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Is a Reference Listed Drug Mandatory in the 505(b)(2) Pathway?

If you are a frequent reader of our blog, you know that the 505(b)(2) pathway can facilitate a cheaper, faster drug approval route. This is accomplished by relying on: 1) safety and efficacy data from published literature and/or 2) the agency’s assessment of safety and efficacy of a FDA-approved product, known as the “reference listed drug”, or RLD*. While many 505(b)(2) applications can and should use an RLD, the necessity of an RLD in a 505(b)(2) application is a common misconception. In fact, there are many situations where using an RLD doesn’t make sense from a scientific or strategic perspective. In this post, we will discuss some considerations involved in choosing a “No RLD” strategy.

In some cases, an RLD is simply not necessary. Active pharmaceutical ingredients (APIs) with a long history of use may have enough publicly available data to “cover all the bases” for safety or efficacy. Premier Consulting recently worked with a sponsor developing a product with an API that was part of a class of drugs with a long history of use. Because of this extensive history, much was known about this API’s of mechanism of action, safety, and side effects. Upon further investigation, all of the information needed to satisfy the FDA’s safety requirements could be found in published literature. This included nonclinical data, drug interaction information, mechanism of action, local effects and safety information. Therefore, the sponsor only needed to provide evidence of efficacy, which was accomplished by a Phase 3 study that was already underway. Since there was no reliance on data previously accepted by the FDA, a “No RLD” strategy could be used.

The twist to this story is that this same product could have cited an RLD in the application. While this would have been a reasonable approach, the RLD under consideration was on patent for many more years. If this RLD had been used in the application, the filing would have been subject to patent infringement litigation and a 30-month stay on approval. Therefore, while an RLD can prevent unnecessary duplication of studies of efficacy and safety, it can also have important legal implications. Clearly, this decision shouldn’t be taken lightly!

With the option of “RLD” vs “No RLD” on the table, of course the sponsor chose the “No RLD” strategy. This is just one of many situations where a “no RLD” strategy can be used. With all the options available in a 505(b)(2) pathway, working with an experienced regulatory team can help save you time and money. So whether your application has an RLD, no RLD, or you need help deciding which is the best strategy, the experts at Premier Consulting can help you plan the best path forward.

*The Orange Book refers to a Reference Listed Drug, or RLD, for a generic and its correlating 505(j) approval pathway. For 505(b)(2) pathway, the Orange Book uses the term Listed Drug. For simplification and the purposes of this article, we are using the term RLD for both 505(j) and 505(b)(2) applications.