Lawmakers at a House subcommittee hearing on Tuesday asserted that findings from investigations into the handling of fraudulent data submitted to the Food and Drug Administration to gain marketing approval for the antibiotic Ketek show that the integrity of the entire drug approval process is in doubt.

Their comments came during a House Energy and Commerce subcommittee hearing in which witnesses testified that FDA ignored warning signs of fraud in a clinical study of the drug and that its manufacturer, Sanofi-Aventis, also turned a blind eye to the suspect data.

The handling of the fraud-ridden clinical study of the antibiotic “illustrates the failure by all stakeholders — FDA, drug companies, third-party monitors, and Institutional Review Boards — to ensure the integrity of clinical trials used to support the safety and approval of new drug applications,” said Rep. Bart Stupak, D-Mich. Stupak is chairman of the Oversight Subcommittee, which conducted the hearing.

“Beyond the harm to the public health from millions of prescriptions written for this drug by doctors who relied on the FDA, this investigation raises questions about the very integrity of the drug approval process,” said Rep. John D. Dingell, D-Mich., chairman of the Energy and Commerce Committee. If FDA suspects fraud exists and ignores it, “then this committee has the duty to probe as deeply as necessary to determine whether the entire approval process itself has been compromised,” Dingell said.

Iowa Republican Sen. Charles E. Grassley echoed the concerns of the Democratic lawmakers, testifying that the head of FDA’s office of Division of Scientific Investigations told his staff that “investigating drug companies is a ‘losing game’ and the chances of getting a warning letter is zero.”

“I find that attitude extremely troubling, as I’m sure you do as well,” Grassley told the subcommittee. “We rely on the FDA to ensure that the drugs in our medicine cabinets are safe and effective,” he said.

The lawmakers’ comments came on a day in which the panel heard testimony that FDA investigators had repeatedly failed to get higher-ups to respond to abundant signs of sloppy, if not fraudulent, data in a clinical trial of Ketek known as study 3014. The investigators had been subpoenaed to appear before the panel.

One of the clinical investigators in the study, Dr. Anne Kirkman-Campbell, was convicted for submitting fraudulent data in the study and is serving a jail sentence of almost five years. “In the case of Study 3014, there were sirens, red flags, and bull horns, but it looks like the company and the FDA kept ears plugged and blinders on,” Grassley said based on his own investigation of Ketek.

The continuing unwillingness of the FDA to answer questions and supply documents creates further doubts about the agency’s handling of Ketek, Democrats said. The Health and Human Services Department notified the subcommittee yesterday that it would not comply with a subpoena seeking the briefing book used by FDA Commissioner Andrew C. von Eschenbach for an earlier hearing on Ketek.

“There appears to be a continued effort to keep secret the documents we have requested,” Stupak said. “This only causes members to further question what could be so damaging in the materials that the administration wants to stonewall our bipartisan subpoena?”

What is in the briefing books that HHS Secretary Michael O. Leavitt “does not want either my Republican colleagues or our side to see?” asked Dingell. “Is there evidence of perjury?”

HHS said in a letter to Dingell that it has “serious concerns” about providing the material requested, saying disclosure would make it difficult for advisors to provide “full and frank” advice to agency officials concerning congressional testimony.

Subcommittee Republicans shied away from charging that the entire drug approval process may be in doubt, but were unsparing in their criticism of the handling of the data in the Ketek trial. “It appears that standards of conduct and ethics were only optional,” said Rep. Greg Walden, R-Ore. They also hammered FDA inaction to debar investigators who falsify clinical trial data, saying that the agency still hasn’t begun proceedings to keep Kirkman-Campbell from overseeing clinical trials in the future.

“When it comes to excluding the worst of the worst — convicted felons — FDA’s debarment process seems to be non-existent,” said Rep. Joe L. Barton of Texas, the senior Republican on the Energy and Commerce Committee, citing the findings of a minority staff report. “It is inexcusable that the FDA can’t quickly debar convicted felons. In addition to bringing this problem to the administration’s attention, I will introduce legislation to reduce FDA’s budget when they don’t enforce the law,” he added.

The panel heard from three FDA criminal investigators who investigated study 3014 for fraud or misconduct.

The decision making process used by Aventis to evaluate signs of fraud coming from the clinical trial was “illogical” and “ineffective” and “could have led them to not come to the proper conclusion,” said Douglas Loveland, one of the three FDA investigators. The company relied on a statistical analysis to determine whether fraud existed when it should have investigated the matter more fully, Loveland said. The company determined based on that analysis that there was no fraud, he said.

“The problem is not so much was it fraud or was it sloppy; we want reliable data at the FDA,” he added. “Whether it’s fraud or sloppy, it’s not reliable.” The company’s threshold was that the data had to be fraudulent to not be submitted, indicating that the company was willing to submit sloppy data, Loveland said.

Loveland said he could not prove beyond a reasonable doubt that Aventis knew the clinical data was falsified on the day the company submitted it to FDA. He said that is the standard he has to meet to bring a case to court.

But he added the company that Aventis hired to monitor the trial, PPD Inc., picked up the signs of fraud and relayed them to Aventis. “They were loud signals, they were bright signals, they were repetitive signals. Aventis should have known.”

Another FDA investigator, Robert West, was asked why he believed Aventis should be criminally investigated for knowledge of the data in Study 3014. “I felt at the time that it was sort of like blatant disregard for information that they were receiving from the field,” West said, adding that he continues to feel that way today.

Ann Marie Cisneros, a former PPD employee, said Aventis was not a victim of the fraud committed by Kirkman-Campbell. Cisneros, who had responsibility for monitoring Kirkman-Campbell’s clinical trial site while at PPD, said a number of red flags were apparent before Cisneros conducted the site visit. “She enrolled patients within minutes of each other and upwards of 30 patients per day. She enrolled patients at times and on days when the office was closed. Once we started reviewing patient charts, we discovered that every informed consent had a discrepancy. Most of the consents looked like they had been initialed by someone other than the patient.” Kirkman received $400 for each patient she enrolled, according to testimony at the hearing.

Cisneros said she grew so concerned about patient safety that she called Copernicus, the company that operated an Institutional Review Board (IRB), to oversee the safety of patients in the study. “An IRB, which is under contract to the drug sponsor, has as its primary purpose patient advocacy,” Cisneros explained. “It is allowed to contact patients directly and is duty-bound to report to the FDA any unanticipated problems involving risks to subjects and serious noncompliance with regulations,” Cisneros said. “I spoke with someone who I understood to the be the president of the company and was told that, while she shared my concerns, she preferred to wait and see what actions Aventis took. I never heard from the IRB again.”

Cisneros added that she e-mailed results of the site visit to the head of quality assurance at PPD and copied Aventis personnel on the findings, and also took part in a teleconference between PPD and Aventis in which she identified issues found in the site visit. “What brings me here today is my disbelief at Aventis’s statements that it did not suspect that fraud was being committed. Mr. Chairman, I knew it, PPD knew it, and Aventis knew it.”

Sharon Hill Price, the CEO of the IRB Copernicus, said no one on her staff was aware of a call being received by Cisneros. Document searches didn’t reveal evidence of a call until Jan. 23 of this year when Copernicus found documentation of an anonymous call that appeared to be one from Cisneros made on Feb. 21, 2002, according to Price. “For some reason, and contrary to both procedure and training, this memorandum was not forwarded to a supervisor.”

Paul Herbert Chew, a Sanofi-Aventis executive, testified that study 3014 “was unusually large and complex, involving the coordination of over 1,800 investigators treating over 24,000 patients in a brief time period.” At the time of the study, “Aventis believed that the compliance monitoring efforts were appropriate to the task at hand,” adding, for example, that some “93,000 weekly and other monitoring calls were made to the investigator sites.”

Allegations of deviations from good clinical practices were investigated by Aventis at the Kirkman-Campbell site but “criminal fraud was subsequently discovered by FDA at that site,” Chew testified.

“We believe Aventis was unable to confirm at the time that fraud had occurred at the Kirkman-Campbell site as opposed to good clinical practice deviations,” Chew said. “It is important to note that FDA criminal investigators have tools at their disposal, such as interviewing patients and various investigative techniques, that typically are unavailable to study sponsors and monitors.” Ultimately, FDA did not rely on the results of study 3014 to support Ketek’s approval, he said, adding that the company has adopted systems to strengthen the evaluation and selection of doctors conducting clinical trials.

In his testimony, Grassley focused on the unwillingness of FDA and HHS to make FDA criminal investigator West available to his staff for interviews. It now appears that the reason is FDA “did not want anyone to know that it didn’t further investigate whether or not Aventis submitted fraudulent data knowingly to the FDA,” Grassley said. “The FDA did that even though Agent West recommended, in the summer of 2003 — almost five years ago — to high level officials at the FDA that it needed to create a mini-task force [to] look into Aventis.

“So who’s responsible? Everyone seemed to be pointing the finger at someone else” at FDA, Grassley said.

Meanwhile, HHS Spokeswoman Christina Pearson later defended the refusal of HHS to respond to the subpoena for the briefing book. “I mean no disrespect but we have responded in a full manner, having provided over 80,000 pages of information and numerous staff for interviews,” she said.

“This is not about the content of a briefing book — it’s about a fundamental principal that we believe the constitution protects. To give over this briefing book may ultimately compromise frank advice from staff to senior officials, our operations and ability to have robust, informed conversations with senior officials and Congress,” she said.