INSIDE THE FDA The Business and Politics Behind the Drugs We Take and the Food We Eat Fran Hawthorne John Wiley & Sons, Inc. To the generations: my parents, Lillianand Edward Hawthorne and my children, Mallory and Joey Contents Introduction v Chapter 1: Case Study: Chasing Cancer 1 Chapter 2: Beyond Science 23 Chapter 3: The First 100 Years 35 Chapter 4: cYou Don 9t Know Which Agency Is in Charge d 65 Chapter 5: Truckloads of Paper 79 Chapter 6: Case Study: The Return of Thalidomide 109 Chapter 7: How Picky Is the FDA? 123 Chapter 8: How Powerful Is Industry?
143 Chapter 9: Case Study: The Death of Monica George 179 Chapter 10: When Consumers Get Angry 191 Chapter 11: A Political Pawn 209 Chapter 12: FDA and DNA 233 Chapter 13: The FDA Meets Madison Avenue 253 Chapter 14: Frivolous Drugs? 273 Chapter 15: The Next 100 Years 285 Acknowledgments 309 Notes 311 Bibliography 329 Index 333 iv Introduction he Holiday Inn in Bethesda, Maryland, is an unassuming stucco building tucked sideways off a slow commercial street, across from a Pizza Hut, a gas station, and a mini-mart. You enter from the side driveway and climb up a ... more. less.
wide, curving staircase to reach the Versailles II ballroom on the second floor.<br><br> On a sunny February morning in 2004, as week-old snow lingered in piles at the edge of the sidewalk, it was standing room only in that ballroom. Some three hundred people had come 4parents, grandparents, siblings, and friends, bearing posters and white satin ribbons 4to talk to the United States Food and Drug Administration about the medicine that had killed someone they loved. The long room was decorated in shades of beige and blue, with textured beige wallpaper, beige-and-brown carpeting in a fleur-de-lis motif, and a turquoise ceiling studded with 16 crystal chandeliers.<br><br> At one end, three tables had been arranged in a large cU d for the two panels of 36 outside experts who had been summoned to advise the FDA, along with a few agency staffers. Facing them were rows of burgundy-and-purple brocade chairs, a battery of TV cameras, and a microphone for the audience. They came from Rhode Island and California, from Texas and Colorado, Arizona and Pennsylvania.<br><br> Most of them were middle-aged, the men in b usiness suits, the women in nice slacks. One mother quoted the Book o f Revelations; another wore a button supporting Democratic Senator John Edwards for president. A 10-year-old girl read an Archie comic book, while a boy of about six played with his GameBoy.<br><br> In the hall outside the ballroom, one blonde woman asked another, cWas your daughter suicidal? d They came with tales of the anguish and horror that they and their families had lived through after a teenage son, daughter, grandchild, or friend had started taking an antidepressant medication legally prescribed by their doctor and approved by the FDA. While on the medication, the teenagers had killed themselves, or someone else, or tried to. The fami v lies blamed the drugs, and they wanted the FDA to do something to prevent more horror stories.<br><br> Tom and Kathy Woodward. Their 17-year-old daughter Julie had hung hersel f in the garage six months earlier, after seven days on Zoloft. Terri Williams.<br><br> Her 14-year-old son Jacobhad hung himself in the attic with a b elt while taking Prozac. A friend held up a picture of Jacob in his football uniform. Corey Baadsgaard with his father, Jay.<br><br> Corey had used first Paxil, then Effexo r Then he woke up in a juvenile detention center one morning. Apparently, he had carried a hunting rifle to school and held his class hostage, but he didn 9t remember any of that. cThese drugs are hell.<br><br> Look what they 9ve done to my son! d Jay Baadsgaard shouted, his voice hoarse. He strode out of the ballroom, slamming the door behind him. Glenn McIntosh.<br><br> His daughter Caitlin hung herself in the girls 9 bathroom in her middle school when she was 12; she had been using Paxil and Zoloft. She had been a straight-A student and had hoped to be a veterinarian. Eileen and Todd Shivak.<br><br> Their 11-year-old son Michael had taken Paxil. He was still alive. But he had tried to slash his wrists in class, had run in front of a moving car, and was now afraid of doctors, teachers, and police.<br><br> cHis peers think of him as a freak, d the Shivaks said. One after another, more than 60 people spoke. The medications had all been approved by the FDA years ago, starting in 1988 for adults.<br><br> Millions of people said the pills had saved them from unbearable depression, anxiety, compulsive behavior, panic attacks, and stomach pains. Yet the medicines had been controversial almost from the start, because of their ability to alter people 9s moods and personality so powerfully. Almost 13 years earlier the FDA had convened a similar meeting of outside experts to discuss whether these pills led to suicidal tendencies in adults; some of the same people now in the audience at the Holiday Inn had been there, too.<br><br> Bac k then, emotions had been so intense that the chairman of the advisory panel had worn a bulletproof vest. The Church of Scientology had condemned Prozac. A small study by two Harvard researchers had seemed to show that people on Prozac were prone to suicidal thoughts, and patients and their families had sued Eli Lilly and Company, the manufacturer of the drug.<br><br> In 1989 a Kentucky p rinting press operator named Joseph Wesbecker had killed eight co-workers p lus himself with an assault rifle and wounded a dozen others a few weeks after he started taking Prozac. The FDA panel back then recommended furthe r research. Still, the FDA had decided that the drugs were beneficial and safe fo r most people, based on the weight of scientific studies, and should stay on the market.<br><br> For patients under 18, there was the added concern about how these powerful chemicals might affect brains that were still developing. Children 9s brain chemistry is different from that of adults. So even if the drugs were completely safe for adults and helped ease their depression, that did not mean they were necessarily safe or helpful for children.<br><br> Only Prozac had ever been officially authorized as an antidepressant for this age group. Studies on the other drugs (most of them belonging to a class known as selective serotonin reuptake inhibitors, or SSRIs) had not clearly shown that they worked significantly better than a placebo, or fake drug. N evertheless, doctors could legally prescribe any of the medications for any age, and they did: The usage rate for children under 18 jumped more than threefold from the early 1990s to 2001, according to a study by Washington State University; the FDA reported that almost 11 million prescriptions fo r that age group were written in 2002.<br><br> If there was no sure proof that the SSRIs were effective for youths, neither had any clinical trials on patients clearly and definitively demonstrated that the medications increased the risk of suicide 4or at least, that was what the medical community believed. The companies that produced the drugs, anxious not to lose this rich market, insisted that the families 9 stories were only anecdotal 4though heartbreaking 4aberrations. What made things even more difficult to sort out was that the patients taking the pills were unhappy to begin with, by definition, and might have tended toward suicide with or without the medications.<br><br> It was also hard to define what to consider a csuicide attempt. d Slapping yourself on the head? Stabbing yourself with a pencil during an exam For that matter, even as the use of the antidepressants had been rising, the overall rate of teenage suicide in the United States had dropped in the late 1990s. So maybe the pills were actually helping to reduce the number o f suicides.<br><br> The FDA had issued a warning specifically about Paxil in June 2003 after the drug 9s manufacturer, GlaxoSmithKline, submitted studies that showed a higher level of what might be suicidal thoughts and incidents among adoles- cents and younger children taking that drug, compared with patients taking a p lacebo. (Most of the data about Paxil was not made public, and the New York state attorney general, Eliot Spitzer, sued GlaxoSmithKline a year later for withholding the trial results.) In October came a stronger FDA warning about the whole group of antidepressants. The warnings did not forbid doctors from using these medicines, however.<br><br> There still seemed to be no definitive p roof, either that the drugs led to an increased risk of suicide, or that any drug but Prozac worked in youngsters. The FDA commissioned Columbia University to conduct yet another study. Meanwhile, in December, the British equivalent of the FDA took a stronger step, warning doctors in the United Kingdom to shun all antidepressants but Prozac for children.<br><br> Most of the speakers at the Holiday Inn called for stricter labels on the drugs, and some urged that only trained specialists, not generalists or pediatricians, should be allowed to prescribe them. Some demanded an outright ban. They wanted the FDA to protect their children.<br><br> Yet many of them were skeptical that the regulators would. Dawn Rider exuded anair of competence and confidence; she was a tall woman with a bright red jacket and long, thick, dark hair. Her 14-yearold son had died after taking Prozac.<br><br> Then her husband was given Paxil to help him cope with the death, and his attempt to withdraw from that drug destroyed their marriage, she told the crowd in the ballroom. During the lunch break, I asked her what she hoped the FDA would do. cI don 9t have a lot of faith in the FDA, d she replied.<br><br> cThere 9s too much sway from the pharmaceutical industry. dShe pointed particularly to the fact that Mitchell E. Daniels Jr., a former Lilly executive, had been the White House b udget director and was running for the Republican nomination for governo r of Indiana. (He would later be elected.) And somehow it was only Lilly 9s drug Prozac that had been approved for children.<br><br> cI was sitting there, watching them [on the FDA panel] today. I almost noticed bored expressions. d cIt 9s clear that the FDA is a political entity, d Tom Woodward told the three dozen panelists. cUnder the Bush administration, the FDA is putting the drug industry over the interests of the public. d The FDA ?<br><br> The Food and Drug Administration, the agency that was created in 1906 to make sure that Americans were never again poisoned en masse the way Upton Sinclair described in his novel The Jungle ? That poll after poll has always shown is one of the most trusted arms of the entire government? For almost a century, the FDA has been the Good Housekeeping seal of approval, the Nobel Prize, and Ivory soap (99 and 44 D 100 percent pure) com b ined.<br><br> No medicine or medical device can be sold in the United States unless the FDA pronounces that it is safe and that it works. No packaged food can make health claims unless its label is approved by the FDA. Americans count on this agency to make sure that we have a steady stream of wonderful new p ills that are potent and perfectly safe at the same time, as well as a supermarket full of goodies that we can gobble up without worrying about food poisoning.<br><br> We also count on this government agency to be on our side against powerful drug and food companies and to resist political pressure. We trust the FDA so that we do not have to stop and read the label of every can o f soup and bottle of aspirin we buy. In fact, we pretty much assume that it will p rotect us from everything short of nuclear war.<br><br> Undoubtedly, most Americans do not completely understand how this influential government office works. We probably overstate its clout in some categories, like restaurants, and don 9t realizehow far its power extends into other areas, like microwave ovens and pet food. Some people think it tests every drug that is sold, and or that it inspects all food products.<br><br> (Neither o f these is true.) Still, we know the basics: If the FDA lets us down, we are not j ust personally disappointed, betrayed, and angry. We could be dead. To say you have lost faith in the FDA is like saying motherhood and apple pie have gone rotten 4literally, in fact, since the FDA is supposed to ensure that apple pie is safe to eat if you buy it prepackaged from the supermarket.<br><br> (Not i f you eat it in a restaurant, however.) So how could this mighty agency that we have relied on for a century mess up so badly? Why didn 9t it catch the suicide problem before it ever approved the first SSRI? How can it be legal for doctors to give teenagers drugs that the FDA never approved for kids?<br><br> Why didn 9t the FDA know about the GlaxoSmithKline studies? The parents who came to the Holiday Inn had once trusted the FDA to keep their children safe. And it had failed them.<br><br> B efore I started covering health care as a reporter and editor at I nstitutional I nvestor magazine in the early 1990s, I probably had more or less the same vague knowledge of the FDA that most Americans do. Luckily, I never had much reason to be concerned with the products it oversees. I come from a healthy, long-lived family, and my husband, my kids, and I have rarely needed a prescription except for the occasional antibiotic.<br><br> Nor have I had to be a caretaker for my parents or other aging relatives who do take a lot of medication. As for the cF d in FDA, well, I 9ve always worried more about the calories in my food than any contaminants. Once I began writing about the pharmaceutical industry and health insurance, I got to meet the FDA that the drug companies know.<br><br> To these companies, it is the all-powerful, arbitrary, nitpicky naysayer that keeps their desperately needed medicines off the market until they run a zillion unnecessary tests to p rove things they already proved. The agency is unreliable, one week saying it wants to help manufacturers get their products out to patients quickly, then the next week panicking after too many reports of dangerous side effects. It is mysterious; there is no way of knowing just what a companymust do to move its product past the regulatory box-checkers.<br><br> At best, the FDA is a bunch o f b ureaucrats who mean well but are scared to be the first to approve something new. Most of all, the agency must be obeyed. It is almost impossible to get through a 10-minute interview with a pharmaceutical executive without hearing at least one complaint or fear about the FDA.<br><br> Of course that is a one-sided view, and the other side can overwhelm you as soon as you walk into an advisory committee hearing, such as the one at the Holiday Inn. There were so many stories at that hearing that I stopped taking notes. It was too much suffering, too many horrible new examples, one afte r another, without enough time to absorb the horror of the first ones.<br><br> And it was p ainful to be there, to picture my own kids 9 faces 4to be too lucky. The drug companies were wrong; the problem was not that the FDA was keeping good medicines off the market in order to enforce overly stringent rules. The p roblem was clearly that the FDA had givenin too easily to the drug companies 9 pressure, had skimped on its due diligence, and had let dangerous p roducts into the marketplace.<br><br> I wondered how it felt to be one of the FDA staffers listening to those stories at the Holiday Inn, knowing that maybe something you had done had caused a family so much pain. A few weeks after the hearing, I asked Dr. Robert J.<br><br> Temple that question. Heavyset and a bit shorter than average, with longish salt-and-pepper hair that flips over his collar, a thick mustache, round eyeglasses, and thick dark eyebrows, Temple is the FDA 9s associate director of medical policy and its resident expert on clinical drug trials. He started working at the agency in 1972, just as it was in the midst of laying out the scientific processesthat would define modern drug testing, and he has been in the midst of it ever since.<br><br> In his job capacity, Temple was one of the three dozen people at the U-shaped table, though he was not a member of the advisory panels and could not vote on any recommendations. He gave a short laugh at my question. cThey 9re very moving stories, d he replied calmly.<br><br> cThe fundamental problem, d and he leaned forward as though to share a secret, cis you don 9t know whether in fact their attribution is correct. Long before there were antidepressants, people committed homicides and suicides. It 9s well known that depression is a cause of suicide. d In other words, yes, the families 9 tales were sad, but heartbreak is not scientific p roof.<br><br> Just because someone takes Pill A and thencommits Act B, that does not prove that A caused B. What else was happening in the person 9s life that could have led to Act B? What had other people done when they were taking Pill A?<br><br> The FDA could not base its decisions on emotion. First and foremost, before worrying about drug companies 9 profits, before even worrying about consumers 9 anxieties or medical needs, the FDA had to look at the science. Maybe.<br><br> But as a reporter at newspapers in California and New Jersey over the years and as the former political reporter for Institutional Investor , I have spent enough time covering politics at the local, state, and federal levels to know that the FDA 9s decisions could not always be purely scientific. The FDA is a government agency. Its commissioner is appointedby the president.<br><br> Its b udget and commissioner have to be approved by Congress. Its officials can b e hauled before a congressional committee for interrogation at any time. Its major decisions are usually vetted by the Department of Health and Human Services, if not the White House.<br><br> On top of all that, the FDA regulates the industry 4pharmaceuticals 4with the most powerful lobbying force in Washington, D.C. Of course all those players try to influence FDA decisions on issues they care about, and of course, the FDA gives in when the pressure is too great. I f there are three hundred parents whose children become violent after taking drugs like Paxil and those three hundred parents shout loud enough, Congress, the White House, the pharmaceutical industry, and the FDA will hear.<br><br> Marion Goff of Rhode Island, one of the parents at the Holiday Inn, knew exactly what she was doing when she brought a friend to the hearing 4Stephanie Chafee, wife of Republican senator Lincoln Chafee. Chafee stood nearby, silently, whileGoff told the FDA experts how one of he r twin daughters, then age nine, had taken Zoloft and Paxil. Goff had once found the girl on the window ledge, with one leg already out the window.<br><br> The girl had also tried to stab herself repeatedly. And there is a lot more to the FDA jigsaw puzzle. Now that I was covering health care, I naturally began noticing constant references to the FDA in the news, even in the most unlikely articles.<br><br> The agency warned pregnant women against using sophisticated ultrasound equipment to take csouvenir d pictures of embryos. Blood banks complained that the FDA was making them ask too many questions of potential donors, about AIDS, West Nile disease, and SARS. A factory in China, certified by the FDA to manufacture ingredients for various medicines, was dumping untreated chemical waste.<br><br> Cell phone users wanted the FDA to find out if their phones might cause brain cancer. Was there anything the agency didn 9t regulate? Indeed, it seemed to have its finger in many of the most controversial and important pies at the American supper table: genetic engineering of plants and animals, abortion, mad cow disease, obesity, drug prices, cloning, Baby Boomer vanity drugs, illegal steroid use by athletes, drug ads on TV.<br><br> How could I fit something this huge into a single book? A s it turned out, perhaps the grieving parents at the Holiday Inn should not have been so cynical. At the conclusion of the hearing that afternoon, the two scientific advisory committees recommended that the FDA immediately issue stronger warnings to doctors about the risks to children, without waiting for Columbia University to complete its analysis.<br><br> In its official decision a month and a half later, the agency went even further. First, it asked the manufacturers themselves to place warnings right on package labels, which were more likely to be seen by doctors and patients on an ongoing basis. It also put out a health advisory to physicians and other caregivers to cclosely monitor all patients being placed on therapy with these drugs for worsening depression and suici- dal thinking, d especially at the beginning of treatment 4 all patients, not just children.<br><br> This was pretty impressive. The FDA really listens to ordinary people, acts fast, and bucks the big drug companies. The New York Times claimed the new warnings were a break with the FDA 9s normal, more cautious p rocedures, because there was no clea r -cut evidence of danger from cwell-controlled d human trials.<br><br> But then several newspapers reported that, in fact, even before the hearing at the Holiday Inn, the FDA did have such evidence 4and kept it hidden. In studying data from more than 4,000 participants in clinical trials, an FDA drug safety analyst, Dr. Andrew D.<br><br> Mosholder, said he found that children on antidepressants were almost twice as likely to become suicidal as those on p lacebos. The agency refused to let him testify about his findings at the hearing and never showed the panelists his report, however. With the incident hitting newspaper headlines across the country,the chairman of the Senate Finance Committee, Charles Grassley of Iowa, launched an investigation that came up with further charges of FDA manipulation.<br><br> cYou don 9t just ask someone to clam up, d the senator told the Wall Street Journal. cIf there 9s any dou b t, they ought to put out the caution to the public at large. d All that was on top of the Paxil trial results that GlaxoSmithKline and the FDA had kept from the public. So had the FDA actually tilted in favor of the pharmaceutical companies by squelching reports critical of their drugs, even while it seemed to be listening to the patients?<br><br> Well, that was not necessarily the case, either. Bob Temple, the expert on clinical trials, told reporters that Mosholder 9s report was cpremature d because too much of the underlying data was unreliable 4for instance, some of the supposed examples of suicide attempts were vague and might not have been real attempts. He said the FDA did not want to spread unsubstantiated fears, thereby discouraging severely depressed people from getting treatment that might help them.<br><br> And FDA officials claimed the law did not allow them to reveal GlaxoSmithKline 9s proprietary trial results. Even before I had a chance to ask, Dr. Steven Galson, the acting head of the FDA 9s Center for Drug Evaluation and Research, insisted in an interview with me that cstories that we 9re somehow suppressing people, that 9s the farthest from the truth. d Later that summer, the Columbia University report did back up Mosholder 9s findings, but only after digging into the data more deeply.<br><br> Finally, anothe r meeting of outside experts in September called for yet stricter warning labels, and the FDA officialdom agreed to implement those changes. In fact, the agency said it would even go back and reanalyze its data on adult suicidal behavior. Temple admitted that all the clinical trials, taken together, seemed to show can increase in suicidal thinking and action. d At a hearing soon afterwards, members of Congress from both parties p ounded on the FDA for hiding Mosholder 9s report and other information.<br><br> cThe FDA 9s lack of cooperation, d declared Congressman Joe L. Barton o f Texas, cleaves me wondering whether this is sheer ineptitude or something fa r worse. d cNo agency charged with the public health should have behaved with such indifference to the public safety as is evidenced in this case, d intoned Congressman Peter Deutch of Florida. The House and Senate both launched investigations.<br><br> Two more possibilities, then. Maybe the brouhaha over the Mosholder report p roved that the FDA truly operates the way Temple described it, as an ivory tower of pure science. It is so careful and so insistently scientific that, even under tremendous pressure from consumers, the press, and politicians, it will not issue half-baked announcements until it has all the facts.<br><br> And if new data cast doubt on its previous findings, it is so scientifically pure that, rather than stonewall, it will pore through all of its research yet again. Or maybe, like any institution, it just tried to cover up its own mistakes. Protector of the consumer?<br><br> Pawn of industry? Pure scientists? Political p laything?<br><br> N ow I really needed to write this book. I had to put all the jigsaw pieces together and decide what the FDA is 4this sprawling, scientific, political, nitpicky, pioneering, admired, feared, detested, trusted agency. CHAPTER 1 Case Study: Chasing Cancer aro Armen, Russ Herndon, Pramod Srivastava, and Renu Gupta started p racticing at nine in the morning on the day after Labor Day, 2003.<br><br> They gathered in a small, green-carpeted conference room just off the seven-floo r atrium of the DoubleTree hotel in Rockville, Maryland, half an hour outside Washington, D.C. Across from their room, bathed in the atrium 9s soft yellow light, three small waterfalls trickled down an indoor stone wall. Okay, what would the reviewers from the Food and Drug Administration be likely to ask when they met that afternoon?<br><br> The four of them worked for a New York City company called Antigenics Inc. one of countless new, small firms trying to use a niche of biotechnology to tackle cancer. Srivastava and Gupta, both born in India and deeply intereste d in philosophy, were the scientists.<br><br> Herndon was the businessman, outgoing and boyish-looking. Armen was pretty much everything: CEO, co-founder, fundraiser, public spokesman, elder statesman, and driving force. Antigenics 9 particular approach was based on work that Srivastava had begun as a graduate student 25 years earlier at the Centre for Cellular and Molecular Biology in Hyderabad,India.<br><br> That work focused on a kind of protein known as heat-shock proteins, or stress proteins, which are found in all cells of all living organisms, including cancer cells. Under normal 1 circumstances, these proteins play a major role in transporting another kind o f p rotein called antigens within a cell (and thus they have an even more colorful nickname, chaperones). Antigens, for their part, stimulate the body 9s immune system to respond to infection or disease.<br><br> In theory, you could extract and p urify the heat-shock proteins that had chaperoned an antigen that stimulated a response to a certain cancer. Then the extracted heat-shock proteins could be made into a vaccine that would contain some trace of that specific antigen and its cancer 4the cantigenic fingerprint d of that cancer. If a patient got tha t vaccine, unique to his or her cancer, the immune system might be reprogrammed to home in on cancer cells bearing the antigenic fingerprint.<br><br> It would not prevent anyone from getting cancer, but it could stop the cance r from spreading. That was the theory, anyway. A number of universities and research institutes in the United States and Europe were also studying the heat-shock protein p rocess, and so far the buzz about Antigenics among scientists and on Wall Street was cautiously positive.<br><br> The vaccine, which was called Oncophage, had already proved itself in animal experiments, in tests for safety, and even in the first stage of clinical trials on cancer patients. A trial of colorectal cance r p atients had just reported some good news about survival rates. Now 650 p eople with kidney cancer and 350 with skin cancer were participating in further tests at more than 130 sites around the world.<br><br> As soon as doctors removed a patient 9s tumor, the specimen was frozen in dry ice and rushed to Antigenics 9 labs in Woburn and Lexington, Massachusetts, b oth near Boston. There, scientists had 24 hours in which to extract the heat-shock proteins 4they needed a minimum of seven grams of tumor 4and p rocess them into a vaccine. For the next three weeks the vaccines were tested for purity, sterility, and composition.<br><br> Finally, at least four vials were flown back to each patient and injected 4one a week for four weeks, then biweekly. The stuff looked like a small glass of Sprite. Of course, these were only tests.<br><br> Oncophage was still far from being a safe, workable drug, let alone a cure for cancer. The Antigenics scientists figured they would need at least two more years of clinical testing, checking to see i f the cancer had spread, b efore they would be ready to seek official FDA approval. So there really wasn 9t much reason to be hanging out at the FDA 9s headquarters in Rockville.<br><br> But Antigenics had requested this special meeting because a problem had cropped up. The FDA had recently reorganized. Some 200 reviewers who specialized in protein-based drugs, including staffers who had been working with Antigenics for almost a decade, were about to be shifted to a different branch of the agency.<br><br> That meant that a whole new crew of scientists would be taking over the review of Oncophage 4scientists who did not know Antigenics 9 people, its drug, or its history. What made the situation even dicier was that Antigenics wasn 9t exactly following standard operating procedure. Over the past several years, the company had been negotiating off and on with the FDA in hopes o f convincing the regulators that its drug was unique and should be able to bypass some of the normal requirements for quality control.<br><br> Antigenics was hardly alone; biotech firms right and left were flooding the FDA with revolutionary science, demanding exemptions and challenging traditional testing standards. For instance, in order to make sure that volunteers in experimental drug trials 4and, ultimately, patients in the general population 4are not swallowing something dangerous, the FDA obviously needs data from the manufacture r about the potency and safety of the drug being tested. But the agency also goes a step further, asking manufacturers to explain how they will test their drugs to obtain the potency and safety data.<br><br> The idea is to reassure doctors that the drug they are prescribing is consistent bottle after bottle and that the method o f measuring is accurate. So the manufacturers have to provide details about the tests they use to check a drug 4known as assays 4even before a human subject can swallow the first pill or be injected with the first dose. With a traditional chemical drug, measuring is fairly routine.<br><br> However, vaccines are much more variable because they are made from living material, which is inherently inconsistent. And vaccines made to order from the p atient 9s own tumor are even more variable, a totally new creature for the FDA. cIt 9s not straightforward, because it 9s a personalized cancer vaccine, d Dr.<br><br> Elma S. Hawkins, a veteran of the industry, explained to me a couple o f months after the meeting in Rockville, when she was Antigenics 9 vice chairman. Garo Armen had been talking with Dr.<br><br> Philip Noguchi, acting director of the FDA 9s Office of Cellular, Tissue, and Gene Therapies, to ge t advice on developing the assays. Another problem, Hawkins said, is that everything just happened too quickly. Since there are only about 35,000 people in the United States with kidney cancer, Antigenics had been told it would take ten years to recruit its goal of 650 patients.<br><br> Instead, it filled its ranks in less than three years. cWe accrued p atients fast into a trial that everybody said was impossible to do. The clinical trial went at lightning speed. d But the p aperwork of collecting forms from each trial site did not go as speedily.<br><br> cNot everything was documented at the FDA the way they would like it to be, d Hawkins said. So Antigenics had neither collected all the data that it was supposed to, no r given the FDA the explanation ofits assays. Now the new FDA reviewers had sent Antigenics a letter asking for some of that missing information.<br><br> A little before two o 9clock, the Antigenics crew headed past the Twin- b roo k Metro station, some three blocks to the FDA headquarters. The 18-story, dark brown-and-grey monolith stands out in its spare, suburban Maryland neighborhood mainly because of its ugliness and bulk. Row after row o f windows and steel look down onto a gently sloping hill marked with scattered stands of skinny trees.<br><br> In front, the building crams almost right up against the street, with room for just two wooden benches, seven large concrete p lanters 4the kind that are built for security, not beauty 4and a single bike rack. Across the street sits a strip mall with a video store, a surplus furniture outlet, and a mailing service. As soon as the group from Antigenics got to the meeting, Armen could tell there was a bigger problem than they had practiced for.<br><br> cWhen I saw the body language, I knew something was going on, d he recalled later. cI tried to soften them. That backfired.<br><br> I tried to tell them about the fact that we were doing this b ecause it was supported by an enormous amount of science and that we were doing it because there was a terrific unmet need. They didn 9t even look at me. d Antigenics couldn 9t document how it would test the safety of the drug that i t was putting into its subjects? Then the FDA, in good conscience, could not allow any more people to be p laced at risk.<br><br> As of that moment, the kidney trial was placedon partial clinical hold. No new p atients would be permitted to try the vaccine. D r.<br><br> Garo H. Armen is short and trim, with thinning hair, a light brown goatee generously flecked with grey, and what seems a perpetual small smile o f confidence. cNever ever in the last ten years d 4the lifetime of Anti- genics 4 cdid I ever think about giving up, d he insisted, eight weeks after the clinical hold was issued.<br><br> He was born in 1953 to an Armenian family in Istanbul, Turkey, which meant that his forebears had somehow survived the massacres and mass deportations of Armenians in the Ottoman Empire during the late nineteenth and early twentieth centuries. His father, an auto parts dealer, sent him to the United States in 1970 because the 17-year-old was getting a little too outspoken about Armenian independence. Armen headed for New York City, to the semi-suburban borough of Queens, where he had some distant relatives.<br><br> Besides, the local public university, Queens College, charged only $200 tuition and offered an English course for students who did not speak the language. Armen blended easily into the borough 9s ethnic stew of Italians, Irish, Jews, Greeks, blacks, Poles, and Puerto Ricans. Because he was interested in science, Armen studied chemistry at Queens College and earned a PhD in physical chemistry at City University of New York in 1979.<br><br> At Brookhaven National Laboratories in nearby Long Island, he did research on photosynthesis and energy production. But by then Armen had discovered the thrill of the stock market. In 1981 he took his science background to Wall Street and became a stoc k analyst specializing in chemicals at E.<br><br> F. Hutton & Company. Five years late r he moved to Dean Witter Reynolds as a senior vice president of research with a specialty in chemical and pharmaceutical companies.<br><br> (Biotech firms like Antigenics may have a reputation for self-destructing after short-lived bursts of glory, but so far it is Armen 9s two Wall Street alma maters that have disappeared. Hutton was acquired by Shearson Lehman Brothers in 1988, and the Dean Witter name was erased in 2001, four years after the company merged with Morgan Stanley Group Inc.) N ext leap: In 1990 Armen opened his own money management firm, Armen Partners. Instead of just analyzing stocks for others to buy, he did the buying and selling himself, taking a cut of 20 percent of any profits he made.<br><br> At its p eak, Armen Partners was handling $75 million of Armen 9s own money plus that of select wealthy individuals. His specialty was biotechnology companies. N aturally, he got a lot of hot tips about the newest cures for cancer or obesity.<br><br> cMost of them didn 9t turn out to be anything, d Armen recalled. A few did, however. He made his name launching a cancer business for Immunex Lederle There was also an Irish company named Elan Corporation that was working on an intriguing approach to Alzheimer 9s disease.<br><br> Then, on June 15, 1993 4Armen is very precise about this 4a scientist named Dr. Pramod K. Srivastava showed up with an idea about how heat-shock proteins could be p urified and made into a vaccine for cancer.<br><br> Another hot tip. But this one seemed more promising than most. Like Armen, Srivastava was an immigrant with a passion for science.<br><br> His background was about as elite as it gets in India: He came from the northern city of Allahabad, one of the most important places in both Hindu mythology and modern Indian history, and from a relatively high-ranking caste o f p rofessionals in the Hindu hierarchy. His father was a civil servant and retired Army officer. There is, moreover, hardly a scientific discipline or foreign language that Srivastava hasn 9t studied.<br><br> He has a bachelor 9s degree in biology and chemistry, a master 9s in botany, a PhD in biochemistry, and at age 47 he enrolled in medical school at the University ofConnecticut (where he also ran the Center for Immunotherapy of Cancer and Infections Diseases). Having earned his degrees on three continents, Srivastava has at least a working knowledge of Bengali, English, French, German, Hindi, Japanese, and Urdu. At graduate school in Hyderabad in the early 1980s, Srivastava more or less stumbled into cancer research after a friend showed him a cancer cell in a lab.<br><br> cI couldn 9t get over how weird and strange the cancer cells looked, how different from the normal cells, d he later told an interviewer. Scientists had already managed to vaccinate mice against cancer by injecting them with weakened tumor cells, so Srivastava broke that process down to the next level. Using a centrifuge, he separated the tumor cells into various components, then tried vaccinating mice with different sample parts.<br><br> The one that worked, he found, was the heat-shock protein. However, as he kept experimenting, he realized that the heat-shock proteins had to be bound to short pieces of othe r proteins called peptides . Then Srivastava put aside his research for a few years to come to the United States for a postdoctoral fellowship in genetics at Yale University.<br><br> After their first meeting in New York, Armen and Srivastava continued to tal k p eriodically for ten months. cEvery time we peeled a layer, d Armen said, cit looked better and better. d Armen also had a personal reason for his interest, b ecause his mother had had breast cancer. Although it seemed to go into remission, she died of a stroke when he was 19.<br><br> Finally, in 1994, Armen decided to junk Wall Street, essentially close up his money management firm, and leap to a new career once again. He and Srivastava formed Antigenics to commercialize the heat-shock protein idea. Armen contributed $250,000 of his own money and raised $150,000 from p rivate investors such as a former Dean Witter analyst and the founder of the hedge fund Oracle Investment Management in Greenwich, Connecticut.<br><br> (He did not tap the investors in Armen Partners because cI thought that would be unethical. This was a very, very early stage development, d far riskier than the kinds of investments his firm typically made for its clients. Ten years later, Armen claimed, those same investors pounced on him for keeping them out of such a good deal.<br><br> cYou can 9t win, d he sighed.) The new firm rented a small office on the ninth floor o f one of the most famous landmarks in New York, the art deco Rockefeller Center complex on Fifth Avenue. Srivastava and about eight other scientists continued to work in his lab at Fordham University several miles north in the Bronx. Armen and Srivastava decided to start with pancreatic cancer, kidney cancer, and a kind of skin cancer known as melanoma.<br><br> There were a couple of reasons for this approach: People with those particular diseases have few alternative treatments. Also, Antigenics would need a tumor big enough to provide seven grams for processing, and not all varieties of tumors are that large. But Garo Armen had no intention of limiting himself to kidneys, pancreases, and skin.<br><br> The company 9s methodology 4its platform, in scientific jargon 4could wor k for all cancers, he believed. In fact, he told me, because it is based on the immune system, the Antigenics approach could have applications fo r neurological diseases, cardiovascular disease, infectious diseases, and conditions associated with aging. cIf we execute well, we have the technology to become the Microsoft of this industry 4that level of dominance.<br><br> We believe that we are the masters of the immune system. d N o, he didn 9t just mean the Microsoft of cancer. He meant the Micro-soft of all biotechnology. R ussell H.<br><br> Herndon had just finished a speech at a meeting of the Biotechnology Industry Organization, the main trade group for biotech firms, when Garo Armen and Pramod Srivastava came up to him one day in 1994. As the vice president of regulatory affairs at Genzyme Corporation 4a relatively big and established company, for a biotech 4Herndon handled paperwork and conversations with the Food and Drug Administration. Among other things, he had dealt with the regulators on a type of cell therapy based on the principal of using the patient 9s own body to heal itself.<br><br> An easy conversationalist, with light hair and round, brown eyes, Herndon had earned a bachelor 9s degree in b iology, taken courses at Harvard Business School, and worked for an eclectic collection of other small firms before Genzyme. For their part, the pair from Antigenics knew the science behind their heat-shock proteins, and they knew the business world. They had plans for moving ahead on their research, raising more money, possibly partnering with a big pharmaceutical company, and marketing their vaccine.<br><br> But they had no idea how to approach the government, how to get the approvals they would need to test their drug in humans, or even what approvals were required. cWe 9ve just formed this company, and we would love to get your advice as to who we should talk to at the FDA, and what sorts of questions they might ask, d they said to Herndon. cWhat would the product be classified as?<br><br> What are some of the problems we might encounter? d It was the beginning of Garo Armen 9s crash course in the FDA. There are four basic steps that any company must take in moving a potential drug from lab to market in the United States: tests on animals (known as p reclinical trials), trials on a small group of healthy volunteers to ensure tha t the drug is safe (known as Phase I clinical trials), then two progressively large r trials on people with the disease to test both safety and effectiveness (known as Phase II and III clinical trials). Animal trials are not regulated by the FDA, but in order to test anything on humans, a drug company must submit what is called an investigational new drug application, or IND 4a huge document that summarizes the animal test results, explains the manufacturing process, and outlines the human testing plans in detail.<br><br> Then, after Phase III, the company files an application to actually start selling the drug. For vaccines like Oncophage, the filing is called a biologics license application, or BLA; fo r chemical- b ased drugs, it is a new drug application, or NDA. (There is more on this process in Chapter 5.) By 1995 Armen figured he was ready to seek the FDA 9s go-ahead to start Phase I testing on humans, and he came up with what he thought was the b rilliant idea of having the IND prepared by the medical staff at Memorial Sloan-Kettering Cancer Center in New York, where Srivastava had worked following his stint at Yale.<br><br> The hospital had experience handling the FDA 9s red tape, after all. But that plan did not last long. As Armen put it, in his typical blend of European formality and ironic self-awareness, cAfter a few months I came to the realization that the movement at Sloan-Kettering was at such a snail 9s pace that my temperament didn 9t allow me to put up with it. d Antigenics would have to file its own application with the FDA.<br><br> So Armen contacted Mark Boulding, a partner with the Washington, D.C. firm of Fox, Bennett, and Turner who, he hadbeen told, specialized in regulatory law. Boulding met him at Srivastava 9s Fordham labs.<br><br> Armen quickly learned that the FDA 9s safety requirements are levels above what he had been accustomed to. For instance, he could not simply hand in his animal toxicity test results. cOur experience with animals suggested no toxicity.<br><br> That didn 9t matter. We had to run [separate] toxicology testing d on human subjects in Phase I. Moreover, the manufacturing process that Antigenics had been using to churn out samples for research purposes a t Fordham would have to be upgraded.<br><br> cWe had to have a certain quality of air; certain parts of the manufacturing had to be segmented to guard against cross-contamination. cAll of a sudden, lightning went over my head, d Armen recalled. cThe FDA was not a trivial thing.<br><br> I said, 8Holy Moses, we have to go and bring in some talent that really understands this stuff. 9 d But he said he was not upset at the work that lay ahead. cI was happy, because I now knew what needs to be done. d Throughout this time Armen had kept in contact with Russ Herndon, calling him every six months or so with more questions. As far as Herndon was concerned, Antigenics had a fascinating scientific theory that probably was not as good in reality as it sounded.<br><br> Meanwhile, one of his colleagues at Genzyme, Elma Hawkins, was analyzing Antigenics for another reason. It was her job to scout out possible acquisitions for Genzyme. And she wanted Antigenics.<br><br> Hawkins is a native of South Africa who retains a slight accent and a calenda r from that country on her office wall. In a peripatetic career, she spent he r adolescence in London, including two years studying at the Royal Ballet, then headed back to Pretoria for college. A professor on sab b atical from the University of Alabama recruited her for her PhD in medicinal chemistry, with a specialization in cancer.<br><br> From there Hawkins went to Warner-Lambert Company in Michigan, where she shepherded three widely varying drugs through the FDA, and to Boston, where she did research at Tufts University and grew skin at a biotech. After orchestrating Genzyme 9s purchase of that b iotech, Hawkins created the new company 9s molecular oncology unit. She is short and sturdy, with rimless oval glasses and wavy, red- b rown hair that brushes her shoulders.<br><br> cI was so impressed by the thoroughness of the science. It was a really different way of approaching the treatment of cancer, d she said of her first view of Antigenics. But unless the company could get the FDA to approve its p lans for Phases I, II, and III, it was not worth buying.<br><br> So Hawkins offered to help teach Armen the ropes of working with the regulators. The next thing she knew, she was commuting from her home in Boston to Antigenics 9 New York headquarters every weekend 4without pay 4 from February through July of 1996. cI didn 9t think he 9d take me up on that offer to that degree, d she admitted a little ruefully.<br><br> That spring, Armen also spoke for an hour on the phone with Phil Noguchi, the FDA official. cI said we want to file an IND, but we want to have a pre-IND meeting 4I didn 9t know what the hell those terms are. d A pre-IND meeting occurs when people from a drug company meet with the FDA staff to discuss the specifics of their plans for human trials. The idea is that if the company can find out what the FDA wants in the IND beforehand, then it should be easier to write an application that will be approved.<br><br> This can b e particularly important for a fledgling biotech like Antigenics. It 9s probably the scientists 9 first application, so they need to understand the process. And their cutting-edge technology may be new to the FDA.<br><br> As Armen described things, cI thought it was critical for us to sit down with the agency and explain to them the nuances of our technology. The world 9s first personalized protein therapeutic 4there 9s no regulation that governs a personalized protein therapeutic. Unless we acquainted the agency with the kind of details that were critical, we would be at a disadvantage. d He cited one potential stumbling block: Drugs in Phase I are supposed to tested only on healthy volunteers.<br><br> By definition, however, the Oncophage vaccine could not possibly be tried on healthy people, because it had to be made from the trial subjects 9 own tumors, and therefore, Antigenics needed people with cancerous tumors. The FDA agreed to waive the Phase I rule. N oguchi, Armen 9s main contact at the regulatory agency, is hardly a scary figure.<br><br> Slightly built, his straight black hair speckled with grey, he speaks calmly and quietly, as careful as Armenis charismatic. He wears the sparkling csummer blue d uniform of a captain in the U.S. Public Health Service Commissioned Corps.<br><br> (Many people at the FDA are members of this little-known branch of the national uniformed services, which was founded in 1798 to care for sick and injured merchant marines.) He, too, has an immigrant 9s story, but this one goes back through two generations of racism. Noguchi tells it without any apparent bitterness. His grandparents came from Japan, took up farming near Sacramento, California, and then were interned with other Japanese-Americans during World War II.<br><br> After the war, his father had to sweep floors for a while despite a degree in architecture and engineering from the University of California at Berkeley; his mother, a nurse, rode in the back of the bus with ccoloreds d in Washington, D.C. By Phil Noguchi 9s generation, at least, things had gotten better. He was bornin Sacramento in 1949 and moved to Washington, D.C.<br><br> for medical school at George Washington University. There he joined a Public Health Service summer internship program, working in the National Institutes of Health 9s Division of Biological Standards; when the division was transferred to the FDA in 1972, he followed with it. Then Naguchi heard about a deal where the p rogram would pay his tuition ($2,600 a year at the time) if he promised to spend two years doing research for the government.<br><br> He signed because of the money. But he stayed, he said, because of the scientific camaraderie and respect. cEveryone 9s opinion makes a difference.<br><br> You 9re a junior staf f scientist, but if your research has been in a certain area of monoclonal antibodies, and you review a protocol, that factors into how the FDA reviews a p articular program. d FDA rules prohibit Noguchi from talking specifically about Antigenics or its p roducts, but he is certainly mindful that science is changing rapidly all around the six-floor outpost where the Oncophage reviewers work, some two miles from the main FDA offices. cWhen there are areas involving new techniques, d he explained, a couple of months after Antigenics was placed on the clinical hold, cwhat we strive to do is to be open about what we have requested and why. Each product is looked at individually.<br><br> Together, we can brainstorm and come up with tests that are going to be meaningful. Almost anything that 9s b eing done out there can be accommodated. d However, he also warned that when it comes to vaccines made from a patient 9s cancer cells, which a numbe r of companies besides Antigenics are working on, cthe mechanism of action isn 9t known. We have had a plethora of trials in which the results are highly inconsistent. d To Armen, the FDA as personified by Noguchi seemed flexible and reasonable.<br><br> cPhil Noguchi said, 8We will work with you. We 9re not going to stop this product from being developed. We 9re not going to ask you to do something that is scientifically impossible. 9 d In order to prepare for the pre-IND meeting, Armen, Hawkins, Srivastava, and a few other scientists from Antigenics created a slideshow of over 40 slides, outlining the rationale and the science behind their vaccine, and also detailing the animal toxicity data.<br><br> It was not difficult, according to Armen: Each person worked on the preparations for two to three days a week over several weeks, cpulling data, analyzing, tabulating so it was compatible with the agency 9s standards. d The meeting itself lasted two hours and was relatively low-key. Armen was pleasantly surprised by the sophisticated level of queries from the ten or so FDA staffers. cWhat impressed me was their questions about taking it to the next level, and the next. d The bottom line: cThey said go ahead, prepare the IND. d The only problem was, Genzyme had decided not to acquire Antigenics afte r all.<br><br> At around $75 million, Elma Hawkins said, the price tag was just too high, considering that call there was, was Garo and Pramod and a bunch of patents. d But that did not signal the end of Hawkins 9 relationship with the company. cGaro in his very persuasive way told me, 8On Monday you 9ll come and wor k for me. 9 d A rmen had set a goal of getting the IND approved by the end of 1996. Since the FDA has 30 days in which to make its decision 4if the agency does no t reject the submission within that time, it is automatically approved 4that essentially meant filing the massive application by around Thanksgiving.<br><br> The filing would run 1,600 pages in three volumes, with six copies of each. cElma put in 24/7 for a month and a half, d Armen said. As the self-imposed deadline neared, about five other staffers joined her for allnighters.<br><br> cAt three in the morning we 9re all standing there, punching holes, assembling volumes and volumes of work, d Hawkins recalled. cI read and reread everything. d Spouses were lassoed to come in and proofread. The firm 9s five printers spit out copy after copy.<br><br> The group ordered in pizza and Chinese food and took turns grabbing naps on the floor and the couch in Armen 9s office; amazingly, in all the frenzy, no tomato or soy sauce spilled on the pages. cThere were nights I never slept. All I was seeing was the deadline, d said Hawkins.<br><br> Luckily her old ballet training had taught her how to focus with little sleep. By the last night, Armen said, celeven of us were working until two-thirty in the morning. d Driving home on the Long Island Expressway, cit was the first time ever that I fell asleep at the wheel d 4just for a few seconds. But they made it.<br><br> They filed around Thanksgiving and got the go-ahead by late December. A year afterwards, Hawkins went back to reread that IND. cI found maybe one spelling mistake. d T he first Phase I trial began in November 1997 with pancreatic cance r p atients at Memorial Sloan-Kettering 4patients who were given perhaps a year more to live.<br><br> In other words, they might be spending the last year of thei r lives helping science. And they didn 9t have much to lose. Ten people ultimately joined the trial, but it was hard to find appropriate subjects.<br><br> cI 9d hear about the patient in the morning and grab my little box o f Styrofoam and dry ice, d Hawkins recalled. She would wait in the operating room while doctors removed the tumor, hovering, trying to make sure they saved seven grams for her after doing their biopsy. (If the cancer had spread to the liver, the doctor simply sewed the patient back up; the patient would not live long enough to participate effectively in a trial.) Then Hawkins would grab her precious grams of tumor, pack them in the dry ice, and dash for the Delta Air Lines Shuttle 4she was building up frequent flyer miles 4to Antigenics 9 Massachusetts lab for processing.<br><br> She repeated this dash every week or two for several months. Then she stopped playing courier, and the samples were more officially delivered by Federal Express. Because the FDA, in approving the IND, had essentially approved Antigenics 9 blueprint for all three phases of trials, Hawkins and her colleagues did no t expect much contact with the regulators for the next few years.<br><br> Every year they were required to submit a report detailing both the number of patients enrolled in their ongoing tests and the number who had experienced what is known as an adverse event 4which means not just side effects from the drug, b ut any sort of medical complication. In addition, Antigenics would need to file a formal request for a new protocolbefore beginning any subsequent trial, describing what it intended to study, the names and background of the scientists (known as investigators) who would be conducting the study, the criteria that would be used to determine toxicity, and samples of the informed consent form that patients had signed. The new protocol request is typically about one-inch thick and takes about a month to compile, Hawkins said, but she implied that it is no big deal; it is organizational work that the company would want to do anyway, even if the FDA did not exist.<br><br> After all, a company would certainly need to line up its investigators and make sure they were qualified, and patients by law have to give their informed consent. So, even while the test on pancreatic tumors at Memorial Sloan-Kettering was unde r way, Antigenics launched two more 4a study of 36 people with melanoma and another involving 42 kidney cancer patients, both at the University o f Texas M.D. Anderson Cancer Center in Houston.<br><br> The bigger problem was that more trials demanded more money. In November 1999 Garo Armen went back to his Wall Street and pharmaceutical contacts for an infusion of $39 million. That still was not enough, and so in February 2000, with exquisite timing, Antigenics sold its first shares of stock to the public.<br><br> This move raised $67.3 million. A month later, the stock market slide began. Antigenics plowed ahead.<br><br> After six years of sporadic conversations, Armen lured Russ Herndon to join him full-time as chief operating officer, over lunch in 2001. (Later, the company would reorganize and Herndon would become p resident of commercial operations.) As the work expanded, Antigenics began constructing an 80,000-square-foot, two-story, corrugated-metal second home in an office park in Lexington, Massachusetts, a suburb of Boston best known for the battle that launched the American Revolution. By winter 2004, the facility would replace the Woburn labs and house most of Antigenics 9 220 employees, including all of its manufacturing work, with options to double the space and a lease that could be extended to 30 years.<br><br> The company also moved its New York operations to larger quarters on the 21st and 22nd floors o f another building at Rockefeller Center. Connected by an internal spiral staircase, the new digs combine elegant, dark, wood furniture and paneling with industrial blue-grey carpet and basic white walls and cubicles. Armen 9s small executive suite, overlooking the Rockefeller Center skating rink, has a foldout bed for his next all-nighter.<br><br> And the trials grew; in addition to the kidney, melanoma, pancreatic, and colorectal studies, the Oncophage vaccine was being tested on lung cancer and lymphoma, and Antigenics also was investigating a genital herpes vaccine and a vaccine for leukemia. Because the target populations for its kidney and melanoma uses are so small, Oncophage was granted so-called corphan drug d status from the FDA, which provides tax credits and an extra stretch o f marketing exclusivity to companies that make medicines for rare diseases. And because Oncophage is aimed at life-threatening conditions that have few other treatments, the FDA also put the drug on its cfast track d designation, which meant the agency would consider the application under somewhat more lenient criteria than normal.<br><br> cYou take advantage of everything you can, d Herndon told me. In the midst of all this work, Elan 4the Irish company with the Alzheimer 9s drug that Garo Armen had invested in back in his Wall Street days 4 b lew up. It was by that point a global, $2 billion company, and Armen was on the board of directors.<br><br> However, it suddenly halted the Alzheimer 9s trials because p atients were developing a potentially deadly brain inflammation. Moreover, investors and Wall Street analysts started raising questions about the company 9s accounting methodology, a convoluted system that involved 55 separate joint ventures and partnerships and evoked all-too-recent memories of the collapse of Enron Corporation. In July 2002, after the stock had plunged 96 percent and the two top executives resigned, Armen was named chairman.<br><br> Investors did not blame Armen or the other board members for the mess; indeed, Wall Street was impressed with the fact that Armen personally answered questions at his first press conference as chairman, rather than handing the burden off to Elan 9s remaining managers. But the pressure to fix the company was intense. So now, on top of running Antigenics, Armen had to reassure Wall Street about Elan while finding ways to shed its assets, lay off workers, anddo something about those joint ventures and partnerships.<br><br> It took six months before a new chief executive was hired. Then the FDA reorganized the way it reviewed protein- b ased drugs. And the Antigenics crew set off for their meeting in Rockville.<br><br> A rmen said he asked just two questions after the FDA reviewers read aloud their prepared statement putting Oncophage on clinical hold. cWhat does this mean? d and cHow am I going to explain this? d As he recalled, one of the FDA people told him, cI don 9t care what you tell investors. d Armen replied: cI don 9t mean investors. What am I going to tell doctors and patients who have no treatment options 4 8I am going to take a p otential hope away from you 9? d In fact, the clinical hold did not mean that Antigenics would have to pull its treatment away from anyone.<br><br> Patients already in the Phase III trial could continue. New patients could even be admitted to other trials. The only change was that no new patients could begin the Phase III kidney and melanoma trials.<br><br> But it was also a fact that Armen did have to worry about investors. A ruling like this is what Wall Street calls a cmaterial event d 4something that could have a significant effect on a company 9s finances. After all, if Antigenics never managed to supply enough information to get the hold lifted, the FDA would be unlikely to ever approve the drug.<br><br> No drug, no revenue. The fou r Antigenics executives knew that they would have to make a public announcement by the next day, which would not be fun. Because everything must be precise when it comes to science, government regulations, and financial statements, Armen and his colleagues wanted a copy of the statement that the FDA staff had read aloud to them.<br><br> That way, they could use the exact wording in their own public announcement. There would be no misunderstandings or misinterpretations. Sorry, the FDA review ers told them, but the statement could not be given out until it had gone through the agency 9s formal review process 4certainly not today.<br><br> In the end, the FDA staffers read the letter aloud again, slowly, several times, while the four from Antigenics scribbled it down like stenographers. Then Armen and his colleagues headed back to the DoubleTree hotel. cHoly crap, d Herndon remembered thinking.<br><br> cWe 9ve got to figure out what it is they want and get it to them as fast as possible. d Armen later d