BETHESDA, Md. -- An FDA advisory committee on Mondayconfirmed its preliminary support for the AIDS drug ddI andprepared today to review ddC under a strong admonition fromFDA Commissioner David Kessler to continue use of surrogatemarkers to fast-track potentially life-saving drugs.
After reviewing clinical end point data on Monday, theAntiviral Drug Products Advisory Committee voted 7-2 torecommend approval of Bristol-Meyers Squibb Co.'s ddI(dideoxyinosine). The vote affirmed a decision the committeemade last July based on a surrogate marker, the improvementin CD4 cell counts.
Approval was recommended for patients who are HIV-positiveand cannot tolerate or fail to respond to Burroughs WellcomeCo.'s AZT treatment, or who have demonstrated significantclinical or immunologic deterioration during AZT therapy.
But the committee also voted 7-2 against expanding ddI's labelindication to include patients with low CD4 T-lymphocyte cellcounts despite several months of AZT therapy.
Most members said there was inadequate data to support alabel indicating that AZT non-responders should switch to ddIor indicating how long AZT should be administered to a non-responsive patient before ddI would be approved as analternative.
Kessler hailed the committee's vote. "We took a risk when weapproved ddI," he said. "Today, I think, on balance, we havebeen proved right."
Kessler said the committee's July decision is a model foraccelerated approval, which the FDA published as a regulationin the Federal Register on April 15. The regulation requiresconsideration of accelerated approval for serious or life-threatening diseases when "approval can be reliably based onevidence of the drug's effect on a surrogate end point thatreasonably suggests clinical benefit or an evidence of the drug'seffect on a clinical end point other than survival or irreversiblemorbidity, pending completion of any necessary studies toestablish and define the degree of clinical benefits to thepatients."
The procedure would also be considered "in extraordinarycircumstances" for carefully controlled administration of highlytoxic drugs for serious or life-threatening diseases, Kessler said.
The new regulation "makes it FDA policy to accept less data fora potentially life-threatening disease than we might like toaccept," Kessler said. If "an equally convincing surrogatemarker exists" for Hoffmann La Roche Inc.'s ddc(dideoxycytidine), Kessler told the committee, "you shouldrecommend invoking the accelerated approval policy."
The committee will discuss Roche's new drug application forddC today and will consider whether to recommend approvalbased on interim data from clinical trials of ddC alone and incombination with AZT. Like Bristol-Meyers' NDA in July,Roche's NDA is based on interim analysis of changes in CD4 cellcounts.
July's approval, based on surrogate markers, was made only"with serious reservations" and the stipulation that Bristol-Meyers present clinical end point data as soon as they wereavailable.
On Monday, the majority of committee members said the datashowed a statistically significant reduction in the primaryclinical end point of new AIDS-defining events or death forpatients who received a dose of 500 mg. of ddI daily.
However, members were disappointed that there is noevidence for any increase in the survival rate for patients whoreceived the drug, said committee Chairman Henry Masur, chiefof the National Institutes of Health's Critical Care MedicalDepartment.
The data also failed to show any statistically significant clinicalbenefit from a higher dose (750 mg. per day). An FDAspokesman said this may be a false negative rate produced bythe high drop-out rate among high-dose patients due to highertoxicity.
Unanswered questions remain about this and other issues, suchas the unchanged survival rates and a higher rate ofpancreatitis in ddI patients compared with AZT patients, saidJames Kahn, lead investigator of the ddI trials at the Universityof California, San Francisco, and San Francisco General Hospital.
Masur noted that when the committee recommended approvalfor ddI in July, "we decided we would accept surrogate endpoints." Although the committee remains uneasy about thisdecision, acceptance of the use of surrogate end points is veryimportant because it means the drug industry will use "verydifferent drug design processes," said David Feigol, director ofthe FDA's division of antibiotics.
Immune Response Corp.'s AIDS vaccine, for which doseresponse trials will be unblinded this week, is a product thatlikely will benefit from the accelerated approvals process,Montgomery Securities analyst Brandon Fradd told BioWorld.
Immune Response (NASDAQ:IMNR) has announced plans tocomplete Phase II/III trials of the vaccine in September, andthe company's presentation of C4 T-cell counts and severalother surrogate markers could qualify it for an early approval,Fradd said.
"It seems likely that there will be an accelerated approval ofthis in 1993," he said.
-- Kris Herbst BioWorld Washington Bureau
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