Section 505(b)(2) of the Food, Drug, and Cosmetic Act describes a 505(b)(2) new drug application (NDA) as an application where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This type of information can be sourced from the published literature and/or from the Agency’s findings of safety and efficacy for a previously approved drug, or what is known as a listed drug (LD). The LD is defined in 21 CFR §314.3 as “a new drug product that has been approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety and effectiveness or under section 505(j)(6) of the Federal Food, Drug, and Cosmetic Act, and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.”

Identifying a Listed Drug

How do you know if a drug product is considered an LD? The answer is continued in 21 CFR §314.3, in which “listed drug status is evidenced by the drug product’s identification in the current edition of FDA’s ‘Approved Drug Products With Therapeutic Equivalence Evaluations’ (the list) as an approved drug. A drug product is deemed to be a listed drug on the date of approval for the NDA or ANDA for that drug product.”

Drug products that are designated as a reference listed drug (RLD) in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, or the Orange Book as it is more commonly called, can be used as LDs for the 505(b)(2) pathway. These approved drugs with the RLD designation can also be used as the basis of approval for new generic drugs in an abbreviated NDA (ANDA). Generic drugs, on the other hand, usually cannot be used as the basis of approval for any new drugs because safety and efficacy has not been demonstrated (there are exceptions, see one below). Stay tuned for more information about a new guidance on “Referencing Approved Drug Products in ANDA Submissions” in an upcoming blog!

An applicant should choose an LD that is the most similar to their new drug product and get their choice approved by the Agency (although the Agency may reject this choice if they think another product is more appropriate). Ideally, all exclusivity and patents should be expired by the time of NDA filing, as patent owners can impose a 30-month stay on FDA approval if patent infringement occurs. The Orange Book lists any exclusivity or patent protection remaining for the LDs.

Other Listed Drug Considerations

What happens if the Orange Book lists a desired LD as discontinued? In Premier Consulting’s experience, as long as the drug was not withdrawn due to reasons of safety or efficacy, the NDA for the product in question is still considered the LD. However, as the physical LD is not available, the applicant may submit controlled correspondence to the Agency asking if an appropriate equivalent can be used as the comparator in the bridging studies.

For example, the Agency required a relative bioavailability study comparing naloxone released from Targiniq^®, a combination product of oxycodone and naloxone, to intravenous naloxone. However, the LD for injectable naloxone, Narcan^®, was discontinued for reasons other than safety and efficacy. Therefore, the Sponsor had to substitute a generic (now designated as the reference standard in the new Orange Book) for naloxone in order to bridge to the safety and efficacy information from the Narcan label.

Bridging to a Listed Drug

In order to rely on the previous findings of safety and efficacy for an LD, the applicant must establish a scientific or clinical bridge to demonstrate the similarity of their product to the LD. This is often accomplished through a Phase 1 bridging study. Adrug is considered bioequivalent to an LD if the rate (C_max, or maximum plasma concentration of the drug) and extent of absorption (AUC, or area under the curve) do not show a significant difference from the rate and extent of absorption of the LD. Both products must be administered at the same molar dose of the therapeutic ingredient under similar experimental conditions (21 CFR §320.23). For bioequivalence, the 90% confidence interval for each parameter must fall between 0.80 and 1.25.

Depending on how factors such as route of administration, dosage, or indication differ between the test product and the LD, Phase 2 and/or Phase 3 studies from the approved product label may be relied upon in lieu of sponsor-conducted studies if bioequivalence is established. Even if bioequivalence fails, some information from the approved product labeling may still be applicable. If the test product has equal or greater bioavailability than the LD, efficacy findings for the LD might be relied upon. On the other hand, if the test product has equal or lesser bioavailability, safety findings for the LD might be used.

In summary, relying on a Listed Drug can reduce the number of studies needed for approval of a 505(b)(2) drug product. However, knowing how to leverage this data can be a challenge without experience in interpreting the rules and regulations. To learn more about choosing the right LD for your drug product or developing a bridging strategy, contact us.