FDA Issues Draft Guidance Clarifying Three-Year New Clinical Investigation Exclusivity

The U.S. Food and Drug Administration (FDA) just issued a much-anticipated guidance on New Clinical Investigation exclusivity (also known as three-year exclusivity) for new drug applications (NDAs) and NDA supplements.¹ FDA’s draft guidance is organized in a question-and-answer format that covers the statutory and regulatory eligibility criteria and provides recommendations on requests for exclusivity. 

For years, FDA’s approach to three-year exclusivity demanded an understanding of policy and precedent scattered across regulatory preambles, select exclusivity determinations released under Freedom of Information Act requests, and published court opinions. This draft guidance offers a consolidated articulation of FDA’s current three-year exclusivity policy and interpretive framework.

Below, we provide a brief summary of FDA’s standard for eligibility for three-year exclusivity and a discussion of several key examples.

Three-Year Exclusivity Framework

The Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA regulations establish the criteria for qualifying for three-year exclusivity.² An NDA or a supplemental NDA may qualify for exclusivity if it –

• Contains a previously-approved active moiety³ and
• Contains reports of new clinical investigations that are –
  • not bioavailability studies
  • essential to the approval of the application (or supplement) and
  • conducted or sponsored by the applicant⁴

As suggested above, both NDAs and supplemental NDAs are eligible for exclusivity. In the case of NDA supplements (typically efficacy supplements), three-year exclusivity attaches to the changes approved in the supplement that were supported by the new clinical investigation(s) essential to the supplement's approval and conducted or sponsored by the applicant submitting the supplement. In this case, exclusivity does not cover the previously approved conditions of approval for the NDA being supplemented

FDA considers eligibility requests on an application-by-application basis. Applicants who believe their drug product is eligible for exclusivity must submit to FDA, per 21 CFR 314.50(j), the following information, prior to approval:

• A statement that the applicant is claiming exclusivity
• A reference to the appropriate paragraph under § 314.108 that supports its claim
• Information to show that the NDA contains “new clinical investigations” (other than bioavailability studies) that are “essential to approval of the NDA or supplement” and “were conducted or sponsored by the applicant”

The Appendix section of the guidance provides representative language that may aid in preparing an exclusivity request.

Mechanistically, the draft guidance lays out a process that leans heavily on FDA’s Office of Generic Drug Policy. Specifically, the draft guidance explains that the process for making three-year exclusivity determinations involves coordination between several offices in the Center for Drug Evaluation and Research (CDER) within FDA, namely, the Office of New Drugs (OND) and the Office of Generic Drugs (OGD). The applicable review division in OND provides OGD with the exclusivity summary to aid OGD’s eligibility determination. As needed, the Office of Generic Drug Policy may consult with CDER’s Exclusivity Board for advice regarding a pending exclusivity matter. After OGD Policy determines that a product is eligible for three-year exclusivity, the relevant information is reflected in an update to the Orange Book. FDA updates exclusivity-related information in the Orange Book approximately every 2 weeks.

Areas of Clarification

The draft guidance addresses several foundational interpretive issues, the basic mechanisms of requesting and obtaining exclusivity, and key interpretive criteria and policy. For example, FDA delves further into the meaning of regulatory terms such as “bioavailability study”, “clinical investigation,” “new clinical investigation,” and “essential to approval”. FDA also explains what type of information the Agency expects to see in an exclusivity request, for example, to support that a clinical investigation is “new” or “conducted or sponsored” by the applicant.

Other discussions focus on threshold eligibility issues. For instance, the guidance clarifies that studies that only administer a placebo to subjects are not typically considered to meet the definition of a clinical investigation for purposes of the exclusivity regulations and would not qualify the product for three-year exclusivity. The guidance also clarifies that the drug used in the clinical investigation need not be the same as that approved for the application to qualify for exclusivity, provided that the relevant statutory and regulatory exclusivity requirements are met.⁵ For example, a clinical investigation that “used a similar or earlier version of the drug product in development, which contains the same active moiety or combination of active moieties as the version of the drug in the approved application,” could be eligible.

FDA also sheds light on more niche topics that have evolved in drug development since the framework was established in the 1980s and 1990s. For example, the response to QB.8 explains that when a study involves multiple cohorts or treatment arms (at least one of which was previously relied upon to approve an application), another cohort or treatment arm may still qualify as a new clinical investigation under certain circumstances. This determination will be made on a case-by-case basis through application of a multifactorial approach to determine whether a cohort or treatment arm constitutes a distinct new clinical investigation. FDA will consider in its analysis whether there is an acceptable scientific or medical reason for the separate cohort or treatment arm; whether the separate cohort or treatment arm evaluates different patient populations and/or different drug products; and whether the separate cohort or treatment arm was prespecified in the protocol. Such a policy is intended to “encourage efficiencies” in clinical trial design and to incentivize sponsors to submit results from distinct cohorts or treatment arms as soon as they are available, thereby enabling new information to be included in drug labeling more quickly.

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FDA’s draft guidance provides long-awaited clarity to an area of regulatory practice that has historically required navigating multiple resources. This guidance consolidates FDA’s policy and practice into a single document with extensive footnote references that provide the underpinnings for the Agency’s positions. Comments on this guidance are due on May 4, 2026.

For background on another key exclusivity pathway – five-year new chemical entity exclusivity – FDA’s previous guidance on New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products (Oct. 2014) remains a useful resource.⁶ The authors are longstanding followers of exclusivity issues and are pleased to discuss any questions that may arise.