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Key Inflection Point in a Drug’s Time to Market: Choice of Regulatory Pathway

Traditional drug development follows a standard process beginning with nonclinical studies and moving into clinical studies, all with the purpose of proving a new drug candidate is safe and effective. When the U.S. opened up an alternate path, 505(b)(2), the primary purpose was to utilize existing data and knowledge, minimize costly animal and human studies, and cut down on the lengthy time to market for new life-saving drugs. But how much savings is possible by utilizing the 505(b)(2) pathway? Could choosing a 505(b)(2) route to market for a drug candidate save upwards of $20 million in development cost and more than 2 years in development time? You might be surprised by the answer.

A Comparison of the Regulatory Pathways

A new drug product can be approved by the US Food and Drug Administration (FDA) via one of three regulatory pathways covered under Section 505 of the Federal Food, Drug, and Cosmetic Act:

  • 505(b)(1) new drug application (NDA), or an application that contains full reports of investigations of safety and effectiveness;
  • 505(j) abbreviated new drug application (ANDA) or generic drug application wherein the application contains information to show that the proposed product is identical to a previously approved product in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use (among other things) – noting that there are allowable formulation differences for certain routes of administration; or
  • 505(b)(2), which is a combination of the 505(b)(1) and 505(j) pathways and involves full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by the application (or for which the applicant has not obtained a “right of reference”).


The 505(b)(2) NDA regulatory pathway was created by the Hatch-Waxman Amendments of 1984, in part, to help avoid unnecessary duplication of studies already performed on a previously approved product. Similar to a 505(j) application, a 505(b)(2) may “rely” on the Agency’s previous findings of safety and/or efficacy of a reference product (the “listed drug” in the case of a 505(b)(2) application or a “reference listed drug” for a 505(j)) to reduce the burden for approval in terms of number of studies required. Alternatively, a 505(b)(2) application may also rely on information from other publicly available sources, such as the published clinical literature, provided an adequate scientific bridge can be established that links the Sponsor’s product to the product or products referenced in the literature studies.

In a 505(b)(1), all information required for approval must be completed de novo by the Sponsor with the proposed product, including required nonclinical (animal) pharmacology, pharmacokinetics, and toxicology studies, preformulation studies, analytical methods development, stability work on the active ingredient and dosage form, and all clinical studies (Phase 1, 2, and 3). On the other hand, a 505(j) application is based largely on establishment of bioequivalence to a reference product using established methods (although methods validation may still be required).

A 505(b)(2) program differs from these other regulatory pathways in that 505(b)(2)s are unique and can vary greatly in terms of size and structure. A 505(b)(2) program could involve no clinical studies, with reliance on all literature to support both safety and efficacy of a product; or, a simple program may just involve single bioequivalence study bridging the Sponsor’s product to a listed drug to demonstrate safety and efficacy through similarity in systemic exposure to the approved product. 505(b)(2) programs can also be larger, involving a single pivotal study, with support provided by safety information from a listed drug or published literature. Alternatively, some 505(b)(2) programs rely only on nonclinical information from a publicly available source, while a full clinical program is required.  The key aspects of product planning as outlined in the figure below are described in more detail on our 505(b)(2) guide.

In addition to the size and complexity of the program, the 505(b)(2) pathway differs from 505(b)(1) in terms of the order of the steps. For instance, while a Pre-IND meeting with 505(b)(1) generally occurs after nonclinical work and formulation development, a Pre-IND meeting in 505(b)(2) is often the beginning of the process. In many cases, the goals of this meeting also differ between the regulatory pathways. For 505(b)(2), the Pre-IND is focused on gaining FDA input and concurrence with the development strategy, including what studies are required and what publicly available information can be relied upon in the eventual NDA application. In some cases, a Pre-IND meeting for 505(b)(2) can function more like a Pre-NDA meeting, depending on the complexity of the program.

As discussed above, the number of studies are also often different, with a 505(b)(2) program potentially requiring no studies or a single bioequivalence study, compared to a full 505(b)(1) program. In some cases, a Phase 3 study may be conducted, but with fewer patients and supported by a Phase 2 study or data available from the published literature. The timing of studies differs between the 2 regulatory pathways; as 505(b)(2) relies on pre-existing data, nonclinical and clinical studies can often be run in parallel rather than sequentially, shortening the overall time to market for the Sponsor’s product. The timing of when clinical trial material (CTM) is required also may differ between the two pathways. In a 505(b)(2) program that involves demonstration of clinical bioequivalence (Phase 1), CTM should be representative of the commercial manufacturing process, including packaging. As a consequence, CMC work should be invested prior to initiating even Phase 1 studies.

Taken together, these differences between 505(b)(1) and 505(b)(2) represent a formidable, multifaceted challenge. In 505(b)(2), mishandling of these steps, particularly those early on, could result in product-development failure. Alternatively, when managed skillfully, the 505(b)(2) pathway can result in important victories for a sponsor, including promoting interest from investors, demonstrating a clear path to approval, and reducing costs and time to market.

Why Choose Premier Consulting to Help Navigate the 505(b)(2) Regulatory Pathway?

In one recent example, Company A initiated product development discussions with FDA through a regulatory consultant using existing 505(b)(1) guidance. The result of their first Pre-IND meeting was a recommendation from FDA to conduct many clinical trials estimated to cost $25 million and take longer than 3 years. Company A did not have funding for the plan and sought assistance from Premier Consulting to rescue the project. Through analysis of the product’s scientific and medical viability, Premier Consulting identified a possible solution. The previous development program did not make use of existing data from outside sources, a unique possibility in the 505(b)(2) pathway. Armed with this new information and following Premier Consulting’s approach and recommendations, Company A conducted another Pre-IND meeting with FDA. The Agency reversed its decision and required only a single Phase 1 bioequivalence study, which reduced the initial 3-year plan to mere months and cost less than 10% of the initial projected total. The key is in the experience and relationship with FDA, and in the expertise leveraging relevant existing data. The difference is Premier Consulting.

505(b)(2) Can Reduce Cost and Time to Market

Using the 505(b)(2) regulatory pathway, a Sponsor may be able to provide safety and effectiveness data for NDA approval without expending the same amount of money and time required to complete all the requisite studies de novo, resulting in a less expensive and faster route to approval compared with the traditional 505(b)(1) development path.

The range in complexity in 505(b)(2) programs is wide. Learn more about ways Premier Consulting can help navigate the 505(b)(2) regulatory approval pathway successfully, or contact us here.