AIDSWEEKLY Plus; Monday, October 19, 1998
Daniel J. DeNoon, Senior Editor
There are more potential combinations of new AIDS therapies than can be tested in randomized trials. This leaves observational databases as the only means of evaluating these combinations.
But such evaluations are fraught with danger, warned Andrew N. Phillips of the Royal Free Center for HIV Medicine, London, U.K.
"In other disease areas important discrepancies between results from databases/cohorts and randomized trials have been identified," Phillips said in a plenary address to the American Society for Microbiology's 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 24-27, 1998, in San Diego, California.
He pointed to the example of beta carotene use for prevention of cardiovascular disease. Observational cohorts suggested that beta carotene prevented disease, but a later clinical trial demonstrated that its use actually increased risk of disease.
Databases, Phillips noted, are data collected regularly as part of the routine clinical care of unselected patients. Such data inherently lacks the hallmark of a clinical trial: blinded randomization of subjects with similar prognoses to the treatment options being compared. The inevitable incorporation of bias into databases raises serious questions as to how - and when - they can answer questions about treatment efficacy and safety.
Unfortunately, there appears to be no realistic alternative to the use of databases in evaluating modern AIDS therapies.
"We have more drugs than we can possibly test in combination," said David Cooper of the University of New South Wales, Sydney, Australia.
Michael Saag of the University of Alabama, Birmingham, agreed.
"As therapies get more complicated, clinical trials get more complicated," he said. "It's going to be better use of databases that will determine clinical therapies in the future."
Phillips raised two central questions: Can databases be used to compare therapy regimens when direct clinical-trial data is lacking? Is it valid to look at databases and untangle their biases?
"If in the future we are going to do this thing, we are going to need sufficient numbers," he said. "We will need very large databases."
After analyzing databases incorporating data from patients receiving nucleoside-based antiretroviral regimens and comparing this data to that collected in randomized clinical trials, Phillips reached three general conclusions:
* Observational databases can give results similar to those seen in clinical trials - but not always.
* Observational databases are unlikely to reliably discern small differences between treatment regimens.
* Only randomized clinical trials can guarantee unbiased results.
"Where there is clinical uncertainty we must face up to the fact and randomize [into clinical trials]," he said.
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