Bethesda, Md. -- Seated in a semicircle before a standing room-only crowd at the FDA's Parklawn Building, twelve expertsgathered Tuesday to sift through the wreckage of thedisastrous Phase II clinical trial of the experimental hepatitis Bdrug fialuridine (FIAU), which killed five people. The specialsession of the agency's Antiviral Drugs Advisory Committeewas convened to examine possible explanations for theunexpected and fatal toxicities of FIAU and the long-termimplications for other drugs of its class, called nucleosideanalogs (which work by intervening at the level of DNA to stopviral replication).
FIAU was licensed by Eli Lilly & Co. in August 1992 from theSan Rafael, Calif.-based biotech company OclassenPharmaceuticals Inc.
National Institutes of Health (NIH) physician Jay Hoofnagle,principal investigator for the FIAU trial, said the drug willnever be tested in humans again. "FIAU is a piece of history,"he said, adding that clinical trial procedures will be re-evaluated as a result of the FIAU experience, with thepossibility that further controls and precautions will beimposed on human studies of drugs.
Panelists expressed concern and confusion over how such apotent and toxic drug slipped undetected through the checksand balances of the preclinical and clinical developmentprocess. They agreed that further basic research still needs tobe done in order to explain the mechanism of action by whichFIAU destroyed the liver function of seven of 10 patients whoreceived the drug in the Phase II trial.
The trial was halted in the early hours of the morning of June26, 1993, after the two patients who had received the drug forthe longest duration began exhibiting severe side effects. Sincethat time, of the 10 patients, five have died, two have requiredliver transplants and three others have escaped serioustoxicities to date.
The panel heard testimony from nucleoside analog experts, NIHinvestigators and one patient, Paul Melstrom of Phoenix, Ariz.,who participated in a pilot trial of FIAU prior to the calamitousPhase II trial and claims that he has suffered "permanent,irreversible peripheral neuropathies" as a result. Melstrom wassharply critical of the NIH's handling of the FIAU trial andcalled for a congressional investigation to determine potentialwrongdoing. The FDA initiated a formal review of the FIAUinvestigational new drug (IND) application in July and expectsto issue a preliminary report of its findings by early October.
Melstrom criticized the practice of NIH investigators during theFIAU trial of ascribing all of his symptoms to "unknownetiology," instead of seriously considering that they might bedrug-related. Hoofnagle argued that the fatal toxicity of thetrial was liver failure, not peripheral toxicities.
The working hypothesis presented by NIH researchers andother experts was that FIAU wreaked havoc in the cells of trialparticipants by injuring the subcellular engines of life,mitochondria, which are responsible for aerobic metabolism.Aerobic metabolism provides the body's basic source of energy.When mitochondria fail, the body's backup system is anaerobicmetabolism, a far less efficient form of energy generation thatproduces toxic byproducts. One of those byproducts is lacticacid, and too much lactic acid causes lactic acidosis.
All of the patients who died or experienced serious livertoxicities after receiving FIAU suffered from a severe,intractable form of lactic acidosis that, according to Hoofnagle,has never been seen before. Essentially, the theory goes, theirmitochondria ceased to function.
One of the burning questions of the day was why the toxicitiesseen in the Phase II trial were not detected in any preclinicaltesting of the drug, including animal studies in mice, rats,monkeys and dogs. Hoofnagle said early testing of FIAU inanimals and pilot studies in humans did not reveal anytoxicities that hinted at the lethal potency of FIAU. However,animal studies were not designed to look at mitochondrialfunction, or even to closely track liver function.
Hoofnagle said the only positive outcome of the tragedy wouldbe if it generates basic research into mitochondrial damage. Hesaid that no nucleoside analog should be developed withoutextensive animal studies investigating mitochondrial function.
FIAU had shown remarkable efficacy in early studies. A pilottrial using a dose of 1 mg/kg/day FIAU produced a "markedsuppression" of hepatitis B virus (HBV) DNA in all patientstested. NIH investigators then conducted a second trial in 24patients using two different dose levels -- 0.1 mg/kg/day and0.25 mg/kg/day -- administered over 28 days. Again, evenwith the lower dosages, the drug produced a suppression ofHBV DNA in roughly 90 percent of patients.
Convinced that the drug should be tested over a longer timeperiod, Hoofnagle and his colleagues designed a Phase II trialplanned to enroll 24 patients to be treated with either 0.1mg/kg/day or 0.25 mg/kg/day for 24 weeks. It was this trialthat ended in disaster.
Donald Abrams, assistant director of the AIDS division of SanFrancisco General Hospital and a member of the advisorycommittee, called the FIAU trial a "sobering and terrifying"reminder of the dangers inherent in clinical research.
"The people that participate in these early trials need to begiven a degree of honor," added committee member AnaPujols-McKee, medical director of the Philadelphia Departmentof Health. "There is heroism in their willingness to try newtherapies."
-- Lisa Piercey Business Editor
(c) 1997 American Health Consultants. All rights reserved.