Saturday, January 5, 2013
Thursday, January 3, 2013
Linda Campbell was not quite 4 years old when her appendix burst, spilling its bacteria-rich contents throughout her abdomen. She was in severe pain, had a high fever, and wouldn't stop crying. Her parents, in a state of panic, brought her to the emergency room in Atlanta, where they lived. Knowing that Campbell's organs were beginning to fail and her heart was on the brink of shutting down, doctors rushed her into surgery.
Today, removing an appendix leaves only a few droplet-size scars. But back then, in the 1960s, the procedure was much more involved. As Campbell recalls, an anesthesiologist told her to count backward from 10 while he flooded her lungs with anesthetic ether gas, allowing a surgeon to slice into her torso, cut out her earthworm-size appendix, and drain her abdomen of infectious slop, leaving behind a lengthy, longitudinal scar.
The operation was successful, but not long after Campbell returned home, her mother sensed that something was wrong. The calm, precocious girl who went into the surgery was not the same one who emerged. Campbell began flinging food from her high chair. She suffered random episodes of uncontrollable vomiting. She threw violent temper tantrums during the day and had disturbing dreams at night. "They were about people being cut open, lots of blood, lots of violence," Campbell remembers. She refused to be alone, but avoided anyone outside her immediate circle. Her parents took her to physicians and therapists. None could determine the cause of her distress. When she was in eighth grade, her parents pulled her from school for rehabilitation.
Over time, Campbell's most severe symptoms subsided, and she learned how to cope with those that remained. She managed to move on, become an accountant, and start a family of her own, but she wasn't cured. Her nightmares continued, and nearly anything could trigger a panic attack: car horns, sudden bright lights, wearing tight-fitting pants or snug collars, even lying flat in a bed. She explored the possibility of post-traumatic stress disorder with her therapists, but could not identify a triggering event. One clue that did eventually surface, though, hinted at a possibly traumatic experience. During a session with a hypnotherapist, Campbell remembered an image, accompanied by an acute feeling of fear, of a man looming over her.
Then, one fall afternoon in 2006, four decades after her symptoms began, Campbell met an anesthesiologist at a hypnotherapy workshop. Over lunch, she found herself telling the anesthesiologist about her condition. She mentioned the appendectomy she'd had not long before everything changed.
The anesthesiologist was intrigued. He told her about a phenomenon that had sometimes accompanied early gas anesthetics, particularly ether, in which patients reacted to the gas by coughing and choking, as if they were suffocating.
The comment sparked something in Campbell. "I started having all these flashes," she remembers. "The flashes were me being on the table. The flashes were of the room. The flashes were of the bright lights over me." A man—the same one from her memory?—was there. At some point, the room went black. "And then I got to the place where I was on the table, and I just remember feeling terror," she says. "That's all I remember. I don't see anything. I don't feel anything. It's absolute, abject terror. And the feeling that I am dying." At that moment, Campbell realized that something had happened to her during her appendectomy, something that changed her forever. After several years of investigation, she figured it out: she had woken up on the table.
This experience is called "intraoperative recall" or "anesthesia awareness," and it's more common than you might think. Although studies diverge, most experts estimate that for every 1,000 patients who undergo general anesthesia each year in the United States, one to two will experience awareness. Patients who awake hear surgeons' small talk, the swish and stretch of organs, the suctioning of blood; they feel the probing of fingers, the yanks and tugs on innards; they smell cauterized flesh and singed hair. But because one of the first steps of surgery is to tape patients' eyes shut, they can't see. And because another common step is to paralyze patients to prevent muscle twitching, they have no way to alert doctors that they are awake.
Many of these cases are benign: vague, hazy flashbacks. But up to 70 percent of patients who experience awareness suffer long-term psychological distress, including PTSD—a rate five times higher than that of soldiers returning from Iraq and Afghanistan. Campbell now understands that this is what happened to her, although she didn't believe it at first. "The whole idea of anesthesia awareness seemed over-the-top," she told me. "It took years to begin to say, 'I think this is what happened to me.' " She describes her memories of the surgery like those from a car accident: the moments before and after are clear, but the actual event is a shadowy blur of emotion. She searched online for people with similar experiences, found a coalition of victims, and eventually traveled up the East Coast to speak with some of them. They all shared a constellation of symptoms: nightmares, fear of confinement, the inability to lie flat (many sleep in chairs), and a sense of having died and returned to life. Campbell (whose name and certain other identifying details have been changed) struggles especially with the knowledge that there is no way for her to prove that she woke up, and that many, if not most, people might not believe her. "Anesthesia awareness is an intrapersonal event," she says. "No one else sees it. No one else knows it. You're the only one."
The past year in fitness has been alternately inspiring, vexing and diverting, as my revisiting of all of the Phys Ed columns published in 2012 makes clear. Taken as a whole, the latest exercise-related science tells us that the right types and amounts of exercise will almost certainly lengthen your life,strengthen your brain, affect your waistline and even clear debris from inside your body's cells. But too much exercise, other 2012 science intimates, might have undesirable effects on your heart, while popping painkillers, donning stilettos and sitting and reading this column likewise have their costs.
With New Year's exercise resolutions still fresh and hopefully unbroken on this, day two of 2013, it now seems like the perfect time to review these and other lessons of the past year in fitness science.
First, since I am habitually both overscheduled and indolent, I was delighted to report, as I did in June, that the "sweet sport" for health benefits seems to come from jogging or moderately working out for only a brief period a few times a week.
Specifically, an encouraging 2012 study of 52,656 American adults found that those who ran 1 to 20 miles per week at an average pace of about 10 or 11 minutes per mile — my leisurely jogging speed, in fact — lived longer, on average, than sedentary adults. They also lived longer than the group (admittedly small) who ran more than 20 miles per week.
"These data certainly support the idea that more running is not needed to produce extra health and mortality benefits," Dr. Carl J. Lavie, a cardiologist in New Orleans and co-author of the study told me. "If anything," he said, "it appears that less running is associated with the best protection from mortality risk."
Similarly, in a study from Denmark that I wrote about in September, a group of pudgy young men lost more weight after 13 weeks of exercising moderately for about 30 minutes several times a week than a separate group who worked out twice as much.
The men who exercised the most, the study authors discovered, also subsequently ate more than the moderate exercisers.
Even more striking, however, the vigorous exercisers subsequently sat around more each day than did the men who had exercised less, motion sensors worn by all of the volunteers showed.
"They were fatigued," said Mads Rosenkilde, a Ph.D. candidate at the University of Copenhagen and the study's co-author.
Meanwhile, the men who had worked out for only about 30 minutes seemed to be energized by their new routines. They stood up, walked, stretched and even bounced in place more than they once had. "It looks like they were taking the stairs now, not the elevators, and just moving around more," Mr. Rosenkilde said. "It was little things, but they add up."
And that idea was, in fact, perhaps the most dominant exercise-science theme of 2012: that little things add up, with both positive and pernicious effects. Another of my favorite studies of 2012 found that a mere 10 minutes of daily physical activity increased life spans in adults by almost two years, even if the adults remained significantly overweight.
But the inverse of that finding proved to be equally true: not fitting periods of activity into a person's daily life also affected life span. Perhaps the most chilling sentence that I wrote all year reported that, according to a large study of Western adults, "Every single hour of television watched after the age of 25 reduces the viewer's life expectancy by 21.8 minutes."
I am watching much less television these days.
But not all of the new fitness science I covered this year was quite so sobering or, to be honest, consequential. Some of the more practical studies simply validated common sense, including reports that to succeed in ball sports, keep your eye on the ball; during hot-weather exercise, pour cold water over your head; and, finally, on the day before a marathon, eat a lot.
But when I think about the science that has most affected how I plan my life, I return again and again to those studies showing that physical activity alters how long and how well we live. My days of heedless youth are behind me. So I won't soon forget the study I wrote about in September detailing how moderate, frequent physical activity in midlife can delay the onset of illness and frailty in old age. Exercise won't prevent you from aging, of course. Only death does that. But this study and others from this year underscore that staying active, even in moderate doses, dramatically improves how your aging body feels and responds.
Unsettled, to say the least. A recent analysis from The Cochrane Collaboration, an international group that reviews scientific evidence, concluded that general health checkups for adults did not help patients live longer or healthier lives.
I thought about that the other day as I worked my way through the morning appointments. Some patients were there for management of their ongoing diseases, like diabetes and hypertension. But many were there for a general checkup, often prompted by minor symptoms.
One 43-year-old man came because of shoulder pain. It took just a few minutes of questions and physical exam to attribute the pain to muscle strain from lifting weights, with the simple prescription to lay off the weights for a few weeks.
For an internist, though, this is a golden opportunity — a minor symptom gets a patient into my office, which becomes a prime opportunity to address general health. Like many healthy people, he hadn't been to a doctor in years, so there was lots to do.
I checked his blood pressure to screen for the "silent killer" of hypertension. I noticed that he hadn't had a tetanus booster in 10 years, not to mention an annual flu shot. I ordered a blood test for cholesterol. I went through his family medical history in case there were any particular diseases we should be on the lookout for.
We discussed a healthy diet and exercise. I screened for H.I.V., depression, domestic violence, smoking, and drug and alcohol abuse.
It was a lot to pack in for a visit about shoulder pain, but screening is where we get the most bang for the buck, or so we've been told. If our detailed interview uncovered one serious illness in the making, we'd be poised to treat it earlier, not later. This is the essence of primary care medicine.
So to read the new report suggesting that these exhaustive (and exhausting!) general checkups may not impact morbidity and mortality was dispiriting.
The study was a meta-analysis, in which the authors scoured the literature and came up with 16 randomized trials in which one group of patients had general checkups and the other group did not. Two-thirds of the trials, covering more than 150,000 patients, followed the patients long enough — nearly a decade — to track actual death rates.
Patients in the checkup group received many more new diagnoses; one trial found a 20 percent increase. But they did not live longer. They died from cancer and heart disease at the same rates as their peers who did not have checkups.
The visit with my patient ran well over our allotted time. The next several patients were delayed because I'd scrambled to cover all the bases that constitute general health. (The same bases, incidentally, that are being tabulated as a measure of my "quality.") But are we — as the study might suggest — wasting our collective breath here?
Certainly the study had drawbacks. By the time a trial is planned, executed, published and then later reviewed in a meta-analysis, it is of course outdated to some degree. So in some of the trials, the medical practices may not reflect what we are actually doing today. And the group that did not have checkups may have actually received a fair bit of general health screening along the way if they, like my patient, saw a doctor for a sore shoulder and walked out with a cholesterol analysis and a flu shot. Additionally, not enough data were collected to permit conclusions about the potential harms of general checkups — excess medications, harmful tests, false-positive diagnoses.
Still, it would have been nice to see a hint of a benefit for checkups in this analysis, given how much effort and time is invested in screening. We strive to practice evidence-based medicine, and if general checkups don't help our patients live healthier and longer lives, then maybe we should be focusing our resources elsewhere.
Of course it can also be argued that this analysis, like most studies, offers us only averaged data for a population of people. It does not give us specifics for an individual person. There may be certain types of patients who do benefit from check-ups, and others who may be harmed.
So I'm not – yet — telling my patients to skip checkups altogether. Certainly those in robust health need not slavishly adhere to the annual physical. In any case, it's not so much the annual "physical," but rather the "history-taking," that is critical. It's the detailed conversation that is much more likely to uncover lurking medical issues than the physical exam or blood tests.
What the meta-analysis can't quantify, of course, is the value of establishing a doctor-patient relationship before one gets sick. I feel fortunate to have been with many of my patients for years, a few for a decade or two. If you stick together long enough, you'll be there when something comes up. Treatment is immeasurably easier when it's not taking place between strangers. It's hard to place a numerical value on that.
Danielle Ofri is an associate professor of medicine at New York University School of Medicine and editor in chief of the Bellevue Literary Review. Her most recent book is "Medicine in Translation: Journeys With My Patients."
Tuesday, January 1, 2013
I was 19 when I first saw him -- in a class taught by a famous neuropsychologist, Karl Pribram. I'd see Tom at the coffee house, the library, and around campus. He seemed perennially enthusiastic, and had an exaggerated way of moving that made him seem unusually focused. I found it uncomfortable to make eye contact with him, not because he seemed threatening, but because his gaze was so intense.
"Please forgive me for asking this, but I do this with everybody. Could you tell me your name again and how it is that I know you?"
Once Tom and I were sitting next to each other when Pribram told the class about a colleague of his who had just died a few days earlier. Pribram paused to look out over the classroom and told us that his colleague had been one of the greatest neuropsychologists of all time. Pribram then lowered his head and stared at the floor for such a long time I thought he might have discovered something there. Without lifting his head, he told us that his colleague had been a close friend, and had telephoned a month earlier to say he had just been diagnosed with a brain tumor growing in his temporal lobe. The doctors said that he would gradually lose his memory -- not his ability to form new memories, but his ability to retrieve old ones ... in short, to understand who he was.
Tom's hand shot up. To my amazement, he suggested that Pribram was overstating the connection between temporal-lobe memory and overall identity. Temporal lobe or not, you still like the same things, Tom argued -- your sensory systems aren't affected. If you're patient and kind, or a jerk, he said, such personality traits aren't governed by the temporal lobes.
Pribram was unruffled. Many of us don't realize the connection between memory and self, he explained. Who you are is the sum total of all that you've experienced. Where you went to school, who your friends were, all the things you've done or -- just as importantly -- all the things you've always hoped to do. Whether you prefer chocolate ice cream or vanilla, action movies or comedies, is part of the story, but the ability to know those preferences through accumulated memory is what defines you as a person. This seemed right to me. I'm not just someone who likes chocolate ice cream, I'm someone who knows, who remembers that I like chocolate ice cream. And I remember my favorite places to eat it, and the people I've eaten it with.
From a friend, Pribram had learned that his colleague had decided to go to the Caribbean for a vacation with his wife. One day he just walked out into the ocean and never came back. He couldn't swim; he must have gone out with the intention of not coming back -- before the damage from the tumor could take hold, Pribram said.Pribram walked up to the lectern and gripped it with both hands. When they had spoken last, his colleague seemed more sad than frightened. He was worried about the loss of self more than the loss of memory. He'd still have his intelligence, the doctors said, but no memories. "What good is one without the other?" his colleague had asked. That was the last time Pribram spoke to him.
The room was silent for 10 or 15 seconds -- stone silent. I looked over at Tom's notebook. "Neuropsychologist contemplates losing his mind," Tom had written.
If he had lived, Pribram's colleague would have experienced what neuroscientists call retrograde amnesia. This is the kind of amnesia that is most often dredged up as a plot element in bad comedies and cheap mystery stories; so-and-so gets hit on the head and then can't remember who he is anymore, wanders around aimlessly, finding himself in zany predicaments, until he gets hit on the head again and his memory remarkably returns. This almost never occurs in real life. Although retrograde amnesia is real, it's usually the result of a tumor, stroke, or other organic brain trauma. It isn't restored by a knock on the head. Because they can still form new memories, patients with retrograde amnesia are acutely aware that they have a cognitive deficit, are painfully knowledgeable about what they are losing.
Tom and I crossed paths years again later when we were both working for a research company. He was part of a team designing virtual musical instruments for non-musicians, like Guitar Hero or Rock Band, seeking to give customers an awesome music-playing experience after zero hours of practice. I saw Tom in the halls from time to time, said hello, saw him at a couple of company jam sessions; he was a really good keyboard player.
Sometime after I left the research company to begin my first academic job, I ran into a woman from the company who asked if I'd heard the news about Tom.
"He has an inoperable brain tumor, temporal lobe. The doctors say he has four months to live. I just visited him. You might want to drop by and say hello."
"Well I ... I don't really know him. I mean, we said hi in the halls and stuff. But, I don't know him ... I don't think we've ever had a conversation longer than two minutes."
"It doesn't matter," she said. "He doesn't really have anything to do, other than to visit with people. I think he'd really appreciate it." She gave me Tom's number, saying I should phone first, because he has good days and bad.
I phoned and a caregiver answered. We made an appointment for the following Thursday at 1:00 pm. "He's not so good first thing in the morning. The drugs. And some days aren't good at all. Call first, around 11:00 in the morning, and I'll let you know how he's doing. Apart from that, I should warn you, he doesn't remember very much -- the tumor has wiped out his memories of the past."
Sunday, December 30, 2012
THE doctor was dumbfounded: a drug that used to cost $50 was now selling for $28,000 for a 5-milliliter vial.
The physician, Dr. Ladislas Lazaro IV, remembered occasionally prescribing this anti-inflammatory, named H.P. Acthar Gel, for gout back in the early 1990s. Then the drug seemed to fade from view. Dr. Lazaro had all but forgotten about it, until a sales representative from a company called Questcor Pharmaceuticals appeared at his office and suggested that he try it for various rheumatologic conditions.
"I've never seen anything like this," Dr. Lazaro, a rheumatologist in Lafayette, La., says of the price increase.
How the price of this drug rose so far, so fast is a story for these troubled times in American health care — a tale of aggressive marketing, questionable medicine and, not least, out-of-control costs. At the center of it is Questcor, which turned the once-obscure Acthar into a hugely profitable wonder drug and itself into one of Wall Street's highest fliers.
At least until recently, that is. Now some doctors, insurance companies and investors are beginning to have doubts about whether the drug is really any better than much cheaper alternatives. Short-sellers have written scathing criticisms of the company, questioning its marketing tactics and predicting that its shareholders are highly vulnerable.
That Acthar is even a potential blockbuster is a remarkable turn of events, considering that the drug was developed in the 1950s by a division of Armour & Company, the meatpacking company that once ruled the Union Stock Yards of Chicago. As in the 1950s, Acthar is still extracted from the pituitary glands of slaughtered pigs — essentially a byproduct of the meatpacking industry.
The most important use of Acthar has been to treat infantile spasms, also known as West syndrome, a rare, sometimes fatal epileptic disorder that generally strikes before the age of 1.
For several years, Questcor, which is based in Anaheim, lost money on Acthar because the drug's market was so small. In 2007, it raised the price overnight, to more than $23,000 a vial, from $1,650, bringing the cost of a typical course of treatment for infantile spasms to above $100,000. It said it needed the high price to keep the drug on the market.
"We have this drug at a very high price right now because, really, our principal market is infantile spasms," Don M. Bailey, Questcor's chief executive, told analysts in 2009. "And we only have about 800 patients a year. It's a very, very small — tiny — market."
Companies often charge stratospheric prices for drugs for rare diseases — known as orphan drugs — and Acthar's price is not as high as some. Society generally tolerates those costs to encourage drug companies to develop crucial, possibly lifesaving drugs for these often neglected diseases.
But Questcor did almost no research or development to bring Acthar to market, merely buying the rights to the drug from its previous owner for $100,000 in 2001. And while the manufacturing of Acthar is complex, it accounts for only about 1 cent of every dollar that Questcor charges for the drug.
Moreover, the tiny "orphan" market soon became much bigger. Before long, Questcor began marketing the drug for multiple sclerosis, nephrotic syndrome and rheumatologic conditions, even though there is little evidence that Acthar is more effective for those other conditions than alternatives that are far cheaper. And the company did so without being required to prove that the drug actually works. That is because Acthar was approved for use in 1952, before the Food and Drug Administration required clinical trials to show a drug is effective for a particular disease. Acthar is essentially grandfathered in.
Today, only about 10 percent of the drug's sales are for infantile spasms. The new uses, Mr. Bailey has told analysts, represent multibillion-dollar opportunities for Acthar and Questcor, its sole maker.
The results have been beyond even the company's wildest dreams. Sales of Acthar, which accounts for essentially all of Questcor's sales, totaled nearly $350 million in the first nine months this year, up 145 percent from the period a year earlier. In the same period, Questcor's earnings per share nearly tripled, to $2.12. In the five years after the big Acthar price increase in August 2007, Questcor shares rose from around 60 cents to about $50, in one of the best performances of any stock in any industry.
But in September, the shares plummeted after Aetna, the big insurer, said it would no longer pay for Acthar, except to treat infantile spasms, because of lack of evidence the drug worked for other diseases. The stock now trades at $26.93.
Peter Wickersham, senior vice president for cost of care at Prime Therapeutics, a pharmacy benefits manager that has found the drug is possibly being overused, says the huge increase in Acthar's price for patients "just invites the type of scrutiny that it's received."
Questcor, meanwhile, has disclosed that the United States attorney's office in Philadelphia is investigating its marketing practices. The company hasn't been accused of wrongdoing.
Mr. Bailey, Questcor's C.E.O., defends his company's practices. He says that when Questcor raised Acthar's price, it did not initially intend to market the drug for other uses. It simply responded to demand. "Nobody predicted this," he said. "Nobody."
He also says that Questcor isn't competing with low-price alternatives, but that it is marketing the drug as a treatment when those alternatives fail. Used that way — for instance, as a last chance to avert kidney failure — insurers are still paying for the drug at least 85 percent of the time, he says.
Still, given that Questcor is now pursuing billion-dollar opportunities far beyond the treatment of infantile spasms, is the high, orphan-drug price still justified?
"We could lower the price and make less money," Mr. Bailey says, "and then we would be sued by our shareholders."
Whatever the case, one group of shareholders has done pretty well for itself. Over the last two years, as the company's share price mainly soared, Questcor insiders have sold more than $100 million of stock.
THE story of Questcor's wonder drug begins in Rochester, Minn. It was there, at the Mayo Clinic, that Dr. Philip S. Hench spent more than 20 years searching for what he called Substance X.
Dr. Hench, a rheumatologist, hypothesized that the body could make a compound that stilled the immune system's attacks on the joints of people with rheumatoid arthritis.
It turned out that another Mayo researcher, Dr. Edward C. Kendall, had isolated six hormones made by the adrenals, the small glands atop the kidneys that are chiefly responsible for releasing stress hormones. When a few patients were injected with one of the hormones in 1948, their symptoms subsided.
But that hormone, now known as cortisone, was then hard to synthesize. So Dr. Hench thought of injecting another substance that would stimulate the body to produce its own cortisone and othersteroid hormones. That substance was adrenocorticotropic hormone, or ACTH, which is made by the pituitary gland.
Dr. Hench obtained some ACTH from the Armour meatpacking company, which was extracting it from pigs as part of an effort to develop markets for leftover animal parts. (Its big success was Dial soap, introduced in 1948.)
When ACTH was injected into the first arthritis patient in February 1949, the results were as good as with cortisone, spurring a huge spike in demand for animal glands. By 1950, thousands of patients, not only those with arthritis but also those with gout, lupus, ulcerative colitis and many other diseases, had been treated with either cortisone or ACTH.
That year, Dr. Hench, Dr. Kendall and a third scientist were awarded the Nobel Prize in medicine.
In 1952, Armour won approval from the F.D.A. for H.P. Acthar Gel, or "highly purified" ACTH mixed with gelatin (another animal byproduct) to make it last longer in the body and require fewer injections. The label said the drug could be used to treat about 50 diseases.
But by the 1980s, drug companies had learned to synthesize steroids like prednisone, and those became the treatment of choice. In 1995, when the F.D.A. found numerous quality control problems at the factory manufacturing Acthar, the drug's owner at the time, Rhône-Poulenc Rorer, decided to discontinue the product rather than invest in manufacturing improvements.
That decision provoked an outcry from some patient groups and pediatric neurologists, who said the drug was the best treatment for infantile spasms. So Rhône-Poulenc, which became Aventis after a merger, continued to make a limited supply that was rationed to treat only infantile spasms or severe flare-ups of multiple sclerosis. With Aventis losing several million dollars a year on the drug, on sales of only about a half-million dollars, the company looked for a way out.
It sold the drug in 2001 to Questcor for $100,000 as well as a 1 percent royalty on annual sales over $10 million. At the time, Questcor, formed by a merger of two small companies in 1999, was losing money and looking for drugs to market. With help from Aventis, Questcor set up its own, somewhat more modern manufacturing through a contractor on Prince Edward Island, Canada.
Questcor immediately raised the price of Acthar to $700 a vial, from $40, and the price rose gradually after that. By the end of 2006, Acthar sales were about $12 million a year, but the company was still losing money.
In May 2007, James L. Fares, left as chief executive and was replaced, initially on an interim basis, by Mr. Bailey, who had joined the board a year earlier. A mechanical engineer by training, Mr. Bailey had retired in 2000 from a 10-year run as chief executive of Comarco, a military contractor and telecommunications concern.
Three months later, Questcor announced the huge price jump, aimed at repositioning Acthar as a specialty drug. The move prompted protests from parents and pediatric neurologists.
"It made us so sick to the stomach — just the fact that something like that could happen overnight with a drug my child needed to live," says Christina Culver of Colorado Springs. "It's just like someone saying, 'I'm going to charge you for oxygen now.' "
Ms. Culver's son Tyler was in the hospital, being treated for infantile spasms, just as the price increase hit. Tyler was due to leave the hospital, and Ms. Culver and her husband, Randy, were to continue the injections at home. Then the Culvers' insurer, Blue Cross Blue Shield, refused to pay the new high price. After a storm of publicity, the insurer backed down.
Questcor, however, hasn't, and has continued to raise the price, now at more than $28,400 a vial. Insurers generally pay for Acthar because it is considered the best treatment for infantile spasms. They also tend to pay for other approved uses if cheaper drugs have been tried first. And Questcor has carefully executed the orphan-drug playbook. Patients who cannot pay are given the drug free. The company helps with insurance co-payments, to make sure that a patient's inability to make a co-payment doesn't stand in the way of the drug being used and the insurer paying $28,000 a vial.
In other words, Questcor shifts the cost onto insurance companies while staving off consumer protests. It has a staff of 30 people who do nothing but work on insurance reimbursements — about one staff member for each of the roughly 30 prescriptions it gets in a typical day for all uses.
Questcor executives argue that with the free drug program and the ample supply, patients have better access to Acthar now than when it was cheaper and often in short supply.
"We believe we've been good stewards of this product," Mr. Bailey says.
Dr. Lawrence Brown, a neurologist at the Children's Hospital of Philadelphia and the president of the Child Neurology Foundation, says of Questcor: "They have gone out of their way to help every kid who needs the medicine to get it quickly and efficiently."
This year, the foundation awarded its first corporate citizenship award to Questcor. Dr. Brown says Questcor's donations — the amount has not been disclosed — to the foundation didn't influence the award.
STILL, the price remains a sticking point.
At Children's National Medical Center in Washington, "we've been instructed not to hospitalize a child with spasms unless the authorization has been procured to pay for it," said Dr. Phillip L. Pearl, chief of child neurology. In practice, however, no child has been turned away.
Dr. Shaun Hussain of Mattel Children's Hospital in Los Angeles said that the studies showing Acthar to be better than far cheaper steroids used too low a dose of steroids.
At his hospital, he reported at a medical meeting this month, 18 of 30 babies were successfully treated with two weeks' worth of a high-dose oral steroid. Only the 12 who did not respond were switched to Acthar, with five of them successfully treated.
Given that the steroids cost $200 for each baby, compared with about $125,000 for Acthar, the approach saved more than $2 million. "We have to look at the cost to the health care system," Dr. Hussain said.
Mr. Bailey says the new price was set to make the company viable based solely on sales for infantile spasms. Executives assumed at the time that the high price would preclude other uses.
But to Questcor's surprise, he says, some prescriptions continued to trickle in to treat the periodic flare-ups that plague people with multiple sclerosis.
So Questcor began hiring sales representatives to promote the drug for that use. Then it hired a sales force to promote the drug as a treatment for nephrotic syndrome, a kidney injury that can lead to kidney failure. In June, it began selling to rheumatologists.
For all these diseases, there are cheaper alternatives. Oral prednisone, which might be used for some rheumatological diseases, can cost $10 a month. Intravenous steroids, used to treat multiple sclerosis flares, cost several hundred dollars.
Because Acthar was approved for these conditions decades ago, Questcor has not had to do large clinical trials to show that the drug works. It has paid for some small studies, mainly by individual doctors, who then publish a paper that the sales force can present to doctors.
The study that justified calling on rheumatologists involved five patients with rare conditions, all of them treated by a single doctor. All the patients had much improvement on Acthar after failing to benefit from more standard therapies, the doctor, Todd Levine, said in a Questcor conference call.
Still, it appears that at least a couple of small studies that may have raised questions about the drug have been suspended.
"From my standpoint it just didn't work," said Dr. Sungchun Lee, a Phoenix nephrologist who stopped a small study testing Acthar as a treatment for nephrotic syndrome. "I think they were O.K. with me stopping because we weren't getting the results," he said.
Another study that was terminated sought to determine whether multiple sclerosis patients who did not have a good response to steroids should be treated with either another round of steroids or with Acthar. The study was halted midway through "to analyze data," according to the summary of the trial on the federal clinical trial database.
A negative result could have jeopardized already growing sales for multiple sclerosis. The company says the trial fell hopelessly behind its goal in recruiting patients.
Given the scarce data, and the high price, most doctors do not use Acthar for multiple sclerosis, nephrotic syndrome or rheumatology.
"It's absurd," says Dr. Douglas R. Jeffery, a multiple sclerosis specialist in Advance, N.C. "There's never a clinical setting where I can justify spending $23,000 to treat an M.S. relapse."
But some doctors say Acthar can be effective in cases that are not well treated by steroids. They say that there is emerging evidence that Acthar does more than just stimulate the body to produce its own steroids.
"It really looks like the ACTH does bring something different to the table that standard steroids don't," said Dr. Ben W. Thrower, director of the multiple sclerosis institute at the Shepherd Center, a hospital in Atlanta. Dr. Thrower, who is a paid speaker for Questcor, said his institute had tried Acthar for about 60 of its 3,000 patients, ones who did not respond to steroid treatment. Acthar made the symptoms subside in about half of them.
GIVEN Acthar's price, Questcor does not need many prescriptions to make a good business. A course of treatment for nephrotic syndrome can run $250,000, while a shorter treatment for a multiple sclerosis relapse typically costs $40,000.
Questcor sales representatives who are lucky enough or skillful enough to have a big prescriber in their territory can reap bonuses of $50,000 a quarter, according to former employees of the company.
Executives are paid well, too. In 2009, Mr. Bailey hired his daughter Kirsten Fereday as director of business analytics and evaluation, a job that paid $275,000 in cash and stock last year.
Mr. Bailey and Steve Cartt, Questcor's chief operating officer, say the company's marketing has been aboveboard and that the company is now starting to sponsor more studies. "This wasn't possible until the drug was financially viable," Mr. Bailey said.
Patients report mixed results. Sharon Keller of Austin, Tex., who has nephrotic syndrome, tried Acthar after two other drugs had not worked. But she stopped, she says, because side effects including mood swings and weight gain were "much worse than I'd ever experienced."
"I almost had to fight with my doctor not to push it on me," Ms. Keller, 59, says. She says her insurer was charged $130,000 for her drug, including a vial she did not use. "I have a Cadillac in my refrigerator," she says of that leftover vial.
ONE big uncertainty hanging over Questcor is competition. As an old drug without patent protection, Acthar would seem to be a sitting duck for generic rivals. And other versions of ACTH have been sold in the past.
Yet Questcor is now arguing that its studies show that Acthar, despite the "highly purified" in its name, actually contains other substances from the pig pituitary glands that account for some of its effectiveness. The company does not intend to say what those other ingredients are, thus making it extremely hard for a generic company to copy Acthar.
"Coca-Cola is not going to tell you what Coke contains, either," Mr. Bailey says.
Whether such an argument will work remains to be seen. Even if it does, competitors could still sell other forms of ACTH. Novartis, which sells a synthetic version called Synacthen in Europe, has applied for a United States trademark, a sign that the drug might be brought to this country.
A small Maryland company, Cerium Pharmaceuticals, recently won orphan-drug designation from the F.D.A. for Synacthen to be used to treat infantile spasms. But that does not necessarily mean that Cerium has the rights to the drug or intends to market it.
Cerium is run by Gregg Lapointe, a former Questcor board member. He declined to comment for this article.
Still, Synacthen, or other versions of ACTH, might have to go through lengthy trials before being approved, and would have to be approved for one disease at a time.
So there is at least a chance that Questcor might maintain its high-priced dominance for a long time. In the meantime, the company plans to systematically expand the marketing of the drug to treat other diseases, starting with those already on the label.
Given that Acthar has many potential uses, Mr. Bailey says, Questcor sees no reason to come up with other drugs. The company has been buying back its stock, helping to underpin the price, and recently said it would start paying a dividend.
"We'll take it where it goes," Mr. Bailey says of Acthar. "It's taken us to places we never expected."