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Jill Wechsler is BioPharm International's Washington Editor, firstname.lastname@example.org.
The FDA is under attack from all sides. Many influential members of Congress either don't trust the agency to monitor the industry appropriately, or have found it politically expedient to keep sounding alarms about inadequate oversight of food and drug safety and clinical research. The good news is that there seems to be a growing consensus that FDA needs a major infusion of cash to regain its stature as an effective science-based regulatory agency.
The US Food and Drug Administration (FDA) is under attack from all sides. Many influential members of Congress either don't trust the agency to monitor the industry appropriately, or have found it politically expedient to keep sounding alarms about inadequate oversight of food and drug safety and clinical research. Congressional leaders question whether FDA requires sufficient testing before approving new products for market. The heparin scandal has intensified scrutiny of how well FDA monitors drug manufacturing and imports. That issue even prompted Rep. Bart Stupak (D-MI), chairman of an important House subcommittee, to call for FDA commissioner Andrew von Eschenbach and other officials to resign due to a "total lack of leadership" at the agency.
Late last year, House appropriators killed a direct-to-consumer advertising user fee authorized by the FDA Amendments Act (FDAAA) largely because they felt that FDA does not regulate drug advertising forcefully enough. And they nixed funding for the new Reagan-Udall Foundation because of fears that it will permit biopharmaceutical executives to exert more influence on agency research programs.
At the annual meeting of the Food and Drug Law Institute (FDLI) in March, Carl Peck, former director of the Center for Drug Evaluation and Research (CDER), described FDA as operating in a "guerrilla environment" created by "ambitious politicians, media competing for headlines, and opportunistic academics." A case in point, he noted, was a widely cited study in the New England Journal of Medicine indicating that new drugs approved close to user fee deadlines turn out to be less safe than those approved without any pressure to meet review timeframes. But FDA said that it's not true. CDER Deputy Director Douglas Throckmorton responded that agency approval and withdrawal data are "considerably different" from what the analysts reported. FDA plans to submit its findings to the New England Journal of Medicine, but even a strong refutation is unlikely to make front-page news.
FDA is having difficulty meeting the high expectations of all its constituencies because of an ever-expanding portfolio of oversight and regulatory responsibilities, coupled with depleted resources and a decimated work force. The need to establish a host of new rules and policies to implement FDAAA makes matters worse, at least for the short run.
The situation has become so serious that John Jenkins, director of CDER's Office of New Drugs, is giving review division chiefs leeway to "reduce work as needed on a case-by-case basis," even if that means missing user fee review deadlines. Jenkins explained to reporters that his office cannot keep up with growing requests to meet with sponsors, to provide special protocol assessments for innovative therapies, to fulfill information demands from Congress, and still meet stated user fee timelines. Jenkins noted that there is "no specific end date" to the possibility of missing Prescription Drug User Fee Act (PDUFA) deadlines because it may take years to hire all the necessary personnel to remedy the situation.
For manufacturers, this raises the prospect of added delays and higher costs in bringing new treatments to market. FDA approved only 19 innovative new drugs in 2007: 17 new molecular entities plus two novel biotech therapies. That's way down from the peak of 53 new drugs in 1996, but in line with a steady decline in new drug approvals since 2002. Manufacturers believe this trend reflects a "new environment" at the agency, noting that FDA reviewers are issuing more nonapprovable and approvable letters and routinely request additional studies. FDA officials counter that they have not changed standards, but have become better at detecting and defining safety problems.
CDER Director Janet Woodcock faces the daunting task of dealing with resource issues while reshaping the organization to handle added postmarket safety initiatives. CDER has gained the funding to add some 400 staffers, but the task of hiring and training a whole new cadre of reviewers and analysts will consume considerable time and energy.
Meanwhile, Woodcock is taking steps to expand drug safety monitoring and ensure safe medication use. In late February, CDER announced a new Safety First initiative to orchestrate collaborative oversight of risk issues and avoid clashes between CDER's new drug review offices and the Office of Surveillance and Epidemiology (OSE). A Safety First steering committee is clarifying internal processes for managing significant safety issues, Woodcock said in a staff memo. High-level managers have been named to every drug review office to monitor and coordinate assessment of safety issues. OSE has lead regulatory responsibility for observational epidemiologic studies and medication error prevention, including review of proprietary names, packaging, and container labeling. But safety officers won't get a veto over approvals, as some parties recommended.
To handle these and other new postmarket surveillance activities, CDER has expanded OSE from three to five divisions to better monitor adverse events, weigh safety issues in applications, and review risk management plans. And OSE Director Gerald Dal Pan heads up an expanded staff that oversees OSE management and communications and policy development.
In March, FDA launched the Risk Evaluation and Mitigation Strategies (REMS) policy authorized by FDAAA. The agency published a list of drugs that fit the REMS criteria because they have some kind of restricted distribution system, with training or certification requirements for prescribers and other controls on drug dispensing and patient use. Manufacturers of the 25 drugs on the list have to file REMS plans by September 21, 2008. Meanwhile, FDA is preparing guidance on REMS content and format to clarify requirements for manufacturers developing new therapies that raise patient safety issues.
Another FDA initiative is to publicize information on emerging drug safety signals as they emerge. The same week that FDA unveiled its REMS policy, it also announced new safety reviews related to cardio signals involving leading AIDS therapies, GlaxoSmithKline's Ziagen (abacavir) and Bristol-Myers Squibb's Videx (didanosine). The agency also said it would conduct a safety review of Johnson & Johnson's Regranex (becaplermin) skin gel for diabetics to determine links to cancer and death. And FDA reported it is investigating a possible connection between suicidality and Merck's widely used asthma treatment Singulair (montelukast).
The good news is that there seems to be a growing consensus that FDA needs a major infusion of cash to regain its stature as an effective science-based regulatory agency. Senator Edward Kennedy (D-MA), chairman of the Senate Health, Education, Labor, and Pensions Committee, gained approval of an amendment to the Senate budget resolution for 2009 that supports an additional $71 million for FDA in the coming year. That would bring FDA's total budget to $2.2 billion if adopted by Congress. That fits recommendations from agency advocates to double FDA's budget over the next five years—from $1.9 billion in 2009 to $3.7 billion by 2013. Congress' Government Account-ability Office is developing a report on FDA resource needs, which should add more fuel to the debate.
Even FDA Commissioner Andrew von Eschenbach has dropped the usual official inhibitions about asking publicly for more money than his superiors have proposed. In a speech at the National Press Club in February, he acknowledged that FDA's resources "have not kept pace" with its growing responsibilities. In a similar address at the March FDLI meeting, von Eschenbach described FDA as a "patient in peril" because of expanding responsibilities made more complex by globalization, bioterrorism, just-in-time delivery demands, and a continuing need for crisis control. He noted that increased FDA reliance on user fees limits the agency's flexibility and urged "full backing" for the Reagan-Udall Foundation. "FDA needs to be stronger, bigger, and better," he said, if it is to continue to be "the world's gold standard as a regulatory agency."
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, email@example.com