FDA Feeling The Heat

January 19, 2007 Evelyn Pringle

Over the past year, the Bush administration's FDA has been the focus of non-stop investigations and with the Democrats in control of Congress, a long overdue overhaul of the agency is in the cards.

The Government Accountability Office has identified serious problems within the FDA. In an April 21, 2006, report, the GAO found the FDA's performance "disorganized," "bureaucratic," and undermined by infighting between drug evaluation administrators whose allegiance is with the pharmaceutical industry, and the Office of Drug Safety.

According to the GAO, the drug safety office is under-funded, lacks independence and lacks decision-making responsibility. It also criticized the way FDA scientists were prevented from speaking at advisory committee meetings on drugs they were studying.

Investigators point to a major conflict within the Office of New Drugs because it is not only responsible for approving a drug in the first place, it is also responsible for taking regulatory action related to the safety of drugs once they are on the market.

The GAO report said that day-to-day oversight of safety issues is still hampered by poor information, lack of legal authority to order drug company studies, and bickering between the powerful FDA bureau that reviews drugs for approval and a smaller safety office.

To improve postmarketing safety, the GAO recommends that Congress expand the FDA’s authority to require drug companies to conduct studies when additional data is needed.

Another report was released on June 26, 2006, titled, “Prescription for Harm: The Decline in FDA Enforcement Activity,” after an investigation was commissioned by the House Committee on Government Reform to evaluate the FDA's enforcement activities related to the pharmaceutical industry under the Bush administration.

When requesting the investigation, Rep. Waxman, wrote to the committee Chairman specifically asking for “attention to cases where career investigators believed official action to protect the public health was warranted but could not proceed.”

For the investigation, in addition to reviewing the FDA documents, the investigators obtained information from current and former FDA officials and independent experts.

The experts consulted included Dr. Jerry Avorn, Professor of Medicine at Harvard Medical School; Dr. Michael Wilkes, Vice Dean of Medical Education at the University of California at Davis School of Medicine; and Sammie Young, former Director of Compliance at FDA’s Bureau of Biologics and a 29-year veteran of the agency.

As to methods available for enforcement, when a serious violation of FDA standards is found during an inspection, the FDA has the statutory authority to seize or recall products, impose civil fines, or initiate criminal action.

However, most often the FDA will send the manufacturer either a “warning letter” or a “notice of violation,” which is also called an “untitled letter.” A warning letter notifies a company of violations, requires a written response, and warns that failure to correct the violations can lead to additional enforcement action.

Under FDA procedures, the agency must evaluate the response to a warning letter to determine whether the violations have been corrected. If the firm’s response is inadequate, the agency must take other enforcement action “as necessary to achieve correction."

An untitled letter is less serious and informs a company of the violations but does not require a written response or warn that enforcement action may follow if violations are not corrected. An untitled letter also does not require an FDA follow-up.

The Prescription for Harm investigation found that there has been a sharp decline in FDA enforcement actions against pharmaceutical companies since December 2001. After reviewing the records, in a May 25, 2006, letter, Dr. Avorn told the Reform Committee, "In all of FDA's once-proud recent history, I cannot recall a time of greater concern about its work on the part of doctors, patients, and policy researchers."

"In overview," he said, "there appears to have been a sharp drop-off in the number of warning letters FDA has issued in recent years, from an average well over 1,000 for the period 1992 - 2001 to an average of only about 700 for the years 2002 - 2004."

"It is unlikely," Dr Avorn advised, "that the behavior of the regulated industries improved so much during these years to account for a reduction of 300 warning letters per year."

Another expert consulted for the investigation, Dr. Wilkes, stated in a June 10, 2006, letter to Rep. Waxman:

"Today the snake oil salesman need not travel in horse and cart nor even in automobiles — they use the internet and the mail to make the same outrageous claims with products that contain sometimes dangerous ingredients and often inert useless ingredients.

"And the Food and Drug Administration seems unable and unwilling to step in to protect the American public."

The Report cites examples of serious problems that were ignored, including a GlaxoSmithKline plant in Puerto Rico, where the FDA's field inspectors found several violations between 2002 and 2004, and even recommended that the facility be closed. Yet it was not until 2005, that the FDA censured Glaxo, and even then it did not impose a fine, shut down the plant, or order a recall of the products it was unable to seize.

In some cases, the Report states, FDA headquarters rejected the recommendations of field inspectors despite findings that violations led to multiple deaths or serious injuries. Internal agency documents obtained during the investigation reveal that in at least 138 cases over the last 5 years, the FDA failed to take actions recommended by field inspectors.

The problems identified by inspectors in these cases included 110 where drug labeling and new drug application requirements were violated; 99 cases where manufacturing standards were violated; and 2 cases where firms failed to report adverse drug events. And over 40% of the files, the report said, involved multiple types of violations.

In nearly half of the cases, the FDA took no enforcement action against the firm and in the remaining cases, it took action that was weaker than recommended by the field inspectors.

Most interesting is the fact that during the Congressional investigation, the FDA provided no records from the Office of Chief Counsel, even though a previous investigation had attributed a sudden decline in enforcement actions to the issuance of a change in FDA policy by then Chief Counsel, Mr Daniel Troy, in September 2001, that required all warning letters and untitled letters to be approved by his office before being issued.

According to the revised procedures, the Chief Counsel is required to “state in writing the reason for nonconcurrence” whenever it objects to an enforcement action. Yet when the FDA was asked to explain why there were no records from Mr. Troy's office, FDA staff claimed that the Office of the Chief Counsel does not maintain copies of its decisions or recommendations, or even a record of which files it has reviewed.

The FDA was slammed again when the Institute of Medicine released a September 22, 2006, report that said that the nation’s drug safety system is impaired by “serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in [FDA] that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement."

The report listed the agency's lack of stable leadership in recent years, and the detrimental effect on personnel; the failure to provide the agency with the necessary authority to regulate post-marketing assessments and enforce compliance; the undue influence caused by the agency's dependence on user fees; and the impact of stacking advisory committees with members that have clear conflicts of interest.

A recent session of the Senate Committee on Health, Education, Labor, and Pensions, gave the Democrats the first opportunity to show how they intend to deal with the major problems at the FDA, so aptly identified by investigations over the past year.

A November 17, 2006, hearing was held to push forward Senate Bill 3807, the "Enhancing Drug Safe and Innovation Act of 2006," previously introduced by outgoing chairman, Senator Michael Enzi (R-WY), and incoming chairman, Senator Edward Kennedy (D-MA), who began working on the bill shortly after the Vioxx disaster.

At the hearing, critics called for stricter conflict of interest rules for advisory panels. Merrill Goozner, Director of Integrity in Science Center for Science in the Public Interest, testified about the conflicts of interest involving the expert panel that reviewed the COX-2 inhibitors, and how the panel decided that Vioxx was safe enough to stay on the market, even though its maker, Merck, had already removed it from the market.

Mr. Goozner told the Senators that ten of the 32 scientists on the committee had financial ties to the drugs' makers. "Had their votes been eliminated," he said, "two of the drugs in the class would have been voted down by the panel."

The president of Consumers Union, Jim Guest, testified that improvements are needed to prevent future disasters like Vioxx and called for a rule requiring that at least 90% of the members who decide whether a drug should be approved be free of conflicts of interest.

Dr. Steven Nissen, of the Cleveland Clinic, who has served on advisory panels, testified to "a crisis in public confidence in the FDA following an unprecedented series of revelations about drug and device safety" and called the Senate reform bill a "major step forward."

"I served on a 2001 Advisory Panel that recommended a warning label for Vioxx," he told the Senators, "but it took 14 months before the FDA could secure agreement from the company to accept a weakly written warning."

Dr. Nissen also said improvements "in the Advisory Committee process will help to ensure that FDA consultants are less likely to be influenced by financial conflicts of interest."

In 2005, a law was passed that required panel members to make full disclosure of all financial ties to Big Pharma. However, after reviewing the disclosure forms submitted, the FDA is still permitted to grant waivers that allow experts to sit on panels even if they have financial ties to a drug company.

On April 21, 2006, the Boston Globe discussed the practical effects of the law since it was enacted and quoted FDA critics as saying "the new transparency has changed little, and scientists who have conflicts of interest can still guide FDA decision making."

In less than 6 months, the Globe determined, close to 100 waivers had been granted.

Congressman Hinchey is the author of an amendment to the spending bill that funds the FDA, which would ban waivers. "Plain and simple," he says, "if a doctor or scientist has a personal, financial stake in a drug they should not be allowed to sit on an FDA advisory panel and determine whether that drug is safe."

In response to the FDA's renewed push to maintain its ability to grant waivers, on July 24, 2006, Rep Hinchey released a statement stating, "The FDA continues to demonstrate a lack of commitment to ensuring that all of its advisory panels are filled with members who have no conflicts of interest with the drug or device being reviewed."

"Saying that there are not enough potential advisory panel members available without conflicts, as the FDA argues, is an empty claim," he said.

Most disturbing, he said is that the FDA denies only 1% of the waivers requested. "When the FDA is handing out waivers 99 percent of the time," he states, "it is a clear sign that the system is broken."

No doubt in attempt subdue the hornet's brought on by the investigations into the approval of Ketek based on fraudulent studies, in late July 2006, the FDA announced a series of changes it plans to make in the methods used to evaluate clinical trials.

One would require a company to notify the FDA immediately if it believes a researcher has committed fraud during a clinical trial. As it is now, drugs companies are trusted to remove unreliable data and are not required to report any fraudulent activity to the FDA until they actually submit the new drug application.

The agency also says it plans to clarify which adverse events must be reported to the review boards that monitor the studies and standardize the forms used to collect information and revise the rules on how patients may qualify to participate in clinical trials.

The new FDA commissioner was confirmed on December 7, 2006, but critics say the agency is incapable of change under the Bush regime. Rep. Hinchey released a statement stating: "Unfortunately, the Senate's confirmation of Dr. Andrew von Eschenbach represents anything but a fresh start for one of the most troubled agencies in the federal government."

"I have not seen anything substantive from Dr. von Eschenbach," he stated, "to make me believe that the mismanagement, misplaced priorities, and ineptitude of the agency's leadership will change during his tenure."

"Among many other things," he said, "Dr. von Eschenbach has presided over the FDA as it issued a new rule that prevents Americans from filing lawsuits against drug companies if they or a loved one become seriously ill or die as the result of a particular drug."

"And in just the last few days," Rep. Hinchey reported, "the FDA has approved numerous waivers for panelists on its advisory boards who have financial conflicts of interest with drugs and devices they are reviewing."

Houston attorney, Robert Kwok, makes the point that "fortunately, there are just two years left in this administration, so Dr von Eschenbach's term may be short."

"But he can still do a lot of damage in that time," he warns, "to the rights of Americans, their health, and their privacy."

(This article is written as part of a series on pharmaceutical litigation and is sponsored by Robert Kwok & Associated, LLP)