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Back to Basics: 505(b)(2) FAQs Part 3: Regulatory Strategies

As the 505(b)(2) expert, Premier Consulting is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved-marketed products, we thought it would be worth providing a refresher. Here is Part 3 in our series of frequently asked questions (FAQs). Stay tuned to this blog for more FAQs and Premier Consulting’s responses in the coming weeks.

Marketing Exclusivity

Q1:  505(b)(1) vs. 505(b)(2) – what are the timeline differences for the possible intrusion of generic competitors (assuming that the 505(b)(2) was assigned 5 years of exclusivity)?

Most new chemical entities (that is active moieties that have not previously been approved by the FDA) are approved via the 505(b)(1) pathway, and are assigned 5 years of marketing exclusivity if clinical studies* were performed. This means that a generic (ANDA) application for the product cannot be filed until the end of the 5th year, or the end of the 4th year if a certification of patent invalidity or noninfringement (Paragraph IV challenge) is submitted in the application. Products approved via the 505(b)(2) pathway, however, may be assigned 0, 3, 5, or 7 years of marketing exclusivity depending on the regulatory situation (see Q3 below). Assuming a 505(b)(2)-approved product is a new chemical entity and is therefore assigned 5 years of marketing exclusivity, as per the question, then the theoretical timeline for potential generic competition is the same as for a 505(b)(1)-approved product: 5 years. In reality, as current ANDA review times can exceed 3 years**, most products with 5 years exclusivity are on the market for 6-8 years before the arrival of generic competition.

*As per the definition of “clinical investigations” defined in 21 CFR 314.108
**The progressive GDUFA performance goals are expected to reduce FDA review time.

Q2: For the unapproved drugs that are on market (NCE), would regulatory exclusivity be 5 years?

Unapproved drugs are eligible for 5 years of marketing exclusivity, if they have never been approved by the FDA, known as a new chemical entity (NCE) or new molecular entity (NME). Although most products that have been approved (current and discontinued) are listed in the Orange Book, some are not listed. Premier Consulting can perform a search of the Federal Register to find if evidence of a prior approval or withdrawal of application is listed.

Q3: How is the exclusivity period determined for a 505(b)(2) application?

The FDA determines whether a drug product receives exclusivity at the time of NDA approval. Exclusivity periods are not available for Phase 1-only programs, 3 years for products that required Phase 2 and/or 3 (clinical) studies* for approval, 5 years for an NCE, and 7 years for an orphan drug. However, granting marketing exclusivity can be complicated for some products and can result in lengthy litigation, particularly for products designated as orphan. See our previous blogs on exclusivity for further discussion and examples.

*As per the definition of “clinical investigations” defined in 21 CFR 314.108

Patent Certification

Q4: Can you explain the situation regarding potential Paragraph IV legal issues prior to approval?

NDAs approved via the 505(b)(2) pathway and that rely on a Listed Drug are subject to the same patent regulations as products approved via the 505(j) pathway (ANDAs). Briefly, this means that the company filing the 505(b)(2) application must certify that there are no patents listed in the Orange Book (Paragraph I), that all patents have already expired (Paragraph II), that the application should be approved after all patents expire (Paragraph III), or that any patents are invalid or not being infringed upon (Paragraph IV). If the latter, the company holding the application for the Listed Drug product can file a patent infringement suit within 45 days of notification by FDA, and a 30-month stay on the application’s approval takes effect unless the sponsor can successfully defend the suit earlier than this. Until then, FDA can only tentatively approve the 505(b)(2) application. In practical terms, as either option will usually delay the approval of the 505(b)(2) application by several years, it is best to be aware of the patent situation as early as possible.

Q5: If the patent of parent drug is still effective, can its prodrug be filed as 505(b)(2)?

In this case, the parent drug will be used as the Listed Drug for approval of the 505(b)(2) application. This will require certification against each existing unexpired patent for the Listed Drug in the Orange Book, as summarized in Q4.

Rx to OTC Switch

Q6: How do we decide if we go OTC or NDA?

If a drug product does not comply with the requirements of an OTC drug monograph (21 CFR Part 330), it must be approved as an NDA (or an ANDA if an innovator, or Reference Listed Drug product exists) as per the respective requirements under 21 CFR Part 314. The product can be approved for OTC use if the sponsor can demonstrate that it is safe and effective for use by consumers without the assistance of a healthcare professional. If already approved, the 505(b)(2) pathway is appropriate for a switch from prescription to OTC status.


The 505(b)(2) regulatory pathway allows for the approval of a broad range of products that represent a broad range of regulatory and patent scenarios. It is therefore not surprising that the outcomes for exclusivity determinations and patent certifications can be highly variable and occasionally litigated. Similarly, an Rx to OTC switch is almost always a unique scenario with unique requirements for approval. Experience with the 505(b)(2) pathway is naturally important in assessing the options and outcomes for a proposed drug product.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways that Premier Consulting’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Other installments in “Back to Basics: 505(b)(2) FAQs”:


Angela Drew, Ph.D.
Product Ideation Consultant