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

505b2 infographic 1200x627In recent years 505(b)(2) approvals have experienced double-digit growth. Many companies are electing to pursue 505(b)(2) applications to obtain a new drug approval (NDA). A 505(b)(2) application is a hybrid between the FDA's traditional NDA and an abbreviated new drug application (ANDA). These submission types were made possible in 1984 by the adoption of the Hatch-Waxman Act. The act was created to allow for generic competition and increased innovation in the pharmaceutical arena. A true generic or ANDA demonstrates that the drug is identical to an already approved product based on bioequivalence data and chemical equivalence. 

It is advantageous for a product to be approved via the 505(b)(2) route for several reasons. These applications rely on existing safety and efficacy data in applications approved by the FDA. Thus, the cost and timeline to develop these products are lower as fewer studies are required. Because these drugs rely on previously generated safety data, the adverse event profile is better understood. While ANDAs are eligible for 180 days of market exclusivity if it is the first generic to market, a 505(b)(2) application may be granted between three and seven years of market exclusivity: three years if clinical trials (other than bioavailability (BA) / bioequivalency (BE) studies) are required, five years for a new chemical entity (NCE), and seven years for an orphan drug.

505(b)(2) submissions contain full reports of investigations of safety and effectiveness; however, some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. To be considered a 505(b)(2) application, the product must involve changes to a previously approved drug product (i.e., a new dosage form, new strength, new routes of administration). In contrast, an ANDA is a generic drug product that is identical to the reference listed drug (RLD).

A 505(b)(2) application can be approved based on data from studies not conducted by the applicant, relying on the FDA’s previous findings of safety and effectiveness of an approved drug, provided the proposed drug has characteristics in common with the approved drug. The sponsor’s application may also rely on clinical and preclinical studies’ data from published literature without the right of reference. 

Drugs that are targeted for the 505(b)(2) pathway are often variations of well understood commercial products. Therefore, the applicant will have to submit limited information known as bridging documentation to demonstrate the proposed drug and the approved drug product have similar bioavailability and/or bioequivalency. Since 2004, the top three reasons for 505(b)(2) applications are: new formulation or manufacturer, new dosage form, and new combination of active ingredients.

Examples of products eligible for the 505(b)(2) approval process include but are not limited to the following: 

  • Change in the route of administration

  • Conversion to lower or higher strength 

  • Change in the route of administration of dosage form or dosage regimen

  • Change in the formulation

  • Substitution of an active pharmaceutical ingredient (API) in a combination product 

  • New molecular entity (NME) 

  • Conversion from prescription drug (Rx) to over-the-counter (OTC) drug

  • Drug with new ingredients from animal or botanical sources (naturally derived or recombinant)

  • A bioequivalent product

Sponsors are encouraged to review the FDA guidance documents before requesting meetings with the Agency. The guidance document "Determining Whether to Submit an ANDA or a 505(b)(2) Application," finalized in May 2019, provides direction regarding whether the 505(b)(2) pathway is feasible. This document also notes that if a duplicate drug has already been filed as an ANDA the FDA will refuse to file a 505(b)(2) application for approval in which case the application may be able to be revised and submitted as an ANDA. It is important to note that the guidance document doesn’t provide specific details regarding the development of the drug and what is or is not required.

An applicant must fully understand the FDA’s expectations to provide the appropriate information in the application and avoid any potential deficiency letter in response to the drug product application. Since sponsors frequently misunderstand which studies need to be conducted to support a 505(b)(2) application, it is critical to have open discussions with the FDA early in the process. For a successful project, sponsors should initiate the 505(b)(2) program with the FDA by requesting a pre-IND meeting. This meeting can be conducted prior to any actual cGMP work being undertaken and should follow the draft guidance “Formal Meetings Between FDA and Sponsors or Applicants of PDUFA Products.”

At the pre-IND meeting, the organization should seek to obtain FDA input and agreement with its proposed strategy, which includes the proposed manufacturing process, product composition, analytical plans, and clinical studies. The organization should also seek Agency agreement regarding the RLD to be utilized for comparison purposes, and it is typically selected based upon the similarities between the commercial product and the proposed 505(b)(2). As previously mentioned, since a large portion of data will be incorporated into the submission by referencing existing data, the pre-IND meeting outcome should result in FDA agreement of a minimal need for additional clinical trials. Depending upon the situation and the proposed changes, the Agency may require further efficacy/safety trials in situations such as: targeted use in special populations (pediatric), newly proposed indication, BA/BE conditions were not met, or determination of the efficacy of a new route of administration.

It is worth mentioning that all studies agreed upon must be conducted using the proposed commercial product, manufactured under cGMP conditions. It is important to consider the advantages of the 505(b)(2) pathway to drug approval. There is the reduced timeline and cost to approval, reduced risk due to prior knowledge of the behavior of the active ingredient, and potential market exclusivity. 

Alcami has over 30 years of experience developing and manufacturing products going through the 505(b)(2) pathway. All of our facilities have an excellent inspection history with regulatory authorities including FDA, TGA, PMDA, MHRA, Health Canada, MPA, IMB, DEA, EPA, OSHA and more. Our in-house regulatory and CMC expertise provides guidance on the latest industry guidelines and the best approach tailored to each client’s specific needs.

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