Monday, December 06, 2004

Watching The Detectives

In an earlier post, which set off a flurry of fairly esoteric discussion in the comments section, I discussed the increasingly prominent role that pharmaceutical companies have been playing in setting the parameters of the clinical research concerning the drugs that they are sponsoring for approval by the FDA. The industry is using its financial leverage to dictate the terms of the studies, including which findings will be published and which will not. In addition, the economic enticement of generous research grants is leading to a conflict of interest by which researchers, universities and doctors are embellishing the results of studies in order to please the drug sponsors themselves - thus paving the way for future economic enrichment.

That post also began to explore other facets of the story, namely that the FDA itself has been, in many ways, coopted by the very industry it is charged with regulating, and how the increasingly cozy relationship between the two theoretical adversaries has caused the FDA to overlook and hesitate to act on emerging problems with drugs and side effects - as exemplified by the Vioxx episode. In the context of this somewhat troubling dynamic between overseer and regulated, I also introduced what is a dangerous scheme for removing incentives for drug companies to diligently monitor drug safety as well as curtailing the protections for ordinary citizens who are injured by the negligence, recklessness, and malfeasance on the part of those companies.

This "scheme" is a court closing initiative that the Bush administration is dubiously calling "tort reform." In this context, tort reform would translate into a system by which a drug company is granted near-absolute immunity for any drug that has received FDA approval. Even though its independence, objectivity and scientific rigor have been compromised, and despite the fact that results from the studies it will review have been skewed in favor of the pharmaceutical companies, once the FDA approves a drug, the company producing the medication will be let off the hook for any impropriety in the process, or any subsequently detected defects.

While this court closing proposal is disturbing based on what was discussed in the previous post, there is an article in
today's New York Times that highlights some ways in which the problems with the FDA may actually be worse than anticipated, making such a drastic measure even more pernicious.

The story begins in the early 1990's as the Clinton administration was exploring ways to speed up the drug approval regime - a priority given the exigencies of the AIDS crisis as well as other life threatening illnesses that were impacting the nation and the world. The pharmaceutical industry and the government agreed, in a seemingly win-win situation, to establish a system by which large contributions from the industry to the FDA would be used to hire more reviewers and expedite the new drug review process. In order to insure that the contributions would continue to be dedicated to new drug reviews, there were minimum levels of funding built in to the agreement. The problem's have arisen as a result of the general lack of funding for the administrative state that has been characteristic of the Bush/Cheney White House.

But Congressional financing has lagged the agency's escalating payroll costs. To meet the "trigger" and keep fees flowing, agency officials have been forced to shift dollars from other programs into new drug reviews. This shifting has increased the agency's focus on the reviews even beyond what the drug industry had negotiated.

In 1992, the agency's drug center spent 53 percent of its budget on new drug reviews. The rest went to survey programs, laboratories and other efforts that in part helped ensure that drugs already on the market were safe. In 2003, 79 percent of the agency's drug center budget went to new drug reviews. Everything else has gotten squeezed.
Unfortunately, one of the vital functions performed by the FDA that has "gotten squeezed" is the responsibility to monitor drug safety post-approval. This role is particularly important because the FDA cannot require drug makers to test already approved medicines. This regulatory body is the one institution that has the incentive, theoretically, to insure that drugs already on the market are safe for patients. But now that the funding for post-approval testing has either gone to pay for enormous tax cuts for the wealthiest Americans, or been diverted to new drug review procedures, the FDA has sacrificed key aspects of its watchdog responsibilities. In its wake, the FDA has let the industry monitor itself. This exacerbates the conflict because the drug companies do not have an interest in detecting side effects and complications that would hamper sales and profitability. Imagine how much further the incentive will drop if drug companies don't have to consider the economic impact of lawsuits for unsafe drugs.

Indeed, the agency now relies almost entirely on the willingness of drug makers to report problems that crop up after a drug has been approved to ensure the safety of the nation's drug supply...

Presently, the main drug program to catalog the dangers of drugs is a computer listing of side-effects. It is a passive system, meaning that doctors report side effects only when they think of it and have the time. The system receives almost 400,000 reports a year, but these represent a small fraction of the total, all agree. Most reports are delivered by drug makers, who hear about side effects from physicians.

The side effects tracking system can signal problems only when a drug causes an effect like liver failure that is normally very rare. If a drug increases the number of heart attacks, a problem that is very common normally, the system is useless, Dr. Woodcock of the F.D.A. said.
This laissez-faire regulatory structure would be a problematic under even the most ideal of circumstances because no matter how rigorous, pre-approval studies will never be able to simulate the size and breadth of a drug's use once it has entered the stream of commerce. Whereas a pre-approval study might cover thousands, post-approval use could total well into the millions, making it possible that potentially dangerous side effects would go undetected in the smaller samples, or go unnoticed because the post-approval monitoring was not looking for common ailments.

The current arrangement is far from optimal, however. As discussed in the prior post, the actual pre-approval studies are manipulated and embellished in order to produce results most favorable to the drug industry. In addition, the recent increase in funding for the review process has resulted in an assembly line of inadequately tested drugs, approved on the basis of distorted results, that enter the market without any significant post-approval monitoring. This confluence of factors is creating a perfect storm of regulatory neglect.
Almost every argument about the 1992 agreement revolves around review times and whether new drug reviews are as careful as in the past. Many outside the agency say the rapid review timelines adopted as part of the agreement have made the agency's drug reviews sloppy, leading the agency to approve drugs like Vioxx that should never have gotten onto the market. Merck withdrew Vioxx in September after a test showed that it doubled the risk of heart attacks.

The agreement that accepted such a large proportion of industry financing "made a bad situation worse," Dr. David J. Graham, a reviewer in the agency's office of drug safety who harshly criticized the agency before a Congressional panel last month, said in an interview. "The agency was already far too focused on approvals and not on safety."

"And if this problem isn't fixed," Dr. Graham said, "future Vioxx-like catastrophes are inevitable"...

Dr. Strom of the University of Pennsylvania said the F.D.A.'s almost complete focus on approving new drugs at the expense of ensuring the safety of medicines that patients are already taking is wrong.

"They're getting all these drugs on the market a whole lot sooner and not looking at what happens once they get there," he said.
The article also discusses two additional factors that have diminished the efficacy of the FDA's oversight capacity. First, the FDA has grown increasingly timid and reluctant to challenge drug companies to institute further testing for side effects post-approval because of the FDA's reliance on industry financing. Second, there is a tension created when the same body that approves a drug must determine later on if that decision was correct.
Dr. Graham of the F.D.A. told a Senate panel last month, is the conflicts that inevitably arise when those who approve a drug must later decide whether their own decisions were mistaken.
Consider for a moment the magnitude of the problem: pre-approval studies are compromised by industry influence, approval is made easier by increased funding for the review process, post-approval monitoring by the FDA is made nearly impossible due to a diversion of funds to new drug review, industry self-monitoring is a dysfunctional process rife with conflicts of interest, there is institutional reluctance on the part of the FDA to confront drug companies, a conflict exists by which the FDA is more reluctant to find fault with its own approval process, and the Bush administration wants to make FDA approval a grant of immunity for lawsuits relating to the underlying drugs. While I am no chemist, I can say that is a formula for disaster.

Outgoing Health and Human Services Secretary Tommy Thompson, upon his retirement, announced his endorsement of a plan to create an independent body to monitor the safety of drugs post-approval. This would lessen the funding pressures currently afflicting the FDA by separating out the drug monitoring functions and leaving the FDA to deal exclusively with the approval process. This would also eliminate the conflict inherent in requiring the same agency to report on its own mistakes made in the approval process. In addition, this new body could improve on the half-hearted and conflicted attempts at safety monitoring currently undertaken by the industry itself. It's a shame that Thompson chose his retirement to advocate for a system that could help to improve the safety and efficacy of valuable medications and treatments. It is not clear to what extent, if any, his successor will take up this cause. In the meantime, as citizens we are all exposed by the failures of the system, yet the GOP leadership pushes toward closing courts off to any citizne seeking to address an injury arising from the breakdown. That kind of immunity is bad for the patient.

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