The Pink Sheet “For Generic Vancocin, An Advisory Committee Role Reversal” August 3, 2009
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee does not typically review specific drugs. But on Aug. 4, FDA’s Office of Generic Drugs will ask the committee for its advice on bioequivalence standards for ViroPharma’s Vancocin (vancomycin).
Currently OGD recommends that an applicant seeking marketing approval for generic vancomycin demonstrate bioequivalence to Vancocin through in vitro dissolution studies.
According to FDA’s briefing documents, Vancocin – which is indicated to treat staphylococcal enterocolitis and antibiotic-based associated pseudomembranous colitis caused by Clostridium difficile – is highly soluble over a wide range of pH values and acts locally in the GI tract. For this reason, comparing dissolutions rates in media of varying pH values which represent conditions in the GI tract is the most suitable approach for comparing generic vancomycin and Vancocin.
ViroPharma, however, argues that those requirements are essentially the Biopharmaceutics Classification System-based biowaiver, which was developed using healthy GI parameters to predict the absorption of systemically acting drugs from the healthy gut and was not intended for use in predicting in vivo performance of locally acting GI drugs.
In addition, the dissolution standard does not address the conditions of the in vivo environment of the diseased GI tract in which Vancocin is used, the brand firm argues. The generic’s dissolution and solubility would never be studied using relevant physiological conditions, including decreased fluid volumes, elevated pHs, and altered fluid composition.
In 2006, FDA issued BE recommendations for vancomycin capsules in a draft guidance, changing the standard from clinical endpoint studies to the in vitro dissolution BE method for BCS Class I drugs based on academic inquiry into the physiologic parameters of the healthy human GI tract. In light of that evidence, FDA waived the requirement that BE must be demonstrated with in vivo data.
Of the four BCS drug classes, FDA has extended the biowaiver to only BCS Class I drugs. In 2006, Vancocin was characterized as Class I and deemed eligible for a biowaiver.
However, ViroPharma insists that Vancocin is not a BCS drug at all. The BCS explicitly did not consider locally acting drugs such as Vancocin in its validation development, it argues, and furthermore, Vancocin is not rapidly dissolving.
Both FDA and ViroPharma’s briefing documents note that the shift to in vitro dissolution BE for vancomycin relied in part on faulty data from a generics company that showed vancomycin is rapidly dissolving. ViroPharma objected to the data and when FDA took a closer look, it confirmed that vancomycin is not rapidly dissolving.
In March of 2006, ViroPharma filed a petition with FDA, seeking to stay approval of all ANDAs that reference Vancocin, saying acceptance of in vitro bioequivalence standards was “fatally flawed” and should not have been issued without prior public discussion.
Most recently, ViroPharma has taken the unusual step of challenging the assertions in the agency’s briefing documents – most importantly the fact that Vancocin was approved based on dissolution studies, a point the sponsor emphatically denies. Other inaccuracies, according to a ViroPharma letter sent to the docket on July 31, include OGD’s misrepresentation of a historical document and misconstruing key facts regarding acarbose ANDAs.
When the committee met last summer to discuss bioequivalence, ViroPharma treated the panel as a make-or-break event in trying to convince FDA to change its approval standards.
During that meeting, ViroPharma was relegated to presenting data during the open public hearing, but this time the company will get equal billing as a presenter, although generic firms may present as well. But the fact that ViroPharma is inching its way up the agenda, instead of having to face generics in the marketplace, could be a sign that it’s making progress to get FDA to change its mind.
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