A 2nd colorful article from yesterday's Boston Globe. (Thestreet.com nailed bpur fiasco's.)
FDA hits Fla. doctor in Biopure clinical test
Failure to report deaths, 'events' cited
By Jeffrey Krasner, Globe Staff, 12/12/2003
Florida doctor who participated in a pivotal clinical trial of Biopure Corp.'s artificial blood waited as long as a year before properly reporting serious complications in the trial, according to a warning letter sent by the US Food and Drug Administration.
Dr. Ben R. Thebaut of Palm Beach Gardens failed to make timely reports about 10 serious ''adverse events,'' including two deaths, the FDA said in the letter, dated Oct. 23. The letter said he also failed to obtain informed consent from some patients before using them in the test of the experimental blood substitute, which is derived from cow's blood.
Thebaut could not be reached for comment. He is one of 14 doctors who participated in the clinical trial of Hemopure whose work is being reviewed by the FDA, according to the Cambridge-based company. None of the others have received warning letters, Biopure said.
The disclosure came as the company told investors that its auditors will probably include a ''going concern'' opinion in its annual report, a warning that the firm could go out of business.
Biopure has raised $52.8 million this year through private sales of its stock. But Biopure needs an additional $10 million to keep its doors open through October, chief executive Thomas A. Moore said in a conference call yesterday.
The FDA letter raises concerns about the Cambridge company's make-or-break effort to win approval for Hemopure, which has been in development for nearly 20 years. After delays, the firm filed its application to the FDA in July 2002 -- nearly two years after the clinical trials were completed. In October 2002, the FDA accepted the application for review.
Biopure is seeking approval of Hemopure as a substitute for human blood in patients who require transfusions after elective orthopedic surgery, such as a knee replacement.
The FDA had questions, and in October Biopure said it couldn't answer all of the FDA's questions until next summer. It layed off 72 out of 225 employees to conserve cash. Thebaut is one of 46 doctors in North America, Europe, and Africa who participated in the phase 3 study of Hemopure. Such a study is intended to provide definitive results showing a drug or biological treatment like Hemopure is safe and effective. Thebaut treated 24 patients, or about 3.5 percent of the 693 enrolled in the trial.
The FDA letter levels blistering criticism at Thebaut, a distinguished orthopedist who practiced at several Boston hospitals, including Massachusetts General.
''You failed to protect the rights, safety and welfare of subjects under your care and you failed to ensure that the investigation was conducted according to the investigational plan,'' wrote Steven A. Masiello, director of the Office of Compliance at the FDA's Center for Biologics Evaluation and Research. ''You failed to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation.''
Among the specific findings of FDA investigators:
Thebaut did not obtain proper informed consent from some patients in the study. Instead, six of them signed consent forms after they had undergone screening tests. One patient was infused with Hemopure even though a complication during surgery should have disqualified the patient.
The doctor also did not report adverse events -- serious complications -- until as much as a year after they occurred. Such reports were supposed to be given to the institutional review board overseeing Thebaut's study in writing within five days.
The investigators noted that Thebaut didn't sign patient consent forms until long after patients had signed them. That suggested Thebaut might not have even been present when patients were informed of the potential benefits and risks of the trial. Thebaut, in a response to investigators' questions, attributed his late signatures to an ''administrative oversight,'' the letter said.
Such violations could prevent a doctor from participating in further FDA-regulated clinical trials, according to an FDA official who asked not to be named. The agency could also seek a court order preventing the doctor from making future violations of federal regulations governing clinical trials.
Moore, in an interview, said the warning letter is a matter between the FDA and Thebaut. ''We had 46 investigators,'' said Moore. ''This doctor is only one of them. The FDA audited 14 sites. As far as we know, we can't say we're sure, this is the only warning letter that was sent.''
Of Thebaut's 24 patients, 10 suffered adverse events, which included fever, chest pain, fluid overload, infection, and a ''cerebrovascular accident.'' Two patients died, or about 12.5 percent of the total 16 deaths suffered by patients in the trial. Moore noted that the FDA letter doesn't specify whether the patients suffering such complications were treated with Hemopure, or were members of the control group transfused with real blood.
Biopure, in announcing its year-end results yesterday, disclosed other difficulties. The company said it would have to write off $773,000 of Hemopure already produced because it is approaching its expiration date. Hemopure has been approved for sale in South Africa, but the company still hasn't sold any in that country, according to yesterday's report. For the year ended Oct. 31, Biopure lost $47.1 million, compared with $45.8 million in fiscal 2002.
Biopure shares yesterday gained 14 cents to close at $2.89.
Jeffrey Krasner can be reached at krasner@globe.com.
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