FDA Overhaul Gains Momentum

CONGRESS IS MOVING toward reauthorization of a 15-year-old program under which drugmakers pay the government hundreds of millions of dollars in annual fees for reviews of their prospective new products. The Bush Administration and the pharmaceutical industry had hoped for a "clean bill," unfettered by additional provisions. But in the wake of several high-profile controversies regarding drug safety, lawmakers from both political parties have seized on the legislation as the best opportunity in years to overhaul the Food & Drug Administration.

"FDA should be the gold standard for safety. But its luster has been tarnished in recent years by its failure to protect the American people from unsafe drugs," says Sen. Edward M. Kennedy (D-Mass.), chairman of the Senate Health, Education, Labor & Pensions Committee. Along with ranking member Sen. Michael B. Enzi (R-Wyo.), Kennedy is cosponsoring legislation that would reauthorize the Prescription Drug User Fee Act of 1992 (PDUFA). FDA's authority to collect the fees expires on Sept. 30, the end of the current fiscal year.

The bill (S. 1082), which the Senate approved on May 9, largely follows a proposal that FDA submitted to Congress earlier this year under which pharmaceutical companies would pay the agency about $393 million in fees annually through fiscal 2012, up from $305 million in fiscal 2007. Because the fees provide roughly half the funding for FDA's drug review budget, the legislation is considered "must pass" by both government and industry officials. The House, which has just begun working on the issue, is expected to approve similar legislation this summer. Differences between the bills would have to be worked out and then voted on by each chamber.

"The reauthorization of this law plays a significant role in FDA's continued ability to make drug therapies available to the American public in a timely fashion without sacrificing the quality of the approval decisions," says FDA Commissioner Andrew C. von Eschenbach. Before Congress created the user-fee program 15 years ago, FDA faced a serious backlog in its review of New Drug Applications. Despite statutory requirements to conduct reviews within six months, it was taking the agency more than 30 months on average to evaluate new medicines.

"By allowing FDA to levy user fees on pharmaceutical companies to supplement shortfalls in appropriated funding, the agency was able to hire much-needed staff," explains Alan R. Goldhammer, deputy vice president of regulatory affairs for the Pharmaceutical Research & Manufacturers of America (PhRMA), the brand-name drug industry's trade association. With the increased funding, he says, FDA has completed its reviews in a "thorough and timely manner, bringing medicines to patients more quickly, without compromising its exacting standards for evaluating safety and efficacy."

Critics don't see it that way. They claim that efforts to speed the approval of new drugs have allowed a number of dangerous prescription medicines to mistakenly reach pharmacy shelves. In 2002, the General Accounting Office (now the Government Accountability Office), the investigative arm of Congress, found that "a higher percentage of drugs has been withdrawn from the market for safety reasons since [PDUFA] was enacted." Most notably, Rezulin, a diabetes drug used by about 750,000 Americans, was withdrawn from the market in 2000 after it was linked to at least 63 deaths from liver poisoning.

Then in 2004, Merck was forced to pull its blockbuster painkiller Vioxx from the market after evidence emerged that the arthritis drug significantly increased the risk of heart attack and stroke. The recent disclosure that GlaxoSmithKline's diabetes drug Avandia may be associated with a significantly increased likelihood of heart attacks further buttresses the claim that FDA lacks the authority to ensure that drugs already on the market are safe.

IN RESPONSE to these highly publicized lapses, FDA asked the Institute of Medicine (IOM)—part of the National Academies—to conduct an independent assessment of the agency's system for evaluating the health risks and ensuring the safety of medicines after they hit the market. IOM's report, issued last September by a 15-member blue-ribbon panel of government advisers, concluded that FDA has neither the resources nor the authority to adequately monitor and ensure drug safety. Citing a history of intra-agency squabbling, the committee said there is tension and mistrust between the scientists who assess New Drug Applications and those who collect and analyze reports of adverse effects after medicines enter the larger patient population.

Aiming to restore the public's shaken confidence in the nation's drug supply, Sens. Kennedy and Enzi crafted a measure that calls for a fundamental change in the way FDA conducts business, requiring the agency to focus on the entire life cycle of a drug-not just the years prior to its approval, but also the experience of patients who later take the medicine. "Right now, FDA has its hands tied when it tries to manage the risks of drugs already on the market," Enzi says. "This bill will strengthen FDA's authority and give it new tools to take measured and appropriate steps when the agency's postmarket surveillance signals potential dangers from a drug or therapy. Pulling a drug from the market and denying patients who need it shouldn't be the only tool available to FDA."

THE LEGISLATION would more than double the number of scientists assigned to FDA's Office of Drug Safety, which currently has a staff of about 90. It would also create a computerized surveillance system, under which millions of medical insurance and pharmacy records would be scanned for signs of trouble with newly approved medications. FDA currently relies on anecdotal reports from doctors. The bill would also give FDA the legal authority to compel companies to conduct additional safety studies on products already on the market, and the agency would be given the power to change warning labels without having to engage in protracted negotiations with drug manufacturers, which is now often the case.

"This legislation will bring FDA into the 21st century," Sen. Kennedy remarked after the Senate vote. "It greatly improves the way FDA oversees the safety of drugs. It recognizes that when patients are in danger, FDA should not have to wait to get legal opinions to decide how to protect health. It should be able to act immediately, and our bill gives it that authority."

Lawmakers also agreed to impose substantial penalties on companies that fail to comply with FDA's orders for label revisions or additional studies of medications. "The civil monetary penalties that were in the bill didn't pack enough punch to get the attention of corporations," said Sen. Charles E. Grassley (R-Iowa). His amendment increased the minimum fine under the bill from $10,000 to $250,000 and doubled the maximum fine from $1 million to $2 million. "These penalties need to be more than just an insignificant cost of doing business in order to affect behavior," Grassley asserted.

The Senate measure also addresses complaints about direct-to-consumer advertising of prescription medicines by allowing FDA to slap companies with a $150,000 fine for running a false or misleading ad and up to $300,000 for an additional offense. The drug industry contends the ads provide doctors and patients with educational information about diseases and treatment options. But critics charge they inflate demand for expensive brand-name drugs and interfere with the patient-doctor relationship.

The bill as originally proposed included a provision that would have given FDA the discretion to force drugmakers to wait two years before airing advertisements for newly approved medications. But the measure was dropped after several senators protested that such a restriction would violate the first amendment rights of pharmaceutical companies. "My key concern with the underlying bill is the recognition that the ban on free speech is based on what the FDA does not know, not what it knows," said Sen. Pat Roberts (R-Kan.). "In other words, the government would ban free speech even though it cannot identify an adverse event to support the ban."

In addition to avoiding restrictions on advertising, drug companies scored another major victory when the Senate voted in May to block an attempt to legalize imports of lower priced medicines. The industry argues that consumers could not be sure that foreign-made drugs are safe and effective. "Simply put, the importation of medicines from foreign countries, in our view, is equivalent to importing into America the soaring epidemic of dangerous counterfeits around the world," says PhRMA President W. J. (Billy) Tauzin.

Lawmakers initially approved an amendment proposed by Sen. Byron Dorgan (D-N.D.) that would have allowed drug importation from Canada and 18 other industrialized nations. But facing the threat of a White House veto, the Senate accepted a proposal by Sen. Thad Cochran (R-Miss.) that would require the Department of Health & Human Services to certify that the imports "pose no additional risks to the public's health and safety" and would significantly reduce costs for consumers. Because federal health officials have repeatedly said they cannot guarantee the safety of any foreign drug, Cochran's amendment effectively nullified the importation plan.

Dorgan argued that his proposal would allow only drugs manufactured in FDA-approved facilities to be imported. But Cochran said he was mainly concerned about counterfeit drugs. "We want Americans to continue to have access to safe and effective drugs that are approved by FDA, but we must not create opportunities for potentially dangerous drug products from foreign countries to reach the American consumer," he declared.

Lawmakers also decided to hold off, at least temporarily, on adding language that would give FDA the authority to approve generic versions of expensive brand-name biotechnology drugs, known as biogenerics or follow-on biologics. Unlike conventional pharmaceuticals, biotech drugs typically are genetically altered proteins that are difficult to replicate, and generic versions are not currently permitted. If an agreement can be reached on a system for FDA to review and approve biogenerics, Kennedy has said he would insert the provisions when House and Senate negotiators eventually meet to reconcile differences in their legislative plans.

The proposal (S. 623) before the Senate, introduced by New York Democrats Charles E. Schumer and Hillary Rodham Clinton, calls for an abbreviated approval process to review biogenerics that are highly similar to the original product. It would also give FDA the discretion on a case-by-case basis to determine what studies are needed to determine a drug's safety and whether it's comparable to the brand-name drug. "The Senate has recognized that their constituents are demanding safe, effective, and more affordable versions of these life-saving medicines and are looking to Congress to act to get them the help they need," says Kathleen Jaeger, president of the Generic Pharmaceutical Association. "The science exists to ensure the safety and efficacy of biogenerics," she adds. "Now it's time to give FDA the authority and flexibility to put a workable pathway in place."

The biotech and pharmaceutical industries insist that generic manufacturers should be required to submit human clinical data to show that their products are just as safe as any other new drug-a costly and time-consuming process. "We believe that unless clinical trials are conducted to show the safety and effectiveness of follow-on biologics-a requirement alarmingly absent in bills introduced to date-patients would have no assurance that the product they are taking is safe," says Caroline Loew, PhRMA's senior vice president for science and regulatory affairs. Brand-name drugmakers also believe that such a contentious issue should be dealt with separately and not be allowed to slow progress on the user-fee legislation.

Tauzin, who chaired the House Energy & Commerce Committee in his former role as a Republican congressman from Louisiana, says his group is satisfied with the bill passed by the Senate. "In general, it will preserve and even strengthen FDA's ability to do its job," he remarks. "The significant increases in user fees will provide FDA the resources necessary to improve and modernize its already strong drug safety monitoring system."

He says the agency will be able to hire more staff for drug safety activities, enhance its use of epidemiology studies and large medical databases that contain a wealth of safety information, modernize its adverse reaction reporting system used to collect and aggregate safety data, and better evaluate risk communication and risk management programs.

CONSUMER GROUPS have had a mixed reaction to the Senate measure and hope the House gives FDA enough resources, as well as the independence, to fully exercise its regulatory role. "Congress is telling FDA that they must put safety first," says Paul Brown, a consumer health care advocate for the U.S. Public Interest Research Group. "For too long, the D in FDA has stood for 'dysfunctional.' The American public will no longer tolerate dangerous and deadly drugs like Vioxx, Paxil, and Accutane approved by an agency that has been much too cozy with the industry it is supposed to be regulating."

William K. Vaughan, senior policy adviser for Consumers Union, publisher of Consumer Reports, says the Senate reforms will help ensure that patients and doctors know more about the risks of their medicines. "Too many lives have been lost because FDA has been too slow to act or didn't have the power to change a warning label or require a follow-up safety study. It's now up to the House to get the strongest possible reforms approved so patients can have faith in the medicines they take each day," Vaughan says.

Other groups argue that Congress should scrap the user-fee program altogether because the cash creates an unavoidable conflict of interest. "The agency has become dependent for its funding upon the very industry over which it has regulatory authority," says Peter Lurie, deputy director of Public Citizen's Health Research Group. Since the fee system was established, the organization contends, FDA has treated the drug industry more as a client than a business to be regulated. "Protecting the integrity of drug approvals is a legitimate federal function and one that should therefore be wholly funded from federal coffers," Lurie asserts. Kennedy has indicated a desire to reduce FDA's reliance on industry money. But in an era of tight federal budgets, he says user fees are essential to FDA's drug review operations.

Attention now turns to the House, which is considering a bill drafted by Rep. Frank Pallone Jr. (D-N.J.), chairman of the House Energy & Commerce Subcommittee on Health. It contains many of the Senate features, including $225 million more in drug industry user fees and the active monitoring of huge medical databases to detect safety problems.

"For far too many years, the focus of FDA has been to improve the amount of time it takes to approve new drugs," Pallone says. "Unfortunately, this has caused an imbalance between the preapproval process and the postmarket monitoring of drugs. We must fix this imbalance and focus more of our attention on what happens with drugs once they reach the marketplace. Assessing the risk of a drug once it is on the market is just as important, if not more, than before it is approved."

The House proposal goes further than the Senate bill by requiring that all new drugs display a symbol to alert consumers that they are new to the marketplace. It would also establish guidelines for how the drug industry must register and report their clinical trials to make them publicly accessible. The Senate bill gives FDA two-and-a-half years to develop guidelines for making some, but not all, clinical trial results public.

"The House has the opportunity to pass real reforms that will give FDA the power to act quickly and decisively when drug safety problems arise," Vaughan says. "This proposal should help put an end to incidents like Vioxx, where the public was kept in the dark about possible health risks."