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 its heels. The agency, some charge, is going slow on approvals due to a risk-averse culture deepened through the experience of Vioxx and other product safety crises. Resignations are up, morale is down and the put-upon bureaucrats are laying low, the story goes. Others complain that reviewers are subject to political and corporate pressure through PDUFA and a nefarious web of relationships.

Actually, these criticisms are mild compared with the conclusions of the agency's own Science Board, which has written that “FDA's inability to keep up with scientific advances means that American lives are at risk.” In a series of interviews conducted just before the Science Board report was issued, MM&M sought to sort out fact from opinion, and to gain an insight into the thinking of FDA reviewers.

First a fact everyone agrees on: NDA approvals are down. A decade ago, 39 new chemical entities made it to market. In 2005 the number was down to 18, then 17 in 2006, and another 17 in the first 10 months of 2007. But as Kenneth Kaitin, director of Tufts Center for Study of Drug Development, points out, approvals have not decreased as a percentage of submissions. “The issue for the industry is that the whole process has become more complex and cumbersome,” he says, causing a slowdown of pipeline products ready for submission. While regulatory issues and the increased requirements to demonstrate safety are part of the problem, so is the difficulty in recruiting for clinical studies, as is the shift in the types of drugs being studied from “GP indications” like upper respiratory infections to cancer, Parkinson's disease and other chronic disorders.

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

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

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

Scott Gottlieb, fellow, American Enterprise Institute and former FDA deputy commissioner, takes a similar slant. Comparisons with marketed products, he says, have always been the case. “The law might say that FDA can only determine whether a product is safe and effective, but making that decision involves taking into consideration what's already on the market.” He does concede that now “the discussion may be a bit more prominent.” He hears anecdotally from companies that they are being asked to develop more data in support of their applications, and that reviews that might have been approved just a couple of years ago are now being delayed. While the drug review program is difficult to quantify, he “suspects that there are specific pockets of the agency where there is a greater degree of caution,” citing as an example the anti-infective group, which is certainly “not accepting certain kinds of data they would have accepted maybe a year or two ago.”

There is also another wrinkle in the debate, what you might call “preemptive suicide”—the number of products under development like Pfizer's torcetrapib and Bayer's asoprisnil that get aborted before an application is ever filed. In less-stringent days they might well have taken a chance on getting marketing OKs, John Kamp says, but now it seems wise to cut their costs. Companies know that FDA reviewers are getting tougher, he says, and so they “scuttle their products rather than have the agency turn them down.”

Is Vioxx to blame?

Essner is not alone in tracing FDA's more cautious attitude to post-Vioxx trauma, though he seems to be the only industry CEO to speak so openly. Maybe that's what impending retirement will do for you. According to the Government Accountability Project, Vioxx caused between 88,000 and 139,000 heart attacks, of which about one-third proved fatal. Whistleblower David Graham, who went public with the data, claims that his superiors tried to keep him from publishing them and even contacted scientific journals in an attempt to discredit him. He's found a ready audience in Congress. That's enough to traumatize any government agency, and Kaitin describes FDA reviewers as being under constant attack, Vioxx having been the catalyst. Citing the Avandia controversy (see sidebar, page 47), he says “it's become a gotcha thing.” People like Dr. Steven Nissen, he says, “have established a tremendous reputation as the watchdogs of the medical profession,” and unlike perennial critics 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 very credible.”

Wayne Pines agrees that FDA reviewers are risk averse, though he adds, “that's not a criticism. There's something to be said for cautious introductions of new drugs into the market, but it does slow down drug development and makes drug development more expensive.” And yes, Gottlieb believes, the political environment has changed, making it fashionable to attack 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 on reviewers runs the other way—to give approvals in order to please sponsors, and they blame PDUFA (the user fee legislation) and its deadline system.

Several critics cited Dan Carpenter's analysis of the correlation between approval dates and subsequent problems, which shows, he says, that “some of the drugs that are approved right before the deadlines are somewhat more likely to encounter post-marketing safety problems.” (MM&M, February 2007)

Kaitin calls the argument that user fees have influenced drug approvals “patently ridiculous.” He points out that in the UK user fees fund not just about half of the review process, as they do in the US, but a full 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 application so I'd better approve it.” Yes, he concedes, reviewers “are now brought in with the notion that their goal is to help drugs reach the marketplace,” but that's not because money from industry is coming into the agency. “In an ideal world FDA would be totally funded by congressional appropriations,” he believes, so what he finds intolerable is when people make speeches in Congress about fees corrupting the process, “yet not one of them would vote for increased appropriations.”

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

Like some others, Ross sees the AIDS crisis of the '70s and '80s as a pivotal turning point in the agency's culture. What caused a political storm was that there were promising drugs under review but not ready for approval. “The agency had to change its way of doing things, and that was good,” Ross believes, “but that model has been exported to other areas where it doesn't necessarily work as well.” 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 lot of the political pressure came by way of telling us not to be such sticklers and just approve these things.” The management of the Center for Drug Evaluation and Research, he says, “had as its goal to get it done on time,” to the exclusion of other essential criteria.

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

Spotlight on reviewers

Given such a climate, it's no wonder that we found a consensus 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 of that has to do with the fact that this administration has allowed the agency to operate without a confirmed commissioner for a lot of the years that it's been in office.…Meanwhile the agency has been the target of a barrage of attacks from 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 Public Interest and former FDA associate commissioner: “Public pressure is terribly bad for morale, and shows tremendous disrespect for people who work very, very hard.”

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

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

James G. Dickinson, editor, fdaweb.com: “User fees have been a disaster for the agency's morale and outlook, shifting its bias from consumer protector to industry handmaiden. There is a lot of denial about this, but the very fact that there is denial confirms the risk to the agency's core mission.”

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

Congress and the whistleblowers

Ross is no anti-industry crusader. An anecdote reflects his ambivalence. When Graham went public to criticize the agency, “I was just furious,” Ross recalls. But when he said so to his wife, she reminded him, “But David, 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 called to testify by a congressional committee, as he was legally required to do. Eventually he felt forced to resign when he felt threatened by von Eschenbach for pursuing a case of fraudulent data that his politically appointed superiors didn't want to hear about. One investigator actually went to jail, Ross recalls, but FDA's internal investigation of the company was quashed at a higher level.

Pitts also takes a dim view of people who go outside the agency to complain. A professional, he maintains, should not “weep and whine and try to get decisions made that are based on politics rather than on science.” Whistleblowers, he acknowledges, at least deserve “grudging respect” for letting it be known who they are, “but what is truly damaging are the silent leakers” who try to force political pressure on FDA decisions. “The motive 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 PDUFA reauthorization is a step in the right direction. According to Gottlieb, “It provides a good opportunity to improve the drug program, and provides a lot of targeted resources that the agency has needed for many years.” The legislation gives FDA more power to assure drug safety by requiring post-marketing studies and follow-up studies agreed on at the time of approval. Kamp looks forward to the day “drugs are better targeted to the patient population,” and says the statute will help move us toward that goal.

Gottlieb sees an underlying problem with the changing attitude toward drug safety. “We used to look mostly at whether or not there was acute toxicity that occurred close to the administration of the drug. Now we're investing an awful lot of energy trying to determine whether or not drugs have latent risks.” He doesn't see how traditional clinical studies can predict that, while Dickinson observes that FDA, having learned the Vioxx lesson, is tapping into databases to spot adverse events early on. He is less optimistic about FDA's systemic problems. “The archaic ‘stovepipe' organizational infrastructure of the agency is in conflict with the computer age and the communications challenge of e-mail and the Internet,” he says. Also, the recent high turnover rates have all but destroyed both the agency's institutional memory and its competence.

Dickinson believes the whole structure needs to be replaced by a more collegial and open infrastructure. Unfortunately he doesn't see it coming from the current leadership. “Von Eschenbach means well,” he says, “but the position has become so political that I doubt any commissioner is capable of affecting the necessary seismic change.”

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