After months of analyzing data submitted by concerned researchers, the Food and Drug Administration announced that the data it has seen so far do not back up claims that a particular generic version of clozapine is not equivalent to the brand-name product. However, the FDA stopped short of completely vindicating the specific manufacturer’s product, the primary target of the questions.

Questions about the equivalence of generic versions of the atypical antipsychotic medication have been stirring for about a year and a half. Last fall those questions made mainstream news with a reported legal battle between one generic drug maker, Zenith-Goldline Pharmaceuticals (ZGP), and the marketer of the brand-name product Clozaril, Novartis AG (Psychiatric News, December 15, 2000).

ZGP threatened to sue Novartis for restraint of trade and unfair business practices after news accounts labeling ZGP’s clozapine product as inferior were linked to Novartis-supported researchers. In court documents, IVAX alleged that Novartis went so far as to have the researchers submit data to the FDA purporting to prove that ZGP’s generic version was not bioequivalent to the Novartis brand.

ZGP fought back with a public relations campaign of its own, hoping to shore up the reputation of its generic product, which had been successful in taking roughly 35 percent of the market for clozapine sales in the United States.

Late last month the FDA issued its statement on the issue and posted one of its "Drug Information Pages" on its Web site addressing the clozapine questions.

The FDA reviewed studies from researchers at the University of Texas Health Sciences Center in San Antonio and the Minnesota state psychiatric system, which claimed that the ZGP version of clozapine was not bioequivalent to the brand-name product from Novartis. According to the FDA statement, their review "found that the cited studies were not conducted in a manner that could evaluate whether the generic version is unsafe or ineffective." The FDA said it is continuing to monitor reports regarding the ZGP product and has recommended that ZGP conduct a new full bioequivalence study.

The stronger data submitted to the FDA purporting to show nonequivalence were from a study done by Larry Ereshefsky, Pharm.D., at the University of Texas Health Sciences Center in San Antonio. In December Ereshefsky told Psychiatric News that although his study was not a full bioequivalence study that would meet FDA standards, he felt his results did raise questions regarding the bioequivalence of the ZGP product. The FDA, in its statement, agreed that the study did not meet its standards and also noted that in the FDA’s own inspection of the study site, some "irregularities" were found in how the study was conducted "that cast doubt on the results." Ereshefsky did not respond to requests by Psychiatric News for comment on the FDA’s findings.

The FDA noted that the Minnesota study also failed to provide any solid evidence of a problem with the ZGP product.

However, the FDA’s statement was not seen as a vindication for ZGP. The FDA’s recommendation that ZGP conduct a full new bioequivalence study is seen by some in the pharmaceutical industry as a warning to the company that its product may be vulnerable. Although the two specific studies reviewed did not provide sufficient evidence for the FDA to take regulatory action, further studies in the future could provide the evidence needed to take such action, including potentially pulling the product from the market should it prove to not be bioequivalent. A spokesperson for IVAX Corp., ZGP’s parent company, declined to comment on the FDA’s recommendation, except to say that "the company stands behind its product."

The FDA’s Clozapine Drug Information Page is posted at www.fda.gov/cder/drug/infopage/clozapine/clozapine.htm. ▪