Implications of Recent Third Circuit Court of Appeals Decision for FDA Drug Approval Framework

This article originally appeared in the Food and Drug Law Journal and is available here via Open Access.


A recent Third Circuit Court of Appeals decision in United States v. Vepuri has the potential to undermine the legal framework for drug approvals in the United States. Specifically, this decision could shield copycat products from U.S. Food and Drug Administration (FDA) enforcement action and allow them to enter the market without FDA pre-approval. The loophole created by this decision is accompanied by concerns about product quality, patient safety, and other issues that would be flagged in a premarket review.

I. Introduction

The ongoing U.S. Fifth Circuit Court of Appeals litigation challenging the U.S. Food and Drug Administration’s (FDA’s) approval of mifepristone has generated a great deal of attention and concern about the implications for FDA drug approval decisions.1 This Article discusses a recent decision by the U.S. Court of Appeals for the Third Circuit that has generated far less attention but also has the potential to undermine the legal framework for FDA drug approvals. The Third Circuit’s decision in United States v. Vepuri2 potentially allows any firm manufacturing a copycat drug to market it without FDA approval and without fear of FDA enforcement action under 21 U.S.C. § 355(a), provided the copycat has the same chemical composition and labeling as a drug specifically approved by FDA pursuant to a new drug application (NDA) or an abbreviated new drug application (ANDA).

II. Background

In July, the Third Circuit Court of Appeals upheld an earlier decision of the district court to dismiss part of a criminal indictment against KVK-Tech, Inc. (“KVK-Tech”) and two KVK-Tech executives (Murty Vepuri and Ashvin Panchal) on the grounds that the conduct alleged in the indictment did not constitute an offense under 21 U.S.C. § 355(a).3 As further discussed below, § 355(a) prohibits a person from introducing a “new drug” into interstate commerce without an effective application in place.4

KVK-Tech manufactured hydroxyzine, a generic prescription drug indicated for the treatment of anxiety and tension.5 KVK-Tech had three approved ANDAs to market different strengths of hydroxyzine.6 Contrary to the ANDAs, KVK-Tech had been introducing hydroxyzine into interstate commerce that KVK-Tech had manufactured using active pharmaceutical ingredient (API) sourced from a facility in Mexico that was not listed in the ANDAs or otherwise approved by FDA.7

KVK-Tech had stated in its ANDAs that the hydroxyzine active ingredient would be sourced from a UCB Pharma, S.A facility in Belgium.8 In 2008, two years after the initial approvals, Panchal appropriately filed an application supplement and obtained approval to source the active ingredient from a different company, a Cosma, S.p.A facility in Italy.9 Despite having two approved options for sourcing API, in October 2010, Vepuri authorized the purchase of three shipments of active ingredient from a Dr. Reddy’s Laboratories (DRL) facility in Mexico not listed in the approved ANDAs.10

FDA only discovered this unauthorized API substitution in June 2013, when it refused to permit a fourth shipment of DRL API to enter the United States on the grounds that KVK-Tech’s ANDA did not list the DRL facility as an approved API source.11 By that time, however, KVK-Tech had already received the three prior shipments of API from DRL’s Mexico facility, which the government alleged was used to manufacture 368,000 bottles of hydroxyzine KVK-Tech distributed to customers.12

Following the border refusal, FDA inspected KVK-Tech, and Panchal made several false statements to FDA about where KVK-Tech was sourcing its API. For example, during a 2013 inspection, Panchal told FDA investigators that KVK-Tech had not received prior shipments of API from Mexico.13 When confronted with photographs to the contrary, Panchal indicated that he was not aware that UCB (the approved API manufacturer) shipped API from Mexico.14 In several communications with FDA during and after the 2013 inspection, Panchal and Vepuri falsely blamed the use of the unapproved DRL API on the incompetence of a former employee and made other false statements to FDA.15

As further discussed in the underlying district court decision, FDA had issued a warning letter to DRL’s Mexican facility for violations of Current Good Manufacturing Practices (CGMP) in June 2011.16 The warning letter was based on violations discovered during an FDA inspection of the DRL facility conducted in November 2010, and was unrelated to the API shipments to KVK-Tech.17 The CGMP violations were serious enough that, the following month, FDA also placed the facility on import alert, thereby authorizing the detention of all DRL API shipped to the United States.18 The three shipments of DRL API utilized by KVK-Tech in the hydroxyzine it distributed occurred in January, March, and May of 2011, shortly before the import alert was issued in July 2011.19 The import alert remained in effect until July 2012.20

The defendants were indicted on several offenses. One of the offenses was a criminal conspiracy with several identified objects (or goals) of the conspiracy, including “with the intent to defraud and mislead, introducing or delivering for introduction, and causing the introduction or delivery for introduction, into interstate commerce of unapproved new drugs in violation of Title 21 United States Code, Sections 331(d) and 355(a)[.]”21 The district court struck down this portion of the indictment, and the Third Circuit upheld that decision.22

III. Decision by the Third Circuit

The Third Circuit’s ruling hinges on a somewhat complicated interpretation of the term “new drug” as it is used in § 355(a), which provides: “No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) [concerning NDAs] or (j) [concerning ANDAs] is effective with respect to such drug.”23

To determine the meaning of “new drug” in § 355(a), the Third Circuit looks to the definition of the term at 21 U.S.C. § 321(p). The court parses the statutory language and finds, in relevant part, that § 321(p) defines “new drug” as “‘any drug . . . the composition of which is such that such drug is not’ . . . generally recognized among experts as safe and effective for the use ‘suggested in the labeling thereof.’”24 The court concludes, therefore, “[t]he text of § 321(p) . . . defines a ‘new drug’ in terms of its composition and labeling.”25 Additionally, a new drug under § 321(p) cannot be a grandfathered drug under the Food and Drugs Act of June 30, 1906, but this provision was not at issue in the case.26

The Third Circuit notes that the Federal Food, Drug, and Cosmetic Act does not define the word “composition,” but explains in a footnote that “FDA has long interpreted the term to refer only to a drug’s chemical makeup—the ‘name and amount of each active and inactive ingredient.’ And, a drug’s ‘composition’ does not include the location or identity of the manufacturer of those ingredients.”27

To support the position that the alleged conduct did constitute an offense under § 355(a), the government’s first theory was that because the API was sourced from a facility not listed in the ANDAs, the hydroxyzine KVK-Tech distributed was not the same “new drug” as the one with an effective approval.28 Relying on the reasoning discussed above, however, the Third Circuit disagreed, holding that because the hydroxyzine manufactured with the API from Mexico “has the same [chemical] composition and labeling as the hydroxyzine for which an approval of an ANDA is effective, the government could not rely on the premise that the two drugs are different.”29 Accordingly, the government’s argument that they were two different drugs did not state an offense of conspiracy to violate § 355(a).30

Although FDA had issued a warning letter to DRL for producing adulterated API and placed the company on an import alert, the government did not argue that the composition of the KVK-Tech hydroxyzine was not the same “new drug” because of the use of the adulterated API. Presumably this was because the government did not think it needed to show adulteration to successfully seek unapproved drug charges under § 355(a). As a result of the government’s silence on the issue of adulteration, the court did not consider that the source of API could, in fact, have an effect on the “composition” of the drug, if, for example, the API were adulterated, as was the case with the DRL API substituted by KVK-Tech. Although we do not endorse the Third Circuit’s very narrow interpretation of the term “new drug,” we would argue that adulterated API almost certainly alters the composition of the drug and therefore creates a “new drug” even under the Third Circuit’s reasoning.31 The government, however, understandably omitted discussion of adulteration in the § 355(a) charges, because that section does not mention adulteration in the plain language of the provision.32

The government’s second theory of liability was that “because . . . the ‘new drug’ was manufactured at a facility not included in the approved ANDA[,] . . . the approved ANDA stopped being ‘effective’ with respect to that drug.”33 Relying on the Supreme Court’s decision in Weinberger v. Hynson, Westcott & Dunning, Inc.,34 the Third Circuit rejected this second theory of liability as well, holding that “the approval of an NDA or ANDA ceases being effective only when it has been withdrawn or suspended.”35

IV. Broader Implications of the Vepuri Decision

The Vepuri case has potentially wide-ranging implications for FDA’s regulation of drugs approved under either an NDA or an ANDA.

For example, the Third Circuit decision undermines the statutory framework requiring applicants to file supplements for approval of certain changes to approved applications. Under 21 U.S.C. § 356a, “a drug made with a major manufacturing change may be distributed only if, before the distribution of the drug as so made, the holder involved submits to the [FDA] a supplemental application for such change and the [FDA] approves the application.” Other non-major changes to an application require notification to FDA either in a supplemental application or in the annual report filed to the application.36

To further expound on this point, a supplement for a major change, e.g., the change of an API supplier, provides the agency with information about the quality of the new API to ensure it has the same physicochemical properties as the approved ingredient. A new source for an active ingredient has the potential to significantly impact the impurity profile of a drug substance. The supplement should demonstrate the API supplier’s ability to produce the product as specified and should also provide stability data. A supplement also serves as a notification to FDA to conduct surveillance inspections of the facility to ensure compliance with applicable regulations, including but not limited to CGMP.

A sponsor could rely on the reasoning in the KVK-Tech case to make changes to a drug subject to an approved application without ever filing a supplement, claiming that those changes do not affect the composition or labeling of the drug. The sponsor could argue that those changes do not create a “new drug” and thus the approved application is still in effect, obviating any reason to file a supplement to the application. If this were the case, FDA would never be made aware of all manner of changes to an approved application, including major differences such as changes to API suppliers that could result in poor quality, contaminated, or adulterated drug product affecting patient safety.

Conveniently, the Third Circuit brushes over § 356a in a footnote, stating that “despite its apparent relevancy,” the court declined to further consider it because the government did not “rely on § 356a to establish that the defendants conspired to violate § 355(a).”37 The district court, for its part, explicitly cited § 356a in support of that court’s “[ready acknowledgment] that the place of manufacture of a drug is critical” and its belief that “the [district court’s] ruling will not deprive the FDA of its ability to remedy this type of noncompliance.”38 And yet those statements by the district court do not seem to hold true under the Third Circuit’s reasoning, which appears to render those statutory requirements voluntary, or at least challengeable by a sponsor as just described.

Also troubling, relying on the Third Circuit decision, companies could entirely forego submitting an application to FDA, claim that they are manufacturing drugs with chemical compositions and labeling identical to approved NDA and ANDA drug products, and argue that they were not introducing unapproved new drugs into interstate commerce in violation of 21 U.S.C. § 355(a). Ultimately, if this copycat tactic proved to be successful, it would serve as a serious disincentive for companies to file an ANDA. Why do so, if you could qualify under an existing NDA or ANDA by simply distributing a product with identical chemical compositions and labeling? Similarly, companies could also be dissuaded from conducting clinical research supporting an NDA if other companies could quickly begin distributing a drug product with an identical chemical composition and labeling under the umbrella of the very same approved NDA. In this latter case, private litigants could bring patent infringement suits to help ward off copycat products, but FDA would be powerless to do so.

V. Conclusion

After balancing the implications of letting the decision stand with the likelihood of success on appeal, the government did not file a petition for a writ of certiorari with the Supreme Court.39 Overturning the decision would certainly have been beneficial, but losing the appeal would have created precedent for all federal courts, extending the reach, and the consequences, of a very unfortunate decision that is limited currently to the Third Circuit.

Rather than appeal, the agency may be planning to seek a legislative solution to this loophole for future applications. Our suggested fix is to amend the language of § 355(a) to read “No person shall introduce or deliver for introduction into interstate commerce any new drug unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug and such drug conforms to the approved application.” The Third Circuit gives a nod to this option in the decision itself, stating that “to the extent that our decision has identified a gap in the FDA’s ability to regulate the drugs that are introduced into interstate commerce, Congress has the tools necessary to fill it.”40


1. See All. for Hippocratic Med. v. U.S. Food & Drug Administration, 78 F.4th 210 (5th Cir. 2023).

2. 74 F.4th 141 (3d. Cir. 2023).

3. Id. at 143–44.

4. 21 U.S.C. § 355(a)

5. 74 F.4th at 143.

6. Id. at 144.

7. Id.

8. Id.

9. Id.

10. Id.

11. Id.

12. Id.

13. Id.

14. Id.

15. Id.

16. United States v. Vepuri, No. CR 21-132, 2022 WL 541772, at *2 (E.D. Pa. Feb. 23, 2022).

17. FDA Warning Letter: Dr. Reddy’s Laboratories (June 3, 2011), 58679.htm (last visited Nov. 10, 2023).

18. 2022 WL 541772 at *2.

19. Id.

20. Id.

21. 74 F.4th at 145.

22. Id.

23. 21 U.S.C. § 355(a) (emphasis added).

24. 74 F.4th at 147 (emphasis original).

25. Id.

26. See 21 U.S.C. § 321(p)(1).

27. Vepuri, 74 F.4th at 150, n.8 (quoting U.S. FOOD & DRUG ADMIN., GUIDELINE FOR THE FORMAT AND CONTENT OF THE SUMMARY FOR NEW DRUG AND ANTIBIOTIC APPLICATIONS—GUIDANCE FOR INDUSTRY (Feb. 1987) and 21 U.S.C. § 355(b)(1)(A)) (citations omitted).

28. Id. at 149.

29. Id. at 150.

30. Id.

31. The warning letter to DRL cited the facility for not validating the analytical methods used to test its APIs and for the failure of its quality unit to ensure the APIs manufactured met intended specifications for quality and purity, among other violations. These violations not only rendered the API adulterated but raise such serious questions about the chemical composition of the API itself, that it could not reasonably be considered identical to the approved sources of API identified in the ANDAs. See FDA Warning Letter, supra note 17.

32. Separate provisions under 21 U.S.C. § 331 prohibit introducing into interstate commerce an adulterated drug (or causing a drug already in interstate commerce to become adulterated). 21 U.S.C. § 331(a) and (b).

33. 74 F.4th at 150.

34. 412 U.S. 609, 633 (1973).

35. 74 F.4th at 151.

36. 21 U.S.C. § 356a(d). See also 21 C.F.R. § 314.70.

37. 74 F.4th at 145, n.3.

38. 2022 WL 541772 at *7.

39. See Sup. Ct. R. 13 (a timely petition for certiorari must be filed within 90 days after entry of judgment).

40. 74 F.4th at 149, n.7.

Ashley, D., Auchincloss, K., and Oestreich, E. Implications of Recent Third Circuit Court of Appeals Decision for FDA Drug Approval Framework. Food and Drug Law Journal. 2023. Vol. 78, no. 3. p. 257-262.

WHO’s 6 Principles For An AI Regulatory Framework For Medical Product Development

This article was originally published as a guest column in Life Science Connect’s Outsourced Pharma.

In mid-October 2023, the WHO published a paper titled Regulatory Considerations on Artificial Intelligence for Health,1 identifying the key principles that international regulatory frameworks for artificial intelligence (AI) should address and are, in fact, starting to coalesce around. The paper was developed in consultation with WHO’s Working Group on Regulatory Considerations (WG-RC) on AI for Health, whose members include regulatory authorities, policy makers, academics, and representatives from industry. The document is intended to serve as a resource for regulators, providing a list of 18 regulatory considerations to address in their emerging regulatory frameworks. It should be noted that the scope of the document extends beyond medical product development and is also intended to inform healthcare delivery.

The 18 regulatory considerations discussed in the paper fall under six broad categories: documentation and transparency, risk management, intended use and validation, data quality, privacy and data protection, and engagement and collaboration. Many of these themes, like transparency, risk management, and validation, have been discussed by the FDA and the European Medicines Agency (EMA), in public forums or in publications. Considering WHO’s global mandate, WHO’s paper also focuses on issues that are not necessarily prioritized by national authorities, such as international collaboration and the challenges in navigating national privacy laws and data protection regulations.

1. Documentation and Transparency

In line with several key regulators, WHO identifies transparency and documentation as the cornerstone for any effective AI regulatory framework. Referencing AI’s ability to self-improve, WHO emphasizes the importance of regulators “to be able to trace back the development process and to have appropriate documentation of essential steps and decision points.”2 This echoes similar points made by both FDA and EMA in recent reflection papers. In the May 2023 discussion paper Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products, FDA noted that documentation is needed across the entire medical product life cycle and stated that “accountability and transparency are essential for the development of trustworthy AI.”3

Importantly, WHO also identifies effective documentation as an essential tool to guard against bias and to establish trust. EMA in its Reflection Paper on the Use of Artificial Intelligence (AI) in the Medicinal Product Lifecycle4 encouraged sponsors to document areas of potential risk for bias or discriminatory outcomes prior to using a particular data set.

2. Risk Management

Considering AI’s self-learning capabilities, WHO recommends a total life cycle approach to risk management. Specifically, WHO states that a “life cycle approach can facilitate continuous AI learning and product improvement while providing effective safeguards.”5 To properly evaluate risk in pre-market development, WHO encourages developers to consider risk in terms of the intended use of the AI system and the clinical context. WHO identifies the International Medical Device Regulators Forum (IMDRF) Risk Framework for Software as a Medical Device (SaMD)as a reasonable approach for regulators to adopt to support risk assessment.

In the post-market, WHO recommends manufacturers develop post-market surveillance plans that specify how manufacturers will monitor, identify, and respond to emerging risks. WHO recommends that an active reporting and investigative function be established. While referencing CONSORT-AI as an appropriate resource, WHO stops short of endorsing a specific reporting standard.

3. Validation

Again, acknowledging the likelihood of AI-related change, WHO emphasizes the importance of conducting analytical and clinical validation throughout the product life cycle. Analytical validation, also known as “technical validation,” is defined as the process of “validating the AI system using data but without performing interventional or clinical studies.”7 This process requires careful documentation of the development and data selection processes. Analytic validation also can include a benchmarking exercise where the model is compared to other tools and established performance standards. To facilitate this process, WHO notes that benchmarking software is being developed as part of the Open Code Initiative.8

Clinical validation is a process by which an AI product or tool is assessed in the context of its intended use. WHO again references the IMDRF on clinical evaluation of SaMD as an effective risk-based approach for determining the amount of real-world data manufacturers should collect to evaluate a tool’s intended use. The adoption of a specific approach to clinical validation by a regulator should also be dependent upon the resources and expertise available in that country.

4. Data Considerations

While recognizing data as the “most important ingredient for training AI/ML (machine learning) algorithms,” WHO highlights the challenge in identifying and defining good quality data. The difficulty in thinking about data lies in the numerous dimensions upon which it can be analyzed. WHO encourages regulators and developers to classify data based upon the 10 V’s: volume, veracity, validity, vocabulary, velocity, vagueness, variability, venue, variety, and value. Armed with this classification system, developers can then home in on key data challenges within their development programs. Some key data challenges highlighted by WHO include data management, data inconsistency, data usability, and data integrity.

WHO recognizes data as the most important ingredient for AI/ML algorithms, primarily because AI can readily amplify biases that exist in training data sets. Along these lines, WHO notes that improper data source selection can result in selection bias “when data used to provide the model are not fully representative of the actual data that the model may receive or the environment in which the model will function.”9 Thus, inappropriate data selection can easily distort a model’s output, which can undermine the generalizability of a model and raise ethical considerations.

5. Privacy and Data Protection

WHO identifies the patchwork of different data protection regulations and privacy laws as a significant barrier to the further development of AI-enabled medical products. Indeed, WHO notes that “some 145 countries and regions have data protection regulations and privacy laws that regulate the collection, use, disclosure and security of personal information.”10 Many of these countries have their own definitions and interpretations of “privacy,” “confidentiality,” “identifiable,” “anonymous,” and “consent,” among other concepts. The jurisdictional scope of each country or region’s regulations may overlap and may restrict cross-border transfers of data.

To reduce barriers to cooperation among regulators and sponsors, WHO recommends agencies consider regulatory sandboxes — a tool that was socialized during COVID-19. These sandboxes can help regulators acquire “a better understanding of the AI systems during the development phase and before they are placed on the market.”11 Sandboxes provide a limited form of regulatory waiver that allow developers the opportunity to test new technologies without regulatory repercussions as well as provide regulators the opportunity to consider and test new regulatory approaches.

6. Engagement and Collaboration

WHO concludes the paper stating that greater collaboration among all stakeholders can improve the quality and safety of AI in general. Using case studies from an array of health authorities around the globe, WHO encourages regulators to position themselves as facilitators of innovation and partners in development. A broad engagement strategy, one that collaborates with patient advocacy groups, academia, healthcare professionals, industry, and other domestic government partners is encouraged.


WHO’s timely document highlights the key principles that international regulators are beginning to build their regulatory frameworks upon. Common to all regulators is the importance of and emphasis on transparency, documentation, and effective risk management. The alignment of these principles is critical when it comes to international collaboration among stakeholders, as it can help improve the quality and safety of AI in healthcare. Data quality as well as divergent privacy laws and data protection regulations across jurisdictions will continue to pose a challenge to regulators and developers alike.


  1. World Health Organization (WHO), “Regulatory Considerations on Artificial Intelligence for Health,” October 2023,
  2. Ibid., page 8.
  3. Food and Drug Administration (FDA), “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products,” May 2023,
  4. European Medicines Agency (EMA), “Reflection Paper on the Use of Artificial Intelligence (AI) in the Medicinal Product Lifecycle,” July 2023,
  5. WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 29.
  6. International Medical Device Regulators Forum (IMDRF), “Software as a Medical Device: Possible Framework for Risk Categorization and Corresponding Considerations,” September 2014,
  7. WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 22.
  8. United Nations, ITU, “Open Code Initiative,”
  9. WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 28.
  10. Ibid., page 33.
  11. Ibid., page 37.

An Overview of FDA Efforts to Encourage DHT Use in Drug and Biological Product Development

This article was originally published in Clinical Tech Leader.

Digital health technology (DHT) is increasingly permeating the medical products industry due to its use in general wellness applications, medical devices intended to diagnose, treat, or prevent disease, and as a tool in clinical research. The FDA has issued numerous guidances on topics related to the regulation of such technologies as medical devices.1 However, there is less information available on how FDA intends to manage the use of DHTs in the context of clinical research to support the development of medical products.

Recognizing this gap, in its most recent Prescription Drug User Fee Act (PDUFA VII) commitment letter, FDA agreed to establish “a DHT framework document [to] guide the use of DHT-derived data in regulatory decision-makings for drugs and biological products.”2

Framework for the Use of Digital Health Technologies in Drug and Biological Product Development

To meet this PDUFA VII commitment, FDA issued its Framework for the Use of Digital Health Technologies in Drug and Biological Product Development in late March 2023.3 While neither a legally binding document nor an agency guidance, the framework represents the agency’s road map for developing an approach to the use of DHTs in regulatory decision-making related to drug and biological product development. Drug developers who are using or intend to use DHTs in their product development activities should pay close attention to this framework and opportunities to engage with FDA as it crafts its regulatory agenda.

The framework, at the outset, defines DHTs as “systems that use computing platforms, connectivity, software, and/or sensors for healthcare and related uses. They include technologies intended for use as a medical product, in a medical product, or as an adjunct to other medical products (devices, drugs, and biologics). DHTs may also be used to develop or study medical products.”4

With respect to their use in clinical research, DHTs may include wearable, implantable, or software applications on mobile devices, among other approaches. DHTs allow for remote data acquisition in a clinical study and enable new study designs, such as decentralized clinical trials. This may confer significant benefits for research by expanding the patient populations that may participate in clinical studies and enabling the collection of data in real time, continuously, and in real-world settings rather than a clinical study site. However, to keep pace with the rapid development and use of DHTs in clinical trials, FDA must also build its capacity to understand and evaluate such technologies.5

The framework details the agency’s plan to effectively identify and address the challenges with the use of DHT in drug and biological product development, encompassing the agency’s internal efforts as well as engagement with external stakeholders.

Internal FDA Efforts

With respect to internal efforts, the framework outlines five workstreams,6 and while all are important, there are a few highlights.

The framework first explains that FDA created a DHT Steering Committee, which drafted and published the framework.7 The Committee includes members from the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Digital Health Center of Excellence (DHCoE), the Oncology Center of Excellence (OCE), and the commissioner’s office.8  

The framework also includes plans to create consistent regulatory approaches to DHTs across review divisions and centers.9 Specifically, the framework states “review divisions and centers should have consistent approaches to the review and evaluation of submissions that contain DHT-related data. The DHT Steering Committee will help facilitate consistent approaches to the review and evaluation of such submissions.”10 While plans to harmonize guidelines/standards across product centers to facilitate and increase the use of DHTs in product development is a noble goal, implementation could be a challenge. If and how the collaboration across product centers evolves will be critical to operationalizing the framework and to achieving the agency’s DHT goals more generally.

Other internal workstreams include an evaluation of statistical considerations in the analysis of DHT-derived data and improving technical expertise and training. On the latter, there are several sub-workstreams, such as: (i) Verification and Validation; (ii) Use of a Participant’s Own DHT or General-Purpose Computing Platform; (iii) Upgrades and Updates of DHTs in Drug Development; (iv) Artificial Intelligence and Machine Learning; and (v) Technical Consultation of Experts and Staff Training.11

In addition to the above internal workstreams, and consistent with PDUFA VII, FDA has committed to improving its IT capabilities to support the review of DHT-generated data and will coordinate this effort with the agency’s enterprise-wide modernization activities.12 The framework stresses three subpoints with respect to the IT capabilities piece: (i) improving “its internal systems to support the review of DHT-related submissions”; (ii) creating a secure cloud technology to improve its infrastructure and analytics environment … enabl[ing] FDA to effectively receive, aggregate, store, and process large volumes of data from drug trials conducted using DHTs”; and (iii) creating standards to “make DHT data analyzable” (CDER and CBER would collaborate with DHCoE to create those data standards for DHT-generated data sets).13

One significant limitation, or challenge, is that it appears that FDA plans to create its own internal technology systems. Government agencies, including the FDA, have not possessed the technological know-how to stand up internal systems to effectively collect, analyze, and act on data in real time. In some instances, FDA has relied on the private sector for its technology systems, including Big Data analytics, which have been successful. Thus, FDA might want to reconsider its ability to develop in-house IT capabilities in the DHT space specifically, but also more generally for its enterprise-wide modernization efforts.

Overall, while the framework generally envisions a strategically sound internal approach for overseeing DHTs in drug and biological development, the weaknesses or challenges largely lie in the implementation and operationalization. For example, harmonizing standards for DHTs across product centers and review divisions is laudable but may be difficult in practice, and funneling resources to in-house development of IT systems to handle DHT data is risky.

External FDA Efforts and Guidances

In addition to detailing its internal workings, the agency also describes its plans to engage with external stakeholders, including regulated industry, “to better understand the challenges and opportunities associated with using DHTs” in regulatory decision-making for drugs and biological products.14 Such external engagement opportunities include the publication of guidances, public meetings, and demonstration selections,15 among others like sponsor meetings and the drug qualification tool/program.

With respect to guidances, FDA already has published two draft guidances on the use of DHTs in drug development and plans to publish at least two additional draft guidances. The draft guidances currently available include Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, which was published in December 2021,16 and Electronic Systems, Electronic Records, … in Clinical Investigations: Questions and Answers, which was published in March 2023.17 In addition, there are several other guidances not specific to DHTs that are nonetheless relevant to the use of DHTs in clinical investigations.

Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

The draft guidance on use of DHT for remote data acquisition proposed recommendations to facilitate the use of DHTs in clinical investigations, including, for example, “selection of DHTs that are suitable for use in clinical investigations”; “verification and validation of DHTs for use in clinical investigations”; “use of DHTs to collect data for trial endpoints”; “identification of risks associated with the use of DHTs during clinical investigations”; and “management of risks related to the use of DHTs in clinical investigations.”18

Electronic Systems, Electronic Records, … in Clinical Investigations: Questions and Answers

The draft guidance on electronic systems and records discusses commonly asked questions and provides answers related to the applicability of Part 11 to electronic records, electronic signatures, and electronic systems used in clinical investigations, including the use of DHT-derived data.19 Further, the draft guidance makes recommendations for using DHT data and use of DHT in clinical trials.20

Other Guidances

On June 6, 2023, FDA issued draft guidance from the International Council for Harmonisation on Good Clinical Practices (GCP) E6(R3) and opened the docket for public comment, with comments due by September 6.21 This FDA draft guidance (embodying the ICH guideline) aims to maintain a flexible GCP framework that ensures the safety of clinical trial participants and data, while also advancing new principles that modernize clinical trials and support more efficient approaches to trial design and conduct.22

One way the FDA guidance envisages modernizing clinical trials is encouraging the use of DHTs, particularly fit-for-purpose innovative DHTs.23 The draft guidance states: “[f]or example, innovative digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct.”24 Additionally, the draft guidance stresses the fit-for-purpose nature of DHTs, stressing that “the use of technology in the conduct of clinical trials should be adapted to fit the participant characteristics and the particular trial design. This guideline is intended to be media neutral to enable the use of different technologies for the purposes of documentation.”25

Equally important, the draft guidance acknowledges that, while DHTs can easily be embedded into current healthcare infrastructure, they simultaneously “aid in keeping clinical trial conduct in line with advancing science and technological developments.”26 Indeed, when finalized, the FDA draft guidance would establish harmonized GCP standards for conducting and modernizing clinical trials, which would include, for example, decentralizing some or all elements of these studies, using DHTs and real-world data, and leveraging more complex designs.

Commissioner Califf, in a press release with the issuance of the draft guidance, echoed the guidance themes, emphasizing the importance of creating “a more robust clinical trial ecosystem” and encouraging the use of innovative trial designs and health technologies…to truly advance clinical trials and generate meaningful results.”27 More generally, Commissioner Califf, FDA senior leadership, and other draft guidances and initiatives relevant for DHTs have emphasized how DHTs like patient wearables and sensors may create a robust, efficient, and modernized clinical research system by facilitating patient enrollment in clinical trials, improving patient population diversity,28 and perhaps improving the accuracy of data collected, among other laudable benefits for clinical trial modernization.

And finally, as we discuss in a separate article, two guidances29 issued during the COVID-19 public health emergency that facilitated the use of DHTs in clinical investigations will be revised before Nov. 7, 2023, to either sunset at a later date or to continue indefinitely as traditional guidances. Of particular interest is CDER’s Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002).30 FDA’s goal in issuing this guidance was to provide general considerations and recommendations to help sponsors in ensuring the safety of clinical trial participants, maintaining compliance with GCP, and minimizing risks to trial integrity and interruptions for the duration of the COVID-19 PHE.31 One component of this effort encouraged the use of DHTs to allow for remote site monitoring and remote clinical visits for trial participants. FDA released a final version of this guidance at the end of September, with a slightly different title to encompass a broader array of emergency circumstances: Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions to Due to Disasters and Public Health Emergencies.32 The final guidance is similar to the COVID version, and recommends approaches that sponsors of clinical trials of medical products can consider when there is a major disruption to clinical trial operations during a disaster or public health emergency.

Looking Forward

Looking forward, the framework stresses the agency’s commitment to publishing two more draft guidances related to DHTs use in drug development this fiscal year: Decentralized Clinical Trials for Drugs, Biological Products, and Devices, a draft of which FDA issued on May 3, 2023, not long after the agency released the framework, and Regulatory Considerations for Prescription Drug Use-Related Software.33 The framework also stresses the agency’s commitment to publishing more guidances, consistent with the PDUFA VII commitment letter that emphasized that draft guidances in identified areas of need informed by stakeholder engagement would be a priority for the agency.34

In addition to the publication of final and draft guidances, the framework discusses the agency’s plans to host five public meetings facilitating dialogue between the agency and patients, academic researchers, and regulated industry including biopharmaceutical companies and digital health companies. Topics will include, for example, understanding priorities for the development of DHTs to support clinical investigations; identifying approaches to DHT verification and validation; understanding DHT data processing and analysis to inform the need for novel analytical techniques; addressing the regulatory acceptance of safety monitoring tools that utilize AI and ML-based algorithms for pharmacovigilance purposes; and understanding emerging issues.35 

Relatedly, and consistent with the framework’s themes, including engagement with industry, on October 11, 2023, the FDA announced the establishment of a Digital Health Advisory Committee to help the agency “explore the complex, scientific and technical issues related to digital health technologies.”36 This advisory committee is one forum, or opportunity, for industry to engage on digital health issues. The committee will include nine voting members in addition to several temporary members added to specific panels based on topics. The agency has opened its nomination portal — and will be open for industry/private sector participation until December 11. The committee will help the agency on cross-cutting issues that affect multiple product centers, while digital health product-specific issues will remain in their respective advisory committees and explore issues related to DHTs, such as artificial intelligence/machine learning (AI/ML), augmented reality, virtual reality, digital therapeutics, wearables, remote patient monitoring, and software.37 Indeed, the announcement for the advisory committee is consistent with the agency’s recent strategic priorities — namely, advancing “health equity in part through expanding access by bringing prevention, wellness, and healthcare to all people where they live — at home, at work, in big cities, and rural communities. DHTs are critical for achieving this transformation in care delivery.”38

Important for regulated industry, including DHT developers, the agency plans to identify and implement at least three demonstration projects “to inform methodologies for efficient DHT evaluation in drug development.”39 The agency, according to the framework and the PDUFA VII Commitment Letter, is particularly interested in the following topics: “validation methods for specific technologies, endpoint development, analytic approaches to missing data, use of multi-channel inputs to characterize an endpoint, evaluation of continuous data versus discrete measurements, use and limitations of DHTs in DCTs, and other related issues.”40

In view of FDA’s emphasis on external engagement, the developers of DHTs, as well as regulated industry writ large, should avail themselves of the multiple and varied opportunities to dialogue with the agency — commenting on draft guidances, engaging at the public meetings, or proposing and implementing demonstration projects or pilots. The agency is explicitly calling on, and relying on, regulated industry and DHT developers in particular to provide feedback in the DHT space and to meet the framework’s objectives. This includes, of course, identifying both challenges and solutions/opportunities in using DHTs in drug and biologics development.


While the framework is a solid baseline from which to work, it is a high-level document that generally reiterates goals the agency has already agreed to in PDUFA VII. Acknowledging an information gap, the document is a road map for the public that signals how FDA intends to approach the process for gathering information to better inform its decision-making around the regulation of DHTs for drug development. The agency commits to numerous internal and external actions as part of that process; thus, it will be critically important for all stakeholders, including patients, DHT manufacturers, and drug and biologics companies, to avail themselves of the numerous opportunities to engage with the FDA and offer substantive input. Now is the time to provide FDA with insight into the benefits and challenges of the use of DHTs in clinical research and to offer regulatory solutions. The biggest challenge for FDA will be in digesting that information and turning it into a cohesive regulatory scheme that is flexible and adaptable to ever-changing technology, but which can also be applied consistently across review divisions and centers.


1. See e.g., Policy for Device Software Functions and Mobile Medical Applications and Software as a Medical Device (SAMD): Clinical Evaluation, among many others included on FDA’s website, which lists guidances with “digital health content”,

2. FDA, “Framework for the Use of Digital Health Technologies in Drug and Biological Product Development,” See also Comments on the Agency’s Framework can be submitted to the docket (FDA-2022-N-3319) until May 23, 2023.

3. See the Framework. See also Comments on the Agency’s Framework can be submitted to the docket (FDA-2022-N-3319) until May 23, 2023.

4. Framework at Page 3.


6. Framework at Pages 8-11, “DHT Steering Committee,” “Technical Expertise and Training,” “Consistency of Evaluations Across Review Divisions,” “Statistical Considerations in the Analyses of DHT-Derived Data,” and “IT Capabilities.”

7. Framework at Page 8-9.

8. Framework at Pages 8-9.

9. Framework at Page 11.

10. Framework at Page 11.

11. Framework at Pages 9-11.

12. Framework at Pages 11-12.

13. Framework at Page 12.

14. Framework at Page 12.

15. Framework at Pages 12-26.



18. Framework at Page 13; see Guidance Document.

19. Framework at Page 13; see Guidance Document.

20. See the Guidance Document.

21. FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, See the FDA Docket, available here, Note that the draft guidance tracks with ICH’s recently updated E6(R3) draft guideline, and that guideline was drafted to describe how to deal with technological innovations for clinical trials, among other goals.

22. FDA Draft Guidance on E6(R3) Good Clinical Practice, available here,

23. Id. at 2.

24. Id.

25. Id.

26. Id.

27. FDA News Release, June 6, 2023, available here,

28. Regarding (ii) in particular, improving the diversity of clinical trials has been a particular priority for FDA. See, for example, April 2022 draft guidance describing how sponsors should ensure their trials reach and include more underrepresented racial and ethnic groups, available here,

29. CDER Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002), and CDRH’s “Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring during the Coronavirus Disease 2019 Public Health Emergency (Revised)” (FDA-2020-D-1138),

30. Guidance available here,

31. See id.


33. Framework at Page 14. See also CDRH’s List of Proposed Guidances for FY2024,

34. Framework at Page 14. The PDUFA VII Commitment Letter at Page 66.

35. The Framework discusses each of these categories in greater detail, see Framework at Pages 14 and 15.




39. Framework at Page 15.

40. Framework at Page 15.

Comparing FDA and EMA Approaches to AI/ML in Drug Development and Manufacture

This article was originally published as a guest column in Outsourced Pharma.

Considering the feverish pace of innovation in the field of AI/ML and the inevitable impact this family of technologies has on drug development, an overview of the approaches to AI/ML regulation by the leading medical product regulatory authorities, the FDA and European Medicines Agency (EMA), is timely. Below, we outline the documents and guidances the two regulators have released thus far, comparing and contrasting their areas of focus and concern.

A Comparison of the Definitions of AI and ML

Despite the lack of a universally accepted definition of AI among experts,1 both regulatory agencies have settled on a working definition of AI.

In its definition, FDA acknowledges the breadth and multidisciplinary nature of the field, defining AI as “[a] branch of computer science, statistics, and engineering that uses algorithms or models to perform tasks and exhibit behaviors such as learning, making decisions, and making predictions.”2 Meanwhile, FDA identifies ML as a subset of AI that allows “[m]odels to be developed by ML training algorithms through analysis of data, without being explicitly programmed.”3

EMA, however, takes a more mechanistic approach, defining AI as “systems displaying intelligent behavior by analyzing data and taking actions with some degree of autonomy to achieve specific goals.”4 Meanwhile, EMA’s definition of ML — “models [that] are trained from data without explicit programming” — mirrors FDA’s ML definition.

The FDA’s Approach

In May 2023, FDA began to consider the implications of AI/ML technologies for drug development with the publication of two discussion papers: Artificial Intelligence in Drug Manufacturing5 and Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products.6 These two discussion papers highlight the agency’s areas of concern related to the incorporation of AI/ML in drug development and manufacturing.

Chief among these concerns are the governance, accountability, and transparency of AI/ML systems. For ML models, transparency and accountability are particularly challenging considering they are sub symbolic, or a “stack of equations — a thicket of often hard-to-interpret operations on numbers.”7 Thus, the nature of these systems makes its outputs difficult to interpret, presenting obvious regulatory challenges. To address these challenges, the FDA emphasizes the importance of “tracking and recording … key steps and decisions, including the rationale for any deviations and procedures that enable vigilant oversight and auditing.”8 The problem of transparency and accountability is further compounded by competitive concerns, as many of these models are proprietary.

Data quality is another concern the FDA addresses in its discussion papers, noting that the application of AI/ML systems in drug manufacturing can significantly increase the frequency and volume of data exchanges in the manufacturing process, thereby exponentially increasing the quantity of data. This increase in data output may require new considerations relating to data storage, retention, and security. In terms of data input, sponsors must be cognizant of any preexisting biases in the training data, as ML systems can easily duplicate or even amplify these biases.

The FDA also highlights reliability as another area of focus and concern. As recent experiences with large language models may attest, some AI systems are prone to hallucination, “a phenomenon where AI generates a convincing but completely made-up answer.”9 Indeed, in a recent study on AI hallucination, a group of researchers prompted a chatbot to generate a list of research proposals with reliable references. Of the 178 references provided by the chatbot, 69 did not have a digital object identifier (DOI), while 28 did not turn up on internet searches.10 Thus, FDA’s concern about reliability seems well founded, especially in the context of a drug development program.

The EMA’s Approach

Following the FDA’s recent publications, the EMA released a reflection paper11 advocating for a risk-based approach that considers patient safety and the reliability of development data. In April 2021, the European Union (EU) introduced a coordinated plan and a regulation proposal for AI, aimed at promoting innovation and ensuring AI benefits society. The reflection paper is an extension of this plan, outlining considerations for AI usage in drug development and emphasizing regulatory oversight based on risk assessment. It highlights three key concerns, specifically, the need for:12

  • risk-based oversight,
  • the establishment of strong governance for AI deployments, and
  • guidelines covering data reliability, transparency, and patient monitoring.

The paper categorizes the risk of AI application in drug development stages. AI use in early drug discovery is deemed low risk, while its use in clinical trials spans various risk levels depending on factors like human oversight and potential impact on regulatory decisions. To manage risks, the paper recommends transparent AI models (the idea to fully trace information flow within a ML model), cautious handling of issues like overfitting (the result of non-optimal modeling practices wherein you learn details from training data that cannot be generalized to new data), and appropriate performance assessment metrics. Ethical and privacy issues, such as human agency and oversight, technical robustness and safety, privacy and data governance, transparency, accountability, societal and environmental well-being, diversity, non-discrimination, and fairness, are addressed and outlined.

Specific considerations for AI usage include ensuring accurate AI-generated text through quality review procedures and high-risk AI decisions in precision medicine settings, AI use in manufacturing adhering to quality risk management principles, and the importance of regulatory interactions during development. The reflection paper acknowledges that it is not an exhaustive source of regulatory insight on AI but serves as a starting point for further discussions. Stakeholders can provide feedback until Dec. 31, 2023.


While both the FDA and the EMA strive to provide a framework that balances innovation and patient safety, nuances emerge in their respective approaches. Stakeholder input and evolving industry practices are critical to shaping future regulatory guidelines. Collaboration among regulators, manufacturers, and researchers will be pivotal in fostering a transparent, accountable, and efficient AI ecosystem that enhances the development and deployment of medical products for the betterment of global health.

  1. Stanford University, “Artificial Intelligence and Life in 2030,” 2016, 12;
  2. FDA, “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products,” (May 2023),
  3. Ibid.
  4. EMA, “5 Reflection paper on the use of Artificial Intelligence (AI) in 6 the medicinal product lifecycle.” 13 July 2023,
  5. FDA, “Artificial Intelligence in Drug Manufacturing,” May 2023,
  6. FDA, “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products,” May 2023,
  7. Mitchell, Melanie. Artificial Intelligence: A Guide for Thinking Humans, p. 12.
  8. FDA, “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products,” p. 20.
  9. Athaluri SA, Manthena SV, Kesapragada VSRKM, Yarlagadda V, Dave T, Duddumpudi RTS. Exploring the Boundaries of Reality: Investigating the Phenomenon of Artificial Intelligence Hallucination in Scientific Writing Through ChatGPT References. Cureus. 2023 Apr 11;15(4):e37432. doi: 10.7759/cureus.37432. PMID: 37182055; PMCID: PMC10173677.
  10. Ibid.
  11. European Medicines Agency. (2023, July 13). Reflection Paper on the Use of Artificial Intelligence (AI) in the Medicinal Product Lifecycle. European Medicines Agency.
  12. European Medicines Agency. (2021, August 16). Artificial Intelligence in Medicine Regulation. European Medicines Agency.

Clinical Trial Diversity, Flexibility Championed by the Food and Drug Omnibus Reform Act

This article was originally published as a guest column in Clinical Leader.

The Food and Drug Omnibus Reform Act (FDORA),1 signed into law by President Biden on Dec. 29, 2022, which we initially wrote about in February with regard to inspections, also includes numerous provisions intended to modernize clinical trials. These provisions enact and expand upon FDA initiatives over the last decade and could go a long way toward advancing clinical research. The provisions are broadly divided into two categories: (1) encouraging the enrollment of more diverse patient populations in clinical studies; and (2) facilitating novel clinical trial designs and methods for conducting clinical trials, in part by continuing certain flexibilities initiated during the COVID-19 public health emergency.

Clinical Trial Diversity

The diversity (or lack thereof) of patients enrolled in clinical trials has long been a topic of consideration and concern for those in the public health field. There is evidence that minorities, women, the elderly, children, and other demographic subgroups are underrepresented in clinical research, leading to gaps in understanding the safety and efficacy of certain drugs used in those populations.

In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) recognized this gap and required the FDA to report on and create an Action Plan to improve the analysis of demographic subgroup data in clinical trials, expand the inclusion of such data in labeling, and make such data more available and transparent to the public.2 In the decade following FDASIA, the FDA took numerous steps to implement this FDASIA provision, including issuing the required report in August 2013, followed by the Action Plan in 2014, and convening a public meeting in between.3

The FDA’s efforts culminated in a draft guidance released in April 2022 (contemplated in the 2014 Action Plan), which encourages the inclusion of diverse patient populations in research conducted to support marketing applications for medical products.4 The draft guidance, titled Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, describes when diversity action plans are recommended, the timing for submission of such plans, and the suggested content.

FDORA sections 3601-3604 further promote clinical trial diversity by enacting into law a requirement for diversity action plans as well as requiring additional public communications and information gathering to facilitate diversity in clinical trials, as described below.5

§ 3601. Diversity action plans for clinical studies

  • Amends the FD&C Act to require a “diversity action plan” for all Phase 3 or other pivotal studies (excluding bioequivalence and bioavailability studies) for drugs and biological products and for many medical devices.
  • The diversity action plan must include the sponsor’s goals for enrollment in the clinical study, the rationale for such goals, and an explanation of how it intends to meet the goals. The plan must be submitted with the clinical study protocol.
  • The FDA may waive the requirement for a diversity action plan in certain circumstances, including “based on what is known or what can be determined about the prevalence or incidence of the disease or condition for which the new drug is under investigation” or if conducting the study in accordance with a diversity action plan “would otherwise be impracticable” or is against the interests of public health during a public health emergency.
  • Applies to clinical trials for which enrollment begins 180 days after publication of the final guidance described in § 3602. See § 3602(c).

§ 3602. Guidance on diversity action plans for clinical studies

  • Requires the FDA to issue or update guidance (e.g., the April 2022 draft guidance) on the requirement for clinical trial diversity action plans, including on their format and content, modifications to such plans, public posting by a sponsor of key information from a diversity action plan that would be useful to patients and providers, criteria the FDA will use when determining whether to grant a waiver for the requirement to follow a diversity action plan, and regular reporting to the FDA on the sponsor’s progress in achieving the goals described in the diversity action plan.
  • Draft guidance is due 12 months after enactment of FDORA (by Dec. 29, 2023); final guidance must be published within nine months of the close of the comment period of the draft guidance.

§ 3603. Public workshops to enhance clinical study diversity

  • Requires the FDA, in consultation with drug and medical device sponsors, clinical research organizations, academia, patients, and other stakeholders, to convene one or more public workshops to solicit input from stakeholders on “increasing the enrollment of historically underrepresented populations in clinical studies and encouraging clinical study participation that reflects the prevalence of the disease or condition among demographic subgroups[.]”
  • The FDA must establish a public docket in association with the meeting and must publish a report on the topics discussed at the meeting(s) within 180 days after the public comment period closes.

§ 3604. Annual summary report on progress to increase diversity in clinical studies

  • Requires the FDA to publish an annual report beginning two years after enactment of FDORA (Dec. 29, 2024) summarizing, in aggregate, diversity action plans received by the FDA, whether the clinical studies conducted under diversity action plans met the enrollment goals in the action plans, and if not, the reasons provided for why not.

Clinical Trial Flexibilities

Similar to efforts surrounding clinical trial diversity, the FDA and other stakeholders have been considering novel clinical trial designs for at least a decade, including whether the FDA’s regulatory framework must be modified to accommodate the oversight of such trials and allow evidence generated from those studies to satisfy the “substantial evidence” statutory standard.6

The FDA held a public hearing to solicit input on a broad effort to “encourag[e] the use of innovative models that may enhance the effectiveness and efficiency of the clinical trial enterprise”7 in 2012 and was subsequently granted new authorities related to novel clinical trial design and real-world evidence (RWE)/real-world data (RWD) in the 21st Century Cures Act of 2016.These efforts continued in PDUFA VI (FY18–FY22) and PDUFA VII (FY23–FY27), both of which include commitments related to RWE/RWD and to advancing the FDA’s capacity to review complex innovative trial designs, including Bayesian and adaptive protocols.9 As a result, the FDA has issued several guidance documents reflecting updated thinking on clinical trial design, trial conduct and compliance with good clinical practice (GCP), and the collection and analysis of data.10

A number of these initiatives were further advanced during the COVID-19 pandemic through flexibilities the FDA exercised to protect the safety of patients and investigators and to ensure adherence to GCP, while also minimizing disruptions to clinical research. The efforts are described in a guidance the FDA issued early in the pandemic that allowed for certain accommodations in the conduct of clinical trials.11 For example, the guidance described when it could be appropriate to conduct remote clinical visits for study participants, remotely monitor clinical sites, and ship investigational product to local providers for administration. The flexibilities outlined in the guidance were intended to address challenges associated with quarantines, travel restrictions, supply chain interruptions, and other disruptions associated with COVID-19.

With the termination of the public health emergency on May 11, 2023, many of the FDA’s guidances issued during the pandemic will sunset.12 Notably, the FDA has indicated that the guidance on the conduct of clinical trials will remain in effect for 180 days after the end of the PHE as a transitional period.13 This dovetails with a provision in FDORA that requires the FDA to hold a public meeting to better understand the effectiveness of the clinical trial flexibilities the FDA exercised during the pandemic. Two other sections of FDORA related to decentralized clinical trials, novel clinical trial designs and digital health technology in clinical trials, continue the progress on clinical trial modernization. Below, we describe these three provisions of FDORA in more detail.

§ 3605. Public meeting on clinical study flexibilities initiated in response to COVID-19 pandemic

  • Within 180 days from the end of the public health emergency (by Nov. 7, 2023), the FDA must hold a public meeting to discuss FDA recommendations during COVID-19 to mitigate disruption of clinical studies, including as described in the guidance.
  • The FDA must issue a report summarizing the discussion at the public meeting. Topics to be included for discussion at the meeting include, but are not limited to:
    • the frequency with which sponsors availed themselves of the flexibilities in the guidance;
    • characteristics of the sponsors, studies, and patient populations impacted by such recommendations;
    • impact of those flexibilities on patient access to clinical studies, especially underrepresented patient populations; and
    • recommendations for incorporating these flexibilities into new guidance to improve clinical study enrollment and diversity.

§ 3606. Decentralized clinical studies

  • Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance to advance the use of decentralized clinical trials. The guidance must address numerous aspects of decentralized trials, including recommendations related to:
    • collecting data remotely, considering the security and privacy of such options (e.g., digital health technology, telehealth, local providers and labs, and patient experience data);
    • minimizing or reducing burdens on subject enrollment and participation (e.g., digital health technology, telehealth, local providers/labs, home visits, direct engagement with study participants, direct shipping of investigational drug to the study participants, electronic informed consent, and partnerships with community organizations);
    • evaluating the protocol design of decentralized trials and data collected in decentralized trials, including whether evaluations will be different than for non-decentralized trials;
    • using decentralized clinical trials to maximize participant diversity;
    • validating digital technologies and establishing appropriate clinical endpoints for use in decentralized trials;
    • combining centralized and decentralized clinical trial approaches; and
    • oversight of decentralized clinical trial sites, including remote oversight.

§ 3607. Modernizing clinical trials

  • Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance regarding appropriate use of digital health technologies in clinical trials to improve diversity in recruiting and retention of participants and to facilitate novel clinical trial designs; final guidance must be published within 18 months after the close of comment period on the draft guidance.
  • Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance on the use of “seamless, concurrent, and other innovative clinical trial designs” to support development and review of new drugs; final guidance must be published 18 months after the close of comment period on the draft guidance.
  • Directs the FDA to work with foreign regulators to facilitate international harmonization of the regulation and use of decentralized trials, digital health technology, and seamless, concurrent, and other adaptive or innovative clinical trial designs.

The FDA has already begun to implement the FDORA clinical trials provisions with the issuance of the required guidance on decentralized clinical trials in early May, described in more detail in a separate article.14 Given the short timeframes, we expect the other guidances (diversity action plans, digital health technology, modernizing clinical trials) to be forthcoming shortly and for the FDA to implement the remaining provisions, such as public meetings and reports, in a timely manner. The FDORA guidances are likely to build on the agency’s efforts over the last 10 years, including the already existing guidances discussed in this article. You would be well served to familiarize yourself with the current draft guidances and FDA reports and activities to prepare for the future.


  1. Food and Drug Omnibus Reform Act, as included in the Consolidated Appropriations Act of 2023, Pub. Law 117- 328,
  2. Food and Drug Administration Safety and Innovation Act (FDASIA) § 907,
  3. Reporting of Inclusion of Demographic Subgroups in Clinical Trials and Data Analysis in Applications for Drugs, Biologics, and Devices, FDA-2013-N-0745,; Notice of Public Meeting, April 1, 2014, Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, August 2014,
  4. Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Draft Guidance, April 2022, FDA also issued a guidance in November 2020 on diversity, titled Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs
  5. FDORA, supra note 1.
  6. The FD&C Act (section 505(d)) requires a sponsor to demonstrate with “substantial evidence” that a drug is safe and effective, and defines substantial evidence as “evidence consisting of adequate and well-controlled investigations, including clinical investigations[.]” FDA has traditionally required two randomized, controlled clinical trials as substantial evidence, but has recently expanded its view of what may meet the statutory standard. See e.g., Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, Draft Guidance, Dec. 2019,
  7. Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing, March 7, 2012,
  8. 21st Century Cures Act §§ 3021, 3022, Pub. Law 114-255,
  9. PDUFA VI Commitment Letter, (see e.g., sections I.6 and J.4); PDUFA VII Commitment Letter, (see e.g., sections K.6 and L.4).
  10. See, FDA webpage listing clinical trials guidance documents,
  11. FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health Emergency, March 2020, updated Aug 2021,
  12. Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023),
  13. Id.
  14. Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023,

FDA Releases Draft Guidance on Decentralized Clinical Trials

This article was originally published as a guest column in Clinical Leader.

In early May, two weeks prior to the expiration of the COVID-19 Public Health Emergency declaration, FDA released the draft guidance Decentralized Clinical Trials for Drugs, Biological Products, and Devices.1 The timing of this draft guidance is notable as the document builds upon many of the recommendations FDA provided in the March 2020 guidance Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency2 (which we covered back in 2020 for Clinical Leader here) which were intended to help sponsors continue their trials throughout the COVID-19 crisis. During the public health emergency, with many trial participants and personnel in isolation, per local COVID-19 control policies, FDA detailed several approaches sponsors could take to maintain continuity of their clinical trials, such as the use of electronic informed consent, use of digital health technologies to conduct assessments, use of local healthcare providers to administer trial procedures, and the direct shipment of investigational products to trial participants, among other measures. Thus, the May 2023 guidance on decentralized trials marks a continuation of FDA’s thinking on the decentralization of clinical trials.

The draft guidance fulfills Section 3606(a) of the Food and Drug Omnibus Reform Act (FDORA)3 requiring the agency to issue guidance on decentralized clinical trials (DCTs) by Dec. 29, 2023. Authored by all three medical product review centers, as well as the Oncology Center of Excellence, the draft guidance recommends a risk-based approach to the conduct and oversight of decentralized clinical trials.

The draft guidance identifies DCTS as trials wherein some or all trial-related activities occur outside of traditional clinical trial sites. More specifically, DCTs incorporate the use of local healthcare facilities, local healthcare providers (HCPs), and local clinical laboratory facilities; visits to trial participants’ homes; and direct distribution of the investigational product to the trial participant. Trials where some activities are conducted at the traditional trial site while other activities, such as follow-up assessments, are conducted remotely are termed “hybrid” clinical trials by the agency.

As noted, FDA recommends a risk-based approach when considering a decentralized trial design – noting that investigational products that are “simple to administer or use, have well-characterized safety profiles, and do not require complex medical assessments”4 are the most appropriate and well suited for evaluation in DCTs. The FDA cautions sponsors to be mindful of potential differences in data accuracy and consistency between DCT and conventional trials conducted at a physical site. While these variances may not impact the validity of trial results that seek to establish superiority of one treatment over another, they could impact the accuracy of results in a trial that aims to establish non-inferiority. For example, the effectiveness of a drug tested in a DCT may not be identical to the effectiveness of the same drug tested in a traditional trial that employs an active control, as evaluations performed by local healthcare providers in DCTs may be less precise and more variable than those conducted by dedicated trial personnel at site-based trials.

Beyond defining DCTs and identifying the appropriate situations for their use, the draft guidance provides key recommendations on the innovative approaches sponsors can use to decentralize trials and move trials outside of traditional sites. The draft guidance also includes some important considerations on safety and data security that are likely to arise in remote contexts.

Remote Trial Visits

The draft guidance affirms that telehealth visits can be used instead of in-person trial site visits, especially if no in-person interaction is needed. This was an innovation that FDA introduced in the March 2020 Conduct of Clinical Trials guidance, although it should be noted that the need for alternatives to in-person site visits to facilitate enrollment and conduct of clinical trials was recognized by FDA well before the pandemic. For example, a 2015 Federal Register notice sought comment and recommendations on innovative mechanisms to increase clinical trial enrollment, such as the use of telehealth visits.5

In addition to telehealth visits, the draft guidance also provides sponsors with the option to use local HCPs, who are not officially trial personnel. Importantly, the services local HCPs provide should not differ from the services they are qualified to perform in clinical practice. In addition, the activities local HCPs may provide should not require unique or detailed knowledge of the trial protocol or the investigational product.

Should telehealth technologies or local HCPs be used to facilitate decentralized trials, the trial protocol should detail how adverse events will be remotely identified, evaluated, and managed. Additionally, in the interest of trial efficiency and patient experience, sponsors are responsible for training trial personnel on the technology used to conduct a telehealth visit.

Digital Health Technologies

Although digital health technologies (DHTs) are among most common tools used in DCTs, the draft guidance does not focus extensively on this topic as it is well covered in the December 2021 draft guidance Digital Health Technologies for Remote Data Acquisition in Clinical Investigations6 [Editor’s note: Covered by Clinical Leader here.] However, the draft guidance does note that sponsors may permit trial participants to use their own DHTs in trials, as long as the sponsor also provides the same DHTs to other participants, so they are not excluded.

Direct Shipment of Investigational Products

The draft guidance confirms that the direct distribution of the investigational product (IP) to trial participants at their homes or other remote location is acceptable. However, should this method distribution be used, sponsors should describe in the protocol how the physical integrity and stability of the IP will be maintained during shipment. Similarly, the protocol should describe how investigators will track and document the receipt of IP by trial participants, as well as how participants should dispose of unused IPs and how this should be documented. IPs that are considered good candidates for direct shipment include those with long shelf lives and good stability profiles.

The draft guidance also notes that sponsors may also use a central distribution service to ship IP directly to trial participants. The investigator, however, must still control the release of the IP by the distributor, as well as monitor receipt and use by trial participants, as specified in the protocol.

Administration of the Investigational Product

As discussed above, sponsors should consider the nature of the IP when determining whether to administer it outside of traditional trial sites. FDA advises that IPs that involve complex administration procedures, have a high-risk safety profile, or are in early stages of development may require in-person supervision by the investigator at a trial site. Similarly, investigators should also consider the safety profile (e.g., risk of hypersensitivity, abuse potential) in determining the type of local care that participants may need to have access to if an adverse event occurs.

Informed Consent and Institutional Review Board Oversight

While discussed extensively in the March 2020 Conduct of Clinical Trials guidance, the DCT draft guidance also addresses the use of remote informed consent, albeit briefly. Specifically, the draft guidance confirms that investigators may obtain electronic informed consent remotely provided that all regulations under 21 CFR Part 50 are met. FDA also recommends that investigators have a central Institutional Review Board (IRB) to facilitate the review of the protocol and the informed consent documents.

Roles and Responsibilities

FDA notes that sponsors’ responsibilities are the same in DCTs as they are in traditional site-based trials. Due to the potential of multiple sources of data collection, sponsors should ensure their data management plan specifies data origin, data flow, and the methods used for data collection and includes a list of vendors involved in data collection, handling, and management. The draft guidance also recommends sponsors detail all operational aspects of a DCT in a trial protocol, while case report forms should identify when and where data is collected.

FDA recognizes that DCTs add complexity to the investigator’s role in overseeing trial conduct, as some decentralized features necessitate additional training and careful coordination of remote activities. FDA reiterates that local HCPs may perform trial-related procedures at a participant’s home or other local healthcare facility. However, local HCPs need not and should not be listed as sub-investigators on Form FDA 1572. The draft guidance also states that some trial protocols may permit the use of clinical laboratory facilities close to the trial participant, although designated clinical laboratory facilities are preferred to minimize variability.

Safety Monitoring

As with site-based trials, safety monitoring plans should describe how participants are expected to respond to and report adverse events, specifically noting where to seek local medical care if needed. In addition, the draft guidance also notes that trial participants should be able to contact trial personnel to report adverse events and arrange for telehealth visits if necessary. Lastly, the safety monitoring report should also describe the information collected by a digital health tool – detailing how the information will be used and monitored and how personnel or participants should respond to electronic alerts.

Software Considerations

The FDA notes that software can be used for multiple purposes in a DCT, including managing electronic informed consent, capturing and storing reports, managing electronic case forms, scheduling trial visits, and tracking IPs shipped directly to participants. Software programs used to produce and process trial records are subject to 21CFR Part 11 and must ensure data reliability, security, privacy, and confidentiality. Real-time video interactions, however, such as telehealth visits, are considered by FDA as live exchanges of information between trial personnel and trial participants and thus are not considered electronic records and subject to 21 CFR Part 11.

The FDA is accepting public comments on the draft guidance until August 1, 2023. All written comments should be identified with the docket number FDA-2022-D-2870.


  1. FDA, Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023,
  2. FDA, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, Guidance, March 2021,
  3. H.R. 2617; Food and Drug Omnibus Reform Act (FDORA),
  4. Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, Lines 63 – 65.
  5. 80 FR 66543, October 29, 2015,
  6. FDA, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Draft Guidance, December 2021,

EMA-FDA Parallel Scientific Advice: Optimizing Development of Medicines in the Global Age

Thor, S., Vetter, T., Marcal, A., Kweder, S. EMA-FDA Parallel Scientific Advice: Optimizing Development of Medicines in the Global Age. Ther Innov Regul Sci 57, 656–661 (2023).

This article was published in Therapeutic Innovation & Regulatory Science on March 4, 2023. It is reprinted here under a Creative Commons Attribution 4.0 International License and can be downloaded through the button at right.


As medicines development continues towards a globalized approach, both the pharmaceutical industry and regulatory agencies increasingly seek opportunities to proactively engage early in product development. The parallel scientific advice program shared by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) provides a mechanism for experts to concurrently engage in scientific discourse with sponsors on key issues during the development phase of new medicinal products (drugs, biologicals, vaccines, and advanced therapies).


Regulators at both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) support and foster increasingly globalized approaches to medicines development. Covering a broad range of relevant topics in medicines development, both Agencies participate in multilateral fora such as the International Council on Harmonization (ICH), International Coalition of Medicines Regulatory Authorities (ICMRA), and the World Health Organization (WHO) to address topics such as standards setting and policy convergence at the global level. On a smaller scale, the two Agencies lead more than 30 technical working groups or “clusters” where members exchange perspectives and experiences on regulatory science topics.1 The cluster meetings are opportunities for regulatory experts to discuss amongst themselves challenges and difficult applications of regulatory science and policy based on the priorities of the Agencies and are not intended to serve as a forum for advising sponsors. There are situations, however, in which a developer can benefit from scientific advice on a product development program from both Agencies concurrently, and where convergent advice on the same or similar product-based scientific questions could benefit public health and facilitate patient access to needed therapies. To meet this need, EMA and FDA established a sponsor-initiated, product-specific exchange: the parallel scientific advice (PSA) program.2

PSA provides a mechanism for EMA and FDA experts, upon request by the applicant, to concurrently advise sponsors on scientific issues during the development of new medicinal products (drugs, biologicals, vaccines, and advanced therapies). Importantly, as part of the process the two agencies engage with each other to compare perspectives in advance of and during the actual interaction with the sponsor. This voluntary program was launched in 20053 with four goals: increase dialogue between the two agencies and sponsors from the beginning of the lifecycle of a new product; provide a deeper understanding of the bases of regulatory decisions; optimize product development; and avoid unnecessary testing.

To initiate a PSA request, the applicant, herein referred to as ‘sponsor’, emails a request to each Agency.4 The request is expected to be brief and state the rationale for why the PSA would be beneficial, the proposed scientific questions to the Agencies, and desired goals for the meeting. If both Agencies agree to accept the request, the sponsor can move forward with preparing a full meeting package according to EMA’s Scientific Advice Working Party (SAWP) procedure schedule.5 A bilateral meeting between EMA and FDA takes place approximately 35 days after EMA validates the meeting package. After the bilateral meeting, preliminary feedback from each Agency is shared with the sponsor in writing. This could include preliminary responses to the sponsor’s questions or requests for the sponsor to clarify or expand a concept or proposed pathway. At approximately 65 days after validation, a trilateral meeting with the sponsor, EMA, and FDA is held. Written advice from each Agency to the sponsor follows this meeting, from EMA within ten days and within 30 days from FDA.

In 2022, we, scientists overseeing PSA at EMA and FDA, conducted a program review covering the five years from 2017 through 2021. The review included more intensive examination of a sub-cohort of submissions in calendar year 2020 to examine how well timelines were met. This paper shares the results and insights from our review and describes best practices for sponsors considering PSA.


We independently conducted records searches in FDA and EMA files for PSA procedures requested in calendar years 2017 through 2021. The records were then merged and reviewed for accuracy and completeness. The requests were first categorized by whether they were accepted and, if not accepted, the reason. We also stratified the requests by the therapeutic area of each application’s subject product, and whether any accepted requests were later withdrawn by the sponsor. Further, we examined detailed timelines of procedural steps from the seven PSAs accepted during 2020. We selected 2020 for this sub-cohort year because when we began the records review in January 2022, the 2020 calendar year was the most recent year when all procedures had been completed and therefore had all aspects of their timelines fully characterized. For these we noted the dates of each request, acceptance, meeting package validation, and provision of the EMA Final Advice Letter.


The 5-year review identified a total of 37 PSA requests (see Table 1). Of these, 26 (70%) were accepted to participate. Even when requests are accepted, there were times when the sponsor chose not to proceed with submitting a meeting package or formally withdrew the request. This happened four times over the 5-year period, leaving 22 completed PSA procedures, ranging from four to seven per year, as shown in Fig. 1. In no case was a request accepted and later one or both Agencies decided to discontinue the process. We note that the COVID-19 global pandemic was ongoing during the 2020 and 2021 years of this dataset. Though regulatory operations shifted to a nearly entirely virtual environment during that time, this shift did not affect the PSA program as virtual operations were already a necessary component of PSA. Further, the number of accepted requests did not decline during the pandemic years, despite both Agencies needing to shift many resources to address COVID-19 related public health needs.

Table 1, PSA Requests 2017–2021

Total requests37
Accepted requests26 (70%)
Withdrawn/package not submitted4 (15%)
Completed procedures22

Figure 1

PSA requested and accepted decisions by year (2017–2021).

Of the accepted requests, the majority were in the therapeutic area that combines submissions for Gastroenterology, Inborn Errors of Metabolism, Rare Diseases, and Medical Genetics. We combined these into a single category for purposes of this report because during the period of our cohort FDA shifted its organizational structure and categorization of submissions. As shown in Fig. 2, Oncology, Anti-infectives, Cardiology/Nephrology, and Neurology were also areas with multiple PSA requests. Other therapeutic areas included accepted requests in Ophthalmology, Dermatology, Cardio-metabolic diseases, Pulmonology, Rheumatology, Advanced Therapies, and Hematology.

Figure 2

Accepted PSA requests (N = 26) by product category 2017–2021.

As previously stated, to be accepted for PSA both Agencies must agree to the request. Over the five years of our review cohort, eleven requests were not accepted (see Fig. 3). Four requests were not accepted because they were made very early in development, such as when the product had not been the subject of a pre-Investigational New Drug (pre-IND) application or IND application at FDA. Another four requests were not accepted because the request had a device component, which would not have been within EMA’s advice remit at the time (though this remit has since changed, and the EMA no longer discourages PSA submissions for products containing a device component). The other three denials involved circumstances where one or both agencies felt that PSA was not a good option for other more varied or nuanced reasons.

Figure 3

PSA requests: reason for not accepted (N = 11*) *At the time of these requests, EMA did not accept PSAs with a medical device component.

Timeline data from the 2020 PSA cohort is displayed in Fig. 4. There was an average of 13 calendar days between the PSA request and the Agencies’ acceptance. Then the PSAs spent an average of 67 days in the phase of meeting package preparation and validation. Once the meeting package is validated, the Agencies begin review. During this review time multiple milestone events take place, specifically a bilateral meeting of FDA and EMA to discuss their respective reviews, followed by issuance of draft comments and further questions to the sponsor and then a trilateral meeting of the Agencies with the sponsor. A final advice letter (FAL) from EMA is issued in follow-up to the trilateral within ten days, and FDA’s meeting minutes are provided within 30 days. For six of the seven PSAs in the 2020 cohort, the average Agency review time was 79 days. There was one outlying PSA with a review time of 105 days. This PSA occurred over the period when the EMA SAWP has its annual August recess. As this is a predictable outlier that will always increase review time duration by one month, we did not include that PSA in the average for Agency review time. When we include this outlier, the average time spent under Agency review for the seven PSAs in the 2020 cohort is 83 days. Subsequent to our analysis of the 2020 cohort, we revised and published a timeline that describes each phase of PSA (Table 2).

Figure 4

Selected Milestones for PSA Procedures in 2020. *PSA occurred over EMA SAWP August recess; not included in average. **Sponsor requested a pre-submission meeting with EMA.

Table 2, PSA Timeline


Adding Value

For more than 15 years, PSA has been an opportunity for sponsors who are developing medicines across regulatory regions. It allows a sponsor to submit the same background and supporting material to both FDA and EMA and seek their respective advice simultaneously on the same issues. The Agencies do not commit to harmonizing advice, as each has its own regulatory frameworks. However, during a bilateral meeting they can discuss the sponsor’s questions and focus on sharing information and their perspectives in order to identify areas of convergence and divergence. In sharing their respective preliminary feedback with the sponsor in writing, including requests for further clarification and discussion, the sponsor is provided an opportunity to plan for more in-depth discussion during the subsequent trilateral meeting.

Our observation is that bringing EMA, FDA, and sponsor perspectives to a PSA trilateral setting provides a rich opportunity for all. It is common for PSA trilateral discussions to result in convergence in advice on approaches to a product’s development even though full harmonization is not always possible. And in cases of divergence, the trilateral meeting is an opportunity for the sponsor to offer proposals for how to meet both regulators’ requirements without having to explain each regulator’s perspective to the other. Even when Agencies maintain differing perspectives, an important benefit of PSA is that all parties in the process understand the reason(s) for the divergence.

Increasing Awareness and Understanding

Typically, sponsors pursue a more traditional model of seeking advice from each Agency independently, often in series, which requires expending resources on preparing for two separate meetings where the scientific questions are often nearly identical and the burden of having to articulate one Agency’s views to the other is carried by the sponsor. When discussing PSA at a 2017 public workshop on expedited programs and regulatory harmonization, participants noted that the PSA process is not well understood by sponsors, especially the expected timelines of PSA procedures.6 In our observation neither our Agencies nor industry have promoted it widely and little has been written about this process. We have sought to increase awareness and understanding through public presentations,7 collaborating with sponsors on educational efforts,8 the publication of a new timetable,9 and this review.

Data from our 5-year review show that uptake of the PSA pathway has been limited- just four to seven procedures annually over the last five years. As described in the General Principles for PSA,2 PSA procedures are designed to generally correspond with the EMA’s SAWP timeline3 and the FDA Type B meeting10 timeline. Results from our 2020 cohort were consistent with these timelines. The cohort showed an average acceptance turnaround time of PSA requests at 13 calendar days; FDA Type B meeting requests are allowed up to 21 days for a response. The average review time for the cohort was 79 days, which is consistent with previously published SAWP PSA timetables predicting 75 days from the validation of the PSA meeting package to receipt of final advice.

The time from acceptance of the PSA to the validation of the meeting package varied from 47 to 93 days, with a mean of 67 days. Variation in time spent in this phase is largely within the sponsor’s control. For example, this phase may be quite short if the sponsor quickly submits a robust meeting package after their PSA request is accepted. It may be longer if the sponsor submits a deficient meeting package or requests a pre-submission meeting with EMA. The latter was the case with Product 5, shown in Fig. 4, which spent 93 days in the validation phase. Also, in some cases the sponsor delays the submission of their meeting package, for example when they are awaiting additional data.

Looking Ahead

We have been overseeing, coordinating, and participating in the PSA program, some of us for more than a decade. Although not easy to quantify, our experience has been that once underway the outcome of the process is remarkably productive and positive for all parties. The interactions between the two regulators are critical and serve as a form of peer discussion, an opportunity to expand thinking and explore ways to address common challenges in drug development together, especially in areas where there is little experience or thorny scientific issues at hand. Products discussed under PSA are often products with no simple path forward. Therefore, EMA and FDA exploring alternative or innovative approaches together adds great value to the advice ultimately rendered to the sponsor. Such potential for value underpinned the launch of an FDA-EMA PSA pilot for complex generic products in 2021, with the hope that PSA will be a tool for optimizing global development of products for which traditional bioequivalence methods are challenging.11

Based on our experience and the analyses presented here, we suggest a few strategies to sponsors who are considering PSA. First, consider the timing of your request. It is strongly recommended to have begun the pre-IND or IND process at FDA on your product before requesting PSA, so that there is a baseline for reference. With the foundations and background of your product’s development plan already understood, your PSA questions can be focused on the specifics of global development that merit consideration for convergence. If timing is important to you, we further suggest that you factor into your planning the August recess of the SAWP and approximately two weeks for the Agencies’ review of your PSA request.

Second, research existing guidance on the topic to see where you can expect there is alignment across the two Agencies and where there is not. Some areas where PSA may be most appropriate are for innovative products or new scientific or regulatory concepts that have not been the subject of published guidance. Examples include advanced therapies, biosimilars, or use of novel/surrogate endpoints. Innovative manufacturing and non-clinical concepts and questions are also appropriate.

Third, consider the public health benefit of your product. PSA requires extra investment of resources from both Agencies, so the program’s focus is on products that address unmet medical needs, rare diseases, pediatric populations, or other areas of importance to patients and public health. In fact, the majority of accepted requests during the cohort period have been for rare disease therapies, pediatric populations, or advanced therapy medicinal products. Be sure to explain your product’s potential public health benefits in your request letter.

Finally, make the best possible use of the trilateral meeting. It is key to prioritize and address the issues raised in the preliminary feedback from FDA and EMA in a well-structured presentation enabling thorough and efficient discussion. This 90-min meeting is your avenue for probing both Agencies on opportunities for convergence. Hence, make sure you focus on the most critical scientific questions, and prepare proposals and rationales that address the issues noted in the preliminary feedback you received from each Agency.


PSA is a longstanding EMA and FDA collaboration that continues to have strong support within both Agencies. The PSA program offers an opportunity for companies to simultaneously consult international regulators for advice on the development of important medical products, with the intent of optimizing development and deepening their understanding of regulatory decision making. Our experience has shown that the PSA program can provide timely and insightful advice on the most challenging aspects of global development. Sponsors wishing to seek PSA should consult the General Principles for Parallel Scientific Advice2 for further guidance.


  1. Tania Teixeira, Sandra L. Kweder, and Agnes Saint-Raymond. Are the European Medicines Agency, US Food and Drug Administration, and Other International Regulators Talking to Each Other?
  3. PSA Pilot Program Launch 2005.
  4. Email addresses: and
  5. EMA Scientific Advice Working Party (SAWP).
  6. Elizabeth Richardson, Gregory Daniel, David R. Joy, Sandra L. Kweder, Diane M. Maloney, Miranda J. Raggio, and Jonathan P. Jarow. Regional Approaches to Expedited Drug Development and Review: Can Regulatory Harmonization Improve Outcomes?
  7. FDA Small Business and Industry Alliance Webinar: FDA-EMA Parallel Scientific Advice Program. March 2022.
  8. Parallel Scientific Advice: Increasing International Dialogue Early in the Product Lifecycle. Drug Information Association Global Annual Meeting. May 2021.
  9. PSA Timetable.
  10. Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants. May 2009.
  11. FDA-EMA PSA Pilot Complex Generics.

Authors and Affiliations

  1. Shannon Thor, Europe Office, US Food and Drug Administration, Silver Spring, Maryland, USA
  2. Thorsten Vetter, Scientific Advice Office, European Medicines Agency, Amsterdam, The Netherlands
  3. Anabela Marcal, International Affairs Department, European Medicines Agency, Amsterdam, The Netherlands
  4. Sandra Kweder, Office of Global Policy and Strategy, US Food and Drug Administration, Silver Spring, Maryland, USA (Sandra Kweder’s contributions were during the time of FDA employment.)

FDA Releases Final Guidance on RWD/RWE Submissions for Drugs and Biologics

This article was originally published as a guest column in Clinical Leader.

Over the past month, the FDA has continued to build out its real-world evidence program with the release of the final guidance, Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products. The brief process-focused guidance describes the recommended approach sponsors should use to identify if and how real-world data (RWD) and real-world evidence (RWE) are incorporated in their regulatory submissions. The FDA notes that this guidance specifically applies to investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) that contain RWD and RWE. The guidance does not, however, address or comment on review standards for submissions containing RWD or RWE.

Focus on Product Safety and Effectiveness

In this guidance, the FDA signals that its primary focus regarding RWD and RWE is on their use to support product effectiveness and safety. Particularly, the FDA advises that sponsors only flag a submission’s inclusion of RWD and RWE if they are intended to support a regulatory decision on a product’s safety and efficacy. As a rule of thumb, the FDA suggests “sponsors and applicants not identify submissions that contain RWD/RWE if those data are not intended to support product labeling.”1 Examples of submission types that do not need to be flagged for incorporating RWD or RWE include those that use RWD to generate hypotheses or studies that include RWD in exploratory models or simulations, studies that use RWD to validate an endpoint, and studies that use RWE to qualify a Drug Development Tool (DDT).

These guiderails will likely have implications for the type of public data that both sponsors and stakeholders will have access to on the use and regulatory acceptance of RWE. The FDA notes that the internal tracking of these submissions is intended to inform the “FDA’s understanding of the scope and use of RWD and RWE submitted to support regulatory decisions…”2 However, this focus likely limits the scope of the FDA’s public reporting of RWE submissions. Under PDUFA VII, the FDA has committed to reporting aggregate and anonymized information on RWE submissions to CDER and CBER starting no later than June 2024. Thus, sponsors and stakeholders can expect the future report to focus only on RWE submissions supporting product labeling rather than other uses.

Key Data Points for Tracking

The sample submission checklist included in the appendix titled Sample Presentation of Information to be Included with Submissions Containing RWD/RWE provides further insight into the data points the FDA is looking to collect on RWD and RWE use. In addition to the product name and targeted disease or medical condition, the FDA suggests sponsors identify their purpose for using RWD or RWE as part of the submission, the study design using RWD to generate RWE, and RWD sources used to generate RWE. Per the sample list of purposes for RWD and RWE, the FDA anticipates the most common uses of RWD and RWE will be:

  • to support safety and/or effectiveness for a product not previously approved by the FDA;
  • to support labeling changes for an approved product; and
  • to support or satisfy a postmarketing requirement or postmarketing commitment (PMR/PMC).

In both the body and appendix of the guidance, the FDA also lists the anticipated study designs likely to involve RWD to support a regulatory approval. The list broadly aligns with the current clinical trial landscape and includes randomized controlled trials with pragmatic elements, single-arm trials using RWD in an external control arm, and non-interventional or observational studies. The FDA is also interested in collecting data on the types of RWD sources sponsors use to generate RWE. The FDA’s sample list of RWD sources, which is not intended to be exhaustive, includes electronic health records data, medical claims data, product or disease registry data, and data collected from digital health technologies in non-research settings.

As noted, the submission checklist included in the appendix is helpful in providing a glimpse into the FDA’s current understanding of the RWE landscape and a preview of the data points the agency is looking to track on RWD and RWE use for regulatory purposes. Just as important, however, are the data points that the FDA did not include in the submission checklist. Notably, the FDA does not request information on the data standard sponsors used to structure large data sets. To date, the agency has remained silent on preferred common data standards. However, per the FDA’s 2021 draft guidance titled Data Standards for Drug and Biological Product Submissions Containing Real-World Data,3 “FDA plans to issue further guidance and/or to update the Catalog with standards for study data that are derived from RWD sources.”4

The guidance was authored by the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER), in consultation with the Center for Biologics Evaluation and Research (CBER) and the Oncology Center of Excellence (OCE). Notably, the Center for Devices and Radiological Health (CDRH) is not listed as a co-author, signaling that the FDA may not be taking an “inter-center” approach to RWE regulatory policy. This is further underscored by the fact that the 2017 guidance on RWE use for medical device applications, Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices,5 was authored by only CDRH and CBER, not CDER. As of now, the FDA has not provided recommendations on how to flag device submissions as using or containing RWD or RWE.


  1. FDA, Guidance for Industry, “Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products,” September 2022,
  2. Ibid.
  4. Ibid.

4 Pitfalls to Avoid With RWE for Regulatory Submissions

This article was originally published as a guest column in Clinical Leader.

The FDA’s release of four draft guidances on real-world evidence (RWE) at the tail end of 2021 is a productive step toward implementing FDA’s RWE program. The draft guidances are expansive, providing recommendations to sponsors seeking to use real-world data (RWD) derived from medical claims data, electronic health records (EHRs), and registries to support regulatory submissions. However, despite the scope of these documents, a survey of comments letters submitted in response to the draft guidances reveals a widespread need, specifically among drug developers, to understand how the agency will implement these guidances in practice. In an attempt to solicit concrete examples, several sponsors requested the agency develop an online dashboard that publishes all of the agency’s decisions, both positive and negative, on regulatory submissions that incorporate RWE.

Despite the lack of a central catalog of all RWE-related regulatory decisions, there are a handful of product approvals and FDA reviews that highlight both best practices and common pitfalls sponsors face when incorporating RWE in regulatory submissions. These decisions show that the use of RWE to support regulatory decision-making is often challenged by both methodological and process issues. In terms of process, the primary mistake made by sponsors is failing to share a prespecified protocol and statistical analysis plan (SAP) with the agency prior to submission. From a methodological perspective, unsuccessful RWE submissions are often plagued by missing data, small patient populations, and a lack of objective endpoints. Approvals based on or supported by RWE, such as Ibrance (palbociclib) for male breast cancer and Prograf (tacrolimus) to prevent organ rejection post lung transplant, demonstrate how to successfully address the myriad challenges of working with RWD.

1. Failing to Share a Prespecified Protocol and SAP

As noted, the most common mistake sponsors make when seeking to leverage observational studies to support or demonstrate a product’s safety and efficacy is failing to share a prespecified protocol and SAP with the agency. The FDA emphasizes the importance of up-front transparency to guard against this risk, noting in its real-world evidence framework that multiple analyses in electronic data sets can be done quickly and inexpensively, “making it possible to conduct numerous retrospective studies until the desired result is obtained….”1 The four recent guidances also recognize this as a potential risk to undermining study validity and recommend sponsors:

“Provide draft versions of their proposed protocol and statistical analysis plan (SAP) for Agency review and comment, prior to finalizing these documents and before conducting the study analyses.”2

2. Missing Data

One of the most common methodological deficiencies identified in FDA reviews of RWE studies is missing data. Unlike clinical trials, wherein patient visits and data collection are prespecified, “real-world” patient visits are often irregular and data collection uneven, leading to spotty and inconsistent electronic health record (EHR) data. In turn, incomplete EHR data can make it difficult to define baseline characteristics for observational cohorts, obfuscating efforts to establish comparability with an active trial cohort.  This problem has hobbled several attempts to use RWE studies to support oncology product approvals. In these cases, the sponsor was unable to provide complete documentation on essential baseline characteristics such as previous treatment regimens, tumor stage, and Eastern Cooperative Oncology Group (ECOG) scores. FDA reviewers noted that the failure to capture previous treatment regimens introduces confounding bias, while missing dates, such as the date of diagnosis or start of first treatment, can introduce bias into the study in favor of the investigational product.

In successful RWE applications, the majority of these important clinical details are well documented. For example, FDA notes in the supplemental review of palbociclib for male breast cancer that “In this study, real world tumor response data was generally available for several lines of therapy.”3 The reviewer also notes that real-world data sets were complete and included birth date, metastatic sites, and first metastatic treatment. Unstructured source data in the form of clinician assessments and radiology reports were also included in the submission.4

3. Small Patient Cohorts

Incomplete EHR data has significant downstream effects on a sponsor’s ability to use RWE for regulatory purposes. In an attempt to achieve comparability with active trial cohorts, sponsors often have to disqualify patients with incomplete data elements from analyses, further whittling down a data set that may already be pretty small.  For oncology and rare disease applications, small patient populations are already a common issue, which the use of RWE can compound. This has hindered several attempts to use RWE to support approval. Even in successful RWE applications, like palbociclib, the reviewer still called out the small sample size as a key deficiency. 

To address the issue of small patient populations, FDA has in recent guidance identified both data linkage and the combining of data as possible solutions. However, the guidance recognizes that these methods also introduce a new set of methodological problems, notably data heterogeneity. In the draft guidance Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products (September 2021), FDA states:

“For studies that require combining data from multiple data sources or study sites, FDA recommends demonstrating whether and how data from different sources can be obtained and integrated with acceptable quality, given the potential for heterogeneity in population characteristics, clinical practices, and coding across data sources.”5

In addition to undermining attempts to combine two different data sets, differences in population characteristics, clinical practice, and coding have derailed efforts to use observational cohorts to define standard clinical practice in the context of superiority trials. Again, many attempts to use RWE for oncology indications have failed due to differences in treatment locations and treatment classifications which prevented sponsors from being able to draw direct comparisons between the investigational product and the standard of care.

4. Lack of Objective Endpoints

A third common roadblock to the acceptance of RWE studies for regulatory purposes is the difficulty in uniformly capturing clinical outcomes in EHR or claims data. In recent guidance, FDA emphasized the enormous impact that variability in physician practice, specifically in regard to diagnoses and coding, have on capturing clinical outcomes. To address this risk, FDA recommends sponsors use RWD sources to capture outcomes with more objective “well-defined diagnostic criteria,” such as death, stroke, or myocardial infarction.

Using RWE for oncology indications is particularly tricky as many commonly used oncology endpoints are subjective and time-bound. Tumor response rates and progression free survival (PFS), for example, are inherently subjective and rely on visual assessments of radiographic images, often generating wide variability. These outcomes are also difficult to validate, as most EHR records do not incorporate the radiographic image. Meanwhile, time to treatment discontinuation (TTD) and overall survival (OS) is particularly subject to confounding bias due to treatments beyond disease progression. As noted, FDA’s answer to these issues is to encourage sponsors to use RWD for conditions or diseases with straightforward and objective outcomes. It is telling, then, that the only drug to have received approval based on an observational study is tacrolimus for lung transplant recipients, wherein the primary endpoint was post-transplant survival.

Considering the methodological issues sponsors face in working with RWD, FDA’s cautious stepwise approach to implementing the RWE program is understandable, but it is frustrating to some. As drug developers and the agency continue to wrestle with these methodological issues, we can expect that successful RWE regulatory submissions will continue to be for drugs with well-established safety and efficacy profiles.   


  1. FDA, Framework for FDA’s Real World Evidence Program, December 2018, p22,
  2. FDA, Draft Guidance for Industry, “Considerations for the Use  of Real-World Data and Real World Evidence to Support Regulatory Decision-Making for Drug and Biological Products,” December 2021,
  3. Maria T. Nguyen, Kevin Wright, Barbara Fuller, and Lashawn Griffiths, sNDA 207103-S-008, Multi-Discipline Review, 5 March 2019, 50,
  4. Ibid.
  5. Food and Drug Administration, “Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products, Draft Guidance for Industry,” September 2021,

Update on Ongoing User Fee Negotiations

Greenleaf Regulatory Landscape Series

The Food and Drug Administration (FDA or the Agency) user fee programs help to provide funding for the Agency to achieve its mission of protecting the public health and providing safe and effective medical products to patients in the United States.1 The user fee programs provide the FDA with financial support to meet specified performance goals and commitments related to medical product submissions. These specific performance goals and commitments are negotiated and agreed upon between the FDA and industry in the years leading up to the reauthorizations and must be sent to Congress for review and approval.

All medical product user fees are renegotiated every five years. As the Prescription Drug User Fee Amendments (PDUFA VI), the Biosimilar User Fee Amendments (BsUFA II), and the Medical Device User Fee Amendments (MDUFA IV) are also set to expire on September 30, 2022, it is expected that all three user fee program extensions will be part of the same legislative package.2,3 The next set of authorizations for these programs will cover Fiscal Years 2023 to 2027.

Below is a summary of the current status of the PDUFA, BsUFA, and MDUFA negotiations as well as a description of the key commitments being discussed between the FDA and industry.


PDUFA VII will build upon the progress of past programs by providing the FDA with the resources and tools it needs to keep pace with advances in drug development. Considering recent scientific breakthroughs in cell and gene therapy and the bolus of investigational new drug (IND) applications for advanced biological therapies received by the Agency, PDUFA VII seeks to provide the Center for Biologics Evaluation and Research (CBER) with the funding and authority to hire additional staff to meet this demand. With negotiations being held virtually against the backdrop of the COVID-19 pandemic, PDUFA VII also aims to formalize some of the lessons learned from the pandemic, including guidance and workshops on the use of alternative tools to assess manufacturing facilities and additional resources to support the broader use of digital health tools (DHTs). The commitment letter,4 which was made public in late August 2021, includes the following commitments: 

Strengthen Scientific Dialogue. Recognizing the need for further dialogue between the Agency and sponsors, the FDA will formalize the INTERACT meeting framework as well as establish a similar meeting type for the Center for Drug Evaluation and Research (CDER). Both industry and the FDA also discussed the possibility of sharing metrics related to all PDUFA meeting types and associated interactions.

Promote Innovation. To shorten review timelines for certain approved therapies and support efficacy endpoint development for rare diseases, PDUFA VII will establish the Split Real Time Application Review (STAR), modeled after CDER’s Real Time Oncology Review (RTOR).5

Support Advanced Biological Therapies. As noted, CBER will likely be provided dedicated resources to ensure the timely review of all applications for innovative biological therapies. Negotiations also focused on including the patient voice in gene therapy development programs as well as the potential for a workshop on how sponsors could leverage prior knowledge to accelerate gene therapy development. The FDA and industry also discussed a proposal on potential guidance dedicated to clarifying evidentiary standards for the RMAT program.6

Modernize Evidence Generation and Drug Development Tools. To advance the use of real-world evidence (RWE), both industry and the Agency discussed the establishment of a pilot program to develop new methods for using real-world data (RWD) in regulatory decision-making, including in the review of applications.7 Both industry and the FDA expressed an interest in continuing the Model Informed Drug Development (MIDD) paired meeting program. Issuance of guidance related to Complex Innovative Designs (CID) is also included in the commitment letter.8

Advance IT Infrastructure. PDUFA VII will also modernize data and information technology (IT) capacity and capabilities, including the adoption of cloud-based technologies as described in the FDA’s Technology Modernization Action Plan as well as technology convergence across the review centers more broadly.9 Both industry and the FDA also discussed potential programs and initiatives that could inform the evaluation of DHT-generated data.10

Next Steps

The initial draft of the PDUFA commitment letter has been published and is currently open to comment.11 The letter will also be reviewed and discussed at a public meeting on September 28, 2021.

PDUFA VII Negotiation Process


With negotiations recently completed on the heels of the PDUFA VII negotiations, BSUFA III will likely include several commitments that were agreed to in PDUFA VII, such as the development of guidance on alternative tools to assess manufacturing facilities, the dedication of resources to modernize the FDA’s data and information technology capabilities, and resources to enhance hiring and retention. Additional focus areas from the BSUFA III negotiations are outlined below:

Greater Collaboration Between Sponsors and the FDA. To improve collaboration between the Agency and sponsors, the commitment letter will likely include a new Biosimilar Biological Product Development (BPD) meeting type in which the Agency can provide focused targeted feedback. Modifications to the timelines and processes for Type 4 meetings are also likely.12

Regulatory Science Program. To facilitate more efficient biosimilar and interchangeable product development, as well as enhance regulatory decision-making, both the FDA and industry appeared to have agreed to funding a BsUFA Regulatory Science Program, modeled on the successful GDUFA Regulatory Science Program.13

Expedited Application Review. During negotiations, industry and the FDA discussed best practices for application review and opportunities for implementing those best practices into FDA documents and procedures.14

Next Steps

The BsUFA commitment letter is currently being reviewed by the Department of Health and Human Services (HHS), the Office of Personnel Management, and the Biden Administration. The BsUFA letter will also be open to public comment and discussed in a public meeting, likely to be held in mid-fall 2021, before being sent to Capitol Hill. 

BsUFA III Negotiation Process


The MDUFA V negotiations have also been shaped by the experience of the FDA, industry, and other stakeholder groups during the COVID-19 pandemic. Both the FDA and industry want to keep elements of the regulatory flexibility that was provided during the pandemic as well as the increased amount of interaction between sponsors and the Agency. Additionally, for MDUFA V, both groups want to carry over many of the commitments and goals that were set during MDUFA IV. This approach aims to help maintain the status quo and ensure stability and continuity for the premarket review program in light of the many adjustments that the Agency had to make to manage the additional workload brought on by the COVID-19 pandemic. This approach will also provide additional time to achieve some of the commitments outlined in MDUFA IV that have not yet been met.15

Several proposals made by each group during the MDUFA V negotiations are still under discussion. These proposals include the following:

Hiring Targets and Vacancies. Throughout the negotiations there has been significant discussion regarding the number of vacancies for full-time equivalent (FTE) staff positions tied to user fees and the salaries for these positions. As part of MDUFA V, industry has proposed that annual specific numerical hiring targets be set in order to increase the formality of these goals, including increased transparency and prioritization by the Agency.16

Review of MDUFA IV One-Time Costs. Industry has proposed a review of funding for one-time costs from MDUFA IV including renewing funding for certain programs but not others. More specifically, industry would like to continue funding for “initiatives for patient engagement, recruitment, retention, and the independent assessment” while not renewing as part of MDUFA V funding “the investment to stand up time reporting” or “the IT investment to support digital health.” Other programs would require further discussion in order to be extended with MDUFA V funding, including “IT enhancements for premarket review work; real-world evidence; standards conformity assessment; and third party review.” In addition, industry has proposed to reinstate 5th year offset fees as the carryover balance has grown to a significant level.17

Device Safety. The FDA has presented a proposal to enhance its capabilities related to postmarket surveillance to allow the Agency “to more accurately and precisely identify the scope of potential concerns, to more efficiently resolve device performance and patient safety issues, and to provide timely and clear communications with patients and healthcare providers.”18 Although industry supports these enhanced capabilities, they noted during the negotiations that MDUFA funding has statutorily been limited to only premarket activities, and this significant change for industry-based funding would require statutory changes.

The Total Product Life Cycle Advisory Program (TAP). The FDA has presented the TAP program as a new model for frequent and rapid FDA interaction with sponsors that would also provide valuable feedback from external stakeholders such as payers and providers. The FDA described the program as including the hiring of new premarket review staff with different levels of expertise as well as inviting external stakeholder groups to participate in the process. The FDA also explained that the program aims to provide a more iterative engagement process with sponsors that could lead to higher quality submissions and fewer review cycles. Industry has voiced serious concern that many elements of the TAP program as currently outlined, such as convening private payers, seem to go beyond the scope of MDUFA and could require statutory changes. Industry is also concerned that this model could lead to more complex reviews and thereby increased program costs. Lastly, industry noted that there are already several FDA premarket programs that provide sponsors with increased engagement with the FDA as well as opportunities to discuss coverage with payers.19

Next Steps

The FDA and industry will continue to meet throughout the coming year to develop an agreed-upon commitment letter to present to Congress. All stakeholder groups are encouraged to participate in the ongoing public negotiations. The most recent FDA-industry meeting was scheduled for May 19, 2021, but meeting minutes have not yet been published.20 Public records also show that several additional stakeholder consultation meetings were scheduled through the end of August.21

MDUFA V Negotiation Process22

1. Food and Drug Administration Website, FDA User Fee Programs,

2. Although not discussed in this memo, the Generic Drug User Fee Act (GDUFA) has the same end date and will likely be a part of the same legislative package as PDUFA, BsUFA, and MDUFA.

3. Derek Gingery, “PDUFA VII Negotiations Completed, Commitment Letter Ratification Ongoing,” Pink Sheet, 22 March 2021,

4. FDA, PDUFA VII Commitment Letter, August 2021,

5. PDUFA Reauthorization Meeting Summary, FDA and Industry Pre-Market Subgroup, 27 January 2021,

6. PDUFA Reauthorization Meeting Summary, FDA and Industry CBER Breakout Subgroup, 10 November 2021, 

7. PDUFA Reauthorization Meeting Summary, FDA and Industry Pre-Market Subgroup, 21 January 2021,

8. PDUFA Reauthorization Meeting Summary, FDA and Industry Negotiation Regulatory Decision Tools Subgroup, 1 December 2021,

9. PDUFA Reauthorization Meeting Summary, FDA and Industry Digital Health and Informatics, 27 January 2021,

10. PDUFA Reauthorization Meeting Summary, FDA and Industry Digital Health and Informatics, 16 December 2021,

11. FDA, PDUFA VII Commitment Letter, August 2021,

12. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 27 April 2021,

13. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 13 April 2021,

14. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 20 April 2021,

15. Meeting Minutes, FDA–Industry MDUFA V Reauthorization Meeting, 28 April 2021,

16. Ibid.

17. Ibid.

18. Ibid.

19. Ibid.

20. Ibid.

21. FDA Webpage, Stakeholder Consultation Meetings – Medical Device User Fee Amendments 2023 (MDUFA V),

22. FDA Webpage, Medical Device User Fee Amendments 2023 (MDUFA V),

11 records
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