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505(b)(1) versus 505(b)(2): They Are Not the Same

The 505(b)(2) pathway can yield significant benefits in drug development cost and time. But what are the differences between 505(b)(1) and 505(b)(2)?

Drug development pathways in the United States are referred to by their corresponding section in the Food, Drug, and Cosmetics Act: 505(b)(1), 505(b)(2), and 505(j). There are other pathways to approval for biologics (BLA) and medical devices (510k and PMA), but for this back-to-basics article we will compare the innovative small-molecule pathways for approval: 505(b)(1) and 505(b)(2).

New drug application and approval pathways in the U.S.

505(b)(1): Traditional drug development via the 505(b)(1) pathway is typically used for novel drugs that have not previously been studied or approved. 505(b)(1) drug development requires the sponsor to conduct all studies needed to demonstrate the safety and efficacy of the drug.

505(b)(2): The Hatch-Waxman Amendments of 1984 were designed to prevent the duplication of existing studies via the creation of the 505(b)(2) pathway. A 505(b)(2) program must demonstrate safety and efficacy to the same standards as a 505(b)(1) program. However, existing data from studies not conducted by or for the sponsor, and for which the sponsor does not have right of reference, may be used to meet some or all of the safety and efficacy requirements. This usually means a 505(b)(2) drug product can be developed with less risk, in less time, and at lower cost (if done well) than a 505(b)(1) product. The large variation in types and strategic efficiencies of 505(b)(2) development programs creates a large range of time/cost estimates, but all are well below estimates for a 505(b)(1) program.

505(j) ANDA: Abbreviated new drug, or generic, approval requires a Sponsor to demonstrate bioequivalence to an innovator drug in lieu of replicating efficacy and safety studies. Generics are delayed from gaining marketing approval until the patent and marketing exclusivity for the innovator product have expired, the patents have been successfully challenged, or the application holder of the innovator product agrees to waive the exclusivity for the generic applicant.

The differences in NDA drug development

505(b)(2) programs by definition require fewer and/or smaller studies than 505(b)(1) products require, and the costs are significantly less in every phase of development. Additionally, it is more likely that nonclinical and clinical commitments for a 505(b)(2) product can be met post-market.

A lack of familiarity with the nuances of the 505(b)(2) pathway may also result in a larger development program than needed.

How do we know this? Premier Consulting is frequently asked to “rescue” poorly planned development programs that have stalled for various reasons, including study cost/time blowouts or an inability to identify or meet the FDA’s requirements. Realigning a nonclinical or clinical development program with innovative 505(b)(2)-specific strategies can get a sponsor back on track.

Also, while collecting data from FDA approval documents for our proprietary 505(b)(2) database, we often find programs that conducted large numbers of unnecessary studies that are typical of 505(b)(1) programs or just representative of a lack of strategic planning. The FDA has declared that certain studies were not required, and sometimes not even reviewed, for that reason. Unnecessary studies add time and cost and result in bloated development programs.

The need for early strategic assessment

While taking full advantage of the 505(b)(2) pathway can reap significant benefits in drug development cost and time, 505(b)(2) development does not always turn out to be faster, less risky, and less costly than 505(b)(1). The difference lies in what choices are made from the beginning of development. A strategic assessment helps prevent common industry missteps by identifying the target market, cost for development, medical need, and regulatory strategy from the beginning. We conduct a strategic assessment that evaluates a development program based on the four pillars of drug development.

The questions that need to be asked right from the product concept stage include:

  • How do I use a target product profile to position my product for the optimal market?
  • What current prescribing habits and medical standard of care should be considered, and how do they impact product differentiation and market uptake?
  • How can I utilize the existing science to optimize the formulation and reduce the size and scope of the clinical and nonclinical studies?
  • What are the regulatory opportunities? Which studies are/are not necessary for 505(b)(2) approval, and will my development program fulfill all of the regulatory requirements? How has the FDA’s thinking on a topic changed over time?

Even if your development program is already underway, it can benefit from a mid-program strategic assessment and gap analysis. To learn more about Premier Consulting’s early strategic assessment and to align your product and take best advantage of the opportunities available via 505(b)(2), contact us.


Angela Drew, PhD
Product Ideation Consultant