On June 30, 1906, President Theodore Roosevelt signed into law the Federal Food & Drug Act that established the Division of Chemistry in the US Department of Agriculture. In 1927 the division's name was changed to the Food, Drug & Insecticide Administration, which in turn became the Food & Drug Administration in 1930.
Though having shed insecticides, the FDA at 100 still regulates fully one-fourth of the US economy, and everyone working in the healthcare field daily feels its impact on his or her work.
To assess the FDA's current status and reputation, we turned to some of those in the best position to make an objective judgment: FDA alumni who only recently held high positions in the agency but who, having left, can speak openly and frankly. (See the panel at the bottom of the page.) The first question each one was asked was designed to establish how we got to where we are today: What would you say are the five most important milestones in FDA history?
The formative landmarks
The first post-1906 milestone, everyone agreed, was the Food, Drug, and Cosmetic Act of 1938, which, following the elixir of sulfanilamide disaster that killed 107 patients, required proof of safety before new drugs could be marketed. Next, the barely avoided thalidomide tragedy triggered the Kefauver-Harris amendments of 1962, requiring evidence not only of safety but also of efficacy. The legislation also gave the FDA new powers over labeling and advertising.
In 1992 the Prescription Drug User Fee Act (PDUFA) instituted payment of fees for new product applications, ensuring their prompt review. Marc Scheineson, who was responsible for negotiating this landmark legislation, recalls that he tried hard to include the generic manufacturers in this system, but “they kicked and screamed and fought to be exempted,” resistance that some have come to regret now that a flood of generic applications is delaying approvals. Dan Troy stresses that the premise of PDUFA makes it clear that not approving drugs can also harm patients by delaying helpful therapies.
Several nominated the Dietary Supplement Health and Education Act of 1994 as their fourth candidate, because, along with the Nutrition Labeling Education Act, it added consumer education to the FDA's portfolio. Scheineson comments ironically that the introduction of these nutrition labels have been so successful that “there are now no obese Americans.”
Wayne Pines includes in his list the 1958 and 1960 food and color additive amendments and, as a negative milestone, the refusal by Congress in 1977 to let the FDA ban saccharine after a public outcry, thereby teaching “FDA many lessons about public responsiveness.” A similar lesson might be considered the 2000 5-4 Supreme Court decision denying the agency the right to regulate tobacco as a drug, with Dan Troy, incidentally, representing Brown and Williamson on the winning side.
Troy cites the Hatch-Waxman act for speeding the rise of generics, while Susan Wood points out that a number of the turning points in the FDA's evolution came in response to the health needs of women and children. Cases in point: The victims of the sulfanilamide poisoning were primarily children, thalidomide hurt fetuses and the risks of DES and the Dalkon Shield led to the lifting in 1993 of the exclusion of women of childbearing age in clinical studies. The final example she cites is that patient package inserts were introduced as part of the approval of the first oral contraceptives.
The mission evolves
As this chronology makes clear, the agency's mission has evolved, starting with protecting the American public against adulterated and unsafe nostrums, then against unsafe and ineffective prescription products and in recent years shifting from just regulation to becoming more of an industry partner in drug development. This means, says Scheineson, that the FDA is now expected “not to be anti-business or adversarial all the time but to realize that in many cases, public health is protected by new drug reviews and approvals.”
So the next logical question we asked was whether the FDA remains true to its expanded mission.
Wayne Pines says yes. “Anyone who has worked there has a sense of that mission of consumer protection and public health enhancement,” he explains. “It is remarkable how uniform FDA staffers are in believing in the mission, and spending every day trying to fulfill it.” As a result, “FDA remains the worldwide gold standard for any regulatory endeavor.”
Dan Troy agrees that the agency has tried very hard to remain true to its mission, though “it's often hard in an environment that overreacts to risk.”
Peter Pitts, however, has another slant. While admitting that there are two types of “Kesslerites,” those who love and those who hate his activism as commissioner, he believes that Kessler went “beyond what the agency was legally permitted to do, and I think that set it back a bit,” leading Congress to put a lot of restrictions on the FDA. To rein in future commissioners, Congress also ruled that their appointments be subject to Senate confirmation, a provision that is expected to complicate the pending confirmation of Dr. Andrew von Eschenbach.
Filing contrary opinions are Areta Kupchyk and Susan Wood, who feel, in Kupchyk's words, that “FDA has compromised its mission by not using science in its decisions and letting politics creep in,” referring primarily to the refusal to let Plan B, the morning-after pill, be sold without prescription. Dr. Wood, of course, resigned in protest over this issue, and we will hear more about her complaint in reply to a subsequent question.
How safe is safe?
First, though, let's explore the hotly debated accusations that the FDA is not doing enough to keep dangerous drugs off the market.
We asked our panelists several safety-related questions: Is there a real problem or only exaggerated concern? How useful are post-marketing studies? Are the demands for tighter regulation meaningful as long as the FDA isn't given additional funds? And will placing clinical studies online empower either physicians or the public?
Peter Pitts is not alone in pointing out that the public has unrealistic expectations about drug safety. “People woke up after the Vioxx withdrawal and said, ‘Oh my God—who let that happen? That's not permissible.' It goes back to political figures who say no drug should be approved unless it's 100% safe. But that's a completely ridiculous thing to say.” Kupchyk points out that every time a new drug is approved, it's a gamble, though the odds could perhaps be improved if the FDA had more resources. She also believes that there are pressures that make it difficult for the agency to do post-launch monitoring.
Scheineson, too, is aware of the inherent uncertainties in ensuring drug safety. “You can't wait until a drug has been tested in a million people over five to 10 years or we'd never get new drugs on the market.” The way the system is supposed to work, he says, “is that you minimize risk, you disclose risk, but you can never eliminate it.” That means that drug approvals are based on manageable data. “Then, if there are still questions that can't be answered until the product is used in a wider patient population for a longer time, you monitor that through post-approval studies or through adverse events reporting.”
So should we be concerned, as the FDA recently reported, that two-thirds of the post-approval studies it required as a condition of NDA approval have never been started? “If those studies are agreed to, they should be conducted,” Scheineson says, but he points out that the FDA loses a lot of its leverage once a product is approved. “It's not that these drugs are not safe. [Post-approval studies] are more of a belt and suspenders approach, because you want some questions to be answered.” He is critical of people like David Graham, who used to be in the Bureau of Drug Safety, for stirring up the public by charging that senior officials override reviewers who express concerns about safety. “It's a totally unfair accusation,” says Scheineson, and has put the FDA on the defensive when it should be publicizing, as in the Kessler days, what it is doing to protect the public.
Wood concedes that the faster you bring products to market, the more likely it is that adverse events will occur once it is widely used, though “to some degree the issue is one of resources.” If more funding were dedicated to safety both pre- and post-marketing, there might be fewer problems, but she also points out that other countries have different strategies, such as periodic renewal of licensing, for post-marketing monitoring.
Pines, too, believes that we need a more systematic way of evaluating drugs once they're on the market, and that the FDA should be more aggressive in enforcing its requirements for post-marketing studies. “Failure of FDA to follow up … will truly undermine public confidence in the drug approval process and in drug safety generally,” he fears.
But as Troy sees it, failure to complete these studies does not necessarily point to negligence on the companies' part. “They may be trying to enroll patients, but that's very hard to do once the product is available.” Anyway, the FDA will always be criticized by one side for being too risk averse and on the other for not being risk averse enough, implying (though he didn't use those words) that that is part of the job description. As for increasing appropriations for better monitoring, sure he says, you can always spend more money, “but the agency does a very good job with the resources it's given.”
Pitts disagrees. “Absolutely, more money is required,” he says. “If people want better post-marketing surveillance, it's a real ‘show me the money' situation. Same thing if people want quicker approval of generics. You simply can't mandate certain things and not fund them.” Doing more with less sounds good, but it's just rhetoric. He also believes that commitments made should be commitments kept, suggesting that perhaps the FDA should be given the authority to take punitive action if they're not. Speaking of money, by the way, Scheineson points out that the Department of Agriculture, with one-third of the FDA's jurisdiction, has three times the budget.
Wayne Pines seems to sum up the general consensus about drug safety when he says: “I do not believe there is any underlying problem with drug safety. The recent publicized episodes are the exception rather than the norm. The challenge is to educate consumers and patients better about benefits and risks. This is an educational challenge that the drug industry should undertake.”
As to whether the safety controversies damaged the FDA's reputation, Pitts cites a December 2004 Associated Press poll that asked whether the respondents thought the FDA had the ability to ensure the safety of prescription drugs. Twenty-seven percent said they were very confident; an additional 50% were somewhat confident.
Finally, as for posting study data on the Internet, Troy thinks the jury is still out. He makes two additional points. For one thing, it's neither useful or helpful to require companies to turn over trade secrets. Furthermore, companies face a painful paradox. “If they talk about a clinical study that's outside the label, it's a criminal act and the state attorneys general and the media will come after them. On the other hand, if they don't post the data, they're accused of covering up. They're caught in a complete Catch-22 position.”
To Scheineson, the posting issue calls for better regulation. “What's occurring now is that there is just a flood of information, the chaff as well as the wheat. Data—regardless of validity or the strength of the research—is all being dumped on the Web site, so the project has lost focus.” Pitts observes that the system has become a legal strategy, not a public health strategy. “You bury everything by giving them everything. It's hiding facts in plain sight.” Kupchyk also has her doubts as to whether posting clinical trials on the Internet makes a meaningful contribution. “To expect physicians and especially the public to analyze these data is an illusion,” she says, “just a reactive measure to appease concerns.” A better way to use the Internet, she thinks, would be to post the summary basis of approval of new drugs, especially if these summaries provided more data.
Plan B and Plan C
If you feel that our panelists display too much agreement, wait for the next topic: the FDA's failure to act on Barr's application to let the morning-after pill become available without prescription. First, a review
of the facts. For the sake of objectivity, let's quote the February 24 decision of the US District Court for the Eastern District of New York deciding on the motion by the FDA to quash the plaintiffs' request to obtain pertinent documents and to depose top agency officials.
Document 24 of the District Court says: “Despite virtually unanimous support by senior review staff for the approval of the Plan B switch application, however, senior management at the FDA issued a not-approvable letter in May 2004. ...” Also, two FDA advisory committees, meeting jointly, voted 28-0 that the drug was safe to use without prescription. Also according to the record, Dr. John Jenkins, Director of the Office of New Drugs, wrote that “… the available data clearly support a conclusion that Plan B meets the statutory and regulatory requirements for availability without prescription for all age groups.”
That comment about age is pivotal, because his superiors overruled him on the basis that it had not been proved safe for adolescents. In the words of Janet Woodcock, OTC sales could lead to “extreme promiscuous behavior” and “lead adolescents to form sex-based cults. ...” Jonca Bull, MD, deputy director of the Office of Drug Evaluation, termed this opinion “speculative and unbalanced,” adding that “the agency's regulatory mandate is not to regulate behavior and morality. ...”
That's the sequence of events that led Susan Wood to resign, saying, “I can no longer serve as staff when scientific and clinical evidence, fully evaluated and recommended by the professional staff, has been overruled.” So we asked her (and the other panelists): Was this a case of political interference?
Wood wants to be clear that since she wasn't in the room when the negative decisions were made, she doesn't know exactly how it happened, but that she does know that the usual procedure was short-
circuited when the review was pulled out of the normal process and the staff was overruled. “In recent memory, people who've been there 10 or 20 years had never seen anything quite like it. It was really quite extraordinary.” Asked whether she felt the ensuing publicity had damaged the FDA's reputation, she replies firmly: “Its reputation suffered not because of what anyone said but because of what they did.” She adds, “My concern is that the agency has lost its independence, lost in some cases the ability to make decisions based on the evidence,” thus damaging not only the agency's reputation but also damaging the morale of people working there.
Kupchyk agrees with Wood, calling the Plan B ruling a purely political decision. During her tenure at the FDA, she acknowledges, Kessler leveraged politics to promote public health issues, as when he tried to regulate tobacco, but “I don't recall any instance of such political intervention.”
But not everyone agrees.
Pitts says flatly: “I was there. I was involved, and there was no interference from anyone outside the building.” His view is that “there was a lot of disagreement within the agency on a very contentious issue. Clearly, people who work at FDA are both scientists and individuals. When products … are contentious both from a scientific regulatory and from a personal political position, there are going to be fireworks.” Plan B got caught up in a political maelstrom because science has plenty of gray areas, he says, “and I think Plan B had plenty of gray areas.”
The fireworks Pitts refers to still have sufficient spark that two of our respondent chose not to discuss Plan B: Scheineson, because his firm does some work for Barr, and Troy, without giving a reason, though he did add that while he was at the FDA, he was enormously impressed by the generally nonpolitical nature of the drug review process. As for Scheineson, his only comment is that the FDA's survival “depends on science-based decision making. It can't be political and it can't be doctrinaire and it can't be dogmatic.” Thousands of decisions that adhere to these standards are made all the time, he points out, but the media focus on the one or two episodes that are controversial.
To heal the Plan B wounds, Scheineson believes that the FDA needs a “Teflon-coated” commissioner, and that's where things get sticky. When Lester Crawford was nominated to become permanent commissioner in 2005, two Democratic senators held up his confirmation until they were given a promise by HHS secretary Michael Leavitt that the Plan B decision would be made by September of that year. And action was announced—but it was simply to delay the decision further. That infuriated Senators Murray and Clinton, who felt they had been double-crossed, so that now they have vowed to hold up the von Eschenbach nomination and not to let themselves “be fooled again.” Said Senator Murray: “If they don't come to a decision on Plan B, the White House is going to need a Plan C on their nominee.”
The commissioner quandary
What makes this scenario so problematic is that in the five-plus years that President Bush has been in office, there has been a permanent commissioner for only the equivalent of a year, and acting commissioners, while having all the authority of those confirmed by the Senate, are hardly teflon-coated. It takes a confirmed commissioner, Pitts says, to put his or her mark on the agency, or in Pines' words, “The agency needs strong, visible, credible leadership—a commissioner who speaks out when appropriate on public health issues.”
Von Eschenbach should be able to fill that role as far as Troy is concerned, for he has a fine reputation as a physician, scientist and National Cancer Institute administrator. Even some FDA critics such as Kupchyk agree that he has the required scientific and medical background, though it remains to be seen whether he will provide the necessary leadership. Wood, for her part, is skeptical. “You would like to see a commissioner who reasserts the agency's independence,” she says, and as acting commissioner, he has not done so. She also fears that it will be difficult for anyone to do the job properly, claiming that the long periods without a permanent, full-time commissioner reflect “a lack of interest or priority by the administration in whatever the FDA does.”
Pitts agrees that the long stretches of acting commissioners have been a problem, and he draws an analogy. “It's like when you're living with your girlfriend and she says, let's get married. You say, why? We're living together now. But your girlfriend says, it does make a difference—and so it does. I think the same is true with acting versus a confirmed commissioner. Even though acting commissioners can fulfill 100% of the functions, they always have to be circumspect about becoming a trailblazer or being aggressive.” Pitts goes on to point out that the FDA is a very hierarchical organization, and that without a confirmed commissioner, power tends to devolve to the Center directors, at the expense of the commissioner's authority.
Scheineson uses another analogy about the lack of a permanent commissioner: “It's like castration.” A confident, secure and respected commissioner is “the chief defender of FDA,” he says, citing the example of David Kessler. Eventually, however, Kessler lost the confidence of the president who had appointed him—and that confidence, in Scheineson's opinion, is equally desirable, since an FDA commissioner who's not totally accountable and loyal can do a lot of harm. “That's why they want to ensure that whoever fills that position does the right thing scientifically but also implements administration policy.”
If von Eschenbach can (a) be confirmed and (b) meet those criteria, he may prove to be he commissioner everyone is hoping for.
Getting ready for the future
While Mark McClellan was commissioner, he instituted a program called Critical Path. Not all our panelists agree on the value of this program or even on what it is. On the positive side, Pines sees a lot of potential, and Troy calls it “a very important and worthy endeavor,” one that seeks to make the drug development system work more efficiently, especially in light of the advent of such new categories as biomarkers. We should not, he believes, rely on bigger and bigger clinical trials.
He does acknowledge that it's still a little amorphous and also that it needs more money.
Wood sees Critical Path as an attempt to use the FDA's in-house knowledge so as to be able to assist in product development by transferring this knowledge across product lines and even across companies To Kupchyk, on the other hand, it looks like no more than the continuous effort to be more efficient, and also partly like a PR effort to reassure Congress and the public.
Pitts recently met with Nobel laureate Joshua Lederberg and quotes him as saying about Critical Path: “The real question should be, Is innovation feasible?” For his own part, Pitts describes the FDA as doing its job “in more or less exactly the same way they were doing it 20 years ago,” while “the pharmaceutical industry is moving in leaps and bounds in the science of drug development.” That disconnect is a problem, and part of the solution will be for the FDA “to help industry fail faster,” so as to correct the current situation where some 50% of drugs that make it to Phase 3 never get approved. If successful, therefore, Critical Path will “save industry a boatload of money and free up a lot of time that will allow the FDA to put its resources toward more productive things.”
On that hopeful note, let's wish the FDA a happy birthday. May the next 100 years see as many achievements as the century just past, starting with solutions to the current problems. The agency's task is nothing less than to protect and improve the health of all Americans, and even if not everyone is always pleased with how it goes about doing it, it is in everyone's best interest to support it in its mission.