A New Orange Book Tool: Reference Listed Drugs by ANDA Reference Standard List

May 17, 2017By Kurt R. Karst

Since it was first published in 1980, the Orange Book has undergone a lot of change. Over the decades we’ve seen the publication transform and evolve from a paper edition to an electronic database, and now to an app (see our previous post here).  Although the Orange Book has become more complex to navigate, the first edition was rather simple, with two primary sections and several subsections:

I.    Preface

A.    Introduction

B.    Definitions

C.    General Policies Governing the List

D.    Legal status of the List

E.    Precautions to Users of the List

F.    Codes and Specific Policies for Therapeutic Equivalence Evaluations

G.    Description of Special Situations

H.    Updating Procedures

II.    Listings

A.    Format Guide

B.    Drug Product List

C.    Trade Name Index

D.    Application Holder Index

E.    Application Holder Abbreviation List

F.    Appendix: Prescription Drug Products Deemed Approved – Pending Resolution of Safety or Effectiveness Issues

Today, the Orange Book contains a preface and six Drug Product Lists, either in their entirety, or by reference to an FDA website containing the full list:

  1. Prescription Drug Product List
  2. OTC Drug Product List
  3. Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics Evaluation and Research List
  4. Discontinued Drug Product List
  5. Orphan Products Designations and Approvals List
  6. Drug Products Which Must Demonstrate in vivo Bioavailability Only if Product Fails to Achieve Adequate Dissolution

(Although the Orange Book used to contain a list of ANDA suitability petitions approved by FDA, that list is now posted separately on FDA’s website. . . . but the list has not been updated in nearly three years!)

The Orange Book also contains three appendices (Product Name Index; Product Name Index Listed by Applicant; and Uniform Terms) and a Patent and Exclusivity Information Addendum (divided into Patent and Exclusivity Lists and Patent and Exclusivity Terms) that are updated monthly. (In the first few editions of the Orange Book, FDA listed in an appendix – later named the “DESI Addendum” – those drug products still in the Drug Efficacy Study Implementation program administrative process.)

But in addition to what appears in the printed version of the Orange Book, there is other information FDA maintains that is important to drug manufacturers and that we consider to be an extension of the Orange Book. Some of that information is identified on FDA’s Orange Book website as “Additional Resources.”  Thus, for example, for many years now FDA has published “Additions/Deletions for Prescription and OTC Drug Product Lists” and has provided monthly “Orange Book Data Files.” Those files can be quite helpful in pinpointing when a particular change occurred with respect to a particular drug product listing. (Other extensions of the Orange Book include the daily updated “Newly Added Patents or Delisted Patents” electronic Orange Book search function . . . and perhaps even the recently published ANDA “Program Fee List,” which FDA prepared for GDUFA II user fee purposes, but that can assist with determining what ANDAs listed in the discontinued section of the Orange Book have merely been discontinued and which have had their approval withdrawn.)

FDA’s latest additional resource is a list called “Reference Listed Drugs by ANDA Reference Standard List.”  Dated April 2017 and published last week for the first time, the new list is described by FDA as follows:

This list refers to drug products approved under an Abbreviated New Drug Application (ANDA) that FDA has selected as reference standards and the associated reference listed drugs (RLDs). The purpose of this list is to assist applicants submitting an ANDA to seek approval of a generic drug in identifying an RLD when an ANDA RS has been selected. If the applicant has a question about which listed drug it should refer to as the RLD, the applicant may consult with FDA (refer to section 1.4 Reference Listed Drug and Reference Standard of the Orange Book Preface for more information).

This list is updated monthly. Information in this list is sorted by Active Ingredient(s), Dosage Form, Route, Trade Name, Applicant Name and Strength. Additional information included are marketing status (RX, OTC, DISCN), Application Number, Product Number, and approval date of the Reference Standard.

The new list is an outgrowth of FDA’s retooling of the 37th (2017) edition of the Orange Book to identify RLDs (i.e., NDA-approved drug products) and Reference Standards (i.e., an NDA- or ANDA-approved drug product used for bioequivalence testing purposes) and carves out of the Orange Book a select category of ANDA-approved Reference Standards. We previously posted on the retooling of the Orange Book and FDA’s guidance document, titled “Referencing Approved Drug Products in ANDA Submissions,” which delves into the details of RLD and Reference Standard status and designation.