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All Antiretrovirals in US Ought to Be Tested for HIV Resistance, FDA Suggests in New Guidance


All antiretroviral drugs in development and already on the market in the United States should be tested for HIV resistance, the US Food and Drug Administration suggested in a new draft guidance for industry.

The document, filed on Nov. 26, is designed to encourage drug makers to collect data that, when made publicly available in product labeling and FDA reviews, could be useful to diagnostics firms, physicians, regulatory agencies, and the drug makers themselves.

The upshot for drug and diagnostics makers and pharmacogenomics tool providers is that the guidance may provide evidence of an incremental step toward broader use of pharmacogenomics.

The draft guidance, entitled “Role of HIV Drug Resistance Testing in Antiretroviral Drug Development,” calls for drug makers to begin drug resistance testing as early as possible during drug development, and at each stage thereafter. The agency said such testing would allow a “comprehensive” evaluation of a new antiretroviral’s resistance and cross-resistance profile in order to promote “more rational” use of drug combinations, according to the document.

Industry has 90 days to comment on the draft guidance. The FDA will make the draft a formal guidance document soon after it digests the comments.

HIV-resistance testing “is the first good example of ‘theranostics,’ because what drug you prescribe depends upon what the resistance pattern is,” said Mike Largen, a consultant with Largen Associates in Chapel Hill, NC.

Specifically, Celera Diagnostics, which manufactures one of the two FDA-approved HIV-genotyping tests for drug resistance (the other is made by Bayer), is interested in the downstream use of drug industry data coming out of HIV drug resistance testing. “We know [drug makers] design and test now with new compounds. We’re going to look at how HIV genotyping helps in the management of HIV positive patients,” said Joe Henkhaus, senior director of market development at the Applera unit.

Drug companies will submit the drug-resistance data in the appendices of NDAs or NDA supplements, according to an FDA spokesperson.

As HIV adapts to existing antiretrovirals, and as pharma counters with new drugs, diagnostic companies keep pace with their own updates to existing tests. “Earlier this year we made a submission to the FDA for our latest algorithm that identifies mutations where we added mutations for new drugs,” Henkhaus said, referring to the company’s ViroSeq product [see PGx Reporter, 2/19/04]. Celera most recently added new mutations to its diagnostic in February.

For diagnostics firms already invested in viral drug resistance, the new guidance may provide a glimpse of the regulatory environment that will develop around other treatments.

“I think that the companies that are interested in HIV resistance testing certainly have a long-term interest in HCV, particularly as HCV drugs develop,” said Largen. “Companies that have a base expertise in resistance testing are interested in extending that platform,” he added.

Pharma’s Data

Drug-resistance testing in HIV is nothing new. “Anybody that’s going to put a drug on the market that is an antiretroviral for HIV will characterize the mutations that confer resistance,” said Eric Shulse, Celera Diagnostics’ senior director of business development. “Some of them do it in-house now that there are approved tests, some of them will go to laboratories that offer it as a service.”

The HIV drug market is sufficiently mature that there are a number of known resistance mutations and cross-resistance patterns, so it is already a necessity that drug developers test for resistance, said Largen. But there is still a long way to go before full market penetration of HIV resistance testing, he added.

Drug developers are trying to achieve a first indication for treatment in people with drug resistance, “because that’s the fastest, most inexpensive way to get a drug approved,” said Robert Schaefer, an assistant professor of medicine in the Stanford Division of Infectious Diseases who maintains the Stanford HIV Drug Resistance Database (

These companies can do a short study of “maybe six months’ duration” to evaluate the drug in a failing treatment regimen, whereas attempting to place the drug in first-line therapy, “since therapy works so well,” would take a several years of study, Schaefer said.

The Boeringer-Ingelheim antiretroviral tipranovir, which is still in development, has been positioned as a salvage therapy, and “a lot of people” think it might work better against resistant viruses than as an upfront therapy, said Schaefer.

Other drugs, regardless of how they are positioned, seem to work in both situations with similar effectiveness, he added.

Drug-resistant strains are being propagated in the US and elsewhere, raising the importance of HIV drug resistance testing, “both from the perspective of the treatment of affected individuals, as well as the development of drugs,” said Shulse.

Genotyping costs about $300 to $400, while a test of both phenotype and genotype costs $1,100 to $1,200, said Largen.

For clinicians using HIV drug-resistance tests, there is not enough information available to direct treatment once a frontline therapy has failed — the FDA is asking drug makers to conduct more research to change the situation, said Schaefer. “There are excellent recommendations for upfront therapy, but if you have somebody who’s failed one regimen, there’s not a single guideline,” he said.

The HIV Drug Resistance Database includes drug resistance data Schaefer collects generally after drugs have been approved. “All this data that they’re submitting to the FDA, I think eventually we’ll be requesting too,” he said.

The draft guidance grew out of a November 1999 meeting prompted by a working group composed of pharma companies, diagnostic companies, three FDA centers, and academics, said Shulse. At the meeting, there was a “general consensus” that resistance testing needed part of the drug development and submission data sent to [the Center for Drug Evaluation and Research], he said.

The draft guidance is available at

— CW

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