2023 FDA Regulatory Developments

August T. Horvath

The year 2023 saw several significant regulatory developments and policy initiatives involving FDA. Here is a brief selection of the regulatory “greatest hits” from the past year.

Food and Drug Omnibus Reform Act

At the end of 2022 (December 29), President Biden signed into law the Food and Drug Omnibus Reform Act (FDORA), which amended the Federal Food, Drug, and Cosmetic Act (FDCA) to give FDA new authority and mandates. The legislation reformed the process of accelerated marketing approval for products whose release is deemed urgent by FDA. FDA can now require the sponsor to have confirmatory trials underway before being granted accelerated approval, and provides for expedited withdrawal of a previously granted approval if the confirmatory trials fail to confirm a clinical benefit. The law also provided for the establishment of an inter-agency Accelerated Approval Council, which was convened in 2023 and included representatives of the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Oncology Center of Excellence. The council’s activities in 2023 were limited to two meetings concerned with agenda-setting and high-level policy discussion.[1]

FDORA also gave FDA new authority to mandate diversity of race, gender, ethnicity, and socioeconomic status in clinical trials, a subject that has been the subject of growing industry consensus for some years. Under the new law, sponsors must submit a diversity action plan for any Stage 3 clinical trial, including goals for enrollment and a plan for meeting them. As also required by the law, FDA held its first public workshop, in association with the Clinical Trials Transformation Initiative, by videoconference on November 29–30, 2023.[2]

Several provisions of FDORA sought to update drug reform to take account of the rise of biologics. One provision, paralleling those already in place for drugs, required biologics license holders to submit marketing status reports to FDA by June 27, 2023, confirming that their products’ Purple Book listings are accurate, and to notify FDA when a biological product is withdrawn from the market. Another provision extended the Qualified Infectious Disease Product program, heretofore available only to conventional chemical drugs, to biologics. The effect of these and other biologics-related provisions of FDORA is to normalize the regulatory treatment of biologics under a regime similar to that in place for drugs.

Modernization of Cosmetics Reform Act

Along with FDORA, the government enacted long-awaited reform of the federal regulatory regime for cosmetics, in the form of the Modernization of Cosmetics Regulation Act (MoCRA), which went into effect on December 29, 2023, the first anniversary of its enactment. This law imposes new requirements on manufacturers and distributors of cosmetics (defined by the FDCA as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body . . . for cleansing, beautifying, promoting attractiveness, or altering the appearance,” and therefore including many products that might commonly be considered cleansers or personal care products), including registration of facilities, reporting of product listings, reporting serious adverse health events, and fragrance allergen labeling. These requirements are patterned after ones that exist for drugs, which therefore are being relied upon for guidance in the absence of detailed implementing regulations and enforcement precedent for these nascent requirements.

Cannabidiol (CBD) Regulation

Early in 2023, FDA announced that it had concluded that “existing regulatory frameworks for foods and supplements are not appropriate for cannabidiol” and that it will work with Congress to establish a new regulatory paradigm for CBD products.[3] This statement coincided with the denial of three citizen petitions requesting that FDA regulate CBD products under the existing dietary supplement regime. FDA cited special safety concerns purportedly associated with CBD and stated that it will continue to issue warning letters regarding clear violations of the FDCA while it works with Congress on comprehensive regulation. Since the 2018 Farm Bill removed cannabis from the Controlled Substances Act, CBD occupied a regulatory no-man’s-land between food, drug, and supplement categories, limiting FDA’s regulatory authority while it spent the intervening years contemplating which category, if any, it would regulate CBD under.

FDA Guidance on Clinical Trials

FDA issued several guidance documents on best practices for clinical trials in 2023. This guidance addressed not only research practices going to the validity of clinical trials, but also ethical concerns such as informed patient consent.

Good Clinical Practice E6(R3) Draft Guideline

On May 19, FDA issued draft guidance intended to bring U.S. practice and regulation into conformance with Good Clinical Practice, described as “an international, ethical, scientific and quality standard for the conduct of trials that involve human participants.”[4] By its terms, this extensive set of principles applies to “interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities,” but they may also have more general applicability to drug-related clinical research. The guideline includes protections for the well-being, privacy, and safety of participants, as well as for diverse participant enrollment. Most principals are worded generally, as the guideline seeks to be flexible to accommodate the wide variety of clinical trial methodologies.

Final Guidance on Informed Consent

In August, FDA issued its final guidance “to assist institutional review boards (IRBs), clinical investigators, and sponsors in complying with FDA’s informed consent regulations for clinical investigations.”[5] The guidance supersedes prior guidance issued in 1998 and finalizes a draft form of the guidance issued in 2014, and “first present[s] general guidance on FDA’s regulatory requirements for informed consent and a discussion of the roles of IRBs, clinical investigators, sponsors, and FDA related to informed consent, followed by a series of frequently asked questions.”[6]

Electronic Systems and Signatures Draft Guidance

FDA issued draft guidance on the use of electronic systems, records, and signatures in clinical trials for foods, medical products, tobacco products, and animal drugs in March.[7] “The guidance provides recommendations regarding the requirements, including the requirements under 21 CFR part 11, under which FDA considers electronic systems, electronic records, and electronic signatures to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.”[8] The bulk of the guidance is in question-and-answer format, and it seeks to clarify record-keeping and data submission requirements relating to clinical trial patient information and research data.

Draft Guidance on Single-Study Substantial Evidence of Effectiveness

In September, FDA released draft guidance regarding what it may consider to be substantial evidence of clinical effectiveness based on one randomized controlled trial plus other confirmatory evidence, as opposed to the two randomized controlled trials which have been the default standard.[9] FDA noted that this alternative has existed since 1997, when Congress amended Section 505(d) of the FDCA to give FDA discretion to consider such evidence. The bulk of this document discusses the types of confirmatory evidence that could support effectiveness when combined with a single clinical trial, including clinical trials of the same product from a related indication, mechanistic or pharmacodynamic evidence, evidence from relevant animal models, evidence from related products, and various kinds of real-world experience.

Advanced Manufacturing Technologies Designation Program Guidance

FDA closed out the year by issuing draft guidance on “advanced manufacturing technologies” (AMT), which it defines as “an innovative pharmaceutical manufacturing technology or approach that has the potential to improve the reliability and robustness of the manufacturing process and supply chain and increase timely access to quality medicines for the American public.”[10] The impetus for this guidance was FDORA, which included amendments to FDCA § 506L requiring the establishment of such a program. FDA encourages the development of such technologies and issued its draft guidance for comment. The draft guidance concerns the criteria for formulating and submitting a request for AMT designation, as well as the proposed benefits associated with successfully obtaining such a designation. These proposed benefits include prioritized interaction with FDA, such as “timely advice and . . . additional communication, in the form of written correspondence or meetings” with AMT designation holders and other parties working with the

[1]   U.S. Food & Drug Admin., Accelerated Approval Council Activities Report, CY 2023, https://www.fda.gov/media/174154/download.

[2]   Recordings and slide decks from the workshop are available at the Clinical Trials Transformation Initiative web site. Virtual Public Workshop to Enhance Clinical Study Diversity (FDORA), Clinical Trials Transformation Initiative (Nov. 29–30, 2023), https://ctti-clinicaltrials.org/virtual-public-workshop-to-enhance-clinical-study-diversity/.

[3]   Press Release, Statement from Janet Woodcock, U.S. Food & Drug Admin., FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward (Jan. 26, 2023), https://www.fda.gov/news-events/press-announcements/fda-concludes-existing-regulatory-frameworks-foods-and-supplements-are-not-appropriate-cannabidiol.

[4]   U.S. Food & Drug Admin., E6(R3) Good Clinical Practice (GCP) Draft Guideline 1 (May 19, 2023), https://www.fda.gov/media/169090/download.

[5]   U.S. Food & Drug Admin., Informed Consent—Guidance for IRBs, Clinical Investigators, and Sponsors (Aug. 2023), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent.

[6]   Id.

[7]   U.S. Food & Drug Admin., Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers—Guidance for Industry (Mar. 2023), https://www.fda.gov/media/166215/download.

[8]   Id. at 1–2.

[9]   U.S. Food & Drug Admin., Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence—Guidance for Industry (Sept. 2023), https://www.fda.gov/media/172166/download.

[10]  U.S. Food & Drug Admin., Advanced Manufacturing Technologies Designation Program— Guidance for Industry (Dec. 2023), https://www.fda.gov/media/174651/download.