Identification of and comparison to a Reference Listed Drug (“RLD”) and Reference Standards (“RS”) are the lynchpin of generic drug development and approval. It’s therefore no surprise that, upon significantly updating the Orange Book in January 2017, FDA dedicated an entire guidance to fundamental definitions and procedures relating to RLDs and RSs. Now, on the 40th anniversary of the Orange Book, FDA has updated and finalized this guidance, formally titled Referencing Approved Drug Products in ANDA Submissions, as part of its ongoing Drug Competition Action Plan.
Admittedly, very little has changed between the draft and final versions of the guidance Referencing Approved Drug Products in ANDA Submissions. Subtle changes dominated, including a shift in the language used to discuss ANDAs approved under section 505(j): the draft guidance generally referred to ANDAs as drugs that are “the same” as their RLDs while the new version chose the much more precise word, “duplicates.” Given that FDA has shifted its interpretation of the PDUFA exception for “same product as another product” from therapeutic equivalence to pharmaceutical equivalence, it could be that the use of “duplicate” rather than “same” was intended to avoid revisiting discussions of whether same drug, in this case, means therapeutic equivalents or pharmaceutical equivalents. Regardless, this choice of language makes it very clear when FDA is referring to true ANDAs rather than suitability petition ANDAs or pharmaceutical equivalents approved as 505(b)(2) NDAs.
The most notable change in the guidance document is practical. Previously, sponsors seeking designation of an additional RLD or RS were required to submit a Citizen Petition; a Controlled Correspondence could be used for such a request only when no RLD or RS was designated. Because, unless a Citizen Petition is subject to Section 505(q) of the FDC Act, FDA responds at a snail’s pace, Citizen Petitions for new RLDs or RSs languished for years. Now, the final guidance directs all requests for new RLDs and RSs through the Controlled Correspondence pathway, subjecting them to PDUFA response deadlines of 60 days for non-complex questions and 120 days for complex questions. Theoretically, designation of RLDs and RSs should not be complex, but even if such requests are considered complex, a 120 day response timeline is significantly preferred to no discernable timeframe. A question remains, however, of how and when FDA will deal with the many outstanding Citizen Petitions requesting a new RLD or RS, particularly because Controlled Correspondence PDUFA goals do not apply when the Controlled Correspondence is related to a pending Citizen Petition; in such a case, the PDUFA timeline starts only after FDA has responded to the Citizen Petition in question.
There are some other small but notable changes in the final version of the guidance. In the final version, FDA explains that it can move a listed drug product to the Discontinued Section of the Orange Book if the “listed drug is not available for sale.” Previously, FDA would only move a listed drug to the Discontinued Section after an applicant notifies FDA that it is withdrawing the listed drug from sale or if FDA determines that the listed drug has been withdrawn; the final guidance appears to change the policy so that FDA can merely determine that a product is “not available for sale.” Whether this means that FDA will move a product of its own volition based on an inability to obtain the product on the open market is yet to be seen, but it certainly seems as though FDA is giving itself more leeway to proactively move products to the Discontinued List. Similarly, FDA previously had stated that it would select a new RS based, among other elements, on “units sold,” but the final guidance revises this factor to “commercial data,” which, again, provides FDA more flexibility to interpret the term “commercial data” so that it is not bound to select an RS based specifically on “units sold.”
FDA included a few other revisions. The final guidance also notes that authorized generics can be used as an RS, but suggests that additional documentation may be required; sponsors are directed to contact Office of Generic Drugs for more information. The guidance suggests that all in vitro testing be performed in the RS, even though not specifically required under FDA regulations. And, even though the 2017 guidance made clear that only NDAs approved under 505(c) are eligible as RLDs, the final version made it expressly clear that ANDAs cannot serve as RLDs (so please stop asking!).
In sum, the revised guidance isn’t game changing, but the procedural elements should help facilitate the designation of additional RLDs or RSs. The little changes throughout will likely have minimal effect, but to the extent that they do, they provide FDA more flexibility than the draft version. Regardless, both versions are certainly helpful for generic manufacturers navigating the generic drug approval system to do what they do best – making copies.