Last year, FDA issued a letter to the medical device industry warning medical device firms of concerns related to fraudulent and unreliable laboratory testing data in premarket submissions, which we blogged about here.  This was followed last September with warning letters issued to two Chinese firms performing biocompatibility testing, citing violations of 21 C.F.R. Part 58 – Good Laboratory Practices Nonclinical Laboratory Studies, regarding concerns about the quality and integrity of data generated by the labs.

FDA has recently issued an updated Notifications on Data Integrity – Medical Devices.  Within the Notification, FDA references a General Correspondence Letter (GCL) sent on February 26, 2025.

In the GCL, FDA notes it has identified multiple test reports from studies that include “cytotoxicity studies that contain identical or nearly identical results from different dates, sensitization studies (Guinea Pig Maximization Tests) that contain identical sets of guinea pig pretreatment body weights for different groups on different dates, and a large animal safety and performance study for a staple line reinforcement device that contains implausible bleeding assessments and pre-to-post procedure weight gains in Bama pigs.”  FDA states that it has no reason to believe that any data are reliable.  The GCL indicates that data will be rejected until the lab demonstrates that the issues described are adequately addressed.

FDA’s Notification states that it has identified unreliable testing data during review of 510(k)s, which has resulted in FDA being unable to clear the device.  As in the earlier letter to industry, the current FDA Notification recommends that sponsors of device studies and manufacturers of devices “carefully evaluate the third parties they engage to conduct safety, performance, and cybersecurity testing and to independently verify all testing results before submitting to the FDA.”  As discussed in the previous post, this is easier said than done given many firms lack in house expertise, and it is impossible to identify if data in a report received may be identical to data that the third party has provided to another sponsor.

Given FDA’s continued focus on data integrity, sponsors should check to be sure there have been no issues raised with third party labs they are using prior to testing.  We’ll continue to follow this issue.

In August 2023, the U.S. Department of Health and Human Services (“HHS”), based on the federal Controlled Substances Act’s (“CSA’s”) Eight Factor Analysis, recommended that the Drug Enforcement Administration (“DEA”) reschedule marijuana from schedule I to schedule III.  The U.S. Department of Justice subsequently conducted a separate Eight Factor Analysis and concurred with HHS’ rescheduling recommendation.  DEA published a Notice of Proposed Rulemaking (“NPRM”), signed by Attorney General Merrick Garland, proposing to reschedule marijuana in May 2024 that elicited over 43,500 comments.  In January a public hearing began to receive factual evidence and testimony on whether marijuana should be rescheduled.  The hearing is currently on hold pending an appeal by several of the parties.

There exists confusion as to what rescheduling marijuana to schedule III would mean so we thought we would clear up some of the misunderstanding about schedule III requirements.

Even scheduling to less restrictive schedule III would continue to have significant implications for marijuana-related businesses.  The NPRM states that if marijuana is rescheduled to schedule III, “the regulatory controls applicable to schedule III controlled substances would apply, as appropriate, along with existing marijuana-specific requirements and any additional controls that might be implemented, including those that might be implemented to meet U.S. treaty obligations.”  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 44,597, 44,621 (May 21, 2024).

Unless marijuana is descheduled, that is decontrolled entirely, or there are marijuana-specific exemptions, even after rescheduling to schedule III, marijuana cultivators, producers, and processors, distributors, importers, exporters, dispensers, and practitioners, will be subject to specific regulatory requirements under the CSA and DEA regulations.  Requirements will vary depending on the registered business activity.

If rescheduled to schedule III, marijuana businesses would be required to obtain DEA registrations, take initial and biennial inventories of marijuana on-hand, maintain transaction records, file theft and significant loss reports, and label and secure products appropriately.  Dispensing marijuana to patients, as required for other schedule III substances, would require a prescription issued for legitimate medical purpose by a DEA-registered and state licensed practitioner.  21 U.S.C. 829(b).  Pharmacists would be required to exercise their corresponding responsibility under the CSA to ensure that marijuana is prescribed and dispensed for legitimate medical purpose.  21 C.F.R. § 1306.04(a).

Marijuana activities would be subject to CSA criminal prohibitions under 21 U.S.C. §§ 841-844.  Schedules of Controlled Substances, 44,621.  Marijuana would also remain subject to applicable provisions of the Food, Drug and Cosmetics Act.  Id.

Marijuana down-rescheduled to schedule III would still be regulated for legitimate medical, scientific and industrial use.  Rescheduling would not authorized marijuana for adult recreational use.

On Friday, March 21, 2025, FDA announced that it was further delaying the effective date for the ACNU final rule until May 27, 2025. We wrote about the December 26, 2024 publication of the final rule (89 FR 105288) here.  Originally, the Nonprescription Drug Product with an Additional Condition for Nonprescription Use (ACNU) final rule was to become effective January 27, 2025. However, shortly before the effective date, on January 20, 2025, during his first day in office, the President issued a memorandum titled, “Regulatory Freeze Pending Review” which ordered that with respect to rules that had been published in the Federal Register, but had not taken effect, agencies consider postponing the rules’ effective dates for 60 days from the date of the memorandum (i.e., until March 21, 2025) for the purpose of reviewing any questions of fact, law, and policy the rules may raise.  FDA then delayed the effective date. The effective date has now been delayed again for another approximately 60 days with the exact new date depending on when the notice is published in the Federal Register.

As we have also previously reported, many in industry were disappointed with the final rule when FDA declined to address several significant issues identified in the comments to the proposed rule including the “fail first” approach that requires FDA to make the determination that labeling alone is insufficient to ensure the safe and effective nonprescription use of a drug. Additionally, FDA’s interpretation of a clinically meaningful difference between a prescription drug and a nonprescription drug when the only difference is the existence of an ACNU raises interesting legal issues that may merit additional fleshing out.

Whether FDA is able to use this additional time to address any of these or other substantive issues remains to be seen, as does whether the next deadline leads to another delay, the regulation becoming effective or something else entirely.  It’s already been a long time coming. Despite the proclamation requiring the repeal of ten regulations for every new one regulation, the new Secretary of Health and Human Services has expressed support for policies that enhance consumer access to self-care options including safe and effective OTC drugs, so it is not out of the question. Moreover, assuming the final rule does eventually come into effect, how it is applied may not be quite how it was envisioned originally.

Integral to the careful balance Congress struck when passing the Hatch-Waxman Amendments, the patent term extension (PTE) is intended to restore patent life that was consumed during regulatory review of an FDA-regulated product.  Even though the PTE provisions established in the Drug Price Competition and Patent Restoration Act are forty-plus years old, courts are still grappling with questions about how to best implement the Patent Term Extension.  And just last week, a new question was answered by the Federal Circuit: how is a patent term extension calculated for a reissued patent?  Is it based on the issue date of the original patent or the reissued patent?

On March 13, 2025, the Federal Circuit ventured into the world of reissued patents and PTE.  (FDA has already been there, of course, with respect to 180-day exclusivity.)  In Merck Sharp & Dohme Corp. v. Aurobindo Pharma, Ltd. et al., the Court looked at the term “the patent” in the PTE statute at 35 U.S.C. § 156(c) to assess whether the regulatory review period should be calculated using the issuance date of the original patent or the reissued patent.  The question is important because the result of that determination could drastically reduce the amount of patent term to be restored.

Questions of the applicability of the PTE statute to reissued patents arose because Plaintiff-Appellee Merck sought extension of a patent listed in the Orange Book after approval of its BRIDION (sugammadex), indicated to reverse neuromuscular blockade, that initially was issued in December 2003 but reissued in January 2014 with the original claims and twelve new claims relating to the drug product.  Merck applied for a patent term extension on the reissued patent, claiming the start of the regulatory review period as April 2004 and termination at the approval of the BRIDION NDA in December 2015.  With this long regulatory review period, the PTO granted the statutory-maximum five-year patent term extension.  This PTE calculation was based on the original patent, but generic filers challenged that decision, arguing that the issuance date of the reissued patent is the operative date for calculating the regulatory review period.  In the generic filers’ view, the regulatory review period should have started in January 2014 when the patent was reissued rather than in April 2004, when the IND was opened, because the reissued patent did not exist in April 2004.  The plain text of 35 U.S.C. § 156(c), the generic filers contended, required the PTO to calculate the regulatory review period based on the issue date of “the patent” for which PTE was sought, which, in this case, was the reissued patent.  The District Court disagreed with generic filers, finding that 35 U.S.C. § 156 should be read in light of the rest of the statute, and that “the patent” in subsection 156(c) must refer to the original patent rather than the reissued patent.

The Federal Circuit upheld the District Court’s position, noting that the language of 35 U.S.C. § 156 “standing alone is ambiguous” and “unclear whether ‘the patent’ refers to the original or reissued patent.”  So the Federal Circuit looked at the “the specific context in which that language is used, and the broader context of the statute as a whole.”  Specifically, the Court focused on the purpose: “to compensate pharmaceutical companies for the effective truncation of their patent terms while waiting for regulatory approval of new drug applications.”   The Court thus explained that interpreting “the patent” in 35 U.S.C. § 156(c) is the best reading, as it “compensates Merck for the period of exclusivity lost due to regulatory delay.”   The Court continued: “[t]here is no reason why the Hatch-Waxman Act’s purpose would be served by disabling extensions of the unexpired term solely based on a patent holder’s decision to seek reissue, and Aurobindo offers none.”  Thus, “[t]he only construction that comports with the purpose of the Hatch-Waxman Act is one that extends PTE to patent owners who were actually disabled from benefiting from patent protection during the pendency of regulatory review.”  Accordingly, in the context of reissued patents, “the patent” in subsection 156(c) refers to the original patent based on the purpose and context of the PTE provisions.

The American Conference Institute’s 21st Annual Paragraph IV Disputes is scheduled to take place from April 29-30, 2025 at The Altman Building in New York, NY.  Widely recognized as the industry gold standard, the conference unites leaders from brand-name and generic drug companies, alongside federal judges, the U.S. PTO’s PTAB, the FTC, and the FDA, to tackle the critical legal, regulatory, and business issues shaping pharmaceutical patent litigation.  Those of us in the Hatch-Waxman community look forward to attending this premier conference.  It’s always a kind of “family reunion” – a “Cheers”-type atmosphere where everyone knows your name.

Focusing on pre-suit strategies, case filings, final adjudications, and everything in between, this conference provides unparalleled insights and actionable takeaways for navigating the complex and high-stakes world of Paragraph IV disputes.  Key topics to be addressed this year include:

• Status of the Inflation Reduction Act and Future Drug Price Negotiations
• AI’s Impact on Drug Discovery and Patent Law
• Focus on Litigation and Agency Decisions Following the Demise of the Chevron Doctrine in Loper V. Raimondo
• Exploring the On-Sale Bar and Applicability of Prior Art
• Orange Book Delisting Attempts
• Navigating ODP and Patent Family Dynamics

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will speak at a two-part session: Part I – Chevron Overturned: Examining Challenges Against the FDA and How the Death of the Doctrine Could Impact Drug Approvals and Exclusivities; and Part II – Anticipating the New Administration’s Impact on FDA Policies and Regulations.

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount.  The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference!

Hyman, Phelps & McNamara, P.C. Director Ricardo Carvajal will be moderating a session at the Food and Drug Law Institute’s (“FDLI’s”) upcoming 1-day conference on Food and Dietary Supplement Safety and Regulation, scheduled to take place on March 25. Join us for timely, in-depth discussions of current issues arising in litigation, food ingredient regulation, and labeling. The agenda and registration information are available here. To save 15%, sign up with the discount code SaveOnFood25.

The American Conference Institute’s 12th Annual Legal, Regulatory, and Compliance Forum on Cosmetics & Personal Care is scheduled to take place from March 27-28, 2025, at the New York City Bar Association, New York, NY.  The conference is the premier event on cosmetics and personal care products, where industry leaders will provide essential updates on compliance with Modernization of Cosmetics Regulation Act of 2022 (MoCRA), state legislative reforms, and new FTC advertising guidelines.

This event provides a comprehensive guide to the latest developments affecting articles intended for cleansing, beautifying, promoting attractiveness, or altering the appearance.  Key highlights for 2025 include:

• Navigating MoCRA’s New Requirements and FDA Enforcement Actions
• Addressing ESG Risks and Environmental Marketing Claims in the Beauty Industry
• Comprehending the Impact of Extended Producer Responsibility (EPR) and Recyclability Regulations on Manufacturing and Packaging
• Tackling Contaminants: Benzene, PFAS, and Asbestos Safety Concerns
• Managing Influencer Marketing and FTC Compliance in Advertising
• Exploring Global Market Entry: Regulatory Challenges in China and Latin America
• Safeguarding Data Privacy and Trade Secrets in the evolving AI-driven landscape

Hyman, Phelps & McNamara, P.C.’s John Claud will speak at a session titled “Beauty in Developing World Markets: Contrasting Opportunities and Challenges in the Latin American and Chinese Cosmetics Markets,” where he will explore two areas of global focus for the cosmetics industry: Latin America and China.

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We’ll see you at the conference!

In the past three months, FDA has released two guidance documents related to artificial intelligence (AI) enabled medical devices: (1) a final guidance titled Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence-Enabled Device Software Functions (PCCP Guidance, which we blogged about here) was issued in December 2024; and (2) a draft guidance document titled Artificial Intelligence-Enabled Device Software Functions: Lifecycle Management and Marketing Submission Recommendations (Draft AI Guidance, which we blogged about here) was issued in February 2025.  Both guidance documents recommend data management practices for collecting data for use in developing, tuning, and testing an artificial intelligence model and making changes to said model.  Data management practices encompass data collection, processing, storage, annotation, control, and use, and are an important means of identifying and mitigating bias in AI models, thereby ensuring the integrity of the health data output by these models.

We were struck by the level of detail expected by FDA for processes related to data management, especially for data collected and used early in development to train an initial AI model, which may occur before a manufacturer decides to move forward with device development under design controls.

While there is a natural tendency to speak of research and development (R&D) as a single activity, in practice there is often a line between the initial research performed in the “sandbox” to establish technological feasibility and the development work needed to bring the technology through testing, manufacturing, and market entry.  The former may not follow a rigorous and controlled process, but if technology developed in the sandbox shows promise, it moves from research to development, where a formal design controls process is followed to establish requirements, specifications, processes for manufacturing and/or maintenance, and to conduct verification and validation testing.

For non-AI-enabled devices, the early feasibility research may not directly affect the development process, i.e., the final, finished device can be fully developed, transferred to a controlled manufacturing environment, and tested under a design controls process.  For software incorporating AI models, however, FDA notes that the performance and behavior of AI systems rely heavily on the quality, diversity, and quantity of data used to train and tune them, which means there is an FDA expectation that developers will have controls in place for data management even before they know if the technology will ever leave the sandbox.

Here, we will describe the recommendations in FDA’s guidance documents for collection and processing of data that will be used for training, tuning, and testing AI models and what to include in a marketing submission for AI-enabled software. Before training begins, a Data Collection Protocol (DCP) may be developed and is specifically recommended as a section within a modification protocol within a PCCP.

The DCP should describe how data will be collected, including the inclusion and exclusion criteria for data.  The inclusion criteria may include elements such as, but not limited to, the patient’s age, weight, height, race, ethnicity, sex, and disease severity, consistent with the intended patient population for the final product, which may not be known in the early days in the sandbox.  Although bias may be difficult to eliminate completely, FDA recommends that manufacturers, as a starting point, ensure that the test data sufficiently represents the intended use (target) population of a medical device.  FDA notes the use of data collected outside the U.S. (OUS) is another potential confounding factor to be considered in data collection.  OUS data may introduce bias if the OUS population “does not reflect the U.S. population due to differences in demographics, practice of medicine, or standard of care.”  The DCP may also define the sources of the data (e.g., inpatient hospital, out-patient clinic), date range for the data, and location of the data collection sites (e.g., different geographical locations), along with any acquisition conditions (e.g., data acquisition device).  The DCP should define if data will be collected prospectively or retrospectively, and whether data will be sequentially acquired or randomly sampled.  Some disease conditions may not be as prevalent and the DCP should describe any enrichment strategies to ensure subgroups are represented.  The DCP should follow applicable regulations governing human subject protections, where applicable. In the context of a PCCP, the DCP should also address when new data should be acquired and/or older data removed to ensure the datasets remain current with respect to acquisition technologies, clinical practices, changes in the patient population, and disease management.  A robust DCP can help ensure data used to train AI models are unbiased and representative, which will promote generalizability to the intended use population and avoids perpetuating biases or idiosyncrasies from the data itself.

The manufacturer should have defined processes in place to assess the quality of the data collected under the DCP, including processes to ensure data consistency, completeness, authenticity, transparency, and integrity.  If data are excluded because of data quality issues, the rationale and criteria for the exclusions should be documented in the DCP. This is important as FDA will expect the data used for training to be representative of the type of data that could be used in clinical practice with the final product. In addition, the manufacturer should define if the process for the checking data quality is a manual or automated process. The DCP should address if there are missing data elements (e.g., if an image was obtained but patient demographic information is not available) and when it is acceptable and/or when data quality issues warrant an investigation before proceeding.

If the data collected will be annotated (e.g., adding labels or tags to raw data), as is done in semi-supervised or supervised machine learning, the annotation process and credentials of the annotators should be documented.

Another important element of the DCP is defining what data will be used for training, tuning, and testing the AI model, the independence of the data (e.g., sampled from completely different clinical sites), and any data cleaning or processing performed on the training or tuning data.  The manufacturer should have processes in place that define how the datasets will be stored and who will have access to each dataset.  This should include controls to prevent unauthorized access and manipulation of the data.  The test data should be sequestered, not cleaned, and not used for the development of the AI Model with a process in place to prevent unauthorized access.

In order to evaluate the AI model output, manufacturers may need to establish a reference standard.  A reference standard is the “most suitable standard to define the true condition for each patient/case/record.”  A reference standard may be used during “training, tuning, testing or all three.”  When using a reference standard, the manufacturer should define how it will be determined and the uncertainty associated with that method.  For example, if clinical interpretation is the reference standard, the manufacturer should define the qualifications of the clinician performing the interpretation, number of clinicians, data provided, and how the results will be combined and/or adjudicated.

As data used in the research sandbox can impact the final AI-enabled medical device, developing robust data management practices in the early stages of AI model development are important to avoid problems and costly rework later in development.  Doing so will help ensure a more generalizable model and a more seamless transition from the research sandbox into design controls and, ultimately, a future market authorization.

Late last month, the Department of Justice filed a short statement regarding administrative law judges (ALJs).  The statement, issued by the Department’s Chief of Staff Chad Mizelle, states in its entirety:

Today the Department of Justice determined that multiple layers of removal restrictions shielding administrative law judges (ALJs) are unconstitutional.

Unelected and constitutionally unaccountable ALJs have exercised immense power for far too long. In accordance with Supreme Court precedent, the Department is restoring constitutional accountability so that Executive Branch officials answer to the President and to the people.

This statement followed a February 20, 2025 letter from Acting Solicitor General Sarah Harris to President Pro Tempore of the Senate Charles Grassley stating the same and noting that “the Department will no longer defend” the layers of removal restrictions for ALJs in court.  The letter stated that the Department had already taken this position in ongoing litigation, referencing a pending case before the U.S. Court of Appeals for the Third Circuit, Axalta Coating Systems LLC v. FAA, No. 23-2376.  This position breaks with almost 80 years of tradition and constitutional and statutory interpretation.

Since the enactment of the Administrative Procedure Act (APA) in 1946, ALJs have served an important role in conducting fair and impartial administrative hearings on behalf of agencies, typically submitting findings of facts and recommendations to agency heads used in adjudication.  The APA specifically instituted certain removal protections to ensure that the ALJs conducted hearings with impartiality and with independent decision-making.  See 5 U.S.C. § 556(b).  (For an in-depth review of the history of ALJs and the removal protections enacted by the APA, see Brief of Amicus Curiae Federal Administrative Law Judges Conference 8-20, SEC v. Jarkesy, No. 22-859 (Sept. 1, 2023)).

The constitutionality of ALJs has been a hot legal topic of late.  In a decision last year, United States v. Jarkesy, 603 U.S. 109 (2024), the Supreme Court upheld a decision by the U.S. Court of Appeals for the Fifth Circuit that the Securities and Exchange Commission’s (SEC) use of an administrative proceeding conducted by an SEC ALJ to impose a civil penalty violated the Seventh Amendment’s right to a jury trial.  The Court only decided Jarkesy on the Seventh Amendment issue and did not reach two other issues that the Fifth Circuit found were unconstitutional.  The first was whether Congress violated the nondelegation doctrine by allowing the SEC, without proper guidance, to choose whether to litigate the underlying civil penalty case in federal court or adjudicate it within the SEC.  The second issue was whether the insulation of SEC ALJs from executive supervision with two layers of “for-cause” removal protections violated the separation of powers.  When the decision came out, we (correctly) predicted that Jarkesy would have an impact on other administrative proceedings conducted by federal agencies (see our post here).

The constitutionality of DEA ALJs has already been challenged within the Fifth Circuit, relying on the appeal court’s decision in Jarkesy, including the nondelegation doctrine issue.  See Inmar Rx Solutions v. Garland, No. 3:23-cv-2883-E (N.D. Tex. Dec. 29, 2023).  And last week, consistent with the DOJ statement, the government advised the district court in that case that it would no longer defend the removal restrictions in that litigation.  See Defendant’s Notice of Change in Position, Inmar Rx Solutions, Inc. v. Bondi, No. 3:23-cv-2883-E, ECF No. 25-1 (N.D. Tex. Feb. 24, 2025).

The impact of this position statement—and how it will play out in federal courts with the new administration—is unclear.  It is possible this position may make it more difficult for litigants challenging the constitutionality of a proceeding presided by an ALJ, because the new administration has made it clear that they can remove the ALJ if they want to do so.  A series of recent cases has held that, unless there is evidence that the President wants to remove an official but cannot do so because of statutory limitations on his power, “there is no judiciable harm presented.”  Barlow-Ahsan v. Kijakazi, 2023 U.S. Dist. LEXIS 185877, at *24-25 (E.D. Pa. Oct. 17, 2023) (citing cases).  And even then, a litigant must show that “the agency action would not have been taken but for the President’s inability to remove the officer.”  Id. at *25.

Regardless, the status of ALJ hearings remains uncertain.  Many of our readers are familiar with ALJ hearings, especially those conducted before DEA, CMS, and USDA.  And for all litigants in those hearings, certainty in the process and impartiality are essential.  At this point, it is not clear what further steps the new administration may take or the effect the Department’s new position may have on litigants in ALJ hearings.  We will continue to monitor and keep you informed.

The American Conference Institute’s 3rd Annual Forum on Advanced Therapeutics is scheduled to take place from March 19-20, 2025, at the Seaport Hotel in Boston, MA.  The conference will bring together industry leaders to explore evolving market trends, regulatory frameworks, and intellectual property strategies shaping the future of advanced therapeutics. From funding innovations and AI in drug discovery to navigating legal and compliance challenges, this conference will provide you with the opportunity to gain the insights you need to drive scientific advancements to global market success.

This collaborative endeavor drives forward the most groundbreaking developments in advanced therapeutics, marrying scientific discovery with strategic business and legal acumen for global impact. Attend to engage with leading industry thought leaders and legal pioneers who will illuminate the path from groundbreaking research to global market success.

Conference co-chairs include Derek Johnson (Managing Director and General Counsel, Portal Innovations) and Lulu Wang (Head of IP, Orna Therapeutics).  Hyman, Phelps & McNamara, P.C.’s Charles Raver will speak during a panel discussion, titled “Preparing to Launch Preparing to Launch: Designing Your Commercialization Blueprint for Advanced Therapies and Companion Diagnostics,” where the panelists will provide actionable insights into creating a streamlined pre-commercialization plan that aligns regulatory compliance with commercial objectives.

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

As anticipated, the International Council for Harmonization (ICH) published the Good Clinical Practice (GCP) guideline E6(R3) Principles and Annex 1 on January 6, 2025. While ICH E6(R3) was still in the development phase, the FDA released a draft guidance in May 2023 in the form of the draft ICH E6(R3).  No word yet on whether FDA will issue guidance endorsing the final ICH E6(R3). The European Medicines Agency (EMA) has adopted  E6(R3) Principles and Annex 1 to take effect on July 23, 2025, and other ICH member nations and regions are still in the process of adopting E6(R3). Meanwhile, Annex 2, which provides guidance on pragmatic and decentralized clinical trials as well as trials incorporating real-world data, is expected to be finalized by ICH later in 2025.

This Revision 3 has been a long-awaited update and modernizes clinical trial conduct by  integrating evolving technologies and emphasizing a Quality by Design framework along with Risk Proportionality. E6(R3) specifically acknowledges the rise of innovative trial designs such as adaptive and decentralized methods, while also encouraging the use of electronic informed consent and remote monitoring. The guideline expands its focus on data governance and clearly defines the roles and responsibilities of sponsors, investigators, and service providers.  Ultimately, the guideline encourages a risk-based and proportionate approach to clinical trials that prioritizes the safety and rights of study participants while ensuring robust data quality.  Below, we explore some of the key themes seen in the changes.

Quality by Design

One of the most significant shifts in E6(R3) is its endorsement of a Quality by Design approach, requiring sponsors to proactively identify and mitigate risks throughout the trial lifecycle. This aligns with the broader trend toward risk-based monitoring and oversight extending risk-based principles to trial planning, design, conduct, monitoring, and reporting.

Risk Proportionality

A new Risk Proportionality section has been added under Principles, emphasizing that “[c]linical trial processes, measures, and approaches should be implemented in a way that… avoids unnecessary burden on participants and investigators.”

More Varied Clinical Trial Designs

To address a “one-size-fits-all” approach to clinical trials, E6(R3) expanded the approach to trial design to allow for more varied trial designs including adaptive designs and recognition of technological advances in trial design and conduct such as remote monitoring.

Clarification of Roles and Responsibilities

The Roles & Responsibilities section was added to provide clearer expectations for all trial stakeholders. Notably, sponsor oversight and accountability is enhanced with investigators required to be qualified through education, training, and experience and they must demonstrate sufficient resources and facilities to properly conduct the trial, reinforcing ethical standards and patient protections through strengthened oversight for the clinical trial and documentation.

Patient Safety

Annex 1 also includes more detailed sections outlining  the responsibilities and functions of the  Institutional Review Board/Independent Ethics Committee (IRB/IEC), sponsor and investigator with an emphasis on the rights and safety of trial participants.

Focus on Data Integrity

The Data Governance section of Annex 1 provides comprehensive guidance for investigators and sponsors on managing data integrity, traceability, and security throughout the clinical trial lifecycle recognizing the increasing complexities and importance of data security. It emphasizes that “the quality and amount of the information generated in a clinical trial should be sufficient to address trial objectives” and emphasizes that systems and processes must be designed and implemented in a way that is proportionate to the risks to participants and the reliability of trial results. Key processes include ensuring the protection of trial participants’ data confidentiality, managing computerized systems appropriately, safeguarding critical trial elements (such as randomization and blinding), and supporting key decision-making steps like data finalization and unblinding. Additionally, the guidelines require robust procedures covering the entire data life cycle—from data capture, with appropriate metadata and audit trails, to data correction, transfer, and eventual finalization for analysis.

Implications for Future of Clinical Research

R3 represents an important evolution in GCP, shifting away from a prescriptive model toward a more flexible, risk-based approach. By integrating modern trial methodologies and technologies, it provides a framework for conducting clinical research more efficiently while maintaining the highest standards of ethics, data integrity, and patient safety.

As stakeholders begin implementing R3, many questions remain regarding its practical application. How regulators will interpret and enforce its provisions may not become clear for some time. Until then, sponsors and investigators should carefully review their trial protocols, monitoring strategies, and data management systems to align with this new landscape and take advantage of the new approaches.

The American Conference Institute’s popular “FDA Boot Camp” – now in its 43rd iteration – is scheduled to take place from March 19-20, 2025, at the NY Bar Association in New York, NY . The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.  And it is exactly that!

The conference equips legal professionals without prior regulatory experience, as well as life sciences executives involved with FDA-regulated products, with a comprehensive understanding of fundamental FDA principles.  This is achieved through firsthand insights, real-world examples, and case studies from FDA-regulated products.

This year’s conference co-chairs are Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, and Morgan, Lewis & Bockius LLP’s Maarika L. Kimbrell. They will be joined by an esteemed panel of top FDA regulatory leaders covering essential topics, including:

• Navigating the Approval Process for Drugs and Biologics
• Clarifying the Clinical Trial Process for Drugs and Biologics
• Understanding the Structure of the FDA and the Roles of Its Three Major Centers: CDER, CBER, and CDRH
• Hatch-Waxman and BPCIA Fundamentals: Understanding Follow-On Products and the Rules for Generic Entry
• Good Manufacturing Practices (cGMPs): Discovering the Unique Role of cGMPs in the Post-Approval Process
• Advertising, Promotions, and Related First Amendment Concerns
• Understanding the Scope of FDA Enforcement Authority and Actions

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-999-FDA25.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

The ongoing DOGE-led reductions to the federal workforce and recent sweeping policy changes have spawned many questions for compliance officers and quality managers in FDA-regulated companies. How will the cuts at FDA impact inspections and enforcement? Will there be a heightened appetite for mergers and acquisitions in the space? How will the imposition of tariffs and a burgeoning trade war affect domestic drug production and companies’ supply chain demands? Does the stand down of FCPA enforcement mean that it’s okay to bribe foreign officials now?

With all the change we are witnessing in the American model of regulation and governance, it might be tempting to ask if we are suddenly living in a post-compliance world.

The answer to that is still “no,” the current state of world and governmental events notwithstanding. For one thing, the possible answers to our rhetorical questions above are not final yet and will take years to sort out. Also, to be sure, quality still matters in the drug and device industries. M&A rises and falls on due diligence along with other factors like market conditions and growth opportunities, so compliance and quality are vital links in any deal chain. Trusting suppliers is still fundamental to any drug or device manufacturer. And the Department of Justice will still pursue viable civil and criminal cases, if not under the FCPA then under other statutes like the False Claims Act, Title 18 fraud and conspiracy, and even RICO.

So, yes, compliance and quality still matter, a lot. And they still matter to companies looking for certainty and security in turbulent times. Organizations should want to instill good habits in their employees to make compliance easy and rewarding, looking both internally and externally.

Communication of an organization’s compliance culture is key because a significant disparity often exists between how C-suite executives and lower-level employees perceive it. A 2025 study reported by Radical Compliance found that while senior management often believes in the robustness of their ethical culture, employees at other levels do not.

Some communication techniques may be better at emphasizing the importances of compliance and quality, to make the associated good habits easy, and to ensure that a company’s program is well designed, is applied earnestly and in good faith, and works in actual practice.

Clarity of purpose is a good place to start. If a compliance or quality program exists only as bargaining chip to use with regulators, that’s not a formula to instill good habits. But company leaders must look to their own values and understand and embrace them before they can communicate them on to the rest of management and down the chain. In other words, communicating specific ideas and concerns that apply to a specific business model are more likely to be effective than trying to improvise about vague or inconsistent issues.

Tailored messaging is vital, because at no company is “the chain” comprised of people that think and act uniformly. They have different duties, different concerns, and will react to different triggers. A one-size-fits all approach to communication of important principles is therefore less likely to be successful.

Dialogue is also key. It can be difficult to maintain interest during one-sided, one way instruction. Engagement with employees makes feedback—and thus interest—more likely and consistent. And, frankly, it is a useful tool to manage potential whistleblowers by addressing concerns before they mushroom. One of the most crucial aspects of compliance communication is creating an open line, both up and down the chain.

Finally, effective compliance and quality communication is not a one-off event. It’s on ongoing conversation aided by effective, recurrent training that serves as a continuous reminder and puts good habits within easy reach. Again, it’s also a useful tool to manage problems when they do arise. It’s hard to communicate in a crisis, but when one hits, the ongoing conversation should ideally lead to remedies that are easier to implement.

Bad compliance and quality habits are like the cookies in the cupboard you might be trying to cut back on: if you never introduce them into your home, plant, or management offices, the risks they pose go down. Good habits that include effective, thoughtful communications provide clarity, understanding, and by hopefully avoiding crises, profitability. But the conversation probably works best when it goes from the C-suite to the shop floor and back.

HPM Counsel John W.M. Claud is the former Assistant Director of the Corporate Compliance and Policy Unit at the U.S. Department of Justice’s Consumer Protection Branch. These are condensed thoughts from his speech “Communicating Regulatory Impact to Your Organization: Advanced Procedures for Compliance Success,” which he delivered at the 2025 Q1 Productions Life Science Regulatory Intelligence & Strategy Conference.

As the device industry is well aware, one of the greyest areas in device regulation (of which there are many) is determining when changes to a 510(k)-cleared device trigger the need for a new clearance.  FDA requires a new 510(k) clearance when a modification to an existing 510(k)-cleared device (or other existing device subject to 510(k) requirements) “could significantly affect the safety or effectiveness of the device.” See 21 C.F.R. § 807.81(a)(3). Manufacturers must evaluate device changes in the first instance to determine whether a new 510(k) is needed or, instead, whether documentation of the change and rationale for not seeking 510(k) clearance is sufficient. This evaluation can be challenging and getting it wrong can mean a manufacturer could run into trouble if FDA later determines that its justification for not seeking clearance is inadequate.

To help in evaluating device changes, manufacturers commonly refer to FDA’s guidance “Deciding When to Submit a 510(k) for a Change to an Existing Device,” which provides FDA’s interpretation of the changes it believes could significantly affect the safety or effectiveness of a device. The guidance includes examples of changes and flowcharts that frequently make their way into formal company procedures. But this guidance has its limitations. Many of the examples FDA provides are obvious cases (at either end of the spectrum) that are unhelpful in evaluating changes that are neither clearly significant or insignificant. Additionally, manufacturers typically need to conduct a risk-based assessment of device changes to determine whether they significantly affect the safety or effectiveness of a specific device. Such assessments are highly individualized and difficult to map onto the few examples provided by FDA in its guidance.

Manufacturers should, therefore, welcome any additional source of examples of device changes to aid in evaluating their own. One potentially underutilized resource for this is FDA Warning Letters (WLs). Industry commonly thinks of WLs as only citing quality system violations.  While quality system violations are often cited, we identified more than eighty WLs that appear to cite companies for failing to seek clearance for device changes that FDA believed could significantly affect safety or effectiveness.  These letters offer real-world examples of device changes that FDA believed required a new 510(k) or internal documentation that FDA found inadequately evaluated such changes.

For example, in an October 13, 2023 WL to ReNovo, Inc., FDA stated that several of the company’s products required a new 510(k) due to “smaller diameter shafts,” “smaller diameter lumens,” “smaller tip elements,” and/or “longer shafts” than the originally cleared products. Based on FDA’s guidance, dimensional changes only require a new 510(k) if a risk-based assessment identifies new or significantly modified risks resulting from the changes.  In the WL, though, FDA faults the company for “not evaluat[ing] how cleaning and re-sterilization of the additional OEM models with different designs could affect the performance specifications and reliability of [the new device models].”

Likewise, in a November 8, 2022 WL to Abbott Point of Care Ltd., FDA found that several changes to an in vitro diagnostic device could affect the safety or effectiveness of the device, including:

1. Process change for IgM component that replaced monoclonal antibody product in a live animal with production in cell culture.
2. Increase in the amount of caprine and murine IgG and introducing murine IgM in the sample inlet.
3. Change in reagent from one that requires reconstitution to one that is already in solution.
4. Change in cartridge and gasket diameters to accommodate a new sensor chip.

FDA also found that analytical sensitivity and precision testing provided by Abbott was inadequate to confirm the impact of such changes on the clinical performance of its device. Instead, FDA stated that a direct comparison of the modified and original device was required and key performance data, such as clinical accuracy, should have been documented to support the design changes.

As these two WL examples demonstrate, FDA’s determination that a new 510(k) is required may not be based on the inherent significance of a change and may, instead, be based on the lack of documented data supporting that a change does not significantly affect safety and effectiveness. This underscores the importance of these evaluations and the value of reviewing relevant WLs to identify common gaps in documentation that can lead to FDA requiring a new 510(k).

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Determining whether a device change requires a new 510(k) is a critical aspect of regulatory compliance. While FDA guidance, and the flowcharts and examples it contains, are essential tools, WLs provide an untapped source of real-world insights into FDA’s expectations. By analyzing WLs, manufacturers can better understand the types of changes that require a new 510(k) and avoid common gaps in generating the data and documentation in cases where a new 510(k) is not required. Notably, FDA’s public WL database only goes back to 2020.  This can limit the type of information that can be gained from WLs.  Thus, when evaluating your next set of device changes and whether a new 510(k) is needed, you may want to consult a third-party database (or an advisor that has access to such a database) to help with this search.

The multi-decade battle over FDA’s power to regulate Laboratory Developed Tests (LDTs) had its day in court earlier this week.  On February 19, 2025, Judge Sean Jordan in the Eastern District of Texas heard oral arguments in American Clinical Laboratory Association (ACLA) and the Association for Molecular Pathology’s (AMP)[1] lawsuit against the Department of Health and Human Services.  ACLA and AMP are both challenging the legal validity of FDA’s Final LDT Rule that was issued last July.  The arguments lasted nearly three hours.  Judge Jordan began with asking the parties a foundational question: how do you define LDTs?  Without giving any indication of which way he was leaning, he asked multiple follow-up questions of both sides on topics ranging from the roles of analytical and clinical validity to the history of the FDCA and CLIA.  Citing the May 6 compliance date for Stage 1 of the LDT Rule, both ACLA and AMP asked that Judge Jordan issue his ruling expeditiously.  Judge Jordan said he would issue a decision as soon as possible.

Perhaps most notable in yesterday’s argument, though, was what didn’t happen.  Given the numerous changes in policy by the Trump administration, there had been much speculation that the government would now take a different position on this Biden-era rule.  It did not.  Department of Justice counsel strongly defended the rule throughout the hearing.  Interestingly, counsel focused his arguments exclusively on parrying legal attacks, rather than arguing why the rule was necessary to protect patients.  In contrast, AMP and ACLA both asserted that the rule would harm medical care. Perhaps anticipating a less than favorable outcome, DOJ counsel several times asked to be allowed to submit a brief on the question of the remedy in the event of an adverse ruling.

As our readers will recall, the LDT rule will bring, by FDA’s estimates, hundreds of thousands of laboratory tests under FDA’s regulatory purview.  Despite this impending massive change in regulatory scope, the President and his Department of Government Efficiency (DOGE) fired hundreds of FDA employees this past weekend.  Many of the fired employees were within the Center for Devices and Radiological Health—the Center that is tasked with regulating all devices, including in vitro diagnostics, which FDA argues includes LDTs.  These firings will stretch the Center’s resources to take on its existing workload, let alone handle thousands of complex and innovative LDTs.  We have previously raised concerns about the number of resources that will realistically be needed for CDRH to regulate LDTs (see our prior post here).

A major concern for laboratories, particularly those who have introduced new tests since the final rule was issued, will be availability of resources to review pre-submissions ahead of the Stage 4 and 5 implementation dates.  Notably, the last question Judge Jordan asked of ACLA was on this specific point.  Judge Jordan asked ACLA for confirmation that he understood correctly that pre-market submission was the major burden for labs and that while pre-market submission compliance dates are still several years away, labs should be preparing now to meet FDA’s pre-market expectations.  ACLA, of course, confirmed that was true.

Labs that will need to gain clearance/approval for their tests will need to begin the process soon to ensure they understand FDA’s expectations for analytical and clinical validity.  (That, of course, is not unique to labs with LDTs; kit manufacturers also need to obtain those insights well before they begin studies.)  The process for gaining this alignment is through the pre-submission program.  The last time CDRH was significantly resource constrained (i.e., during COVID), however, the Center stopped reviewing nearly all pre-submissions (see our prior post here).  A surge in pre-subs from labs combined with a shortage of qualified reviewers will almost certainly lead to significant delays in getting feedback, or, as happened during COVID, receiving no feedback at all.  If this happens, laboratories will not be able to anticipate what data FDA wants.

The first phase of the rule, which takes effect in less than three months, requires laboratories to have certain policies and procedures in place to begin handling complaints, reporting Medical Device Reports, and reporting corrections/removals.  While not terribly informative, under the prior administration, FDA held a webinar to outline the requirements of this Stage.  The materials from this webinar are still available on FDA’s website (here).

FDA had been scheduled to hold a webinar on the Stage 2 (May 2026) requirements related to the investigational device requirements for LDTs later this month.  Since the new administration took office, however, the webinar page has been taken down from FDA’s website.  This raises the question of whether and to what extent, if the rule moves forward, will FDA provide any tools to help laboratories as they seek to comply with these new requirements.

The LDT Rule itself provides no operational guidance, but only a definition.  The preamble to the Rule references planned or possible guidances more than 200 times, highlighting nearly a dozen areas for guidance development.  In fact, FDA has three guidances on its “A list” planned for this fiscal year that are specifically related to the LDT Rule or IVD (which FDA says includes LDTs) labeling (see here).  It’s unclear at this time whether any of these guidances will be issued, if the rule moves forward.

In addition, we understand that at this time FDA is unable to consult outside experts.  This restriction could significantly affect the Agency from learning from clinical and technical experts about the benefits and risks of certain tests as well as interpreting the clinical context of MDRs that it would start to receive if Stage 1 goes into effect.  As those that have worked with FDA know, the Agency is not an expert on all disease states or technologies.  This knowledge gap may be further exacerbated with MDRs for novel LDTs.  This inability to consult external experts could make communicating with FDA on important topics of safety and effectiveness even more challenging.

Taken together, should the rule go into effect, CDRH may be even less prepared for LDT regulation than it was a short time ago.  Thirty-three years after FDA first said it could regulate LDTs, we now wait to see if the court will allow the rule to stand.

[1] Hyman, Phelps & McNamara represents AMP in this litigation.