Interesting negative article on the FDA approval of Claritin.
Focuses on the serendipity of the process, how luck, timing, and marketing can play huge roles. Makes many good points, though the author doesn't hide his bias against the drug (stemming from his personal experience with it.)
Doc
[IN TWO PARTS BECAUSE OF SIZE]
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Claritin and Schering-Plough: A Prescription for Profit
nytimes.com
March 11, 2001
By STEPHEN S. HALL
It had been yet another miserable, nose-dripping, red-eyed spring a couple of years ago, when I finally went to see an allergy specialist. I've been battered by seasonal allergies all my life but relied on family doctors and, more recently, "primary-care physicians" for relief. In a kind of a pharmaceutical version of playing catch with Dad, my father and I shared his hay-fever pills when I was growing up. They were smooth, round yellow tablets, etched with a tiny red corporate symbol that was as delicate as a Chinese ideograph. At a time before people routinely gobbled down a half dozen medicines a day, those pills held a kind of mythic power for me, not only because they could make the misery of allergies disappear but also because they were prescription drugs -- inherently more powerful, more inaccessible, more special.
Those yellow pills were called Chlor-Trimeton, manufactured by the Schering-Plough Corporation, first as a prescription drug and then, after 1976, as an over-the-counter medication. It definitely worked, but it knocked me out. I remember days when I felt glazed by sleepiness. Even as the high tide in my nose and throat subsided, I felt mentally waterlogged.
For the most part, I managed to get by with over-the-counter medications until that spring in 1999, when I decided I needed something stronger. After rummaging through a cabinet in the examining room, my new allergist handed me a week's supply of Claritin, also made by Schering-Plough. Claritin was, and still is, the most frequently dispensed drug sample in the United States, part of the nearly $8 billion worth of free drug samples that pharmaceutical companies distribute to doctors annually. I had seen the ads on TV -- who hadn't? I figured I'd give it a try.
Claritin had several other distinctions: it was by then the best-selling antihistamine in the United States, indeed the most profitable antihistamine of all time, with annual sales of more than $2billion. And it was the most aggressively marketed drug to American consumers. Claritin is a drug for our time: designed to relieve symptoms and improve "quality of life," hardly lifesaving or even curative, expensive as hell. A month's supply of Claritin currently costs about $80 or $85 in the United States, even though it is an over-the-counter drug in dozens of other countries, where it usually costs $10 or $15. The high domestic price is paired with an enormous potential market: an estimated 35 million Americans suffer seasonal allergies, and many of us will be feeling that first tickle of dread later this month, when spring tree pollen begins to barge into our air passages like molecular roustabouts.
So I went home and tried it. The little white pill was easy to swallow and had to be taken only once a day. There was just one problem: it didn't work. It didn't relieve my runny nose and red-rimmed, gunked-up eyes. When I told my allergist, he didn't seem particularly surprised. Only about 30 to 40 percent of his patients, he said, found the drug helpful. And, he added, that estimate was "generous." I was surprised, perhaps naively, by this remark. I figured a "blockbuster" drug would be efficacious in more than 50 percent of the people who took it. The percentage he mentioned, incidentally, is certainly debatable; in fact a debate broke out later between my allergist and his partner, who thought 50 or 55 percent was more like it. Even so, it made me wonder: $80 for a drug that works only half the time?
Claritin has been singled out as a prime example of greed by the American pharmaceutical industry, notably last summer by Al Gore during his presidential campaign, and there has been a constant stream of negative press about Schering-Plough's efforts to get the basic patent on Claritin extended beyond its 2002 expiration. Schering-Plough has argued that the patent should be extended because the Food and Drug Administration review of Claritin was unusually "protracted" (which, in fact, it was). To press its case in Washington, the company has paid millions of dollars in political contributions and assembled a high-powered, strange-bedfellows team of lobbyists (including the former senators Howard Baker and Dennis DeConcini, the Gore confidant Peter Knight and Linda Daschle, wife of the Senate minority leader, Tom Daschle); it has also encouraged repeated attempts by Congressional supporters to insert language favorable to Schering into legislation at the last instant.
Claritin's 77-month odyssey through the F.D.A. approval process was indeed lengthy, as a General Accounting Office report, issued last August, documents. That report prompted me to read through the transcripts of old F.D.A. meetings, obtain other documents through Freedom of Information requests and speak to doctors about allergy medications in general. As I learned more about the approval of Claritin, I realized that the biography of this one drug reveals a great deal about why prescription drugs cost so much to bring to market, and also why health-care economists like Uwe E. Reinhardt of Princeton University argue that we are paying premium prices for new drugs like these without actually knowing if they are better than the drugs they've replaced. The Claritin story is an unauthorized biography, in the sense that Schering-Plough declined to grant any interviews and responded only to written questions.
It is above all a case study of how a drug company creates a blockbuster. There are no villains, no broken laws -- just an enormous expenditure of money, a highly sophisticated understanding of food and drug laws, daring marketing, a great deal of luck. Making it all possible is a financial system that ultimately passes along the high price of a modest drug to third-party payers -- and you.
Claritin's journey from lab bench to marketplace was nearly epic in the time it took, the vicissitudes encountered and the plot twists along the way. In June 1980, when Schering filed a patent for the group of chemical compounds that included the drug that would eventually be known as Claritin, the world of drug development was quite different. It typically cost a pharmaceutical company roughly $200 million to $250 million to develop a new drug; that cost is estimated to be closer to $500 million today, a figure that also accounts for failures along the way. A patent lasted 17 years from the date it was issued; it now lasts 20 years from the date the application is filed. And the effective patent life of a new drug -- the amount of time a company can expect to enjoy an exclusive run in the marketplace -- was about eight years; the average effective patent life of a drug has nearly doubled since then. The Schering patent, issued Aug. 4, 1981, stated that the compounds, including the future Claritin, were "useful as antihistamines with little or no sedative effects." Pharmaceutical companies rarely disclose the cost of bringing a specific drug to market, but it's a safe bet that it took at least several hundred million dollars to deliver on the promise of those nine words.
Loratadine (pronounced "low-RAT-a-deen") -- the generic name for Claritin -- was one of several second-generation antihistamines that emerged from drug-company laboratories in the 1980's. They worked by essentially the same simple mechanism as the first-generation antihistamines developed immediately after World War II, like Chlor-Trimeton. When pollen bumps into certain immune-system cells just beneath the lining of the nose, eyes or respiratory passages, it provokes an immunological overreaction in susceptible people. Thus perturbed, these "mast cells" shudder with the molecular equivalent of uncontrollable weeping; they churn out at least 15 different inflammatory molecules, many of which contribute to the allergic reaction. One of those molecules, unleashed instantaneously, is called histamine.
When these roving histamine molecules attach to receptors on nearby nerve cells, you feel an itch or a sneeze or a scratchy, ticklish palate. When they dock onto receptors in nearby blood vessels, the vessels become porous and leaky, and fluids begin to ooze into the tissues of your nose and eyes. Antihistamine drugs work because the active ingredient is a molecule that fits like a cap onto the histamine receptor, blocking the signal that causes itchy, watery symptoms.
Everyone agrees these drugs are effective, but just how effective is very difficult to say. All the antihistamine drugs, new and old, are plagued by high placebo effects. "It's a question of how bad a placebo effect you have," says Dr. Peter S. Creticos, head of the allergy and clinical immunology division at the Johns Hopkins University School of Medicine. "The placebo effect can be anywhere from 20 to 40 percent."
Complicating the process of determining efficacy is how the data are gathered: patients in these trials typically assess their own degree of symptom relief, which many allergists concede makes the data somewhat subjective.
Then there's the sponsorship of the science. Because the placebo effect is so high, large numbers of patients must be enlisted in clinical trials to achieve a robust, or statistically "significant," result, which means that only drug companies can afford the expense. Studies sponsored by drug companies tend to show an advantage for the company's own products. Zyrtec, an antihistamine produced by Pfizer, for example, has been shown to be more potent than other drugs in its antihistamine effect -- in a study sponsored by Pfizer. Desloratadine, currently awaiting F.D.A. approval as the next generation "super-Claritin," is said to relieve nasal stuffiness, unlike other antihistamines -- in a study done by Schering. And Allegra, produced by Aventis, was recently shown to be equal to Zyrtec -- in a study sponsored by Aventis. "They're going to take that study all the way to the bank," one academic allergist chuckled. Which is precisely the point. Scientific studies of these drugs serve as marketing tools, providing drug-company salesmen with their best lines.
The first-generation antihistamines, now sold over the counter as Chlor-Trimeton, Benadryl, Tavist and others, are still considered pretty effective medicines. In fact, many allergists told me that they are at least equivalent in medical potency to newer drugs like Claritin and Allegra. But the first-generation molecules cross the blood-brain barrier and get into the central nervous system, causing drowsiness. The second-generation drugs have been medicinally engineered to stay out of the brain. As a result, they cause little or no sedation.
A nonsedating antihistamine was clearly a desirable drug, and Schering-Plough had been looking for one since the 1960's. In fact, the company thought it had one in a compound called azatadine. The drug is still sold as Optimine, and if you've never heard of it, that's because the compound looked deceptively nonsedating when it was tested in cats and showed its true, somnolent colors only during human testing. Next came loratadine. Following years of testing, Schering formally submitted what is known as a New Drug Application, or N.D.A., to the Food and Drug Administration on Oct. 31, 1986, seeking approval of loratadine.
Schering was not the first company to knock on the F.D.A.'s door with a nonsedating antihistamine. Seldane (terfenadine), manufactured by Marion Merrell Dow, had been approved the year before, and Hismanal (astemizole) was already under F.D.A. review. Because a similar nonsedating antihistamine was already on the market, the F.D.A. assigned Claritin its lowest priority for review -- it was considered, according to an F.D.A. classification system no longer in use, a drug that "essentially duplicates in medical importance and therapeutic usage one or more already marketed drugs, offering little or no therapeutic gain over existing therapies." Technically, Claritin started out as a "me too" drug.
Schering-Plough doggedly pursued the approval of Claritin, spurred, no doubt, by the phenomenal success of Seldane. But it wasn't easy. Over six and a half years, Schering filed 37 major amendments to its application. The company decided to switch the formulation from capsules to tablets, and it took more than two years to show that the capsules used in clinical trials were pharmacologically identical to the tablets it intended to sell. Among the many obstacles Schering had to overcome, the first was to convince F.D.A. reviewers of the drug's main selling point: that it could be effective without causing drowsiness.
To approve a new drug, the F.D.A. must be convinced that it is both safe and effective. As a practical matter, that often means arriving at a balance between potency and side effects. Drug companies routinely submit notebooks of dictionary girth full of experimental results establishing a drug's safety profile, first in animals and then in human subjects. In establishing the effectiveness of a new drug, however, a company has only to show in well-designed trials that a drug is more effective than a sugar pill, and if there is already an equivalent drug on the market for the same use, that it is at least equally effective.
The effectiveness of loratadine had been an area of F.D.A. concern as early as January 1987, just months after Schering filed its application. Dr. Sherwin D. Straus, the F.D.A. medical officer assigned to review the drug, told the company that a 10-milligram dose of Claritin -- the amount marketed today -- did not appear to be very effective. He reiterated that point in public on Oct. 23, 1987, when the F.D.A.'s Pulmonary-Allergy Drugs Advisory Committee met at the agency headquarters in Rockville, Md., to consider Schering's application for loratadine. (This panel of outside experts doesn't formally approve new drugs, but makes influential recommendations to the agency.)
Establishing a drug's safety and efficacy is not a pretty business. A parade of Schering representatives described a staggering amount of data from animal tests in mice, rats, guinea pigs, cats and monkeys, including the "mouse-paw edema test" (in which mice have their paws cut off and weighed to see how successfully an antihistamine inhibits swelling). In several studies, extremely high doses of the drug, consumed daily for up to two years, produced borderline evidence of liver-tumor formation in rats and male mice, but otherwise loratadine appeared very clean. Indeed, the company maintains that the drug's "excellent safety profile is well established" by 10 billion "patient days" of experience in the marketplace.
After preclinical animal tests, Schering began to test loratadine in thousands of human patients, first to establish its safety and then to prove its effectiveness. The company ultimately submitted three so-called "pivotal" clinical trials to support the drug's safety and efficacy. Schering conducted what is considered the gold standard in drug testing -- randomized, double-blind trials pitting Claritin against both placebo and one of several already approved antihistamines -- and the results reveal just how vexing the placebo effect can be. In one study, for example, people taking Claritin experienced a 46 percent improvement in symptoms at the end of the trial; patients taking a placebo reported 35percent improvement. In another trial, Claritin produced 43 percent improvement versus 32 percent on placebo. As part of these same studies, physicians examined the patients and, unaware of which treatment each had received, assessed their condition; these doctors concluded that anywhere from 37 to 47 percent of patients taking the sugar pill showed a "good or excellent response to treatment."
When it was his turn to speak, Straus engaged in a little bureaucratic soft-shoe, complimenting the Schering team's presentations as "a tough act to follow." Then he tried to demolish the heart of Schering's application. Straus didn't doubt that loratadine worked as an antihistamine, he said; he just doubted that it worked at the 10-milligram dose. In fact, at one point he claimed that "10 milligrams is not very different than placebo clinically." The reason the dose was so low, he argued, is that evidence of sedation began to crop up at higher, more effective doses.
What he didn't say -- but what everyone understood -- is that using a higher, more effective dose of Claritin would affect how the drug was described on the label. The term "nonsedating" was considered a critical marketing point. A single adjective or phrase contained in the F.D.A.-approved label -- no more sedating than a sugar pill," for example -- can form the basis of claims made by company salesmen to doctors, the basis of words that throb in the bold type of advertisements, even the basis of lawsuits filed against competitors. Those seemingly eye-glazing, hairsplitting distinctions provide the foundation for multimillion-dollar marketing campaigns.
The clash over effectiveness was crystallized in one edgy exchange between Straus and Dr. Anthony Nicholson, a British neuroscientist, one of the Schering-sponsored clinical researchers, over the interpretation of a study that compared loratadine to a sedating antihistamine called tripolidine. "We are not actually in the business of saying one drug is better than the other," Nicholson told Straus. "We are in the business of saying whether a drug is acceptable in terms of its performance profile."
"But how can you say it is acceptable in terms of its performance profile," Straus replied, "without comparing it to what else is out there?"
"We compare it with placebo," Nicholson said.
"So you compare it to nothing."
"Yes."
"And it is better than nothing."
"Yes."
"All right," Straus said. "I can't argue with that."
The Schering representatives gave as good as they got. One suggested that Straus was guilty of statistical mischief; he had selectively looked at variables, subsets and time points, "and this is, as I am sure everybody in this audience knows, the perfect method of proving any claim one wants." Dr. William Darrow, a senior vice president at Schering, acknowledged that Straus's concerns were legitimate, "but for us the question is whether we have demonstrated consistently superiority and adequate efficacy over placebo by the 10-milligram dose. And we stand on our data there."
In a sense, they were both right. Schering had shown, according to the requirements of the law, that a 10-milligram dose of loratadine was more effective, and no more sedating, than placebo. And Straus had argued, to the satisfaction of at least some people on the committee, that while the drug might be more effective than placebo, it was not a whole lot more effective.
Perhaps the most startling assertion made at that 1987 meeting came not from Straus, however, but from Leslie Hendeles, a pharmacology professor at the University of Florida, and it is as relevant to allergy sufferers today as it was back then. He suggested that most of the patients in Schering's Claritin studies would have been better off being treated with a different class of allergy medication altogether -- steroid nasal sprays. "Certainly, in this kind of patient that was selected for this study," he said to the gathering, "most clinicians would probably use intranasal steroids to provide very prompt and sustained relief, rather than antihistamines." To treat full-blown allergy symptoms with an antihistamine, he continued, was "pharmacologically irrational."
Hendeles and other experts made a similar point to me recently: steroid nasal sprays, like Flonase and Schering's own Nasonex, shut off an allergic reaction that's already under way. In 1998, the Annals of Allergy, Asthma and Immunology published treatment guidelines stating that these nasal sprays "are the most effective medication class for controlling symptoms" of allergies. The popular antihistamines are valuable at preventing an allergy attack from getting under way if taken ahead of time and seem to be effective against eye symptoms, but they rarely bring quick and substantial relief of nasal symptoms once histamine has already begun to wreak havoc. "We don't use these medicines correctly," said Peter Creticos of Johns Hopkins. "As I tell patients, by the time the process starts, the horse is already out of the barn in terms of the antihistamines. You turn the process off by using a nasal steroid." |
