Atelling scene unfolded in the lobby ofa suburban Maryland hotel on 18February. On the third and final day

of a gruelling public conference, expertadvisers to the US Food and Drug Adminis-tration (FDA) held in their hands the fatesof three blockbuster painkillers, known asCOX-2 inhibitors. To make their assess-ment, the experts had to balance the drugs’value in treating arthritis against mountingevidence that they cause heart attacks andstrokes. Billions of dollars in revenues fordrug companies — and the welfare of mil-lions of patients — hung in the balance.

But when a mid-morning break was calledand the 32 advisers wandered out for coffee,they were largely ignored by the throng ofreporters at the event. Instead, the journalistsclustered around a boyish-looking FDA sci-entist who was holding forth for a television

camera. They plied him with questions abouthis views on the issues before the panel, dili-gently jotting down his every response.

In the middle of the media scrum wasDavid Graham, a career physician at theFDA. Graham came to public prominencelast November at a US Senate hearing, whenhe pronounced his employer “incapable” ofensuring the safety of drugs after they wereapproved for sale in the United States.

His scathing testimony set alarm bellsringing on Capitol Hill and raised some fundamental questions about the FDA: is theagency scientifically,structurally or politicallycapable of ensuring the safety of some 10,000pharmaceuticals now used by Americans? Orhas the complexity, size and pace of the busi-ness, and the power of the drug manufactur-ers,exceeded the regulator’s ability to cope?

Graham had told senators on 18 Novem-

ber that just one of the COX-2 inhibitors —Vioxx — had caused at least 26,000 deathsfrom heart attacks in the five years beforeMerck withdrew it from the market last Sep-tember.An epidemiologist in the FDA’s Officeof Drug Safety, Graham had conducted astudy using the massive database of KaiserPermanente, a health-maintenance organiza-tion based in California. Last August, armedwith its results,he warned his bosses that highdoses of Vioxx significantly increased the riskof heart attack and sudden death. The agencydid not act — and even approved the drug’suse in children with rheumatoid arthritis inthe weeks before Merck withdrew it.

The FDA’s Office of New Drugs — whereany new medicine must pass muster before itcan be sold — approved Vioxx in 1999. It washeavily promoted by Merck as an alternativeto standard arthritis medications because itdidn’t cause stomach bleeding, and it soonbecame a huge success, with worldwide salesof $2.5 billion in 2003 alone. Then, last Sep-tember, a Merck-sponsored trial examiningwhether the pill might prevent precancerouscolon tumours found that Vioxx doubled therisk of heart attacks and strokes in patientsusing it for more than 18 months.

Critics — including plaintiffs in the raft oflawsuits against Merck that swiftly followedthe drug’s withdrawal — complained that asearly as 1999, studies had flagged Vioxx’spotential for causing heart attacks andstrokes. They implied that the FDA should

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The past year has seen a beleaguered Food and Drug Administration publicly denounced asunable to protect the US public. As the politicalpressure mounts, Meredith Wadman joins thethe agency’s hunt for a remedy to its ills.

The safety catch

Eye of the storm: FDA scientistDavid Graham (left) testifies at a

Senate hearing on the safety ofthe painkiller Vioxx.

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have identified the problem and pulled themedicine from the market.

In his Senate testimony,Graham endorsedthat point of view. He added that Vioxx wasprobably far from a one-off event. It wasbound to repeat itself, he said, because theFDA’s organizational structure and corporateculture were biased towards approval of newdrugs.Safety monitoring of drugs already outthere,he said,took second place.

Graham further complained that thereviewers at the Office of New Drugs whoapprove therapeutics in the first place have avested interest in the drugs’ success, and areliable to ignore or overrule post-marketsafety concerns raised by staff scientists inthe smaller Office of Drug Safety. Asked toidentify other established drugs about whichhe had serious safety reservations, Grahamnamed five, including Pfizer’s Bextra,another COX-2 inhibitor. “The FDA as cur-rently configured,” he concluded, “is inca-pable of protecting America against anotherVioxx.We are virtually defenceless.”

Rapid responseThe initial congressional response was swiftand emphatic. Senator Chuck Grassley(Republican, Iowa), chairman of the SenateCommittee on Finance where Graham testi-fied, chided the FDA for ignoring dangersignals and failing to heed the warnings ofits own scientists. Senator Michael Enzi(Republican, Wyoming), who chairs anotherSenate committee with direct jurisdictionover the FDA, scolded its officials at a hear-ing earlier this month saying that “doingnothing to address the current controversiesis not an option”. Grassley is shortlyexpected to introduce legislation, togetherwith Senator Christopher Dodd (Democrat,Connecticut), that would boost the powerand autonomy of the Office of Drug Safety.

Yet top FDA officials say that the agency’sperformance remains strong. “The safety ofthe drug supply right now is better than it hasever been,” says Janet Woodcock, the FDA’sacting deputy commissioner foroperations, who from 1994 to2004 ran the agency’s Center forDrug Evaluation and Research(CDER), which houses both theOffice of New Drugs and theOffice of Drug Safety.

Woodcock argues that someagency critics fail to understandthat risk and benefit are inextricably linkedfor any drug — and that calls to assess onewithout the other betray this basic misun-derstanding. The point, she says, isn’t thatsome drugs with risky side effects shouldn’tbe approved, but that their risks and benefitsneed to be carefully weighed both by the reg-ulatory authorities who first approve themand by the physicians and patients who ulti-mately use them.

And despite the wave of bad publicity that

shrouded the FDA last winter,its public imageremains fairly healthy. For decades, polls havesuggested that its public approval hovers at theheady level — for a government agency — ofabout 75%. And a February survey of 1,200people by the Kaiser Family Foundationfound that 77% thought the agency was doinga reasonable job of ensuring drug safety.

Nonetheless, by almost any measure, thepast year has been a rocky one for the FDA.InMarch 2004, Mark McClellan decampedafter just 17 months from a commissioner’sposition that had sat vacant for nearly twoyears prior to his arrival. Soon after that, theagency came under fire for suppressing the

report of a staff scientist whocautioned that popular ‘SSRI’antidepressants could causesuicidal tendencies in youngpeople. And in early October,just a few days after Merck with-drew Vioxx, the FDA’s compe-tence in ensuring the safety ofvaccines destined for the US

market was called into question when Britishauthorities abruptly closed a flu vaccineplant in Liverpool owned by US companyChiron.This halved the United States’supplyof vaccine for the coming winter and pro-voked a public uproar.

David Kessler, who ran the agency from1990 to 1997 and is now dean of the medicalschool at the University of California, SanFrancisco, thinks that the cumulative impactof events has been considerable.“It certainly

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began to shake confidence, not only in thepublic but within the medical community,”Kessler says.“For the first time, I have physi-cian colleagues asking me if they can believewhat the FDA is saying.”

Full stretchSome of the 1,600 scientists and physicianswho work at the CDER privately admit thatthey are stretched to fulfil the agency’s mis-sion. With an average annual salary of$128,000, many are forsaking more lucra-tive careers in the private sector — oftenbecause they find FDA work satisfying andvaluable.

“I tell my kids I have one of the most inter-esting jobs in the world,” says RachelBehrman, a physician who began working asa drug reviewer in 1989 and is now deputydirector of the CDER’s Office of Medical Pol-icy.“And I go to bed every night thinking I’vedone something important.”

But the current crises, combined with thefact that 30% of the FDA’s work force is eligi-ble for retirement over the next five years,hasagency-watchers worried that retention ofhigh-quality staff is going to become a toughchallenge.“If we continue to pound and beatup on the agency, we are going to lose verygood people,”says Kessler.

Worries about the pressure on FDA staffsurfaced in 2002, when the GovernmentAccountability Office assessed the impact ofa 1992 law that introduced industry fees topay for speedier drug reviews. It found that

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“The FDA as currentlyconfigured is incapableof protecting Americaagainst another Vioxx.We are virtuallydefenceless.”

— David Graham

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the law had boosted reviewer workloads, cuttheir training and resulted in annual attri-tion rates among FDA scientists of about10% — roughly twice the level found at theNational Institutes of Health or the Centersfor Disease Control and Prevention.

And a survey of 400 FDA scientists con-ducted for another 2002 government study— but not published until December 2004,when it was accessed by the Union of Con-cerned Scientists under the Freedom ofInformation Act — found a group of peopleseriously concerned about the agency’s abil-ity to protect the public from dangerous sideeffects in approved drugs. In that survey,19% said that they were “not confident at all”in the FDA’s ability to monitor the safety ofdrugs once they are on the market; only 6%were “completely confident” in that ability.And 18% said that they had been pressuredto approve new drugs despite reservationsabout their safety,efficacy or quality.

Testing timesThe COX-2 controversy has left someobservers asking whether the CDER, withan annual budget of about $500 million,has the resources to police a prescriptiondrugs market that is now worth more than$160 billion annually in the United States.Some also argue that the FDA lacks the legal authority it needs to monitor estab-lished drugs.

Before a drug is approved, the onus restson the manufacturer to demonstrate its safetyand efficacy. Once the FDA approves a medi-cine for marketing, that balance shifts. Theagency can ask — but not require — compa-nies to pay for and conduct post-market safetystudies; and it cannot limit the use of a drug toparticular medical subspecialities, as it canwith medical devices.Nor does it have explicit

authority to beef up warnings on drug labels.Instead, it negotiates label changes in often-protracted discussions with manufacturers.In the case of Vioxx, a change to the label toinclude a “precaution” about the risk of heartattack at high doses took 18 months for theagency to negotiate with Merck.

That kind of outcome begs for additionallegal muscle for the FDA, says WilliamSchultz, a Washington lawyer who was theagency’s deputy commissioner for policy inthe mid-1990s. “It’s the post-market piecethat really needs the attention,” he says.“Patients have got to realize how little weknow when a drug goes on the market.”

There are other thorny problems in ensur-ing post-market safety. The FDA, for exam-ple, doesn’t set out systematically to monitordangerous side effects. Instead,it relies on a reactive, ‘passive’reporting system in which doc-tors report possible cases of sideeffects only when it occurs tothem that a particular ailmentmay be the reaction to a drug.The system, by its nature, willseldom detect dangerous sideeffects that are already common in the popu-lation, such as the heart attacks and strokesprompted by the COX-2 inhibitors (see page557). It is thought that the 400,000-oddreports that the FDA gets in this way each yearrepresent only a small fraction of actualadverse events.

Then there is the fact that the 1992 lawthat instituted industry-paid fees did so onthe condition that the FDA met tight drug-review timelines and otherwise boosted performance standards. To achieve this —and so keep hundreds of millions of dollarsin industry fees flowing into the agency —the drug centre was forced to raid other

budgets. The upshot: in President Bush’sproposed 2006 budget, new-drug reviewconsumes roughly 80% of the CDER’s bud-get; only about 6% of it is designated forpost-market surveillance.

The 1992 law “sapped resources fromother very needed areas, away from drugsafety, away from compliance”, says Kessler.Post-market monitoring “absolutely needsmore resources.You can’t just have resourcesgo into new drug review”,he adds.

Independent thoughtIn at least some quarters on Capitol Hill,that message is being heard. The bill beingdrawn up by Grassley and Dodd would cre-ate a fully funded Center for Drug Safetyindependent of the CDER with authority todemand label changes from drugmakers. “Itdoesn’t make sense to have the office thatreviews the safety of drugs under the thumbof the office that puts the drugs on the mar-ket in the first place,” Grassley told the Con-sumer Federation of America last month.

Acting FDA commissioner Lester Craw-ford, who has been nominated by PresidentBush for the permanent post, told senators athis nomination hearing on 17 March that heis “open to discussing”an independent officeof drug safety. Crawford has also announcedthat a new board for overseeing drug safety— an advisory board of mainly FDAemployees — will publicize worrisome side effects more quickly than has happenedin the past. Critics immediately assailed theboard as toothless, because it will lack thepower to require label changes or to pulldrugs from the market. But Crawford saysthat it will herald a new era of public open-ness at the agency.

Still, some agency-watchers fear that therelatively low profile of Crawford’s nomina-tion and confirmation process, together with

the reluctance of the conservativeCongress to antagonize its allies inindustry, suggest that even the tensof thousands of deaths attributed toVioxx may be insufficient to initiateany real strengthening of the FDA.

The agency’s history demon-strates that “major changes comeafter disasters”, says Schultz. And

the Vioxx case may not rise to that thresholdin the public mind. At the end of the three-day advisory panel meeting back in February,the experts voted narrowly to allow Vioxxback onto the market, subject to careful constraints. They also voted to give patientscontinued access to Pfizer’s two COX-2inhibitors,Celebrex and Bextra.

Graham, for one, was not impressed.“Despite the biggest drug-safety catastrophein the history of the United States,” he notedwith his trademark earnestness, “people areheavily invested in the status quo.” ■

Meredith Wadman is a freelance writer based

in Washington DC.

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Balancing act: Janet Woodcock argues that the key to drug regulation is weighing up risks and benefits.

“For the first time,I have physiciancolleagues askingme if they canbelieve what theFDA is saying.”

— David Kessler

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