In April 2022, FDA released a proposed draft guidance (FDA Dock. No. 2022-D-0108) involving pH adjusters in drug development relating to ophthalmic, parenteral, or otic drug products. The Draft Guidance suggests that FDA may entertain proposed ANDA formulations that differ in the pH adjuster in the ANDA formulation as compared to the Reference Listed Drug (RLD). This may be important for ANDA developers because typically the proposed ANDA drug product will match the RLD formulation composition so that the ANDA drug product is Q1/Q2 to the RLD. But savvy RLD holders will also have patents that match the RLD formulation, usually with spot on patent claims (e.g., a so-called “picture claim”) that cause potential infringement issues for the ANDA developers. And of course there’s nothing wrong with a patent holder obtaining broad and narrower formulation patent claims. It’s part of a good strategy as part of its return on investment. But for ANDA developers the FDA and IP legal interplay, well, come into play. FDA requires ANDA developers to prove bioequivalency. For most drug products such as solid oral doses, ANDA developers have some free reign to swap out inactive ingredients yet still show bioequivalency. For some products, like ophthalmic, parenteral, and otic drugs, the FDA requires a stricter identity of the inactive ingredients. And thus, if an ANDA developer has to copy the RLD’s formulation to be deemed Q1/Q2, and assuming the brand company has a formulation patent directly on the RLD formulation, then it’s harder for the ANDA developer to argue non-infringement. Every case is fact specific and there is no general rule that patent infringement must occur.
FDA regulations govern what the ANDA drug product must and then need not contain viz the RLD. For parenterals, 21 C.F.R. §317.94(a)(9)(iii) states that the ANDA formulation has to contain the same inactive ingredients in the same concentration as the RLD, except “an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.” In other words, the ANDA developer can swap out the preservative, buffer or antioxidant (or change the concentrations of the same ingredients) so long as that swap can be justified.
Under §314.94(a)(9)(iv), for ophthalmic and otic drugs, the ANDA developer “may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, substance to adjust tonicity, or thickening agent provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product, except that, in a product intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for the purpose of claiming a therapeutic advantage over or difference from the listed drug, e.g., by using a balanced salt solution as a diluent as opposed to an isotonic saline solution, or by making a significant change in the pH or other change that may raise questions of irritability.” In other words, the developer can swap out the preservative, buffer, tonicity adjuster, or thickening agent (or change the concentrations of those) so long as the swap can be justified.
The Draft Guidance identifies pH adjusters as a possible exception to the exception and accordingly, ANDA developers can seek a waiver of the same-ingredient requirement. The FDA is not stating that pH adjusters are now part of list in §314.91(a)(9)(iii) or (iv). Rather, the FDA is saying that if the ANDA developer wants to swap out the pH adjuster or use the same adjuster but in a different concentration, then the developer has to file an official waiver request under §314.99(b).
Requesting a Waiver under §314.99(b) For pH Adjuster Changes
As mentioned above, the ANDA developer can either swap out the pH adjuster or use the same adjuster but in a different concentration. The developer has to justify, based on science, such changes to the FDA. That science can come from the ANDA testing, from literature support, from the rationale used in approving the RLD itself, and other FDA waivers granted in other ANDA products. A key consideration will be on the safety and efficacy of the proposed ANDA product. For example, if the pH proposed is very low (very acidic) will it burn the person’s eye or burn the ear when dropped in? Or will the pH affect the drug product itself by causing clumping or particulates in an injection? FDA stated that a waiver will not be granted if the proposed pH adjuster change: forms a different form of the active ingredient than the RLD in the final product; or uses or forms a novel inactive ingredient in the final product that has not been used in an FDA-approved drug product, the safety of which cannot be established without clinical testing.
Typically, ANDA developers will file controlled correspondence seeking FDA input as to which of the ANDA proposed formulation will match (be Q1/Q2 to) the RLD. The Draft Guidance states that the Waiver for a pH adjuster change is not appropriate for a controlled correspondence at the outset. If the proposed formulation(s) do not match the RLD formulation and the differences are such that the developer believes that the differences can be justified under the pH adjustment waiver process, then the developer has to file the §314.99(b) waiver, with the requisite justifications. If the developer chooses not to follow the advanced controlled correspondence route and goes straight to the ANDA filing, then the applicant is advised to file the pH adjuster waiver at the same time. Otherwise, the ANDA developer will get a “refuse to receive” letter presumably because the as-filed ANDA formulation does not match the RLD and is not Q1/Q2.
We should finally note that simply because the FDA has permitted a pH adjustment waiver to be filed does not mean that the FDA will grant the waiver. The FDA’s change in position is based on its experience with pH adjusters but this should not imply that the FDA will use that experience to grant each waiver. Indeed despite the Draft Guidance permitting a Waiver to be filed, the FDA may nonetheless require matching.
Implications of the pH Adjustment Waiver For Branded and Generic Drug Companies
As mentioned above, the patent implications are important. First, current branded drug companies have already obtained issued patents on its drug formulations. It cannot file new patents on the current formulation given that the approved and marketed RLD drug is prior art to itself. But if an ANDA developer can now change certain pH adjusters, that ingredient or concentration change may now provide an ANDA developer with a design-around noninfringement strategy. Previous ANDA filers may have filed the ANDA, engaged in typical Paragraph IV patent litigation, lost, and have the ANDA approval blocked. But new ANDA filers can take a new approach.
For branded drug companies that are still in development, the IP strategy should include investigating how pH adjuster changes (different ingredients or changes in concentration) can be patented. That is, sometimes a branded company has a tunnel vision and obtains patents only on its formulation, but fails to consider the generic company mindset. As this Draft Guidance indicates, with flexibility comes a change of mindset. Brand companies should always ask, “how would a generic company design around my patents yet still be bioequivalent?”
Also, for newly approved branded drugs, the FDA may later in time issue a Product Specific Guidance (PSG) identifying certain considerations for ANDA developers. Brand companies can assist the FDA in promulgating a relevant PSG by submitting bona fide scientific information, probably in the form of a Citizen Petition. But as with any CP filed, the company should ensure that the information is truthful, accurate, and scientifically sound, otherwise there may be some anti-competition claim made later.
For generic drug companies, certainly the flexibility on pH adjustment waiver is potentially good news as it may provide a new noninfringement position that might not have existed before. ANDA sponsors that have already filed, litigated, and lost (assume for this purpose it was related to the pH), this ANDA sponsor may decide to re-formulate to potentially design around the relevant patents. The reformulation may implicate new Paragraph IV certifications and notifications (i.e., a new Paragraph IV notice letter), but that activity may help in getting the ANDA finally approved. For new ANDA development, this pH adjustment waiver may help in an initial design-around noninfringement strategy. That will improve the Paragraph IV strategy.
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