In an Unusual Move, FDA Denies RLD Designation for an Orange Book Listed Drug

By Kurt R. Karst –      

As you might imagine, we’re pretty avid FDA docket watchers.  As followers of this blog know, we track FDA petition decisions and regularly update our popular FDA Citizen Petition Tracker.  Keeping close tabs on FDA decisions and announcements posted on Regulations.gov allows us to stay on top of what’s going on at the Agency and in the FDA-regulated industry.  It also allows us to follow trends and identify outlier decisions.  One of those outlier decisions popped up late last week when we returned to the office the morning after enjoying the Independence Day fireworks in Washington, D.C. celebrating America’s 237th birthday.  

On July 3, 2013, FDA denied a January 2, 2013 Citizen Petition (Docket No. FDA-2013-P-0040) submitted by Lupin Pharmaceuticals, Inc. (“Lupin”) requesting that the Agency amend the Orange Book to assign Reference Listed Drug (“RLD”) status to Roxane’s ANDA No. 077728 for Calcium Acetate Capsules, 667 mg (equivalent to 169 mg calcium).  The drug product approved under ANDA No. 077728 is a generic version of PhosLo (calcium acetate) Gelcaps, 667 mg, which FDA originally approved on April 2, 2001 under NDA No. 021160.  PhosLo Gelcaps is listed in the Orange Book as the RLD for ANDA submission purposes.  That is, it is the reference standard for purposes of demonstrating bioequivalence.  (See our previous post on the difference between what we’ve termed the “big RLD” and the “little rld.”)  In addition to Roxane’s ANDA No. 077728, the Orange Book also lists Paddock’s ANDA No. 091312 as an AB-rated generic version of PhosLo Gelcaps. 

Lupin’s petition requesting that FDA designate Roxane’s ANDA No. 077728 as a second RLD contends that, to the best of the company’s knowledge, neither PhosLo Gelcaps approved under NDA No. 021160, nor the AB-rated generic equivalent approved under Paddock’s ANDA No. 091312 is available on the market.  Therefore, according to Lupin, it is unable to procure product sample to conduct bioequivalence testing, and FDA should  designated Roxane’s ANDA No. 077728 as an RLD because that product is available on the market.

FDA stated the Agency’s policy for designating RLDs way back in 1992 in the preamble to the Agency’s final regulations implementing certain provisions of the 1984 Hatch-Waxman Amendments.  There (57 Fed. Reg. 17,950, 17,958 (Apr. 28, 1992)), FDA stated:

FDA will designate all reference listed drugs.  Generally, the reference listed drug will be the NDA drug product for a single source drug product.  For multiple source NDA drug products or multiple source drug products without an NDA, the reference listed drug generally will be the market leader as determined by FDA on the basis of commercial data.  FDA recognizes that, for multiple source products, a product not designated as the listed drug and not shown bioequivalent to the listed drug may be shielded from direct generic competition.  If an applicant believes that there are sound reasons for designating another drug as a reference listed drug, it should consult FDA. Once FDA designates that reference listed drug, that drug will continue to be the reference standard even if the drug is later replaced as the market leader.  

FDA’s policy is further described in the preface to the Orange Book:

By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart.  Such variations could result if generic drugs were compared to different reference listed drugs.  However, in some instances when multiple NDAs are approved for a single drug product, a product not designated as the reference listed drug and not shown to be bioequivalent to the reference listed drug may be shielded from generic competition.  A firm wishing to market a generic version of an NDA listed drug that is not designated as the reference listed drug may petition the Agency through the Citizen Petition procedure . . . .

Over the years, FDA has received and responded to several citizen petitions requesting that the Agency assign RLD status to various NDA and ANDA approved drug products.  For example, off the tops of our heads, FDA has granted RLD designation petitions in Docket Nos. FDA-2012-P-1127, FDA-2012-P-1043, FDA-2011-P-0606, FDA-2011-P-0059, and in various decisions concerning levothyroxine (see, e.g., here, here, and here).  

FDA’s regular granting of RLD designation petitions has let most folks to consider them as merely administrative red tape, and to assume that FDA would grant an RLD designation petition after a perfunctory review of the petition and relevant facts.  But FDA’s recent denial of Lupin’s RLD designation petition – to our knowledge, the first instance in which FDA has denied such a petition – shows that the answer to “Who is buried in Grant’s tomb?” (a “gimme question” popularized by Groucho Marx during the 1940s and 1950s on the “You Bet Your Life” quiz show so that a contestant could get at least one question correct) may not always be “General Grant, of course!”

In denying Lupin’s petition, FDA relied on the reported existence of an authorized generic version of PhosLo Gelcaps:

We have determined that you have not stated sufficient grounds to establish the need to designate an additional RLD for Calcium Acetate Capsules, 667 mg (eq. to 169 mg calcium).  Based on our records, PhosLo is still being marketed under its NDA as an authorized generic.  An ANDA applicant may use the authorized generic version of the current RLD as the reference standard in the in vivo bioequivalence study with proper documentation.  Because the RLD is still available as an authorized generic under NDA 21-160, FDA does not agree that the Roxane drug product approved under ANDA 77-728 should be designated as an additional RLD.  You have not provided any other basis for justifying designation of Roxane's product as an additional RLD.

The “records” referenced in FDA’s petition denial is the Agency’s Listing of Authorized Generics, which is a database of authorized generic versions of approved drug products created as a result of FDC Act § 505(t) added by the 2007 FDA Amendments Act.  Under FDC Act § 505(t), an “authorized generic drug” is defined as a listed drug as defined in 21 C.F.R. § 314.3 that has been approved under FDC Act § 505(c) and “is marketed, sold, or distributed directly or indirectly to retail class of trade with either labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trade mark that differs from that of the listed drug.”

FDA’s treatment of the marketing of an authorized generic version of a listed drug as a basis for precluding designation of an additional RLD means that companies considering petitioning FDA will need to consult the Agency’s Listing of Authorized Generics before making an RLD designation request.  A quick review of some pending RLD designation petitions shows that FDA’s decision on Lupin’s PhosLo Gelcaps petition may not be the last denial of a RLD designation petition.