Friday, July 21, 2006

More Stories About the Fall of the FDA

Related, disturbing stories about how far the US Food and Drug Administration (FDA) has fallen have just come out.

Ketek Approval

We previously posted 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. We also posted about how US Senator Charles Grassley, (Republican - Iowa), chair of the Senate Finance Committee, alleged that the FDA was covering up the process it used to approve Ketek.

Now the New York Times reported that Dr David Graham, now known as an internal FDA whistle-blower, and other FDA scientists challenged the initial approval of Ketek, to no avail. Graham wrote:
It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned.
The Times reported that four other agency officials, including Dr Charles Cooper, Dr David Ross, and Dr Rosemary Johann-Liang, "expressed serious reservations about Ketek."

Senator Grassley commented:

It’s no surprise to learn that the F.D.A. didn’t listen to Dr. Graham on the dangers of Ketek.

The F.D.A. has made it their business to discredit Dr. Graham and others who aren’t willing to cater to the drug companies.
FDA spokesperson Susan Bro countered, "Every issue or question raised during the Ketek review process and subsequently since approval has been rigorously reviewed by the nation’s best physicians, statisticians and epidemiologists both internal and external to the F.D.A."

Vioxx Aftermath

The Associated Press reported (here in USA Today) that Senator Grassley also "asked the inspector general at the Health and Human Services Department to probe whether the Food and Drug Administration and Merck acted in concert to call into question the safety findings made by Dr. David Graham, an FDA drug safety official." The report continued,

In a letter Wednesday, Grassley cited handwritten notes made by the Merck employee documenting an Oct. 13, 2004, conversation with the FDA official that suggests the two collaborated.
The FDA official mentioned an 'opportunity to get (the) message out' on Graham, a longtime employee of the agency, and provide journalists with a company critique of him, according to notes quoted in the letter.

'It is no secret that Dr. Graham was and is a critic of the FDA. However, that does not mean the FDA should scheme with drug sponsors to discredit its own employees,' Grassley said in the letter to Inspector General Daniel Levinson. The FDA, Grassley said, must maintain a 'clear, bright line between the regulated and the regulator.'

This time, FDA spokesperson Bro "had no comment."

Further details provided by AP were:

FDA e-mails seen by The Associated Press indicate that the agency shared in advance with Merck details about a presentation that Graham was to make in France in August 2004 about the dangers of Vioxx. The e-mails suggested that such a practice was commonplace.

Merck then issued a statement saying it stood by the safety of Vioxx. An FDA spokeswoman at the time said removing the drug was 'not on the table.'

The notes excerpted by Grassley indicate the FDA later went even further in helping Merck rebut Graham's work.

The FDA's Dr. Brian Harvey suggested to Merck's Dr. Ned Braunstein 'an official rebuttal on Graham,' according to the notes, which were admitted as evidence in a federal Vioxx trial.

Graham said he was 'quite shocked' to learn about Braunstein's notes.
FDA Employee Survey

The Baltimore Sun reported on a survey by the Union of Concerned Scientists of FDA scientists. The survey was sent to 5918 people, of whom 997 responded. The Sun reported that key findings were:
  • "Fifteen percent of the 997 FDA scientists who answered the questionnaire said they were asked to keep information out of agency documents or alter their conclusions for nonscientific reasons."
  • "Nearly one in three said the FDA doesn't routinely provide complete and accurate information to the public."
  • "37 percent said the agency's leadership wasn't as committed to product safety as to approving products for sale."
  • "Fifty-two percent said their job satisfaction had fallen the last few years, and 70 percent said the agency lacked the resources to carry out its mission."
  • "two out of five scientists saying superiors didn't consistently stand behind staff whose "scientifically defensible positions" might have been politically controversial."
  • "Eighty-one percent of respondents said the agency needed to strengthen its oversight of drugs after they go on sale."
Responses were bi-partisan. Senator Barbara A Mikulsi (Democrat - Maryland) responded, "This agency has been politicized and degraded. Many FDA employees don't feel the FDA is doing enough to protect the public's health and are afraid to speak candidly about it." Senator Grassley responded that the FDA needs "major overhaul and a culture change at the highest levels." He also said it "needs to re-establish its relationship with its own scientists and distance itself from the drug industry. The FDA needs to get rid of its mindset that it's a facilitator for the drug industry and become regulator once again. The FDA's focus should be only on science and the public good."

Spokesperson Bro responded by criticizing the "scientific rigor" of the survey, and charging "This is a counterproductive exercise based on leading questions and innuendo. For centuries, science has depended on rigorous and disciplined processes to distill truth from exploration and debate -these principles above all others guide our daily work at the FDA on behalf of the American public health."

By the way, regarding technical issues about the survey: I agree that a response rate of less than 20% does raise concern about the generalizability of the results of the survey. However, given the content of the responses (and given the content of some written comments made on the sruvey), these results are still very disturbing. And I'm not sure on what Ms Bro's charge that the survey questions were "leading" was based.
Unfortunately, these stories make it even more imperative for doctors and patients to be extremely skeptical about what they are being told about pharmaceutical products, even by the formerly respected FDA.
These stories added together suggests that Senator Grassley's call for a complete overhaul of the FDA is on target. Unfortunately, the FDA, once regarded as a paragon of integrity (albeit one that may have been ponderous, bureaucratic, and sometimes inefficient), seems to have fallen into the same muck that too many other health care organizations, from hospitals to to managed care organizations to pharma and device manufacturers now occupy. Thus now doctors and patients must be extremely skeptical about nearly anything they hear about health care when it is said by someone who could possibly have vested interests other than improving patient care or the integrity of science.

We have a lot of overhauling and much-raking to do. Meanwhile, we have to work in a health care system in which doubt, ambiguity, and skepticism rule.

NOTE: See the takes on this by Pharma Gossip here, here, and here. See a related story by Dr Aubrey Blumsohn on the Scientific Misconduct blog here.

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