Healthy Skepticism Library item: 13025

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Publication type: news

Blum J.
Doctors `Repeatedly or Deliberately' Break FDA Drug-Trial Rules
Bloomberg.com 2008 Feb 29
http://www.bloomberg.com/apps/news?pid=20601202&sid=a3iFD.rCBpA8&refer=healthcare

Full text:

James C. Vestal, a Texas urologist, exposed his patients to ``unnecessary risk’‘ and ``submitted false information in required reports’‘ during the clinical trial of a prostate cancer drug, according to the U.S. Food and Drug Administration.

The agency’s drug division ``believes that you repeatedly or deliberately violated regulations governing the proper conduct of clinical studies,’‘ the FDA said in a letter to Vestal. ``Accordingly, FDA proposes that you be disqualified as a clinical investigator.’‘

The FDA didn’t send the letter starting disciplinary action against Vestal until May 2007, more than three years after his violations of agency rules were detailed in reports by the FDA’s own staff investigators. Vestal continued to conduct drug trials as recently as last year, as he was permitted to do. He has stopped voluntarily while negotiating with the FDA on his case.

The agency has failed to complete disciplinary action against 12 researchers, including Vestal, after proposing that they be disqualified from trials based on findings that they violated rules designed to protect patients and ensure accurate data, FDA records show. Cases have remained unresolved for as long as a decade.

`No Excuse’

``There’s no excuse for that kind of delay whatsoever,’‘ said Arthur L. Caplan, chairman of the medical ethics department at the University of Pennsylvania in Philadelphia. ``When you know there’s a bad apple out there, you’ve got to get rid of that apple in a reasonable period. I’m talking months, not years.’‘

The FDA relies on the results of clinical trials to determine whether drugs and medical devices are safe and effective enough to clear for sale. Delays in disciplining doctors who don’t properly supervise the tests put patients at risk and threaten the validity of the studies, Caplan said.

A Washington lawyer, Philip Katz of the firm Hogan & Hartson, is representing Vestal in his dealings with the FDA on possible disciplinary action, said Thomas Hall, the chief executive officer of Vestal’s practice. Katz declined to comment. Approached outside his home in Arlington, a suburb of Dallas, Vestal declined to comment.

Government investigators, including the inspector general for the Health and Human Services Department, have found flaws in the FDA’s oversight of drug trials. The agency inspected fewer than 1 percent of 350,000 sites where drug trials were conducted from fiscal 2000 through 2005, according to a report released in September by the inspector general.

Republican Representatives Joe Barton of Texas and Ed Whitfield of Kentucky asked the inspector general in March 2007 to investigate why the FDA takes so long to bar doctors from drug testing after finding violations. The inspector general plans a study, according to the office’s Web site.

Riddled With Conflicts

The clinical drug trial industry is poorly regulated and riddled with conflicts of interest, Bloomberg News reported in 2005. The FDA farms out much of the responsibility for overseeing safety to private companies known as institutional review boards. Like the doctors conducting the trials, the boards typically are paid by pharmaceutical companies. Every year, trial participants are injured or die.

The FDA said at the time that it was examining issues raised by the reports, and Senator Charles Grassley, an Iowa Republican, said he would ``make sure that the FDA does their job.’‘

The FDA’s Web site lists 103 researchers it has disqualified from drug and medical device trials since 1964.

The agency’s disciplinary process can involve investigations, meetings and hearings and takes time to allow for ``due process,’‘ said Leslie Ball, director of an FDA division that handles some of the cases. She declined to discuss pending matters.

`Need for Improvement’

``We do recognize there is a need for improvement,’‘ said Joanne Less, another FDA official responsible for overseeing clinical trials. The FDA is developing timelines to regulate how long it takes to punish those who violate its drug-test rules, Less said. The agency may assign case managers to help expedite disciplinary action, FDA officials said.

The FDA also plans to hire more staff. Agency officials couldn’t say how many employees currently are involved in policing drug trial researchers because the responsibilities are spread through different units of the organization.

FDA records show an agency that fails to follow through on its own proposals to bar researchers, allowing them to remain eligible to continue testing drugs and medical devices.

Pending Cases

It’s unclear how many of the researchers under scrutiny from the FDA go on to do more clinical trials. The agency has no public listing of all researchers participating in drug and device studies.

Pending disciplinary cases include Maria Carmen Palazzo, a New Orleans psychiatrist accused by the FDA in 2003 of diagnosing patients with conditions they didn’t have, qualifying them for a drug trial. She challenged the allegations ``point by point,’‘ she said in an interview.

Louis F. Fabre, a Houston doctor, ran a drug trial in which patient Garry Polsgrove died. Fabre or his assistants kept giving a test drug to a patient until the day before his death, ``despite multiple signs and symptoms consistent’‘ with heart injury and drug toxicity, according to an FDA letter to Fabre. Bloomberg News reported on Fabre in 2005, the year the FDA started the process of barring him.

Today, Fabre, who declined to comment, is chairman of Fabre-Kramer Pharmaceuticals Inc., a Houston drug development company.

`It’s Horrible’

``It’s horrible,’‘ said Nancy Gatlin, Polsgrove’s sister, in an interview, referring to the lack of FDA action against Fabre. ``He still gets by with doing whatever he wants to do.’‘

The oldest pending case was brought by the FDA in 1998 against Layne O. Gentry, a Houston doctor. He failed to supervise a drug trial that resulted in the submission of ``false information,’‘ according to the FDA. Gentry challenged the FDA findings.

``They’re going to wait until I die,’‘ Gentry said in an interview. ``They just basically stick you in a corner like a mushroom.’‘

The drug trials involving Vestal, the Texas urologist, were detailed in interviews with the doctor’s former employees and drugmakers, and in 37 pages of FDA documents obtained through a Freedom of Information Act request.

Vestal, 48, graduated from the medical school at Texas A&M University in College Station and is a partner in Urology Associates of North Texas, with 50 doctors in 20 locations in the Dallas-Fort Worth area, according to the group’s Web site.

Drug Trials

In 2002 Vestal was involved in more than a half-dozen clinical trials, said Jennifer Lawton, a former assistant to the doctor. One of the trials was for Novartis AG, based in Basel, Switzerland, according to the company.

Drugmakers, or contract research organizations they hire, pay doctors and others to recruit and treat patients in trials of experimental medicines. The physicians are supposed to admit only appropriate subjects, warn them of possible risks, closely monitor side effects and report data.

One of Vestal’s drug tests involved Eligard, a treatment for patients with advanced prostate cancer. Vestal tested a more powerful, longer-lasting version of Eligard than was on the market. The treatment was developed by Atrix Laboratories Inc., which has since been acquired by Vancouver-based QLT Inc.Sanofi-Aventis SA, the Paris-based drugmaker, markets the medicine in the U.S.

Vestal was one of 22 researchers who signed up 111 U.S. patients to test the new version.

Assistant Overwhelmed

Vestal enrolled three patients in the trial, two of whom the FDA later said should have been excluded for safety reasons. One had a heart attack less than two months before joining the study and another had a cancerous kidney removed eight months earlier.

One of Vestal’s first errors, according to the FDA, was to allow Lawton to serve as his study coordinator. In its May 2007 letter initiating disciplinary action, the FDA faulted Vestal for delegating tasks to Lawton such as obtaining medical histories even though she ``lacked the necessary medical training.’‘

Her experience included drawing blood and working as a lab technician, according to the letter.

Lawton, in an interview for this article, agreed that she was overwhelmed by administering drugs, hooking up IVs, giving injections and completing other tasks for drug trials run by Vestal.

``They had me doing things that only a registered nurse should have done,’‘ Lawton said. ``I didn’t feel comfortable.’‘

Lodging Complaints

Lawton said she complained about her role to Vestal, to a supervisor in the practice and to representatives of drugmakers, including Atrix, who monitored the studies. Therese Hayes, a spokeswoman for Atrix acquirer QLT, declined to comment.

Lawton left the urology group in September 2003, according to the FDA. She says she quit her job in frustration earlier that year.

Vestal accused Lawton of falsely reporting physical exams that were never performed, according to a report by FDA investigators.

``You acknowledged that you signed documents indicating that you performed physical examinations that, in fact, you did not perform,’‘ the agency said in its letter to Vestal. ``You also acknowledged that a majority of vital signs and patient assessments were not done and claimed that these vital signs had been fabricated by your study coordinator.’‘

Lawton denied in an interview for this article that she fabricated the information. She said she hasn’t heard from Vestal since she left the urology group or been contacted by the FDA, which holds researchers such as Vestal accountable for how their studies are conducted. Lawton, 40, said she now works in public relations.

`Number of Irregularities’

A monitor for Atrix visited Vestal’s office in September 2003 and found ``a number of irregularities,’‘ according to the FDA’s letter to the doctor. The Eligard study ended soon thereafter.

Two FDA investigators showed up at Vestal’s office on Jan. 9, 2004, and spent seven days studying patient records and interviewing staff. They wrote a 23-page report detailing the physician’s violations and a four-page synopsis, which the FDA provided in its response to a Freedom of Information Act request.

Among those interviewed by the FDA investigators was Susan Pelletier, who worked in the urology office at the time and helped the practice sort out what happened with the trial after Lawton left. She is quoted in the FDA investigators’ report saying she found specimens that were two weeks old even though they were supposed to be sent out daily.

In an interview for this article, Pelletier said there were unmarked samples of frozen urine stored in a freezer, along with unlabeled vials of serum.

`The Worst Mess’

``Every study that I got my hands onto — it was the worst mess,’‘ Pelletier said of her review of studies Lawton handled. ``I’ve been a researcher for 12 years, and I’ve never seen anything like this.’‘

Pelletier now works as a clinical research coordinator for another firm.

Vestal responded to the FDA investigators’ findings with a letter promising changes in procedures in future drug trials.

The investigators sent their report to headquarters in suburban Washington. More than three years passed.

Former agency employees who oversaw clinical research, including Stan Woollen, said long delays are typical because too few people are doing too much work. The process for disciplining researchers is also too bureaucratic, said Woollen, who wasn’t involved in the Vestal case.

`Dysfunctional’ Process

``The disqualification process has been dysfunctional in the FDA for years,’‘ said Woollen, who retired from the agency in 2006 and worked in a division that regulated clinical trials.

With the FDA taking no action against him, Vestal was free to do more trials. He went on to test experimental prostate cancer treatments made by Myriad Genetics Inc., based in Salt Lake City, Utah, and Novacea Inc., of South San Francisco, California.

Novacea knew that FDA investigators had criticized Vestal for his handling of the Eligard tests. Company officials assumed those issues had been resolved when Vestal began work on their clinical trial in 2006, said company spokesman Paul Laland.

In the May 2007 letter to Vestal, the FDA said that ``you should not remain eligible’‘ to test drugs and medical devices.

Vestal forwarded the FDA letter to Novacea, and the company stopped using him for drug trials, Laland said.

`Sub-investigator’

Vestal was among those testing Myriad’s drug on patients in 2004, according to company spokesman William A. Hockett III. Vestal had been hired by a contractor who later told Myriad of concerns about staff turnover at Vestal’s office. Vestal was made a ``sub-investigator’‘ with fewer responsibilities, Hockett said.

The FDA didn’t send investigators to check whether Vestal followed the rules on the drug studies for Myriad and Novacea, according to an agency database of inspections.

Employees at Atrix, the company that sponsored the Eligard trial, said they submitted two sets of data to the FDA — one including Vestal’s patients, the other excluding them — when it applied for approval of the drug, QLT spokeswoman Hayes said.

The FDA approved the new version of Eligard in 2004, noting that the accuracy of data from Vestal’s patients couldn’t be confirmed. Eligard had $180.9 million in worldwide sales in 2007, according to QLT.