FDA at a Crossroads

Last year was particularly tough for the US Food and Drug Administration. The international heparin crisis erupted just as the agency was digesting a scathing assessment of its capabilities from its advisory Science Board. That report outlined how a depleted work force, obsolete information-technology (IT) systems, and a weak science base prevented FDA from carrying out its mission.

Jill Wechsler

The following months brought more contaminated food, drug-safety problems, a campaign against cough and cold medicines for children, and public airings of internal dissension. FDA recently drew additional fire over the discovery of melamine in baby formula and plastic containers that could harm infants. "FDA is barely hanging on by its fingertips," attorney Peter Barton Hutt told the House Energy and Commerce Committee in early 2008, leading the chorus seeking increased resources for the beleaguered agency.

Since the "Vioxx" debacle four years ago, FDA's credibility has crumbled, opening the door for Congress and the media to play "kick the FDA," commented Alastair Wood in an April 2008 New England Journal of Medicineeditorial. A leading critic is Rep. Rosa DeLauro (D-CT), who chairs the House Appropriations subcommittee that oversees FDA's budget. At an April 2008 meeting about "Science at FDA" sponsored by the Institute of Medicine, DeLauro asserted that FDA needs "urgent and dramatic reform" because it cannot perform basic functions such as keeping track of clinical trials, conducting required inspections, and following up on commitments for postmarket studies. DeLauro blames many of FDA's ills on manufacturers and has blocked funding for the new Reagan–Udall Foundation until its organizers ensure that it's "not just another tool for industry."

She also fears that FDA's Critical Path Initiative may persuade agency scientists that it's more important to develop methods to support product approval than to objectively evaluate safety and efficacy data. DeLauro, moreover, would like a three-year moratorium on direct-to-consumer advertising of newly approved drugs and added curbs on conflicts-of-interest among members of advisory committees.

In Washington This Month

A new administration and new FDA leadership will provide an opportunity for change. This is "a watershed time for FDA and the pharmaceutical industry," says Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). The public is concerned about drug quality and imports, industry is struggling with a productivity crisis, and the global financial meltdown may dry up investment for biomedical innovation, she observed at a fall 2008 meeting sponsored by the Generic Pharmaceutical Association. Woodcock's aims are to restore public confidence in the drug regulatory process, capitalize on advances in science and technology, improve postmarket oversight, and make FDA "the recognized leader in drug regulation."

Food fight

Achieving these goals may require broader changes in FDA's structure and operations to better fit the global world of pharmaceutical and food production. FDA is responsible for ensuring the safety and quality of about 80% of the US food supply, an activity that has suffered from insufficient resources and limited authority. Because the regulatory model for food is different from that for drugs and medical devices, DeLauro and others propose to transfer

FDA's responsibility for food regulation to a new federal agency. Such an entity would assume responsibility for multiple programs (e.g., meat and dairy inspections, import controls, and pesticide regulation) now spread among a dozen government offices. The Department of Health and Human Services has opposed such a move, claiming that food safety is primarily a public-health issue. But much of the food consumed in the US is now produced in foreign regions, and this shift has created a difficult situation for an overloaded public health agency to monitor.

Moving food regulation out of FDA, though, would be highly disruptive, and agency officials are taking steps to demonstrate their ability to prevent and resolve food-contamination problems. A one-year progress report issued in December 2008 details the many initiatives underway for implementing the 2007 Food Protection Plan. FDA is improving analytical methods, conducting more field inspections, establishing new oversight methods, and adopting better approaches for responding to contamination outbreaks.

Agency leaders also propose a less radical change that involves splitting FDA into two directorates—one for food and one for medical products—each headed by an experienced administrator. Food companies, who feel they play second fiddle to drug manufacturers at FDA, support such a move. So do medical-product companies that fear the effects of more restrictive food-import policies.

The political reality is that a major change such as taking the food oversight responsibilities from FDA is not likely to happen anytime soon. The new Obama administration has more crucial tasks at hand in the economic and health arenas, and most members of Congress are unenthusiastic about altering committee oversight responsibilities.

Former FDA official Wayne Pines is skeptical that reorganization will improve agency operations, noting that such efforts usually end up "just moving boxes around and not increasing efficiency." But if Congress follows through on proposals to authorize FDA to regulate tobacco, the modification could provide an opportunity for additional changes in agency structure and operations.

Strong leadership

Improvements in FDA's operations, resources, and infrastructure will be shaped considerably by the next FDA commissioner. Lots of names have been circulating since the election, and the discussion is a sign of the agency's high visibility and importance to the new administration and to Congress. Industry wants to get a new commissioner on board as soon as possible to confront the many management challenges the agency faces, says Alan Goldhammer, vice-president for regulatory affairs of the Pharmaceutical Research and Manufacturers of America (PhRMA). The industry hopes that FDA's new leader will be named and confirmed by the Senate in a few months, instead of languishing at the bottom of the White House appointments list.

One priority for the new commissioner will be to justify continued growth in appropriated funds for the agency's 2010 budget. The Alliance for a Stronger FDA has called for a 20% increase in FDA appropriations to $2.25 billion for next year. That amount contains less than $400 million in new money, a drop in the bucket for most federal agencies.

FDA and industry also hope that Democratic control of the White House and Congress will result in fewer heated attacks on the agency from Capitol Hill. Lawmakers may be less inclined to use FDA as a punching bag, but the agency always will be controversial because of the nature of its operations and the scope of products it regulates, says Pines.

The bottom line for pharmaceutical manufacturers is whether FDA can approve new drugs for market and oversee product development, manufacturing, and marketing in a fair and efficient manner. All the attention on drug safety has raised concerns about a more risk-averse atmosphere at the agency and slowdown in product authorizations. Manufacturers say they're willing to see whether things improve in the coming months before getting too upset about CDER missing user-fee deadlines. "The agency was given a significant number of new authorities and tasks to accomplish and has been hiring and training a lot of new employees," explains Goldhammer. "So it really is this upcoming year that will be critical in looking at performance and benchmarking against [Prescription Drug User Fee Act] goals."

A bright light on the horizon is an increase in the number of innovative new drugs approved by FDA in 2008. The agency experienced a new low in approvals of new molecular entities (NMEs) in 2007, and it looked like 2008 would be just as bad or worse. FDA reviewers were missing review deadlines, demanding additional data, and imposing stiff postmarket monitoring requirements on products that made it through the process. But in November 2008, FDA surpassed the 2007 total of 18 NME approvals and appeared on track to act on several more before year's end. Although it's always easier to show gains from a low starting point, industry and FDA are happy to consider this increase as a sign of hope for the new year.

Fixing the field

Another priority for a new commissioner is to revive FDA's depleted field-inspection force so that it can deal with the rise in food and drug imports and prevent unsafe products from reaching the public. The Office of Regulatory Affairs (ORA), which inspects food and drug manufacturing facilities, is in disarray after years of neglect and underfunding. Most of its top officials have retired or moved to other jobs, leaving the organization without the leadership necessary for making significant operational changes. ORA tried to close outdated field laboratories a few years ago, but met stiff opposition from laboratory employees and their political allies. A slight rise in appropriated funds has provided FDA with resources to hire more field inspectors, but a broader ORA overhaul is on the table.

In May 2008, the FDA Science Board issued an assessment of ORA that described problems generated by globalization, technical advances, and inadequate IT. District laboratories require new equipment for efficient product analysis, and scientists need infrastructure to conduct risk assessments and analysis. The explosion in global manufacturing and the heightened complexity of supply chains, moreover, have increased the potential for counterfeiting and terrorism. The number of drug products manufactured outside the US has doubled since 2001, but FDA's foreign inspections have declined by 37%. Most active pharmaceutical ingredients are imported from abroad, and a growing proportion of clinical trials are conducted in other countries. The heparin incident "brought home the need for vigilance throughout the supply chain" and highlighted the importance of manufacturing controls.

FDA's field force operates on a 70-year-old model that relies on a cadre of generalists to inspect a vast range of operations, from vegetable growers to stent makers and antibiotic producers. With the emergence of complex production methods for biologics, FDA established the small, elite Team Biologics, which has the appropriate expertise to inspect manufacturing sites for those medicines. CDER has sought to replicate that model by developing a highly trained Pharmaceutical Inspectorate to evaluate small-molecule drug manufacturers. That initiative has been slow to develop, though, and its members still have to inspect other products to meet agency needs.

The surge in food and drug contamination incidents in the past two years has generated support for FDA's Beyond our Borders initiative; it is establishing FDA branches overseas to better monitor the growing number of foreign manufacturers of products destined for the US. The agency opened offices in China in November 2008 and plans additional outposts in India, Europe, Latin America, and the Middle East to better track political and economic developments and be on the spot if problems arise (see Cover Story).

But even with more resources and foreign offices, FDA will never be able to inspect every manufacturer on a timely basis. The Science Board suggested that other approaches could support field operations, including certification programs for foreign manufacturers, increased reliance on inspections by foreign regulatory authorities, improved risk management of inspection programs, and more efficient technology-assay procedures validated by FDA. Any improvement in field operations, moreover, will require significant investment in new interoperable information systems for ORA.

Upgrading IT

For an agency that deals with cutting-edge biomedical science, FDA's lack of basic electronic information storage and communication systems is remarkable. FDA's IT infrastructure is "obsolete, unstable, and lacks sufficient controls to ensure continuity of operations," according to the Science Board. Most agency records are on paper and stored in vast document rooms that are difficult to access. Research laboratories lack the computing infrastructure necessary to conduct appropriate analyses and studies. Many of the agency's network servers have exceeded their recommended service life, and the system lacks security and normal backup capability.

A reliable, modern IT system could bring considerable efficiencies to all FDA operations. Information from large health-system databases could uncover signals of adverse events more quickly and effectively than is now possible. And access to clinical-trial data about marketed products could assist reviewers and monitors in evaluating new safety and efficacy problems.

The latest prescription-drug user-fee program, PDUFA IV, has mapped out a plan for establishing an all-electronic submission platform for drugs and biologics based on format and data standards. An e-submission gateway is receiving thousands of postmarket adverse-event reports, and some components of the common technical document application can be filed electronically. Goals for the next five years are to establish an agency-wide eDocument room that will permit information sharing and streamline review operations. An electronic system for registering and listing all regulated products and manufacturing facilities is in the works. The need for such a basic information system was all too apparent last year when FDA failed to correctly identify for inspection the Chinese heparin producer that turned out to be a source of contaminated product.

FDA also is updating its Adverse-Event Reporting System and encouraging medical professionals to report more adverse events electronically. The agency aims to move into the modern age of medical-product safety-information tracking by tapping into electronic health information systems to better detect signals of problems.

These initiatives will require FDA to award some $2.5 billion in contracts for IT and data-management services during the next 10 years. The agency has identified 10 contractors that will shift all systems applications to two new data centers. Ensuring that new information systems fit FDA's unique and complex operations and legal structure will require skilled oversight and informed interaction with the vendors, another challenge for a new commissioner and FDA's chief information office and staff.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com