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Demystifying Orange Book Designations: The New Referencing Approved Drug Products in ANDA Submissions Draft Guidance

Demystifying Orange Book Designations

Since its first appearance in 1980, the Approved Drug Products With Therapeutic Equivalence Evaluations publication (commonly referred to as the Orange Book) has served as a gateway for the emergence of generic drug products via the 505(j) drug approval pathway (and some new drug products submitted through the 505(b)(2) approval pathway). As veterans of the pharmaceutical industry know, the Orange Book (available in electronic and print copies) provides a list of drug products approved by the FDA on the basis of safety and effectiveness that can be used to identify a reference listed drug (or RLD) for submission of an Abbreviated New Drug Application (ANDA). But do not be fooled by the ease of access and wealth of information contained within the Orange Book; it does not list all possible drugs, and not all drugs included in the Orange Book can be used as the RLD for an ANDA.

The primary criterion for inclusion in the Orange Book is any product subject to an application with an approval that has not been withdrawn for reasons of safety or effectiveness. This encompasses not only currently approved and marketed new drug products, but also entries for each dose strength, other approved generic equivalents, and products that have been discontinued not for reasons of safety and effectiveness. Failure to identify the correct reference product for either the ANDA or for product bioequivalence (BE) studies could result in refusal to accept the ANDA (delayed product approval) or even a do-over drug development plan, both of which are not desirable outcomes.

The New Orange Book FDA Draft Guidance

Until recently, the terms RLD, reference standard, and basis of submission had been ill-defined and often a source of confusion among Orange Book users. In an effort to provide clarity and facilitate faster ANDA approvals, the FDA released a new draft guidance document, Referencing Approved Drug Products in ANDA Submissions. The draft guidance provides clear definition of critical terms (RLD, reference standard, and basis of submission), describes how to select an RLD with particular attention to navigating discontinued products, and shares key improvements to the Orange Book.

The RLD, the specific listed drug on which the applicant relies in seeking approval of its ANDA, “is a drug product approved under section 505(c) of the Food, Drug, & Cosmetic Act for which FDA has made a finding of safety and effectiveness.” While both active and discontinued drugs may serve as an RLD, the FDA cautions that discontinued listed drugs must first by evaluated by the Agency to determine the reason for product withdrawal. Previously, the FDA would not approve ANDAs relying on a discontinued RLD until after the formal determination that the product had not been withdrawn for reasons of safety and effectiveness was published in the Federal Register. To expedite ANDA approval, the Agency will now approve ANDAs once a final determination that the listed drug was not withdrawn for reasons of safety and effectiveness has been made, regardless of the publication status.

New RLD and Reference Standard Orange Book Listings

The reference standard, the drug product selected by the FDA that is required to be used for in vivo BE studies, is most often the RLD. But in some cases (e.g., the RLD has been withdrawn from sale for reasons other than safety and effectiveness or is no longer available), the Agency may select a different approved drug to serve as the reference standand. This has in the past caused a dilemma for drug developers because RLDs and reference standards were indistinguishable in the Orange Book. However, effective January 25rd, 2017, the new Orange Book debuted two separate columns for the RLD and reference standard to clearly separate each designation.

The FDA is also expanding their thinking in cases where a new reference standard may be needed, such as in cases where the current selected reference standard is not available in sufficient quantities to perform in vivo bioequivalence studies. If a reference standard is not identified on the active Orange Book list or is not available, applicants may initiate discussion with the FDA through submission of controlled correspondence, to obtain guidance on the appropriate comparator for necessary BE studies.

Errors in RLD Identification on Form FDA 356h

Regardless of the listed drug that is selected for use in vivo bioequivalence studies, it is critical that the ANDA applicant demonstrates that the proposed generic product is equivalent to the RLD by formulation and labeling and not the reference standard (if different). Accordingly, only the RLD should be listed as the basis of submission on Form FDA 356h and not the listed drug used as the reference standard in bioequivalence studies. But mistakes do happen and the FDA acknowledges that. In the event the wrong drug is identified as the RLD in your ANDA, an amendment may be submitted to your pending ANDA or a supplement to a previously approved ANDA to correct the identified RLD (no change to the RLD itself).

Orange Book Insights for 505(b)(2) Applications

While the guidance is obviously geared towards ANDA submissions by its title, there are a few hidden gems that also assist New Drug Application (NDA) submissions via the 505(b)(2) approval pathway. A listed drug within the Orange Book (active or discontinued list) may be relied upon for the Agency’s previous findings of safety and/or efficacy in a 505(b)(2) NDA submission; this may include any drug product previously approved through an NDA (either 505(b)(1) or 505(b)(2)). Strategic selection of a listed drug (if applicable) is pivotal for the development program of a product planned to be submitted through the 505(b)(2) pathway, as Camargo has previously discussed in multiple previous blogs (here, here, here, and here).

The new RLD draft guidance provides a wealth of FDA insights for selecting the correct listed drug that will hopefully reduce errors and confusion in future submissions. But like any reference book or secret decoder ring, its true strength lies in the hands of the user. Contact Camargo to help you navigate Orange Book listings for your next ANDA or 505(b)(2) submission to fuel your drug development program with success.


Author: Stefanie Johns, Ph.D., Scientific and Regulatory Specialist, Camargo Pharmaceutical Services