For those of us that live in areas with seasonal changes, I’m sure everyone has experienced the telltale signs that autumn is right around the corner. These changes are subtle at first but soon gain significance and portend a future that looks different than the present. Individuals who carefully examine the FDA’s Paragraph IV (PIV) Patent Certifications webpage may have noticed some subtle changes to several listings, but the underlying questions are what caused the FDA’s shift and how will those changes impact the future? The FDA had previously published an update to the PIV Patent Certifications webpage on August 19th, and then updated it again on August 26th. Anyone who frequently reviews these listings recognizes that two updates in the span of a week is a bit unusual and far more rapid than normal. Here is a summary of the changes that appear to have taken place between the August 19th version and the current August 26th version.
August 19th Version: Listings for ANDAs referencing Tralement
August 26th Version: Listings for ANDAs referencing Tralement
Note that not all columns from the PIV Patent Certifications webpage have been copied as not all of the columns were populated, nor did they all contain changes relevant to this discussion. Changes associated with the August 26th listing are highlighted in yellow and impact the Date of Submission of the First Applicants and the number of First Applicants. The original date of November 16th posted by the FDA corresponds to the date that is one day after U.S. Patent No. 11,786,548 (‘548 patent) was published in the Orange Book (November 15th), where the submission date published for that patent listing is November 14, 2023. Publication of the November 16th date aligns with the FDA’s regulation at 21 CFR 314.94(a)(12)(viii)(C)(ii), which broadly applies to Amended Certifications. The revised date of November 14, 2023 now corresponds with the patent listing date of the ‘548 patent. We will need to wait to see whether the FDA clarifies why it changed these listings, which resulted in two additional First Filers potentially being eligible for 180-day exclusivity. Perhaps the FDA’s intent hasn’t changed with respect to applications that have been submitted and are pending review where the applicant must amend their existing application. If that is the FDA’s interpretation, then the aforementioned regulation could remain intact. This could explain the changes for those ANDAs referencing Tralement, which were original ANDA filings as evidenced by the New Chemical Entity (NCE) exclusivity that expired on April 30, 2024. Hopefully the FDA will offer some clarification behind this change as it does impact submission strategies for future ANDAs.
Additionally, the FDA updated listings for ANDAs that reference Relistor, where FDA added a listing for a prefilled syringe.
August 19th Version: Listings for ANDAs referencing Relistor
August 26th Version: Listings for ANDAs referencing Relistor
The changes associated with the Relistor updates are a little more obvious in that the FDA added an additional listing for 12 mg/0.6 mL Single-Dose Prefilled Syringes and added additional information for the container closure systems pertaining to each listing. The FDA’s update does also include information that on August 26, 2024, it deferred a 180-day status decision and approved a First Applicant on August 26, 2024, but I did not include that information in the tables as it isn’t entirely relevant to this discussion.
Changes associated with the Relistor updates don’t appear to be particularly monumental for sponsors with pending ANDAs for Methylnaltrexone Bromide Injection. However, this change does have the potential to impact other listings or, more importantly, the lack of listings on the PIV webpage. Generally speaking, the FDA has administered 180-day exclusivity in alignment with what it considers different drug products where those different drug products result in separate line listings in the Orange Book. That could be the basis for the FDA’s decision here where the August 26th listings do correspond to separate line listings for Relistor in the Orange Book. What remains unclear is whether the FDA now intends to begin routinely listing newly approved NDA drug products in the Orange Book based upon differences in container closure with the attendant impact that such will have on PDUFA user fees or whether the FDA will simply align 180-day exclusivity with past Orange Book listings. There are many examples where the FDA has not created separate line listings for products based on differences in container closure, but a recent excellent example can be found with the Orange Book listings for Elucirem NDA 216986, which currently has seven line listings in the Orange Book and those line listings correspond to different strengths. However, much like Relistor, Elucirem offers different container-closure presentations for the same strengths where it is available as both a Single-Dose Vial and a Single-Dose Prefilled Syringe for the following strengths: 3.75 mmol/7.5 mL, 5 mmol/10 mL, and 7.5 mmol/15 mL.
There are certainly other drug products, which won’t be mentioned in this blog, where a difference in container closure may lead to a separate round of 180-day exclusivity based on Orange Book listings. We will all just have to wait and see what changes are headed our way!
