Group Challenges FDA Enforcement Action on Marketed Unapproved Hydrocodone Drug Products; Claims GRAS/E Status Exists for Liquid Cough/Cold Hydrocodone Drug Products

January 8, 2008

We previously reported on FDA’s plans to take enforcement action with respect to firms manufacturing and distributing unapproved drugs containing hydrocodone.  According to the October 1, 2007 FDA Federal Register notice:

Anyone marketing unapproved hydrocodone products that are currently labeled for use in children younger than 6 years of age must end further manufacturing and distribution of the products on or before October 31, 2007. Those marketing any other unapproved hydrocodone drug products must stop manufacturing such products on or before December 31, 2007 and must cease further shipment in interstate commerce on or before March 31, 2008.

FDA intended the notice to wrap up the Agency’s previous conclusions made under the Drug Efficacy Study Implementation (“DESI”) program for certain pre-1962 FDA-approved hydrocodone drug products, which were last addressed in 1982 Federal Register notices. 

In late December 2007, a group known as the “GRAS/E Coalition” submitted a petition for reconsideration and stay of action to FDA requesting that the Agency “reconsider its plan to take enforcement action against those persons who manufacture or ship liquid cough/cold hydrocodone products that are not labeled for use in children under six years of age” (emphasis in original).  The GRAS/E Coalition contends that FDA did not fully consider the possibility that such drug products are Generally Recognized As Safe and Effective (“GRAS/E”) and do not require an approved marketing application.  As an alternative action, the GRAS/E Coalition requests that FDA “stay its enforcement action against manufacturers and shippers of liquid cough/cold hydrocodone products in a manner consistent with its previous actions . . . by extending the grace period for two years until December 31, 2009.” 

The GRAS/E Coalition takes particular issue with a statement in FDA’s June 2006 Compliance Policy Guide on marketed unapproved drugs in which the Agency states that if a final DESI determination classified a drug as effective for its labeled indication, then “FDA still requires approved applications for continued marketing of the drug and all drugs [Identical, Related, or Similar (‘IRS’)] to it – NDA supplements for those drugs with NDAs approved for safety, or new ANDAs or NDAs, as appropriate, for IRS drugs. DESI-effective drugs that do not obtain approval of the required supplement, ANDA, or NDA are subject to enforcement action.”  According to the GRAS/E Coalition petition, this position is contrary to law: 

We believe that the correct interpretation of the law would be that those products that had safety-only NDAs or were IRS to safety-only NDA drug products, that had [Active Pharmaceutical Ingredients (“APIs”)] that were found to be effective under the DESI review, that have been marketed subsequently for a material time and extent for over thirty years without any significant safety issues, and that have been allowed to remain on the market for over forty years due with FDA’s implicit approval can be considered GRAS/E.

GRAS/E status should apply to marketed unapproved liquid cough/cold hydrocodone drug products, according to the petition, because:

(1) there is a long history showing that these products are safe and effective as antussives; (2) [they] are marketed in the same basic dosage form as versions found to be safe and effective; (3) [their] labeling . . . is similar to versions found to be safe and effective; and (4) [they] comport with the applicable compendial criteria, are manufactured in compliance with [current Good Manufacturing Practices], and are required to have all adverse events regarding their use reported to the Agency.

In addition, the GRAS/E Coalition contends that its position is further bolstered by the fact that the Drug Enforcement Administration has regulated the distribution of hydrocodone API for over thirty years as either a Schedule II or Schedule III controlled substance.