WASHINGTON -- AIDS patients and others for whom time iscritical have emphasized the need for an alternative to thelengthy drug-approval process.

And from the researcher's point of view, "it's difficult to justifywaiting 10 years before you can have a clinical trial result,"Deborah Cotton, a professor at the Harvard Medical School, tolda symposium at the American Federation for Clinical Researchhere on Saturday.

Surrogate markers "substitute for clinically meaningfulendpoints that directly measure how a patient feels, functionsor survives," explained physician James Bilstat of the Center forDrug Evaluation and Research at FDA.

Besides AIDS, surrogate markers have been used in clinicaltrials for treatment of stroke, congestive heart failure,osteoporosis, emphysema and other conditions. Cardiac output,for example, was used as a surrogate for survival in trials ofGenentech Inc.'s clot-buster, t-PA.

But the use of surrogate markers seems to create almost asmany problems as it solves, said Cotton. "Many anti-virals havea fairly wide spectrum of anti-bacterial action," she said. "Youcould imagine an anti-viral could change outcome of oneopportunistic infection, but not others, which could falselymake that drug look more effective in terms of its underlyingeffect on HIV.

"This could also affect the time the opportunistic infection isdetected," leading to earlier diagnosis of full-blown AIDS, saidCotton. Imagine an anti-viral that had the unfortunate sideeffect of blurring vision, she explained. Patients would be morelikely to have ophthalmic examinations, with the result thatCMV retinitis would be detected earlier.

Another danger is that other diseases and bad habits mightchange the values of surrogate markers. "For patients withacute pneumonia or chronic fatigue syndrome, we don't knowthe normal level of CD4 cells," said Cotton. "But one studysuggested that CD4 levels are higher in smokers."

Even the most compelling markers can be misleading. MRIscans of Alzheimers' patients correlate fairly well withcognitive deterioration, but Lon Schneider, a physicianaffiliated with the University of Southern California, describedone patient whose MRI scans revealed progressive atrophy, butwho had "little change in cognitive function."Electroencephalograms, once used in trials of hydergine forAlzheimers, did not correlate at all with disease progression,despite pursuasive hand-waving in their support, saidSchneider.

"We concluded that there were no significant legal constraintson approval based on surrogate endpoints," said Bilstat. TheFood, Drug and Cosmetic Act requires evidence of effectivenessto support drug approval, but the FDA has responsibility fordefining effectiveness.

However, surrogates clearly made Cotton queasy. The biggestrisk, she said, is that a potentially valuable drug might appearwanting, and be rejected.

On the other hand, if a drug approved in trials using surrogatemarkers ultimately proved ineffective, recall probably wouldbe difficult, said Cotton. Projecting a slide of a currentadvertisement showing a patient ready to belt anyone whowould expropriate his ulcer medicine that keeps the surgeon'sknife at bay, she said, "Wearing my physician hat, if I have apatient I think is benefitting from the drug, I'm not going to bepleased about somebody taking away my ability to give thatdrug, even if the statistics support recall."

With drugs becoming increasingly expensive and in the contextof the health care system in crisis, the uncertainties ofsurrogate data may prove less than pursuasive to patients,providers and third-partery payors, Cotton warned.

One alternative to the use of surrogates would be to conductsimple trials that would be large enough for clinical and/orsurvival endpoints to emerge rapidly, said Cotton. Andfollowing trials of drugs for life-threatening diseases wheresurrogates are used, Cotton urged continued surveillance untildeath, where possible.

-- David C. Holzman Washington Editor

(c) 1997 American Health Consultants. All rights reserved.

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