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FDA recently released a much-anticipated draft guidance to address these frequent questions:  Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products.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.

In its final rule on laboratory developed tests (LDTs) (see our prior blog here), FDA acknowledged that “some laboratories may lack familiarity, experience, or existing infrastructure for complying with FDA requirements” and made multiple references to a “small entity compliance guidance” that the agency intended to publish to “provide additional guidance to small businesses.”  Laboratories struggling to understand the myriad implications of being regulated as device “manufacturers” were hopeful that additional guidance would shed light on how to apply FDA’s existing medical device regulatory framework to their operations.

Unfortunately, the guidance for small entities recently published by FDA is little more than a summary digest of the multi-hundred-page final rule. The guidance restates the central premise of the final rule, i.e., that LDTs are medical devices and the clinical laboratories that design, manufacture and use them to test patient specimens are manufacturers.  It then reiterates the process and timeframe for phaseout of generalized enforcement discretion for LDTs, lists the categories of LDTs that will, to varying degrees, continue to be subject to enforcement discretion, and repeats that “certain tests” that were historically excluded from enforcement discretion —those offered directly to consumers, those used in blood and tissue donor screening, and those intended for use in public health emergencies — will continue to be ineligible for enforcement discretion.   The guidance also reminds readers of the somewhat illusory protection offered by enforcement discretion, noting that “FDA retains discretion to pursue enforcement action for violations of the FD&C Act at any time and intends to do so when appropriate.”

To be sure, Table 2 provides a handy visual of the categories of LDTs, the timeline for phaseout, and the scope of enforcement discretion for each test category.  However, the guidance provides no new information on how FDA expects laboratories to implement these new requirements.  Section IV, Additional Resources, provides links to previously-issued guidance documents and other educational materials geared to traditional device manufacturers, with no additional commentary on how to apply these requirements to the very different clinical laboratory environment.

The first phaseout milestone is less than a year away; by May 6, 2025 most laboratories will need to demonstrate compliance with Medical Device Reporting (21 C.F.R. § 803), Reporting of Corrections and Removals (21 C.F.R. § 806) and Complaint Files (21 C.F.R. § 820.198).  Below we describe the specific requirements that clinical laboratories will need to meet and identify interpretive questions that may pose challenges to implementation.

Complaint Handling

CLIA regulations, with which all clinical laboratories must already comply, state that a clinical laboratory must “have a system in place to ensure that it documents all complaints and problems reported to the laboratory,” and must “conduct investigations of complaints, when appropriate”.[1] However, the focus of CLIA requirements is on laboratory processes, not specific assays. Furthermore, CLIA regulations are more general and provide more opportunity for customization of complaint handling processes provided the underlying objectives are met.  The CLIA State Operations Manual (SOM) which provides interpretive guidance to investigators conducting laboratory surveys, states that an inspector should “[v]erify that the laboratory documents all complaints and problems reported to the laboratory, and that it has a mechanism to determine which complaints require investigation.” The SOM includes three “probes” to guide evaluation, which focus on (1) the mechanism used by the laboratory to enable individuals to report complaints or problems to the laboratory; (2) the laboratory’s process for informing laboratory personnel of the ability to anonymously report laboratory quality complaints to outside agencies; and (3) the laboratory’s mechanism for referring complaints or problems to its reference laboratory(s), or other offices or agencies, when appropriate, as well as whether the such activity is documented.

Like CLIA, FDA requires device manufacturers to have written procedures that define the complaint handling process and to maintain the complaint files in accordance with their own developed procedures.  However, FDA’s complaint handling requirements for device manufacturers are more detailed and prescriptive in nature, and it is not clear whether they will in practice align with laboratories’ existing complaint handling procedures; FDA may find laboratories’ existing processes insufficient or may impose different or conflicting requirements that increase administrative burdens.

FDA regulations define a complaint expansively, to include “any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.”[2]  The regulations require manufacturers to establish a “formally designated [complaint handling] unit,”[3] which can be accomplished by describing the unit in a procedure and/or including a diagram that identifies individuals, activities, and departments that are charged with “…receiving, reviewing, and evaluating” complaints.[4] Manufacturers maintain complaint files for a “period of time equivalent to the design and expected life of the device, but in no case less than 2 years from the date of release for commercial distribution”  consistent with regulatory requirements for record retention.[5]  In contrast to traditional medical device manufacturers, laboratories do not “commercially release” an IVD device but instead report results based on the performance of the LDT.  It is therefore unclear what the “life expectancy” of an LDT is or when the “commercial distribution” of an LDT begins for the purpose of maintaining complaint files.

As discussed below, complaint handling is closely tied to FDA’s medical device reporting (MDR) and corrective and preventive action (CAPA) requirements.  Laboratories should therefore expect that FDA auditors will, in addition to reviewing complaint handling, also evaluate MDR processes and decisions and consider whether a complaint should have triggered a CAPA.  If a laboratory determines that a complaint does not require further investigation, it will need to document the “reason no investigation was made and the name of the individual responsible for the decision” in the complaint file.[6]  If the laboratory determines that investigation is required, the record of the investigation “shall be maintained by the formally designated unit.”[7]

FDA regulations require specific information to be recorded in complaint files, including, at a minimum: the name of the device, date of the complaint, unique device identifier (UDI), name, address, phone number of the complainant, nature and details of the complaint, dates and results of the investigation, any corrective action taken, and any reply to the complainant. Laboratories will need to ensure the complaints are processed in a “uniform and timely manner.”[8]  Laboratories will need to develop written procedures for complaint handling.  Failure to handle complaints in a consistent and timely manner can be cited as a nonconformance during an FDA inspection. Laboratories will therefore need to describe what does, and does not, constitute a complaint about the LDT. Training of personnel in the “designated complaint handling unit” on FDA requirements for complaint handling will be critical to ensure consistent complaint evaluations.  Timeliness is critical not only for developing appropriate corrective actions but also for evaluating and, when necessary, submitting reportable events to FDA as discussed below.

Medical Device Reporting

In the preamble to the final LDT rule, FDA stated it intends to develop additional education resources for MDR reporting to assist laboratories in coming into compliance with these requirements.  Merely providing links to existing MDR training materials for traditional device manufacturers, as the new compliance guide does, fails to meet FDA’s stated objective.  As stated above, while CLIA requires to have processes for detecting problems, these processes focus on detecting and addressing errors by the laboratory, and not on a specific test in isolation.

The MDR regulations require device manufacturers to “report deaths and serious injuries that your device has or may have caused or contributed to . . .  report certain device malfunctions, and . . . establish and maintain adverse event files.”[9]  The regulations define a “malfunction” as a “failure of a device to meet its performance specifications or otherwise perform as intended.”[10]  Performance specifications “include all claims made in the labeling for the device,” and “the intended performance of a device refers to the intended use for which the device is labeled or marketed.”[11]

In the context of an LDT, it is unclear what FDA will include within the scope of “labeling” and what types of communications will be considered “claims.”  At a minimum, the laboratory report, which typically includes patient information, specimen type, test results, reference ranges, and test interpretation, would foreseeably be considered test labeling, and statements made therein, or by laboratory personnel about the test report, could be considered evidence of the LDT’s intended use.  Treating the test report as labeling could, however, interfere with the laboratory director’s duty to ensure that “consultation is available to the laboratory’s clients on matters relating to the quality of the test results reported and their interpretation concerning specific patient conditions” and could have a chilling effect on the laboratory director’s ability to provide meaningful guidance to healthcare providers about their patients’ test results.[12]

Reporting under the MDR regulation is required within 30 calendar days of “becoming aware” of such an event, unless remedial action is necessary to prevent unreasonable risk of substantial harm to the public health, in which case reporting must occur within 5 work days.[13]   A manufacturer is considered to “become aware” of an event when any of its employees become aware of a reportable event.  It will therefore be imperative that any laboratory employees who receive complaint information notify the group responsible for evaluating such reports as soon as possible.  Given the short timeframe for submitting an MDR, some of the facts surrounding an event may not be known at the time of the initial report, in which case laboratories will need to file supplemental MDR reports.

Laboratories will be responsible for developing MDR procedures, training employees on MDR requirements, training the complaint-handling employees on recognizing and evaluating MDR reportable events, and developing MDR event files.  The learning curve for laboratories will presumably be steep; even seasoned device manufacturers can find themselves at odds with FDA about whether an MDR should have been filed with the agency following an event, so revisions to policies and further training of personnel should be expected.

MDRs must be reported to FDA in electronic format.  Laboratories will need to develop an electronic means of submitting said reports to FDA well in advance of the reporting requirements to ensure they are ready to report as of May 6, 2025.  Laboratories will also need to become familiar with the various codes used in MDR reports.   FDA has seven categories of MDR adverse event codes, and laboratories will need to become familiar with the codes and how to apply them to any adverse events or malfunctions of the device. The codes are organized in a “tree-like hierarchical structure, where higher-level codes are more generic, while lower-level codes are more specific.”[14]

Reports of Corrections and Removals

The final rule also requires most clinical laboratories to begin submitting reports of corrections and removals, and to maintain records of all corrections and removals, whether or not reported, beginning May 6, 2025.  A “correction” means “the repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a device without its physical removal from its point of use to some other location.”[15]  A “removal” means the “physical removal of a device from its point of use to some other location for repair, modification, adjustment, relabeling, destruction, or inspection.”[16]  A correction or removal must be reported to FDA within 10 working days of its initiation, if it was initiated, to “reduce a risk to health posed by the device” or to “remedy a violation of the act caused by the device which may present a risk to health . . . .”.[17]   A “risk to health” means a “reasonable probability that use of, or exposure to, the product will cause serious adverse health consequences or death”; or that “use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences, or an outcome where the probability of serious adverse health consequences is remote.”[18]

Attempting to apply these regulations to LDTs seems, at least on first consideration, an exercise in fitting a square peg in a round hole.  It is by no means obvious what terms such as “repair,” “destruction,” “inspection,” or “physical removal” means in the context of an LDT, which is not a discrete physical object and which does not ever leave the confines of the laboratory.

Even where a correction or removal does not meet the threshold for reporting, a manufacturer must maintain records that include information about the brand name, common or usual name, classification, name and product code if known, and the intended use of the device; the UDI or other identifier used for the device; a description of the event(s) giving rise to the information reported and the corrective or removal action taken; the justification for not reporting the correction or removal action to FDA; and a copy of all communications regarding the correction or removal.  LDTs, however, many do not have a brand name, common or usual name, applicable product code, or a unique identifier.

In addition to the FDA, manufacturers must communicate corrections and removals to the consignees, i.e., the customers to whom a device was distributed.  For corrections and removals reported to the FDA, device manufacturers also must provide FDA a copy of the communication that sent to the consignees that describes the actions they need to take (e.g., return of the device) and when corrections will be implemented.  In the case of LDTs, however, it is unclear who the “consignee” is, since, as noted above, the LDT does not leave the laboratory.  If the consignee is the laboratory performing the LDT, then the laboratory would be required to, essentially, notify itself of the correction or removal and provide FDA a copy of the communication it sends to itself.

Records of corrections and removals must be retained for a “period of 2 years beyond the expected life of the device.”[19] It is unclear how the “expected life” of an LDT would be established; the life of an LDT performed on a specific specimen arguably ceases when the assay is completed, but the LDT test protocol used to perform the specific assay arguably continues to exist as long as the laboratory continues to perform it.

Labeling

We note that while labeling requirements are not being phased in until stage 2 (May 6, 2026), the regulatory requirements in stage 1 appear to assume that at least some labeling requirements – such as UDI, which must be included in complaint files –  will already be implemented). With respect to the UDI requirement, FDA regulations require them to be placed on the device “label.”  But, similar to the challenges noted above regarding interpretation of the term “labeling” for MDR purposes, it is not clear what would constitute the “label” of an LDT, since it comprises multiple elements used in combination by the laboratory, not a discrete finished product sold to third parties. Moreover, to the extent a UDI is intended to facilitate identification of a device throughout its journey from manufacturer through distribution to the end user, it is not clear what purpose it would serve for an LDT, which has no physical existence outside the laboratory.

Conclusion

Laboratories that were hoping for substantive guidance from FDA on how to navigate the unfamiliar, and by no means self-executing, complaint handling, medical device reporting and correction and removal regulations, will need to look elsewhere for advice or use their best judgment and hope for FDA’s understanding if such judgments fail to meet FDA’s unarticulated expectations.

[1] 42 C.F.R. § 493.1233.

[2] 21 C.F.R. § 820.3(b).

[3] Id. § 820.198(a).

[4] Id.

[5] Id. § 820.180(b).

[6] Id. § 820.198(b).

[7] Id. § 820.198(e).

[8] Id. § 820.198(a).

[9] Id. § 803.1.

[10] Id.

[11] Id.

[12] 42 § 493.1407; id. § 493.1445.

[13] 21 C.F.R. § 803.3.

[14] FDA, MDR Adverse Event Codes, at https://www.fda.gov/medical-devices/mandatory-reporting-requirements-manufacturers-importers-and-device-user-facilities/mdr-adverse-event-codes.

[15] Id. § 806.2.

[16] Id.

[17] Id. § 806.10.

[18] Id. § 806.2.

[19] Id. § 806.20.

Among the tools that the government has to enforce the FDC Act is the injunctive power granted by Congress in 21 U.S.C. § 332. That statute provides that courts “shall have jurisdiction, for cause shown, to restrain violations” of the FDC Act. Historically, courts have modified, watered down, or altogether eschewed the traditional equitable requirements for an injunction when considering FDA’s request for injunctive relief. The Supreme Court’s decision in Starbucks Corp. v. McKinney strongly suggests that courts should engage in a different analysis in the future.  

Starbucks was a labor case, but the Court’s decision affects most if not all federal agencies that have injunctive authority. The Court ruled unanimously that the traditional equitable requirements for obtaining an injunction from Winter v. Natural Resources Defense Council, Inc. apply to the National Labor Relations Board. Courts had previously interpreted statutory language to provide for a different pathway, applicable to the agency exercising its enforcement powers. While the decision did not explicitly expand this requirement to other agencies, it’s hard not to see how this doesn’t apply to FDA’s injunction authority.

The Starbucks case revolves around the “Memphis Seven,” Starbucks employees who invited media into their shop to highlight their attempt at unionization. Starbucks fired the Memphis Seven, and the NLRB then began administrative proceedings to investigate. The NLRB also went to federal district court for a preliminary injunction to, among other things, prevent Starbucks from firing the employees.

Relying on Section 10(j) of the National Labor Relations Act (NLRA) of 1914, the District court granted the injunction, which the Sixth Circuit upheld. Both courts used a two-part test to determine first if there was “reasonable cause to believe that unfair labor practices had occurred,” and second, relying on the language from Section 10(j), if an injunction was “just and proper.”

Overturning that decision, Justice Thomas wrote that the statutory language of “just and proper” was not a substitute for the traditional equitable standard from Winter. That standard demands that a party seeking relief “must establish that he is likely to succeed on the merits, that he is likely to suffer irreparable harm in the absence of preliminary relief, that the balance of equities tips in his favor, and that an injunction is in the public interest.”

According to Starbucks, a court reviewing a preliminary injunction under Section 10(j) has to get to “just and proper” through the Winters standard; NLRB’s status as a federal agency with its own statute and specific mission does not dispense with that requirement. While the analysis for permanent injunctive relief will be different, Starbucks strongly suggests that agencies will be subject to the traditional rules of equity.

But the 9-0 decision was not unanimous in its reasoning, as Justice Jackson filed a partial dissent. While she agreed with the decision here, she did not join in the Court’s decision that the traditional pillars of equity apply in all cases where a special statute provides for injunctive relief. Where a statute has a distinct purpose, she wrote, courts should additionally assess the specific public interest that the statute seeks to protect.

Notwithstanding Justice Jackson’s partial dissent, it really seems like FDA now faces a new-yet-old standard for obtaining an injunction.

FDA has a history of relying on the weight that courts give to the public health function of the FDCA to bring injunction suits under Section 332. And while the Winter factors do include consideration of the “public interest,” courts reviewing FDCA injunctions have long modified the traditional four-tiered equitable standard that private litigants face, emphasizing the specific public health interests that the FDCA protects. With Starbucks, that looks to be ending.

For FDA regulated industry, injunctions arise most commonly as a result of negotiated consent decrees, but that does not mean that Starbucks is any less relevant. The decision of whether to agree to a consent decree is necessarily informed by a company’s chances in litigating the threatened injunction case. Starbucks almost certainly changes that calculation. How FDA and regulated industry will respond to this decision will likely play out in district courts across the country in the coming months, so stay tuned for future posts on the Starbucks fallout.

The Drug Enforcement Administration (“DEA”) has received more than 27,000 public comments in response to its May 21, 2024, Notice of Proposed Rulemaking (“NPRM”) to reschedule marijuana from schedule I to schedule III.  However, none may carry more weight than a short comment just over one page in length.  That letter, dated June 19th and signed by nine former DEA Administrators and Acting Administrators, requests that their successor, the current DEA Administrator, hold a hearingon rescheduling.  They opine that “[g]iven the magnitude of the impact of the proposed rule and considering we face an unprecedent drug overdose crisis in this country . . . a hearing on this rulemaking is in the public interest.”  Letter to DEA Administrator Anne Milgram, from Peter Bensinger, et al., (June 19, 2024).  

The decision whether to hold a hearing to address matters of fact and law in the rescheduling rests with the DEA Administrator.  The deadline for requesting a hearing or participating in a hearing was June 20, 2024, but the deadline for all public comments is July 22, 2024.

The request for hearing follows an October 2023 letter preceding the NPRM from six former Administrators and five former Directors of National Drug Policy.  That letter to Attorney General Garland and Administrator Milgram imploredagainst rescheduling, urging them “to follow the science demonstrating marijuana’s high addictive potential and its lack of accepted medical use, as well as the impact rescheduling will have on law enforcement and the ability to prosecute drug trafficking organizations.”  Letter to U.S. Attorney Merrick Garland and DEA Administrator Anne Milgram, from Michele Leonhart, et al., (Oct. 2023). Five former Administrators who signed the October letter also signed the June letter.

The Controlled Substances Act (“CSA”) requires analysis of eight statutory factors for scheduling, rescheduling, or descheduling substances of abuse.  21 U.S.C. § 811(c).  The Department of Justice reviewed Health and Human Services’ August 2023 rescheduling recommendation and conducted a separate review of the eight factors.  NPRM at 44,601.  The NPRM, however, noted that DEA “has not yet made a determination as to its views of the appropriate schedule for marijuana.”  Id. For each factor, the NPRM noted that for DEA, additional information during the rulemaking would inform about the appropriate schedule for marijuana. The NPRM further stated that DEA believes that factual evidence (including scientific data) and expert opinions with additional data on different forms, formulations, delivery methods, dosages, and concentrations “may be relevant.”  Id.

In the June letter, the Administrators characterize marijuana rescheduling to schedule III as “likely the most consequential rulemaking DEA has ever attempted . . . [and] would be the most significant relaxation of narcotics restrictions in the history of the CSA.”  Letter to DEA Administrator Anne Milgram (June 19, 2024).  They say that such a “sweeping change” requires “a robust administrative record.”  Id.

The Administrators point to DEA stating in the NPRM that determining whether marijuana should be rescheduled to schedule III requires “additional data and rigorous scientific analysis” and that the claims about “marijuana’s pharmacological effects, potential for abuse, and implications for public safety” should be subject to a hearing.  Id.  A hearing, they note, would allow outside experts to opine on the latest evidence and be cross-examined.  In addition, a hearing would also allow local leaders, law enforcement, and advocacy organizations to address the subject.  Id.

The Administrators further stress the importance of assessing how such a “major change in drug policy could impact the ongoing and devastating drug abuse crisis facing this country.” Id.  Lastly, they express their belief that a public hearing on rescheduling “would enhance transparency, integrity, and public confidence in this process, regardless of what final resolution is reached.”  Id.

We cannot help but wonder how much weight the current Administrator and DEA will give to the Administrators’ June 2024 request for hearing and the earlier October request to leave marijuana in schedule I.

RAPS Convergence 2024 is set to host a must-attend session on CDRH’s Total Product Life Cycle Advisory Program (TAP), promising attendees an exclusive insight into a pioneering initiative aimed at improving the medical device commercialization landscape.

Session Details:

• A Path to Faster Breakthrough Device Commercialization – CDRH’s Total Product Life Cycle Advisory Program (TAP)
• Thursday, September 19, 2024, 4:30 PM – 5:30 PM
• Session Leader: Adrienne Lenz, RAC – Principal Medical Device Regulatory Expert, Hyman, Phelps & McNamara, P.C.; Presenter: Laura Gottschalk – TAP Advisor, FDA

Session highlights include:

• An in-depth overview of the TAP Pilot
• Options for participant interactions with the FDA
• Real-world experiences and benefits of the TAP Pilot Program
• This session is a must-attend for professionals seeking to understand the intricacies of the TAP Pilot and leverage this program for breakthrough devices. To register visit the official conference website, here.

Meet the Expert: Adrienne R. Lenz

Adrienne R. Lenz, a highly esteemed Principal Medical Device Regulatory Expert at HPM will lead the session. Ms. Lenz brings a wealth of experience, having provided consulting to medical device and combination product manufacturers on a wide range of pre and postmarket regulatory topics. Her expertise includes developing regulatory strategies, preparing regulatory submissions, drafting policies and procedures, and addressing enforcement matters.

Ms. Lenz has an impressive track record in the premarket area, where she prepares IDEs, 510(k)s, de novos, and PMAs, along with pre-submissions and representing clients in pre-submission meetings with the FDA. In the postmarket domain, she advises on design controls, risk management, MDRs, field actions, and QSR compliance, and assists with quality system audits and regulatory due diligence.

About the FDA’s TAP Pilot Program:

CDRH introduced the Voluntary Total Product Life Cycle (TPLC) Advisory Program (TAP) Pilot in late 2022. This program was designed to address the significant challenges known as the “medical device valley of death,” where many technologies fail to reach the market due to developmental hurdles.

To participate in the TAP Pilot, a device must be in its early development stages, have received a Breakthrough Device designation, and not have submitted a Q-Submission request post-Breakthrough status. The TAP Pilot aims to expedite the time from concept to commercialization by improved engagement between developers and the CDRH, increasing the predictability of the review process.

The program is structured to provide early identification and mitigation of risks, as well as aligning expectations regarding evidence generation. Moreover, the TAP Pilot offers opportunities for strategic interactions with non-FDA stakeholders, enhancing the overall developmental ecosystem.

We blogged in February 2022 about the Drug Enforcement Administration’s (“DEA’s”) revocation of Gulf Med Pharmacy’s registration after finding that it failed to exercise its corresponding responsibility by repeatedly filling controlled substance prescriptions that exhibited “obvious red flags of diversion without documenting the resolution of those red flags.”  Last December we blogged on the $275,000 civil penalty imposed by the U.S. District Court for the District of Texas on Zarzamora Healthcare LLC for repeatedly dispensing opioids and other controlled substances “by filling prescriptions while ignoring red flags.”

DEA recently revoked the registration of Coconut Grove Pharmacy (“Coconut Grove”), like Gulf Med Pharmacy also in Florida, for its failure to resolve prescribing red flags and document such resolution.  Coconut Grove Pharmacy; Decision and Order, 89 Fed. Reg. 50,372, 50,377 (June 13, 2024). The Coconut Grove decision introduces no new red flags, but further clarifies DEA’s expectations, especially in the context of Florida’s standard of care.  After issuing an Order to Show Cause and Immediate Suspension of Registration in September 2022, and an administrative hearing in March 2023, DEA adopted the hearing Administrative Law Judge’s (“ALJ’s”) Recommended Decision to revoke Coconut Grove’s registration based on the public interest factors of 21 U.S.C. §823(g)(1).  Id. at 50,372.

Prescribing Red Flags

In the Gulf Med decision, DEA emphasized that “[r]ed flags are circumstances surrounding a prescription that cause a pharmacist to take pause, including signs of diversion or the potential for patient harm.”  Gulf Med Pharmacy; Decision and Order, 86 Fed. Reg. 72,694, 72,703 (Dec. 22, 2021).  The presence of a red flag does not prohibit a pharmacist from filling a controlled substance prescription but “means that there is a potential concern with the prescription, which the pharmacist must address and . . . make a record of its resolution, assuming it is resolvable.”  Id.

The Florida Administrative Code codifies prescribing red flags and establishes a standard of care for pharmacists.  The government’s expert testified that any red flag associated with a controlled substance prescription must be resolved and that resolution documented before dispensing.  89 Fed. Reg. 50,372 at 50,372-73.  DEA noted that “red flag” as used in the Coconut Grove decision refers to “‘things to look for’ identified in [Florida Administrative Code § 64B16-27.810].”  Id. note 13.

Coconut Grove

The expert reviewed the records of seven patients whose prescriptions were filled over almost two years and found no resolutions of red flags.  Id. at 50,373.  Finding no documentation identifying nor resolving the red flags associated with the prescriptions, the expert opined that Coconut Grove’s dispensing “fell below the Florida standard of care” and the pharmacy failed to meet its corresponding responsibility.  Id.

Coconut Grove had noted “verified” on the prescriptions which DEA found “is not sufficient to identify and resolve any red flags that may be present.”  Id. at 50,374.  The ALJ found, and DEA agreed, that the standard of care in Florida requires any red flags for a prescription or a patient must be resolved before dispensing and resolution must be documented.  Id.  Coconut Grove’s failure to do this “render[ed its] dispensing practices outside the usual course of professional practice and in violation of the Florida standard of care.”  Id.

Red Flags at Issue

a.  Prescription Drug Cocktails

The government’s expert opined that a combination of drugs in different classes or drugs with synergistic effects is a “drug-drug interaction red flag.”  Id.  He observed that the Food and Drug Administration has issued a Black Box warning to avoid opioid and benzodiazepine combination “because both drug classes affect the central nervous system, cause respiratory depression, increase the risk of overdose, and have an ‘exponentially higher effect on the body’” when taken together.  Id.  The expert specifically found that:

• Patient A.R. simultaneously filled prescriptions for oxycodone-acetaminophen 10-325 and tramadol, immediate-release opioids, with alprazolam;
• Patient J.C. filled temazepam prescriptions at Coconut Grove and oxycodone prescriptions at a different pharmacy; and
• Patient M.W. filled oxycodone prescriptions at Coconut Grove and alprazolam prescriptions at a different pharmacy.

The expert also found that Patient J.C. simultaneously filled prescriptions for the stimulant methylphenidate and benzodiazepine, a depressant.

b.  Immediate-Release and High Dosage Opioids

The government’s expert asserted that opiate prescriptions alone can create a “therapeutic duplication” red flag when two separate immediate release opioids are prescribed in their highest strength version.  Id.  In addition, “incorrect drug dosage or duration of drug treatment” occurs when immediate-release opioids for treating acute pain are prescribed for chronic pain over extended periods of time.  Id.  The expert cautioned about prescribing 90 Morphine Milligram Equivalents (“MMEs”) per day or greater and that filling immediate-release opioid prescriptions month after month for an extended period constitute red flags.  Id. at 50,374-75.

Specific to Coconut Grove, Patient A.R. filled prescriptions for oxycodone-acetaminophen 10-325 with tramadol, and oxycodone, two immediate-release opioids, and Patient J.K. filled prescriptions for oxycodone-acetaminophen 10-325 also with oxycodone.  Id. at 50,375.

Coconut Grove dispensed immediate-release opioids for extended time periods as the expert found that:

• Patient A.R. filled prescriptions for oxycodone-acetaminophen and tramadol for approximately two years;
• Patient J.K. filled prescriptions oxycodone and oxycodone-acetaminophen 10-325 for a year and a half;
• Patient C.S. filled prescriptions for hydromorphone at its highest strength when an extended strength version was available for over a year and a half;
• Patient J.L. filled prescriptions for high-strength oxycodone 30 mg. monthly for a year and half; and
• Patient M.W. filled prescriptions also for oxycodone 30 mg. monthly for a year. Id.

As for high dosage opioid prescriptions, the expert found that:

• Patient A.R. filled prescriptions for oxycodone and acetaminophen 10-325 and tramadol together totaling 120 MMEs per day;
• Patient C.S. filled prescriptions for the highest strength of hydromorphone (8 mg.) totaling up to 260 MMEs per day;
• Patient J.L. filled prescriptions for the highest strength of oxycodone (30 mg.) totaling approximately 135 MMEs per day;
• Patient M.G. filled prescriptions for oxycodone 30 mg. totaling between 135 and 270 MMEs per day; and
• Patient M.W. filled prescriptions for oxycodone 15 or 30 mg. totaling between 90 and 265 MMEs per day. Id.

c.  Alternating Between Cash and Insurance

According to the government’s expert, patients paying for prescriptions with insurance and for others with cash is a red flag for those paid with cash.  Id.  For these, the expert found that Patient J.C. paid for some medications with insurance while paying for other controlled medications in cash, and Patient M.W. paid cash for oxycodone at Coconut Grove while using insurance for alprazolam at a different pharmacy.  Id.

The expert opined that these red flags, like the others, needed to be resolved before Coconut Grove dispensed.  Patient J.C.’s physician had told Coconut Grove’s Pharmacist-in-Charge that the patient only had limited insurance.  When the pharmacist noted “verified” on the prescription, the expert opined that “is not sufficient to actually resolve a red flag.”  Id.

Public Interest Factors

The Controlled Substances Act provides that DEA may suspend or revoke a registration upon finding that the registrant has committed acts that would render the registration inconsistent with the public interest.  21 U.S.C. § 824(a).  In making the public interest determination for Coconut Grove, DEA agreed with the ALJ’s finding the Government’s evidence showed that the pharmacy’s continued registration would be “inconsistent with the public interest” under two of the five factors of 21 U.S.C. § 823(g)(1).  Factor B was the pharmacy’s experience with dispensing or conducting research with respect to controlled substances while Factor D was compliance with applicable state, federal, or local laws relating to controlled substances.  21 U.S.C. § 823(g)(1)(B), (D).

The Government alleged that Coconut Grove violated numerous federal and state controlled substance laws.  Id. at 50,376.  “A prescription for a controlled substance may only be filled by a pharmacist, acting in the usual course of his professional practice” and “[a] prescription for a controlled substance to be effective must be 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(a), 1306.06.  DEA regulations also establish that “[t]he responsibility for the proper prescribing and dispensing of controlled substances is upon the prescribing practitioner, but a corresponding responsibility rests with the pharmacist who fills the prescription.”  21 C.F.R. § 1306.04(a).  A pharmacist is prohibited “from filling a prescription for a controlled substance when he either knows or has reason to know that the prescription was not written for a legitimate medical purpose.” 86 Fed. Reg. 72,694 at 72,694.

Florida’s Administrative Code requires pharmacists prior to dispensing to “review the patient record and each new and refill prescription . . . to promote therapeutic appropriateness by identifying: (a) Over-utilization or under-utilization; (b) Therapeutic duplication; (c) Drug-disease contraindications; (d) Drug-drug interactions; (e) Incorrect drug dosage or duration of drug treatment; (f) Drug-allergy interactions; [and] (g) Clinical abuse/misuse.”  Fla. Admin. Code § 64B16-27.810(1).  It also requires upon recognizing any one of these that “the pharmacist shall take appropriate steps to avoid or resolve the potential problems which shall, if necessary, include consultation with the prescriber.”  Id. at § 64B16-27.810(2).  The Administrative Code requires that pharmacies maintain a “patient record system,” that “provide[s] for the immediate retrieval of information necessary for the dispensing pharmacist to identify previously dispensed drugs” and “shall record any known allergies, drug reactions, idiosyncrasies, and chronic conditions or disease states of the patient and the identity of any other drugs, including over-the-counter drugs, or devices currently being used by the patient which may relate to prospective drug review.”  Fla. Admin. Code § 64B16-27.800(1), (2).  The regulation requires that pharmacists “ensure that a reasonable effort is made to obtain” this information.  Id. at § 64B16-27.800(2).  It also states that “[t]he pharmacist shall record any related information indicated by a licensed health care practitioner.”  Id.

Lastly, the Florida Administrative Code states that in filling “valid prescriptions for controlled substances,” pharmacists should “exercis[e] sound professional judgment,” and “dispens[e] controlled substances for a legitimate medical purpose in the usual course of professional practice” considering “each patient’s unique situation.”  Fla. Admin. Code § 64B16-27.831.

DEA agreed with the ALJ’s analysis that Coconut Grove’s dispensing fell below Florida’s standard of care and, therefore, was outside the usual course of professional practice by dispensing controlled substance prescriptions to the seven patients without properly addressing and resolving the red flags of abuse and/or diversion.  These red flags included drug cocktails, immediate-release and high dosage opioids, and patients alternating between paying for prescriptions with cash and insurance.  DEA agreed with the ALJ, finding that the pharmacy repeatedly violated federal and state law relating to controlled substances, Factors B and D weighed in favor of revoking the pharmacy’s registration, and continued registration was inconsistent with the public interest.

FDA recently released a new eSTAR template for device pre-submissions and 513(g) Requests for Information, referred to as PreSTAR.  A pre-submission provides the submitter an opportunity to obtain FDA feedback prior to a planned medical device premarket submission.  A 513(g) Request for Information is a means of obtaining FDA’s views about the classification and regulatory requirements for a particular device.

eSTAR Templates

As we have previously explained in our blog post here, eSTAR is an interactive PDF form designed to assist users in creating “complete” submissions. It includes questions about the product, that when answered, reveal additional information that should be supplied with a submission.  It includes “help text” that will assist the applicant in providing complete information.

PreSTAR

The PreSTAR template for pre-submissions and 513(g) Requests for Information is currently voluntary.  There is only one template for both in vitro diagnostic devices and non-in vitro diagnostic devices, which is different from other eSTAR submission templates.  If an applicant chooses to use it, it allows the user to choose either a “Request for Classification Information (513g)”, “Pre-Sub Written Feedback (Q-Sub),” or “Pre-Sub Meeting and Written Feedback (Q-Sub).”  Other planned options, which are not yet available, include: accessory requests, determination meetings, agreement meetings, expedited program entrance requests, study risk determination, expedited program interaction submissions, informational meetings, PMA 100-Day meetings, and submission issue requests.

PreSTAR for Pre-Submissions

The PreSTAR template for pre-submissions will look familiar to those who have been submitting 510(k)s using eSTAR with the same sections for Cover Letter/Letters of Reference, Applicant Information, Standards, General Product Characteristics, System/Kit Components and Accessories, Classification, Labeling, and Literature References.  However, the applicant is not required to include all attachments to complete the submission (e.g., package labeling is optional).  They are, however, required to minimally attach a comprehensive product description which should include the key design features for the principle of operation, how performance is achieved, any components or accessories used with the proposed device, and a description of all proposed interfaces.  Similar to other eSTAR templates, there is a section for indication for use statement.  The applicant is required to provide a proposed indications for use and select whether the device will be prescription use, over-the-counter use, or both.

There are sections in PreSTAR for a pre-submission that differ from the eSTAR template for marketing applications.  One of which is a section for “pre-submission correspondence and previous regulatory interactions.”  Depending on your answers the PreSTAR template will let you know if you should be using the PreSTAR.  For example, if you answer yes to the following question, “Do the provided questions relate to your marketing submission hold letter, CLIA hold letter, Clinical hold letter or an IDE letter?” a pop-up message instructs you to submit a Submission Issue Request (SIR) via eCOPY as the SIR Q-Submission via PreSTAR is currently not available.  If you have had prior submissions or regulatory interactions related to the product that is subject of the PreSTAR pre-submission, the template will require you to add in the submission numbers and attach the prior regulatory feedback.

Another section when used for a pre-submission is “submission characteristics.”  This section requires the applicant to provide an overall purpose of the submission, including goals for the outcome of the interaction with the FDA, what type of future submission the applicant intends to submit, and requires the selection of a maximum of four (4) category topics.  If you choose “not listed (applicant specified),” you will need to provide a category heading.  For each question submitted, the applicant will be required to choose the Topic Category.  While four topics may be applicable for many pre-submissions, this may be challenging for start-ups or applicants with very novel technology where the first pre-submission interaction often covers a broad range of topics, leaving specifics for follow-on pre-submission supplements.  A topic of “overall testing strategy” may be a helpful addition to the template to allow these broader, initial discussions.

The template allows up to ten (10) questions and will indicate when you have reached the limit of questions entered, noting that you can consider submitting separate pre-submissions for additional questions; see our previous blog posts here on pre-submissions and the effect limiting questions may have on speed of innovation of medical devices.   Further, by limiting the number of questions, it may lead sponsors to create more general questions that lack the level of specificity needed to tease out a specific issue or to combine questions in a way that make them more difficult for the Agency to address.  Either way, putting a hard limit on questions is not in the best interest of the pre-submission program.

The applicant can choose the length (i.e., 30 minutes or one hour) and type of meeting (i.e., teleconference or face-to-face) requested.  In addition, the applicant is required to provide a draft agenda with an estimated time for each item on the agenda.  The agenda at this point is usually quite general, with specifics added after receipt of FDA’s written feedback ahead of the meeting.  The applicant provides a list of attendees and if they are requesting any specific FDA staff to attend the meeting.  Additionally, the applicant is required to confirm they will be responsible for submitting the draft meeting minutes and must confirm they understand FDA’s policy against recording the meeting (either with audio or video).

PreSTAR for 513(g) Requests for Information

If the applicant chooses to submit a 513(g) Request for Information, there are two main sections to complete, “General Product Characteristics” and “Description.”   The intent of the questions in the “General Product Characteristics” section of the template is to answer the questions and provide FDA information about the functions the applicant believes are non-medical device functions or exempt device functions (i.e., not subject to premarket review).  In the “Description” section the applicant should describe any medical device functions of the product that would require a premarket submission.  Similar to other eSTAR templates, there is a section for providing the indication for use statement.  We assume this would be related to those functions that the applicant believes are medical device functions, since the applicant is required to select whether the device will be prescription use, over-the-counter use, or both as part of the indications for use statement.  This distinction between what sections are to be completed for non-device function and device functions could be confusing to the sponsor especially since there is no opportunity to explain the intended use of the product (which may include both device and non-device functions).  The template is set up such that it assumes the applicant understands which functions of the product would be subject to regulation, what the classification would be and if the function requires a premarket submission.  For example, the template includes a section for the applicant to classify the device functions by choosing the medical specialty, regulation, and product code.  This seems to defeat the purpose of submitting a 513(g) request, since most applicants are asking the FDA to determine if the product is a device, what the classification regulation might be, and whether a premarket submission (e.g., PMA or 510(k)) is required.

As with the eSTAR templates for premarket submissions, the preSTAR template introduces some complexity into the process that will take users time to navigate.  FDA has not provided any information on whether it remains voluntary or will be required in the future, but if it does become a requirement, as it has for 510(k)s, we hope the Agency will continue to make improvements to allow it to be useful for the wide range of pre-submissions and 513(g) requests that sponsors may submit.