The FDA seems to be under fire from all sides these days,with everyone from drug industry pooh bahs to would-be watchdogs nipping at itsheels. The agency, some charge, is going slow on approvals due to a risk-averseculture deepened through the experience of Vioxx and other product safetycrises. Resignations are up, morale is down and the put-upon bureaucrats arelaying low, the story goes. Others complain that reviewers are subject topolitical and corporate pressure through PDUFA and a nefarious web ofrelationships.

Actually, these criticisms are mild compared with theconclusions of the agency’s own Science Board, which has written that “FDA’sinability to keep up with scientific advances means that American lives are atrisk.” In a series of interviews conducted just before the Science Board reportwas issued, MM&M sought to sort out fact from opinion, and to gain aninsight into the thinking of FDA reviewers.

First a fact everyone agrees on: NDA approvals are down. Adecade ago, 39 new chemical entities made it to market. In 2005 the number wasdown to 18, then 17 in 2006, and another 17 in the first 10 months of 2007. Butas Kenneth Kaitin, director of Tufts Center for Study of Drug Development,points out, approvals have not decreased as a percentage of submissions. “Theissue for the industry is that the whole process has become more complex andcumbersome,” he says, causing a slowdown of pipeline products ready forsubmission. While regulatory issues and the increased requirements to demonstratesafety are part of the problem, so is the difficulty in recruiting for clinicalstudies, as is the shift in the types of drugs being studied from “GPindications” like upper respiratory infections to cancer, Parkinson’s diseaseand other chronic disorders.

So, is FDA really to blame for holding up NDAs?           

Wyeth CEO Bob Essner thinks so. He told the Financial Timesthat following the Vioxx debacle FDA had become overcautious, in effectcreating monopolies by blocking new drugs and demanding that they demonstratesuperiority over those already on the market. “Although that may not be aformal standard,” he acknowledged, “it does appear to be a growing practice.”

Former FDA official Wayne Pines, now president of healthcareand regulatory services at APCO Worldwide, agrees that “reviewers are lookingfor more data comparing new drugs with existing therapies rather than only toplacebo.” But Pines offers a different rationale: “So that the role of the newentity can be properly understood.”

Scott Gottlieb, fellow, American Enterprise Institute andformer FDA deputy commissioner, takes a similar slant. Comparisons withmarketed products, he says, have always been the case. “The law might say thatFDA can only determine whether a product is safe and effective, but making thatdecision involves taking into consideration what’s already on the market.” Hedoes concede that now “the discussion may be a bit more prominent.” He hearsanecdotally from companies that they are being asked to develop more data insupport of their applications, and that reviews that might have been approvedjust a couple of years ago are now being delayed. While the drug review programis difficult to quantify, he “suspects that there are specific pockets of theagency where there is a greater degree of caution,” citing as an example theanti-infective group, which is certainly “not accepting certain kinds of datathey would have accepted maybe a year or two ago.”

There is also another wrinkle in the debate, what you mightcall “preemptive suicide”—the number of products under development likePfizer’s torcetrapib and Bayer’s asoprisnil that get aborted before anapplication is ever filed. In less-stringent days they might well have taken achance on getting marketing OKs, John Kamp says, but now it seems wise to cuttheir costs. Companies know that FDA reviewers are getting tougher, he says,and so they “scuttle their products rather than have the agency turn themdown.”

Is Vioxx to blame?

Essner is not alone in tracing FDA’s more cautious attitudeto post-Vioxx trauma, though he seems to be the only industry CEO to speak soopenly. Maybe that’s what impending retirement will do for you. According tothe Government Accountability Project, Vioxx caused between 88,000 and 139,000heart attacks, of which about one-third proved fatal. Whistleblower DavidGraham, who went public with the data, claims that his superiors tried to keephim from publishing them and even contacted scientific journals in an attemptto discredit him. He’s found a ready audience in Congress. That’s enough totraumatize any government agency, and Kaitin describes FDA reviewers as beingunder constant attack, Vioxx having been the catalyst. Citing the Avandiacontroversy (see sidebar, page 47), he says “it’s become a gotcha thing.”People like Dr. Steven Nissen, he says, “have established a tremendousreputation as the watchdogs of the medical profession,” and unlike perennialcritics like Sidney Wolfe, Nissen doesn’t have an axe to grind. “After all,he’s collected a lot of money from industry…so he comes across as verycredible.”

Wayne Pines agrees that FDA reviewers are risk averse,though he adds, “that’s not a criticism. There’s something to be said forcautious introductions of new drugs into the market, but it does slow down drugdevelopment and makes drug development more expensive.” And yes, Gottliebbelieves, the political environment has changed, making it fashionable toattack the agency. That leads reviewers to go slow or even to say no.

…or is it PDUFA?

Then there are those who believe that the pressure onreviewers runs the other way—to give approvals in order to please sponsors, andthey blame PDUFA (the user fee legislation) and its deadline system.

Several critics cited Dan Carpenter’s analysis of the correlationbetween approval dates and subsequent problems, which shows, he says, that“some of the drugs that are approved right before the deadlines are somewhatmore likely to encounter post-marketing safety problems.” (MM&M, February2007)

Kaitin calls the argument that user fees have influenceddrug approvals “patently ridiculous.” He points out that in the UK user feesfund not just about half of the review process, as they do in the US, but afull 100%, and “the UK isn’t loaded with unsafe drugs.” In any case, he says,individual reviewers don’t think, “I’m being paid to work on this applicationso I’d better approve it.” Yes, he concedes, reviewers “are now brought in withthe notion that their goal is to help drugs reach the marketplace,” but that’s notbecause money from industry is coming into the agency. “In an ideal world FDAwould be totally funded by congressional appropriations,” he believes, so whathe finds intolerable is when people make speeches in Congress about feescorrupting the process, “yet not one of them would vote for increasedappropriations.”

Well, if reviewers don’t feel under obligation to industry,what about their bosses? David Ross, assistant clinical professor, GeorgeWashington University School of Medicine and former deputy director, FDA Officeof Drug Development, says bluntly: “von Eschenbach seems to view FDA as a drugdevelopment agency,” quoting him as saying that “we want to find opportunitiesfor companies to market their drugs.”

Like someothers, Ross sees the AIDS crisis of the ’70s and ’80s as a pivotal turningpoint in the agency’s culture. What caused a political storm was that therewere promising drugs under review but not ready for approval. “The agency hadto change its way of doing things, and that was good,” Ross believes, “but thatmodel has been exported to other areas where it doesn’t necessarily work aswell.” When he worked at FDA “people would say things like, ‘If we approve this[application] early, it will save the company a million dollars a day.’ A lotof the political pressure came by way of telling us not to be such sticklersand just approve these things.” The management of the Center for DrugEvaluation and Research, he says, “had as its goal to get it done on time,” tothe exclusion of other essential criteria.

Let’s give the last word about user fees to one of theagency’s top executives, Dr. Janet Woodcock, deputy commissioner and chiefmedical officer. PDUFA, she wrote in a report on processing risk information,created “a sweatshop environment,” basing her conclusion on a CDER survey todetermine the reason for high rates of turnover. About one-third of respondentssaid they did not feel comfortable expressing differing scientific opinions,and more than a third felt that their work had more impact on productmarketability than on health. Many added that decisions should be based more onscience.

Spotlight on reviewers

Given such a climate, it’s no wonder that we found aconsensus that staff morale is poor. Disagreement arises only when you ask why,as shown by some representative comments:

Kenneth Kaitin: “Morale is very difficult now, and a lot ofthat has to do with the fact that this administration has allowed the agency tooperate without a confirmed commissioner for a lot of the years that it’s beenin office.…Meanwhile the agency has been the target of a barrage of attacksfrom Congress, the public and the media, with nobody able to stand up and say,‘Here is the mission of the FDA, and here is how we work to achieve it.’”

Peter Pitts, president, Center for Medicine in the PublicInterest and former FDA associate commissioner: “Public pressure is terriblybad for morale, and shows tremendous disrespect for people who work very, veryhard.”

David Ross: When he became convinced that “one investigatorfaked [Ketek] data.…I e-mailed the office director about this and said: ‘We’resupposed to present this data to an advisory committee in six days and I wantto talk about it,’ and he said in writing: ‘It wouldn’t be productive to talkabout it in front of the committee.’…I [then] went to Sandra Kweder [deputydirector of the Office of New Drugs] and told her we had a huge problem. Pleasedo something about this or we’re going to get crucified. They did nothing….Ifyou’re one of the reviewers you think, what’s going on here?” Furtherdisillusioning him was Kweder’s comment at a staff meeting that “nobody has theright to second-guess us,” not even Congress.

Scott Gottlieb: “People had to spend half their time to [totestify]…and that made it harder to do their day jobs and more wary to takerisks. That lowered morale and made people more cautious.”            

James G. Dickinson, editor, “User fees have beena disaster for the agency’s morale and outlook, shifting its bias from consumerprotector to industry handmaiden. There is a lot of denial about this, but thevery fact that there is denial confirms the risk to the agency’s core mission.”

Wayne Pines: “Morale is down at FDA due to budgetconstraints—too much work and not enough public and congressional gratitude.”

Congress and the whistleblowers

Ross is no anti-industry crusader. An anecdote reflects hisambivalence. When Graham went public to criticize the agency, “I was justfurious,” Ross recalls. But when he said so to his wife, she reminded him, “ButDavid, you’ve been saying the same things for years.” Unlike Graham, however,Ross tried to work through the system and did not speak publicly until calledto testify by a congressional committee, as he was legally required to do.Eventually he felt forced to resign when he felt threatened by von Eschenbachfor pursuing a case of fraudulent data that his politically appointed superiorsdidn’t want to hear about. One investigator actually went to jail, Rossrecalls, but FDA’s internal investigation of the company was quashed at ahigher level.

Pitts also takes a dim view of people who go outside theagency to complain. A professional, he maintains, should not “weep and whineand try to get decisions made that are based on politics rather than onscience.” Whistleblowers, he acknowledges, at least deserve “grudging respect”for letting it be known who they are, “but what is truly damaging are thesilent leakers” who try to force political pressure on FDA decisions. “Themotive may be either to get drugs approved or not approved—it cuts both ways.”            

Prescribing for FDA’s future

Kamp, Kaitin and Gottlieb agree that the latest PDUFAreauthorization is a step in the right direction. According to Gottlieb, “Itprovides a good opportunity to improve the drug program, and provides a lot oftargeted resources that the agency has needed for many years.” The legislationgives FDA more power to assure drug safety by requiring post-marketing studiesand follow-up studies agreed on at the time of approval. Kamp looks forward tothe day “drugs are better targeted to the patient population,” and says thestatute will help move us toward that goal.

Gottlieb sees an underlying problem with the changingattitude toward drug safety. “We used to look mostly at whether or not therewas acute toxicity that occurred close to the administration of the drug. Nowwe’re investing an awful lot of energy trying to determine whether or not drugshave latent risks.” He doesn’t see how traditional clinical studies can predictthat, while Dickinson observes that FDA, having learned the Vioxx lesson, istapping into databases to spot adverse events early on. He is less optimisticabout FDA’s systemic problems. “The archaic ‘stovepipe’ organizationalinfrastructure of the agency is in conflict with the computer age and thecommunications challenge of e-mail and the Internet,” he says. Also, the recenthigh turnover rates have all but destroyed both the agency’s institutionalmemory and its competence.

Dickinson believes the whole structure needs to be replacedby a more collegial and open infrastructure. Unfortunately he doesn’t see itcoming from the current leadership. “Von Eschenbach means well,” he says, “butthe position has become so political that I doubt any commissioner is capableof affecting the necessary seismic change.”

Ross suggests reviewers should be provided with proceduresto assure good decision-making. “If FDA said you must consider all thefollowing things before giving approval, I think we would be less likely to getundesirable outcomes.” More fundamentally, he believes that “the most importantthing for the agency is twofold: transparency and commitment to science.”