More on the 505(b)(2)/ANDA Proposed Rule

Many changes proposed in this Rule are a result of the passage of the Medicare Modernization Act (MMA).   In this post, we discuss a few issues where FDA is codifying provisions of the MMA for the first time (albeit they have been regulating directly from the statute since its passage in 2003).

An ANDA Can’t Change RLD in Amendment or Supplement and 505(b)(2) Applicant Must Take Care as Well

An “ANDA applicant may not amend or supplement  an ANDA to seek approval of a drug referring to listed drug that is different from the reference listed drug (RLD) identified in the ANDA. An ANDA applicant that seeks to refer to a listed drug different from the RLD identified in the initial ANDA must submit a new ANDA” (emphasis added).  The corollary provisions for a 505(b)(2) applications prohibits the an applicant form “amending or supplementing an application referred to in [section 505(b)(2)] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to the Secretary.”  This wording difference is one of the provisions of the MMA that can create a problem for 505(b)(2) or generic applicants.  So it is important to fully understand the requirement that the applicant may have to submit a new application to make the desired change.

Remember that, as far as 30-month stays and patent certification notice requirements, that no 30-month stay is available if the 505(b)(2) or ANDA is filed prior to any new patent is listed. “Given this limitation on the patents that may give rise to a 30-month stay, the MMA may have created an incentive for a 505(b)(2) or ANDA applicant to seek approval for a change to a drug, or to reference a different listed drug, through an amendment or a supplement, rather than by submitting a new application. To address this concern, section 505(b)(4)(A) and (j)(2)(D)(i) of the FD&C Act ensure that 505(b)(2) and ANDA applicants do not use the amendment or supplement process to evade the possibility of a 30-month stay of approval that otherwise would have applied if the 505(b)(2) applicant sought approval for a drug that is a different drug or if the ANDA applicant sought to refer to a different RLD in the original 505(b)(2) application or ANDA, respectively. Accordingly, we interpret section 505(b)(4)(A) of the FD&C Act in a manner that is consistent with the statutory text, accomplishes the statutory goal of preserving a meaningful opportunity for a single 30-month stay, and reflects, to the extent feasible, Congress’ expressed intent to preserve rather than disrupt FDA processes regarding submission of amendments and supplements to 505(b)(2) applications and ANDAs.”

The FDA also defines and explains what it means by a drug that “is different” relative to a 505(b)(2) application and discusses why they believe their current interpretation is consistent with congressional intent.

Why Referencing a Different RLD for an ANDA Requires a New Application

The FDA described two examples that drive and explain the requirement for submission of a new ANDA if a new (different) RLD must be cited.  One of the examples discusses an ANDA submitted based on an approved ANDA suitability petition (i.e., an ANDA submitted where there is a change in dosage form, strength, route of administration, or change in ingredient in a combination product).  That ANDA must cite the RLD upon which the suitability petition was based.  So once the ANDA is filed, if an NDA is approved for a pharmaceutical equivalent of the drug subject to the petition while the ANDA is still pending, FDA’s position is that the ANDA applicant can no longer cite the approved suitability petition and must now cite the new approved NDA pharmaceutical equivalent as the RLD and BE studies must be conducted against the newly approved NDA designated RLD product.  In this case, the ANDA can no longer be approved and the applicant must file a new ANDA that cites the new pharmaceutically equivalent RLD product as the basis of its ANDA.  In addition, FDA’s requirement that an applicant with a pending ANDA must change its basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition also is intended to ensure that ANDA applicants do not circumvent the patent certification requirements of section 505(j)(2)(A)(vii) and (j)(2)(A)(viii) of the FD&C Act through the suitability petition process.

This “reflects the Agency’s judgment that considerations regarding an ANDA’s limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder” (Venlafaxine ER Citizen Petition Response at 9).

The second example relates to a potential change to an RLD, and is related to a change in the marketing status of a product from Rx to OTC switch.  For instance, if there is an ANDA pending or approved for the Rx version of a product and the innovator obtains an Rx to OTC switch for the product and the innovator makes the change via a new NDA, then the generic applicant cannot change the RLD in its original supplication and must submit a new ANDA citing the new OTC NDA.  If, however, the NDA holder supplements its application for the change and it is done in the same NDA, then the ANDA applicant can obtain approval in its existing application via amendment or supplement.  

When an ANDA applicant seeks to gain a therapeutic equivalence (TE) rating against a second RLD in its application, it does not need to submit a new ANDA because the ANDA applicant is not relying on previous Agency findings of safety or efficacy, but simply is seeking an additional TE rating.  This position was first established when the Levothyroxine Sodium products were first approved as a generic.  An explanation of TE evaluations for the levothyroxine products can be found in the preface of the Orange Book.  In addition, there is nothing that precludes an ANDA applicant from submitting an amendment to a pending application or a supplement to an approved application for a new strength, if the original cited NDA product has obtained approval for the differing strength.

If you think this is complicated, just wait.  We will have some additional mindbenders for your consideration soon.