BETHESDA, Md. _ FDA officials said on Friday that new AIDSdrugs which reduce the number of HIV particles in a patient's bloodwill be considered registrable under the agency's acceleratedapproval program. Until now, the only sure bet for obtainingaccelerated approval has been to show that a drug could boost apatient's CD4 cells.

The official blessing of viral load was hopeful news for developers ofa new and promising class of drugs called protease inhibitors.Protease inhibitors were designed to block viral replication bycleaving the enzyme protease, which enables the virus to mature andreplicate.

Viral burden and CD4 cell counts are considered surrogate markersof disease progression in AIDS, although a direct link betweenfluctuating levels of these two elements in the blood and mortalityhas yet to be conclusively demonstrated. Experts say it could takeyears before enough clinical trials can be completed to "validate" theimpact of either marker on survival or AIDS-related morbidities.

"You don't need to validate viral load as a surrogate marker in orderto get accelerated approval," said David Feigal, director of thedivision of anti-viral drug products at the FDA's Center for DrugEvaluation and Research. "That's a long-term question that does nothave an impact on the registrational status of protease inhibitors."Feigal made the comments during the second day of a meeting hereof the National Task Force on AIDS Drug Development (NTFADD).

Although protease inhibitors have shown a dramatic ability todecrease viral load in patients, levels usually return to baseline withina matter of months due to the virus's ability to mutate and developgenetic resistance to the powerful drugs. Yet protease inhibitorsappear capable of producing a sustained increase in the CD4 cellcounts of AIDS patients even as the virological effects wear off.Researchers aren't sure why.

Some have questioned whether the pathogenesis of AIDS is wellenough understood to allow continued and expanded use ofunvalidated markers as the basis for drug marketing approvals. Butthe FDA has maintained that for life-threatening illnesses, the use ofsurrogate markers serves the public interest.

"One of the features of accelerated approval is that you know less,"explained Feigal. He added that the labeling for drugs licensed on anaccelerated approval basis contain no description of clinical benefit.Post-marketing (Phase IV) studies are required to provideconfirmatory evidence that the drugs produce benefit and to changethe label.

One difficulty in comparing and interpreting the virology results ofnew AIDS drug studies is that viral load can be measured by a varietyof assays, including an older p24 antigen assay, an RNA polymerasechain reaction (PCR) assay or the new kid on the block, a branchedDNA assay developed by Emeryville, Calif.-based Chiron Corp. Theassays have varying degrees of sensitivity.

Another issue discussed by NTFADD members was that of expandedaccess, or `salvage' programs, in which an experimental drug is madewidely available to patients in need before accelerated approval isgranted. Such programs are often used to collect extra safety data thatsupports an accelerated approval application.

However, at least two of the protease inhibitor manufacturers whoseproducts are at the most advanced stage of development _ Merckand Co. Inc., of Whitehouse Station, N.J., and Abbott Laboratories,of Abbott Park, Ill. _ have cited a shortage of drug supply as amajor obstacle to starting expanded access programs. Hoffman-LaRoche, a unit of Roche Holdings Ltd. of Switzerland, has promised tomake its protease inhibitor, Saquinavir, available to 4,000 patients inan expanded access program set to begin in the third quarter of thisyear.

On Friday, FDA Commissioner David Kessler fretted that there arenot sufficient incentives for companies to launch expanded accessprograms, which can be costly, paperwork-laden and, in the contextof limited drug supplies, impossible to conduct.

"With accelerated approval, we have only the power of moralpersuasion when it comes to expanded access," said Kessler. "It's notgoing to work by regulatory fiat. We have to negotiate with thecompanies to solve the problem of salvage therapy." HIV-infectedindividuals have argued passionately for better expanded accessprograms.

Edward Scolnick, Merck's vice president of science and technologyand a NTFADD member, said that Merck could not supply enough ofits protease inhibitor, MK-639, to meet demand even if it had FDAapproval in-hand today. "We're working as fast as we can," he toldAIDS activists who have criticized the company for not having anexpanded access program in place. n

-- Lisa Piercey Washington Editor

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