Pharmaceutical powerhouse Novartis AG is being indirectly accused of promoting the publication of "clearly spurious scientific data used to discredit both generic drugs and the [Food and Drug Administration’s] generic drug approval standards."

The charge was made in a recent written complaint filed with the FDA over questions of bioequivalence between Novartis’s brand-name antipsychotic Clozaril and a generic version of clozapine.

For some time, questions have been quietly popping up about the efficacy and safety of the generic product. Now those questions are the basis of an erupting war between two pharmaceutical giants.

The slowly brewing battle boiled over recently in the popular press with allegations that a specific generic version of clozapine, manufactured and marketed by Zenith Goldline Pharmaceuticals (ZGP), a division of the giant IVAX Corporation, was not bioequivalent to the brand-name product Clozaril, marketed in the United States by Novartis Pharmaceuticals Corporation.

The October 24 issue of the Wall Street Journal reported that the ZGP product was "affecting patients differently than its brand-name version." Staff reporter Thomas M. Burton cited a clinical trial in which "severely ill schizophrenic patients, given identical doses at similar times, have shown that the generic drug was present at lower levels in their bloodstreams than the brand name Clozaril was."

IVAX Corporation quickly fired back, issuing a press release condemning the Wall Street Journal story, with IVAX President Neil Flanzraich saying, "The medical community is sophisticated, and we are confident that the misleading study sponsored by our competitor, Novartis, and the superficial and unbalanced Wall Street Journal article will have no significant effect on our sales of clozapine."

At the same time, Mylan Laboratories, which markets a clozapine generic through its Bertek division, also issued a press release assuring clinicians and patients that its product was bioequivalent to Clozaril. Interestingly, Mylan’s generic clozapine was not questioned in the Wall Street Journal article.

Finally, on October 31, the Generic Pharmaceutical Association (GPhA), an independent trade group representing the manufacturers and distributors of more than 90 percent of all generic prescription medications in the U.S., entered the fray with its written complaint to the FDA. The complaint asked the FDA to "expeditiously evaluate the available data [concerning bio-equivalence between Clozaril and clozapine] and respond appropriately."

The complaint, signed by Carole S. Ben-Maimon, M.D., chair of the GPhA board of directors, also requested "a clear public statement from the FDA in defense of its approach [in documenting bioequivalence of generics] which insures the safety and efficacy of generic drugs."

Harry Rome, a spokesperson for Novartis Pharmaceuticals Corporation, said the company began hearing anecdotal accounts describing how some patients with schizophrenia, stabilized on Clozaril for long periods, started exhibiting more hallucinations and violent outbursts after switching from Clozaril to generic clozapine.

"There was never enough meat to these anecdotal accounts," Rome told Psychiatric News, "to make them adverse drug events, but certainly enough to get people around the country talking." This discussion, Rome said, led Novartis to do a physical examination and dissolution testing on 100 mg tablets made by Novartis versus 100 mg tablets made by ZGP. The results suggested to Novartis that there was, indeed, a difference.

Questions of bioequivalence, however, began with the FDA’s approval of the ZGP clozapine in November 1997. The tests done by ZGP, which led to the product’s approval by the FDA, were done on doses of only 12.5 mg, far below any dose seen clinically. Although dosing of the drug is complicated and can be highly variable, common daily doses of clozapine range as high as 800 mg.

The FDA had granted ZGP a waiver to test the bioequivalence of its product using the significantly lower dose due to concerns over the serious potential side effects that 100 mg tablets can have in normal healthy volunteers. For example, the drug is known to have significant and potentially fatal cardiac toxicity in healthy individuals.

The 12.5 mg dose was indirectly compared with the Novartis 100 mg Clozaril tablet. The FDA rated the ZGP 25 mg and 100 mg tablets "AB"—pharmaceutically and therapeutically equivalent to the brand name product. It was the scientific merits of the FDA waiver for ZGP that was questioned in the Wall Street Journal article.

One of the people who had questioned the bioequivalence of the ZGP product from the outset was Larry Ereshefsky, Pharm.D., a professor of pharmacology and psychiatry at the University of Texas Health Sciences Center in San Antonio, whose study was cited by the Wall Street Journal.

"I felt it was inappropriate," Ereshefsky told Psychiatric News, "that the 100 mg tablet had not been tested in humans, let alone not doing the studies in patients, which can be safely done." After its dissolution testing roused suspicions, Novartis consulted with Ereshefsky and funded a clinical trial led by him to evaluate the bioequivalence of the ZGP product to Clozaril in patients with schizophrenia.

Ereshefsky told Novartis that he wanted to do a large-scale, formal study of bioequivalence. Novartis approved a much smaller and less-expensive protocol evaluating bioavailability parameters, he said.

Along with psychiatrists at the University of Texas Health Sciences Center in San Antonio, Ereshefsky followed 21 patients in a blinded, randomized crossover study of the Clozaril 100 mg tablets and the ZGP clozapine 100 mg tablets. Ereshefsky found differences in the maximum concentration of medication in the blood after oral dosing, with the ZGP tablets producing lower blood levels of the drug. However, the confidence level in the study was below 80 percent, the minimum required for an FDA protocol study.

"What our study did was raise a question," said Ereshefsky. "Did we prove the two were not bioequivalent? No. Did we prove that there is a question that needs to be studied further? Yes. I would love to see someone do a full bioequivalence study on these two drugs."

Although Ereshefsky’s data have been submitted to the FDA for review and for peer-reviewed publication, his work has been blasted by ZGP as having "serious design flaws and drawing erroneous conclusions." An FDA spokesperson told Psychiatric News only that "the agency does not comment on matters pending its review."

"Our study," Ereshefsky said, "was not designed as a formal bioequivalence study, which would lock up the patients on an inpatient unit for six weeks and control absolutely everything about them. It was a real-world study with stabilized outpatients, many of whom are married, working, in school, and all well enough to sign informed consent."

IVAX enlisted schizophrenia heavyweights Stephen M. Goldfinger, M.D., a professor and vice chair in the department of psychiatry at the State University of New York in Brooklyn, and Jacqueline Feldman, M.D., a professor of psychiatry at the University of Alabama and president of the American Association of Community Psychiatry, to refute the legitimacy of Ereshefsky’s study, as well as the anecdotal reports of patient relapse after being switched from brand-name product to generic.

Said Goldfinger, "Those with schizophrenia and other disorders for which clozapine is used have intermittent exacerbations and remissions as part of their illness, even when maintained on constant levels of the same medication."

"In my practice," said Feldman, "I have treated many patients whom I have switched from the brand drug to Zenith Goldline’s product, and I am aware of hundreds of other patients who have been switched, none of whom have experienced any untoward effects or decompensated."

Indeed, data files that the FDA requires each manufacturer to maintain on clozapine patients show that nearly 21,000 patients have been successfully switched to ZGP clozapine from Clozaril. Mylan reports that nearly 22,000 patients are taking its version of clozapine, with only 20 adverse events reported.

So, is the ZGP drug a bad drug? "No, I don’t think so at all," Ereshefsky told Psychiatric News. "I think if you start someone on ZGP and titrate them up, they’ll do just fine. In fact, I recommend that for the cost advantage. And you can switch the majority of people, and they do just fine. But in those people that are a little more ill, or the dose is barely adequate to begin with, you could see problems."

The bottom line, as is often the case, is likely to be more financial than clinical. Novartis has steadily lost market share to ZGP and Mylan since the generics were introduced. Managed care promotes the use of the generics as a cost-savings measure, and the generic manufacturers take advantage of that.

ZGP now claims nearly 35 percent of the total market for clozapine sales in any version. Articles unfavorable to their product, such as the company says the Wall Street Journal article was, could lead to decreased sales. And the company blames Novartis and the Novartis-funded Ereshefsky study.

Although Ereshefsky noted that his study materials were subpoenaed by and handed over to IVAX, rumors of potential legal action against Novartis for unsubstantiated claims and restraint of trade were not confirmed for Psychiatric News by IVAX.