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To List or Not to List – That is the Question

A 505(b)(2) may rely on the FDA’s previous findings of safety and efficacy  of an approved drug product. It is possible to rely on more than one approved drug product.  It is also possible that a 505(b)(2) applicant does not have to rely on any approved drug. The correct choice of listed drug product may allow  a proposed drug product to avoid patent and/or exclusivity issues as shown in the following example.

In September 2014, the FDA approved a 505(b)(2) application for Mitigare (colchicine) Capsules (NDA 204820; Hikma Pharmaceuticals LLC [“Hikma”]) for the prophylaxis of gout flares, and a legal battle ensued. It turns out, unsurprisingly, that Takeda Pharmaceuticals USA (“Takeda”), the holder of NDA 022352 for Colcrys (colchicine) Tablets, had negative opinions about the approval of another single-ingredient oral colchicine product during what should have been their drug’s exclusivity period. In October, both Takeda and a group of companies (collectively “Elliot”) with investment interests in Colcrys sued both Hikma and the FDA, and succeeded in temporarily preventing Mitigare from getting on the market. The reprieve was short-lived, as their motions were denied on January 12, 2015. Both Takeda and Elliot have filed appeals of the decision (as of January 20, 2015), but for now, the supply market for single-ingredient oral colchicine products is no longer monopolized.

Not very long ago, single-ingredient oral colchicine products were widely available in the United States. Colchicine, originally derived from the autumn crocus plant, was first described for the treatment of gout in the first century AD and was brought to the US from France by Benjamin Franklin, who suffered from gout. It continued to be a commonly-used, unapproved treatment for gout until Mutual Pharmaceutical received approval for Colcrys for the treatment of familial Mediterranean fever and treatment of acute flares of gout in July 2009, and for prophylactic treatment of gout in October 2009. Because familial Mediterranean fever is an orphan indication, Colcrys also received 7 years of market exclusivity. As such, the FDA removed unapproved single-ingredient colchicine products from the market, and the price per colchicine tablet rose from less than $1 to around $5 (Kesselheim, 2010). The Colcrys NDA holder (Mutual/URL Pharma initially, and subsequently Takeda) has justified the price increase as the cost of safety studies conducted for FDA approval, but the marked increase in cost for the widely used treatment has been criticized by patients, doctors, and insurers alike (Kesselheim, 2010). To protect their interests, the Colcrys NDA holders have worked diligently to position their product as the de facto listed drug for all future single-ingredient colchicine products, including the filing of a Citizen Petition (by Mutual) requesting that Colcrys and its drug-drug interaction studies be referenced by all single-ingredient oral colchicine products. (The FDA did not agree.) They have also vigorously sued for patent infringement to prevent any generics from coming to market (see Takeda Pharmaceuticals v. Par Pharmaceuticals, 2014; Takeda Pharmaceuticals v. Watson Laboratories, 2014).

Mitigare’s 505(b)(2) Strategy

While the obvious choice was to reference Colcrys, Hikma (through it US agent West-Ward Pharmaceutical Corp.) chose the approved combination product Col-Probenecid (colchicine 0.5 mg and probenecid 500 mg, ANDA 084729; Watson Laboratories) as the listed drug for their single-ingredient colchicine product, Mitigare. This allowed them to rely on the FDA’s previous findings of safety and effectiveness for colchicine (in combination with probenecid) while circumventing the exclusivity periods and patents associated with the single-ingredient Colcrys product. To bolster the application, Hikma utilized published literature to support the efficacy of single-ingredient colchicine products. Additionally, Hikma conducted a handful of previously-agreed-upon safety studies to investigate potential drug-drug interactions. Taken together, the application provided sufficient safety and efficacy data to be granted FDA approval.

Strategic Listing

The FDA has consistently given applicants room to maneuver in their choice of listed drug to rely upon for approval of a 505(b)(2) application. Most importantly, at this time, there is no requirement that an approved pharmaceutical equivalent be cited as the listed drug. Instead, an applicant can make the determination, based upon their planned development program, of which product will best support and fill the information gaps in their application. In fact, Premier Consulting has experience with gaining 505(b)(2) product approvals without listing a drug at all.

While the FDA will not give definitive guidance on the choice of listed drug prior to NDA filing, the issue is certainly open for discussion at Type B meetings. These interactions, and any agreements regarding development strategy arising from the discussions, can be referenced in the NDA application. In the Hikma case described above, the choice of listed drug, including the decision NOT to rely on Colcrys, was discussed with the FDA prior to the submission of the Mitigare 505(b)(2) application. Notably, the Pre-NDA meeting proved useful for outlining the development program, specifically the gaps in information that would need to be addressed for submission. For instance, because Hikma would not be citing the drug-drug interactions from the Colcrys label, they agreed with the FDA to run a panel of drug-drug interaction studies specifically for Mitigare. Hikma and the FDA also reached agreement on how to approach several other safety concerns prior to NDA filing. Thus, working with the FDA, Hikma negotiated and followed through with a 505(b)(2) approval strategy that ultimately proved successful.

The 505(b)(2) approval pathway provides a lot of options for your development program. The path forward (or choice of listed drug) may not be the most obvious one at first, but could be simpler than you imagined.


Kesselheim, A.S. and Solomon, D.H. “Incentives for Drug Development – The Curious Case of Colchicine.” The New England Journal of Medicine, 2010, 362; 22:2045-2047.