Generic industry urges FDA to eliminate citizen petitions for TE ratings for 505(b)(2) products

Regulatory NewsRegulatory News
| 22 September 2022 | By Joanne S. Eglovitch 

Generic drug industry stakeholders told the US Food and Drug Administration (FDA) to eliminate its proposal to require companies to submit citizen petitions for requesting therapeutic equivalence (TE) evaluations for 505(b)(2) applications, saying this process will not work and will hurt the makers of complex generics. They also requested that FDA not remove from the Orange Book drugs that have been discontinued.
These comments were in response to FDA’s draft guidance issued in July. (RELATED: FDA offers new guidance on therapeutic equivalence evaluations, Regulatory Focus, 20 July 2022)
FDA received six comments on the guidance, with many of the responses echoing similar sentiments.
Drugs that can be submitted through the 505(b)(2) pathway include new versions of approved drugs that differ in the reference listed drug (RLD) in terms of active ingredient, dosage form, strength, route of administration, formulation or when there is a new indication. FDA says in the draft guidance that 505(b)(2) applicants would need to submit a citizen petition to request a therapeutic equivalence evaluation.
Teva voiced the harshest criticism of the draft guidance, stating that it “objects to FDA’s use of citizen petitions to assign TE ratings for 505(b)(2) applications that have demonstrated bioequivalence and pharmaceutical equivalence. Teva has submitted comments to FDA on multiple occasions explaining that the citizen petition process for TE ratings for 505(b)(2)s does not work. Teva has also submitted similar comments to CMS pointing out how FDA’s inefficient system for assigning TE ratings for 505(b)(2) applications impedes the appropriate reimbursement of multisource drugs approved under that pathway.”
Citizen petitions hurts makers of complex generics
Teva said it “routinely” submits parenteral generic products via the 505(b)(2) pathway that are not qualitatively and quantitatively (“Q1/Q2”) the same as the listed drug.
The company states that “generally, 505(b)(2) products that request a TE rating represent generic alternatives for certain dosage forms that cannot be approved via 505(j) but that nevertheless are intended to be marketed as generics. Without a TE rating these products cannot be appropriately substituted at the pharmacy or properly reimbursed at lower prices.”
Teva said that it can take years for FDA to resolve a citizen petition requesting assignment of a TE rating for a newly approved 505(b)(2) product, “Forcing consumers to pay higher prices for both the brand product and the 505(b)(2) when the 505(b)(2) product could otherwise be substituted under applicable state law, sold at a lower price, and bring down the price of the brand product as well.”
Instead, the company urged FDA to assign TE ratings to 505(b)(2) products upon approval instead of via a citizen petition.
Teva said it conducted a study on FDA’s response rate for citizen petitions requesting TE ratings for 505(b)(2) products on all petitions requested since 2016. It found that out of the 23 petitions listed, FDA granted two and dismissed two while four petitions were withdrawn and 15 of the 23 petitions (or 65%) remain pending. The average number of days pending is 880; with a range of 189-1,644 days.
“A citizen petition is a highly inefficient, or even impossible, way to gain a TE rating for a 505(b)(2). FDA typically assigns a TE rating immediately after (or shortly after) approving a therapeutically equivalent product under an ANDA. It is hard to understand why FDA would not implement a similar process for 505(b)(2) products that request a TE rating as part of the application and that rely on a bioequivalence-based scientific bridge or biowaiver for approval.”
AAM also wants TE changes
The Association for Accessible Medicines (AAM) also requested that the citizen petitions process be eliminated and that 505(b)(2) applications get a TE rating at the time of submission.
AAM said it “would be far more efficient for FDA to allow 505(b)(2) applicants that can show their products are therapeutically equivalent to an RLD to submit a request for a TE rating at the time they submit their application, and for FDA to consider that request when it is reviewing the application that contains the data that demonstrate TE.”
AAM further noted that “citizen petitions requesting TE evaluations for 505(b)(2) applications can languish unanswered sometimes for years.”
During the time that a citizen petition is pending or being reviewed, “Pharmacies are unable or unwilling to substitute cheaper generic products, and the Centers for Medicare and Medicaid Services (CMS) cannot reimburse the product approved under a 505(b)(2) application as a multisource product at substantial cost savings to the government.”
Apotex concurred and said that submitting a citizen petition to request that a 505(b)(2) NDA is equivalent to the RLD results in unnecessary delays.
“During this lag from approval to citizen petition response/TE rating, pharmacies will not substitute 505(b)(2) NDAs (nor the Centers for Medicare and Medicaid Services (“CMS”) reimburse) that would otherwise already have an AB-/AP-rating if not, for example, encompassing insignificant changes in formulation compared to the RLD, particularly for parenteral products. As FDA and industry know all too well, it may take FDA months or even years to answer such citizen petitions, since they are not specific to approval of a new generic product, and such determination has not been made in advance (e.g., at a tentative approval).”
The Generics Access Project (GAP), a coalition of several patient advocacy organizations, also suggested that the use of citizen petitions be disbanded for the purpose of TE ratings for 505(b)(2) applications.
“It currently takes years for a TE rating to be designated to an FDA approved therapy due to a process that relies on an open-ended citizen petition process. This process does not reflect clinical benefits or science and has seemingly become far less predictable and timely in recent years. Sometimes a TE rating is never assigned, preventing the product from being launched as a generic alternative.”
The group also suggested that FDA allow manufacturers using the 505(b)(2) pathway for complex generics be able to request an automatic TE rating upon approval to “improve the availability, sustainability, and substitutability of complex generics.”
AAM, Apotex and Teva want changes in Orange Book removals
AAM, Apotex, and Teva also urged FDA not to remove products that have been discontinued from the Orange Book. In the guidance, FDA said it will remove therapeutic equivalence codes for a drug product that is moved from the active section to the discontinued drug product list section.
AAM said that “removing TE codes for drug products that are moved from the Active section of the Orange Book to the Discontinued section or that become single-source products is problematic for several reasons, and they are related. In both cases, the fact that the product was rated as TE to an RLD remains important to stakeholders who rely on the TE ratings to understand how to use the product, make coverage determinations, or are otherwise trying to determine if the product is or was TE to the RLD,” said AAM.
Apotex also urged FDA to remove its section on changing a rating drug if it is discontinued is confusing and should be removed.
“Apotex believes that such a process would be counter-productive and create confusion for pharmacies familiar with dispensing the drug or for coverage determinations.” Instead, Apotex requests that FDA provide in the Orange Book a history with explanations of any changes in the TE codes in the Orange Book, including when an RLD has been discontinued or a drug otherwise becomes a single-source product.
Teva also suggested that FDA not remove TE ratings from the Orange Book once they are assigned, even if a drug becomes since-source. “FDA should not remove TE ratings from the Orange Book once they are assigned, even if a drug becomes single-source.”


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