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A KNIGHT RIDDER SPECIAL REPORT

CHIP SOMODEVILLA/DETROIT FREE PRESS Tammie Snyder holds Presley, one of her twin daughters, in New Baltimore, Mich. Snyder was prescribed an asthma drug to prevent premature labor. PRESCRIPTION Patients injured and killed as doctors prescribe drugs for unapproved uses FOR DANGER By Alison Young and Chris Adams Knight Ridder Newspapers

NEW BALTIMORE, Mich. — For the last three standard studies backing an off-label use. But doctors routinely are phobia,” according to case notes from an office visit on Sept. 9, and a half months she was pregnant, Tammie Snyder choosing unapproved therapies that are questionable at best. 2002. had a small medical device strapped to her thigh. It The practice is perfectly legal, widely accepted and defended by The drug’s maker, Johnson & Johnson, has marketed Risperdal pumped a drug called terbutaline through her body to doctors and the American Medical Association — and it’s taking a toll. heavily to doctors who treat elderly patients. prevent her from going into labor too soon. Victims of off-label prescribing whom Knight Ridder interviewed In 1999 the FDA cited Johnson & Johnson for downplaying the On Sept. 17, 2002, Snyder gave birth to two have suffered heart attacks and strokes, had permanent nerve dam- drug’s risks to the elderly and making false and misleading claims healthy girls. Within days, however, her lungs filled age or lost their eyesight. Most said they never were told that the that it could be used not just to treat schizophrenia, but also “for psy- with fluid, her heart began to fail and she was told FDA hadn’t approved their treatments. chotic symptoms associated with a broad range of disorders.” she might need a heart transplant. She recovered, but Based on the FDA’s own data, Knight Ridder estimates that at While doctors are free to prescribe as they wish, the FDA pro- she’s been told she can never have a baby again. Her least 8,000 people became seriously ill last year after taking some of hibits drug-makers from marketing unapproved treatments. heart wouldn’t stand the strain. the nation’s most popular drugs off-label. The true number is likely Despite the FDA’s action, Risperdal has become a popular off- Terbutaline is an asthma drug, and the Food and Drug to be many times higher. label treatment for Alzheimer’s Administration hasn’t approved its use to prevent premature labor. “Sometimes it may help, disease and dementia. About The FDA has warned doctors that the treatment is “potentially dan- sometimes it may do more harm 670,000 such prescriptions were gerous” and may not be effective. Snyder said her doctor never told than good and sometimes it may Growth of off-label prescriptions written last year, up more than her about the warning or that the FDA had approved terbutaline only kill people,” said Arnold An analysis of prescriptions for the three 350 percent from 1998, the to treat asthma. Relman, a former editor of the best-selling drugs in 15 of the top drug classes Knight Ridder analysis found. A six-month Knight Ridder investigation has found that patients prestigious New England Journal shows significant growth in off-label prescribing. Sixty-five percent of Risperdal’s nationwide are being injured and killed as doctors routinely pre- of Medicine. Off-label drugs Drug sales prescriptions last year were for scribe drugs in ways the FDA never certified as safe and effective. Despite the rise in off-label unapproved treatments, generat- Prescriptions for a condition Total retail value of all Moreover, these unapproved prescriptions are soaring. Over the drug use, the FDA has done little not approved by the FDA ing $929 million in retail sales. 96% drug sales in analysis last year, 115 million such prescriptions were written, nearly double to discourage it, and is consider- increase Murphy had been a familiar the number of five years ago, an exclusive Knight Ridder analysis of ing whether to allow drug com- 1997-98 58.6 million $55.5 billion figure at his doctor’s office, prescriptions for the country’s top-selling drugs found. panies greater leeway in pushing 2002-03 115.1 million Off-label complaining of stomach pains, The practice, called off-label prescribing, often is driven by ques- unapproved therapies. $12.9 billion arthritis and the like, often con- tionable research, aggressive drug-company marketing and cavalier vinced that any pain was a sign On-label drugs doctors, and condoned by tepid regulators. On-label that he was dying of cancer. Prescriptions for a condition $42.6 billion Doctors are giving their patients epilepsy drugs for depression George Murphy’s hands, approved by the FDA 84% But he was otherwise fit, his and hot flashes and to help them lose weight. They use antidepres- made strong by years of climb- increase Source: Knight Ridder analysis daughters said, enjoying family of prescribing data from Verispan’s sants to treat premature ejaculation and pain, and powerful antipsy- ing utility poles for Houston 1997-98 222.7 million Physician Drug and Diagnosis Audit dinners, a recent trip to an alli- and its Source Prescription Audit chotics for insomnia and attention deficit disorder. High blood-pres- Lighting & Power, shake with 2002-03 409.3 million for 12 months ending July 31 in gator festival and an active sure pills are prescribed for headaches and anxiety; antibiotics are tremors. His legs, now rigid, 1998 and 2003 social life at his independent used to treat viruses. shuffle as he pushes his walker © 2003 KRT Graphic: Judy Treible, Lee Hulteng living center. Some drugs, in fact, are sold mostly for unapproved purposes. through his studio apartment in The FDA hasn’t approved Eight out of 10 prescriptions for the epilepsy drug Topamax aren’t Deer Park, Texas. Risperdal for the treatment of hypochondria. But Murphy’s family for epilepsy. Thalidomide, the notorious morning-sickness drug that “I wish I didn’t have to use this thing,” he said as the walker members said they weren’t told this. Yaworski declined to be inter- caused horrible birth defects and ushered in today’s FDA drug-safe- snagged on his recliner while he was showing off his Army dog viewed. ty rules, today is on the market, and 99 percent of its prescriptions tags from World War II, a plaque for 40 years of service as a Within a month of starting the drug, Murphy had the first in a are off-label. Mason, his Shriner fez and the oil paintings his wife did a few years series of stroke-like events, called transient ischemic attacks, accord- Knight Ridder reviewed 15 top-selling classes of drugs and found before she died. ing to his family and hospital records. During the worst of them, on that some, such as cholesterol medicines, rarely are given as unap- Murphy, now 85, began having the tremors last year after he had Nov. 14, 2002, Murphy suddenly couldn’t walk, his speech became proved treatments. But three-quarters of anti-seizure medications are a series of stroke-like attacks while taking Risperdal, a powerful slurred and his face drooped. He became easily confused, and doc- prescribed off-label, as are nearly two-thirds of antipsychotics and antipsychotic drug that the FDA has approved only for treating tors at the hospital added dementia to his diagnoses. about one-quarter of antidepressants, the analysis found. schizophrenia. Attack followed attack, but Murphy kept taking his Risperdal. He For patients with rare, intractable or fatal illnesses, off-label pre- Murphy’s family practitioner in Pasadena, Texas, Dr. Dennis was still afraid of getting cancer, his family said. scribing is sometimes appropriate. In other cases, there may be gold- Yaworski, prescribed Risperdal for an off-label purpose: “cancer Then in April 2003, Johnson & Johnson sent a letter to U.S. doc- Cyan Magenta Yellow Black BType 5 25 50 75 100

three months at a time, but stud- ies have found that it’s frequent- What does ly prescribed improperly and that long-term use exposes ‘off-label’ mean? patients to unnecessary side When the FDA okays a new effects. drug, it also approves the One of the worst is tardive instructions, or label, for using dyskinesia, a condition that the drug based on data causes relentless body tremors submitted by the drug company. and facial tics. Baker, now 55, said she was never told about Off-label, or unapproved, uses this, so when she moved into her can include prescribing for: fourth month on the drug she Different diagnosis didn’t realize what was happen- Drug approved to treat one ing when she began to twitch condition, used for a different one every now and then. In her fifth month on Reglan, her symptoms worsened. Her Less severe disease primary care doctor quickly saw Drugs with risky side effects used to treat relatively minor conditions the connection. “It’s the Reglan,” she said he told her. “We have to get you Different length of treatment off it immediately.” Her special- Some drugs are safe when used ist, hearing the news, called for only a short time, but risky Baker at home, angry with her when used long-term for not alerting him to the oncoming symptoms. A patient of a different age “Don’t scream at me,” she Clinical trials often use middle- recalled saying during the June aged people, making many 2001 phone call. “You didn’t drugs off-label for children even warn me. You didn’t tell © 2003 KRT me.” Source: Knight Ridder Washington Bureau MICHAEL STRAVATO/KRT Graphic: Todd Lindeman, Judy Treible “Our father has been taken away from us. Basically the last enjoyable times he could have with us are gone,” said Robbie Today, Baker is out of work; Murphy. George Murphy’s family physician prescribed Risperdal, a schizophrenia drug to help with the 85-year-old’s fear of the tremors make holding a job getting cancer. Within weeks of taking the drug Murphy had a series of stroke-like attacks. impossible. She can sit only for tors warning that Risperdal may short spells; her right leg con- be associated with an increase in stantly bounces, and she end- strokes when prescribed off- lessly wrings her hands. label to elderly dementia She sued the specialist, Dr. patients. Steps to off-Label Gabriel Herman of Fairfax, Va., The public warning came and drug maker Wyeth. Both nearly two years after the drug How a prescription drug approved for one illness declined comment. Wyeth, of maker privately alerted the becomes popular with doctors for treating others: Madison, N.J., has since sold its FDA that there was a problem interest in the drug. In its court with Risperdal, agency officials filings, Wyeth noted that the said in response to questions STEP 1 drug’s label mentioned both the from Knight Ridder. It came Drug is born risk of tardive dyskinesia and six months after drug regulators that the drug is recommended in Canada issued a similar Drug company identifies potential uses for new drug. for short-term therapy. In a court warning and urged doctors in It conducts large-scale clinical trials. filing, Herman has disputed that country to reassess their Baker’s lawsuit. It submits application to the U.S. Food and Drug use of Risperdal to treat dementia. Administration for one or two uses most likely to get FDA officials, in a written approval. The national prescription data statement, said it took several that Knight Ridder examined rounds of questions to the drug STEP 2 reveal the startling breadth of maker before they had enough off-label prescribing. Virtually evidence to have the drug com- Protecting Other Uses every drug has been prescribed pany issue the warning. Company applies for patents, saying drug is effective that way at some point, and Johnson & Johnson, based in for many uses beyond those approved by the FDA many are regularly. New Brunswick, N.J., had no Dr. Nancy Nielsen, an elect- comment. STEP 3 ed official of the American Murphy and his family have Medical Association, doesn’t sued the drug company, which Fueling Interest think doctors have been “cava- in court filings denies any lier” about it. “They have been wrongdoing. His daughter, Company funds research of unapproved uses. in meetings,” she said. “They Robbie Murphy, said: “Our Small, scientifically inconclusive studies are pub- know it works.” father has been taken away lished in medical journals. But individual doctors and from us. Basically the last patients aren’t in a good position enjoyable times he could have STEP 4 to gauge the safety or effective- with us are gone.” ness of off-label treatments, Convincing doctors experts say. Even in the busiest Medical conference speakers, sometimes paid by of practices, doctors see too few Dr. Raymond Woosley, the drug firms, teach doctors about potential off-label uses. patients to assess the drugs’ vice president of health sciences range of side effects. They also at the University of Arizona, Doctors discuss such uses, and outcomes with one have no way of knowing said off-label prescribing puts another. whether the drugs are working, patients at greater risk than when Companies sometimes push off-label uses, even if it’s a placebo effect or doctors follow a drug’s FDA- though FDA prohibits it. whether the patients simply got approved directions. better on their own. “I have no doubt about it,” SOURCE: KNIGHT RIDDER RESEARCH A file family photo of George Murphy taken in June 2002 shows how Medical history is filled with said Woosley, who also is the fit he was shortly before taking Risperdal. examples of doctors who were director of one of the national convinced that an off-label ther- centers for drug research estab- apy was safe and effective, only lished by the federal govern- to be proven disastrously ment. “The caveat is we can’t How to find out wrong. quantify it.” The scope of off-label prescribing if you are taking Often, they based their cer- Few have even tried. One Prescriptions written each year for uses not approved by the FDA for the top three drugs tainty on secondhand anecdotes, study that did was published in in 15 of the top-selling drug classes and some of their off-label uses, Aug. 2002-July 2003: a drug ‘off-label’ small published studies or 1999 in Great Britain. Percent observations from their own Examining about 1,000 chil- Number of off-label To find out if you’re tak- off-label prescriptions, practices. Off-label prescribing dren, researchers found that the Drug Examples ing a drug for an unapproved can continue for years before a class prescriptions in millions of off-label uses number of side effects among or “off-label” purpose, ask thorough clinical trial finds it’s those who were taking off-label Migraines, depression, nerve your doctor or pharmacist. Or Anti-seizure 74% 18.6 ineffective or even dangerous. prescriptions was small, but medications pain, hot flashes, weight loss you can read the drug’s Food Often such trials are never more frequent than for those tak- and Drug Administration- done. Antipsychotics Alzheimer’s disease, attention ing drugs for approved uses. 60% 12 deficit disorder, insomnia, autism approved prescribing infor- In the 1990s, there was Fen- “If you give a medicine in mation, called its label. A Phen, an unapproved cocktail of the right dose, and with good Antibiotics 41% 15.1 Viral and unapproved bacterial infections copy is available from your two prescription appetite sup- information on how a patient pharmacist, or you can look it pressants that was widely pre- with that illness will handle it, Chronic pain syndrome, attention deficit up on the Web or at the scribed until 1997, when the Antidepressants you are less likely to get an 40% 12.4 hyperactivity disorder library in the Physicians’ Mayo Clinic noticed that some adverse drug reaction than if Desk Reference. Fen-Phen patients were suffering you are prescribing outside of Quinolone antibiotics 38% 10.1 Viral and unapproved bacterial infections Be prepared to wade from a rare heart-valve disease. those boundaries,” said one of through tiny type and med- More recently, there was the Difficulty swallowing, hernia, the study’s authors, Imti Proton pump inhibitors 21% 10.5 ical jargon. But you can rampant off-label prescribing of Choonara, a professor in child (stomach acid) pancreatitis learn a lot by focusing on a hormone replacements. Though health at the University of SSRI/SNRI Pain, premature ejaculation, few sections: 20% 12.7 they were approved for treating Nottingham. “Otherwise, there’s antidepressants alcoholism, menopause symptoms Indications and usage: What specific menopause symptoms, no point to anybody studying the drug is approved to treat. such as hot flashes, doctors put medicine. You might as well Antihistamines Ear infections/disorders, upper 19% 9.1 respiratory infections, asthma Contraindications: When millions of women on the drugs say, ‘Here’s a medicine, take it the drug should not be used. for life. They believed hormones as you like and come tell me if Cox-2 arthritis drugs Chronic back pain, gout would prevent heart disease, 17% 7.7 Warnings and precautions: there is a problem.’” breast cancer and Alzheimer’s Just what it sounds like — Doctors don’t have to go very Beta blockers Overactive thyroid, migraines, heart disease, uses the FDA hadn’t 16% 13.1 serious issues for people tak- far off-label before they can put (high blood pressure) rhythm disorders, anxiety approved. They even started ing the drug. Warnings patients in danger. Sometimes, women on the drugs years after Ovarian cysts, menstrual disorders, emphasized with a black box simply prescribing a drug for Birth-control pills 11% 3.3 they had gone through hormone replacement around them are the most seri- longer than it’s approved for can menopause. ACE inhibitors ous of those the FDA issues. cause problems. 11% 5.8 Kidney disorders, leg cramps A massive government-run (high blood pressure) In 2001, Glenna Baker, a Adverse reactions: Infor- study, the Women’s Health mation about side effects, loan officer from Burke, Va., Calcium channel 10% 4.5 Unapproved heart conditions, Initiative, found that hormone came down with a debilitating blockers (heart disease) migraine, cluster headache often with details about what replacement therapy actually percentage of patients expe- stomach disorder that was sus- Irregular heart rhythms, kidney increases a woman’s risk of get- Cholesterol 4% 3.5 rience them. pected to be diabetic gastropare- lowering drugs disorders ting these diseases. sis. She vomited repeatedly, Drug interactions: Explains Many doctors don’t believe Kidney disorders, high blood prompting a specialist to pre- Diabetes medications what other medicines may the findings, theorizing that the 3% 0.4 pressure scribe Reglan. cause problems if taken with study’s outcome would have Source: Knight Ridder analysis of prescribing data from Verispan’s Physician Drug and Diagnosis Audit and its Source Prescription Audit the drug. The FDA has approved the Graphic: Lee Hulteng, Judy Treible © 2003 KRT been different if the women in it drug to be used for less than had started hormone therapy ear- Cyan Magenta Yellow Black BType 52550

CHUCK KENNEDY/KRT Glenna Baker, with mother Joyce in the background, at her home in Burke, Virginia. Baker suffers from tardive dyskinesia. Today, she is out of work; the tremors make holding a job impossible.

lier and had taken it longer. as treatments for bipolar disor- that you’re actually conducting middleman, supplying the drug Despite decades of off-label der earlier this year while at science. Clinical crap-shoot and pumps, then having its nurs- prescribing, drug makers univer- Cornell University. “It’s giving Epilepsy drug for bipolar disorder would probably be better.” es hook up the women to the sally deny that they push these an ineffective treatment for a After Topamax was approved by the FDA in 1996, doctors prescribed it The best use of terbutaline is devices and monitor their uses at doctors. potentially life-threatening ill- only to treat epilepsy, its approved use. Now 79 percent of sales are for a series of three injections to progress. Stanziano wouldn’t “We don’t track what you’re ness. It would be like giving unapproved, or off-label, conditions. calm contractions for about 48 say how many women use calling prescribing for unap- Tylenol for pneumonia.” Topamax prescriptions for one year, Aug. 2002-July 2003* hours or so, enough time to Matria’s pump therapy each proved uses,” said Doug Petkus, Goldberg said that even stud- administer steroids to help the year, but said he hadn’t heard of a spokesman for Wyeth, which ies by the drug’s maker, Johnson Migraine/headache** 1.9 million 45% babies’ underdeveloped lungs, any client who had been serious- makes an antidepressant in the & Johnson, found it didn’t work said Dr. Washington C. Hill, the ly harmed. Knight Ridder analysis as well to treat bipolar disorder. As a Epilepsy/seizure 890,000 21% chairman of obstetrics and gyne- In 1997, however, the FDA as hormone replacement thera- result, company spokeswoman Bipolar disorder 586,000 14% cology at Sarasota Memorial warned U.S. doctors that the py. “We don’t recommend that Lesley Fishman said, the drug Hospital in Florida and a mem- terbutaline pump “has not been our products be used off-label.” maker didn’t seek FDA approval Neuropathy (nerve disorder) 102,700 2% ber of the board of directors of demonstrated to be effective and for treating that condition. the national is potentially dangerous.” Four Over the last year, doctors Schizophrenia 89,900 2% Society for years earlier, the FDA had Once it’s on the market, a wrote 586,000 Topamax pre- Depressive psychosis 85,600 2% Maternal- warned Tokos Medical Corp., drug might be prescribed for a scriptions to treat bipolar disor- Fetal one of the two companies that dozen or more unapproved con- der, Knight Ridder found. Tremors 85,600 2% Medicine. merged to become Matria, about ditions. But doc- promoting unapproved preterm- The FDA approved Topamax Post-traumatic stress 81,300 2% tors still labor therapies despite promises send to stop. in 1996 as a supplemental treat- The terbutaline pump therapy Anxiety, weight loss, other 415,000 10% ment for epilepsy. prescribed for Tammie Snyder women “This case could be viewed It has several potentially seri- in suburban Detroit last year is *Estimates based on survey of doctors. National prescription estimates home with as a conspiracy to circumvent for diagnoses other than migraine/headache, epilepsy/seizure and long-term GRANT JEFFERIES/ the FDA approval process,” an ous side effects. It often causes one of many off-label drug treat- bipolar disorder are subject to a higher level of sampling error. BRADENTON HERALD numbness and tingling in the ments doctors use in an attempt **Johnson & Johnson has applied for FDA approval for migraine prescrip- Dr. Washington FDA compliance officer wrote hands and feet. It can cause to stop preterm labor. Source: Knight Ridder analysis of prescribing data from Verispan’s tions for C. Hill in a memo that year. Physician Drug and Diagnosis Audit and its Source Prescription Audit depression and kidney stones. It Nearly 500,000 babies are Graphic: Judy Treible, Lee Hulteng © 2003 KRT terbutaline Matria officials said they had can slow the thinking of many born prematurely each year, but pills. If they were candid, Hill no information about this, patients, impairing memory and the causes and cures for preterm said, those doctors would admit: because it happened before the making it difficult to choose birth largely elude science. Most “I know it doesn’t work, but it merger. They said Matria does- words. It can cause vision prob- of the treatments are based on cuts down on the phone calls.” n’t promote the off-label use of lems, including a form of glau- hope and a desperate desire to Last year, 63 percent of the terbutaline to doctors. coma that can result in blind- try something. more than 392,000 prescriptions Snyder said she felt betrayed ness. Dr. John Thorp Jr. was part for terbutaline pills were for by her obstetrician, Dr. Federico To stop epileptic seizures, the of a research team for the feder- pregnant women, despite phar- Mariona, a clinical professor at FDA deemed these risks accept- al government’s Agency for maceutical company labels that Wayne State University in able. Healthcare Research and Quality warn against the asthma drug Detroit and a leader in the local Knight Ridder’s analysis of that reviewed the scientific evi- being used this way. medical societies. Mariona did- the last year of prescription data dence for terbutaline and a host While many doctors and n’t respond to repeated requests for Topamax found that doctors of other drugs in preventing mothers passionately believe in for an interview. are giving it to patients for preterm labor. the treatments, especially in the Snyder’s medical records migraine headaches, schizophre- Their report, published in terbutaline pump, the national from nia, bipolar disorder, depression, June, found that the drugs company that is the largest Matria pain, nerve damage and to help weren’t effective in prolonging provider of the therapy is include them lose weight. pregnancy for a long term and ambivalent. signed con- In 1998, Topamax was pre- can cause a wide range of Dr. Gary Stanziano, the vice sent forms scribed only for epileptic harms, including heart-rhythm president for medical affairs at that say, seizures, the data show. Now, 79 disorders and heart failure. Matria Healthcare, based in among percent of Topamax prescrip- “There really is no evidence,” Marietta, Ga., said he had no other tions are for illnesses and condi- Thorp said, noting that early opinion about whether the thera- things, that tions that the drug hasn’t been contractions stop without any py his company sold for about some of the approved to treat, Knight medical intervention 50 to 70 $10,000 a month worked. treatments Ridder’s analysis found. The percent of the time. “There are studies out there that Dr. Federico being pre- firm has asked the FDA to Nonetheless, women across are positive and studies out Mariona put scribed by approve its use for migraines. the country are taking these there that are negative,” Tammie Snyder her doctor Carolyn Bartley nearly went drugs that doctors know very lit- Stanziano said. on a terbutaline may blind in June 2000, a week after tle about. Stanziano and Roberta pump to prevent involve the she began taking Topamax, “I think experiment is too McCaw, Matria general counsel, preterm labor. use of which her psychiatrist prescribed good a word,” said Thorp, a pro- said their company is in the That use is not drugs “out- as a treatment for bipolar, a dis- fessor of obstetrics at the In this family photograph Tammie Snyder holds one of her business of following doctors’ approved by the side of order characterized by bouts of University of North Carolina at newborn daughters in the hospital and reacts to the news that orders, since physicians are the FDA. their label- depression and mania. Chapel Hill. “It implies observa- she has congestive heart failure and may need a heart trans- ones who write prescriptions for ing.” Only “Everywhere I looked, it was tion, measurement, alteration — plant because of the terbutaline she was prescribed. terbutaline pumps. Matria is a after having congestive heart like a watercolor painting, and failure, Snyder said, did she somebody had smeared it,” said learn what those cryptic words the 44-year-old Annapolis, Md., meant. bookkeeper. Laser surgery How the Risky Rx drugs series was done While her heart has improved reduced the pressure in both enough that she doesn’t need a eyes and restored her sight. In Knight Ridder’s investigative series is 1,000 different ailments. Its estimate of the remark an official made years ago and that transplant, Snyder, 30, said her 2001, the maker of Topamax based on dozens of interviews with patients, prevalence of off-label prescribing excluded it has no good estimate. Knight Ridder’s doctors had told her she couldn’t sent a letter to doctors warning doctors, researchers and drug companies, and cancer treatments or pediatric off-label uses, analysis found that 21 percent of the pre- have more children; pregnancy about the kind of sudden glauco- the review of thousands of records from law- because they already are known to have a scriptions examined were for off-label uses, would be too dangerous for her ma Bartley experienced. suits, government hearings and regulatory large percentage of off-label use. When cal- and that some of the drugs had off-label heart. Bartley’s psychiatrist, Dr. actions, medical records and scientific studies. culating whether off-label prescribing had uses as high as 90 percent. Snyder and her husband, Parviz Sahandy, said he hadn’t To calculate how often drugs are pre- grown over the last five years, the study con- To estimate how often patients are harmed Chris, had wanted to have more researched the medical literature scribed off-label, Knight Ridder purchased sidered only the 31 drugs that had been on by this practice, Knight Ridder reviewed the children. Because they used in on Topamax, but that he consid- and reviewed prescribing data routinely the market the entire time. FDA’s database of adverse drug reactions. vitro fertilization to have their ered it effective for bipolar dis- used by the pharmaceutical industry. Prescribing data are for the 12 months The FDA estimates that only 1 to 10 percent twins, they have other frozen order about 50 percent of the Verispan of Yardley, Pa., collects the data ending July 31; sales figures are for the 12 of reactions are reported. Knight Ridder iden- embryos. time. from a monthly survey of 3,400 doctors months ending Aug. 31. tified more than 800 reports filed during 2002 Now, those embryos remain Those who’ve read the stud- with office-based practices. The analysis is perhaps the most compre- of serious reactions involving off-label pre- in limbo. ies are less certain. Knight Ridder analyzed the three top-sell- hensive ever done of off-label prescribing. scriptions for its sample of 45 drugs. Experts “I hate terbutaline. I hate “Topamax is no better than a ing drugs in 15 classes of medications, com- While various reports have quoted the say that means anywhere from 8,000 to what they did,” Chris Snyder placebo,” said Dr. Joseph paring what doctors said they prescribed American Medical Association as estimat- 80,000 people probably were affected. said. Goldberg, a research scientist at them for with the FDA’s approval for each. ing that 50 percent of drugs are prescribed For detailed information about the drugs Zucker Hillside Hospital on The analysis looked at 900 million prescrip- off-label, an association representative said in the Knight Ridder analysis, go to Knight Ridder Newspapers Long Island, N.Y., who pub- tions written in 1998 and 2003 for more than that figure was a misinterpretation of a www.krwashington.com. Researcher Tish Wells contributed to lished a review of epilepsy drugs this report. Cyan Magenta Yellow Black BType

Drug-makers’ a disorder associated with feel- Since 1990, 16 drugs have 341 primary-care physicians and ings of pronounced sleepiness, been pulled from the market for women’s-health doctors. The Medicaid officials were receiving safety reasons. A review of FDA company tested various advertis- claims for its use to treat multiple and other records shows that 11 ing messages about Evista, find- sclerosis fatigue, attention deficit of those were yanked, in part, ing that “PCPs are more promis- promotions boost disorder, depression and “miscel- because physicians didn’t follow ing . . . indicate they will put laneous fatigue.” label instructions or disregarded more patients on Evista . . . and The Medicaid claims topped the FDA’s warnings. think the breast cancer data is $1 million, with one doctor Nonetheless, many physicians more compelling.” responsible for $370,000 of continue to think their practices are Although the FDA had told them, state records show. the best places to assess the worth the company it found “critical From 2000 to 2003, 60 per- and risks of prescription drugs. problems” with the Evista study off-label use by doctors cent of Cephalon’s sales were of Dr. Wasim Niazi, a neurolo- and didn’t approve the drug for Gabitril or Provigil, two drugs for gist from Rockledge, Fla., is a fan preventing breast cancer, accord- which the majority of the written of Topamax, an epilepsy drug ing to FDA records, it allowed BY CHRIS ADAMS prescriptions are off-label. that’s widely prescribed for con- Lilly to make a minor change in AND ALISON YOUNG Questions to ask According to the prescription data ditions the FDA didn’t approve it the drug’s label. The company Knight Ridder Newspapers your doctor that Knight Ridder analyzed, 88 to treat. Niazi said Topamax had inserted three sentences that percent of Gabitril’s retail sales become the most-prescribed drug detailed the precise numbers of MEMPHIS, Tenn. — Dr. about off-label were off-label over the last year. in his practice. He said he had breast cancer cases from the Gary Murray, a cardiologist, was Cephalon has told the hundreds of patients on it and study as well as the following: faced with a common medical prescriptions Securities and Exchange wrote 10 new prescriptions a day. “The effectiveness of (Evista) in dilemma: He had no idea what Commission that the “market for While he also prescribes it for reducing the risk of breast cancer was wrong with his patient. If your doctor has pre- the approved indications of two epilepsy, Niazi said, he mostly has not been established.” Milton Cole, a 71-year-old scribed a drug for a purpose of our three largest products is uses it to treat pain and migraines. That was all Lilly needed to man in generally good health, that the Food and Drug relatively small.” He’s also given it for tremors and do. Company officials got the was complaining of chest pains. Administration hasn’t Even as the company begins to assist with weight loss. He con- word to 1,000 sales representa- A battery of cardiac tests approved, find out why. Here to study whether Gabitril works siders it effective for all these tives. In its plan “Maximizing couldn’t pinpoint the problem. are some questions to ask: for pain, tens of thousands of uses, if his patient can tolerate the the Breast Cancer Label To blunt the pain, Murray gave What is the doctor’s rea- prescriptions for that use were side effects. Change,” it scripted answers to his patient a prescription and son for prescribing the off- filled in the last year, Knight Niazi said the basis for his deal with expected concerns, some free samples of the drug. label treatment? Has the doc- Ridder’s analysis showed. prescribing of Topamax was his including the “relatively small The drug Murray prescribed tor researched the medical lit- Michael Fielder of Kansas own clinical experience and what number of cases” in its study. was Prozac, a popular antidepres- erature and does it support City, Mo., said he’d taken he’d learned from other doctors. The new sales strategy irked sant that isn’t approved by the this use with large, controlled Gabitril for the last 18 months to What studies say about its use- one of Lilly’s competitors, now Food and Drug Administration clinical trials? If not, what is curb the pain of sickle cell ane- fulness means little to him. known as AstraZeneca PLC, the for treating chest pain. Murray the evidence for this use? mia, a debilitating blood disorder. “Most of the literature is garbage maker of tamoxifen, which the later said he had no idea that Are there FDA-approved He got relief only after his doctor driven by the economics,” he FDA has approved to prevent experts had debated for years alternatives? Why aren’t added morphine to the mix. said. And he’s dismissive of clin- breast cancer. whether Prozac caused suicide. they being prescribed When asked for evidence that ical trials that are contrary to his The British company did its Thirteen days after that visit their drug may be useful for own observations. “The real own survey of primary-care and SHAUN HEASLEY/KRT instead? to the doctor, on June 28, 2001, All drugs carry risks of pain, Cephalon officials cited world is different than trials.” women’s-health doctors and Cole’s wife, Amby, found him Amby Cole, of Brighton, Tenn., gets emotional talking about husband Milton’s death. Milton Cole killed himself in June 2001 after being prescribed the antidepressant Prozac for chest pain. side effects, some more than five studies — four of them with found that nearly 65 percent of hanging from a beam in a back others. Ask your doctor: Do I 10 or fewer patients. them learned about Evista from room of their shop. really need this prescription? Fielder is still taking Gabitril, At first glance, the results of a sales reps, not the medical litera- “This was a patient of mine the mammoth U.S. drug maker. Murray didn’t think Cole was a recent whistleblower lawsuit What are the alternatives to because, he said, his doctor clinical study of Evista, an Eli ture. Another survey showed that and I was trying to help him,” A quizzical U.S. District depressed. The Brighton, Tenn., against a company that’s now this therapy? What are the believes it helps. Over the years, Lilly osteoporosis drug, looked 22 percent thought Evista was Murray recalled. “I’m completely Judge Lawrence McKenna of resident was upbeat, busy with part of Pfizer Inc. A former risks and benefits? What is doctors have given him Neurontin, promising. Among other things, FDA-approved for preventing upset. ... I’ll be that way forever.” New York asked whether doc- friends and church, preparing for a employee of the drug company the lowest dose and shortest another epilepsy drug, and Paxil, researchers noticed slightly breast cancer. Many already That a heart specialist even had tors “in any significant number” new grandchild and a new house. said it employed a range of tac- period I can take this drug? the antidepressant, for pain. None fewer breast cancers among were prescribing it that way. free supplies of a drug that’s really based their opinions about Doctors have prescribed anti- tics to boost off-label sales of the Educate yourself about all of them worked well, he said. women who took Evista versus AstraZeneca took the case to usually the province of psychia- drugs on pitches from sales reps. depressants off-label for years to epilepsy drug Neurontin. The side effects. Don’t rely on “When they try out some- those who were given sugar court, demanding that Lilly stop trists says a lot about how drug “Yes, your honor,” said manage chronic pain, and as far widely reported case is pending. the leaflet your pharmacy thing new, sometimes I don’t pills. such practices and divulge the marketing today encourages physi- Gregory Diskant, Schering- as Murray knew, Prozac didn’t Getting around FDA market- provides; it may be incom- think the doctors know if what As baby boomers age, that “call notes” its sales representa- cians to prescribe medications for Plough’s outside attorney. have any serious side effects. He ing rules isn’t difficult. The plete. Detailed information they are using works,” Fielder, could mean the makings of a tives wrote after visits to doctors. unapproved, or off-label, uses. “That’s scary, isn’t it?” the said he had never heard it might agency acknowledges that it’s about side effects is in the 27, said recently. blockbuster drug. The case was settled, and the By offering specialty drugs to judge asked. cause suicide. Articles debating impossible to police the millions Unfortunately for Lilly, can- drug’s FDA-approved label, details are confidential. Evista non-specialists, sending sales- “It is scary. It is scary, but it the issue were published primari- of conversations between drug available at pharmacies or on cer experts didn’t think the num- someday may prove to be good men to doctors’ offices and med- is true,” Diskant said. “You ly in psychiatric journals companies and doctors. the Web. Court records contain dozens bers meant much. for preventing breast cancer, ical conventions, and touting know what the truth is? ... (Sales throughout the 1990s. At the annual conference of of comments by some of the On May 18, 1998, Eli Lilly although Lilly said it was at least their drugs’ benefits on the calls) are the quickest, easiest A Knight Ridder analysis of the American Academy of Pain government’s top health experts convened a focus group of doc- two years away from completing slimmest of evidence, pharma- way for the doctor to learn about government data found that over Management this summer at the about doctors and prescription tors who were attending the the study that may allow it to ceutical companies have sent off- the drug. ...It is a dangerous, the last decade, 40 percent of Adam’s Mark hotel in down- drugs. Many of them aren’t flat- American Society of Clinical apply to the FDA for such a use. label retail sales soaring. largely unregulated phenomena Prozac prescriptions were written town Denver, 75 makers of tering. The assessments about Oncology annual meeting. As for those call notes, some Off-label sales of the top-sell- in the wrong hands.” by nonpsychiatrists. Over the drugs, medical devices and off-label prescribing are worse. Shown the Evista breast cancer were illuminating. ing drugs Knight Ridder studied past year, 500,000 Prozac pre- dietary supplements staffed sales Robert J. Temple, a top offi- data, they responded that the “Told MD about the new hit $12.9 billion in the last year, scriptions were for off-label uses. booths, beckoning doctors with cial in the FDA’s drug division, study was too small, the time indication of EV to prevent producing nearly a quarter of The day Cole came in for his Prozac didn’t help Cole’s trinkets, slick promotional said in a court deposition in 1996: frame too short and the risk of breast cancer,” one sales rep those drugs’ retail sales. checkup, Murray had a drug chest pain. brochures, medical journal arti- “I certainly believe in their good patients having strokes too great. wrote in December 1998. With an aging population, a closet stocked with dozens of Soon, he complained of feel- cles, even stopwatches. faith. I think they are trying. I Promoting the drug to prevent One physician told the sales shift to drug-based health care and medicines that cardiologists ing jittery. His fingers tingled; he At the Merck & Co. booth, don’t believe that they necessarily breast cancer would be “an egre- rep he was “extremely excited the prospect of a massive govern- commonly prescribe, as well as became easily aggravated. Days Connie Mack said Vioxx, the have a capacity to get it right.” gious stretch,” one doctor said. It about the breast data!! Said that ment prescription-insurance plan, some that general practitioners later, he hanged himself. blockbuster arthritis drug, was The FDA’s lawyers said in a also was called an attempt to if his wife were eligible, he prescriptions for unapproved uses and other specialists use. Amby Cole recounted the day approved for certain types of 1998 brief: “While physicians “cash in on a byproduct of the would put her on Evista.” are only likely to accelerate. With little to go on beyond she found him, describing how pain. Then without prompting, may believe that they are in a study.” A proper study to mea- “Sit down detail w/MD,” Promoting this growth is a Cole’s complaints of chest pain, she rubbed her dead husband’s Mack added: “They are using it better position than FDA to eval- sure breast cancer prevention another note read. “Went symbiotic relationship between Murray said, he had a choice be- neck where the rope had hurt pre-emptively, too,” such as uate off-label claims, both the “should last at least 10 years, through entire Evista message physician and drug makers in tween doing nothing and attempt- him. “It was just horrible,” she before surgery, she said. No, it’s evidence and the law say other- preferably 20,” doctors said, w/disclaimer at first to let him which sales representatives rou- ing to ease his patient’s pain. said, her hands trembling. not approved that way, she said, wise. ... Physicians tend to have according to the company’s know I could not talk about stuff tinely target doctors untrained in “I chose Prozac probably She blames drug maker Eli but Merck could send some addi- confidence in their own ability to meeting notes. that was off label unless he the basics of drug therapy and with because I had samples of it,” he Lilly for not warning that Prozac tional information. “They actual- critically assess off-label infor- Even so, the cancer physi- asked questions first. It worked. little time, inclination or indepen- said in an interview. “I thought it can cause suicide, and her lawyer, ly have a whole database now on mation. The studies demonstrate, cians feared that primary-care He asked all about breast can- dent information to assess a med- was a pretty harmless thing to do.” Andy Vickery of Houston, has pre-emptive use,” she said. however, that such confidence is and women’s-health doctors cer.” ication’s usefulness or its risks. The FDA has approved Prozac accused Lilly of overpromoting At the Allergan Inc. booth, a SHAUN HEASLEY/KRT often unwarranted and incorrect.” would prescribe Evista for breast Consider this courtroom con- to treat depression, panic, obses- Prozac to nonpsychiatrists. Lilly representative described an Cardiologist Gary Murray poses in front of the drug closet, where drug samples are stored at his practice in Memphis, Tennessee. Among the available drugs is the antidepressant Michael Wilkes, the vice cancer prevention anyway. Knight Ridder Newspapers versation involving a lawyer rep- sive-compulsive disorder and an settled the case earlier this year. approved use for Botox. She then Prozac, which Milton Cole (left) was prescribed as an off-label treatment for chest pain. Cole killed himself after just weeks on the medication. dean of the medical school at the A month later, Lilly conduct- Researcher Tish Wells contributed to resenting Schering-Plough Corp., eating disorder, but not pain. The amount is confidential. volunteered, “There are physi- University of California, Davis, ed a different survey, this one of this report. Vickery said it was his third cians who have been using it off- doesn’t think that’s surprising. settlement with Lilly over Prozac- label for lower back pain and “I think it is embarrassing that suicide cases and off-label uses. migraine pain. That’s all off- so much of our practice is pre- Big money from off-label drugs Patients in the other two cases label.” Asked about research to Regulating prescription drugs scribing drugs and it’s a joke were given Prozac to treat support such uses, she said, “there how little our students and resi- Percent of prescriptions written for uses not approved by the FDA migraines and for Tourette’s syn- are no major gold-standard stud- How the U.S. government has tried to keep unsafe drugs off the market: dents know about pharmacolo- for some top-selling drugs and resulting retail sales: drome, a neurological condition ies, but the physician community 1906: Congress passes Pure Food and Drug Act after revelations gy,” he said. “And once you Off-label that produces uncontrollable tics. has been using it. ... They’re of worthless, dangerous cure-alls; Bureau of Chemistry formed, graduate, how does a doctor learn Drug name (class) prescriptions Off-label sales Lilly officials said they had telling us it is effective.” She later called Food and Drug Administration about new medicines? It’s from Neurontin (anti-seizure) 90% $1.8 billion settled some lawsuits for eco- offered to send more information. the pharmaceutical companies.” nomic reasons, but wouldn’t One of the biggest booths was 1937: Elixir Sulfanilamide, drug with lethal solvent, kills 107; highlights need for stronger drug laws Wilkes, who studied the issue Topamax (anti-seizure) 79% $643 million comment on specifics. A spokes- for Cephalon Inc., based outside of off-label promotion for the woman, Tarra Ryker, said Lilly Philadelphia. Two big signs 1938: Food, Drug and Cosmetic Act passes; new drugs must be Seroquel (antipsychotic) 78% $778 million FDA in the late 1990s, pointed “does not condone or encourage pitched Gabitril, a drug approved shown safe before marketing to two rigorous studies that con- Risperdal (antipsychotic) 65% $929 million off-label use of any of our med- only to treat seizures. Four sales 1962: Thalidomide, a morning sickness drug not yet approved in cluded that doctors — despite ications, including Prozac.” representatives in blue blazers U.S., causes many birth defects in Europe; Congress says new their protestations to the contrary Bextra (arthritis) 62% $502 million The company long has con- answered questions. drugs also must be proven effective — are swayed by pharmaceutical tended that depression causes Why, one was asked, was an Biaxin XL* (antibiotic) 58% $173 million 1970s: FDA checks effectiveness of more than 3,000 drugs on promotions. suicide, not Prozac. Even so, epilepsy drug being hawked at a the market before 1962 law; one-third found to be useless “What gets marketed hard is Avelox (quinolone antibiotic) 56% $128 million U.S. and British regulators conference for pain doctors? what gets prescribed,” said Jay warned last summer that Paxil, a “Most of the anti-epileptics have 1989: National Institutes of Health study shows off-label pre- scribing of two heart drugs increases deaths; 1990 survey shows Cohen, an adjunct associate pro- Trazodone HCL (antidepressant) 56% $120 million drug in the same class as Prozac, multiple other uses,” replied many doctors still prescribing these drugs off-label fessor of family and preventative may increase the suicide risk for Cephalon’s Janeen Morgan. medicine at the University of $93 million Remeron (antidepressant) 46% children and adolescents, thus Cephalon relies more on off- 1990s: FDA Commissioner David California-San Diego. Kessler cracks down on off-label Zithromax Suspn. (antibiotic) 45% $149 million reviving the debate that has sim- label sales than other companies. The marketing is massive. mered for a decade. Ryker said A Wall Street analyst touted “sig- drug marketing; doctors, drug mak- Over the last decade, the Zyprexa (antipsychotic) 42% $913 million this had no bearing on Prozac. nificant opportunities for off-label ers object; effort bogs down in court number of drug company sales Murray still prescribes Prozac sales” as a reason to be bullish on 1993: Effort by FDA to get reps has more than doubled to Levaquin (quinolone antibiotic) 42% $446 million for pain, but now he warns the company, and Cephalon at American Medical Association, other 94,000, one for every seven doc- patients of possible psychiatric times has aggressively marketed Zithromax Z-Pak (antibiotic) 37% $409 million medical societies to report well- tors in the nation. In 2002, the side effects. its drugs off-label; a 2002 letter researched off-label uses for inclu- value of the free drug samples Cipro (quinolone antibiotic) 30% $291 million from the FDA cited the company sion on drug labels yields few results passed out to physicians reached for making “misleading claims” CHUCK KENNEDY/KRT 1997: Amid reports of heart dam- David Kessler $11.9 billion, up more than 140 Wellbutrin SR (antidepressant) 27% $464 million Federal law prohibits drug about a “variety of unapproved age, FDA pulls half of off-label diet percent since 1996. makers from advertising or pro- uses” for another of its drugs, drug combo Fen-Phen off market due to “unacceptable risk” At the same time, pharmaceuti- Depakote (anti-seizure) 25% $162 million moting off-label drug uses, and Provigil. 2002: NIH’s Women’s Health Initiative study finds off-label use cal companies’ spending for since 1998 the FDA has cited The company’s messages Yasmin 28 (birth control) 25% $46 million of hormone replacement therapy potentially harmful; millions of advertising in the traditional med- companies nearly 70 times for apparently got through to doctors. women taking HRT at risk ical journals fell, according to IMS *Abbott Laboratories attributes some of these off-label figures to possible coding errors; Biaxin improperly promoting their In Maine, for example, state Health, a medical-data company. is approved for acute sinusitis, but 22 percent of the drug’s prescriptions were for chronic sinusitis. 2002: After court challenges, FDA considers relaxing rules If all of the chronic cases were miscoded, the off-label percentage would drop to 35 percent. drugs that way, a review of its Medicaid officials in 2002 noticed CHRISTIAN MURDOCH/COLORADO SPRINGS GAZETTE In addition, there’s evidence CHRIS OCHSNER/KANSAS CITY STAR records shows. a growing amount of Provigil use. against promoting off-label drug uses that when the FDA tries to get Michael Fielder of Kansas City, Missouri, takes an epilepsy drug Source: Knight Ridder analysis of Verispan’s Physician Drug and Diagnosis Audit Above, Scott Murray of Cephalon Inc. talks to a doctor during the annual meeting of the American Academy of Pain and its Source Prescription Audit for the most recent 12 months available Yet off-label promotions are Although approved at the time Management in Denver, Colorado. Right, Amy Jordheim, also of Cephalon talks to Kim Uptergrove, far right, a clinical SOURCE: U.S. FOOD AND DRUG ADMINISTRATION, KNIGHT RIDDER WASHINGTON BUREAU doctors’ attention, they pay little called Gabitril as a treatment for the pain caused by sickle cell Graphic: Todd Lindeman, Judy Treible © 2003 KRT commonplace, as was alleged in only for patients with narcolepsy, nurse and pain management specialist at Memorial Hospital in Colorado Springs. heed. anemia even though this use of the drug lacks FDA approval. Cyan Magenta Yellow Black BType 5 25 50 75 100

Off-label drugs BY CHRIS ADAMS the problem. Her medical records AND ALISON YOUNG show no blood work was done. Knight Ridder Newspapers That was a Thursday. By Sunday, Pettijohn was nauseated WASHINGTON — In 1962, and suffering abdominal pain. a Congress horrified that thou- Her mother packed a plastic bag sands of European babies had slip through with the remaining Avelox pills been deformed by the medica- and took her to the hospital. tion thalidomide ordered the Over the next five days, Food and Drug Administration Pettijohn was incoherent. She to make sure the same thing had a burning rash and her skin never happened in America. began peeling off. She slipped Congress gave the FDA the into a coma, resting on an air power to assess the safety and FDA safety net bed, totally wrapped as though effectiveness of all drugs before she were a severe burn patient. they could be sold on the U.S. By Wednesday, a doctor market. approached Gary and Ruth Forty years later, however, an Pettijohn. ever-growing segment of the “Our problem just got twice American pharmaceutical business as difficult,” he said. “She has is eluding that rigorous scrutiny. two life-threatening conditions Millions of patients are being simultaneously.” given drugs by their doctors that Pettijohn’s liver was in full the FDA hasn’t approved for treat- failure, and she was experiencing ing their particular illnesses. Off- a form of Stevens-Johnson syn- label prescribing, as it’s called, drome, a rare and extreme drug puts patients at risk while offering reaction mentioned on the no assurance the drugs will work. Avelox label. And while the FDA has She had a liver transplant on argued in court that the “risk to Friday. The doctors reported that the public from unproven uses of her old liver had turned to mush drugs and devices is both real and fallen apart in their hands. and substantial,” the agency Soon after the operation, rarely has tried to curb it. When Pettijohn had a heart attack, then it attempted to do so in the another. Her death certificate 1990s, its efforts fizzled. cited Avelox as the prime con- Now as the phenomenon tributing factor in her death. soars — Knight Ridder found The hospital had no comment that off-label prescribing for a about her death. Bayer had no sample of top-selling drugs has comment beyond saying the nearly doubled in the last five death “was promptly and accu- years — the Bush administration rately reported to the FDA,” and has opened the door to doing that it thinks its antibiotic should even less to stop it. be prescribed only for approved Saying recent court rulings conditions. have eroded its power, the FDA has sought public comment on whether drug makers should have As Congress reworked the more leeway to market the unap- nation’s drug-safety laws after proved uses of their profitable thalidomide, it sought to create a drugs. Overseeing the effort is a regulatory system that guaran- Bush appointee who, before teed that the drugs Americans coming to the FDA, helped sue used were safe and effective. the agency over its marketing and Lawmakers in 1962 worried advertising restrictions. that drug makers might be “They certainly are backing tempted to get a medication off,” said Michael Wilkes, the approved for one use and then vice dean at the School of promote it for others. “The initial Medicine at the University of JOYCE MARSHALL/FORT WORTH STAR-TELEGRAM claim would tend to be quite lim- California, Davis. He studied Martha Andreasen, of Bowie, Texas, lives with badly damaged lungs after taking the drug Pacerone. The drug, also called amio- ited,” said a group of senators off-label promotions for the darone, wasn’t FDA-approved for her heart condition. led by the late Tennessee FDA in the 1990s. Democrat Estes Kefauver. In part, the agency is hand- “We as patients have got to antibiotics. of place that you get into trouble. was moderate at best.” “Thereafter, the sky would be cuffed by a conflicted mandate raise the questions ourselves and A study this year funded by ... I am absolutely convinced that Early in the morning of May the limit. ... Extreme claims of from Congress. The FDA is try- take care of our own selves,” said the National Institutes of Health the drug will be used differently 15, Pettijohn’s mother took her any kind could be made.” ing to do many things: Get pow- Jere Goyan, who was FDA com- reviewed 100 emergency room once it’s marketed frequently.” to an emergency room. Going Congress told the FDA to erful drugs to market while pro- missioner from 1979 to 1981. prescriptions for fluoroquinolones Avelox was approved, howev- there, Pettijohn told her mom, require stringent tests before a tecting the public, respect the and found that only 19 were writ- er, and marketed hard by Bayer would be quicker than waiting drug could get to market. Once a First Amendment while regulat- ten for appropriate conditions and Corp. In 1999 and 2001, the FDA for an appointment with their drug passed, a company could ing drug advertising and let doc- The drug Kristen Pettijohn only one was given in the correct admonished company officials for family physician. advertise it only for the approved tors practice as they see fit — took was called Avelox. It’s part dose and for the proper duration. encouraging unapproved uses. Forty-two minutes later, uses. except when they make dumb of a family of antibiotics called The FDA long has been This past May, Pettijohn, a Pettijohn was on her way to the The FDA began reviewing all errors. Given the rapidly grow- fluoroquinolones. aware of the possibility that gregarious 23-year-old nursing drugstore. The doctor had diag- the drugs that had been on the ing number of drugs in the mar- Those powerful but risky Avelox could be misused. student from Batesville, Ind., nosed her with acute bronchitis market as of 1962, when the new ketplace, prescribing is far more drugs are intended for patients Just before it approved Avelox who recently had gotten engaged, and prescribed Avelox. The approval rules kicked in. Of complicated for doctors today. who are fighting particular bacte- in 1999, a member of the picked up the persistent cold that potent antibiotic’s label says it’s 3,443 drugs commonly pre- “There’s some limit to what rial bugs. But they’re widely pre- agency’s expert review panel — had been running through her approved for cases of chronic, or scribed, 1,124, or one-third, were the federal government should scribed off-label for less serious Robert Danner, a critical care family. “Her version was a little long-term, bronchitis, and only deemed useless and taken off the do, I think, because it’s not going illnesses, sometimes even to treat expert at the NIH — offered a worse than ours,” said her father, after blood tests have been taken market, FDA records show. to be effective,” said Dr. Janet viruses, which can’t be killed by warning: “This is exactly the kind Gary Pettijohn. “I would say it to identify the bacteria causing Even though that shows that Woodcock, the director of the doctors often can’t judge drugs’ FDA’s drug division. “You can’t effectiveness, the FDA largely has just Band-Aid and patch some- stayed out of the doctor’s office. thing that has systemic, underly- The agency’s rules say it can ing problems.” Do you have complete information on your prescription? require a drug company to prove But it’s Sometimes FDA-approved labels are dramatically different from the information pharmacies give patients when they pick up prescriptions. that an off-label use is safe and also clear Leaflet from Walgreens compared with the FDA-approved label for the heart drug Cordarone (amiodarone), which is often prescribed for off-label uses: effective. The FDA has said that that the a drug’s “actual use” by doctors agency can show a drug maker’s hasn’t fol- “intent” in selling it. lowed FDA-approved label However, asked in a lawsuit through on Uses: “Because of its life-threatening Warnings: “Several potentially fatal Adverse reactions: Are “very deposition in 1996 if the FDA had its limited side effects and the substantial toxicities, the most important of which common” with the most serious ever considered using the option efforts to management difficulties associated with is pulmonary toxicity ... at rates as high being lung toxicity, a worsening of requiring proof of off-label reduce the its use ... Cordarone is indicated only as 10 to 17 percent in some series of of the arrhythmia and rare serious effectiveness, the agency’s Dr. risks of for the treatment of the following patients. ... Pulmonary toxicity has liver injury. Robert Temple replied: “We think Dr. Janet documented, life-threatening recurrent been fatal about 10 percent of the time Woodcock off-label about this all the time. ... We just drug sales: ventricular arrhythmias” when other ... every effort should be made to utilize don’t know quite how to do it.” Under FDA rules, if a drug treatments have failed. alternative agents first.” Knight Ridder found that the maker knows a drug is being off-label use for some drugs is as used for off-label purposes, it’s high as 90 percent of all pre- required to come forward with scriptions sold for it. evidence supporting those unap- “constipation, loss of appetite, bitter Off-label uses became a con- Possible side effects: ” proved uses. FDA officials said er, cern in the 1990s, under the ys and lung, liv taste in mouth, nausea, vomiting, dizziness, trouble sleeping, in a court deposition that the rule Walgreens leaflet Chest X-ra ormed activist tenure of then- Cautions: should be perf headache, flushing of the face, or decreased sexual, tingling interest. or had not been enforced. “This ye tests “ Commissioner David A. Kessler, Uses: thyroid and e our progress or It says to contact a doctor if the person experiences a variety After the FDA took a our doctor , including muscle pain, vision changes who noted that “medical history medicine is an periodically to monitorects. Consulty y of things major drug company to court in ythmic k for side eff tbeat. is replete with examples of prod- antiarrh chec .” The section cautions about irregular hear 1993 and won a hefty payment used to treat for more details , dizziness and ucts and procedures that were for overt off-label sales pitches, ve based on medical anecdote, not an irregular increased sun sensitivityetus and that there ha. its commissioner vowed to use ... le harm to a f heartbeat. possib ts of permanent blindness evidence, and were thought for such sanctions again to control It may also be been rare repor There is no mention of watching years by most clinicians to be illicit marketing. But FDA offi- used to treat for the pneumonia-like symptoms effective, but later turned out to cials could point to no other case other conditions of pulmonary toxicity mined be useless and sometimes even since then when they have. as deter .” dangerous.” by your doctor Last year, the FDA issued There is no mention of fatal problems, In 1991, the FDA established a 28 violation letters for improper such as pulmonary toxicity task force to examine off-label drug marketing, down from 158 © 2003 KRT Not listed as drug Source: Knight Ridder Washington Bureau uses of drugs and medical devices. in 1998. The agency said it of last resort Graphic: Lee Hulteng, Judy Treible The agency also found that would need nearly twice as many drug companies often had no people to adequately police the incentive to evaluate the merits of industry’s 37,000 advertisements off-label prescribing because they and other promotions each year. might discover that their drugs did- Twenty-four years ago, the FDA responds Walgreens responds n’t work when prescribed off-label FDA said it wanted to ensure Beginning early next year, all patients taking Walgreens spokeswoman Carol Hively said the patient information given and sales would suffer, according that patients got useful, easy-to- amiodarone will receive FDA-approved consumers at the chain’s 4,229 pharmacies is written by an outside to a review of FDA records. understand information about the information about the drug to ensure all risks contractor. The Cordarone information will be revised to reflect more of The drug makers, which are drugs they took. Most still don’t. are disclosed. For other drugs, ask your the drug’s risks, she said. “We asked their editors to relook at their pharmacist for a copy of the FDA label or insert. wording and to rewrite it to reflect the concerns that you brought up.” among the most profitable indus- The bottom line for con- tries in the United States, know sumers: Beware. they can continue to get off-label Cyan Magenta Yellow Black BType 5 25 50 75 100

sales without going through the would require that all amio- expense of proving a drug’s darone prescriptions be accom- effectiveness for the off-label use panied by an FDA-approved to the FDA. patient guide to ensure that con- Also interfering is the patent sumers know exactly what the protection process. Once a drug’s drug is approved for and what its patent lapses, there’s little finan- dangers are. Patients will get the cial interest in taking on the added guides starting early next year. costs of new FDA application. “What you brought to the Based in part on the work of table was the extent of off-label the off-label task force, the FDA use and some specific patient attempted a host of fixes. But a experiences of not getting all of decade later, those efforts largely the information about this drug,” have fallen short: Woodcock said. One push was to have “Obviously this drug is a very companies apply for FDA risky drug,” she said. approval for popular off-label While many cardiologists treatments. While the effort ini- defend amiodarone’s off-label tially produced more applica- use for atrial fibrillation, a recent tions, the numbers have been NIH study challenged their long- dropping. From 1998 to 2002, held beliefs. the number of approvals for new Called AFFIRM, the study uses of existing drugs went from concluded that patients taking 74 to 39, according to the FDA. drugs such as amiodarone to An attempt to revise the control their hearts’ rhythm prescribing labels for doctors has experienced more side effects dragged on for more than 10 and hospitalizations than those years. The agency says its labels given safer drugs to control how are confusing even for doctors, fast their hearts beat. For all its and that fixing them could extra risks, amiodarone was no reduce medication errors. more effective. Proposals to give patients Dr. Claude Lenfant, the more meaningful drug informa- RANDY AMICK/KRT recently retired director of NIH’s tion have been stalled even Gary and Ruth Pettijohn, of Batesville, Indiana, hold a photo of their daughter, Kristen, who died after being prescribed a power- National Heart, Lung and Blood longer. The FDA repeatedly ful antibiotic called Avelox for a condition that was less severe than what the drug is approved to treat. Institute, said amiodarone didn’t backed away from plans, dating appear to be the best treatment to 1979, to ensure that all patients spread that they’re now consid- atrial fibrillation, a common funeral arrangements. She’s Wyeth paid for proclaimed for many patients with atrial fib- get basic information about the ered the standard of care. heart problem similar to atrial homebound and doesn’t have the “Amiodarone From Last to First- rillation. But changing a doctor’s drugs they buy. Opposition has Amiodarone — under the flutter. Like many patients, she strength to clean her house, a Line Antiarrhythmic Therapy” practice “takes place very, very been fierce. Doctors have argued brand name Pacerone — was the said she was never warned of the humiliating letdown for a woman on its glossy purple cover. slowly.” that the information would drug taken by George Cox, a drug’s risks or that her prescrip- who’s been a member of her Wyeth spokesman Doug “I personally feel there’s a frighten patients unnecessarily. Buckner, Mo., man who lost tion was off-label. Her pharmacy town’s Young Homemakers club Petkus said the brochure was system failure,” he said. Today, most of the leaflets nearly all his sight, and by leaflet mentioned nausea and for 30 years. Since she was educational, not promotional. patients get about drugs are part Martha Andreasen of Bowie, dizziness, but not death from dropped by her husband’s health Regardless, Wyeth no longer is of an industry-run voluntary pro- Texas, who’s struggling with lung problems. insurance, the Andreasens now doing any promotion of its amio- Even when it’s aggressive, gram. The quality of the infor- lung damage. Today, Andreasen is tethered pay $800 a month for high-risk darone drug, Cordarone, because the FDA has been unable to stem mation they provide varies wide- Amiodarone can have a dev- to an oxygen tank each night, and insurance and co-payments. Their its patent protection has expired. off-label prescribing. ly, with only about half of the astating effect on the lungs: As at age 54 she’s already made her dining room table sits atop ply- After Cox lost most of his For more than a decade, the leaflets studied meeting FDA many as 17 percent of patients in wood because they can’t afford sight, his Missouri pharmacist FDA has tried to corral the use goals for usefulness, according to some studies experienced lung to finish a repair to the floor. gave him Wyeth’s “First-Line” of Accutane — a drug for severe an FDA-commissioned study damage, and about 10 percent of “The FDA is supposed to brochure, and he passed it on to forms of acne — which can announced last year. them died. Patients taking the protect the general public from the FDA in 2001. cause birth defects. Proposals to restrict drug drug have suffered thyroid, liver situations such as this — or so I The agency wrote back, say- As early as 1990, a frustrated makers’ efforts to get around the and eye problems, including thought,” Andreasen said. ing it can “take action when FDA official wrote that “intensive ban on promoting off-label drug blindness. The FDA approved it Since at least 1988, the FDA unapproved (off-label) uses regulation has not, cannot and uses ran into a blizzard of legal only as a drug of last resort for has warned two drug companies become widespread or endanger will not achieve the Agency’s challenges by the Washington patients with a life-threatening to stop false and misleading pro- the public health,” but until last goal of eliminating pregnancy Legal Foundation, a free-market heart condition called ventricular motions that downplayed amio- month it had done little to try to exposure to Accutane.” At the advocacy group. On free-speech tachycardia. darone’s risks while suggesting it curb the widespread off-label time, the official estimated that 90 grounds, the courts turned away In 1999, Cox, now 75, was as a first-line therapy. The agency prescribing of amiodarone. percent of Accutane’s use by many of the FDA’s arguments; given amiodarone for atrial flutter, sent letters to amiodarone makers In the last year, doctors wrote women was off-label, typically U.S. District Judge Royce a heart condition that isn’t life- in 1989, 1992 and 1998. “Your nearly 2.3 million off-label amio- for mild acne that can be treated Lamberth said the “FDA exag- threatening. He got the prescrip- firm has an intolerable record of darone prescriptions, according with safer drugs. gerates its overall place in the tion a full decade after the FDA compliance with the law,” read to Knight Ridder’s analysis. Even tough new warnings on universe.” began telling the drug’s makers to the 1989 letter to Wyeth, one of That’s 82 percent of all the pre- the drug’s label about suicide, JOYCE MARSHALL/FORT WORTH STAR- Helping the Washington stop promoting it as something TELEGRAM the amiodarone makers. scriptions for the drug. psychosis and depression didn’t Legal Foundation make its case other than a last-resort drug. Andreasen and her husband Wyeth’s promotions contin- In response to Knight stop sales. was Daniel Troy, a prominent Andreasen also was given Terry in a family photo taken ued. From 1999 to 2002, a slick Ridder’s findings, the FDA’s According to an internal com- First Amendment and corporate amiodarone off-label. She had in 2000. magazine-style brochure that Woodcock said the agency pany sales plan for 2001, drug lawyer. Today, Troy is chief maker Roche concluded that counsel of the FDA, a Bush despite extensive media cover- administration appointee who age about those new dangers, has started a process that could “prescribers were apparently substantially rewrite the FDA’s unmoved by this information.” rules on commercial speech, In 2002, the same FDA offi- including those regulating off- cial made another estimate that label drug promotions. 90 percent of Accutane use was The pharmaceutical industry off-label. The company disputes has jumped on the opportunity, the FDA estimate. pushing the agency to relax some of its restrictions on promoting off-label uses. Consumer groups, Thalidomide’s entry into the such as Public Citizen Health U.S. market shows how physi- Research Group, and many con- cians and the drug industry con- gressional Democrats say to do sider the FDA irrelevant. so would invite disaster. The drug was approved in FDA Commissioner Mark B. 1998 for a leprosy-related skin McClellan, a physician, said the condition that’s virtually nonex- agency istent in the United States. would like After studies showed that the

to see KEITH MYERS/KANSAS CITY STAR drug might be useful for treating more evi- George Cox of Buckner, multiple myeloma, a form of dence sub- Missouri, displays promotion- cancer, Celgene Corp. aggres- mitted al brochures for amiodarone. sively sold that idea to doctors. about off- Cox was left blind in one eye One company sales represen- label uses, and almost blind in the other tative went further, telling an stressing after taking the heart drug, he oncologist that the drug, marketed that it was now uses his mower for as Thalomid, is “good for weight important Mark McClellan transportation around town. loss,” could be used “as an for such appetite stimulant” and is a “great treatments to meet the “gold drug for feelings of general well- standard” of FDA approval. being,” according to an FDA doc- To help curb risky off-label What to do ument describing the sales pitch. prescribing, he wants to improve When the doctor asked the FDA’s system for reporting whether the FDA had approved drugs’ side effects, and he wants if you Thalomid for those uses, the better information in the hands of sales rep said, “No, but do you doctors and consumers. The effort experience want some material anyway?” to rewrite the labels doctors read In 2002, the FDA told Celgene will be finished “in a matter of side effects that its existing data on multiple months,” he said. “I think we can Report adverse reactions myeloma wouldn’t be enough to do much better than we have.” when you’re taking any pre- win the agency’s approval. The The FDA has had some suc- scription drug. Doctors are earliest the company says it might cess using its authority to get the supposed to report to the seek authorization as a treatment pharmaceutical industry to study Food and Drug Administra- for that form of cancer is 2005. drugs’ affects on children and put tion when patients experi- Today, 70 percent of that information on the label. ence side effects. Thalomid uses are for multiple Those efforts, begun in the 1990s If you have one, ask your myeloma, while only 1 percent and involving congressional and are for its approved leprosy con- doctor to report it, and fol- agency action, have produced dition. Celgene, in filings with low up to make sure he or some results, although they recent- the Securities and Exchange she does. If the doctor ly have been set back in court. Commission, declared: “We may won’t file the report, do it not be able to attain or maintain yourself on the Web at profitability” if physicians pre- In many ways, the FDA’s www.fda.gov/medwatch/ scribe Thalomid only for patients 1962 mandate to determine how.htm or by calling who are diagnosed with leprosy. whether drugs are safe and effec- 1-800-332-1088. You also tive is irrelevant in today’s mar- can call the company that Knight Ridder Newspapers ket, in which some off-label makes the drug. Researcher Tish Wells contributed to treatments have become so wide- this report. Cyan Magenta Yellow Black BType 5 25 50 75 100

About the series More than 30 newspapers published Knight Ridder’s series about off-label drug use. Below are several editorials and front-page images that show how the series was played.

The off-label use of Pills’ purpose: Off-label demands drug companies submit lengthy studies that document side drugs has delievered use is risky; Information effects and prove the drug’s effective- relief to patients. It has is key to safety ness against a certain disease. And that’s the catch. Because once also resulted in harm The Detroit Free Press, Nov. 5, 2003 the drug comes on the market, all bets basically are off, the series reports. the FDA could easily The Food and Drug Administration is Doctors can prescribe the drug for any prevent charged with keeping the nation’s drug condition, not just the one the FDA supply safe, but it doesn’t do enough to approved. Akron (Ohio) Beacon Journal, control how a drug is used once What to do? Two points: Clearly, the Nov. 10, 2003 approved. federal government will have to regulate Over the past decade, so-called off- the practice more tightly. As a superma- Drugs have become a major part of label use — prescribing a medication for jority of Americans surely would agree, the practice and business of health care. a condition other than the one the FDA patients who enter our nation’s health DETROIT FREE PRESS Many more effective products cover a OK’d — has exploded unchecked. Such system should be confident they’ll be THE MIAMI HERALD wide variety of diseases and conditions. Nov. 3, 2003 treatment is not necessarily wrong; it treated in a way that’s both based on Nov. 2, 2003 In a very competitive industry, drugs are often gives people relief they otherwise good science and within a protective set also eagerly promoted to health-care pro- do not find. But it isn’t necessarily safe, of rules. Commercial air travel is han- fessionals and the general public. The either. dled in exactly that way. Health care increasing role of drugs invites concerns Clearly, the FDA should be more should be, too. about improper uses. The risk in routine- aggressive about going after companies Second, America’s physicians should ly prescribing drugs for treatments other that illegally market off-label uses. But be the first to call for meaningful than those for which they were approved if it hasn’t done so yet, it’s unlikely to reforms. Following an accepted set of — off-label use — is one such concern. under a White House that favors corpo- effective rules doesn’t hurt the medical A fair amount of off-label prescrip- rate freedom over regulation, nor a profession. It helps, by raising patients’ tion is inevitable. For instance, there are Congress swayed by pharmaceutical confidence as well as giving doctors a numerous conditions for which precisely stronger defense against malpractice formulated medications are simply not contributions. The industry — which shuns regula- suits. Those things will work to doctors available. Some diseases are rare and and hospitals’ benefit. affect so few people that drug companies tion so it can be free to find cures — have little financial incentive to invest in should exercise self-restraint. But as drug development. Other illnesses, like long as it’s making money, that’s not Vigilance the cure for AIDS and cancers, require treatment likely, either. Perhaps, if a more critical with multiple drugs in combinations. power structure lands in Washington, off-label drug woes Some off-label uses have proved the industry might scale back so as not to invite tighter regulation or ramped-up Wilkes Barre (Pa.) Times Leader, generally beneficial as well, most Nov. 6, 2003 notably the discovery that regular, small enforcement. Don’t count on it. doses of aspirin protect against heart dis- The unintended consequences of off- ease. Claims abound of other “happy So the responsibility falls to often- harried doctors and to consumers, who label prescribed medications can be a discoveries,” such as an AIDS drug bitter pill. effective in treating ovarian cancer. must ask more questions. Doctors cannot take at face value the The practice is legal, common and All the same, the findings of a Knight defended by doctors and the American Ridder Newspapers study of off-label claims of pharmaceutical sales reps — nor should they ever prescribe a medica- Medical Association. prescription uses offer alarming indica- But the six-month study by Knight tions of the risks. Drugs are improperly tion without reading about its potential risks. No time is no excuse. Ridder showed the practice surprisingly prescribed for the wrong diseases, in common, with 115 million such pre- dosages and for durations unapproved by The broader medical community, WILKES BARRE (Pa.) through med school and continuing scriptions written in the past year. FORT WORTH (Texas) the Food and Drug Administration and Occasionally, the consequences have TIMES LEADER to treat populations not tested for the par- seminars, should teach this issue. STAR-TELEGRAM Disease and pain are managed at a been costly. Even deadly. While doctors ticular usage. The consequences have are free to prescribe medications as they Nov. 2, 2003 proved fatal or severely injurious to rapidly increasing rate through pills, Nov. 2, 2003 not procedures; doctors must know see fit, drug companies are restricted in some patients. The study noted off-label their marketing. Such restrictions can be prescriptions accounted for $21.9 billion more about potential risks as well as benefits. circumvented and may contribute to the in sales in 2002, and free drug samples misunderstanding about the risks of to doctors were valued at $11.9 billion. some drugs. The risks are sure to increase with the Reform Rx drug laws And those existing restrictions may growth in drug therapies and the aggres- be relaxed depending on the outcome of sive marketing of drugs, both their Grand Folks (N.D.) Herald, Nov. 5, public comment being solicited by the approved and off-label uses, to health-care 2003 FDA. professionals, most of whom have neither the time nor the resources to verify the Doctors and regulators alike should In the meantime, concerned patients therapeutic claims of drug representatives. call for tighter restrictions on off-label should ask doctors or pharmacists the The FDA has established regulations drug use. intended use of a drug or read the and guidelines to recognize off-label The Knight Ridder series’ startling FDA’s approved prescribing informa- uses. Its obligation is to protect the pub- conclusion: “A six-month Knight tion. Look for indications and usage, lic health without infringing on manu- Ridder investigation has found that contradictions, warning and precau- facturers’ freedom to tout their products patients nationwide are being injured tions, drug interactions and adverse to doctors. and killed as doctors routinely prescribe reactions. Ask your doctor the reasons One solution is to get the FDA to drugs in ways the Food and Drug for a prescription and if there’s research monitor and aggressively enforce require- Administration never certified as safe to support using the drug. Ask about ments for drug manufacturers to provide and effective.” alternatives. scrupulous documentation about the safe- “Injured and killed.” Hard words — While patients need — and want — ty and effectiveness of unapproved uses. but the series backed up its conclusions to trust their doctors, they also need to Another is to curtail the pressure of sales with hard evidence. have some confidence in the informa- promotions on doctors, who rely on sales Off-label prescribing, as the series tion doctors have concerning medicines representatives for up-to-date information explained, is the doctors’ practice of that are commonly prescribed. It’s a on drugs and their side effects. prescribing a drug for uses that the FDA terrible and unacceptable irony when Patient safety is worth the cost of hasn’t formally approved. The drug- the prescribed treatment causes added beefing up staffing at the Federal Drug approval process is famously long, com- harm, rather than helping to cure or BRADENTON Administration to do the job. plicated and expensive; the FDA comfort. THE CHARLOTTE (Fla.) HERALD (N.C.) OBSERVER Nov. 2, 2003 Nov. 2, 2003 About the writers

Investigative reporter Alison Young part of a six-person Journal team that won the Pulitzer for came from the Detroit Free Press, where stories on Pentagon spending. He graduated from Iowa she was consumer affairs reporter, enter- State University. prise editor and deputy metro editor. Her reporting has won numerous awards, Tish Wells is the Knight Ridder including the Roy W. Howard Award Washington bureau’s researcher and for Public Service for coverage of abuse Web editor. A graduate of the Pratt and neglect in nursing homes and the Institute in New York, Wells also holds Gerald Loeb Award for an investigation a master’s degree in library science from of a deadly national outbreak linked to Sara Lee deli meats. the University of Maryland in College Prior to joining the Free Press in 1993, Young was a chil- Park. She has worked in law firms, the dren’s issues reporter at The Arizona Republic and covered National Library of Medicine in environment issues for the Dallas Times Herald. She is a Bethesda, Md., and as a freelance book graduate of the University of Kansas. researcher. She is an expert in computer-assisted reporting and served as a senior librarian at USA Today and Gannett Investigative reporter Chris Adams News Service for more than a dozen years before joining joined Knight Ridder in 2003 from The Knight Ridder in 1999. Working with Sumana Chatterjee Wall Street Journal, where he covered and Sudarsan Raghavan, she also won a 2002 Overseas health and steel from Washington and Press Club award for Best International Reporting on Pittsburgh. From 1989 to 1996, he Human Rights for the bureau’s chocolate slavery package, reported for The (New Orleans) Times- “A Taste of Slavery.” Picayune. He has won the George Polk Award, the Robert F. Kennedy Award, On the Internet the Worth Bingham Prize, an The series is available on the Knight Ridder Washington MACON (Ga.) Investigative Reporters and Editors Award, three Education bureau’s Web site at www.krwashington.com. Writers Association awards, and the Livingston Award, and MONTEREY COUNTY TELEGRAPH been on teams that won the National Headliner Award and Knight Ridder/Tribune Information (Calif.) HERALD the SPJ/SDX Award for Public Service. He was a finalist Services handled the production of this Nov. 4, 2003 for the Pulitzer Prize in 1996 and 1999, and in 2000 was reprint. Nov. 3, 2003