In a Rare Move, FDA Initiates Procedures to Suspend Approval of an ANDA

By Kurt R. Karst –    

Here’s something you don’t often see: FDA initiating procedures to suspend the approval of an ANDA because of an Agency determination that the Reference Listed Drug (“RLD”) was withdrawn for what the Agency determined were safety or effectiveness reasons. But on December 3, 2015, that’s exactly what FDA did when the Agency sent a letter to Armenpharm, Ltd. (“Armenpharm”) for the company’s Chloramphenicol Capsules, 250 mg (previously marketed under the brand name MYCHEL) approved under ANDA 060851 on June 20, 1967. The story here dovetails nicely with two posts we put up over the past six months providing an analysis of FDA determinations that a drug was withdrawn from sale for reasons of safety or effectiveness (here) and how to bring a drug out of discontinued status (here).

Although there’s a lot of food and drug history here, including the old antibiotic drug approval procedures under Form 5 and Form 6 applications, we’ll begin with a February 7, 2011 Citizen Petition (Docket No. FDA-2011-P-0081) Armenpharm submitted to FDA requesting that the Agency determine that the RLD for ANDA 060851, Parkdale Pharmaceutical’s (“Parkdale’s”) CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, approved on December 8, 1950 under ANDA 060591, was not discontinued for reasons of safety or effectiveness. You see, MYCHEL (ANDA 060851) had not been marketed for a while and Armenpharm wanted to submit a Prior Approval Supplement to FDA for an alternate manufacturing site as part of an effort to remarket the drug. The RLD, however, had been discontinued back in October 2007, and FDA withdrew approval of the application in early 2009, but continued to identify the ANDA in the Discontinued Drug Product List section of the Orange Book. To remarket MYCHEL in light of the discontinuance of ANDA 060591, FDA had to make a determination as to whether or not Parkdale discontinued CHLOROMYCETIN 250 mg for safety or effectiveness reasons.

In July 2012, FDA responded to Armenpharm’s discontinuation petition and issued a notice in the Federal Register providing FDA’s conclusion that Parkdale’s CHLOROMYCETIN 250 mg approved under ANDA 060851 was discontinued for safety or effectiveness reasons. (For an analysis of FDA’s recent track record on responding to discontinuation petitions, see our previous post here.)  According to FDA:

After considering the citizen petition, and based on the information we have at this time, FDA has determined under § 314.161 that CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, were withdrawn for reasons of safety or effectiveness. We have carefully reviewed Agency records concerning the withdrawal of CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, from sale. We have also independently evaluated relevant literature and data for possible postmarketing adverse events. At the time of the approval of CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, there was significant unmet medical need. With the approval of additional therapies with less severe adverse drug effects, FDA has determined that the risks associated with CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, as currently labeled, outweigh the benefits. Most importantly, CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, may cause a number of adverse reactions, the most serious being bone marrow depression (anemia, thrombocytopenia, and granulocytopenia temporally associated with treatment).

FDA also determined that the latest labeling for CHLOROMYCETIN is deficient, that a Risk Evaluation and Mitigation Strategy would be necessary to ensure that the benefits of the drug outweigh its risks, and that additional nonclinical and possibly clinical studies of safety and efficacy would be necessary before the drug product could be remarketed. Given FDA’s determination, FDA removed CHLOROMYCETIN 250 mg from the Orange Book pursuant to FDC Act § 505(j)(7)(C). (Both the 100 mg and 50 mg strengths of CHLOROMYCETIN remain listed in the discontinued section of the Orange Book.)

Under the FDC Act, FDA may refuse to approve an ANDA if the Agency determines that the RLD was withdrawn from sale for reasons of safety or effectiveness. In addition, FDA can withdraw or suspend approval of an ANDA if the RLD is withdrawn from sale for reasons of safety or effectiveness (FDC Act § 505(j)(6)). With respect to an ANDA suspension under FDC Act § 505(j)(6), FDA’s regulation at 21 C.F.R. § 314.161(d) provides that the Agency will initiate a proceeding in accordance with 21 C.F.R. § 314.153(b). That regulation lays out the procedures for suspension of an ANDA when the RLD is voluntarily withdrawn for safety or effectiveness reasons. Specifically, the regulation states, in relevant part:

(1) If a listed drug is voluntarily withdrawn from sale, and the agency determines that the withdrawal from sale was for reasons of safety or effectiveness, the agency will send each holder of an [ANDA] that is subject to suspension as a result of this determination a copy of the agency’s initial decision setting forth the reasons for the determination. . . .

(2) Each [ANDA] holder will have 30 days from the issuance of the initial decision to present, in writing, comments and information bearing on the initial decision. If no comments or information is received, the initial decision will become final at the expiration of 30 days.

(3) Comments and information received within 30 days of the issuance of the initial decision will be considered by the agency and responded to in a final decision.

(4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.

(5) If the final decision affirms the agency’s initial decision that the listed drug was withdrawn for reasons of safety or effectiveness, the decision will be published in the Federal Register in compliance with § 314.152, and will, except as provided in paragraph (b)(6) of this section, suspend approval of all [ANDAs] identified under paragraph (b)(1) of this section and remove from the list the listed drug and any drug whose approval was suspended under this paragraph. The notice will satisfy the requirement of § 314.162(b). . . .

(6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of safety or effectiveness but, based upon information submitted by the holder of an [ANDA], also determines that the reasons for the withdrawal of the listed drug are not relevant to the safety and effectiveness of the drug subject to such [ANDA], the final decision will state that the approval of such [ANDA] is not suspended.

FDA’s December 3, 2015 letter to Armenpharm kicks off the ANDA suspension process by satisfying the first requirement under 21 C.F.R. § 314.153(b), and the letter also explains the remainder of the process. Will Armenpharm respond within 30 days?  Perhaps so. According to FDA’s December 3rd letter, the company previously corresponded with FDA in May 2013 and January 2014, apparently challenging the Agency’s determination on the withdrawal of CHLOROMYCETIN 250 mg.

We’ll keep an eye on this brewing battle. As noted above, an FDA decision to initiate procedures to suspend ANDA approval is pretty rare. (The topic was raised several years ago in the context of Midodrine HCl Tablets [Docket No. FDA-2007-N-0475], but nothing ever came of that.) Also rare is pushback on an FDA proposal to withdraw ANDA approval, but we have that too right now in the context of applications for the prescription laxative Polyethylene Glycol 3350 (see our previous post here).