New Black-Box Warnings and Congressional Hearings on Ketek: "Whose Interest is Being Protected?"

It has not been a happy few days for the pharmaceutical industry.

We previously posted (also 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. Nonetheless, the US Food and Drug Administration (FDA) approved Ketek for use in even relatively mild infections. Back in June, 2006, US Senator Charles Grassley (R-Iowa) announced his intention to figure out why.

On Monday, the US Food and Drug Administration announced that Ketek would no longer be approved for sinusitis and bronchitis, relatively mild infections for which many other antibiotics are available. It also announced more "black-box" warnings for Ketek. (See this report by Bloomberg News, for example.) In preparation for a sub-committee hearing in the US House of Representatives about FDA oversight in this and other cases, Representative Edward Markey (D- Massachusetts) called these warnings "overdue," and suggested there was "no coincidence" about the timing of the FDA announcement prior to the committee hearing. The Associated Press (here via the Washington Times) quoted Markey, "it appears that a healthy dose of congressional oversight has reminded them to do their job and ensure the safety of drugs on the market." The AP also quoted Senator Grassley, "the FDA's action today shows what transparency can do. When a spotlight was turned on the questionable way in which Ketek got approved by the FDA for certain sinus and lung infections, the FDA was held accountable."

Today, reports on the hearings first appeared. Per Reuters,

U.S. lawmakers criticized the Food and Drug Administration's monitoring of the risks of the antibiotic Ketek (Sanofi-Aventis) and some other prescription drugs on Tuesday.

At a hearing on the FDA's drug safety oversight, lawmakers said the agency stifled dissent about the risks of drugs when top managers disagreed. They cited problems with Ketek, Vioxx (Merck & Co. Inc.'s withdrawn arthritis drug) and antidepressants made by several companies.

'With each of these drugs, it appears that the FDA is not seriously questioning whether the risks outweigh the benefits of the new drug,' said Rep. Bart Stupak, a Michigan Democrat who chairs a subcommittee of the House of Representatives Energy and Commerce.

'One must ask, if the FDA is not protecting its client, the American people, whose interest is being protected?' Stupak said.

Iowa Republican Sen. Charles Grassley, a vocal FDA critic, told the committee that 'scientific dissent is discouraged, quashed and sometimes muzzled' inside the agency and 'there's widespread fear of retaliation for speaking up about problems.'

And Anna Wilde Matthews, again in the Wall Street Journal, reported,

A former employee of the Sanofi-Aventis SA contractor that oversaw a clinical trial of the antibiotic Ketek told Congress the drug maker knew there was evidence of a problem with the study before regulators discovered fraud.

The testimony of Ann Marie Cisneros, a former employee of contractor Pharmaceutical Product Development Inc., came as the House Energy and Commerce Committee opened hearings into how the Food and Drug Administration handles drug-safety issues.

Committee Chairman John Dingell, a Democrat from Michigan, called the FDA 'badly broken,' and Rep. Bart Stupak, another Michigan Democrat and chairman of its investigations subcommittee, said the FDA's interactions with the drug industry had become 'incestuous.'

[For balance,] In a statement, Sanofi-Aventis said it was 'unaware at the time' that what appeared to be deviations at the site 'in fact reflected fraud in the conduct of the study.' The company said Aventis 'acted in good faith' in conducting the study and has cooperated with investigations.

The FDA, which had none of its leaders testifying, said in a statement that it 'shares Congress' commitment to drug safety issues' and the agency has announced a number of recent drug-safety initiatives. The agency said it followed 'standard procedures in identifying and communicating risks associated with Ketek.'

Pharmaceutical Product Development said it complied with FDA regulations and its contract with Aventis and reported all issues in the trial to Aventis.

In summary, it appears now that the common wisdom about Ketek was based on "pseudoevidence." (See our relevant post on "pseudoevidence-based medicine.") Unfortunately, these sorts of stories suggest that patients and physicians need to be very skeptical about the integrity of the evidence used to support use of the latest, greatest, and most expensive pharmaceuticals. If the drug industry wants to improve its sagging reputation, it will have to show that it can clean up how it does clinical research. Or perhaps we ought to think about getting drug (and biotechnology and device) companies out of the business of sponsoring clinical research on products in which they have vested interests? Of course, such a change will threaten quite a few peoples' sources of incomes, so we can expect plenty of resistance to it.