Last week, the U.S. Food & Drug Administration (“FDA” or the “Agency”) issued a second discussion paper on the use of artificial intelligence (“AI”) and machine learning (“ML”) with respect to drug and biological products, this time focusing on the use of AI/ML in the drug and biologic development process, “Using Artificial Intelligence & Machine Learning in the Development of Drug & Biological Products” (“Second Discussion Paper”).[1] The Second Discussion Paper was issued by the Center for Drug Evaluation and Research (“CDER”), Center for Biologics Evaluation and Research (“CBER”), and Center for Devices and Radiological Health (“CDRH”), and from a scope perspective, the Second Discussion Paper discusses the use of AI/ML in drug and biologic development, as well as devices intended to be used in combination with drugs or biologics (including, but not limited to, combination products, companion devices, and complementary devices).

In the Second Discussion Paper and associated press release, FDA recognizes the significance of AI/ML in drug[2] development, citing the more than 100 drug and biological product applications—submitted in 2021 alone—that included AI/ML components, and the areas of drug development where AI/ML efforts are already active, including clinical trial design, use of digital health technologies (“DHTs”), and real-world data (“RWD”) analytics. The Second Discussion Paper does not endorse any specific approaches for the use of AI/ML in drug development, but rather seeks feedback from stakeholders that can help inform the Agency’s future regulatory activities.

This client alert provides a high-level overview of the Second Discussion Paper, as well as areas for potential engagement with the Agency on the use of AI/ML in drug development. Comments on the Second Discussion Paper must be submitted to FDA by August 9, 2023.

Current and Potential Uses of AI/ML in Drug Development

In the Second Discussion Paper, FDA highlights the many ways AI/ML is currently or could potentially be used in the drug development process, including:

  • Drug Discovery: FDA notes that early drug discovery is one of the areas in which sponsors have significant interest in utilizing AI/ML. In particular, FDA discusses the ways in which AI/ML has or can be used in the drug identification, selection, and prioritization process, as well as in the compound screening and design process.
  • Nonclinical Research: FDA discusses the ways in which AI/ML could be leveraged to support nonclinical research. FDA notes, for example, that a recurrent neural network, an ML algorithm, may be used to complement traditional pharmacokinetic / pharmacodynamic models in areas of highly complex data analysis.
  • Clinical Research: FDA observes that one of the “most significant applications of AI/ML” is in efforts to streamline and advance clinical research. For instance, FDA discusses AI/ML’s ability to analyze vast amounts of data and the potential to inform the design and efficiency of non-traditional trials, such as decentralized clinical trials. FDA specifically notes AI/ML’s use in a number of areas related to the conduct of clinical research, including recruitment, dose/dosing regimen optimization, adherence, retention, and site selection.
  • Clinical Trial Data Collection, Management, and Analysis, and Clinical Endpoint Assessment: FDA discusses the ways in which AI/ML could be used to collect, manage, and analyze clinical trial data, including the potential role of DHTs to enable the use of AI/ML in clinical trials, the use of AI/ML to enhance data integration and perform data quality assessments, and the use of AI/ML to analyze complex RWD or to build digital twins of patients to analyze how a patient may have progressed on a placebo versus an investigational treatment. FDA also notes the potential use of AI/ML to detect a possible safety signal, or to assess outcomes captured from diverse sources (e.g., DHTs, social media) during a clinical trial.
  • Postmarketing Safety Surveillance: FDA notes the ways in which post-approval pharmacovigilance can be supported by AI/ML, for instance by case processing (e.g., detecting information from source documents to help identify adverse events for individual case safety report (“ICSR”) submission), case evaluation (e.g., assessing the possibility of a causal relationship between the drug and the adverse event), and case submission (e.g., automating reporting rules for submission of ICSRs).
  • Advanced Pharmaceutical Manufacturing: As noted above, CDER previously issued a discussion paper in March 2023 focused on AI/ML in drug manufacturing. Now, in the Second Discussion Paper, FDA elaborates on the ways in which advanced analytics leveraging AI/ML has already been deployed or has potential to support pharmaceutical manufacturing efforts, including enhancing process controls, increasing equipment reliability, monitoring early warnings that a manufacturing process is not in a state of control, detecting recurring problems, and preventing batch losses. FDA specifically notes the potential for AI/ML, in concert with other advanced manufacturing technologies (such as process analytical technology (“PAT”) and continuous manufacturing) to enhance and modernize pharmaceutical manufacturing, and alleviate supply chain and shortage issues. FDA identifies four specific areas in which AI/ML could be applied throughout the entire product manufacturing lifecycle: (1) optimization of process design (e.g., use of digital twins in process design optimization); (2) advanced process control implementation; (3) smart monitoring and maintenance; and (4) trending activities (such as trending of deviations, root causes, and CAPA effectiveness).

Considerations for the Use of AI/ML in Drug Development and Opportunities for Engagement with FDA

FDA acknowledges the potential for AI/ML to accelerate the drug development process and make clinical trials safer and more efficient. The Second Discussion Paper also acknowledges the need for the Agency to assess whether the use of AI/ML in these contexts introduces unique risks and harms, including the potential for limited explainability due to the complexity or proprietary nature of an AI/ML system, questions about reliability, and the potential for bias.

Accordingly, FDA notes a focus on “developing standards for trustworthy AI that address specific characteristics in areas such as explainability, reliability, privacy, safety, security, and bias mitigation.” To help address these issues, FDA intends to consider the applicability of certain overarching standards and practices for the general application of AI/ML, and to seek feedback from stakeholders to help identify specific good practices with respect to AI/ML in the context of drug development.

Overarching Standards and Practices for the Use of AI/ML

FDA intends to explore the potential utility and applicability of overarching standards and practices for the use of AI/ML that are not specific to the drug development context. These include AI/ML principles outlined in federal executive orders, the AI Plan developed by the National Institute for Standards and Technology, and AI/ML standards established by standards organizations. The Second Discussion Paper also acknowledges the potential usefulness of the Agency’s frameworks for software as a medical device (“SaMD”), such as an April 2019 discussion paper that proposed a regulatory framework for modifications to AI-based SaMD, a January 2021 AI “Action Plan” for SaMD, and October 2021 guiding principles to inform the development of Good Machine Learning Practice for AI/ML-based medical devices. It seems likely that the Agency will leverage some principles from these sources in developing AI/ML standards for drug development and the development of devices intended to be used with drugs.

Opportunity for Engagement: Request for Feedback

Although the above-referenced, overarching standards may serve as a useful starting point, FDA seeks feedback from stakeholders that highlights additional or unique considerations for AI/ML deployed in the drug development context. Specifically, FDA solicits feedback on three key areas: (1) human-led governance, accountability, and transparency; (2) quality, reliability, and representativeness of data; and (3) model development, performance, monitoring, and validation. The Agency outlines specific questions within each of these areas in the Second Discussion Paper.

  • With respect to human-led governance, accountability, and transparency, FDA emphasizes the value of governance and accountability in developing trustworthy AI. The Agency seeks feedback about specific use cases in drug development that have the greatest need for regulatory clarity, what transparency means in the use of AI/ML in drug development, the barriers and facilitators of transparency in these contexts, and good practices for providing risk-based, meaningful human involvement.
  • With respect to quality, reliability, and representativeness of data, FDA acknowledges that ensuring “data quality, reliability, and that the data are fit for use (i.e., relevant for the specific intended use and population) can be critical,” and highlights data-related issues such as bias, completeness and accuracy of data, privacy and security, record trails, relevance, replicability, reproducibility, and representativeness. FDA solicits feedback on key practices utilized by stakeholders to help address these issues.
  • Finally, with respect to model development, performance, monitoring, and validation, FDA highlights the importance of evaluating AI/ML models over time to consider the model risk and credibility. For example, FDA acknowledges that there may be overall advantages to selecting a more traditional and parsimonious (i.e., fewer parameters) model over complex models where the models perform similarly. Additionally, the Second Discussion Paper states it may be important to examine corrective actions and real-world performance, conduct postmarket surveillance, verify the software code and calculations, and evaluate the applicability of validation assessments to the context of use. FDA solicits feedback on examples of tools, processes, approaches, and best practices being used by stakeholders to monitor and develop AI/ML models.

Submitting feedback on these questions is an important opportunity to help develop the standards that govern the use of AI/ML in drug development. The comment period closes on August 9, 2023.

Other Opportunities for Engagement

FDA also is coordinating a number of mechanisms for stakeholders to engage with the Agency on AI/ML in drug development, such as a workshop with stakeholders, public meetings, and further Critical Path Innovation, ISTAND Pilot Program, Emerging Technology Program, and Real-World Evidence Program meetings. FDA views these efforts and collaborations as providing “a foundation for a future framework or guidance.” Stakeholders should watch closely for these opportunities.


[1] For a summary and analysis of FDA’s first discussion paper, which focused on the use of AI in drug manufacturing, please see our prior blog post, “FDA Seeks Comments on Agency Actions to Advance Use of AI and Digital Health Technologies in Drug Development.” The first discussion paper, “Artificial Intelligence in Drug Manufacturing,” was issued by the Center for Drug Evaluation and Research (CDER), and is available at https://www.fda.gov/media/165743/download.

[2] For purposes of the Second Discussion Paper, FDA states that all references to “drug” or “drugs” include both human drugs and biological products.

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Photo of Wade Ackerman Wade Ackerman

Wade Ackerman advises companies and trade associations on complex and novel FDA regulatory issues that require coordinated legal, regulatory, and public policy strategies.

Through more than 19 years of experience in private practice and positions within the FDA and on Capitol Hill, Wade…

Wade Ackerman advises companies and trade associations on complex and novel FDA regulatory issues that require coordinated legal, regulatory, and public policy strategies.

Through more than 19 years of experience in private practice and positions within the FDA and on Capitol Hill, Wade has acquired unique insights into the evolving legal and regulatory landscape facing companies marketing FDA-regulated products. He co-leads Covington’s multidisciplinary Digital Health Initiative, which brings together the firm’s considerable global resources to advise life sciences and health technology clients harnessing the power of information technology and data to create new and cutting-edge innovations to improve health and achieve better outcomes for patients.

Until June 2016, Wade served as Senior FDA Counsel to the U.S. Senate Health Education, Labor & Pensions (HELP) Committee Ranking Member Patty Murray (D-WA) and, prior to that, Chairman Tom Harkin (D-IA). While at the HELP Committee, Wade was involved in all major FDA legislative initiatives, oversight hearings, and other Senate HELP Committee activities concerning the FDA and the Federal Food, Drug, and Cosmetic Act. From January 2015 through June 2016, he helped negotiate many of the FDA-related provisions in the 21st Century Cures Act, which included reforms to FDA’s review and approval of new drugs, devices, combination products, and digital health software. He also worked closely with the FDA and other stakeholders as Congress examined legislative reforms in other key areas, including diagnostics and laboratory developed tests, cosmetics, and over-the-counter drugs.

Before taking his Senate role, Wade served for more than five years as Associate Chief Counsel within the FDA’s Office of Chief Counsel. He was responsible for providing legal advice to the FDA’s Center for Drug Evaluation and Research (CDER) and the Office of Commissioner (OC) on a wide range of issues. While at FDA, he also helped to develop and implement the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 and the Drug Quality and Security Act (DQSA) of 2013—both significant reforms to FDA’s regulatory authorities.

Photo of Thomas Cosgrove Thomas Cosgrove

Tom Cosgrove is a partner in Covington’s Food, Drug and Device Practice Group. He joined Covington in 2017 from the Food and Drug Administration (FDA), where he was a senior official charged with ensuring the quality of drugs and therapeutic biologics marketed to…

Tom Cosgrove is a partner in Covington’s Food, Drug and Device Practice Group. He joined Covington in 2017 from the Food and Drug Administration (FDA), where he was a senior official charged with ensuring the quality of drugs and therapeutic biologics marketed to U.S. patients. Tom brings a wealth of experience to bear in helping clients navigate the complex world of pharmaceutical compliance and enforcement in the United States and around the globe.

At FDA, Tom held senior leadership positions within the Office of Compliance in the Center for Drug Evaluation and Research (CDER), including leading the organization as Acting Director in 2016. Beginning in 2014, he led the Office of Manufacturing Quality (OMQ), where he was responsible for CDER’s enforcement activities covering current good manufacturing practice (CGMP) and drug quality. In this role, Tom was responsible for setting FDA’s CGMP enforcement priorities and for clearing warning letters, import alerts, and referrals for civil and criminal enforcement. He also played a central role in the FDA’s deliberations concerning the approval of marketing applications submitted by companies with manufacturing compliance challenges.

As Acting Director of CDER Compliance in 2016, Tom oversaw OMQ as well as the offices responsible for enforcing FDA’s requirements for drug approval and labeling, human drug compounding, drug supply chain security and integrity, and clinical trials and bioequivalence studies.

He is a frequent speaker at conferences and trainings focused on drug quality, compliance, and enforcement at home and abroad.

Photo of Paula Katz Paula Katz

Paula Katz is a regulatory attorney with nearly 20 years of experience in pharmaceutical and medical products compliance and enforcement matters. Prior to joining the firm, Paula was the Director of Guidance and Policy in FDA’s Center for Drug Evaluation and Research, Office…

Paula Katz is a regulatory attorney with nearly 20 years of experience in pharmaceutical and medical products compliance and enforcement matters. Prior to joining the firm, Paula was the Director of Guidance and Policy in FDA’s Center for Drug Evaluation and Research, Office of Manufacturing Quality. At FDA, Paula was responsible for development of current good manufacturing practice (CGMP) and drug quality policy and served as a clearing official on drug quality compliance actions. Paula brings her years of FDA experience to bear in providing clients with practical advice on a wide range of regulatory compliance and enforcement issues, including managing and responding to regulatory inspections, quality and safety reporting, regulatory outreach, product recalls, and investigations. She also routinely advises on regulatory aspects of commercial agreements and life sciences transactions and provides critical subject matter expertise to support commercial and government litigation and investigations.

Photo of Julia Post Julia Post

Julia Post advises companies and trade associations on a broad range of regulatory and policy matters related to drugs, biologics, and other regulated products in both the U.S. and China. Julia has significant experience in advising clients on clinical trial and product development…

Julia Post advises companies and trade associations on a broad range of regulatory and policy matters related to drugs, biologics, and other regulated products in both the U.S. and China. Julia has significant experience in advising clients on clinical trial and product development matters, including informed consent requirements, biospecimen procurement and research use, and other good clinical practice. She advises clients regularly on product life-cycle management issues, including patent linkage frameworks and marketing exclusivity in the U.S. and China.

Julia works with pharmaceutical, medical device, food, and cosmetics clients on complex regulatory compliance matters and helps them develop their advocacy strategies before U.S. and China regulators, at both national and local levels. She regularly assists companies and trade associations on policy issues, including the development and submission of comments on legislative and regulatory proposals. Julia works closely with local counsel throughout the Asia-Pacific region to assist clients with their marketing approval and compliance strategies.

Prior to joining the Food, Drug, and Device practice group, Julia was a member of the Litigation practice group where she focused on representing clients in Hatch-Waxman patent litigation.

Julia has an active pro bono practice at Covington, with a particular focus on reproductive justice matters and representation of third-party caregivers and children in custody cases.

Photo of Christina Kuhn Christina Kuhn

Christina Kuhn advises medical device, pharmaceutical, and biotech companies on a broad range of FDA regulatory strategy and compliance matters. She has experience with cutting-edge and complex medical technologies, including software and digital health products, oncology products, next-generation sequencing, diagnostics, and combination products.…

Christina Kuhn advises medical device, pharmaceutical, and biotech companies on a broad range of FDA regulatory strategy and compliance matters. She has experience with cutting-edge and complex medical technologies, including software and digital health products, oncology products, next-generation sequencing, diagnostics, and combination products.

Christina frequently helps multinational device manufacturers as well as start-up device companies navigate the premarket regulatory process, advising companies on regulatory classification, clinical development strategy, and agency interactions. She also has significant experience counseling medical device companies on postmarket compliance requirements, including those related to advertising and promotion, quality systems and manufacturing, medical device reporting, registration and listing, and recalls. She advises clients on responding to and resolving enforcement actions, such as FDA inspections and Warning Letters as well as Department of Justice investigations.

Christina advises clients on, and performs regulatory due diligence for, corporate transactions, including acquisitions, public offerings, co-development agreements, and clinical trial agreements.

Christina also regularly assists industry associations and medical device and pharmaceutical companies in commenting on FDA guidance documents and rulemaking as well as drafting and analyzing federal legislation.

Christina is a frequent contributor to Covington’s Digital Health and InsideMedicalDevices blogs.

Photo of Dalia Deak Dalia Deak

Dalia Deak is an associate in the firm’s Chambers top-ranked Food, Drug, and Device Practice Group. Dalia draws on her scientific training and years of public health and policy experience to provide strategic and regulatory advice to emerging and leading biotechnology, pharmaceutical, digital…

Dalia Deak is an associate in the firm’s Chambers top-ranked Food, Drug, and Device Practice Group. Dalia draws on her scientific training and years of public health and policy experience to provide strategic and regulatory advice to emerging and leading biotechnology, pharmaceutical, digital health, and medical device companies. She leverages her experience to understand clients’ specific and enterprise-level needs and advises on a broad range of complex regulatory, compliance, and policy matters at the intersection of science, strategy, public health, and law.

A lawyer with scientific training and public health and policy experience, Dalia advises emerging and leading companies on regulatory and strategic matters. Her focus is primarily on matters affecting biotechnology, pharmaceutical, digital health, and medical device products.

Dalia has assisted clients with top-priority issues, like conducting due diligence for FDA-regulated products and companies, responding to clinical holds, and providing advice on advertising and promotion, prevention of healthcare fraud and abuse, and the design and conduct of clinical trials. In doing so, she leverages the valuable in-house experience she gained while on secondment at a biopharmaceutical company to understand the enterprise and stakeholders and translate legal advice into actionable steps that are responsive to the business.

Prior to joining the Food, Drug, and Device practice group, Dalia was a member of the Patent Litigation practice group where she focused on representing clients in pharmaceutical patent litigation. She also maintains an active pro bono practice at Covington, with a particular focus on asylum, reproductive justice, and criminal justice matters.

Before attending law school, Dalia received her M.P.H from the Harvard T.H. Chan School of Public Health, during which she worked as a Research Trainee at Brigham and Women’s Hospital. At Brigham, she researched drug repurposing and U.S. Food & Drug Administration law and policy. Prior to graduate school, Dalia was a research assistant at The Brookings Institution researching drug and device innovation, safety, and evidence issues. She co-authored a report for the U.S. Food & Drug Administration on effective implementation of Unique Device Identifiers (UDIs).

While in law school, Dalia interned for the Honorable Indira Talwani of the U.S. District Court of the District of Massachusetts. She also served as a Health Law Fellow at the Georgetown University O’Neill Institute for National & Global Health Law, where she researched pandemics, international health law, and intellectual property. Dalia was also active in a number of clinics, including Harvard’s Center for Health Law & Policy Innovation and the Immigration and Refugee Advocacy Clinic.

Dalia has published her research in peer-reviewed journals, publicly-available reports, and health law blogs.

Photo of Olivia Dworkin Olivia Dworkin

Olivia Dworkin minimizes regulatory and litigation risks for clients in the medical device, pharmaceutical, biotechnology, eCommerce, and digital health industries through strategic advice on complex FDA issues, helping to bring innovative products to market while ensuring regulatory compliance.

With a focus on cutting-edge…

Olivia Dworkin minimizes regulatory and litigation risks for clients in the medical device, pharmaceutical, biotechnology, eCommerce, and digital health industries through strategic advice on complex FDA issues, helping to bring innovative products to market while ensuring regulatory compliance.

With a focus on cutting-edge medical technologies and digital health products and services, Olivia regularly helps new and established companies navigate a variety of state and federal regulatory, legislative, and compliance matters throughout the total product lifecycle. She has experience counseling clients on the development, FDA regulatory classification, and commercialization of digital health tools, including clinical decision support software, mobile medical applications, general wellness products, medical device data systems, administrative support software, and products that incorporate artificial intelligence, machine learning, and other emerging technologies.

Olivia also assists clients in advocating for legislative and regulatory policies that will support innovation and the safe deployment of digital health tools, including by drafting comments on proposed legislation, frameworks, whitepapers, and guidance documents. Olivia keeps close to the evolving regulatory landscape and is a frequent contributor to Covington’s Digital Health blog. Her work also has been featured in the Journal of Robotics, Artificial Intelligence & Law, Law360, and the Michigan Journal of Law and Mobility.

Prior to joining Covington, Olivia was a fellow at the University of Michigan Veterans Legal Clinic, where she gained valuable experience as the lead attorney successfully representing clients at case evaluations, mediations, and motion hearings. At Michigan Law, Olivia served as Online Editor of the Michigan Journal of Gender and Law, president of the Trial Advocacy Society, and president of the Michigan Law Mock Trial Team. She excelled in national mock trial competitions, earning two Medals for Excellence in Advocacy from the American College of Trial Lawyers and being selected as one of the top sixteen advocates in the country for an elite, invitation-only mock trial tournament.