “data on file” that were based on “pooled DOR” information. FDA stated “[p]ooling data poses analytical problems as differences among studies and study populations can affect the validity and interpretability of such pooled analyses,” and, because the FDA could not verify the presented results, requested Mirati provide data to support its claim for FDA’s review. Additionally, Mirati included disclaimers that the data presented on the website were based on descriptive and post-hoc analyses, which FDA stated is not sufficient to mitigate the overall misleading impression created by the inclusion of the data.

The Mirati letter deals with much more nuanced issues than the letter to kaleo. When dealing with a drug that is approved via the accelerated approval pathway, can efficacy data be presented as consistent with the FDA-required labeling (CFL) and be subject to the “scientifically appropriate and statistically sound” (SASS) standard, generally thought to be a lesser substantiation standard than the traditional regulatory requirements of “substantial evidence” and “substantial clinical experience?”  Even in a CFL world, these presentations likely fall short of the SASS standard where the communication “relies on a study that is inadequate to support the representations or suggestions it presents [and] disclosure of the material limitations of that study does not correct the misleading message conveyed by the communication.”

What these bloggers find interesting about this letter (beyond the CFL analysis) is that because KRAZATI was approved under the accelerated approval pathway, Mirati would have been required to submit all promotional materials for the drug thirty (30) days in advance of the material being used. As FDA did not object to the timing of the submission in the letter, it seems that FDA (likely) received a copy of this website for review, FDA did not comment, and Mirati moved forward with publishing – only to receive an Untitled Letter months later.  Years ago, FDA had much more robust communications about promotional materials with sponsors of accelerated approval products. This Draft Guidance, withdrawn in 2015, outlines FDA’s historical intent to review submissions and provide comments in a timely manner, “usually within 15 working days of the day the materials are received by FDA.” While it is likely not reasonable to maintain this expectation given the volume of materials submitted, it begs the question:  if OPDP cannot review materials and/or provide comments within the thirty (30) day window for accelerated approval products, why bother requiring sponsors to submit their materials in advance in the first place? Just some food for thought.

States better get ready,
Rescheduling may be coming,
You may need to make changes,
You may need to do more,
Than just get on board.
(With apologies to Curtis Mayfield)

By the close of the public comment period for the Drug Enforcement Administration’s (“DEA’s”) proposal to reschedule marijuana two weeks ago, the agency had received over 43,500 comments.  Governors, state cannabis regulators, law enforcement groups and local governments weighed in, as did marijuana advocates and opponents, marijuana industry associations, Members of Congress, federal law enforcement groups, healthcare and human rights groups, unions and trade associations, and private individuals.  Comments ranged from single sentence declarations to lengthy, cogent treatises, expounding on whether to reschedule marijuana from schedule I to schedule III or another schedule under the federal Controlled Substances Act (“CSA”), to leave marijuana in schedule I, or to deschedule altogether.  Regardless of whether DEA holds a public hearing, the issue will not be resolved for some time.

Rescheduling or descheduling from the most stringent schedule under the CSA, should one of those actions occur, would loosen federal manufacturing, import/export, distribution, and security requirements.  Rescheduling out of schedule I would allow for the medical use of FDA-approved prescription drugs dispensed by DEA-registered, state licensed pharmacies pursuant to prescriptions issued by similarly DEA-registered, state licensed practitioners.

While DEA is the primary federal authority that enforces the CSA and its regulations, the states, commonwealths, and territories also regulate marijuana and other controlled substances within their borders.  What has been overlooked is how rescheduling or descheduling may impact how the states and the District of Columbia might have to regulate marijuana.

Every state has enacted its own controlled substances statutes and regulations, many of which mirror the federal CSA and DEA regulations.  While states regulate most controlled substances similarly to regulation at the federal level, DEA and the states often diverge with marijuana.  Marijuana has been in schedule I of the CSA, the most stringent schedule for substances of abuse, since 1970.  21 U.S.C. § 812(c)(c)(10).  Schedule I substances have a high potential for abuse, no currently accepted medical use in treatment in the U.S., and lack accepted safety for use under medical supervision.  21 U.S.C. § 812 (b)(1).  In the most recent eight factor analyses prior to August 2023, in 2016 HHS and DEA concluded that marijuana continued to meet criteria for remaining in schedule I.  Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition To Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).

The states, through their own controlled substance authorities, pharmacy boards, departments of health or legislatures schedule and impose regulatory requirements on substances of abuse and the legitimate entities that handle them.  Some states have authorities that regulate marijuana exclusively.  To date thirty-eight states authorize marijuana in different dosage formulations for specific qualifying medical conditions and twenty-four states authorize adult recreational use of marijuana.  Marijuana use remains illegal in a handful of states.

Depending upon the state, substances of abuse are scheduled, rescheduled or descheduled if, as under the federal CSA, they meet certain criteria.  State scheduling criteria, though differing by state, are also generally consistent with CSA criteria.  About half the states require the same eight factor scheduling analysis as the CSA, and while some states require analysis of additional factors, others require analysis of fewer factors.

States’ controlled substances acts generally mirror the federal CSA.  This internal mandate may conflict with the state’s current allowance of marijuana for medical or recreational uses.  Federal scheduling actions may automatically trigger a number of states to control the substance consistent with the federal CSA.  In some states the regulatory authority is required to take action within a certain period of time, say thirty or sixty days following the final scheduling notice appearing in the Federal Register, or the federal action becomes effective in the state.  Some of those states require a public hearing, after which the state publishes its decision to follow or not follow the federal scheduling action.  States required to automatically schedule, reschedule or deschedule based on what DEA does may lack the authority to schedule marijuana more independently.  A number of states have discretional scheduling authority not tied to federal scheduling.

The federal CSA does not preempt state law unless there is positive conflict between one of its provisions and state law such that they cannot stand together.  21 U.S.C. § 903.  DEA has historically taken the position that in conflicts between the CSA and state law, the stricter governs.

DEA rescheduling marijuana in either schedules II or III may not represent a big change for states that already authorize marijuana for medical use.  However, for states that allow for recreational use of marijuana, even federal rescheduling from schedule I to a less restrictive schedule may trigger a sea change and potential culture shift.

At least half of the states currently regulate marijuana as a schedule I substance under their controlled substances act.  Other states variously control marijuana as a schedule III (Minnesota), schedule VI (Arkansas, Massachusetts, North Carolina and Tennessee), schedule VIA (Alaska), or schedule Z (Maine).  There are some states that do not control marijuana, or they regulate it outside of their controlled substances act.

Were DEA to reschedule marijuana to schedule II or III, or leave it in schedule I, and the states regulate it in a less restrictive schedule or allow continued recreational use, how will the U.S. Department of Justice (“DOJ”) and DEA respond?  Will DOJ and DEA continue to exercise the enforcement discretion generally shown since the Cole Memo was issued in August 2013?  Merrick Garland may not be Attorney General if DEA takes scheduling action on marijuana, but if he is, he may have provided a clue during his confirmation.  He said at that time that it was not the best use of DOJ’s limited resources to prosecute those complying with laws in states that have legalized marijuana and are “effectively regulating marijuana.”  Merrick Garland, Responses to Questions for the Record to Judge Merrick Garland, Nominee to be United States Attorney General 24 (Feb. 28, 2021).  We wonder if the Cole Memo was a holding pattern of sorts until DOJ and DEA resolved the federal/state marijuana divide and having done so, determine that states are not “effectively regulating marijuana” if they regulate marijuana less restrictively.

Rescheduling or descheduling, should either occur, will likely not become effective anytime soon.  In the meantime, authorities should take stock of potential federal rescheduling ramifications by assessing and understanding how it may impact how they regulate marijuana their state.

Increasingly the subject of induced infringement litigation, the viability of the carve-out has been questioned for several years now.  But recently, a new challenge was filed in the District Court for the District of Columbia questioning whether modifications to labeling as a result of patent protections—beyond the mere omission of language—are permissible under the section viii carve-out requirements.  In other words, the case asks how “same” a generic drug’s labeling must be as compared to its Reference Listed Drug.

On July 30, brand name drug sponsor Novartis asked the District Court for a Temporary Restraining Order (here and here) enjoining FDA’s approval of a generic version of its ENTRESTO (sacubitril and valsartan) with certain dosing and indication information carved-out or modified.  That modification to the labeling, Novartis argues, “represents a sharp departure from FDA’s statutory and regulatory mandate to require that a generic drug be the ‘same’ as its reference listed drug.”  This is because the generic—sponsored by MSN Laboratories Private LTD—revised the approved ENTRESTO indication rather than simply omitted portions.  Additionally, Novartis alleged that FDA unlawfully permitted the carve-out of critical safety information of a modified dosing regimen.  Each of these issues, says Novartis, “independently renders the agency’s decision unlawful, and invalidates the agency’s approval of the MSN product.”

ENTRESTO was approved by FDA in July 2015 “to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.”  In February 2021, FDA approved a supplement to the ENTRESTO NDA, which changed the indication such that it now reads “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”  As a result, ENTRESTO is now approved to treat all patients with chronic heart failure, whether classified as having reduced ejection fraction or not, and added a new dosing regimen for specific patients.  Novartis has a patent on the new indication, which claims a modified dosing regimen for use in patients with heart failure with reduced ejection fraction.

While denying a Citizen Petition from Novartis asking FDA to refuse to approve any ANDA that omits the new dosing regimen or changes the indication, FDA approved MSN’s ANDA on July 24, 2024.  FDA, in its Citizen Petition Denial, stated that it retains the authority to approve generic labeling that modifies an approved indication and that it could lawfully approve generic labeling that omits the modified dosing regimen in ENTRESTO’s labeling.  To that end, FDA approved the MSN ANDA without the modified dosing regimen and with the indication “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. Left ventricular ejection fraction (LVEF) is a variable measure, so use clinical judgment in deciding whom to treat.”  From the government’s brief, see here.

Upon denial of the Citizen Petition and approval of the MSN ANDA, Novartis filed suit against FDA arguing that FDA’s actions violate the plain text of the FDCA.  FDA should not have approved the modified indication, as the FDCA requires generic labeling to match the current labeling for the reference listed drug—not the 2015 label that has been discontinued.  Novartis further claims that the MSN labeling is unlawful because it violates the statutory requirement that the indications be “the same.”  While Novartis implicitly questions whether FDA’s regulations are consistent with the statute that requires the same labeling, it points to FDA regulations that permit only the “omission of an indication”—not the modification of the product’s currently approved indication.  Novartis asserts that FDA failed to explain “how a full cloth rewriting of the reference drug’s labeling is consistent with the rest of the ENTRESTO labeling” and that the modified labeling, especially considering the omission of the modified dosing regimen, “renders [the MSN product] both less safe and less effective.”

FDA and intervenor MSN vehemently defend FDA’s approval here.  FDA asserts that “there is no legal or logical basis for Novartis’s claim that generic labeling may only omit a patented use by deleting words from (rather than adding them to)” the RLD’s labeling.  FDA regulations explicitly permit “omission of an indication or other aspect of labeling protected by patent,” which is exactly what FDA approved here when it carved out the use of patients with normal ejection fraction.  FDA further argues that Novartis’s implied preclusion against adding words would lead to absurd results, as the availability of a carve-out would depend on stylistic wording choices in the reference labeling.

Meanwhile, MSN argues that Congress designed the “same labeling” statutory requirements to allow for labeling changes by permitting section viii statements to avoid including language that would infringe a patent.  That’s precisely what FDA did here when it approved the modified label.  According to MSN, Novartis’s reading, which would allow only for changes relating to different manufacturers, product names, or company addresses, is so narrow that it would “render meaningless the section viii statutory provisions because it would not allow generic companies to carve any language from the brand label in order to avoid brand company patents.”  The only way that MSN could have omitted the protected language was to make “minor attendant changes to the label,” and to preclude such modifications “would create a precedent where any brand manufacturer could circumvent section viii statements entirely by carefully wording its indications.”

Both FDA and MSN additionally question whether the carved-out data is actually “critical safety information” as concluded by Novartis.  FDA claims that “Novartis overstates [the data’s] significance” while MSN accuses Novartis of asking the Court to “second-guess FDA’s scientific judgment regarding drug safety and efficacy.”  As a determination of fact, MSN argues, FDA’s assessment here should be treated with respect even under Loper, which, MSN highlights, clearly states that “Section 706 [of the Administrative Procedure Act] does mandate that judicial review of agency policymaking and factfinding be deferential.”  FDA, in responding to the Citizen Petition, laid out a highly reasoned and technical analysis that should be afforded deference, concludes MSN.

At its heart, the question at issue here implicates the survival of the carve-out.  While not quite as “on the nose” as the inducement of infringement cases, Novartis is asking the Court to limit FDA’s authority with respect to the carve-out such that the RLD sponsor’s crafting of the indication would dictate whether a carve-out can even be used.  This case further raises questions about whether deference will continue to be afforded to FDA in the scientific and factual context notwithstanding Loper.  This interesting case is certainly one to watch!

The American Conference Institute (“ACI”) held its 11th Annual Summit for Women Leaders in Life Sciences Law at the Seaport Hotel in Boston, Massachusetts on July 25th & 26th of last week.  Several leading ladies in law at HPM attended the conference and, based on their feedback, gave the annual event an A+ rating.  Our very own Director, Anne Walsh, spoke on a panel titled Navigating Today’s Life Sciences M&A Landscape: Charting the Latest Trends and Challenges in Pharma and Biotech Dealmaking.  As we are all aware, the M&A landscape is an ever-changing place, so there is always something new to learn.  Anne and her fellow panelists engaged the audience with timely and thoughtful insights, each addressing their area of specialty (e.g., FDA, IP, and antitrust).

The weather was great in Boston, and so many talented and inspiring women gathered at the Seaport Hotel to speak on the most pressing issues currently in life sciences.

Substantive topics:

• AI – Leveraging AI in Medical Devices, Harnessing Generative AI in Business Operations and Legal Practice.
• GLP-1s – Exploring the Anticipated Compliance and Litigation Risks.
• Advertising Challenges in Life Sciences.

Highlights:

• CEO Spotlight Interviews.
• Women in Government and Judiciary Roundtable.
• “Mistakes – I’ve Made a Few” Overcoming Bumps in your Career Journey…

Not surprisingly, the impact of Chevron being overturned was a recurring theme throughout the two-day conference. We heard multiple speakers acknowledge that Loper Bright will invite more challenges to government regulation and the need for federal agencies to shore up their rules and regulations to protect past actions and reduce the ripple effects for regulated entities.

This annual summit tends to be a standout conference for women in life sciences law and something that is anticipated all year.  Most importantly, the summit guarantees to empower future generations of women in life sciences.  The focus on networking made it very easy to meet colleagues from all over the country and the world.  We will be sure to put it on our calendars for next year, and hope to see fellow Blog readers in Boston too.

There is a growing consensus among legal experts that after Loper Bright, FDA may rely on non-binding guidance to instruct industry with hopes of charting regulatory pathways that avoid litigation. In areas like biologics, biosimilars, and interchangeable biosimilars, where emerging technologies meet regulatory complexities, this is perhaps a wise strategy. The top line from FDA for any cGMP-governed industry like these is always going to be that quality matters. But in the biologics and biosimilar industries, maintaining quality can be a very nuanced—if not difficult—process.

Last week, FDA issued draft guidance to address the potential complications that arise when sponsors seek to modify products, production processes, or quality controls for approved biologics license application (BLA) biosimilar and interchangeable products. Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers Guidance for Industry is intended to be a roadmap that first describes the change notification process outlined in 21 C.F.R. Part 601.12, and then offers additional information and discussion about what FDA expects to see from applicants who are intent on ensuring quality.

The draft guidance first addresses the kinds of information applicants should develop and collect so that they can evaluate the effects that post-manufacturing changes might have on their products’ identity, strength, quality, purity, or potency. Part 601 delineates those changes as being either major, moderate, or minor.

Major changes may have a substantial effect on quality and require a Prior Approval Supplement (PAS). The draft guidance notes that adding a comparability protocol in a PAS that outlines postapproval chemistry, manufacturing, and controls (CMC) changes can be beneficial, potentially paving the way for reduced future reporting if it sufficiently details a minimal risk for adverse effects from the manufacturing changes.

Biosimilar and interchangeable sponsors with moderate post-manufacturing changes can submit a Change Being Effected in 30 Days (CBE-30) supplement. The draft guidance reminds applicants that FDA must approve or note any missing information in a CBE-30 supplement within 30 days before an applicant distributes the product.

Here again though, both the guidance and the regulations describe how a persuasive filing may have advantages for an applicant. A product described in a well-drafted and persuasive CBE-30 might in turn merit immediate distribution, in effect changing a CBE-30 to a CBE-0. The draft refers industry to other guidances on the factors FDA might consider, and the regulation tells us that they include “substantial similarity with a type of change regularly involving a [CBE] supplement or . . . [where] evidence that the proposed change has been validated in accordance with an approved protocol . . . .” In our experience such a change is rare, but perhaps FDA is of the mind here to clarify how this might happen. As for minor changes that have minimal effect of product quality, the draft guidance notes that applicants can document those in their annual report, as opposed to a discreet filing with the agency.

Between the discussion in the draft guidance and the steps described in Part 601, applicants should have useful instruction of how to notify FDA of postapproval changes. But the draft guidance also includes several helpful takeaways for applicants about the kinds of quality data that they should evaluate. For example, it notes that applicants should conduct comparability exercises before and after the manufacturing change and analyze both the data from those exercises as well as their design. That’s because “postchange biosimilar or interchangeable biosimilar product should be evaluated at the process step most appropriate to detect a change in the quality attributes.” As with any cGMP issue, sponsors taking this on also need to focus on process validation.

And since we’re talking about biosimilars and interchangeables, FDA notes that an applicant should include a “well-qualified, in-house reference material.” This is an important “calibration point” for comparability, ideally enabling applicants to evaluate whether the changed product remains sufficiently similar to the reference product.

When applicants introduce a licensed biosimilar or licensed interchangeable product into a multiproduct manufacturing area, they potentially risk cross-contamination, or loss of controls over personnel, process, or materials. The draft guidance notes that in this situation, purity and identity of the product are the key quality attributes at risk. FDA counsels that sponsors evaluate the multiproduct manufacturing risks based on both the type of product and the potential effects of additional controls. In other words, there are no strict guidelines that span across the biosimilar industry.

Finally, the draft guidance describes the CMC information that FDA recommends applicants submit in support of a supplement for a change in dosage form or strength. That information includes adequate comparability data between the original licensed biosimilar or interchangeable and the proposed new dosage form or strength. It also includes an adequate comparative analytical assessment and validated manufacturing data that supports the change.

As is seen here through the myriad regs and guidances we’ve linked, quality assurance for biologics, biosimilars, and interchangeables is a labyrinthine pursuit, and FDA expects to hear about how applicants are ensuring it. We’ll update this post when FDA issues Final Guidance.

In November 2023, FDA published a proposed rule regarding wound products containing antimicrobials. From a legal perspective, the reason for the proposed rule is that these wound products are some of the few remaining medical devices that have not yet been classified by FDA. As a result, they have been coming to market through the 510(k) process as Class II medical devices since passage of the Medical Device Amendments, nearly 50 years ago. While it is well within FDA’s right to formally classify the products, the position it is taking in the proposed rule is not based in science or evidence, and raises serious commercial speech concerns.

Without providing a single piece of evidence, the premise of the proposed rule is that these wound products with antimicrobials are contributing to the spread of antimicrobial resistance (AMR). FDA’s position is that finalizing this rule will lead to a reduction in morbidity and mortality. However, FDA fails to provide any evidence of deaths or serious injuries associated with the long-standing use of these products. Despite the lack of support for its position that these products pose significant risk, FDA is proposing to upclassify certain wound products with antimicrobials to Class III, and for those remaining in Class II, to impose stringent special controls, ranging from an AMR risk assessment to prohibitions on truthful, scientifically accurate speech.

The Washington Legal Foundation graciously published my article analyzing the rule and discussing the implications to industry if finalized. While the comment period has closed, we will be tracking FDA efforts to finalize the rule. If you have questions about how this might impact you, or would like talk about how you can influence FDA before the rule is finalized, please reach out.

The American Conference Institute (“ACI”) is holding its 10th Anniversary Paragraph IV Disputes Master Symposium from October 15-16, 2024, at the Hyatt Regency McCormick Place in Chicago, Illinois.  Each fall, leading pharmaceutical patent litigators for brand-name and generic drug companies gather at the Paragraph IV Disputes Master Symposium in Chicago to receive up-to-the-minute information on the latest developments affecting Hatch-Waxman litigation and participate in significant peer-to-peer networking opportunities.  Join us to address emerging and growing areas of concern, including the implementation of the Inflation Reduction Act, FTC’s—and now a District Court’s—attack on Orange Book patent listings, and the proposed use of the Bayh Doyle Act.

Other key program highlights this year include:

• Examining the Use of Clinical Trials as Prior Art: How to Thread the Needle on Protecting IP and Mandated Disclosures
• Patent Rights and Supply Chain Dynamics: Understanding How Developments in India May Affect Hatch-Waxman- Generic and Brand Perspectives
• Fireside Chat on Future of FDA Initiatives Affect Small Molecules: Regulatory Initiatives, and Agency Developments for Hatch Waxman Practitioners to Watch

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will moderate a panel discussion, titled “Fireside Chat on the Future of the FDA: Regulatory Initiatives, and Agency Developments for Hatch Waxman Practitioners to Watch.”

You can register for the conference here.  FDA Law Blog readers receive a 10% discount off the tuition fee (promo code D10-999-FDA25).

For several years, FDA has requested that sponsors of drug or biologic led combination products identify essential performance requirements (EPRs) related to the device constituent in their applications.  EPRs were usually requested in the context of design controls, although 21 C.F.R. § 820.30 does not use this term.  In various meetings with the Agency and at conferences, FDA was often asked to clarify this term.  Are EPRs the same as “Essential Performance” as defined in IEC 60601-1 Medical electrical equipment – Part 1: General requirements for basic safety and essential performance?  Are EPRs design outputs that are essential for the proper functioning of the device that are required to be identified per 21 C.F.R. § 820.30(d)?  Are EPRs a new term to describe a subset of design input requirements and specific to combination products?

FDA recently released a much-anticipated draft guidance to address these frequent questions:  Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products.  We were thankful to see that the term, EPR, has been replaced with Essential Drug Delivery Outputs (EDDO), which better aligns with terminology and requirements of the Quality System Regulation.

The draft guidance (June 2024) defines an EDDO as the “design outputs necessary to ensure delivery of the intended drug dose to the intended delivery site.  Drug delivery includes successful product preparation and the initiation, progression, and completion of dose delivery.  EDDOs are system level outputs for which device drug-delivery function is dependent on the device design.”   There is a lot to unpack in this definition and the draft guidance includes sections to help sponsors identify and differentiate which design outputs should be considered EDDOs, and includes appendices with examples demonstrating the process of identifying EDDOs as well as an appendix providing examples of potential EDDOs based on product type that includes prefilled syringes, auto-injectors, on body injectors, pen injectors, jet injectors, nasal sprays, metered dose inhalers, dry powder inhalers, nebulizers, vaginal systems, infusion pumps, and subdermal implants.

While the scope of the guidance indicates that it is intended to address information about EDDOs submitted for drug- or biologic-led combination products, the guidance also covers applicability to 510(k)s, PMAs, and IDEs suggesting that the draft guidance may also apply to the device constituent of cross-labeled combination products, or drug delivery devices not associated with a combination product.

With respect to verification and validation of EDDOs, the draft guidance recommends demonstration that the EDDO is met after preconditioning that includes conditions of storage and shipping.  Design verification testing should include risk-based sampling plans and include evaluation over the shelf-life for EDDOs that may change over time or have age-related failure modes.  Design validation may be covered by clinical studies, pharmacokinetic/pharmacodynamic or bioequivalence/bioavailability studies, literature, simulated bench testing, and/or anthropometric data and should include endpoints that have the capability of validating device performance.

A control strategy should be established to ensure that each lot of the final finished product is manufactured to conform to the design outputs.  A risk-based approach can be used for each EDDO to determine the appropriate control strategy.

Information to include in IND, IDE, and marketing applications is also described within the draft guidance.  Common across application types are a description of the device constituent and performance data.  For marketing applications, a summary of the EDDO information is recommended in the device description with reference to performance data and other supportive information.

Although there are some inconsistencies in the scope of the guidance, it overall should be a valuable resource for developers of drug delivery devices when final.  Comments may be submitted by September 30, 2024.

The American Conference Institute (“ACI”) is holding its 2nd West Coast Editionof its Legal, Regulatory, and Compliance Forum on Cosmetics & Personal Care Products from September 25-26 at the Le Meridien Delfina, Santa Monica, California.  Join distinguished counsel and regulatory experts representing the cosmetics and personal care industry, together with government officials, as they share insights on myriad topics, including:

• Preparing for the next stages of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) implementation
• Analyzing specific California and Washington laws and regulations governing cosmetics and personal care products
• Assessing the latest developments in PFAS legislation and litigation
• Obtaining insights into FTC and NAD Guidelines on Influencers, Consumer Reviews and Endorsements
• Comprehending West Coast product labelling, packaging and recycling laws
• Navigating emerging trends in Clean Beauty and ESG Practices
• Addressing Beauty-Tech and Consumer Privacy protections in the digital era
• Understanding global trade regulations and successfully introducing your products into a dynamic world marketplace
• Implementing IP protections and anti-counterfeiting strategies for your brand

Hyman, Phelps & McNamara, P.C.’s John W.M. Claud will be speaking at the conference in a session titled “Crafting Your Safety Blueprint for Adverse Events and Recalls under MoCRA.”

You can register for the conference here.  FDA Law Blog readers receive a 10% discount off the tuition fee (promo code D10-999-FDA25).

Sometimes it’s difficult to be a plaintiff, putting all your work into just one case. That’s especially true if recent Supreme Court rulings have rendered your matter a quixotic pursuit, doomed to fail for lack of direct causation.

That’s what happened last week in District Court in Maryland. Following the precedent on standing that the Supreme Court handed down in June in FDA v. Alliance for Hippocratic Medicine et al., a judge in Maryland dismissed another suit against FDA for lack of standing.

The plaintiffs in that case—Alliance of Nurses for Healthy Environments, et al v. FDA—were a group of environmentally conscious interest groups that brought suit against FDA to better regulate the use some antimicrobials in livestock and poultry. All the parties agreed that the rampant use of these drugs potentially creates long-term problems, such as the kind of bacterial resistance that potentially makes infections more difficult to treat.

Alliance for Nurses started as a Citizen’s Petition back in 2016, making its way to District Court when FDA took no action. In alleging that antibiotic use was a public health problem that FDA should regulate, the plaintiffs offered several testimonials from ostensibly affected people. They included a nurse that feared bringing resistant infections home to his family, a sportsman fearful to fish downstream from a farm where antibiotics are used, and families that altered their shopping habits to buy organic food that they thought was less likely to be affected by antibiotic use.

In dismissing the suit for lack of standing, the court in Maryland followed the precedent from Hippocratic Medicine. There, SCOTUS dismissed the high-profile lawsuit concerning the abortion drug Mifepristone. The unanimous Court held that the doctor-plaintiffs in Hippocratic Medicine had not suffered direct, causal injury. They were suing on behalf of doctors everywhere who might be affected by the legal use of mifepristone, but none of them alleged actual injury from the drug’s availability. Thus, ruled SCOTUS, they were “unregulated parties who seek to challenge FDA’s regulation of others,” in spite of their indirect link to the actual alleged controversy.

In Alliance for Nurses, the court similarly ruled that the plaintiffs were suing FDA to prevent a harm that had not yet occurred to them. The causation of injury was too speculative, too indirect to support an actual case or controversy under Article III of the U.S. Constitution. As outlined by the court, the chain of causation read like a prosaic Rube Goldberg machine:

The precise ultimate injuries the plaintiffs’ members identify vary. Some allege health injuries, like an increased likelihood of suffering an antibiotic-resistant infection. Others allege harm to recreational and aesthetic interests, like fishing less often to reduce exposure to bacteria-infested water. Still others allege economic injuries, like buying antibiotic-free meat to mitigate the risk of exposure to antibiotic-resistant bacteria or buying separate work clothes so that their care for infected patients does not jeopardize the health of their family members. But all of the injuries the plaintiffs’ members identify come at the end of a causal chain at least as lengthy and uncertain as the one the Alliance for Hippocratic Medicine Court found too speculative and attenuated to establish standing.

We’ve written previously about how decisions from the recent Supreme Court term are likely to weaken FDA’s ability to defend its interpretations of statutory meaning, and may trigger more litigation challenging agency decisions. But in the new world of post-Loper Bright litigation, perhaps the decision in Alliance of Nurses tells us that all is not lost for FDA. Plaintiffs still need to allege that FDA’s actions directly cause or likely will cause injury. Defending lawsuits, FDA may find that standing is something warm to come to when courtrooms seem increasingly cold and lonely.

On July 17, 2024, FDA announced the establishment of a Rare Disease Innovation Hub (the “Hub”) to enhance and improve outcomes for patients with rare diseases and conditions by focusing on rare disease drug and biological product development across the Agency’s Center for Drug Evaluation and Research (“CDER”) and Center for Biologics Evaluation and Research (“CBER”). Importantly, the Hub is intended to establish a new model within FDA, which leverages cross-Agency expertise in providing guidance and conducting reviews for products for rare disease populations. First announced by Dr. Peter Marks at James Valentine’s FDA Rare Disease Town Hall session at the DIA Annual Meeting last month (see Pink Sheet coverage here), this Hub is intended to serve as the Center of Excellence that we in the rare disease community have been calling for its establishment over the last several years.

The creation of the Hub comes on the heels of relentless advocacy by the rare disease community for a Rare Disease Center of Excellence that was first proposed by Hyman, Phelps & McNamara’s own Frank Sasinowski and James Valentine nearly 6 years ago (see the initial call to action here). We commend FDA for implementing this vision (yes, even if called a Hub rather than a Center of Excellence) as it is critical that lessons learned and best practices be implemented more consistently across the Agency as we now have significant experience in the science of small trials and innovative approaches to establishing the safety and effectiveness of orphan drugs.

We also commend and congratulate the legions of rare disease patient advocates and the leadership of the EveryLife Foundation for Rare Diseases (“ELF”) who championed the advocacy efforts that led to this important milestone.

Early Direction for the Rare Disease Innovation Hub

The Hub, which will be co-chaired by Drs. Peter Marks and Patrizia Cavazzoni, spans across both Centers, and will collaborate with the Center for Devices and Radiological Health, Oncology Center of Excellence, Office of Orphan Products Development, and Office of Combination Products.  Thus far, FDA has announced three primary functions for the Hub:

1. Serve as a single point of contact for engagement with rare disease community stakeholders, including patient advocacy organizations, trade organizations, and academia;
2. Enhance inter-Center collaboration on scientific, clinical, and policy issues related to rare disease product development, including approaches related to product review, and promote consistency across Centers and offices; and
3. Advance regulatory science with dedicated workstreams on key opportunities to advance rare disease product development, such as clinical outcome assessments, biomarkers, innovative trial designs, real world evidence, and statistical approaches.

FDA also announced the creation of a new senior leadership position within the Hub, the Director of Strategic Coalitions, who will also serve as the Associate Director of Rare Disease Strategy in CDER, similar to how many Oncology Center of Excellence leadership held positions both within the Center of Excellence but also within the medical product centers.  This individual will play a key role in overseeing the new integrated Hub model and helping to develop and implement its strategic agenda action plan.

Implementation of the Hub, particularly in these early days, will be critical to ensuring its effectiveness, so seeing this and hopefully additional investment in its staffing and infrastructure will be key.

An Opportunity to Leverage the Newly Created Rare Disease Advisory Committee across CDER and CBER

In Frank and James’ 2018 proposal there was also a recommendation for the formation of a Rare Disease Advisory Committee, which would allow FDA access to experts in the science of small trials and other aspects of rare disease research.  As originally proposed, this new Committee could be convened in conjunction with the existing medical specialty area-focused advisory committees, akin to the Drug Safety and Risk Management Advisory Committee.

In December 2023, FDA established the Genetic Metabolic Diseases Advisory Committee (also called “GeMDAC,” which we blogged about here) to advise FDA regarding treatments for genetic metabolic diseases (i.e., those reviewed by the CDER Division of Rare Diseases and Medical Genetics). However, the expertise represented on the committee was to include small population trial design, translational science, and pediatrics, among others, which would be broadly applicable to rare diseases of other etiology. As such, there is an opportunity to leverage the GeMDAC in a similar fashion as the originally-proposed Rare Diseases Advisory Committee.

Earlier this month the FDA announced the first meeting of the GeMDAC will be held on August 2, 2024 to discuss a novel treatment for Niemann-Pick disease type C (and Frank and James are looking forward to being there!).

Next Steps for the Hub and Beyond

The FDA plans on holding an open public meeting this Fall, including a docket for public comment, to provide further information about the Agency’s vision for the Hub and receive feedback from the community to help shape the Hub’s priorities and initiatives.

According to FDA, the new Hub will have special focus on products intended for smaller populations and also for diseases where the natural history is variable and not fully understood. These are exactly the types of things that were addressed at ELF Scientific Workshop in May 2024 which addressed challenges in developing therapies for ultra rare diseases (see our blog about this here, which includes a link to the recording). In fact, at this Scientific Workshop, Frank called for the creation of an alternative effectiveness standard for ultra rare diseases that relies on all available scientifically valid evidence (e.g., clinical pharmacology/biomarkers, animal models, real-world evidence and other externally controlled comparisons [e.g., natural history studies]), not just evidence from adequate and well-controlled studies, which would be consistent with and further the mission of the Hub.

With the establishment of GeMDAC and the Hub (nearly in line with Frank and James’ 2018 proposal), we are eager to see whether sooner than 6 years from now there is a new alternative effectiveness standard for therapies to treat rare diseases where the feasibility of conducting a conventional adequate and well-controlled trial may be daunting or simply not possible (such as for products intended for smaller populations and also for diseases where the natural history is variable and not fully understood!). In the meantime, just as we never stopped advocating for both the Rare Disease Center of Excellence and the Rare Disease Advisory Committee (which are both now, in some fashion, a reality!), we are committed to continuing to help evolve sound regulatory science in order to bring more and better therapies to patients with rare, too often ultra rare, serious conditions.

The Supreme Court’s recent decision in Loper Bright v. Raimondo has done away with Chevron deference to federal agencies’ interpretation of ambiguous statutes, including the FDA. The decision commands that federal judges must make their own decisions in suits against FDA, considering—but not deferring to—the Agency’s interpretation of ambiguous statutory provisions. Stripping FDA of the key tool of deference, Loper Bright will undoubtedly reinvent the way FDA advocates in federal courts.

The majority opinion in Loper Bright finds that this is a necessary change from the now-defunct Chevron regime, demanded by the text of both the Administrative Procedures Act and the Constitution. The majority also insists that it is not forcing judges to walk all the way through the looking glass to a mirror-image world where FDA’s input and interpretation of its own final agency actions are rendered into nonsense. Judges will now consider, but not defer to, FDA’s positions on matters of statutory interpretation if those positions are persuasive. As a result, there is now an open question as to how FDA and their litigation partners at the Department of Justice will respond to this new standard. What is clear is that FDA will consider the impact of Loper Bright in its litigation strategy going forward.

It is important to note that Loper Bright did not do away with consideration of agency expertise.  First, with respect to issues of statutory interpretations, the Court turned the clock back to the 1944 touchstone of Skidmore v. Swift. Substituting Chevron deference with Skidmore deference, courts are now to use “interpretations and opinions” of an agency that are rooted in “specialized experience” to help make decisions. As Loper Bright noted, the degree to which a court would respect and rely on agency judgment would “depend upon the thoroughness evident in its consideration, the validity of its reasoning, its consistency with earlier and later pronouncements, and all those factors which give it power to persuade, if lacking power to control.”

Second, because Chevron deference was about statutory interpretation, even in a post Loper Bright world, the Administrative Procedure Act “does mandate that judicial review of agency policymaking and factfinding be deferential. See §706(2)(A) (agency action to be set aside if ‘arbitrary, capricious, [or] an abuse of discretion’).” The upshot of this would seem to be that the stakes are now much higher as to whether a dispute with the FDA is over a question of law or policy.

In the former category of legal disputes, “courts, not agencies, will decide ‘all relevant questions of law’ arising on review of agency action, §706 (emphasis added)—even those involving ambiguous laws—and set aside any such action inconsistent with the law as they interpret it.” Additionally, there should probably be no expectation that judges will shy away from cases where hyper-technical facts mix with questions of law. In the latter category of policy questions, however, the deferential arbitrary and capricious standard applies.

The dissenting justices in Loper Bright took a dim view of the assumption that in the absence of deference, federal judges will exercise sufficient consideration of agencies’ subject matter expertise in controversial cases. Justice Kagan wrote that “[i]f the majority thinks that the same judges who argue today about where ‘ambiguity’ resides . . . are not going to argue tomorrow about what ‘respect’ requires, I fear it will be gravely disappointed.” Under this view, no matter how effectively FDA advocates for its public health mission and the congressional intent to enable it, future controversies that might be cabined as statutory interpretation and not internal policymaking will prove to be a “font of uncertainty and litigation.”

We have yet to fully understand how far FDA litigation over statutory interpretation has gone through the mirror here. As FDA is left to restructure how it will litigate its way out of the likely surge of lawsuits, the contours around Loper Bright will take years to iron out. Future posts will tackle this shifting new legal landscape as cases develop.

FDA’s Center for Devices and Radiological Health (CDRH) recently partnered with the Digital Medicine Society (DiMe) to host a two-day workshop to help advance the use of patient-generated health data (PGHD) to support improved clinical trials, medical device development, and regulatory science.  The workshop included many sessions and panel discussions that focused on how PGHD can be used in patient care and clinical studies to improve health equity.   The benefits of PGHD, challenges with PGHD, and future of PGHD were discussed by FDA representatives, industry representatives, patient organizations, and patients.

Patient-generated health data are data that are created, recorded, or gathered by patients or caregivers outside of a clinical setting.  PGHD can be derived from Digital Health Technologies, which we have blogged on here, here, and here.  Examples include measuring activity levels with wearables, recording symptoms with mobile applications, and collecting biometric data, such as blood pressure, with medical devices.  PGHD can be used as part of patient care as well as in clinical trials.  In clinical trials, PGHD can be used in clinical outcome assessments (COAs) that describe how a person feels, functions, or survives, which can be valuable endpoints.

One highlight of the workshop was that what matters to regulators, providers, and payors may not align with what matters to patients.  It was also noted that patient-generated data does not always mean patient centered data, meaning that while a patient may be involved in data collection, the data may not be meaningful to them. There is also a connotation that patient-generated data is lower quality and not as reliable, but with current technology, data that are meaningful to patients with high quality and reliability are possible.

Patients want to feel better, have more energy, have the ability to work, and take fewer medications.  Using PGHD can help patients manage their own health and can help sponsors develop endpoints for studying impacts of new treatments that matter to patients.  One patient, who is also a scientist, shared their journey with cancer and how personal use of wearables and over-the-counter medical devices during treatment was able to show correlation between the data they collected and the days they were feeling good and bad.

Patients that spoke also noted that they felt empowered, rather than merely passive recipients of medical services, when PGHD was part of their healthcare or when participating in studies using PGHD.  Another patient shared their journey with diabetes.  This patient had used wearable devices on their own in the past but did not understand how to use the data to manage their health.  When they were prescribed a continuous glucose meter and insulin pump, use of technology as part of their prescribed treatment plan improved both their physical and mental health dramatically and allowed them to go from 11 medications to just insulin.

From the patient’s perspective, security and privacy were identified as key issues by some, but for others, they are so focused on their health that they aren’t necessarily thinking about this, even though it may be very important.  It was noted that many patients don’t understand digital consent, what data they are providing, and for what purpose.  Patients also don’t have the opportunity to make changes to the consent to ensure they are comfortable with the use of their data.

Sponsors need to make sure patients and study participants can use the technology.  It was noted that keeping the cost of wearables low will help with equity, especially in use of PGHD outside of clinical studies.  Where technology is used to generate PGHD for clinical trials of other medical products, sponsors may need to provide WiFi and/or phones to study participants if what the patient has will not meet requirements to avoid excluding patients.

As for the future of PGHD, many panelists were asked how they envision use of PGHD in 2030.  Responses included use of PGHD in risk prevention and avoidance, allowing studies to proceed without placebo, referencing PGHD as just “data” and not “digitally derived,” and having patient experience data collected and taken into account in every study, regulatory, and coverage decision – ultimately a shift to give power to patients.

As this post shares only a few highlights from the enlightening two-day workshop, readers can access more information on CDRH’s and DiMe’s websites.

The Food and Drug Omnibus Reform Act (“FDORA”), enacted in December 2022, added a requirement that sponsors submit Diversity Action Plans (“DAPs”) for certain clinical studies involving drugs, biological products, or devices (codified at 21 U.S.C. § 355(z)(3) and 21 U.S.C. § 360j(g)(9)(A)).  For drugs, the relevant studies are any Phase 3 study or, as appropriate, another pivotal study of a new drug (other than bioavailability or bioequivalence studies).  For devices, the requirement is a bit more nuanced.  A DAP is required for studies of medical devices for which an Investigational Device Exemption (“IDE”) application is required and also for those for which an IDE is not required unless the study is an “exempted investigation” under the regulations.

The statute specifies that DAPs are to include the sponsor’s goals for enrollment in the relevant study, the sponsor’s rationale for such goals, and an explanation of how the sponsor intends to meet these goals. These new requirements apply only to investigations for which enrollment commences 180 days after publication of final guidance required under this section.

The statute also states that DAPs should be “in the form and manner specified by the Secretary in guidance.”  To encourage the development of such guidance, Congress directed FDA to issue a draft guidance not later than 12 months after the date of FDORA’s enactment and to finalize such guidance not later than 9 months after closing the comment period.

FDA issued its draft guidance titled “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies,” (the “Draft Guidance”) which replaces the previous pre-FDORA April 2022 draft guidance of the same name.  The deadline for the Draft Guidance was December 29, 2023, so the draft, issued on June 26, 2024, is about 6 months late under FDORA’s mandate.

We’ve blogged about some of FDA’s efforts to increase diversity in clinical trials previously, and the Draft Guidance itself describes a variety of these efforts.  However, this Draft Guidance, in combination with the relevant provisions in FDORA, represents potentially the biggest change to date in how industry must incorporate these efforts into development programs.

The Draft Guidance

FDA states in the Draft Guidance that unlike most guidances (including the draft guidance it replaced), the Draft Guidance, when finalized, will, in part, have the force of law because FDORA specifically dictates that the “form and manner” for the submission of DAPs are specified in guidance; thus, language regarding the form and manner of such plans in the Draft Guidance, when finalized, will have binding legal effect.

DAP Content

In developing DAPs, the Draft Guidance recommends that sponsors consider whether certain demographic groups may have a different response to a medical product regarding either effectiveness or safety.  This could be based on differential pharmacokinetics (“PK”) or pharmacodynamics (“PD”), possible differences in susceptibility to specific adverse events of concern, or due to differential presentation of the disease or condition.

A DAP must include enrollment goals for a covered clinical study, disaggregated by race, ethnicity, sex, and age group of the clinically relevant population.  Although these are the characteristics required to be included by FDORA, the Draft Guidance notes that other factors (e.g., geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidity) may impact outcomes.  Although not required by FDORA, FDA encourages sponsors to consider such additional factors, which may support subgroup analyses, when developing DAP goals.

The enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population.  On occasion, greater than proportional enrollment of certain populations may be needed to elucidate potentially clinically important differences in responses between subsets of the study population.  Where there is insufficient information on incidence, prevalence, or demographics, the Draft Guidance recommends considering alternative approaches:

• Where a subset of a disease is being studied, it may be acceptable to use prevalence and incidence for the broader disease and base enrollment on the demographic characteristics of that population;
• Where the product is intended for a general use population, it may be acceptable to set enrollment goals based on general U.S. population demographics; or
• Where there are limited or no data to characterize demographic characteristics of the intended use population, it may be acceptable to set enrollment goals based on the general U.S. population demographics.

Where sponsors plan to conduct several clinical studies that may be subject to DAP requirements, the plan for each study should reflect a strategy that leads to an overall proportionate representation, even though individual studies may not.  For rare diseases, although patient numbers may be too small to detect meaningful differences in safety or effectiveness, the Draft Guidance states that consistent representative enrollment may still provide opportunities for hypothesis generation and further study.

A DAP for a multi-national clinical study must describe enrollment goals for the entire study, not just U.S.-enrolled participants, and these goals must be based on the U.S. intended use population.  Interestingly, in recent remarks at an industry conference, Commissioner Califf challenged focusing exclusively on the U.S. population in light of the U.S. role in global health.  The Draft Guidance states that FDA recognizes that the distribution of the disease or condition across the clinically relevant population may differ by geographic region based on several factors (including risk factors, screening practices, and available treatments), and recommends engaging early with FDA review divisions to discuss how to address these factors in the DAP.

DAP Goal Rationales

The sponsor must also provide a rationale for the study’s proposed enrollment goals, including information and analysis to explain how these goals were determined.  As such, the sponsor should include background information on the disease or condition, as well as prevalence and incidence estimates, if available, and any other background information justifying the enrollment goals.  Where a sponsor intends to conduct several clinical studies to support a marketing authorization that may be subject to DAP requirements, the DAP for each study should describe how the enrollment goals of the individual study fit into the sponsor’s goal of having an overall proportionate representation across all of the planned clinical studies, the sponsor’s rationale for the different enrollment goals for each study, and how the individual studies are intended to contribute to the overall enrollment goals for the clinical development program.

For drugs, the rationale should describe data and information, if any, that suggest the potential for differential safety and effectiveness across the clinically relevant population, such as possible differences in PK or PD. Sponsors should describe the relevancy of other characteristics that available data suggest have an impact on clinical outcomes (e.g., socio-economic status, geographic location, comorbidities).

For devices, the rationale should describe data and information, if any, about the potential for differential safety and effectiveness of the device across the clinically relevant populations and available data regarding differences expected to impact safety or effectiveness (e.g., by sex, age or by genetic variations).  Similar to the requirement for drugs, sponsors of device clinical trials should describe, as applicable, the relevance of other population-level or individual characteristics that may impact clinical outcomes (e.g., socio-economic status, geographic location, comorbidities).  Data on relevant factors for device performance (e.g., phenotypic, anatomical, technological, or biological factors) should be evaluated to characterize any differential effects across a diverse population by the relevant demographic characteristics.

Measures to Meet Enrollment Goals

Sponsor plans to meet the specified enrollment goals, including a description of enrollment and retention strategies for the study population, should also be included in the DAP, as well as specific measures to accomplish these goals.  FDA encourages sponsors to consult patients and healthcare providers to assist in developing such strategies.  Examples of these strategies include:

• Sustained community engagement;
• Providing cultural competency and proficiency training for investigators and research staff;
• Improving study participant awareness and knowledge of the clinical study (e.g., providing language assistance);
• Reducing participant burden (e.g., avoiding unnecessary procedures, imaging, and laboratory tests; employing sites for procedures and laboratory tests that are convenient to the specific populations in the enrollment goals; providing transportation assistance; providing dependent care; allowing flexible hours for study visits; reimbursement for costs incurred);
• Limiting study exclusion criteria, selecting study site locations that would facilitate enrollment of a representative study population, and considering accessibility needs of persons with disabilities; and,
• Employing clinical study decentralization when appropriate.

A plan to monitor enrollment goals during the study to help ensure goals are met and to facilitate prompt intervention to address barriers to meeting such goals should also be included.

Timelines for Submission

Drug sponsors must submit their plans to the Investigational New Drug (“IND”) no later than the date on which the sponsor submits the protocol to FDA for the relevant study.  In the Draft Guidance, FDA recommends submitting the DAP earlier when the sponsor is seeking feedback regarding the applicable clinical study (typically at the End-of-Phase 2 meeting).  Sponsors may discuss DAPs with FDA sooner.

For device clinical studies, a DAP must be included at the time of an IDE submission, if applicable. Sponsors of certain studies where an IDE submission is not required are should submit a DAP as part of the premarket notification (e.g., 510(k) submission, De Novo classification request, Premarket Approval (“PMA”) application).

Procedures for Submitting the DAP

Sponsors should describe the DAP clearly and concisely, with limited cross-referencing to previously submitted documents.  The Draft Guidance states that the length should generally not exceed 10 pages, excluding references.  For drugs, the relevant CDER/CBER Division may or may not provide feedback; sponsors with specific questions may include them as a topic for discussion in meetings with FDA.

The status of the DAP submission and any interactions with FDA regarding the DAP should be included in the regulatory history for milestone meetings and marketing submissions.  IND annual reports should also include updates on progress toward meeting enrollment goals; this should include any plans to mitigate outcomes where goals are not on track to be met.

In marketing application submissions, sponsors should provide a brief overview of the DAP, an assessment of whether the relevant enrollment goals were met, and, as appropriate, an explanation of what measures may have contributed to the observed outcomes with respect to the enrollment goals.

For device studies, FDA considers the DAP to be a part of the overall process for generating clinical evidence for the subject device.  Therefore, a sponsor may seek FDA feedback through the Q-submission process before submitting a DAP as part of the IDE application for studies of SR devices.  FDA expects that DAPs for studies not requiring IDE applications may be developed without FDA feedback.

DAP Waivers

According to FDORA, some or all the requirements for a DAP may be waived based on the prevalence or incidence of the disease or condition, because such a plan would make the conduct of a clinical trial impracticable, or because a waiver is necessary to protect public health during a public health emergency.

FDA may waive a requirement either on its own initiative or at a sponsor’s request, and the appropriateness of a waiver is a case-specific determination.  However, the Draft Guidance states that full or partial waivers will only be granted in rare instances.  FDA generally does not intend to waive requirements even if the disease or condition is relatively homogenous.  Instead, this information can be included in the rationale supporting enrollment goals in the DAP.  Recent comments by FDA officials have made it clear that FDA expects that waivers will be rare.

FDA is required to issue a written response to a waiver request within 60 days of receipt.  Therefore, requests should be submitted no later than 60 days before the DAP is required for submission.  FDA strongly encourages sponsors to discuss plans for a waiver early in the planning stages of the study or development program.  If FDA determines that a waiver will be issued, it may consider public communications about the decision.

Analysis

The goal of this Draft Guidance, and DAPs more broadly, is laudable, and we applaud efforts by Congress and FDA to expand involvement in medical product development to populations that have been historically excluded or underrepresented.  Moreover, it is extremely important to understand as best as reasonably possible how medical products affect all populations that may use them.  DAPs for clinical trials are not new inventions, as previously mentioned; however, the new mandates under FDORA are designed to shift these plans from “should” to “must.”

Some unanswered questions remain.  Since it is only the submission of the plan that is required by law, how, if at all, will FDA communicate that a plan does not meet the requirements for submission?   A sponsor could conduct a study that is not initially viewed as pivotal but which ends up being so for its marketing application.  What if no DAP was provided or implemented for that study based on its initial objectives?  It seems like it would be prudent for a sponsor who believes a study could even potentially be pivotal to submit a DAP, even if such possibility appears remote.  The potential cost of not submitting a plan as required by law would appear to outweigh the risk of any potential downside; however, sponsors should assess whether this is the case for their development programs.

It is also not clear what happens if the goals in the DAP are not met.  The current requirements are limited to having a DAP – it remains to be seen how FDA will evaluate whether or what actions it might take if goals are not met or if FDA concludes adequate good faith efforts were not employed to implement the DAP.  The statute and Draft Guidance do not provide for penalties or consequences.  Would any such failure to meet DAP goals be reflected in labeling?  Could the FDA require a post-marketing commitment on a sponsor to conduct another clinical trial that enrolls appropriately diverse patient populations under the original or a revised DAP or could a potential risk signal for a certain population trigger a post-marketing requirement?  Or maybe we will see an increased utilization of and reliance on registries and other real-world evidence to gather this information in the post-market setting.

Another question is the impact on rare disease drug development, where broader populations are small and there may be limited knowledge about differential impacts of disease.  Senior FDA leadership recently described an intention to be “sensible” regarding how to approach these concerns for rare diseases to avoid “slow[ing] down development by significant amounts because of this.”  As the Draft Guidance describes that waivers will be rare, what does this mean for flexibility on the enrollment goals for clinical trials for rare diseases subject to DAP requirements?

Requiring DAPs is an important first step in ensuring that the clinical studies supporting marketing authorization include information about the broad array of individuals who may be treated with new medical products. Nevertheless, implementation will not necessarily answer questions about other under-represented populations, such as multiracial individuals, who according to the 2020 US census, account for 10% of the population or under-represented populations that are not defined on race, ethnicity, sex, or age, such as pregnant and lactating persons who have historically been excluded from clinical research. The Draft Guidance encourages sponsors to consider factors beyond racial and ethnic demographic characteristics when developing DAP enrollment goals, but without clear expectations to enroll these populations, they may continue to be excluded from clinical research.

While the Draft Guidance encourages sponsors to consider many dimensions of clinical trial diversity, even those that extend beyond ethnicity, sex, and race, to enroll populations that represent the patients who will be treated if the product is approved, the question remains how far the Draft Guidance will actually move the needle and result in the data necessary for these patients and their physicians to make informed treatment decisions.  We hope the answers to these and other questions are coming.  As with any new program, it is likely that certain kinks will have to be worked out as we go along.

Comments on the Draft Guidance can be submitted to the docket through September 26, 2024.  This means, under Congress’s direction in FDORA, the FDA should be trying to finalize the Draft Guidance around June 2025.  If FDA meets this timeline, the requirement to submit DAPs for relevant clinical studies would begin around the end of 2025.

On Thursday, the 27^th of June, the Supreme Court issued its decision in Securities and Exchange Commission v. Jarkesy.  The court ruled that the Securities and Exchange Commission (SEC) may not impose fines to penalize securities in its administrative proceedings because that practice violates the Seventh Amendment “right of trial by jury” in all “suits at common law.” This decision likely will impact other federal administrative agencies, including those relevant to our practice.

Here are some brief facts of the case.  SEC charged George Jarkesy Jr. with securities fraud for alleged improper reporting regarding two investment funds that he ran.  An internal SEC process found him guilty and imposed a penalty of $300,000 and disgorgement of $685,000 in illicit profits.  In response, Jarkesy sued, claiming that the agency’s ability to both charge him civil penalties and conduct an administrative judicial proceeding violated his Seventh Amendment right to a trial by jury.

The Seventh amendment provides that in “suits at common law, where the value in controversy shall exceed twenty dollars, the right of trial by jury shall be preserved, and no fact tried by a jury, shall be otherwise reexamined in any court of the United States.”

The first question in the Court’s analysis was whether the claim that the SEC brought is a “suit at common law,” i.e., if the case is legal in nature.  That the claim rested on a federal statute and required the SEC to establish facts that do not match any cause of action known to the common law in 1791 was not dispositive.  Rather the analysis must consider whether the cause of action resembles a common law cause of action and whether the remedy is the sort that traditionally was obtained in a court of law.  According to the Court, the remedy is considered the more important factor.  In fact, the Court asserted that it “is all but dispositive [that] the SEC seeks civil penalties, a form of monetary relief, [because] money damages are the prototypical common law remedy” that could only be enforced in courts of law.

This did not end the analysis, however.  Even if the claim is legal in nature, agencies may avoid a trial by jury when the public rights exception applies.  As described by the Court, this “public rights exception” recognizes that when Congress creates a “public right” it may “assign the matter for decision to an agency without a jury.”  Therefore, the critical question in the Court’s analysis was whether this case involved a public right.

This is where the majority and dissent differ.  The majority answered this question by looking, again, at the nature of the claim for relief.  According to the Court, the matter is presumed to concern a private right if it is “made of the stuff of the traditional actions at common law.”  In other words, the civil penalties did not only determine that the suit was legal in nature, it also determined that the suit did not concern a public right.  The Court acknowledged that the determination as to whether it concerns a public or private right has not been “definitively explained” but stressed that the public right is an exception and should be interpreted narrowly.

The dissent agreed that the critical question is whether the matter concerns a private or public right.  However, it strongly disagreed with the majority on the conclusion.  According to the dissent, where the government is the claimant, it concerns a public right.

Justice Sotomayor’s lengthy dissent discusses the consequences of the Court’s analysis; “Today, for the very first time, this Court holds that Congress violated the Constitution by authorizing a federal agency to adjudicate a statutory right that inheres in the Government in its sovereign capacity.”  As the dissent points out, the federal government has operated for decades on the assumption that many disputes can be adjudicated by ALJs. According to a review of federal law she cited, by 1986 there already were more than 200 federal statutes calling for trials before ALJs.

Some of these laws, including the one allowing the SEC to bring enforcement actions against people like Jarkesy, give the government a choice. That is, they allow federal agencies to bring a proceeding either before an ALJ or before a federal district court that may conduct a jury trial.  So the SEC has the option of retrying Jarkesy in a district court. But, Justice Sotomayor warns that some agencies may not be able to collect certain civil penalties at all because the statutory and regulatory provisions governing those penalties specify that they must proceed administratively, which the Court has now said is unconstitutional.

We note that questions remain, such as whether there are statutes providing for civil penalties that are of a kind that did not already exist under the common law, and how much, if any, of the public rights doctrine remains.  The Court asserts that its ruling is limited to civil penalty suits for fraud.  For an example, the Court points to the Occupational Safety and Health Act of 1970 (OSH Act), a statute that created a federal regulatory regime to promote safe working conditions which created a cause of action not existing under common law.  However, the dissent does not buy this, stating that “the incredible assertion [that the ruling is limited to civil penalty suits for fraud] should fool no one,” and concludes that the Court’s decision “is a massive sea change.”

There is no question that the Jarkesey decision has created significant uncertainty as to the authority of many agencies imposing civil penalties administratively.  The decision likely will have minimal impact on FTC or CPSC cases because Congress or court decisions previously determined that both commissions could only seek civil penalties in court.  The impact on FDA matters could be significant.  FDA has civil money penalty authority relating to clinical trials, devices, foods, drugs, and tobacco; although with the exception of tobacco, FDA has not recently exercised that authority with regularity.  If FDA is prohibited from pursuing the relatively small dollar value tobacco penalty cases administratively, it could affect enforcement.  Bringing an administrative claim is typically much less demanding in time and resources than litigating a jury trial.  The impact on USDA and DEA could be similarly significant.  It should be noted, that the Jarkesy decision does not affect an administrative tribunal’s right to adjudicate equitable (non-monetary damages) issues.

We will be monitoring the effect of this decision on federal agencies and the regulated industry.