The FDA remains firm that it did nothing wrong in its post-marketing review of Vioxx. Critics are equally adamant, citing a systemic failure within the FDA that allowed a medication to remain on the market despite studies indicating the need for serious caution.

Congress and the Institute of Medicine will sort out the details and come to some conclusion, but not without the scrutiny of the American public.

(As GEN went to press, New York City-based Pfizer reported that a cancer clinical trial studying its Celebrex product showed an increased cardiovascular risk over placebo at doses of 400 mg to 800 mg per day. Although Pfizer did not pull Celebrex off the market, the company said it would immediately stop advertising the arthritis drug to consumers.)

These issues come at a time when Americans are questioning the validity of the current health care model, against the backdrop of the flu vaccine shortage and steady increases in the costs of medications and health insurance. The FDA is losing credibility, and the ramifications extend throughout society, note some observers.

If the agency cannot be entrusted to protect the health of Americans, the incentives to purchase medications abroad increase. The FDA’s primary argument, that it cannot ensure the integrity of foreign medications, loses meaning if consumers believe it no longer can ensure the safety of American-made drugs, either.

Such erosion of trust, resulting from what Sen. Chuck Grassley (R-Iowa), chairman of the Senate Committee on Finance, called “one of the worst drug disasters in history,” will undoubtedly affect other areas as well.

“There’s a snowball effect,” notes Lisa Acevedo, J.D., partner, Foley & Lardner ( “It increases the focus on healthcare issues, including tort reform, and we’ll see more criticism and scrutiny on other drugs and companies.”

Independent Office

One of the chief concerns involves the possible creation of an independent office to review post marketing studies.

“A lot of proposals are floating around and a number of senators are considering legislation,” notes Sara Radcliffe, managing director of science and regulatory affairs, BIO.

In testimony before the Senate Finance Committee last Novem-ber, David Graham M.D., associate director for science and medicine in the FDA’s Office of Drug Safety, questioned the wisdom of having post-marketing studies conducted by the same office that “approved the drug in the first place and regards it as its own child.”

However, “a separate entity has drawbacks,” says William Janssen, J.D., partner and chairman of life sciences at Saul Ewing (www. “You’re taking the body most familiar with a drug and divorcing it from the post-marketing side. To abandon that learning seems imprudent.”

Another concern includes speculation that clinical trials may become harder to enroll.

“When I was taking care of patients (and participating in clinical trials), I trusted that the pharmaceutical company was giving me as much up-to-date information as it had,” says Jeffrey Green, Pharm.D., CEO, DataTrak International (

“Now, I would be very resistant to talking a patient into entering a clinical trial. If a physician sees only the 10 to 20 patients he or she enrolled in a given trial, there’s no way to see the larger trends quickly.”

Other concerns, cited by the editors of the Journal of the American Medication Association (JAMA), in an editorial posted November 22, included “reliance upon manufacturers for collecting, evaluating, and reporting data from post-marketing studies of their own products, poor quality of submitted reports, underreporting of adverse outcomesand difficulty in determining whether the adverse event resulted from the drug or the disease it was intended to treat.”

Some of those issues relating to timeliness of information and reporting quality could be addressed by using electronic data capture during clinical trials, Dr. Green says. One of the issues, he continues, is “did Merck have a failure to know, in a real-time fashion?” Paper-based data can take six to nine months to be integrated into a database and analyzed, whereas “an electronic data capture system can track events within 10 seconds.”

The FDA is phasing in electronic submissions. “But, I’m not sure they’re really pushing for it,” adds Dr. Green. “They have guidelines,” but they should insist on having data in a live database by a certain timeframe.

“The Securities and Exchange Commission instituted EDGAR several years ago and implemented it within a few months. Therefore, financial information has a higher priority than patients’ adverse events,” maintains Dr. Green.

Part of the problem, according to James Walsh, author of Silverlake Publishing’s “Liberty in Troubled Times,” is the “revolving door between the FDA and industry. It’s a standard career path to rise through the agency and end up working for drug companies and, most disturbingly, to come back to the FDA.”

The issue, he continues, “is not that it colors any one decision, but that it colors them broadly,” by causing the agency to focus on the issues the industry wants addressed, rather than the issues that most need addressing. “The most profound way industry can influence their regulators is to hug them to their chests,” notes Walsh.

Outsourced Trials

Outsourced clinical trials management offers a good example, says Dr. Green. “Reviewers typically bill $2,000 per visit and about $16 per page to review paper-based clinical trials documentation. Electronic data capture eliminates the need for physical visits by 20 to 70 percent and cuts the per page cost by about half,” he explains.

The implication is that the FDA is reluctant to mandate a change to electronic data capture out of concern for the revenue streams of clinical trials management companies. The alternative view is that the FDA is allowing industry to move at its own pace, with occasional nudges.

It must be said, however, that, “The FDA is so good at what it does that when a problem occurred people were shocked,” Peter Pitts, former associate commissioner for external affairs emphasizes.

“It’s not obvious that the FDA made a fundamental error [regarding Vioxx],” points out Janssen.

Or, as Pitts emphasizes, “No drug is 100 percent safe, 100 percent of the time. All drugs have risks. That people are so shocked means more education is needed for consumers and physicians.

“There are strong economic disincentives to leave a worrisome product on the market,” Janssen says, despite concerns to the contrary expressed by the editors of JAMA. “These (often) are decisions made at the edge of science.”

“In clinical trialsyou’re collecting enough information to support your case and you can’t identify all associated possible risks,” notes Michael Liebman, Ph.D., CSO, Windber Research Institute (www.

“If, for example, you’re doing a study for a drug and you use a microarray that has the potential to show an oncogene, and the oncogene level changed, it could change the interpretation of the study, which has to be reported and defended. So, there’s no incentive to collect maximum information, which decreases the incentive to find additional risks.”

“It’s important not to lose sight of what goes on pre-marketing versus post-marketing,” says Acevedo. “The problem is that is it virtually impossible during trials to identify all of the possible safety issues. Phase III trials are limited in terms of time, and some potential problems won’t become evident then. The FDA doesn’t fail to pay attention to safety,” but it’s impossible to earmark each potential problem, she emphasizes.

Pitts grants that the system “can always be better. Anybody got a proposal?” he asks. “For those who do, I have four words: show me the money.”

Broadened its Focus

In discussing the path of the FDA, he notes that the 99-year-old organization broadened its focus a few years ago from protecting to protecting and advancing America’s healthcare.

“If you don’t advance American health, you’re on the sidelines,” he says. “If the FDA doesn’t engage in creating new and better research tools, it’s not doing its job.”

Pitts cites the “Critical Path” initiative in pharmacogenomics as a means of helping industry fail faster and thereby emulate turn of the [20th] century inventor Thomas Edison, who attributed his great success to failing faster than his competition.

Some would argue, however, that helping industry fail faster should not be the job of the FDA.

“The whole system is big and very involved, and people don’t look to see how it should be structured. We (tend to) look at steps in the process, not the overall process,” Dr. Liebman says. “There is pressure within the FDA to fix the problem, but there needs to be a long-term strategy.”

Instead, he speculates there will be a “knee-jerk reaction, so critics will be appeased. But, the process won’t be improved.”

That, of course, is a real possibility, but so are real improvements. “The FDA’s mission is to protect the public health. There has to be a watchdog, and that is a role the FDA is playing. They’re doing a good job,” says BIO’s Radcliff. “But, any system can be reviewed to see if improvements are needed.”

That sentiment is true for any industry. “The pharmaceutical industry is at a point in time where a lot of its processes need to be examined. Science is starting to show that the simplistic assumptions used aren’t as relevant as once thought,” adds Dr. Liebman.

“Companies need, therefore, to rethink their processes, and whether they make sense in light of the new discoveries and new technology. If you built the process today, would you build it the same way?” To deny problems in a bureaucracy as large as the FDA would, indeed, be shortsighted.

Calls for reform aren’t new. They were heard in the 1970s and in each decade since. They were as resounding when reformer David A. Kessler, M.D., stepped down as FDA commissioner in 1996 as at the beginning of his six-year tenure. And they are being heard now.

To the FDA’s credit, improvements have been made and others are in process. The question now is whether those changes have been sufficient to ensure drug safety as well as to speed approvals.

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