What’s New Pussycat? FDA Assists Drug Sponsors Requesting New Clinical Investigation Exclusivity

Key Takeaways

• FDA explains what must be “new” to qualify for three years of non-patent market exclusivity. In a new draft Q&A guidance, FDA walks sponsors through what makes a clinical investigation “new,” how to support exclusivity requests, and how the agency will evaluate them — aiming to balance innovation incentives with timely generic competition.
• The draft guidance clarifies which studies can qualify as a “new clinical investigation.” FDA confirms that qualifying investigations must be human, non‑bioavailability studies that were not previously relied on for approval, and explains when studies using earlier formulations, mixed‑purpose trials, or discrete cohorts or arms within larger studies may still qualify.
• FDA details process expectations and provides model request language. The draft guidance outlines when and how sponsors should submit three‑year exclusivity claims, emphasizes the need for clear certifications and literature support before approval, and includes an appendix with representative language to standardize and streamline submissions.

In a new draft guidance document, “New Clinical Investigation Exclusivity (3‑Year Exclusivity) for Drug Products: Questions and Answers,” FDA is stepping in to help drug sponsors prepare a request for three years of non-patent market exclusivity for New Drug Applications (“NDAs”) and supplements. Echoing the question at the heart of “What’s New Pussycat?” by Tom Jones, FDA uses a question and answer format to walk sponsors through what must be “new” about their clinical investigations, how to frame and support requests for exclusivity, and how the agency will evaluate such requests.

FDA acknowledges the balance between encouraging broader access to generic drugs and supporting innovative drug development. The draft guidance can help drug sponsors refine their approach to securing a three-year exclusivity period for new clinical investigations. This Bulletin highlights key sections of the draft guidance and offers observations on practical implications for drug development and competition.

Discussion

Background

• Under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act, certain NDAs and NDA supplements that rely on qualifying new clinical investigations can receive a three‑year exclusivity period (separate from any patent protection) during which FDA may not approve 505(b)(2) NDAs or abbreviated NDAs for the same, exclusivity‑protected conditions of approval.¹
• An application may qualify for a three‑year exclusivity period if: (1) it is a 505(b) NDA or supplement for a previously approved active moiety; and (2) it includes reports of new, non‑bioavailability clinical investigations that are essential to approval and conducted or sponsored by the applicant.²
• For NDA supplements, a three-year exclusivity period only protects the new change that the supplement adds, based on new, essential clinical studies run or backed by the sponsor; it does not restart exclusivity for all the drug’s already-approved uses.

New Clinical Investigation

• To qualify for a three-year exclusivity period, the application must include a “new clinical investigation,” defined as a human study in which a drug is given to subjects and cannot be a bioavailability study.
  • A “bioavailability study” measures the rate and extent to which the active ingredient is absorbed and becomes available at the site of action, often using pharmacokinetic or certain pharmacodynamic methods.
  • The guidance classifies a “new clinical investigation” as one where its results have not previously been relied on to show effectiveness for any approved indication or safety for a new patient group. It cannot simply duplicate results from an earlier investigation that FDA already used for those purposes.
  • Applicants can satisfy the “new clinical investigation” requirement through a brief certification and supporting literature search.
• The clinical investigation does not have to use the exact final product.
  • A study of an earlier or similar version (for example, granules) can support a three‑year exclusivity period for a subsequent tablet form with the same active ingredient, if all other regulations are satisfied.
  • A study that only gives placebo to participants will not qualify as a clinical investigation for a three-year exclusivity period, because no actual drug is administered to human subjects in that experiment.
  • FDA notes that a single clinical study can serve multiple purposes, and it will look at the study endpoints, design, and role in the overall evidence package to determine its primary purpose; a study that combines pharmacokinetic and bioavailability measurements with a real safety or effectiveness endpoint may still qualify toward a three‑year exclusivity period.
  • FDA explains that, in some situations, a single cohort or treatment arm within a larger trial can count as its own “new clinical investigation” for a three‑year exclusivity period, and it will make that call on a case-by-case basis, based on multiple factors such as scientific rationale, distinct populations or products, and whether the cohort/arm was prespecified in the protocol.
    • This reflects a form over substance consideration, where FDA is more concerned with substantive innovations than administrative concerns.
    • FDA recommends that applicants proactively discuss such trial designs and cohort/arm considerations with the agency prior to submission to ensure alignment and clarify eligibility for any exclusivity period.

Essential to Approval

• The guidance reiterates that a “new clinical investigation” must be “essential to approval,” meaning that there are no other available data that could have supported approval of the NDA.
  • FDA proposes that an investigation is “essential to approval” only if it is “vital” to the application, such that FDA could not have approved the drug or change as safe and effective based on other available information.
  • Applicants can show an investigation is vital by submitting a literature-based list of relevant published studies, a certification that these do not themselves support approval without the new investigation, and an explanation of why the studies are insufficient.

Conducted or Sponsored by Applicant

• FDA explains that an investigation must be “conducted or sponsored by the applicant.”
  • This requirement is satisfied if, before or during the study, the applicant is listed as the Investigational New Drug (“IND”) sponsor on Form FDA 1571 or the applicant (or its predecessor in interest) provides substantial support for the investigation.
  • Applicants can show “substantial support” either with a CPA-certified statement that they covered at least 50% of study costs, or with an explanation of why their contribution qualifies even if it was under 50%.

Process Considerations

• The guidance outlines that an NDA applicant seeking a three-year exclusivity period should submit, before approval, a clearly identified “314.50(j) [the regulatory provision] Exclusivity Claim” with supporting information showing the NDA contains qualifying new clinical investigations that are essential to approval and conducted or sponsored by the applicant.
• The appendix to the guidance provides representative request language to help applicants structure their three-year exclusivity claims and related certifications in a consistent, ready-to-use format.
• After NDA approval, the Office of New Drugs (“OND”) sends an “Exclusivity Summary” to the Office of Generic Drug Policy, which then evaluates whether the application meets the statutory and regulatory criteria for a three-year exclusivity period.
• OND may seek input from the Center for Drug Evaluation and Research Exclusivity Board, and, if eligibility is confirmed, assigns a specific three-year exclusivity code and expiration date that is added to the Orange Book in a routine biweekly update.

AGG Observations

• Interested parties have 60 days to submit comments by May 4, 2026, and should consider how the agency’s answers to frequently asked questions may affect both their exclusivity strategies and the timing of generic and 505(b)(2) NDA product entries.
• FDA provides answers to common questions relevant to each of the three main elements of the three-year exclusivity analysis: (1) whether there is a new clinical investigation; (2) what studies are essential for approval; and (3) when it is conducted or sponsored by the applicant.
• A sponsor should tailor clinical investigations specifically to address gaps in existing data that are critical for FDA approval of the new indication or product change. For example, a company should focus studies on patient populations, dosing regimens, or endpoints not previously evaluated, ensuring that these investigations generate indispensable evidence not found in the published literature or prior submissions.
• When submitting efficacy supplements, a sponsor should concentrate on clinically substantial modifications such as demonstrating a new use, significant improvement in safety or efficacy, or a new patient population, not minor changes like formulation tweaks or labeling updates. An exclusivity period will only be granted for changes that fundamentally alter the clinical profile or utility of the product.
• An exclusivity period for NDA supplements is limited to the specific clinical change supported by the new investigation. A sponsor should craft exclusivity claims that precisely describe the novel aspect, such as “addition of indication X in pediatric patients,” rather than attempting to broadly protect the entire product or unrelated claims.
• A sponsor must demonstrate that its investigation is vital, meaning the agency could not have approved the application but for the new study.
• Applicants must submit clear exclusivity claims, literature searches, and certifications before approval, following FDA’s recommended format in the appendix to facilitate proper review.

In summary, FDA’s process to award a three-year exclusivity period is rigorous. It is neither automatic nor broadly applicable to all changes or supplements. The process is intended to reward applicants who commit significant resources to conduct or sponsor essential new clinical investigations. In other words, those that fill meaningful gaps in scientific understanding and are indispensable for the approval of the specific product change.

Stakeholders should actively review the draft guidance and consider submitting comments in response to the agency’s recommendations. For assistance with these issues, please contact AGG’s Food & Drug team.

[1] 21 U.S.C. § 355(c)(3)(E)(iii)–(iv), (j)(5)(F)(iii)–(iv).

[2] The guidance does not address eligibility criteria for a three-year exclusivity period for antibiotic drugs.