On Friday, the FDA issued a draft Guidance entitled, “Referencing Approved Drug Products in ANDA Submissions” (here). The document describes what a reference listed drug (RLD) is, what an FDA reference standard (RS) is (a relatively new term with important distinctions from the RLD), and describes how the selection process should occur if the RLD is no longer marketed or removed from sale, as well as what to use for identification as the RLD in your 356h form. It also describes the process for asking FDA to make the determination that a drug product was not removed from the market for reasons of safety or effectiveness.
As we know, all drug products approved for safety or efficacy are cited in the Orange Book and are considered “listed” drugs. The FDA now is making a distinction between the designation of an RLD (the drug upon which an ANDA may be based) and a reference standard (the drug that FDA expects the firm to use for establishing bioequivalence). The two may not be the same in certain circumstances, so read this Guidance carefully, as it is believed that errors in the designation of RLD, RS, or the drug cited as the basis for ANDA submission may result in anything from a refuse-to-receive to an Information Request (IR) at filing time.
A reference listed drug (RLD) is the listed drug to which the ANDA applicant must show its proposed generic drug is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics. An RLD may be a drug product approved under 505(b)(1), or in some cases, under 505(b)(2) of the Act, which are approved under section 505(c) of the Act.
A “reference standard” is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in its bioequivalence testing to establish its product’s bioequivalence (it is usually the RLD, but may be different if the original RLD is no longer marketed).
FDA states in the guidance that “[r]egarding the same labeling requirement, the generic drug must have the same labeling as the RLD, except for differences permitted under the FD&C Act and Agency regulations. Accordingly, an ANDA applicant must compare its proposed product’s labeling to that of the RLD, even if FDA has selected a new reference standard for use in in vivo bioequivalence studies, as described in detail in section III.C. Similarly, in evaluating drug product formulation and inactive ingredients, an ANDA applicant must compare its proposed generic drug to the RLD’s formulation, not the formulation of the reference standard.” (emphasis added) If an ANDA is based on an approved Suitability Petition requesting a change from the RLD, then the applicant still must cite as the RLD in its application, the RLD upon which the petition was based.
Prior to 2017, the column in the electronic Orange Book labeled “RLD”, and the symbol in the printed version identified the RLD at times indicated the drug product FDA selected as both the RLD and the reference standard. This designation at times contributed to the confusion about which drug is the RLD and which drug the FDA considered the reference standard. Starting in 2017, FDA intends to modify the Orange Book to clarify which listed drugs are RLDs and which are reference standards, and to indicate which products in the Discontinued Section an ANDA must use as the RLD.
Thus, while an RLD may be an RS, an RS may not always be an RLD, and it is the RLD that will almost always be the basis for submission! Wow, this will take some getting used to.
What about RLD products that are no longer marketed, but still appear in the Orange Book’s active or discontinued sections? It may be necessary for an applicant to petition the FDA to designate a different RLD or to make a determination that the currently designated RLD was not removed from the market for safety or efficacy reasons. Previously, FDA would not approve an ANDA until it both made that determination and until the notice of such determination was published in the Federal Register. However, in an effort to speed generic drugs to market, the FDA has decided to revise policy and explains the following in the draft Guidance:
“Historically FDA generally did not approve ANDAs for which the Agency had made a determination that the RLD was not withdrawn from sale for reasons of safety or effectiveness until after that determination was published in the Federal Register. In order to expedite the availability of generic drugs, FDA now will approve a generic drug for which it has made a final determination that the RLD was not withdrawn from sale for safety or effectiveness reasons even if that determination has not yet published in the Federal Register, and will proceed with Federal Register publication as expeditiously as is practicable.”
Confused yet? If so, go back and read the entire draft Guidance. If you still are confused, please don’t hesitate to contact one of our regulatory specialists at Lachman Consultants at www.lachmanconsultants.com. We will help you through this new maze of definitions and distinctions.