Monday, May 28, 2007

"That Just Doesn't Happen" - the Ketek Trial Debacle

We previously posted (also here and here) about the ill-fated clinical trial, study 3014, of the antibiotic telithromycin (Ketek) made by Sanofi-Aventis, run by Pharmaceutical Product Development Inc. (PPD). Problems with the trial included fabrication of data at one clinical site, and allegations of manipulation of data at another. The physician in charge of the first site was convicted of mail fraud, and the physician in charge of the second had his license suspended. Although the results of this trial were never published, it still crept into the clinical literature: it was cited in a review article in the New England Journal of Medicine.

The St Petersburg (FL) Times just reported on more details about how the trial was conducted. First, some background...

Aventis devised Study 3014, a clinical drug trial involving 1,800 private physicians and thousands of their patients nationwide.

As is common practice in the industry, Aventis opted to have a third party conduct the study. It paid PPD Inc., one of the world's biggest contract research organizations, some $20-million for the work.

The drugmaker was offering doctors $400 per patient to test Ketek, its new antibiotic for persistent colds and coughs.

Then, here is how things worked at Study 3014's highest patient-volume site:

Anne Kirkman Campbell, a family practice doctor in Gadsden, Ala., signed up 400 patients, more than any other doctor in the country.

Ann Marie Cisneros had worked for PPD for three years when she was sent to check up on Campbell in early 2002. The doctor had recruited more than 1 percent of Gadsden's adult population for the Ketek study.

Cisneros noticed that none of the doctor's staff would look her in the eye. Combing patient files, Cisneros found that the doctor had enrolled her entire staff and several family members in the study.

Patient consent forms had been signed every few minutes and at times when the office was closed. Medical records had been edited, with notations of 'sinusitis' and 'bronchitis' added so patients would qualify for the trial.

'It appeared the patient was coming into the office for one condition and the doctor was writing in something else later,' Cisneros said. 'That's how Dr. Campbell ended up with 407 people.'

By comparison, another local doctor found only 12 patients who met the study criteria.

The Ketek study was demanding; it required that patients come in for three office visits and blood draws over five months. But not a single one of Campbell's patients had dropped out.

'That just doesn't happen, period,' said Cisneros, noting that even small studies experience dropouts.

The doctor didn't appreciate the scrutiny. She told Cisneros that she wouldn't have enrolled so many patients had she known it would trigger an audit.

'That's just scary,' Cisneros said. 'Dr. Campbell didn't get away with it because she hadn't learned the system.'

But the response to Cisneros' findings was at best, lackadaisical...

Certain she had found fraud, Cisneros called her manager at PPD. She also took the unusual step of contacting a consulting partner responsible for ensuring patient safety in clinical trials. Copernicus Group IRB, also paid by the drug company, had access to trial subjects' names and phone numbers. Monitors like Cisneros usually had limited identifying information.

'I wanted them to call some patients and see if they'd really agreed to be in the study,' said Cisneros, who suspected patients were enrolled without their knowledge. 'But the woman at Copernicus said, 'Let's see what Aventis does about this.' '

Spokeswomen for Copernicus and PPD declined to comment.

After Cisneros returned to PPD, she and her bosses had a teleconference with the drugmaker. She said her concerns about the doctor's conduct, including the likelihood that consent forms had been forged, were ignored.

'I walked away from that meeting very frustrated,' Cisneros said. 'I'd never seen a sponsor so lackadaisical about a site.'

A spokeswoman said the Paris-based drugmaker, which has since become Sanofi-Aventis, knew of 'deviations' at Campbell's site but didn't know they amounted to fraud until a subsequent FDA investigation.

'We were aware of issues at that site and had gone in to try to rectify them,' said spokeswoman Lisa Kennedy. 'We strongly object to any characterization of wrongful conduct by Aventis.'

Later, "the U.S. Attorney's Office in Birmingham indicted Dr. Campbell on 21 counts of fraud. She pleaded guilty to one count of mail fraud and was sentenced to 57 months in prison." Dr Campbell, interviewed from prison, charged that Sanofi was part of the problem with the trial.

'They seemed to want to rush you through everything,' said Campbell, who had performed a half-dozen clinical trials for other drugmakers. 'They didn't care how you did it. They wanted the trial over so they could get the data to the FDA.'

Despite Campbell's 'deviations' during the Ketek trial, once it was over Aventis hired her for a second study that spring. The drugmaker also flew Campbell to a conference in San Diego that summer so she could learn how to market Ketek to other physicians.

In the fall of 2002, when the FDA called to schedule a routine audit, Campbell said, Aventis told her to delay the agent for a week.

'Then they flew in two doctors to prep me and four to six girls to go through my files,' said Campbell, who said the drug company's representatives suggested appropriate responses to the FDA's queries.

Sanofi-Aventis' spokeswoman said it is normal for a drug company to help a doctor prepare for a site inspection. She said Campbell was advised to answer the FDA's questions truthfully. The drugmaker ended its relationship with the doctor after the FDA initiated its criminal investigation, she added.

Campbell said she was amazed when the court said the drugmaker was a victim of her fraud and ordered her to pay $925,000 restitution. In a court filing last year, Campbell appealed the restitution order.

Aventis 'had been made aware of the fraud at my site by PPD,' she argued. 'At NO TIME did they (Aventis) attempt to stop my participation.'

Late last month, Campbell's motion was denied.

In any event, data from Dr Campbell's questionable site was just dumped into the hopper with all the other study data. Then it was up to the FDA...

Cisneros, who left PPD for a higher-paying job at a competing company, assumed someone in a position of authority would alert the FDA about Campbell.

But the Ketek study continued uninterrupted. In July 2002, the drugmaker submitted the trial results to the FDA -- including data from all 407 patients at Campbell's site.

While the FDA's drug approval division reviewed the Ketek data, its inspectors were conducting routine audits of the biggest study sites. Their first stop was Campbell's office, where they found such flagrant violations that they immediately called in the agency's criminal division.

FDA investigators visited nine other high-enrolling sites and discovered serious problems at every one. One doctor, whose medical license was on probation at the time of the study, was arrested for cocaine and gun possession soon after. FDA agents referred Campbell and three other doctors for criminal investigation and recommended expanding the inspections to additional sites.

But even as the FDA's Office of Criminal Investigation uncovered widespread problems, the agency's drug approval division proceeded to review the Ketek data.

In addition to its internal review, the FDA often has an outside, advisory group of experts evaluate trial data and recommend whether a drug should be approved. [Dr David] Ross, the FDA scientist, said he expected the Ketek advisory group would be told of concerns about the data's validity in light of the ongoing criminal investigations. He said he was appalled when his boss, Dr. Mark Goldberger, told him not to raise the issue with the outside experts.

'In general, I don't believe spending time on (data integrity) issues in front of the AC (Advisory Committee) will be productive,' Goldberger wrote in an e-mail a few days before the January 2003 meeting.

The FDA recently said that at the time of the advisory meeting it had only preliminary information on problems with the Ketek study and wished to avoid 'compromising the ongoing investigations.'

But Ross said his bosses had plenty of options. 'They could have told the committee what they knew in closed session. Or they could have postponed the meeting,' he said. 'I felt like I was being told to hide things.'

The FDA's advisory committee recommended approving Ketek. After delaying its decision to get anecdotal information on Ketek's safety record overseas, the FDA approved the drug on April 1, 2004.

Last week, there was quite a brouhaha about a new meta-analysis that suggested that rosiglitazone (Avandia, GlaxoSmithKline) had more cardiovascular risks than heretofore believed (see posts here and here, and for just a taste of the bit of the brouhaha related to Health Care Renewal, see this post on In the Pipeline, this post on the Pharma Marketing Blog, and this post on the Pharma Blogsphere.)

That meta-analysis included the results of multiple unpublished clinical trials. These results, in turn, were only made available because GSK had been forced to set up a web-based clinical trials registry by a 2004 settlement of a lawsuit brought by Eliot Spitzer, who charged that GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here.)

Both the Avandia and Paxil cases underlined, in my humble opinion, how pharmaceutical (and other) companies that sponsor clinical trials have often tried to keep the results of these trials secret. Such attempted suppression of research both breaks promises made to the human subjects of clinical research that their participation would go to advance science and improve health care. Such attempted suppression also denies patients and doctors important evidence relevant to decisions about health care interventions, and hence may lead to bad decisions that harm patients.

The Ketek case underlines, in my humble opinion, how pharmaceutical (and other) companies that sponsor clinical research may be at best sloppy in how they let their clinical trials be conducted. Such sloppy science also breaks promises made to human subjects of clinical research that their participation would go to advance science and improve health care. Sloppy trials that produce dubious data will do neither. Furthermore, sloppy science that produces dubious results provides patients and doctors pseudoevidence rather than the best possible evidence relevant to decisions about health care interventions, and hence may also lead to bad decisions that harm patients.

So if pharmaceutical and other health care companies do not want to be regarded by the public as "shifty," maybe they ought to think about making sure that the clinical trials they sponsor are done honestly and well, and that their data results are quickly and accurately released. Or maybe they ought to get out of the business of sponsoring such trials entirely.

Hat-tip to PharmaGossip.

1 comment:

InformaticsMD said...

He said he was appalled when his boss, Dr. Mark Goldberger, told him not to raise the issue with the outside experts. 'In general, I don't believe spending time on (data integrity) issues in front of the AC (Advisory Committee) will be productive,' Goldberger wrote in an e-mail a few days before the January 2003 meeting.

Dr. Mark Goldberger, clearly a world expert on Medical Informatics where protocol is more importnat than serious data integrity issues that could invalidate research results, has a new post:

July 20, 2006

FDA Names First Medical Director for Emerging and Pandemic Threat Preparedness
in the Center for Biologics Evaluation and Research

The Food and Drug Administration (FDA) today announced the appointment of Mark Goldberger, MD, MPH, as Medical Director for Emerging and Pandemic Threat Preparedness in FDA's Center for Biologics Evaluation and Research (CBER). Dr. Goldberger was selected after a national search of eligible candidates. In this newly created position, Dr. Goldberger will serve as a Senior Advisor for CBER's pandemic flu program to plan, coordinate and implement activities related to the development and evaluation of products for emerging and pandemic threats.

"Emerging infectious diseases present a constant challenge for public health agencies, and FDA is committing resources and leadership to combat this growing threat. The creation of this position and Dr Goldberger's appointment together represent an important step forward in that effort." said Acting FDA Commissioner Andrew von Eschenbach, MD. "Dr. Goldberger has been at the forefront of combating other emerging infectious diseases, and we are grateful he has agreed once more to help tackle another monumental challenge, preparing for pandemic influenza and other future threats."

Dr. Goldberger began his career with the agency in 1989 as a medical reviewer, and currently serves as the Director of the Office of Antimicrobial Products in FDA's Center for Drug Evaluation and Research (CDER). He received his medical degree from Columbia University where he also did his Medical Residency and Infectious Diseases Fellowship, and practiced and taught clinical Infectious Diseases for nearly 10 years. He also served as an Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention (CDC), performing outbreak investigations and work on Swine Flu vaccine-associated Guillian-Barre syndrome.

"Dr. Goldberger's expertise and dedication to our public health mission will help enhance our preparedness activities," said Jesse L. Goodman, MD, MPH, Director of CBER. "His regulatory and public health experience with a wide range of infectious diseases and emerging threats, including influenza, SARS, pandemic influenza and West Nile Virus, will be a major asset in our strategic response."

Dr. Goldberger will be part of CBER's Senior Leadership Team, and will chair CBER's Pandemic Influenza Steering Committee (PISC). He will begin meeting with staff over the next few weeks and will be joining the Center full time at the end of August.

I feel safer against Al Queda already.