FDA Faults Drug Testers in Patient-Death Probe : Medicine: Scientists, drug companies are accused of failing to fully disclose potential risks of hepatitis-B treatment. Five people died during trials.
A federal investigation into the deaths of five patients during a test of an experimental hepatitis-B drug has concluded that scientists and drug companies failed to fully disclose the drug’s potential risks.
The researchers in the 15-person, government-sponsored trial were also blinded by misplaced optimism in the drug and failed to recognize its ominous side effects, the investigation found.
In many cases, the researchers neither reduced nor halted use of the medication--even after patients complained about its seeming ill effects, according to Food and Drug Administration documents released Friday.
“There was a pattern here, a series of lapses both with regard to the reporting and the following of protocol,” Dr. Roger Williams, associate director of the FDA’s Center for Drugs Evaluation and Research, said in an interview.
The agency’s documents leave unanswered the question of whether the deaths were preventable and Williams declined to comment on that aspect of the case.
Hepatitis-B, which is caused by a virus, affects as many as 300 million people globally. In the United States, about 300,000 new cases are reported each year, while from 4,000 to 5,000 Americans die from the chronic effects of the infection--cirrhosis of the liver, liver failure and liver cancer.
Scientists have been eager to find a cure for the disease and were hoping that it would lie in the new drug, which is no longer being used.
The regulatory agency said the head of the study, Dr. Jay H. Hoofnagle, a government scientist, neglected to tell participants that a key purpose of the study was to determine the drug’s safety and that he failed to adequately describe the drug’s “foreseeable risks,” such as toxicity to the central nervous system and liver.
The FDA also directed scathing criticism at other investigators and at Eli Lilly & Co., which licensed the compound for the drug on trial, fialuridine, or FIAU, from Oclassen Pharmaceuticals Inc. of San Rafael, Calif., another target for criticism.
The FDA said the pattern of minimizing FIAU’s potential risks began long before the drug trial in question and was established during the early years of its development. In 1991, for example, AIDS researchers began seeing toxic side effects from the drug but the FDA did not learn of them, in one case, until a year after a patient’s death. The failure to communicate about the problems gave rise to an unjustified sense of hope for the drug and ultimately contributed to the fatalities, the FDA said.
The investigation’s conclusions come as another blow to the biomedical research world, which is still reeling from recent disclosures of outright fraud in a massive, international study of treatment options for breast cancer.
The FIAU study, which began in March, 1993, was halted in June but not in time to avert the five deaths. Three other patients had to undergo liver transplants as a result of the drug’s toxic side effects.
In November as a result of the failed trial, the FDA adopted new drug-testing regulations that were proposed by an internal review task force. The new rules require researchers to gather and report more data on potentially adverse effects of trial drugs and to assume that any medical problems in patients may be caused by the test drug.
The task force also found that FIAU researchers missed important warning signals indicating the drug might be dangerous and dismissed patients’ medical problems as the effects of other medications or prior medical conditions.
Hoofnagle, the lead FIAU investigator, was out of town Friday and could not be reached for comment on the FDA’s conclusion that he had committed “significant violations” of the Food, Drug and Cosmetic Act. Hoofnagle is a division director in the National Institute of Diabetes and Digestive and Kidney Diseases.
A spokeswoman for the parent National Institutes of Health said Hoofnagle will comply with the FDA’s requirement that he respond within 15 days.
The NIH also has convened an independent panel to review the incident. Its report is scheduled for release June 2.
In a 1993 interview with The Times, Hoofnagle said that certain symptoms among his patients had gone unrecognized because, he contended, some of FIAU’s toxic effects mimicked the symptoms of chronic hepatitis-B itself.
The FDA also said that Hoofnagle violated protocol by “not immediately reporting by telephone serious, unexpected or alarming adverse experiences” among the study subjects. Hoofnagle also neglected to report the hospitalization of subjects in writing to the drug companies.
The FDA documents are rife with bureaucratic and biomedical research jargon, but occasional passages captured the agency’s case against Hoofnagle. Referring to “Subject 06,” for instance, the FDA listed a series of the patient’s complaints and then concluded:
“Moderate fatigue on May 5, 1993; moderate fatigue and mild liver tenderness on May 5, 1993; moderate abdominal pain on May 25, 1993; moderate fatigue and a 3-week history of right upper quadrant squeezing pain (liver) on June 2, 1993; yet you failed to reduce dosage. The subject decided to stop FIAU on June 15, 1993, due to nausea and vomiting. The subject died on Aug. 31, 1993.”
Officials at Lilly and Oclassen denied any wrongdoing Friday, saying that they would respond in detail to the FDA after examining the agency’s letter.
The FDA’s “warning letters” require recipients to reply, Williams said, “and the response has to be satisfactory to us.”
Possible follow-up actions by the agency include extracting certain assurances for future tests, conducting follow-up inspections or, in the worst-case scenario, disqualifying a scientist from participation in drug trials, Williams said.
Other recipients of FDA letters were researchers at the Veterans Affairs Medical Center in San Diego, the Children’s Hospital in Seattle and the National Institute of Allergy and Infectious Diseases in Bethesda, Md. They were involved in the clinical trials involving a closely related forerunner of FIAU.
