Drug Safety Overhaul Is Urged

Times Staff Writers

The government’s drug safety system is seriously out of balance, devoting too much attention to approving new medications and not enough follow-up to uncovering risky side effects, a blue-ribbon scientific panel concluded in a major report released Friday.

Convened at the request of the Food and Drug Administration after a popular painkiller was linked to heart attacks, the experts in medicine, pharmacology, law and other fields issued a sweeping call for reform. Its 25 recommendations include establishing a fixed term for the FDA commissioner, restricting ubiquitous drug commercials and placing a special cautionary symbol on the packaging of newly approved medications.

The panel found “an imbalance in the regulatory attention and the resources available before and after approval” of new drugs, said Chairwoman Sheila Burke, a former Republican Senate staffer who now is chief operating officer of the Smithsonian. “Staff and resources devoted to pre-approval are substantially greater than those available post-approval.”


The panel urged greater legal authority for FDA regulators to compel drug companies to carry out safety monitoring and called for significant increases in agency funding -- although it failed to spell out exactly how much and where it would come from.

Consumer groups and advocates of overhauling the FDA hailed the report, while the drug industry issued a cautionary reaction. “Though there is always room for improvements, it would be a mistake to accept the notion that the FDA drug safety system is seriously flawed,” Caroline Loew, vice president of the Pharmaceutical Research and Manufacturers of America, said in a statement.

The recommendations will frame a legislative debate over the future of the FDA, expected to be joined in earnest next year when Congress must renew user-fee legislation that provides much of the agency’s funding.

The 15-member panel operated under the auspices of the Institute of Medicine, part of the National Academy of Sciences, which provides scientific advice to the government.

The FDA requested the review after the sudden withdrawal of Vioxx in 2004 generated a firestorm of criticism over its drug safety program. The widely used drug was pulled from the market by manufacturer Merck & Co. after a company-sponsored study confirmed that patients taking Vioxx were more likely to suffer heart attacks than those who did not.

An FDA safety reviewer, Dr. David Graham, had reached the same conclusion months earlier, only to have his warnings dismissed by superiors.

FDA officials on Friday were guarded in their reaction to the report. While praising the panel’s effort, Acting Commissioner Andrew C. von Eschenbach said it would take time to review the findings. “We are at a point where we are assessing and analyzing the report,” he said. “We are very committed to an effort of continuous improvement.”

The head of the agency’s drug review center expressed disappointment that the report focused closely on infighting between the scientists who evaluate new medications and those who monitor their safety after approval.

“I don’t think there is any question that there are some cultural issues in the center,” said Dr. Steven K. Galson, director of the Center for Drug Evaluation and Research. “What the report doesn’t do really well is explain that the vast majority of the interactions within the center are very successful.”

A previous investigation by the congressional Government Accountability Office had also concluded that the center’s powerful new drugs branch -- which gets the lion’s share of funding and staff -- treated the safety office as a sort of bureaucratic stepchild. Some FDA officials complained the new report did not take sufficient note of what it called two years of internal efforts to improve communication, both within the agency and with doctors and patients.

Graham, the FDA’s most well known whistle-blower, saw vindication in the findings, although he said the recommendations did not go far enough. “The language is amazingly harsh,” Graham said of the report. “This ... was written by academicians by consensus, and to have strong language come through as it does means things are terribly, terribly bad at the FDA.”

The report did not mince words:

“The committee found that the drug safety system is impaired by the following factors: serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture that is not optimally functional; and unclear and insufficient regulatory authorities, particularly with respect to enforcement.”

Although some leading reformers -- including Graham -- advocate the creation of an independent safety center within the FDA, the panel took another approach. It urged that a beefed-up safety office should work closely with the new drugs office in reviewing medications and, more important, in tracking potential problems after approval.

“A drug tested on a few hundred or a thousand people is much different when it is being used by millions over a long period of time,” said Burke, the panel chairwoman. “Approval does not signify the end of uncertainty about a drug, and continued monitoring is necessary after approval.”

To drive that point home to patients, the panel urged that newly approved drugs bear a special symbol -- such as a black triangle -- for the first two years after approval, as a reminder that their benefits and risks may not be fully understood. It also recommended a moratorium on advertising directly to patients during that period.

The panel also called on Congress to give the FDA specific legal authority to compel drug companies to carry out safety studies of approved drugs and to establish programs that would work with doctors and patients to mitigate risks. The agency currently must negotiate such steps with manufacturers.

The report’s recommendation to closely integrate the work of FDA drug evaluators and safety reviewers tracks a proposal put forward over the summer in legislation by Sens. Michael B. Enzi (R-Wyo.) and Edward M. Kennedy (D-Mass.). That bill could emerge as the leading congressional proposal for FDA reform.

Another leading advocate of FDA reform, Sen. Charles E. Grassley (R-Iowa), called on President Bush to adopt the report as a blueprint to overhaul the agency. “Mr. President, the ... report is an opportunity to finally address the criticisms lodged against the FDA over the last few years,” Grassley said in a letter delivered to the White House.

But some academic experts worried that the report’s recommendations, if followed to the letter, could have a chilling effect on drug approvals. Dr. Raymond L. Woosley, president of the Critical Path Institute, a nonprofit that works with the FDA and industry to streamline drug development, said the committee should have also addressed the question of bottlenecks in developing drugs for diseases such as Alzheimer’s.

“Many of the things in the report are right on target, but they do not address the broader question of the role of the FDA in getting better healthcare from science,” he said.


Alonso-Zaldivar reported from Washington and Gellene from Los Angeles.



Findings of FDA review

Here are some of the major recommendations of the Institute of Medicine report on reforming the nation’s drug safety system:

* Put a symbol on the packages of new drugs to denote that the medicine’s benefits and risks may not be fully understood. It would remain in place for two years.

* Ban advertising directed at patients during that two-year period.

* Review the risks and benefits of all new drugs after five years.

* Bolster the Food and Drug Administration’s safety staff and give it an integral role in drug approval.

* Give FDA legal authority to order drug companies to conduct safety studies and to institute other precautions to protect patients.

* Modernize and extend the FDA’s databases for tracking serious reactions to prescription drugs.

* Create an Internet registry to post results of clinical drug trials.

* Adopt stronger policies to minimize conflicts of interest among outside advisors who serve on the panels that guide much of the FDA’s work.

* Establish a six-year term for the FDA commissioner, who now serves at the pleasure of the president, to provide stable leadership.

Source: Institute of Medicine report