Since 1984, FDA has had authority to recognize three years of regulatory exclusivity for certain qualifying new drug applications that conduct new clinical investigations essential for its approval. Despite no shortage of controversy, nuance, challenges, and litigation in the intervening decades on its application of these provisions, FDA’s public-facing interpretation of these provisions was limited to slim regulation, citizen petition responses, and court filings. After promising its publication for some time, FDA has issued the draft guidance New Clinical Investigation Exclusivity (3-Year Exclusivity) for Drug Products: Questions and Answers.
The Draft Guidance provides FDA’s most detailed explanation to date of how the agency interprets and applies the statutory requirements for the grant of this exclusivity (known variously as 3-year, new clinical investigation, or NCI exclusivity) under the Hatch-Waxman provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA) as well as procedural expectations for submitting exclusivity requests.
Unlike 5-year new chemical entity exclusivity, which prevents FDA from accepting or approving certain applications for a defined period, 3-year exclusivity generally operates more narrowly by only preventing approval of certain competing applications for the protected conditions of use.
In practice, 3-year exclusivity most commonly arises in connection with approved changes to previously approved drugs, such as new indications, dosing regimens, routes of administration, formulations, or other clinically supported modifications. Specifically, under the FFDCA, FDA may grant 3-year exclusivity to an original or supplemental new drug application (NDA) (either a 505(b)(1) or 505(b)(2) NDA) if the application contains reports of new clinical investigations that are not bioavailability studies, essential to approval of the NDA, and conduct by or for the applicant.
While the Draft Guidance does not break much new ground, it nonetheless serves as a helpful resource for applicants of NDAs seeking the exclusivity as well as applicants of follow-on applications potentially impacted by the grant. At the same time, the Draft Guidance omits certain key issues that have historically generated the greatest uncertainty and dispute regarding the exclusivity, in particular questions regarding the scope (and therefore the impact in practice) of 3-year exclusivity.
Critically, despite the publication of guidance, qualification for and the ultimate scope of 3-year exclusivity remains nuanced and frequently challenged. Interactions with the agency on these issues should be advanced with care, preparation, and a thorough assessment of all applicable considerations.
Key Points of FDA’s Draft Guidance
The Draft Guidance is presented in a Q&A format addressing issues commonly encountered during the NDA review process. Key points include:
- What Constitutes a “Clinical Investigation”? The Draft Guidance reiterates FDA’s position that nonclinical studies and studies limited to bioavailability generally do not qualify for purposes of 3-year exclusivity. Studies that do not include an evaluation of safety or effectiveness endpoints also typically do not qualify, however, studies that include pharmacokinetic components but also evaluate safety or effectiveness endpoints relevant to approval may qualify as clinical investigations.
- What Makes a Clinical Investigation “New”? The Draft Guidance explains that a study may qualify as new even if related data has previously been submitted to FDA, provided that the agency has not previously relied on those results to establish safety or effectiveness for an approved drug product. In other words, a study may still qualify as new if its results were submitted in another regulatory context but were not relied upon to support approval for the relevant conditions of use. However, FDA also notes that studies that duplicate the results of another relied-upon investigation would not qualify.
- What Products Are Studied in an Exclusivity-Qualifying Clinical Investigation? FDA clarifies that the drug product studied in the investigation does not necessarily need to be identical to the product ultimately approved. For example, a clinical investigation involving one formulation may support exclusivity for another formulation if the statutory criteria are otherwise satisfied (including, critically, the “essential to approval” prong noted below). FDA does note that placebo studies on their own would not typically qualify.
- When Is an Investigation “Essential to Approval”? According to the Draft Guidance, a clinical investigation is considered essential when the agency relied on the study because it did not otherwise have sufficient information to determine that the drug was safe and effective for the proposed conditions of approval. Conversely, FDA notes that the mere submission of a clinical investigation does not automatically make the study essential; the investigation must have been necessary to support the approval decision. This interpretation reflects FDA’s focus on the role the study played in the agency’s approval determination rather than simply whether the study was included in the application. We note that it may be a challenge for FDA to consistently distinguish between studies submitted, relied upon, and essential to approval, given FDA review practices broadly.
- What About Novel Trial Designs? FDA addresses situations in which a qualifying investigation represents only part of a larger clinical study. A specific cohort or treatment arm within a broader trial may qualify as a new clinical investigation if it can be treated as a distinct investigation and FDA has not previously relied on those results to support approval. This clarification may be particularly relevant for sponsors conducting (and may reflect the agency’s continued support for using) multi-arm or adaptive trials evaluating multiple indications, dosing regimens, or patient populations within a single protocol. However, we note that FDA is likely to take a multifactorial and case-by-case assessment on this determination.
- How Should Applicants Demonstrate That They Conducted or Sponsored Investigations? FDA recommends that applicants identify each clinical investigation they believe qualifies for exclusivity and provide documentation supporting the relationship between the applicant and study sponsor. Applicants should also provide information demonstrating that the study results were not previously relied upon by FDA and do not duplicate investigations that supported prior approvals. While FDA notes that acquisition of exclusive rights to a study may satisfy this requirement, applicants should carefully consider this limitation when contracting for rights as FDA notes that “nonexclusive” rights would not be sufficient and the agency may interpret this broadly.
- What Are the Procedural Expectations for Exclusivity Requests? In addition to clarifying eligibility criteria, the Draft Guidance outlines FDA’s expectations regarding the procedural aspects of requesting exclusivity. Specifically, FDA recommends that requests for exclusivity be included within the NDA submission, which must include a certification stating that the clinical investigations relied upon, to the best of the applicant’s knowledge, the statutory definition of “new clinical investigations.” FDA also provides representative language that applicants may use when preparing exclusivity requests.
What the Guidance Does Not Address
The Draft Guidance may provide helpful clarification regarding eligibility criteria and procedural expectations but it does not address issues that have historically generated the greatest uncertainty regarding 3-year exclusivity. Most notably, the Draft Guidance does not address in detail the scope of exclusivity protection (that is, how broadly FDA will interpret the conditions of approval protected by exclusivity).
While the guidance provides that for a supplement FDA may recognize exclusivity only for the change(s) approved in the supplement, this issue has frequently been the subject of citizen petitions and litigation, including the scope of exclusivity that FDA will recognize as serial improvements made to a drug. In related filings and documents, FDA has stated that it first asks what unique clinical question the relevant clinical trials answer about the product for the first time.
Then, FDA further looks to the clinically meaningful characteristics of the product that are tied to this clinical question. While it can be broadly understood that 3-year exclusivity for an active moiety will narrow over time, exactly how this is interpreted and applied may be worth close consideration. Whether FDA will further elucidate this interpretation of the statute in a subsequent version of this or another guidance remains to be seen.
Implications for Industry
For drug sponsors, while the Draft Guidance provides greater transparency regarding how FDA evaluates requests for 3-year exclusivity and what information applicants should provide when seeking exclusivity, FDA’s assessment of 3-year exclusivity will likely remain a nuanced exercise that continues to raise new and novel issues for consideration. And because the Draft Guidance does not address the scope of exclusivity protection, companies will likely continue to rely on case-specific FDA decisions, citizen petition outcomes, and litigation to make a more complete assessment for 3-year exclusivity in any given context.
Submissions of requests for 3-year exclusivity should be constructed and considered with care, with plans for 3-year exclusivity ideally established in connection with applicable clinical trial design, to ensure that the resulting clinical investigations are properly recognized.