A Quick Guide to Referencing an Approved Product for ANDA

Background

A generic drug manufacturer refers to a reference listed drug (RLD) (an approved listed drug) to inform the US Food and Drug Administration (FDA) what its product would be like. Usually, it is a “brand” product (new drug application [NDA] holder) until it is in the market. The RLD is used as a basis for submitting an ANDA; in other words, an abbreviated new drug application (ANDA) for a generic drug is a duplicate of its RLD.

Key challenges

However, the problem arises when the “brand” product (the innovator) moves out from the market and is discontinued. The following questions arise.

• What to do when there is no RLD? How to approach the FDA?
• What to do when one wants to refer “an approved product” different from the designated RLD?
• Is the “reference standard” same as the FDA-designated RLD?

Solutions for the Industry

With the aim of helping the generic drug companies on these possible questions, the US FDA has released the guideline “Referencing Approved Drug Products in ANDA Submissions.” The agency intends to alleviate the ANDA applicants from any confusion arising due to the use of RLD and reference standard (RS) and guides on specific points while referencing the listed products in a generic ANDA application.

Besides describing the relevance and importance of selecting an RLD in the ANDA, the guideline emphasizes on specific means through which the prospective applicant may request the FDA to identify and designate an RLD. The major difference between an RLD and an RS, as stressed upon by the agency, is its application during the development and submission process of a generic drug product.

On one hand, it is the responsibility of the generic applicant to make sure that the generic product is identical to the RLD in composition, dosage form, route of administration, strength, etc. On the other hand, the RS can be used only when there is a need to establish bioequivalence (BE) through in vivo BE studies. Ordinarily, the FDA selects the RLD as the RS. In certain cases, an applicant may use an authorized generic version of the RS for the purpose of conducting a BE study.

There is a provision of submitting “controlled correspondence” to the agency if the ANDA applicants have any queries regarding the concerns listed as follows:

• An applicant has certain questions regarding the selection of an RLD.
• The FDA has not designated any RLD.
• The applicant intends to refer an approved product as an RLD that is different from the one designated by the FDA (earlier a citizen petition was expected!).
• An applicant needs to ask the FDA to select an RS.

To facilitate the industry for referencing these listed drugs in the ANDA application (i.e., basis of submission), there is an easy-to-refer table at the end of the guidance (1), part of which has been provided in Table 1:

Table 1. Referencing approved drugs in an ANDA

ANDA: Abbreviated new drug application; FDA: Food and Drug Administration; RLD: Reference listed drug; RS: Reference standard.

Discussion

So now we know how the FDA has alleviated the applicants from the hassle of identifying the RLD and the RS by providing an aid (in the form of this guidance) for smooth development phase of the drug product. The guidance gives the hint regarding the modules and sections wherein the references to identified RLD/RS could be provided as part of the ANDA.

Reference

1. FDA’s Guidance Document. Referencing Approved Drug Products in ANDA Submissions Guidance for Industry (October 2020).

Talk to our experts regarding more on Regulatory services.