Chronic Pain

Under Review: Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation
By Philip J. Hilts
Alfred A. Knof, New York, 2003, $19.95

Over the course of just a few months last year, Americans learned that the U.S. Food and Drug Administration had underestimated the severity of manufacturing problems at Chiron, one of the nation’s leading flu vaccine suppliers; had misunderstood the heightened risk of suicide among children taking certain antidepressants; and had failed to publicize the correlation between deadly heart problems and the blockbuster medicines Vioxx, Celebrex, and Bextra.

President Theodore Roosevelt, who established the agency that would later become the FDA, knew that managing the expectations of a population that both loved and distrusted pharmaceuticals (and the companies that make them) represented a daunting challenge. But he reckoned that if America’s medicines regulator succeeded more often than it failed, the public good would be served. The FDA has succeeded more often than it has failed, and the American public – and the drug industry – have benefited hugely. But the agency’s failures have a way of overshadowing its triumphs.

During the Clinton administration, critics carped that the agency and its overzealous MDs and PhDs were overstepping their mandate, erring on the side of caution to the detriment of patients. Among other things, politicians and drug industry executives argued that the FDA was taking too long to review new drug applications. These same critics said long review times were bad for business and patients alike.

“Reforming” the FDA became a top policy objective during the “Republican revolution” led by then Speaker of the House Newt Gingrich during the mid-1990s. Then, in the early days of the Bush administration, the FDA went under the management consultant’s knife and emerged talking a new kind of language. Achieving “excellence in management practices,” “modernizing IT,” and striving for “efficient risk management” became the new imperatives at the FDA. Management would be “de-layered” – all to “reduce average time to marketing approval” for new medi­cines and medical devices.

This new mantra at the FDA, however, seems to have distracted the agency from that other “core competency” product safety, resulting in a string of dangerous miscalculations.

A different set of critics this time – the media, government-watchdog groups, the medical establishment, even FDA scientists and advisors – are now saying that the agency has tilted too far in the other direction, overemphasizing product-review speed and industry accommodation and sacrificing patient safety issues that come up after drugs have been approved. One of the FDA’s own scientists, a mid-level staffer named David Graham, testified before Congress in November that the Vioxx fiasco was preventable. He revealed that his employer took the assurances of Merck, the drug’s manufacturer, over the warnings of its own senior scientists and advisors. Graham told Congress that as many as 139,000 patients suffered heart problems – 55,000 of whom may have died – as a result of taking Vioxx. And he said both Merck and the FDA are to blame. The only way to prevent future fiascoes, Graham testified, is to create an independent drug-safety review board whose sole responsibility would be to monitor products after they reach the market. He noted that the system at the FDA for catching problems with marketed drugs is largely voluntary and relies upon doctor and drug company reports that are often slow in coming or incomplete.

Within days of Graham’s bombshell, an editorial on the website of the Journal of the American Medical Association reiterated that the FDA is badly in need of an “adverse drug reaction” reporting system whose success does not depend on drug companies to draw attention to problems associated with their big moneymakers. In most cases, after all, there is a disincentive to be honest and swift about product problems. Investors don’t like this kind of product surprise. Last September, the day after Merck announced it was pulling Vioxx, Wall Street erased $27 billion from the firm’s market value; in December, the day Pfizer announced that Celebrex, too, causes heart problems, investors took back $25 billion. Liability specialists reckon Merck will lose another $18 billion to $20 billion settling personal injury suits.

These are dark days indeed for the FDA. But they will pass, and the FDA will press on in its thankless task of keeping America safe from bad drugs, devices, and food. At least this is the lesson that history tells. To hear Philip J. Hilts tell it, the FDA has endured worse. Hilts explains in his well-timed book Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation that controversy and criticism have dogged the FDA ever since it was created to take on tainted food and patent medicine peddlers. It survives because it must.

Say AAAH
To get a sense of just how important the FDA is to America’s economy, consider that the agency is responsible for the regulation and oversight of nearly a fifth of all consumer expenditures in the country. The agency is not merely responsible for the health and well-being of 300 million Americans; it is also essentially responsible for the good behavior of one of the most powerful industries ever created – the American drug industry. There are bound to be misadventures. It’s a wonder that there aren’t more. In 2003 alone, close to three and a half billion prescriptions were dispensed in the United States.

Contrary to what some are now suggesting, however, America does not need a new medicines regulator or a new bureaucracy to oversee the FDA. What America needs is President Bush and the Republican-led Congress to give the FDA the tools, authority, and freedom it needs to succeed. In short, what America needs is a better understanding of the FDA.The agency is overworked, underfunded, poorly managed, and shamefully politicized. It has just 10,700 employees to evaluate and oversee the safety, effectiveness, and promotion of hundreds of thousands of medicines, medical and radiological devices, dietary supplements, food products, and cosmetics. There are around 100,000 drug companies to monitor and more than nine million channels through which food, medical, and cosmetic products are imported. With an annual budget of $1.5 billion, the FDA is responsible for overseeing nearly $1.5 trillion worth of products. And it has been forced to do so with only a whisper of leadership. Over the past four years, the FDA has had a bona fide commissioner for all of 16 months. Over the past 40 years, the average tenure of an FDA commissioner has been four years and five months.

Curiously, consumers on the whole seem satisfied. But as Hilts writes in his insightful and edgy history, nobody stops to think much about the FDA until he or she suffers the real or perceived side effects of its real or perceived failures. Yet other than the military, has any government institution done more to protect the nation against bodily harm? Doubtful, but because the FDA has always been the subject of ideological attacks, it is judged more for its shortcomings than for its quiet successes.

“In some circles, the fashion is still to criticize the ‘government’ and the ‘government regulators’ as if they were occupying armies rather than citizen-soldiers,” writes Hilts. “The FDA has nevertheless proved itself an essential part of modern society. Its history demonstrates that regulatory agencies can not only establish effective protections but make high scientific standards the starting point for industry.”

Hilts tells us that when enemies of the FDA are not actively trying to legislate the agency out of existence, they are attempting to marginalize it by cutting its funding and curbing its authority. No other health-related government agency is forced to do so much with so little money or power. Today, for example, the National Institutes of Health, the government’s medical-research arm that regulates no industry and is responsible for nobody’s health or well-being, operates on a budget of close to $28 billion a year, while the FDA must make do with about one-twentieth of that amount of money. The FDA’s budget is about one-fifth that of the Environmental Protection Agency, which is only responsible for some aspects of public health.

Yet much is demanded of the agency. The politicians who are not trying to upend the FDA want it to help curb health-care costs and foster medical innovation. Industry wants the agency to speed up the approval process, which now takes, on average, less than 12 months, and to reform protocol to take into account clinical-trial innovations. Watchdogs (including the federal government’s own Government Accountability Office) want the FDA to act more proactively and decisively on such matters as food safety, ­alternative medicine, and industry shenanigans connected to political contributions and the $2.7 billion direct-to-consumer advertising juggernaut. Health insurers want the FDA to create a regulatory pathway for generic medicines, against the will of proprietary drug companies.

The American Medical Association and the Association of American Medical Colleges are demanding that the FDA figure out how to create a public registry for clinical-trial data without invading the privacy of patients or revealing confidential product information. And such distinguished observers as Science editor in chief Donald Kennedy, who served as commissioner of the FDA from 1977 to 1979, want the FDA to create and enforce a system that can “detect things that go wrong with an already-marketed drug.”

Writing in the December 3, 2004, edition of Science, Kennedy asserts that in light of the Vioxx scandal, the most useful and important new tool Congress could give the FDA would be a centralized system for tracking how much of a given drug is being used per patient and over how much time, so that a denominator could be established and an adverse reaction rate calculated. He and others have noted that Kaiser Permanente has just such a system in place, which allowed the health insurer to spot the Vioxx problem early through the use of adverse-reaction epidemiology studies. “Instead of complaining about the FDA,” Kennedy writes, “Congress should fund it to support an effective Office of Drug Safety, with the authority needed to encourage physician reporting and a way to audit prescriptions.”

Unlike most FDA finger-waggers, Kennedy acknowledges that what needs to be done and what can be done are quite different. Kaiser, he says, can create a centralized database of patient records, for example, because customers willingly entrust their privacy to Kaiser. The United Kingdom is able to create a national health-records registry not necessarily because the population trusts the government – rather the contrary – but because it’s the law, and the law was passed in Parliament on the promise that it will improve for all what had become an abysmal health-care system that served nobody particularly well.

“If we were to try and give the FDA something like these two systems,” Kennedy says, “you’d hear cries of privacy invasion.” But this is a chasm we must eventually cross. Privacy advocates and antigovernment critics will object, but eventually America will find a way to link the FDA to patient records. National health-record databases are the future. Last year, the United Kingdom began to build a lifelong health-records database for the 50 million patients in its public-health system, which is linked to 30,000 general practitioners and 270 hospitals and clinics in the U.K. Sweden, Denmark, and Japan are talking about the feasibility of creating similar databases in their own countries. Growing populations with new and more complicated health needs will force the matter. No government agency is in a better position than the FDA to manage such a database.

Greed and Goodness
A registry would, of course, be a dramatic expansion of the FDA’s jurisdiction. Privacy advocates won’t be the only ones concerned about this. Bioethicists and academics argue that the FDA has its share of problems without adding on the job of managing a ­clinical-trials database and a citizens’ health registry. Conservatives and industry leaders will not be keen on the idea either, not least because it would be hugely expensive and put valuable information into the hands of government. As Hilts writes, the agency still finds itself trapped between competing constituencies: “Should the department err on the side of safety and the consumers? Or should it err on the side of business freedom until practices [are] proved to be dangerous?” Hilts concedes in his epilogue, “Greed and Goodness,” that despite pressure to do otherwise, the FDA should by now understand the risks that are inherent in the latter choice.

Hilts cites a series of experiments first hatched by J. Scott Armstrong, a management professor at the Wharton School at the University of Pennsylvania, that proved that if asked to play the role of a drug company executive, students put the interests of shareholders before the interests of patients taking the company’s medicines. “The experiment was repeated 91 times, in 10 countries, with 2,000 subjects and 23 different experimenters,” Hilts writes. “If the membership of the company’s board was not artificially altered to include outsiders and specific details about harm were not given, in North America and Europe, 76 percent of the board members took the most irresponsible course. None chose the most responsible course.”

Of course, there are conservative partisans in America who have long felt that it would be best to narrow rather than expand the FDA’s mandate. In 1996, in fact, House Republicans introduced legislation that would have obliterated that mandate. Fortunately, the bill got nowhere. Hilts says that history proves that the Right has never liked the FDA. But he makes note that the Right’s hatred and angst reached its apogee during the days of the Republican revolution. In the House of Representatives in 1996, “the Republican leadership was expected to drive the FDA ‘reform’ through in short order,” Hilts writes. “It was, as the conservative Republicans saw it, a battle of monetary and political force in the service of moral certainty.”

In a column in Reason, science correspondent Ronald Bailey sums up the Right’s mantra: “Being too cautious can kill you. And the FDA is the avatar of bureaucratic caution.” This fixation seems to endure even when tragic events like those involving Vioxx suggest that the FDA is often not cautious enough.

Bailey uses as an example the gene therapy tragedy that took but one life, that of Jesse Gelsinger in September 1999. The FDA shut down similar trials of gene therapy within weeks of the news and launched investigations to find out what had happened. Bailey charges that the FDA overreacted: “The FDA began hastily scrutinizing all gene-therapy trials with an eye to finding not just egregious violations, but even technical paperwork missteps. Spooked bureaucrats who want to stop something that they fear might get them in trouble tend to bury those they regulate in mounds of paper and interrogatories.”

Bailey rightly points out that whether the FDA misunderstands the risks and rewards of new medicines like gene therapy, or simply overreacted to one clinical trial’s tragic result, it is ill-equipped to handle the complexities of emerging technologies that don’t easily fit into standard FDA protocol. Medical therapies will only become more scientifically complex, so the FDA had better hire the staff and purchase the tools necessary to approve the new medicines and then monitor them carefully once they are on the market.

How to Heal the FDA
Staying one step ahead of new technologies, let alone balancing their risks and rewards, is no small challenge – especially for a large bureaucracy without a proper leader. Lester Crawford, the acting boss, is by all accounts a decent man, but he’s a caretaker. The FDA needs a leader strong enough to obtain the money and autonomy the FDA needs to do its job – a leader wise enough to reconcile the competing needs of the public and the hugely powerful industries that it regulates. The agency needs an inspiring manager with a public face that the American people recognize and trust, and a stalwart that industry respects – perhaps even fears just a bit. Now that Michael Leavitt, the former chief of the Environmental Protection Agency and an ideological soul mate of President Bush, has been hired to run the Department of Health and Human Services – whose jurisdiction includes the FDA – the White House and Congress must turn their attention to filling the void at the top of the FDA.

As Kennedy and others have noted over the past few years, the White House and the Republicans on Capitol Hill have wanted to put a politically reliable figure in charge of the FDA. The FDA would benefit more if it got somebody like Walter G. Campbell, who served two tours as chief between 1921 and 1944, for a total of 20 years. Interestingly, Campbell was neither an MD nor a PhD, but a Kentucky lawyer who was handpicked, Hilts tells us, by Harvey Wiley, the agency’s first head and a man who, like Theodore Roosevelt, began his professional life as a Republican only to leave to join the Progressive movement. In addition to giving the FDA stability – he remains the longest-serving chief – Campbell gave the agency armor-coated legitimacy.

The next FDA boss must sometimes turn a deaf ear to politics and find a way to prove to doubters that the agency will never put the business interests of the drug industry ahead of the safety of the public. The next FDA commissioner must continue the “de-layering” of the chain of command to improve communication between the labs and field staff, working to avoid future incidents where serious safety concerns get shouted down or overlooked. Most importantly, the new commissioner must do what is necessary to force Congress to give the agency the budget and authority that it needs to do its job properly. Congress should not be allowed to dither any further. The FDA was created in the first place precisely because Congress was viewed as an unreliable guardian of public health.

As the agency’s first boss, Wiley, a food chemist, persuaded Roosevelt that Congress could not and should not be trusted to police the safety of food and drug products. Hilts writes that “what bothered Wiley, who loved both research and commerce, and participated in both throughout his life, was that in research there was a strong sanction against deceit, while in commerce deceit seemed to be an accepted tactic to achieve profits. There was some disjoint there.” Wiley and Hilts demonize industry a bit much, but not entirely without cause.

The drug industry has competing interests; the FDA should not be put into a similar bind. As Hilts puts it, “The logic of ‘profit alone’ that dominated the companies in the nineteenth century still dominates them today. This is one reason the FDA’s job is difficult, and necessary.” The Vioxx fiasco could have been avoided. But it is also important to remember that Americans should not expect the FDA to squeeze out every last ounce of risk from food and drugs. Neither should politicians, drug industry critics, and reporters. New medical products bring new risks – that is their price. But with a few notorious exceptions, the FDA does everything in its power, given its overextended resources, to keep medicines that are unnecessarily risky off the market – and help the public understand the risks of those that are allowed past its gates.

Because of last year’s scandals, those who denounce the FDA have fresh cause. But there will always be debates about whether the agency’s quiet successes outweigh its misadventures. Yet 100 years after its establishment, this much is not in dispute: the FDA succeeds in its mission more often than not, despite needlessly long odds. It could do even better if it had the money, management, staff, and technology to do its job properly.

Stephan Herrera writes about the business, science, and politics of medicine and health care. He is a contributing editor at Nature Biotechnology and a frequent contributor to the Economist and Technology Review.