Reputation (FDA’s Version)

Today the FDA finds itself in one of the greatest crises in its 100+ year history. It has lost an estimated 15% of its employees to seemingly arbitrary staff cuts, and many of its most experienced leaders have departed. The Department of Health and Human Services is now led by Robert F. Kennedy Jr., an FDA skeptic who has openly expressed his distrust for the agency and its employees. The FDA’s own political leadership seems to share Kennedy’s feelings about the agency’s staff, overruling their decisions and creating an atmosphere of unpredictability. Morale is reportedly tanking, and the agency continues to shed staff through resignations. Public health experts, agency veterans, and even pharmaceutical companies are concerned.

How did things get to this point? The FDA’s acute crisis has been driven by a capricious administration that has taken a dim view of experts across the government. But it has deeper roots. The New York Times published an article, dramatically titled “Inside The Collapse of the FDA,” which suggested that the FDA’s current challenges are the culmination of years of self-inflicted reputational damage. According to the article, years of missteps by the agency, accompanied by a drumbeat of criticism, undermined the public’s trust, making the agency’s current predicament possible, if not inevitable. I have shared a somewhat different view. The FDA’s decline was not a cause of its own actions, but the result of a society-wide collapse in institutional trust, of which the FDA was only one of many victims.

There is no question that trust in the FDA specifically has declined sharply in recent decades. That makes it a good time to ask some basic questions about the agency: What exactly happened to the FDA’s reputation and why has it seemed to erode in recent years? Why is that reputation so important? Can it be recovered? And ultimately, what difference does it make? If, as former FDA Commissioner Robert Califf said in April, “the FDA as we’ve known it is finished”, what are we actually losing?

I happen to have a deeply personal stake in these questions. I spent the formative years of my career working at the FDA’s drug center. Over the past several months, more former colleagues than I can count have left the agency. Some were laid off, others resigned in frustration. My own job as an FDA consultant wasn’t spared. With some time on my hands and a desire to make sense of what was happening, I decided it was time to read Daniel Carpenter’s 2010 history of the FDA’s regulation of drugs, Reputation and Power. The book tells the story of how a small regulatory agency grew to become an indispensable — and sometimes infuriating — player in the pharmaceutical industry, with far more influence than many realize. The FDA not only regulates pharmaceuticals, but created the very system that makes drug development possible today. 

Reputation and Power is a massive and ambitious book — roughly 800 densely written pages. It purports to explain the history of a now century-old government agency, and, in doing so, to present a comprehensive theory of bureaucratic power. 

Despite being published in 2010, it also answers many of the same questions being asked about the agency today. Carpenter is a political scientist who, throughout his career, has concerned himself with questions of bureaucracy, power, and politics. How do bureaucrats obtain and exercise power in a modern administrative state, and how do institutions and incentives shape their actions? And, germane to our discussion, how has the FDA successfully obtained and exercised its power? 

The book’s central thesis is simple. The FDA built itself into a powerful, independent regulator by carefully cultivating its reputation. It was admired by the public, respected by Congress, feared by the pharmaceutical industry, and broadly accepted by scientists and experts. In Carpenter’s framework, these groups served as the reputational “audiences” on which FDA depended for its power and influence — in some cases as constituencies for the agency, and in others, as potential challengers to its power.

The FDA was founded in 1906 with the passage of the Pure Food and Drug Act. In its first three decades, it primarily focused on ensuring food and drugs were properly labeled and not adulterated. Any muscle it had was reactive, not preventive. The agency’s more modern form was shaped by two key moments: 1938, when Congress gave the FDA the authority to approve drugs, and 1962, when Congress gave the FDA the authority to evaluate drugs’ effectiveness and regulate clinical research. In both cases, the legislation was passed following well-publicized tragedies. In 1937, over 100 patients died when a poisonous drug, elixir of sulfanilamide, was introduced to the public without proper testing. The death count would have been far greater had the FDA not gone to extraordinary lengths to take the remaining product off store shelves and out of medicine cabinets. Shortly thereafter, to prevent future disasters, Congress gave the FDA the authority to ensure drugs were safe before they were marketed. Then, in 1962, Congress granted the FDA additional authority after the FDA medical officer Frances Oldham Kelsey averted disaster in the US by declining to approve thalidomide, a drug that was responsible for a wave of devastating birth defects in other countries ¹ .

 “The apparent coupling of tragedy to legislation,” Carpenter wrote, “ … has led many an observer to conclude that catastrophe itself is the mother of U.S. pharmaceutical policy.” Carpenter argues otherwise.The primary driver of these changes, he suggests, was in fact the FDA itself and its allies in Congress, who shaped the public narrative around these crises to the FDA’s advantage.

For some time before the 1937 sulfanilamide crisis, the FDA had been pushing for greater regulatory authority — including the authority to approve drugs. The sulfanilamide story had, in fact, received limited news coverage. The victims were predominantly African-American men, a group largely ignored by the media. It wasn’t until a USDA-coauthored report highlighted the death of a young white girl that public sympathy ultimately spurred Congress to pass the law that gave the FDA authority to review and approve drugs.

The reforms of 1962 were similarly brought about by a timely legislative strategy on the part of the FDA and its allies. As the thalidomide crisis played out across Western Europe, Congress discussed FDA reform in a series of hearings led by Senator Estes Kefauver, a Democrat from Tennessee. The FDA had helped draft reform legislation, but it was foundering in Congress. It was at that crucial moment that Morton Mintz of The Washington Post published an article, “‘Heroine’ of FDA Keeps Bad Drug Off of Market,” on Frances Kelsey’s denial of approval for Thalidomide.

Mintz’s article, published in July, transformed the narrative of FDA reform. In August, Kelsey received a presidential medal from President Kennedy in a widely publicized ceremony. By October, Congress had passed the Kefauver-Harris amendments, authorizing the FDA to regulate drug efficacy. If it seems suspiciously convenient that The Washington Post story emerged at this time, that’s because it was no accident. Senator Kefauver’s own antitrust subcommittee leaked the details of the story to Mintz, who then confirmed its details with the FDA. As Carpenter writes, “Frances Kelsey's public triumph was not a newspaper scoop … but instead a carefully timed leak designed to influence the passage of impending legislation.”

Across these stories, along with countless others in the book, Carpenter highlights two patterns of behavior that helped explain the FDA’s success in advancing its legislative goals and expanding its influence. First, the FDA continued to deftly manage its relationships with its various audiences. In the 1930s, it partnered with Congress and women’s groups. And in the 1960s, the FDA again worked closely with its Congressional allies and leveraged its relationships with leading experts and academics, many of whom testified in favor of agency reforms. Second, in its management of both crises, the FDA demonstrated competence at pivotal moments, proving, to Congress’s satisfaction, that it could effectively carry out its responsibilities. In both its recall of sulfanilamide and its scrutiny of thalidomide, the FDA proved itself to be worthy of the public’s trust.

Despite the significance of the 1938 and 1962 reforms, it was not the legislation that transformed the drug industry, but rather how those legislative authorities were interpreted and wielded by the agency. In Carpenter’s framework, the FDA wields three types of power. It has directive power: for example, the ability to command companies to recall products. It has gatekeeping power via its ability to withhold drugs from the market and, in doing so, to influence how drugs are developed in the first place. And, most critically, it has conceptual power, or the ability to shape the very terms and concepts of drug development itself.

The FDA’s conceptual power is not explicitly granted in its enabling laws, nor is it easily defined, but for those who work in the field of pharmaceuticals and life sciences, it is the proverbial water in which they swim.

As the FDA set the standards for drug approval, it also defined the scientific concepts underlying drug development. The FDA codified the phases of clinical trials for drugs, brought randomized controlled trials into widespread use, and defined the meaning of the words “safety” and “efficacy.” It even determined the nature of scientific expertise needed to develop drugs. The field of pharmacology, for instance, became an integral part of drug development because the FDA demanded it. By codifying abstract scientific concepts in regulations and regulatory decisions, the FDA made them concrete. They said, “let there be efficacy,” and there was efficacy. Drug development as we know has come to depend on these FDA-defined concepts.

The decades following the passage of the 1962 amendments represented the agency at the zenith of its influence. They reshaped medical practice by removing ineffective drugs that had been approved prior to the 1962 law. They reshaped drug development by creating and enforcing requirements for IRBs, phased trials, and more. Pharmaceutical companies began to place “regulatory affairs” departments at the center of their organizations. Courts showed deference to the FDA’s decision-making and the FDA won a string of legal victories that granted it more authority and autonomy. They even reshaped global pharmaceutical regulation, as a growing number of countries adopted the FDA’s regulatory model.

The FDA of the post-1962 era inspired admiration, even as it attracted critics. In the 1960s and 1970s “The Administration stood as one of the world’s most admired public organizations,” writes Carpenter, and its reviews were held up as the global “gold standard” for scientific rigor. The agency faced plenty of controversy and opposition. Pharmaceutical companies complained of the FDA’s “flabby practice” and “dilatory tactics,” while some academics and business leaders blamed the agency for the “drug lag” — a tendency for new drugs to become available in Europe before they were approved in the US. And libertarians and conservatives — particularly economists —  remained opposed to the 1962 amendments. Yet, politically speaking, the opposition was divided and failed to puncture the FDA’s image.

The 1980s marks the emergence of a powerful new reputational audience for the FDA: patient advocates seeking access to new medicines. Cancer and AIDS patients, faced with fatal illnesses, demanded faster access to medicines, and pushed the FDA to reform its approach. In Carpenter’s words,  “ … it was the agency’s moral reputation under attack in the crises of cancer and AIDS. And these threats to moral reputation were far more powerful than drug lag criticism in changing the behavior of the agency.” Many histories of the era suggest that the activists were successful in forcing the FDA to change its practices, and indeed this era saw many FDA reforms. A program of “compassionate use” access made experimental drugs available to patients who had no alternatives. New models of drug review made it possible to approve drugs with fewer trials or the use of faster-to-obtain surrogate endpoints. But in Carpenter’s view, this was not the agency bowing under pressure but rather another example of the agency tactfully responding to its reputational audiences while preserving its principles and power. 

But, according to Carpenter, “the reputation and the power of the Food and Drug Administration in the governance of pharmaceuticals have waned appreciably.” The seeds of the FDAs reputational decline were sown in the increasing political polarization of the 1990s as the agency came under growing scrutiny from politicians ideologically opposed to government regulation. In 1992, the FDA, strapped for funding and under pressure to increase review speeds, started a user fee program: Companies that submitted new drug applications would have to pay the FDA a fee. Although these fees were intended to fund timely reviews, they raised suspicions that the agency was beholden to industry. Meanwhile, patient groups, inspired in part by the activists of the 1980s, had become increasingly professionalized, and with the help of funding from pharmaceutical agencies, they rose in prominence and challenged the agency’s gatekeeping power. A further and even more major hit to the FDA’s reputation came in 2004 when the agency failed to act quickly on mounting evidence that the blockbuster painkiller Vioxx was causing heart attacks and strokes. The user fees that had funded faster approvals did not appear to have made the agency’s safety oversight more responsive.

When I joined the FDA in 2008, Carpenter’s book was nearing publication, and the agency was still working to regain its reputational footing after the Vioxx scandal. Confidence had dropped rapidly. In 2000, 61% of Americans said that the FDA did a good or excellent job ensuring both the safety and efficacy of drugs. By 2006, only 36% held that view. Even before Reputation and Power was published, we were well aware of our imperative to restore the agency’s reputation and public trust. In fact, at the same time I was being onboarded, my colleagues were busy responding to a paper, led by Carpenter, which alleged that the FDA’s rush to get drugs approved in time was leading to more safety problems after the drugs were marketed. (Naturally, we disagreed with his assessment).

These battles would continue to define the agency over the next 15 years. Carpenter, like many contemporary critics of the agency, reserves his greatest admiration for the FDA of the post-1962 era, when the agency established its “gold standard” review process, inspiring fear in the pharmaceutical industry and admiration around the world.

Since Carpenter wrote his book, the agency’s reputation has only continued to decline. The FDA was criticized both for its initial approval of Oxycontin and for failing to respond after the opioid crisis became evident. The agency has also come under fire for its relationship with patient advocates. For example, in 2016, Janet Woodcock, the director of the FDA’s drug review center, overruled her staff and approved Exondys for Duchenne’s muscular dystrophy despite limited evidence that the drug had any benefit. Critics have continued to question the FDA’s use of user fees, even as the FDA’s reliance on those fees has grown. And the FDA suffered what may have been its greatest reputational blow during COVID as public skepticism of the FDA-approved COVID vaccines came to dominate political discourse.

Carpenter, as a political historian, does not spend much time evaluating the FDA’s track record. But he highlights some of the key questions raised by the agency’s critics: Have the FDA’s lengthy reviews delayed access to treatments? Has the FDA been excessively conservative in its approval decisions? Have the FDA’s ambiguous standards made drug review capricious and unpredictable? Has the FDA’s scientific rigor — particularly in its efficacy standards — made drug development needlessly (and sometimes prohibitively) expensive? Has the FDA’s oversight of approved drugs been too limited and lax?

Based on my reading of the book and my own experience, the answer to all of these questions is a qualified “yes.” But Carpenter provides important context. These flaws were not the result of malice or incompetence but of a careful and deliberate balancing between the demands of its different audiences — congress, the public, scientists, and the pharmaceutical industry. The FDA’s approach continues to change as its audiences change and their demands change.

I saw those changes firsthand. By the time I left, it seemed obvious to me that the modern FDA was far better than the one that existed at its reputational zenith in the 1970s. Thanks to user fees, the FDA is vastly better resourced — its headcount more than doubled from 2008 to 2019. A larger workforce has, among other things, translated into faster reviews and more thorough inspections of drug manufacturers — who now span the globe. The drug lag is now gone; in recent years, the FDA has been the fastest reviewer of drugs in the world.

Importantly, the agency is also more open than ever before. In the past, drug approval could be an expensive exercise in trial and error. Carpenter recounts a story of how in 1982, Genentech, a then-upstart biotech company, failed to ask the agency if the trial endpoints it used for a study would be acceptable. It was blindsided when their product was rejected. Today, surprises like this are less likely. The agency routinely meets with drug companies to clarify what it expects from them and publishes detailed explanations of the kinds of evidence it expects to see.

Meanwhile, the influence of patient advocates — along with some remarkable new drugs for cancer and other serious diseases — has introduced a powerful counterbalance against the agency’s tendency towards conservatism. As drugs for rare diseases and targeted cancer treatments have become more widespread, the agency has become more willing to accept small trials and trials without placebo controls. For all their flaws, these smaller trials make it possible for drugmakers to develop drugs that might otherwise be prohibitively expensive or logistically impossible to research.

And while the agency was rightfully criticized for its handling of COVID tests, particularly early in the pandemic, the agency’s rapid approval of COVID vaccines was a triumph —  spurred in part by the agency’s reputational need to respond quickly during a public health crisis. The FDA did more than just authorize these vaccines — they helped make their rapid development possible. Operation Warp Speed was coined by the FDA’s vaccine center director, Peter Marks. At the start of the pandemic, the FDA quickly issued guidance, setting a bar that could assure public confidence while still getting the vaccines developed and authorized quickly. They provided frequent adviceas vaccine makers prepared and undertook their trials. And safe, effective vaccines were in fact authorized in record time, with reviewers working around the clock to complete their analysis of the study data. This triumph, of course, was followed by one of the sharpest reputational declines in the FDA’s history.

How did it happen that the FDA saw its greatest success accompanied by its greatest reputational decline? The agency certainly erred in its handling of COVID, particularly with its early missteps around testing. But the FDA’s greatest reputational declines came later as reactions to the COVID vaccines became politically polarized. Since Carpenter wrote his book, the media environment has changed. The FDA’s mistakes and missteps are now more visible than ever, dissenting voices are easier to find, and the FDA — along with other elite institutions — has less control over the messages is audiences receives. The FDA’s current predicament is just one symptom of a problem that extends far beyond just the FDA — established experts everywhere are being challenged.

As institutions like the FDA come under increasing threat, we need to ask: What would the effects of a less powerful FDA be? What parts of the institution are worth defending and preserving?

This will require us to look beyond Carpenter’s book. Even at nearly 800 pages, his work covers only a fraction of the FDA’s responsibilities. Vast areas of the FDA’s remit, including its inspections of manufacturing facilities and its oversight of generic drugs, are barely addressed. But Carpenter’s account helps us cast the FDA — and its contributions to pharmaceutical progress — in a new light.

First and foremost, Carpenter shows that the FDA does not just enforce regulatory requirements and review drugs. The FDA was engaged in a project of scientific translation, bringing ideas from academia, including pharmacology, statistics, and clinical medicine, and transforming them into enforceable regulatory requirements. A smart, scrupulous regulator, closely aligned with its audiences in research and academia, can act as a kind of industry accelerator, bringing new scientific developments rapidly into widespread practice.

There is no better example than the FDA’s insistence on randomized controlled trials. Even before the 1962 amendments that allowed the FDA to review drugs for efficacy, segments of the pharmaceutical industry were starting to adopt RCTs. But it was the FDA’s demand for rigorous evidence that cemented the clinical trial’s role in drug development. So, too, with other research practices that only became commonplace after the FDA demanded them: multiplicity adjustment, pre-registration of trials, and more. These methods are often framed by critics as bureaucratic requirements, but they are in fact truth-finding technologies, and the FDA has accelerated their adoption.

The FDA has also accelerated pharmaceutical progress through its ability to shape categories, to define what counts as legitimate evidence, and create shared concepts.  The agency’s conceptual power underlies a regulatory system that makes drug development challenging but also legible and navigable. Carpenter argues that the FDA’s conceptual power “allows for the standardization necessary to scientific progress.” The FDA establishes the standards and terminology we use to evaluate and compare drugs so that the pharmaceutical industry can focus on making the drugs better.

What would have happened without the FDA’s exercise of conceptual power? One possibility is that the development of pharmaceuticals could have been swept into the same morass that characterizes the rest of healthcare, turning into a barely-navigable quagmire of regulations and institutional rules that render genuine innovation difficult. In most of healthcare, it takes an estimated 17 years for the typical research finding to make its way into clinical practice. Healthcare has been notoriously slow even in adopting simple technologies such as electronic records and email. If healthcare is an impenetrable swamp, the FDA has transformed drug development into a smooth, if expensive, toll road.

Oddly enough, perhaps no development better illustrates the FDA’s conceptual power than the rise of the Chinese pharmaceutical industry. In 2015, China began a series of regulatory reforms aimed at increasing the speed and rigor of its drug reviews. Chinese officials sought to harmonize their drug development regulations with those of the FDA and other global authorities. They enlisted regulatory experts from the United States to help them in their capacity-building efforts. Those changes are now credited with spurring an explosion in Chinese drug development. According to a Bloomberg report, Chinese drugs now represent 26% of global drug licensing deals, up from almost none in 2015 when China’s regulatory reforms began. The drugs licensed by Chinese companies include important medical advances, such as improved treatments for cancer.

One can tell the story of the rise of Chinese biotech as a symbol of China’s rising power, as a threat to the United States’ own biotechnology industry, or as a hopeful story about the potential for Chinese innovation to benefit humanity. But it is also a story about the reputation of the FDA, whose regulatory approach was largely copied by China. Through the FDA’s scientific standards and regulations, which rendered drug development tractable and legible, the FDA paved the way for pharmaceutical innovation across the world.

There are many lessons, big and small, to be taken from Carpenter’s book. But at its core, it presents a great underdog story. A small, savvy regulator rose to globe-spanning power and influence. In this story, the FDA is a complicated and flawed character. Its ambition could turn into hubris; its commitment to rigor could turn towards imperiousness; and its attention to reputational risks could undermine its ability to ensure drug safety. That complexity makes the book hard to summarize. It is not entirely a success story or a cautionary tale; it is part of an ongoing story of how bureaucratic power and influence is gained and how it can leverage transformative change.

But if we take anything away from this book, I hope it teaches us that the FDA is a far more complex and consequential organization than even many of its most ardent boosters and detractors realize. Its power and reputation have formed the scaffolding upon which an entire industry — upon which billions depend — has been built. As the agency’s reputation continues to unravel, we will need more works like Reputation and Power to help us understand the consequences.