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505(b)(2) Application Changes: What You Need to Know

Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 was enacted in order to address concerns that had potential to delay access to more affordable drugs. The FDA has been implementing the MMA via the statute since it was enacted in 2003. Now, based on its experience with the implementation and the outcomes of recent court cases, the FDA is amending the regulations that are relevant to those sections of the MMA.

On October 6, 2016, the FDA issued its Final Rule on 21 CFR Parts 314 and 320, Abbreviated New Drug Applications and 505(b)(2) Applications to fully implement this section. These provisions in effect alter certain aspects of the Hatch-Waxman regulations governing the regulatory and legal status of 505(b)(2) NDA submissions.

Which of these changes are likely to have the most significance to sponsors filing new 505(b)(2) applications?

Companies submitting 505(b)(2) applications relying on the FDA’s finding of safety and/or efficacy from an approved product for which they have no right of reference may provide a Listed Drug(s) for that data, and if they do must certify that the proposed new product does not infringe on all patents for the Listed Drug(s). There has been ambiguity over how the Listed Drug is defined and how that listed drug relates to the proposed 505(b)(2) new product. This has generated litigation from innovator companies against ANDA/505(b)(2) applicants based on the innovator’s interpretation of the extent to which a use Patent covers the indication for the new 505(b)(2) product.

First Change: 505(b)(2) Application Definition, Carve Out of Specific Indications

Under the recently updated regulations, the FDA has revised the definition of a 505(b)(2) application to clarify that not all of the investigations and data in the innovator’s NDA are relevant to the approval and thus might allow an ANDA/505(b)(2) sponsor to carve out specific indications for their 505(b)(2) product that do not infringe on the unexpired patents. The revised definition in 21 CFR 314.3(b) states:

“A 505(b)(2) application is an NDA submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for a drug for which at least some of  the investigations described in section 505(b)(1)(A) of the Federal Food, Drug, and Cosmetic Act and relied upon by the applicant for approval of the NDA were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”

Second Change: Use Codes

A second major change is intended to address what the FDA calls overbroad or ambiguous use codes by specifying that the NDA holder’s use code must describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could be asserted. The sponsor of a 505(b)(2) NDA must certify that the new product does not infringe upon any unexpired use patents for those drugs for that indication. This is now clearly spelled out in 21 CFR 314.50(i)(iii):

“(iii) Method-of-use patent. (A) If information that is submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 is for a method-of-use patent, and the labeling for the drug product for which the applicant is seeking approval does not include an indication or other condition of use that is covered by the method-of-use patent, a statement explaining that the method-of-use patent does not claim a proposed indication or other condition of use.

Also directed toward the use of overbroad use patent descriptions is a revision to 21 CFR § 314.53(c)(2)(ii)(R). This revision is an effort to strengthen the ability of “third parties,” i.e., ANDA/505(b)(2) applicants to challenge overbroad use codes by submitting a written request to the FDA. The FDA in turn sends the description of the dispute to the NDA holder, who has 30 days to verify, amend or withdraw the use code in a response narrative, including a signed verification that the information in the response is accurate and complete, under penalty of perjury. Interestingly, the revision does not state what will occur if the response is not timely, i.e., after the 30 day clock has run down. The final version of this portion of the rule was scaled back considerably from the scope in the proposed rule, which would have granted the FDA more latitude in interpreting the response from the NDA holder. Premier Consulting has had direct experience in several situations where applicants have been potentially blocked by overbroad use patent listings.

Third Change: Pharmaceutical Equivalent

Prior to the publication of the Final Rule, the FDA used  the term “pharmaceutical equivalent” extensively in their (non-binding) guidance on 505(b)(2)s. Now, the FDA defines the term in the regulation and specifies the requirements connected to pharmaceutical equivalents for 505(b)(2) applications. The definition is:

“Pharmaceutical equivalents are drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.”

Thus, the FDA seems to be positioning the rule to require a specific LD if there is what they view as an approved pharmaceutical equivalent to a proposed product if there is reliance on an LD. If there is more than one approved “pharmaceutical equivalent” the applicant is free to choose. What is not clearly specified is that you still are not obligated to rely on an LD given the proper circumstances, i.e., data.

See these changes below in 21 CFR 314.54 (a)(1):

(iii) Identification of each listed drug for which the FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug’s application holder, and listed drug’s approved application NDA number. The listed drug(s) identified as relied upon must include a drug product approved in an NDA that:

(A) Is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted; and

(B) Was approved before the original 505(b)(2) application was submitted.

(vi) Any patent certification or statement required under section 505(b)(2) of the Federal Food, Drug, Cosmetic Act with respect to any relevant patents that claim the listed drug(s) or that claim any other drugs on which investigations relied on by the applicant for approval of the application were conducted, or that claim a use for the listed or other drug(s). A 505(b)(2) applicant seeking approval of a drug that is pharmaceutically equivalent to a listed drug approved in an NDA implicitly relies upon one such pharmaceutically equivalent listed drug.

However, if there is more than one pharmaceutical equivalent listed drug, the applicant is only required to rely on one. Premier Consulting has successfully assisted in negotiations with the FDA on several occasions regarding the selection of pharmaceutical equivalent LDs while the Guidance was the repository of the term.

Where Do You Go from Here?

The changes to the regulation can have a significant impact on a number of the most critical aspects of development for 505(b)(2) products. These changes range from clarifying or redefining terms to clearly specifying how patents may be referenced to emphasizing the importance of selecting the most appropriate listed drugs.

Implementation of these changes may have unforeseen consequences and can be difficult for a sponsor company to fully comply with. Premier Consulting can help your company navigate through these new uncharted waters. Please contact us for more information.


Ruth Stevens, PhD, MBA
Strategic Advisor