Study used to sup­port di­a­betes drug Avan­dia is de­nounced in FDA re­view

Austin American-Statesman - - WORLD & NATION - By Gar­diner Har­ris

WASHINGTON — A fed­eral drug of­fi­cial dealt a se­vere blow Fri­day to the pop­u­lar di­a­betes drug Avan­dia, is­su­ing a scathing re­view of a ma­jor clin­i­cal trial that its man­u­fac­turer has been us­ing to ar­gue that the drug was safe.

The re­viewer, Dr. Thomas Marciniak of the Food and Drug Ad­min­is­tra­tion, found a dozen in­stances in which pa­tients tak­ing Avan­dia ap­peared to have se­ri­ous heart prob­lems that were not counted in the study’s tally of ad­verse events.

Such re­peated mis­takes “should not be found even as sin­gle oc­cur­rences” and “sug­gest se­ri­ous flaws with trial con­duct,” Marciniak wrote.

The de­tailed re­port could prove cru­cial next week, when a panel of ex­perts meets to con­sider whether to rec­om­mend to the FDA that the man­u­fac­turer, Glax­oSmithK­line, with­draw Avan­dia from the mar­ket or re­strict its sale.

The panel’s de­ci­sion will have broad con­se­quences for the com­pany, the FDA and per­haps even the en­tire process by which med­i­cal prod­ucts are ap­proved. The agency rarely does clin­i­cal tri­als on its own, depend­ing on drug com­pa­nies to con­duct them ap­pro­pri­ately.

Avan­dia, which helps pa­tients get bet­ter con­trol of their blood sugar lev­els, has al­ready come un­der in­tense crit­i­cism. It has been shown to in­crease the risks of bone frac­tures and to cause swelling that can lead to heart fail­ure and eye prob­lems. And a num­ber of stud­ies, in­clud­ing some by Glax­oSmithK­line, sug­gest that it could in­crease the risks of heart at- Dr. Thomas Marciniak of the FDA said he found omis­sions in a drug trial re­port that sug­gest Avan­dia raises the risk of stroke and heart prob­lems. tack, stroke and death.

Glax­oSmithK­line has re­lied heav­ily on the ma­jor clin­i­cal trial, nick­named Record, to demon­strate that those risks are ex­ag­ger­ated.

Marciniak’s re­view of the Record study calls that as­ser­tion into ques­tion. He found one case in which a seizure pa­tient was hos­pi­tal­ized for bleed­ing in the brain, but all men­tion of the episode was deleted from records. An­other pa­tient was hos­pi­tal­ized for 67 days af­ter a se­vere stroke, but the study record showed no sign of a car­dio­vas­cu­lar prob­lem.

An­other pa­tient died af­ter be­ing hos­pi­tal­ized for a se­ri­ous heart prob­lem, but the death was listed as aris­ing from an un­known cause and not as be­ing heart-re­lated.

Cor­rectly in­ter­preted, he con­cluded, the study ac­tu­ally sup­ports crit­ics’ con­tentions that Avan­dia may cause heart attacks and strokes.

“One does not have to be a math­e­ma­ti­cian or to per­form cal­cu­la­tions,” he wrote, to come to the con­clu­sion that a com­bined look at all the tri­als of Avan­dia would demon­strate that it causes heart attacks.

Mary Anne Rhyne, a spokes­woman for Glax­oSmithK­line, said, “The Record study was con­ducted ac­cord­ing to good clin­i­cal prac­tices, and the data are re­li­able.”

Marciniak’s re­view is part of a re­assess­ment of Avan­dia’s safety by FDA med­i­cal of­fi­cers to ed­u­cate the panel meet­ing Tues­day and Wed­nes­day.

De­bate about Avan­dia’s safety and how to han­dle re­ports of its dangers has split the food and drug agency and led to fierce re­crim­i­na­tions, staff de­par­tures and ques­tions from Congress.

It was the FDA’s de­lay in is­su­ing stronger warn­ings about Avan­dia that led Congress in 2007 to give the agency greater pow­ers over drug mak­ers.

Within the FDA, some of­fi­cials in­sist that the ev­i­dence is mixed and oth­ers say it is strong enough to merit the drug’s with­drawal. An ad­vi­sory meet­ing in 2007 con­cluded that Avan­dia did in­crease heart at­tack risks but that it should stay on the mar­ket.

Al­though en­docri­nol­o­gists have ad­vised against its use, Avan­dia re­mains pop­u­lar — with nearly 2 mil­lion pre­scrip­tions last year. If the drug were to be with­drawn, Glax­oSmithK­line — al­ready fac­ing law­suits claim­ing Avan­dia caused in­juries — would likely see its li­a­bil­ity soar.

Paul Sakuma

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