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Thursday, May 8th, 2003


Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation

by Philip J Hilts


A review by Jerome Groopman

In 1990, I was appointed to chair the Food and Drug Administration's Advisory Committee on Biological Response Modifiers, known as BRMs. BRMs were among the first products of America's burgeoning biotech industry, and they were closely watched not only by the clinical community but also by Wall Street. Our initial meeting was convened to evaluate a protein called interleukin-2 that potently stimulates the body's T cells. Dr. Steven Rosenberg of the National Cancer Institute had pioneered the use of interleukin-2 as an immune booster against cancer. Our specific charge was to assess the safety and the efficacy of this protein as a therapy for kidney cancer. The biotech company developing interleukin-2, Cetus, was based in California. The fortunes of the company seemed to be riding on the approval of this product.

Reams of documents were sent out to the members of my committee prior to our public deliberations. As I waded through the hundreds of pages detailing Cetus's laboratory and clinical studies of interleukin-2, it became clear that this was not going to be a simple judgment. At the doses given in the experimental trials, interleukin-2 often caused life-threatening pulmonary and cardiac side effects that necessitated hospitalization in the intensive care unit. Moreover, the evidence for regression of cancer in these patients was scant. There were a handful of positive outcomes, amounting to a few percent of the total cases treated. Standard treatments for metastatic kidney cancer included a chemotherapy drug called Vinblastine and a hormone called Megace. Neither was particularly effective, but each was markedly less toxic than interleukin-2.

To complicate matters, the clinical data on these standard therapies were largely historical: there was no prospective randomized study comparing Megace or Vinblastine (or a combination of the two) with a placebo control or with interleukin-2. Equally vexing, kidney cancer can follow a highly variable course, with some tumors growing rapidly and causing death within months and others behaving in a much less aggressive manner. This made it difficult to establish whether the anecdotes of response to interleukin-2 were a clear advance over standard therapy, or which subset of the larger population with the cancer might most appropriately be treated.

The advisory committee sat before a large audience, like a panel of judges hearing a case in a courtroom. Yet there was a significant difference: our role was to make recommendations to the FDA, and it was the FDA that made the final decision about whether the experimental therapy would be approved or not. Still, our advice carried great weight. At the front of the audience sat representatives from the Cetus corporation. In addition to their presentations on the study data, we would hear from a patient with kidney cancer who was a member of an advocacy group pressing to have the therapy approved. Behind these presenters was a large group numbering in the hundreds. Some were journalists covering the hearing; many were stock analysts whose firms had placed bets on our vote.

Cetus introduced its data on interleukin-2 treatment, and then the patient with kidney cancer pleaded for approval, decrying how little there was to do for the disease and arguing that desperate disorders necessitated desperate measures. His plaintive presentation was all too familiar to me and to the other members of the advisory committee. We were all, at one time or another, clinicians struggling to find a way to retard the rampant spread of an aggressive tumor. But we were also acutely aware of how much harm we could do with our treatments, how the remaining time for such cancer patients could be truncated by the toxicities of the therapy. Not infrequently, after we prescribed such debilitating drugs, we stood at the bedside wondering whether we had really done what was best for our patients.

Following testimony from Cetus and the patient, representatives from the FDA dissected the results of the clinical trials. It was not a pretty picture. The design and the execution of the studies did not clearly show what was an optimal dose of interleukin-2 to achieve a benefit, or indeed if any significant benefit resulted from the therapy. As the company set forth its rebuttal, members of the committee probed more deeply with pointed questions. The journalists in the audience scribbled furiously. The stock analysts ran in and out of the auditorium to call their investment houses. I later learned that the share prices of Cetus fluctuated wildly with the tone and the content of the debate. Commerce was driving the discourse as strongly as science.

All of us on the committee wanted a good new drug against kidney cancer. We fully grasped the financial stakes, but we focused on the data before us. After more than eight hours of agonizing discussion, the committee voted to recommend that the FDA not approve interleukin-2. Rather, we instructed the Cetus corporation to work closely with the agency to identify an optimal and safe dose for a patient group that might truly benefit from it. Some in the audience saw this as a triumph of science and a prudent position that had not bent to commercial pressures. Others could hardly contain their anger, claiming that once again a cold-hearted bureaucracy had prevailed. Wall Street punished the company; its shares plummeted.

Like most medical researchers and clinicians, I joined the advisory committee with mixed feelings about the FDA. I was suspicious that the agency was an ossified organization. I learned through the interleukin-2 deliberation that this view was simplistic. The position of having to weigh the risks and the benefits of a toxic therapy for a terrible disease was not a comfortable or easy perch. I clung to a single consolation after the negative vote: that because of prior pressure from AIDS activists, mechanisms had been forced upon the FDA to allow patients with life-threatening diseases to have access to drugs still in experimental testing — if their physicians agreed and if the company was willing to provide the drug at no cost. This so-called "compassionate use" had worked well during the months before the formal approval of AZT. A compassionate-use program had also been instituted by Cetus in anticipation of approval of interleukin-2. While that approval had not been granted, patients still could receive the therapy on an individual basis until the company was able to organize sufficient data to demonstrate convincingly the safety and the efficacy of the treatment. That took place about a year later, and interleukin-2 was then approved as a treatment for kidney cancer.

Philip J. Hilts's book forcefully captures the complexity and the drama of the government's attempt to oversee the imperfect science of medical treatment. It is a genuinely important book, rich in history, accurate in detail, unflinching in analysis. Above all, it causes us to think differently about the FDA, which has so often served as a convenient whipping boy for frustrated constituencies across the political spectrum. As I read Hilts's book, I understood how far the agency had come to enable our committee to soberly evaluate drugs like interleukin-2. I also learned of the deficiencies in the workings of the agency, and what needs to be done to close the gaps in current law.

Hilts traces a tense arc, each chapter profiling a personality and a period that were linked to a fundamental change in the functioning of the FDA. These are nuanced portraits. He begins with Harvey Washington Wiley, one of the first federal regulators of food and drugs, who predated the agency. Wiley was a fiercely independent chemist from Indiana, a Union soldier in the Civil War, an apprentice to a country doctor in Kentucky, and ultimately the head of the science department at Purdue University. An enthusiast for the scientific method, he analyzed the composition of everything from wood to water. In 1883, Wiley joined the Department of Agriculture as its chief chemist. He believed that there was a fundamental similarity between science and business: both should be free and unfettered, so as to allow competition. But Wiley recognized one critical difference between the two enterprises. As Hilts observes,

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 here. Wiley could not understand deception about food and drugs, substances that to him were sacramental. They were nature's chemistry. How could one corrupt what was produced by God and nature, and needed for life by humans?

It was the pursuit of this question that brought Wiley to apply his keen experimental acumen to what were called patent medicines. Their name derived from the patent or proprietary nature of the formulas, which were held in secret. Marketing for these putative medications, which had names such as the Grand Restorative, the Universal Vegetable Pill, and Wheeler's Nerve Vitalizer, occupied a large fraction of the nation's advertising budget. So formidable forces confronted Wiley in his effort to regulate patent medicines. Time and again bills introduced in Congress were defeated by the Republican leadership, particularly Nelson W. Aldrich of Rhode Island, who was a grocery wholesaler and had close ties with the baking powder and chemical industries.

It was Theodore Roosevelt who set out to civilize capitalism in the marketplace of food and drugs. Like many in the Republican Party and in his social class, Roosevelt began as a laissez-faire advocate who opposed governmental meddling in most corners of the public realm. But Samuel Gompers succeeded in opening his eyes. As a young state legislator, Roosevelt was invited by Gompers to witness the deep misery of Manhattan's tenements. There was something inherently wrong, Roosevelt concluded, in how the poor and the vulnerable were blithely exploited by the rich and the powerful. Seeing himself as a combative man of action, Roosevelt decided that unregulated capitalism was really a form of bullying. "This became a principle for Roosevelt in many affairs of government: free commerce was essential, but it would come to nothing, worse than nothing, if the rules of enterprise favored one group and bullied another," Hilts writes. "Roosevelt liked to speak of the nation in a grand way, as if it had a single character, which he wanted to shape. He came to feel that not only enterprise but also fairness was required if toughness of spirit was not to slacken into laziness or arrogance. Roosevelt, an enthusiast of business and an admirer of progress, feared that the streak of unfairness he sometimes saw displayed in nineteenth-century capitalism, in its harshness and self-concern, would be the unmaking of the whole American enterprise."

Roosevelt carried this sensibility into his presidency. Upton Sinclair's novel The Jungle had stirred the nation like no other exposé before it, and the book furnished Roosevelt with the ammunition that he needed to cut down his opponents. He battled to pass the Pure Food and Drug Act in Congress, and finally, in 1902 and 1906, the bills reached his desk. These legislative milestones led to the creation of the FDA. Still, as Hilts emphasizes, the initial legislation had numerous loopholes, necessitating some forty additional laws that gradually gave the agency more duties and more powers.

Hilts's absorbing narrative is a long documentation of the grim fact that mendacity and greed have never left the food and drug industries. Each president since Roosevelt was forced to balance the powerful interests of business with the public welfare, at least until the thalidomide debacle in 1959 — a catastrophe of unparalleled proportion — finally fixed clinical science as the centerpiece of federal regulation. Prior to that disaster, drug companies could test experimental therapies by simply sending them out to doctors for use, without organized clinical trials comparing the drug with a placebo or standard therapy. All of this distribution occurred before any formal approval for sale. Moreover, the requirements to report to the FDA on the safety of the drugs were meager. "When a company submitted its application to put a drug on the market," Hilts writes,

there were no rules. The companies had no particular scientific or medical guidance from the FDA about what evidence was required to show a drug safe and effective. Drugs were often given to humans before they were tested on animals; there were no rules against it, and for a long time the FDA did not object. When things went wrong with the drugs, the FDA was often the last to know, and the slowest to act when it did know. There was a fear within the FDA of acting against the companies' wishes. So the agency made some special effort to work, like cleaner fish on the sides of the companies, without disturbing the great-toothed creatures. Even when reports of seriously toxic drugs were given to the FDA, they were not made public by the agency because the companies requested it. In one case, scientists from NIH starting tests of a heart drug asked the FDA for information in its files about how toxic the drug was; the FDA refused to send it over. Moreover, in the 1950s and early 1960s the FDA was not a brilliant keeper of records. It did not know all the drugs on the market, or what was happening with them.

This radically changed when Dr. Frances Kelsey, a shy forty-eight-year-old mother of two with an M.D. and a Ph.D. from the University of Chicago, joined the FDA and was asked to review an application from the drug company Richardson-Merrell for the use of thalidomide as an anti-nausea and sedative medication. She was disturbed by the lack of coherent data on safety, and by several hints that the drug posed real risks. The company dismissed her concerns. But Kelsey would not relent from pressing Richardson-Merrell for the truth. Ultimately she discovered that the company had distributed samples of thalidomide to some twenty thousand patients "experimentally," and that thousands of mothers who took the drug during pregnancy delivered children lacking the long bones of the arms and legs, a syndrome termed phocomelia. Some babies had other horrific complications as well, including the absence of a bowel opening or ear canals and segmented intestines. It turned out that the German company Grünenthal, which had licensed the drug to Richardson-Merrell, had lied about the safety studies in animals — there were almost no such studies prior to human testing. Moreover, Richardson-Merrell had decided not to report to the FDA problems with the drug that it had observed in the clinic.

Kelsey's stubborn insistence on data led to a new law in 1962. All drug experiments in humans now had to be approved in advance by the FDA, and records had to be kept on adverse reactions to these experimental treatments. Moreover, patients had to be asked for their consent, and had to give it, before entering into a clinical trial. It was, Hilts points out, a sea change not only in regulation but in the culture of American medicine: "Nations had long wrestled with charlatans, frauds, and criminals who pressed useless and dangerous substances on customers," he observes. "But the final arbiter was an 'expert,' not empirical scientific evidence. The old standard allowed 'experienced' doctors to declare what was safe and what worked. The new law was a direct threat to that authority and the AMA's house of delegates unsuccessfully demanded outright repeal of the new law, at least as far as it suggested that a drug's effectiveness could be determined by scientific tests. For the first time, experts were in second place and investigations themselves were essential."

Yet the road of rational regulation did not run smoothly. Hilts attributes the detours and the obstacles to the growing power of conservatives who weakened the FDA. Like their forebears in the nineteenth century, Ronald Reagan and Newt Gingrich harbored a deep suspicion of federal interference in commerce. Once again, industry successfully lobbied government officials to limit the FDA's power, with disastrous consequences. Consider only the example of Reye's syndrome, for which children who have a viral infection such as influenza or chicken pox and take aspirin are at risk. About a week after the viral infection, they experience nausea and vomiting; a range of changes in cognitive function from amnesia to lethargy to coma; and liver failure. The syndrome has a death rate of some twenty percent. Among the survivors, about one-third have permanent mental retardation or seizure disorders.

Several studies, including those by the Centers for Disease Control, gave support to the link between aspirin therapy for the flu or chicken pox and Reye's syndrome. But the companies that manufactured aspirin intervened. They succeeded in squelching negative reports by the CDC and physician organizations, and they lobbied the Office of Management and Budget to cancel regulatory measures that affected the prescription of aspirin to children with these viral infections. Hilts also shows how pharmaceutical companies such as Bayer funded a front organization, the American Reye's Syndrome Association, which tried to directly target parents, suggesting that they diagnose the syndrome themselves and then tell their doctors how to diagnose it. All of this was done to prevent a decline in profit. "The instructions in the brochure were an elaborate ruse," Hilts writes. "They said that no one knew the cause of Reye's and listed an array of possible causes, including 'genetic factors ... pesticides, chemical wastes, afla-toxins, etc., and medications used to control vomiting and fever such as antiemetics, aspirin and acetaminophen.'"

That last bit was particularly deceptive, because it diverted parents away from the proper treatment for fevers. The brochure went on to give a long explanation of what to look for in order to diagnose your child; it also said that the disease was impossible to rule out or to confirm without a blood test. It asserted that "since many doctors are not familiar with RS, and the symptoms can be mistaken for meningitis, encephalitis, diabetes, poisoning, or especially in older children and adults, drug overdose, it is important to remind them about Reye's." The aspirin makers began to broadcast ads that began by declaring: "Stay tuned for a medical bulletin on Reye's syndrome." The subsequent message declared that the cause of Reye's was unknown, and aspirin was never mentioned. Hilts estimates that the watered-down warnings about aspirin that finally emerged could account for the deaths of some 113 children during the period from November, 1981 to November, 1983.

From the beginning of his book, Hilts shows his cards. He believes that science should drive policy, and that the FDA is a much maligned and misunderstood agency. Yet he is not an apologist for the agency: he shines a light also on its failings and its flaws. Its shortcomings came into sharpest focus in the midst of the AIDS crisis, when lethargy, ignorance, prejudice, and a lack of leadership resulted in an unforgivable ignorance about the burgeoning epidemic. It was the ferocity of AIDS advocates and the frustrations of clinical scientists that pushed the FDA into gear. After initial intransigence, AIDS drugs were approved in record time, and a so-called "parallel track" was taken in development whereby formal placebo clinical trials were conducted in tandem with compassionate distribution of the drug to needy individuals who did not qualify for the clinical studies. (That paradigm informed our deliberations on kidney cancer and interleukin-2.)

Hilts is also critical of the FDA for its failure to regulate the vast and lucrative herbal supplement and natural foods industries. His criticisms provide the context for a proper understanding of the recent controversy about ephedra. A loosely regulated weight-loss product containing ephedra was linked to the death in February of the Baltimore Orioles pitcher Steve Bechler. It turns out that the conventional wisdom that Mother Nature is a benevolent goddess, that her fruits consistently fortify our health, is narrow and naïve. Many plants and herbs are poisonous. Moreover, when "natural supplements" are prepared and sold in health food stores and supermarkets, the purity of the products is far from uniform. Such products have passed through the largest remaining loophole in federal legislation. Adverse reactions are not reported in an organized and structured way, because herbal products still are not classified as medicines, even though biologically they are medicines. Drug companies shoulder the burden of proof to demonstrate to the FDA that their medications are safe before they are marketed, but with dietary supplements the burden of proof rests with the FDA.

Tommy Thompson, the secretary of health and human services, averred in a recent news conference that he would not use products containing ephedra or give them to his loved ones. Yet Dr. Mark B. McClellen, the recently appointed commissioner of the FDA, seems to have taken only half-steps after the uproar over Bechler's death. While the companies will now have to adhere to good manufacturing practices and accurately label their herbal products, they still will not be held to the scientific standards of drug development with regard to proof of safety and efficacy. So the last chapter of Hilts's book is yet to be written. The struggle between sober science and raw commerce continues.

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