Key FDA Updates: Substantial Evidence, Gene Therapy Development and AI-Enabled Early-Phase Clinical Trials

FDA Issues Revised Draft Guidance on Substantial Evidence of Effectiveness

On June 24, 2026, the U.S. Food and Drug Administration (FDA) released a draft update to its 2019 draft guidance titled “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” that, when finalized, will supersede FDA’s longstanding 1998 guidance on providing clinical evidence of effectiveness. While the statutory standard remains unchanged, the guidance provides clarity on how sponsors planning to submit new drug applications (NDAs), biologics license applications (BLAs), or supplements to NDAs or BLAs may, in some cases, “rely on one scientifically rigorous adequate and well-controlled clinical investigation with confirmatory evidence to satisfy the statutory substantial evidence standard under Section 505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).” The guidance also outlines FDA’s views on the role of confirmatory evidence and the circumstances under which regulatory flexibility may be applied. The key points are as follows:

• Single-Trial Pathway: FDA confirms the general concept that one scientifically rigorous adequate and well-controlled clinical investigation that is supported by a “highly persuasive trial” or a “source of strong confirmatory evidence” may be able to satisfy the statutory substantial evidence standard under FD&C Act § 505(d). Sponsors should assess whether a single-trial pathway is viable and engage FDA prior to initiating the single trial.

• Confirmatory Evidence: Depending on the facts, FDA generally expects strong confirmatory evidence to arise from or include related trial data (e.g., related indications or same pharmacological class, trials in different stages of the same disease, infections arising from the same pathogen), mechanistic evidence, natural history data or real-world data, where such evidence is scientifically sound and legally permissible.

• What May Be Considered a Highly Persuasive Trial: When strong confirmatory evidence may not be available while planning a single adequate and well-controlled trial, FDA expects that a single highly persuasive trial will: (1) be designed to produce persuasive, generalizable, clinically meaningful results that apply to U.S. clinical practice; (2) enroll a broad, representative population; (3) use appropriate controls and current standards of care; (4) have enough power to show a real treatment effect; (5) have results supported by clinically meaningful primary and secondary endpoints, strong statistical evidence and consistency across key subgroups; and (6) have high-quality trial conduct with strong follow-up, minimal missing data and robust findings.

• FDA Assessment of Evidence Strength: In determining whether an application supports approval, FDA will evaluate a range of factors relevant to the strength and reliability of the evidence presented. These include the safety profile and benefit-risk balance, key trial design elements, the quality of trial conduct, and the clinical and statistical persuasiveness of the trial results and analyses. FDA will also consider the source and strength of any confirmatory evidence, disease-specific considerations (such as severity and available treatment options) and the overall quality of the development program. Finally, FDA will assess whether it is ethical and practicable to conduct more than one adequate and well-controlled trial.

• Regulatory Flexibility in Certain Contexts: In appropriate circumstances, FDA may apply flexibility in specific areas such as certain trial designs and analysis plans, endpoints and success criteria for the primary statistical analysis. For example, clinical circumstances where flexibility may be warranted involve serious, rare or unmet-need conditions. However, even where flexibility is applied, sponsors must still demonstrate substantial evidence of effectiveness.

• Independent Safety Assessment: A clinical trial that is sufficient to establish effectiveness may not provide an adequate safety database. Sponsors should therefore plan separately for safety assessment and benefit-risk evaluation, including the possibility of additional safety data collection or postmarketing requirements.

FDA also noted that, when scientifically justified and legally permitted, a sponsor may rely on the known effectiveness of an approved drug to demonstrate substantial evidence of effectiveness for a new use or condition without needing to conduct new adequate and well-controlled clinical investigations for that use. For example, evidence supporting similarity in the disease course, drug pharmacology and known effectiveness of the drug in adults may be able to support the effectiveness of a drug for pediatric use. Additionally, new dose, regimen, route, or dosage form effectiveness may be able to be supported by the original trial when combined with evidence showing similar pharmacokinetics profiles or that any differences in pharmacokinetics are not clinically meaningful. However, it is important to recognize that additional safety data may still be needed on a case-by-case basis.

This new guidance may significantly impact drug development and labeling changes in practical ways. For example, the guidance could affect FDA’s flexibility, including the recognition that ethical and practical recruitment issues are important and may be particularly helpful in rare disease drug development where it is difficult to recruit and treat hard-to-find and often sick patients. Also, the guidance could impact FDA’s willingness to potentially allow for new pediatric indications with non-clinical evidence that may lead to earlier availability of important drugs to treat children in need. However, the guidance is silent on whether such changes will “count” towards a grant of pediatric exclusivity by FDA under the Pediatric Research Equity Act (PREA) or whether actual pediatric clinical studies will be required in order to satisfy PREA requirements. 

Moreover, the guidance touches on how an applicant’s reliance on data concerning a different drug to support approval may raise legal and regulatory concerns. For example, reliance on FDA’s finding of safety and effectiveness for another drug may convert the application to a 505(b)(2) application, and in turn require various obligations (e.g., patent certifications or statements) and result in the delay of submission or approval in accordance with the statutory exclusivity provisions, whereas owning or having a right of reference to the data concerning the other drug may eliminate such legal and regulatory concerns. In the biological product context, an applicant cannot simply rely on FDA’s previous determination of safety, purity and potency to support approval of a section 351(a) BLA as certain applicable requirements under the section 351(k) pathway are required to be met. As such, reliance on other data not owned by the BLA applicant and for which the BLA applicant does not have a right of reference may raise additional legal considerations and ultimately prevent a sponsor from gaining approval under the new guidance.

FDA Issues Draft Guidance on Leveraging Prior Knowledge for Human Gene Therapy Products Incorporating Genome Editing

Human gene therapy incorporating genome editing is a rapidly expanding field that often faces significant regulatory roadblocks, particularly for rare disease indications with small patient populations. On June 3, 2026, in an effort to assist stakeholders in advancing product development of human gene therapy products incorporating ex-vivo and in vivo genome editing of human somatic cells, FDA issued draft guidance titled “Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing.” Specifically, this guidance outlines the type of prior knowledge that may be scientifically appropriate for purposes of advancing product development of such products.

FDA defines “prior knowledge” as the combination of (1) public knowledge (i.e., medical or scientific information that is generally accepted by experts qualified by scientific training and experience in the relevant field) and (2) platform knowledge (i.e., knowledge gained from developing and manufacturing similar products and processes such as shared editing methods, delivery systems or manufacturing processes). Examples of prior knowledge that may be able to be leveraged include:

• Chemistry, Manufacturing, and Controls (CMC): Analytical methods and validation data, lot release specifications, specific stability data for certain products, comparability data, process characterization/validation, and facility information.

• Nonclinical: In vitro, in silico, new approach methodologies, in vivo studies using an analogous animal product, and nonclinical data from studies evaluating a relevant product for another indication may be leveraged. FDA recommends a stepwise approach.

• Clinical: Prior clinical data may inform or otherwise support aspects of the design of a clinical trial (e.g., dose-limiting toxicity definitions, monitoring intervals, dose selection, exposure-response evaluation, biodistribution, vector shedding, and immunogenicity), trial conduct or analysis (e.g., for purposes of abbreviating the safety database, efficacy database, PK, and DDI liability), and potentially future licensure and long-term follow-up studies. Sponsors planning to leverage clinical data or general prior knowledge are encouraged to engage with FDA in the early stages of product development.

Sponsors must scientifically justify the applicability of leveraged knowledge to their specific product. Additionally, similarity must be demonstrated across manufacturing processes, formulations, cell sources, routes of administration, dosing regimens and other relevant parameters. Moreover, sponsors planning to leverage prior knowledge are encouraged to engage with FDA as early as possible in the product development lifecycle (e.g., through INTERACT and pre-IND meetings) to avoid any issues later in development.

Sponsors developing human gene therapy products incorporating genome editing should carefully assess whether and how prior knowledge may support their CMC, nonclinical, clinical, and long-term follow-up strategies, while ensuring that any reliance on prior knowledge is scientifically justified and appropriately documented. In addition, human gene therapy sponsors should also consider leveraging FDA’s overall flexibility and guidance as set forth in the Substantial Evidence of Effectiveness guidance noted above when designing trials and gaining agency buy-in to a new development program.

Comment Period Concludes for RFI on Proposed Pilot Program to Explore Effects of AI-Enabled Technologies in Early-Phase Clinical Trials

On April 29, 2026, FDA published a Federal Register notice entitled “AI-Enabled Optimization of Early-Phase Clinical Trials Pilot Program; Request for Information” [Docket No. FDA-2026-N-4390] requesting stakeholder input on a proposed pilot program that would assess how artificial intelligence (AI)-enabled technologies may improve the efficiency, speed and quality of decision-making in early-phase clinical trials. Specifically, this request for information (RFI) sought input on:

• Pilot Program Design and Implementation: Scope and focus, participant selection criteria, collaboration models, operational structure and needs, timeline, milestones, and mechanisms for knowledge sharing while protecting proprietary information.

• Evaluation Metrics and Success Criteria: Trial efficiency and speed, decision quality, participant safety, data integrity, AI system performance, trustworthiness, comparative evaluation, and qualitative outcomes.

June 29th marked the conclusion of the comment period.

Although this RFI does not impose new legal requirements, it provides a meaningful signal of FDA’s regulatory thinking regarding the use of AI-enabled technologies in early-phase clinical trials.

---

McGuireWoods’ FDA & Life Sciences Practice Group closely monitors FDA guidance and enforcement trends. For assistance assessing how these latest developments may affect your development program, FDA engagement strategy, or regulatory submissions, please contact the authors or any member of McGuireWoods’ FDA & Life Sciences Practice Group.