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Reference Listed Drugs (RLDs):Can More Than One Be Used?

Recently we considered the case of a 505(b)(2) NDA without an RLD.  So let’s ask if  a 505(b)(2) NDA have more than one RLD? In a word, the answer is “yes”!

When using the 505(b)(2) regulatory pathway, Sponsors may rely on the Agency’s previous findings of safety and/or efficacy of an already approved product which is termed the Reference Listed Drug (RLD). The RLD is often an approved product consisting of the same active moiety but in a different dosage form or strength. The Sponsor is expected to show why reliance on data for the RLD is scientifically appropriate for the new product. To do this, a “scientific bridge” to the RLD can be created through clinical BA/BE studies, in vitro studies, or nonclinical studies.

If more than one product containing the active moiety being tested has been approved, it is possible to have more than one RLD. The benefit of having multiple RLDs is that each RLD may provide additional data to satisfy NDA requirements. For example, one RLD may provide a history of safe and effective clinical use, while another more recently approved RLD may provide additional nonclinical data that meets current standards for approval. Thus, the 2 RLDs together would provide clinical and nonclinical support for the proposed product.

Another instance where multiple RLDs can be used is when a Sponsor is developing a combination product consisting of 2 active moieties. In this case, each approved active moiety will typically be used as an RLD. A scientific bridge between the new product and each RLD will need to be established.