WASHINGTON _ The long-running debate over competing heartattack drugs streptokinase and t-PA has drawn renewed attention thisweek due to a report in The Wall Street Journal that a Congressionalsubcommittee has begun a preliminary inquiry of Genentech Inc.'sscientific conduct and to the publication of dueling articles in a topmedical journal.Genentech's stock (NASDAQ:GNE) fell as much as $2.75 per share onThursday in response to the news but closed the day at $46.25, downonly 63 cents.The House Energy and Commerce Committee's subcommittee onOversight and Investigations is gathering information about theconduct of the 41,000-patient Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial which comparedGenentech's $2,200-per-dose t-PA to streptokinase, a drug marketedby Astra AB and Kabi Pharmacia AB of Sweden that costs one-tenth asmuch. Both drugs are classified as clot-busters, or thrombolytics.Staff members of the subcommittee are not free to comment on thematter and it was unclear what prompted the inquiry. Investigations ofthis type can result in Congressional hearings, an internal report or noaction at all, depending on the data generated by preliminaryinvestigative work.Sources in the medical community suggested that one focal point of theCongressional inquiry may be the behavior of Genentech's salesrepresentatives in promoting the use of an accelerated regimen for t-PAto hospitals. The GUSTO trial results were based on a weight-adjusteddose of t-PA delivered over 90 minutes concomitantly with intravenous(IV) heparin. The FDA-approved t-PA regimen is IV infusion overthree hours.Genentech applied for FDA approval of the accelerated t-PA regimenlast October but the agency has not yet granted it. Companies arebarred from promoting drugs for anything but FDA-approvedindications and regimens. Since the GUSTO results were released oneyear ago, Genentech's share of the thrombolytic market has risen from50 percent to 70 percent.According to Genentech spokesman Jim Weiss, the South SanFrancisco company has offered its assistance to subcommittee staff andwas told, "We'll be in touch with you." Analyst Carol Werther, ofCowen & Co. in Boston, dismissed the investigation on Thursday as"political posturing" and predicted that the GUSTO study would holdup under Congressional scrutiny.Conclusion Stands"GUSTO's major conclusion stands; Activase (t-PA) saves more livesby opening arteries faster," said Genentech's president and chiefexecutive officer Kirk Raab. "Given the facts and the level of scrutinyalready applied to GUSTO, I am completely confident that no group ofexperts, be they medical or political, can legitimately refute thatfinding."Although it is very preliminary, the investigation is potentiallyawkward for Raab, who has been a high-profile participant in thehealth care reform debate on Capitol Hill. Raab is the chairman of theBiotechnology Industry Organization .Biotechnology executives were jubilant just a few weeks ago whenRep. John Dingell (D-Mich.), who chairs the Energy and CommerceCommittee, announced his opposition to the concept of an advisorycouncil on breakthrough drugs. Committee member and biotechnologyadvocate Rep. Lynn Schenk (D-Calif.) was credited with persuadingDingell to take a stand on the issue.However, two senior members of the Energy and Commercecommittee, Rep. Ron Wyden (D-Ore.) and Rep. Henry Waxman (D-Calif.), have been vocal critics of the drug industry and high-priceddrugs. "This is a really dicey situation," said one congressional aidewho asked not to be identified. "It's wrapped up in the whole healthcare reform issue because the drug is so expensive."Congressional scrutiny is not a new experience for Genentech _ in thelate 1980's t-PA and Genentech were the focus of a hearing onscientific misconduct that focused on cardiologists who had financialties to the company.Simply put, the GUSTO trial results showed that, out of 100 heartattack victims, 93 survive with streptokinase and 94 survive with t-PA,a t-PA survival advantage of 1 percentage point. The study also foundthat t-PA patients had an increased risk of a disabling or fatal stroke butconcluded that the overall risk to benefit ratio was positive.The May 15 edition of the Annals of Internal Medicine contains twoarticles and two editorials offering opposing views of these results. Oneof the authors of an article criticizing the interpretation of GUSTOresults is Victor Marder of the University of Rochester in New York.Marder was on the steering committee of the GUSTO trial.Marder told BioWorld that out of 1,000 patients, t-PA saved 10 extralives but caused four extra lethal or disabling strokes, a fact whichproves that the reported t-PA advantage was "biologically unimportantand statistically insignificant." He said that whatever small absolutebenefit t-PA offered, it only pertained to heart attack victims who reachthe hospital less than four hours after the onset of symptoms. Mostheart attack victims in the U.S. do not reach a hospital in this timeframe.More Surgery For t-PA PatientsAnother issue raised by Marder was that the rate of coronary arterybypass graft (CABG) surgery performed on t-PA patients in theGUSTO trial was eight to 10 times higher than that in the streptokinasepatients. Such a difference could skew outcomes, he said.Marder said he has requested data from the GUSTO coordinatingcommittee that could clarify and explain the difference in CABG ratesbut that he has had difficulty obtaining the information. "Open andinformed evaluation of study results is essential to advancing scientificunderstanding," the article he co-authored states.Genentech's Weiss said that Marder's criticisms of GUSTO are notnew. "t-PA has the potential to save 1,700 lives per year. That's notinsignificant," said Weiss. "Physicians have been exposed over andover again to these criticisms and they're still choosing to use t-PA."Eric Bates, associate professor of internal medicine at the University ofMichigan's Medical School and a GUSTO steering committee memberwho is a self-described t-PA advocate, said that the t-PA-streptokinasedebate has been elevated to "an unfortunate level.""I think it's polarized and attracting more than its fair share of attentionbased on the other issues surrounding myocardial infarction (heartattacks) and medicine in general," he said.But a cardiologist who asked not to be identified said the debate israising profound issues. "This debate touches on the interactionbetween clinical trials, the drug industry, truth, market share, clinicalpractice, and conflicts of interest. How do clinical trial results really gettranslated into practice? That's the real question."

-- Lisa Piercey Washington Editor

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