WASHINGTON _ At least two new drug applications (NDA) forliposomal antifungal agents are likely to land on the FDA's doorstepbefore the end of 1995 and the agency is scrambling to refine itsregulatory strategy for this new class of drugs.
Experts from the Antiviral Drugs Advisory Committee (ADAC) thisweek rejected the idea _ raised by FDA officials _ of placing thecompounds on an "accelerated approval" track.
The Liposome Co. (TLC), of Princeton, N.J., Liposome TechnologyInc. (LTI) of Menlo Park, Calif., and Fujisawa Pharmaceutical Co.Ltd., of Japan, (which has U.S. marketing rights to Boulder, Co.-based NeXstar Pharmaceuticals Inc.'s AmBisome) are all currentlytesting liposomal formulations of the already-approved antifungalagent, amphotericin B, in Phase III trials.
At Monday's ADAC meeting, experts grappled with clinical trialdesign issues that they will undoubtedly revisit if and when the NDAsfor liposomal antifungals start rolling in. The question of whatevidence will be deemed acceptable to "prove" the efficacy of theseagents is clearly the $64,000 question.
At stake is a market that some place at $500 million worldwide, withroughly $200 million of that in the U.S. Although both TLC and LTIare pursuing relatively narrow second-line therapy indications fortheir drugs, (i.e., patients with a specific fungal infection that havefailed or are intolerant to amphotericin B) most analysts believe thatthe drugs, if approved, will be used extensively off-label.
Although early-stage clinical studies have demonstrated thatliposomal forms of amphotericin B produce significantly less severeside effects than the "naked" drug, questions remain about theirpotency. Are they less toxic merely because they deliver less drugand thus are less effective? Only large, randomized, double-blindedand controlled trials may answer that question definitively.
Conducting pivotal, comparative studies of liposomal antifungalagents has not been easy, according to David Feigal, director of theDivision of Antiviral Drug Products at the FDA. The biggestproblem: Trials accrue patients at a glacial pace. Feigal said thewidespread use of fungal prophylactic therapies (which makespatients ineligible to join trials), the availability of oral antifungalagents (which patients prefer to intravenous injections), thewidespread use of experimental drugs on a `compassionate use' basis(which also renders patients ineligible), and the many "competing"trials of different liposomal antifungal agents have hampered researchin the field.
How slow are these trials going? One researcher who asked not to beidentified told BioWorld that a company with 50 clinical centersparticipating in its protocol might garner about five eligible andevaluable patients per month. Meanwhile, some companies arerunning out of cash.
"These trials may be beyond the financial capabilities of thecompanies that are sponsoring them," noted Thomas Walsh, a guestspeaker at the ADAC meeting and a researcher at the NationalCancer Institute.
Despite the problems, companies like TLC (with its drug Abelcet)and LTI (with its drug Amphocil) have forged ahead with theirpivotal clinical trials, even though they won't be ready in time for theNDA filings. Instead, the NDA filings will be based upon the use ofso-called "historical controls" _ data bases of carefully selectedpatients whose clinical fates under "standard" therapy can becompared to the fates of patients treated with the new drugs in anuncontrolled setting. Most, if not all, of the NDAs for liposomalantifungals will incorporate uncontrolled data that will have to becompared to historical controls.
The results of the larger, controlled studies could rehabilitate thetattered image of liposome technology, which made an inauspiciousdebut on the American regulatory stage in 1993 when the FDA'sOncologic Drugs Advisory Committee (ODAC) resoundinglyrejected Vestar Inc.'s DaunoXome, a liposomal form of daunorubicin(San Dimas, Calif.-based Vestar merged with NeXagen Inc. earlierthis year to form NeXstar).
Last month, ODAC recommended LTI's DOX-SL (a liposomal formof doxorubicin) for accelerated approval, but couldn't agree onwhether the trial data was "adequate and well-controlled." ODACmembers were harshly critical of the company's data at the meeting.Analysts said the quality of the NDAs submitted for liposomalantifungals and their subsequent fate may either validate or invalidatethe technology once and for all.
"The FDA has a `show-me' attitude about liposomes in general," saidMatthew Geller, an analyst at Oppenheimer & Co. "We're finally atthe point now where we will have proof-of-principle data from largePhase III trials. Liposomes have been around for a long time and a lotof skepticism has developed about them in the scientific community."
Yet the FDA, in an apparent attempt to lighten the regulatory load forcompanies, asked experts at last Monday's meeting whether or not,under certain circumstances, liposomal antifungals should beconsidered for "accelerated approval." Accelerated approval is aconditional form of drug licensure that requires companies to conductconfirmatory post-marketing safety and efficacy trials.
However, ADAC members rejected the idea that liposomalantifungals be released into widespread use before their efficacy isquantified. Many argued that conditional licensure would make iteven more difficult for companies to recruit patients for thecontrolled clinical trials needed to validate the drugs. n
-- Lisa Piercey Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.