research-for-hire

Drug Trials Hide Conflicts for Doctors\ New York Times, The (NY) - Sunday, May 16, 1999\ Author: KURT EICHENWALD and GINA KOLATA\ Abstract: Article Research for Hire, first of two, on clinical drug\ research that has become multimillion-dollar industry; hundreds of\ testing and drug companies working with private doctors have turned\ patients into \'commodities,\' bought and traded as physicians are\ enticed into usingthem as test subjects; practice gives drug companies\ get access to vast new pool of subjects, but also raises serious\ ethical questions by injecting money into delicate doctor-patient\ relationship, usually without patient even realizing it; ten-month New\ York Times investigation studies contracts and other confidential\ documents that reveal system that fuels pharmaceutical renaissance, is\ fraught with conflicts of interest, places premium on speed and\ meeting quotas, and relies on Government and private monitoring that\ can be easily fooled; drug companies and contractors offer large\ payments to doctors, nurses and other medical staff to recruit\ patients, some getting finder\'s fees for merely referring patients to\ studies; companies use doctors as clinical investigators regardless of\ their speciality; example is Dr Peter Arcan\'s enlistment of patient\ Thomas W Parham in inappropriate prostate trial for SmithKline\ Beecham; other cases also cited; Drs David S Shimm, Jay Grossman,\ Robert M Califf and others on both sides of issue comment; photos;\ diagram tracing how typical drug comes to market (L)\ When Thomas W. Parham visited his doctor in the summer of 1995, he\ expected just another routine checkup. But his doctor had something\ else in mind.\ \ The doctor, Peter Arcan, suggested Mr. Parham might want to join a\ study of a new drug to shrink enlarged prostates, according to records\ of the encounter. Mr. Parham was puzzled -- his prostate was fine. But\ Dr. Arcan brushed aside the retired metal worker\'s questions, saying\ the experimental drug might prevent future problems. Satisfied, Mr.\ Parham, a 64-year-old resident of La Habra, Calif., agreed to\ participate.\ \ But there was one question Mr. Parham did not ask: What was in it for\ Dr. Arcan?\ \ The answer was money. The drug\'s maker, SmithKline Beecham P.L.C., was\ paying \$1,610 for each patient that doctors signed up -- money that\ covered study expenses while allowing a portion to end up as profit\ for Dr. Arcan and his associates.\ \ Mr. Parham had no idea. \"Nothing was mentioned about money,\" he said\ in an interview. \"It\'s a situation where you have faith in your\ doctor.\" Through his secretary, Dr. Arcan declined comment.\ \ With his decision, Mr. Parham had unwittingly joined hundreds of\ thousands of other patients recruited by their personal physicians\ into a booming venture: the business of testing experimental drugs on\ people.\ \ Once clinical research was a staid enterprise primarily administered\ by academic researchers driven by a desire for knowledge, fame or\ career advancement. Now, it is a multibillion-dollar industry, with\ hundreds of testing and drug companies working with thousands of\ private doctors.\ \ In this new industry, patients have become commodities, bought and\ traded by testing companies and doctors. Almost daily, the industry\ urges doctors to join the gold rush, bombarding them with faxes and\ letters blaring such come-ons as \"Improve Your Cash Flow\" and\ \"Discover the Secret For Obtaining More Funded Studies.\" In an era of\ managed care, the pleas are seductive: the number of private doctors\ in research since 1990 has almost tripled, and top recruiters can earn\ as much as \$500,000 to \$1 million a year.\ \ This new system is a boon for drug companies because it reaches out to\ a vast pool of test subjects who have never before been available for\ experimentation. But it also injects the interests of a giant industry\ into the delicate doctor-patient relationship, usually without the\ patient realizing it.\ \ These changes have prompted little public debate, mostly because the\ full scope of what is happening is hidden. The industry treats\ research agreements as corporate secrets and contractually forbids\ doctors to disclose them. As a result, few people outside the\ industry, including Government officials, have seen the contracts or\ know the magnitude of the money involved.\ \ But in a 10-month investigation, The New York Times obtained such\ contracts and thousands of other confidential documents that present a\ view of the research industry that has never before been available.\ \ These records, and interviews with participants, reveal a system\ fueling a pharmaceutical renaissance, but fraught with conflicts of\ interest; that places a premium on speed and meeting quotas; that\ relies on Government and private monitoring that can be easily fooled\ and that some researchers said is inadequate, and that secretly offers\ a share of the cash to other health professionals who might influence\ patients to join a study. At bottom, the only thing separating a\ trusting patient from a study that could be inappropriate or\ potentially harmful is the judgment of a doctor torn by these unseen\ conflicts and pressures.\ \ The documents, including contracts, protocols or related financial\ records from more than 300 recent drug studies, were provided by a\ number of people in the industry concerned about its direction. The\ Times also conducted a computer analysis of more than 200,000 filings\ with the Government and related data submitted by doctors who want to\ conduct research, and interviewed doctors, patients, ethicists,\ industry executives and Government officials.\ \ These are among the specific findings of The Times\'s investigation:\ \ *Drug companies and their contractors offer large payments to doctors,\ nurses and other medical staff to encourage them to recruit patients\ quickly. And doctors do not even have to conduct trials to get paid:\ There are finder\'s fees for those who refer their patients to other\ doctors conducting research.\ \ *Doctors who recruit the most patients receive additional perquisites,\ such as the right to claim a coveted authorship of published papers\ about the studies -- even though the true author is a ghost writer\ using an analysis from the drug company. Those who fail to meet the\ recruitment goals are usually dropped from future studies.\ \ *Testing companies often use doctors as clinical investigators\ regardless of their specialty, at times leaving patients in the care\ of doctors who know little about their condition. For example,\ psychiatrists have conducted Pap smears and asthma specialists have\ dispensed experimental psychiatric drugs.\ \ *A growing number of doctors conducting drug research have limited\ experience as clinical investigators, raising questions among some\ experts about the quality of their data.\ \ In interviews, industry officials and researchers said the emerging\ drug-approval system was dedicated to quality and offers significant\ benefits. Since patients are seeing their own doctors, researchers\ said, it adds a level of continuity and personal contact to the\ process -- something unavailable from full-time researchers.\ \ Moreover, industry officials said, the new pool of test subjects is a\ resource of incalculable value that is allowing the development of an\ avalanche of new compounds. Drug tests \"can get delayed if the\ patients aren\'t out there and available,\" said Chris Kuebler, the\ chairman and chief executive at Covance Inc., a giant testing company.\ \ But some experts said patients were being pushed to participate in the\ studies because of the financial interests of their doctors.\ \ Doctors working as researchers \"are enticing and cajoling patients who\ are in no position to resist their blandishments to enter clinical\ studies,\" said Dr. David S. Shimm, a member of the ethics committee at\ Porter Adventist Hospital in Denver who has written about research\ conflicts.\ \ \"What the patients are not seeing is that the clinical investigator is\ really a dual agent with divided loyalties between the patient and the\ pharmaceutical company,\" he said.\ \ While patients must sign detailed consent forms to enroll in drug\ studies, they are often in no position to question their doctor\'s\ suggestion that they join.\ \ \"The physician has enormous power over you,\" said Uwe E. Reinhardt, a\ health care economist at Princeton University, who himself recently\ agreed to participate in a clinical trial run by his doctor -- in part\ because he feared annoying him -- and who had no idea that money might\ be involved. \"You want to keep his favor. If you say no, you\'ll worry\ that he may not like you.\"\ \ That is what happened with Mr. Parham and Dr. Arcan. In joining the\ study, Mr. Parham said: \"I just followed his advice, just like if he\ said to take two aspirin instead of one. He\'s a doctor and I\'m not.\"\ \ In truth, Mr. Parham should never have been signed up for the prostate\ study. According to his medical records, he had been hospitalized the\ previous year with a chronic slow heart rate, a condition that\ specifically disqualified him for the study. But, saying that Mr.\ Parham\'s heart rate was only mildly slow, an administrator handling\ the paperwork for Dr. Arcan sought an exemption from SmithKline. Based\ on those representations, the drug company granted the exemption; it\ was not told about Mr. Parham\'s earlier hospitalization.\ \ Soon after joining, Mr. Parham complained of fatigue, a symptom of his\ slow heart rate. Dr. Arcan dismissed the complaints as emotional.\ Within weeks, Mr. Parham asked to be dropped from the study. Days\ later he was hospitalized and given a pacemaker; Mr. Parham never\ brought legal action and it is impossible to know whether his\ participation in the study affected his heart condition.\ \ His experience underscores a potential danger of the emerging\ drug-testing system: Doctors with money at stake may persuade patients\ to take drugs that are inappropriate or even unsafe. Under the current\ system of monitoring, such actions are almost impossible to catch and\ no statistics are collected on such events. Within the industry, most\ of the planning focuses on conducting studies quickly. Patient issues,\ some researchers said, are often lost in the rush.\ \ \"You go to the trade meetings on clinical research; you go for two\ entire days, and patients are not mentioned,\" said Dr. Robert M.\ Califf, the director of the Duke Clinical Research Institute, an\ academic drug-testing center in Durham, N.C., affiliated with Duke\ University. \"The patient is an object to make money. Having patients\ is just the dirty price for doing business.\"\ \ The Incentives Putting a Price On Every Patient\ \ The letter last July from Merck & Company was nothing if not\ sympathetic. The company recognized that doctors involved in its study\ of a hypertension medication were having trouble finding qualified\ patients. And so, with the letter, Merck offered a little\ encouragement for them to work harder.\ \ Instead of paying \$2,955 for each test subject enrolled, Merck offered\ \$500 more in the study comparing the drug Losartan with a placebo. For\ those doctors who enrolled their quota of 14 patients by Sept. 30, the\ company would kick in an additional \$2,000 -- making that 14th patient\ worth \$5,455 if recruited in time, and the entire group potentially\ worth more than \$50,000.\ \ \"We will forward the first check as soon as the first four additional\ patients are enrolled,\" the letter said.\ \ After discovering how effective paying doctors to recruit patients can\ be, the drug industry has opened the financial floodgates. Special\ cash bonuses for signing up specified numbers of people by a given\ date, a practice once unheard of in clinical research, are becoming\ part of the landscape. Moreover, those payments -- to private doctors,\ research firms and even to university medical centers -- are only one\ of a number of incentives that are being dangled by drug and testing\ companies to entice the medical community.\ \ There are payments to everyone in the system who can come up with a\ patient, from other doctors who refer them for research to the study\ coordinators in the researcher\'s office who screen patients to see if\ they qualify.\ \ None of these benefits are scrutinized by Government regulators, who\ said in interviews that they saw little difference between providing\ grants for university research and paying doctors directly. For\ academics \"the money is just as important as with the internal\ medicine guy trying to beat the H.M.O.,\" said Dr. Murray M. Lumpkin,\ the deputy director of the Center for Drug Evaluation and Research at\ the Food and Drug Administration.\ \ But unlike block grants, today\'s incentives can grow almost day by\ day, if the doctor works the way the drug companies want. And the\ variety of the incentives is almost endless.\ \ The most basic form of compensation is a flat fee paid for each\ patient enrolled. The amount of money paid to the researchers varies\ widely, depending on the complexity of the study, the number of tests\ involved and the difficulty in finding patients.\ \ For example, in 1996, a study of a migraine drug sponsored by Janssen\ Pharmaceutica, a unit of Johnson & Johnson, paid doctors \$3,600 for\ each enrollment. Another study that year sponsored by Organon Inc. on\ a new birth control pill paid \$1,100 for each patient. And a\ Wyeth-Ayerst study of drugs for hormone replacement in women paid\ \$4,581.\ \ While all of these payments were made to specific clinics, the exact\ amounts on a single test could vary slightly by region, or even by\ clinic.\ \ Many executives from drug or testing companies refused to discuss\ their research programs, citing confidentiality. Those who did grant\ interviews gave consistent explanations of their payments: They are\ necessary compensation for the doctors\' work.\ \ \"We set up contracts that hopefully reimburse investigators adequately\ for the time they put in to screen patients, bring them in, and\ provide data to us that is as clean as possible,\" Dr. Elizabeth\ Stoner, the vice president for clinical research and contract\ management at Merck Research Laboratories in Rahway, N.J., said.\ \ Additional payments can be made, she said, when there is \"additional\ effort above and beyond what they anticipated.\"\ \ But doctors who are particularly successful in recruiting study\ patients and keeping down their costs can make huge profits.\ \ \"There are physicians who can net about \$500,000 to \$1 million a year\ doing clinical research,\" said Ismail A. Shalaby, the chief executive\ of Nema Research Inc., a network of doctors and hospitals in the\ Baltimore area performing clinical research. \"And that is not bad.\"\ \ The benefits to the doctors who conduct research are not simply\ financial. Once, researchers said, the names that appeared on papers\ describing drug studies were those of the actual authors. That is no\ longer always the case. Today, the coveted right to claim authorship\ is often just another reward for doctors who recruit the most patients\ -- even if they wrote nothing and analyzed no data.\ \ \"They used to ask you to write,\" said Dr. Thierry Le Jemtel, a\ cardiologist at Montefiore Medical Center in the Bronx who is a\ longtime academic researcher. \"Now, they send you a paper all written\ by a medical writer\" hired by the drug company.\ \ Dr. Jay Grossman, a private-practice doctor who is an allergy and\ respiratory specialist with Vivra Asthma and Allergy Inc. in Tucson,\ Ariz., said he was often a lead author on publications because he had\ been a top patient recruiter in the clinical trials, even though he\ rarely did much -- if any -- of the actual writing. \"That\'s common,\"\ he said. \"It\'s orchestrated by the drug company\'s medical writer.\"\ \ For example, Dr. Grossman cited a study for a SmithKline Beecham\ asthma medication that was published in The Journal of Asthma and\ another on an allergy medication sponsored by Boehringer Ingelheim\ Pharmaceutical published in The Journal of Allergy and Clinical\ Immunology. While the articles are written by a drug company writer,\ Dr. Grossman said, he often suggests modifications.\ \ As drug companies compete for top study doctors who will quickly\ accrue patients, a financial arms race has developed, with each\ company seeking new ways to use cash and benefits to spur the\ research.\ \ One practice is to offer finder\'s fees to doctors who are not\ conducting studies for referring patients to doctors who are. For\ example, a letter from a testing company handling the research on a\ vaginal suppository for the Bayer Corporation in 1996 promised \"a \$75\ referral fee for physicians and area/federally funded clinics, i.e.,\ Planned Parenthood, etc.\"\ \ Even study coordinators -- the nurses and medical assistants who\ oversee the administrative details of a study and screen patients to\ see if they qualify -- are offered fees for finding test subjects. In\ 1995, for example, Pharmaceutical Product Development Inc. of\ Wilmington, N.C., which coordinates drug tests, needed a way to speed\ up enrollment in a study of a drug developed by the Zambon Corporation\ in East Rutherford, N.J.\ \ So the company sent a fax to medical staff members who were screening\ patients around the country, offering them bonuses for fast\ enrollment.\ \ \"EVERY study coordinator has the chance to receive \$750 just by\ reaching the enrollment goal of 30 evaluable patients,\" the fax said.\ \"So GET BUSY!\"\ \ The stepped-up competition among drug companies for the services of\ doctors led to the development of cash bonuses for them, one of the\ most controversial incentives now offered. But even companies that\ were uncomfortable with the idea found it hard to resist.\ \ \"It\'s a tough issue,\" said Dr. Cynthia M. Dunn, the director of the\ Clinical Research Institute at the University of Rochester and a\ former drug industry executive. \"On one hand, many companies recognize\ it\'s part of what we have to do to be competitive. On the other hand,\ they recognize they are setting up potential conflicts of interest\"\ for doctors.\ \ Some large drug companies have refused to offer bonuses out of ethical\ concerns. \"You don\'t want to provide an advantage that can be\ misinterpreted,\" said Dr. Joseph Camardo, the senior vice president of\ clinical research and development for Wyeth-Ayerst Research in Radnor,\ Pa.\ \ The bonuses all reward the same behavior: enrolling patients fast. For\ example, a contract last year by Ibah Inc., a testing company owned by\ Omnicare Inc., provided a \$750 bonus for each patient enrolled by June\ 15 or \$500 for those enrolled between June 15 and July 16 -- upping\ the ante for doctors whose enrollments were lagging.\ \ Such incentives outrage some experts. Bonuses in clinical research are\ \"inappropriate, potentially illegal and certainly unethical,\" Dr.\ Robert Tenery, a Dallas doctor who is the chairman of the council on\ ethical and judicial affairs for the American Medical Association,\ said of such payments in general. \"Why would you get an extra \$500?\ How can you explain the rationale? Maybe you took a patient who really\ didn\'t need to be enrolled.\"\ \ If something goes wrong, doctors might never be able to escape the\ nagging doubt that the bonus program was to blame. \"How would you like\ to confront the family when a family member got hurt, and you got a\ bonus for enrolling?\" asked Michael Leahey, the director of the office\ of clinical trials at Columbia-Presbyterian Medical Center in New\ York.\ \ A system that offers so much cash and so many benefits for quick\ recruitment assumes that doctors would never allow money to distort\ their judgment -- in this case by causing them to put undue pressure\ on reluctant patients or to include patients who do not qualify. But\ the assumption that doctors can resist financial temptations has been\ proved wrong repeatedly in other situations.\ \ For example, throughout much of the 1980\'s, doctors could refer\ patients to treatment centers -- such as physical or radiation therapy\ sites -- in which they had a stake. The practice was outlawed after\ studies found that doctors were overusing treatments and tests when\ they had financial interests in the centers that provided them. A 1992\ study published in The New England Journal of Medicine found that\ doctors with investments in radiation sites prescribed such treatment\ as much as 60 percent more often than those without the financial\ conflict.\ \ With such studies demonstrating the effects of financial incentives on\ doctors, experts who have studied these conflicts said they were\ troubled by the emergence of research for hire.\ \ \"You have a recipe for trouble or abuse,\" said Marc A. Rodwin, an\ associate professor of law and public policy at the School of Public\ and Environmental Affairs at Indiana University and the author of a\ book on financial conflicts in medicine. \"The risk is that the doctor\ will subconsciously downplay the risks or overplay the benefits\" of a\ particular study in order to persuade a patient to participate.\ \ Complicating matters, companies sometimes fail to consider how\ difficult it will be to find patients to meet the requirements they\ set for admission into a study. Then, when recruitment falls short of\ expectations, they offer to pay more to meet an unrealistic goal --\ looking, for example, for patients with a disease that their drug can\ treat but who have no other health problems that could affect the\ study.\ \ \"The simplest solution that inexperienced people think of first is to\ increase the number of sites or to increase the amount of money you\'re\ offering,\" said Dr. Bert Spilker, the senior vice president of\ scientific and regulatory affairs at the Pharmaceutical Research and\ Manufacturers of America, the trade group for large drug companies.\ \"You can offer to triple the amount of money and it will make zero\ difference if the doctors are doing everything they can do. It may be\ that the patients don\'t exist.\"\ \ But, with so much money dangling in front of them, doctors could be\ tempted to bend the rules to get patients into studies, and could get\ away with it, according to Dr. Martha L. Elks, an associate dean at\ Morehouse School of Medicine in Atlanta. \"Let\'s say you\'re dealing\ with an angina study where the requirement for entry is a certain\ level of pain on a certain number of days of the week,\" Dr. Elks said.\ And \"suppose the patient\'s history is not quite that but is\ borderline.\"\ \ Dr. Elks said she overheard two doctors talking recently about\ bonuses. One was telling the other that he would get \$500 if he could\ sign up some patients in the next 24 hours.\ \ \"I knew this guy,\" Dr. Elks said. \"He is a practitioner of the highest\ ethics.\" But, she said, \"he was talking about how to massage entry\ criteria.\"\ \ Dr. Elks said she then noisily cleared her throat. \"I sort of\ a-hummed,\" she said, at which point the doctors \"stepped back for a\ minute,\" suddenly realizing what one of them had been saying.\ \ What happened next, she said, she was not privy to know.\ \ The Doctors Drug Trials Provide New Source of Income\ \ The year was 1989, and Dr. Stuart R. Weiss was bored with private practice.\ \ To liven up his work, the San Diego endocrinologist tried his hand at\ drug studies. It was an audacious idea -- at the time most trials were\ conducted by university scientists. But Dr. Weiss worked hard to\ convince a skeptical drug industry to take a chance on someone with\ his background.\ \ \"I beat the bushes,\" he said. \"I lobbied long and hard with several\ organizations to give me a shot.\"\ \ Eventually, he focused on a Merck study of a new drug to treat\ osteoporosis, a degenerative bone disease. To show his eagerness, he\ offered to fly to New Jersey to meet with Merck executives at their\ world headquarters. Then Dr. Weiss went further, spending his own\ money to buy an expensive piece of equipment that measures bone\ density. Merck finally gave in, asking him to find 20 patients.\ \ He came up with 40.\ \ And there, in the entrepreneurial spirit displayed by Dr. Weiss, lay\ the solution to a problem that was suddenly dogging the pharmaceutical\ industry -- the slow pace of research in university laboratories.\ \ For decades, drug companies had been able to increase their prices\ almost at will, and thus had little incentive to develop new products.\ For the comparatively small number of drugs the companies did test,\ they turned to a trusted group of medical school researchers who\ dictated how trials were conducted. And the drug companies had to wait\ in line: Research financed by Government grants was far more\ prestigious; in the eyes of many academics, drug-company trials were\ to research what McDonald\'s hamburgers were to food.\ \ In those days, researchers were reimbursed much differently than they\ are today. Payments went to the university, not to the investigator.\ The university doctors were often paid a flat fee for their work, no\ matter how many patients they actually enrolled.\ \ Then, in the early 1990\'s, the economics of drug development changed.\ Managed care put the squeeze on drug prices, leaving companies one\ option: increase the number of drugs they were selling. As a result,\ the companies began a rush to drug development, something that was\ aided by reforms at the Food and Drug Administration that speeded up\ the approval process for new drugs.\ \ Companies at first turned to their coterie of medical school\ researchers, but found the academic world was incapable of adapting\ rapidly to the increasingly intense competition.\ \ \"We had concretized bureaucracies,\" Dr. David R. Bickers, chairman of\ the dermatology department at Columbia University\'s College of\ Physicians and Surgeons, said of the academic response. \"And for\ companies, time is money. Companies figure that out.\"\ \ Quickly, the drug companies began recruiting a new breed of\ private-practice doctors like Dr. Weiss, willing to mine their patient\ base for research subjects.\ \ The transformation is evident in a Times computer analysis of\ thousands of forms submitted each year to the Food and Drug\ Administration from doctors wanting to conduct research. According to\ the analysis, 11,662 private doctors conducted drug studies in 1997,\ almost three times the number in 1990, when 4,307 doctors conducted\ such studies. And while the number of researchers and medical schools\ also grew in that period -- to 4,431 from 2,225 -- their share of the\ business dropped from a third, to a quarter of the total, according to\ the analysis.\ \ Private-practice doctors in research said the change was for the\ better, because the doctor was not simply tending to the patient\'s\ needs for the few weeks of a study, but often for a lifetime. \"Even\ though the physician may want to make money, the moment he sits across\ from the patient, he is not only responsible to himself, he is\ responsible to that patient,\" said Dr. Norman Zinner, a Los Angeles\ doctor who in 1994 formed Affiliated Research Centers, an organization\ of private-practice urologists who conduct drug studies. \"I have got\ to look you in the eye. I have got to see you again.\"\ \ Not only that, these doctors said, but participation in research\ allows them to know the latest ideas for treatment. \"I really feel I\ can offer my patients more,\" said Dr. Grossman of Vivra Asthma and\ Allergy. \"I know more what the cutting edge is. I know what will be\ the recommended therapy two years from now.\"\ \ Because anyone licensed to practice medicine is eligible to be a\ researcher, medical communities have been transformed in towns where\ the onslaught of managed care spawned legions of doctors scrambling to\ replace lost income. In 1980, when clinical research was the fief of\ medical schools, there were only eight projects in Tucson, Ariz., and\ all but two were at hospitals affiliated with the University of\ Arizona. Today, researchers are scattered in offices dotting the city\ -- in places like the sun-baked barrios and the homely strip malls --\ conducting 157 studies in 1997 alone. Drug studies, and with them the\ competition for patients, have become as common in Tucson as the\ towering saguaro cactus.\ \ Now, with federally financed research on the wane, it is the academic\ researchers who are banging on the doors of the drug companies, asking\ for a second chance. But they are finding it hard to keep up with the\ private doctors, who have shown themselves more willing to sign\ contracts overnight, advertise widely, offer financial incentives for\ patients and open their offices at unusual times to accommodate\ patient schedules.\ \ \"It\'s very difficult to conduct drug studies at the medical school\ because of the competition\" from private doctors, said Dr. Mark A.\ Brown, a pediatric asthma specialist at the University of Arizona.\ \"It\'s difficult to find patients.\"\ \ To keep up with the competition from private doctors, some academic\ medical centers have recently begun setting up research divisions to\ draw on their own private patients for drug studies. But it is a\ fledgling effort, limited to a handful of universities.\ \ Still, some junior faculty members are now abandoning academia to get\ into the drug-study business. Dr. Andrew Cutler, a psychiatrist, left\ the faculty at the University of Chicago to join the Psychiatric\ Institute of Florida in Orlando, a private practice with a research\ business. Then last year, he formed his own company, Coordinated\ Research of Florida, to perform drug studies full time.\ \ Without a patient base to draw from for studies, Dr. Cutler found\ other ways to recruit subjects, including serving as a nursing home\ consultant.\ \ \"I will strategically pick a nursing home that has a large population\ that meets the criteria for a study,\" he said. \"If there is a large\ community practice in town, I may work out a referral arrangement, or\ make them a co-investigator, and the arrangement is that they would be\ providing the patients.\"\ \ But the industry is not passively waiting for doctors to knock on its\ door. Instead, over the last few years it has been aggressively\ recruiting doctors with the lure of cash. Every day, in hundreds of\ medical offices around the country, blandishments arrive by fax, mail\ and E-mail, encouraging doctors to grab their piece of the research\ pie.\ \ \"Discover the secret for obtaining more funded studies,\" says a 1992\ letter to doctors from Research Investigator\'s Source, which charges\ \$275 to place doctors\' profiles on lists of researchers consulted by\ drug companies.\ \ A 1998 letter from Clinmark Dotcom, an on-line listing service for\ researchers based in Irvine, Calif., offered to list doctors for \$350\ the first year and \$195 in the second. But the letter made no secret\ about the reasons to join.\ \ \"Investigator grants average \$43,000 per study,\" it said.\ \ Then there are the ubiquitous seminars, sponsored by the industry,\ with enticing titles to attract doctors, both fledgling and\ experienced in studies. Some teach the basics, with such titles as\ \"How to Find Clinical Trials: A Physician\'s Perspective\" and \"How to\ Develop or Evaluate a Patient Recruitment Media Plan.\"\ \ But nothing captured the transformation of research more than a\ seminar on clinical trials in Nashville, sponsored in 1996 by\ Associates of Clinical Pharmacology, a professional association.\ \ The title? \"Successful Patient Recruitment: The Heart and Soul of Your\ Business.\"\ \ Quality Questions Testing Puts Value On Speed Above All\ \ Doctors and drug company executives milled around a racing car parked\ on the floor of the John B. Hynes Veterans Memorial Convention Center\ in Boston last year, waiting their turn to be photographed at the\ wheel. Nearby, other images of speed dotted the exhibit hall at the\ annual meeting of the Drug Information Association, an industry trade\ group. Checkered flags appeared on corporate booths and T-shirts. One\ exhibit featured a giant photograph of a cheetah; another showed a\ mural of a horse race.\ \ To some at the meeting on drug development in the global marketplace,\ the images were a perfect metaphor for the industry today: The push to\ finish trials quickly and move the drugs onto the market has\ overshadowed every other goal.\ \ \"A few years ago it was \'better, faster, cheaper,\' \" said M. Jane\ Ganter, the editor in chief of Applied Clinical Trials, an industry\ publication. \"Nobody is saying \'better\' or \'cheaper\' anymore. The big\ emphasis is on speed.\"\ \ The driving forces behind the desire for faster studies are the\ industry\'s financial stakes. With the clock ticking on a new drug\'s\ patent even as it is being tested, every day\'s delay is revenue that\ will never be earned. \"Time is money,\" said James Patricelli, an\ analyst of the drug-testing industry with Dain Rauscher Wessels.\ \"Speed is the key.\"\ \ But some in the industry worry that such singlemindedness has led\ testing companies to tap an increasing number of doctors with little\ or no experience in drug testing and only a fuzzy understanding of the\ rules.\ \ The Times analysis showed that during the 1990\'s, 70 percent of the\ doctors conducting human experiments had been involved in three or\ fewer previous drug studies, a number unlikely to give them mastery\ over the process. A quarter of all doctors who did human experiments\ in 1997, the last year for which complete data are available,\ conducted only one experiment.\ \ \"Some of the companies would be embarrassed if they saw the quality of\ the people doing the research,\" said Dr. Angela Bowen, the president\ of the Western Institutional Review Board, a private ethics board\ based in Olympia, Wash., that reviews proposed research on human\ subjects. \"I call them clueless.\"\ \ One reason may be the predominance of generalists taking part in the\ studies. The studies test drugs for particular diseases, like asthma,\ in which a doctor\'s experience and specialized training are crucial in\ making assessments such as distinguishing between drug reactions and\ disease symptoms. But doctors conducting clinical trials often have no\ particular expertise in the disease they are treating. The Times\ computer analysis showed that the largest single group of doctors\ conducting investigations was general internists; one in five was\ either a general internist or a family practitioner. These, of course,\ are the doctors most Americans see for checkups and are thus the\ industry\'s most efficient recruiters.\ \ But some doctors who do clinical research say that they often are\ offered studies that would require them to stretch far beyond their\ areas of medical expertise.\ \ \"I wouldn\'t do studies for hematology or neurology or lung disease or\ epilepsy,\" said Dr. Roy Fleischmann, the chief executive of\ Rheumatology Research International, a national network of clinical\ research sites that specialize in arthritis and skeletal diseases.\ But, he said, \"We get calls about them all the time.\"\ \ Not every doctor has the power to refuse.\ \ \"There was a lot of pressure for me to do things I did not feel\ comfortable doing,\" said Dr. Claudia Baldassano, a psychiatrist and\ neurologist who worked for a commercial research center on the East\ Coast. \"They thought because I have an M.D., I should be comfortable\ doing all studies.\"\ \ She said, for example, that she was asked to do Pap smears as part of\ a study of hormone replacement and was asked to treat patients with\ diabetes.\ \ \"I said I hadn\'t done a Pap smear since medical school, and I didn\'t\ feel comfortable,\" she said.\ \ For the diabetes study, \"I said how could you expect a physician who\ is not trained\" as a diabetes specialist to run the trials, she said.\ \"I was told by a vice president of operations that I could do diabetic\ studies with my eyes closed.\"\ \ In the end, Dr. Baldassano stood her ground on the diabetes study, but\ participated in the one on hormone replacement. She resigned from the\ business after just a few months, and now works in academic research.\ \ Why would drug companies accept research even from doctors who doubt\ their own expertise? Because, experts said, the industry has grown so\ quickly that no one has yet developed a good measurement of quality.\ Drug companies are left to review two factors: speed and cost. Systems\ of measurement for quality \"haven\'t been established to differentiate\ these companies,\" said Mr. Patricelli of Dain Rauscher.\ \ In an attempt to protect the quality of data and patients, the\ Government and industry have put into effect some means of oversight.\ The first line of defense for the integrity of the data is the\ dispatch of study monitors employed by the testing companies to the\ doctors\' offices to pore over the test results.\ \ But the explosive growth of the industry has left experienced monitors\ in short supply.\ \ As a result, \"They utilize some people who have very little experience\ in the disease entity, or the drug, or in pharmacology,\" said Dr.\ Fleischmann of Rheumatology Research International. The monitors\ \"don\'t understand what they are doing.\"\ \ \"They are looking for boxes to fill in,\" he said.\ \ For example, he said, the most common form of arthritis,\ osteoarthritis, is also called \"degenerative joint disease.\" A testing\ company monitor who came to examine his data announced that his\ patients were not qualified for the study because she did not know the\ two terms meant the same thing, he said.\ \ \"If they don\'t have that knowledge,\" Dr. Fleischmann asked, \"how can\ they read a chart and know what is real and what is not real?\"\ \ Some experts said there was a decided difference between the quality\ of monitors who work for the drug industry and those who work for the\ testing companies. Monitors sent by testing companies can be so\ unknowledgeable, said Margaret Chokreff, the president of Margaret\ Chokreff & Associates, which works with a network of private doctors\ conducting research in Ohio, that she and her nursing staff must\ sometimes train them about their own studies.\ \ The monitors\' sole task is protecting data, not patients. That job\ falls largely to the patchwork system of ethics boards, bodies that\ are required by Federal law to approve research proposals involving\ humans. The main responsibility of these panels is to insure that test\ candidates are fully informed of the benefits and risks of a\ particular study and that they are not coerced to participate.\ \ But the review boards last year fell under criticism from Government\ officials for reviewing too many studies too quickly and for lacking\ expertise. And while these boards will get involved in deciding the\ appropriate language to be used for an advertisement for patients,\ they do not consider whether patients should be told of their doctors\'\ financial stake.\ \ Dr. Shimm of Porter Adventist Hospital in Denver recalled that when he\ served on an ethics board at a university medical school, a good deal\ of time was spent discussing whether payments to patient volunteers\ were coercive. The concern was that patients might enter studies for\ the money rather than out of altruism, the ideal that is sought. But,\ immediately after such a discussion at one meeting, another proposal\ came up in which a doctor stood to receive thousands of dollars from\ the drug company for each patient recruited.\ \ \"I said, \'Wait a minute,\' \" Dr. Shimm said. \"If it is coercive to pay\ a patient \$500, why is it not coercive to pay the clinical\ investigator \$5,000?\"\ \ But other members of the research board were not interested in the topic.\ \ \"I was told,\" Dr. Shimm said, \"to sit down and shut up.\"\ \ Next: Inside a research fraud.\ \ Cost-Cutting Gives Rise to New Research Industry\ \ Drug companies used to supervise all their research, from the\ discovery of the drugs to the animal tests to the preliminary human\ tests to the large studies involving hundreds or thousands of\ patients.\ \ No more. A multibillion-dollar industry has sprung up to take care of\ all that and more, including designing the studies, finding doctors\ and patients, analyzing the data, meeting with the Food and Drug\ Administration, writing the scientific papers and preparing the\ truckload of documents that must be submitted before a drug is\ approved.\ \ These new companies have sliced the drug-testing business in every\ possible way. Some are little more than a Rolodex of the names of\ doctors willing to help test drugs. Others are major corporations,\ essentially drug companies without the drugs.\ \ It is an industry that arose to fill a need: the enormous pressure\ that began around 1992 from managed care companies and health insurers\ on drug companies to hold down prices, according to industry analysts.\ Until then, the drug companies had been profitable, making money\ mostly by increasing prices, not by developing new drugs.\ \ The companies now had to find a new way of generating profits. \"Their\ vulnerability became transparent to the world,\" said James Patricelli,\ an industry analyst with Dain Rauscher Wessels in Minneapolis. \"What\ you had was a drug industry that suddenly had to make investments in\ its future.\"\ \ The companies\' response was to search for blockbusters -- the Prozacs\ and Viagras hidden within the laboratory chemicals. The Food and Drug\ Administration gave the companies another incentive by speeding up its\ approval process, with the median review time for new drug\ applications dropping from more than 22 months in 1990 to just over 14\ months in 1997, according to the F.D.A.\ \ \"The industry has flip-flopped,\" said Kim Lamon, corporate senior vice\ president with Covance Inc., a giant drug-testing and development\ company. \"There is a push for novel, innovative, blockbuster drugs,\ and to be the first or second to market.\"\ \ Drug companies found they had to put more effort and money into\ finding drugs while at the same time slashing their development costs.\ For many, their solution was to largely dismantle their divisions that\ ran clinical trials and to turn the work over to smaller companies\ that emerged to fill the need.\ \ \"Everyone had auditors, kids right out of college, telling us how to\ do it cheaply,\" said Dr. Cynthia M. Dunn, a former vice president for\ medical affairs at Fisons, a British drug maker later acquired by\ Rhone-Poulenc Rorer Inc., and now the director of the Clinical\ Research Institute at the University of Rochester. \"They really pushed\ the outsourcing.\"\ \ With the new companies came a variety of new names. Contract research\ organizations were composed of companies that ran parts or all of the\ clinical trials. Site management organizations -- groups of doctors\ willing to offer their services to conduct trials -- soon followed.\ \ The growth in this sector has been enormous. Roughly \$3.2 billion was\ paid to the contract research organizations in 1997, up 52 percent\ from just two years earlier, when payments were \$2.1 billion.\ \ Covance, one of the largest contract research organizations, doubled\ its staff and revenues from 1994 to 1998. Today, the Princeton, N.J.,\ company is an industry giant, with 7,000 employees and more than \$700\ million in revenues in 1998.\ \ \"It\'s an industry that has been growing and growing and growing,\" said\ Ismail A. Shalaby, the chief executive of Nema Research Inc., a\ clinical research network based in Baltimore. \"A drug company doesn\'t\ have to invest a lot of its own time and money to develop a drug\ anymore.\"\ \ In fact, some industry experts said, a drug company barely even needs\ to be a drug company any more. For example, Neurobiological\ Technologies Inc. in Richmond, Calif., has no factories, 11 employees,\ 3 scientists and less than \$1 million in cash. Yet it is using the new\ testing industry to conduct huge clinical trials, involving dozens of\ research sites and doctors around the country.\ \ \"You could have a company of one person, working out of their home,\ with no office, develop a drug,\" said Dr. Bert Spilker, a senior vice\ president of scientific and regulatory affairs with the Pharmaceutical\ Research and Manufacturers of America, a trade association. \"You could\ have totally virtual companies.\"\ \ Longtime members of the industry marvel at the change, which has\ occurred in just a few years.\ \ \"One called me; they had two employees,\" said Dr. Leigh Thompson, a\ drug-industry consultant in Charleston, S.C., who is a former chief\ scientific officer at Eli Lilly. \"They have a molecule and hope but\ nothing else.\"\ \ A Doctor\'s Drug Trials Turn Into Fraud\ New York Times, The (NY) - Monday, May 17, 1999\ Author: KURT EICHENWALD and GINA KOLATA\ Abstract: Second article in two-part series, Research for Hire, on\ pharmaceutical renaissance in clinical testing of drugs on humans, in\ which patients have become commodities and which is fraught with\ conflicts of interest among doctors; focuses on weaknesses that have\ emerged in testing system in recent years, as pharmaceutical industry\ has switched from career researchers at academic medical centers,\ whose professional reputations are forged on quality of their data, to\ thousands of private-practice doctors to whom testing has become\ extremely lucrative sideline; while researchers now have enormous\ financial incentive to cheat, methods of monitoring their activities\ remain basically same; cites corruption at Southern California\ Research Institute run by Dr Robert Fiddes as example of ease with\ which testing system can be compromised; Fiddes who transformed sleepy\ medical practice in Whittier, Calif, into medical juggernaut is\ serving prison term for conducting research fraud--cutting corners,\ enrolling fictitious patients and fabricating data to keep millions of\ dollars flowing from drug industry; investigations were never\ initiated, even though Fiddes\'s employees alerted monitors to their\ suspicions; warnings were filed away, while Fiddes\'s sterling\ reputation as researcher grew; photos (L)\ If ever there was a wonder boy in the lucrative business of drug\ testing, it was Dr. Robert Fiddes.\ \ In just a few years, Dr. Fiddes transformed his sleepy medical\ practice here into a research juggernaut, recruiting patients for drug\ experiments at a breakneck pace. His success made him a magnet for an\ industry desperately scouring the nation for test subjects. Companies\ large and small showered him not only with more than 170 studies to\ conduct, but with millions of dollars in compensation for his work.\ \ Life was good. With bank accounts bulging, Dr. Fiddes and his wife\ could afford to drive matching BMW\'s; a Ferrari parked in his garage\ was ready for special occasions. After a short time in research, the\ once small-time family practitioner was planning his dream house on a\ Cayman Islands beach and envisioning the day he would make millions\ more by selling shares in his business to the public.\ \ But amid the glitter and cash was a fact that no one outside his\ office knew: It was all a scam.\ \ For Dr. Fiddes was conducting research fraud of audacious proportions,\ cutting corners and inventing data to keep the money flowing from the\ drug industry. Fictitious patients were enrolled in studies. Blood\ pressure readings were fabricated. Bodily fluids that met certain lab\ values were kept on hand in the office refrigerator, ready to be\ substituted for the urine or blood of patients who did not qualify for\ studies.\ \ Monitors for the Government and the industry never noticed any\ problems with Dr. Fiddes\'s bogus paperwork, which they reviewed during\ routine audits. Even when some of Dr. Fiddes\'s employees alerted those\ monitors to their suspicions, no investigations were initiated.\ Instead, their warnings were filed away, while Dr. Fiddes\'s sterling\ reputation as a researcher grew.\ \ Finally, in June 1996, the scheme started to unravel when the manager\ of a neighboring doctor\'s office, Dennelle Del Valle, told a\ Government auditor rumors of crimes, lies and fraud she had heard from\ Dr. Fiddes\'s own employees. Eventually, to prove the claims, Ms. Del\ Valle slipped a piece of paper into the auditor\'s hand. On it was\ written a telephone number and a single name: Susan. It was the tip\ that would lead the Government to Susan Lester, a former employee of\ Dr. Fiddes who not only knew what had happened, but had a few records\ that seemed to back up her story.\ \ So began the multiyear investigation of Dr. Fiddes\'s Southern\ California Research Institute, a testing operation that was one of the\ most corrupt research enterprises ever discovered by law enforcement.\ The case is set to wind to a close this week, with the scheduled\ sentencing of the last co-conspirator. But in its wake is wreckage:\ Dr. Fiddes and several accomplices pleaded guilty to fraud, drug-study\ results for virtually every company in the business were compromised\ and the reliability of the private system for testing drugs for safety\ and efficacy has been thrown into question.\ \ Dr. Fiddes \"was putting the health of all these patients at risk,\"\ said Alan Knox, the former chief financial officer of Dr. Fiddes\'s\ research center, who resigned just months after taking the job when\ the investigation led him to learn of the fraud. \"But he was also\ skewing samples that could affect the whole American public.\"\ \ The abuses of this one doctor point to weaknesses in the new system\ developed in recent years for testing experimental drugs. No longer\ does the pharmaceutical industry rely on career researchers at\ academic medical centers, whose professional reputations are forged on\ the quality of their data. Rather, the industry has turned to\ thousands of private-practice doctors, for whom testing drugs has\ become a sideline for making money.\ \ While the researchers and their incentives have changed, the methods\ of monitoring what they do remain basically the same even though now,\ since they are paid for each patient they recruit, researchers have an\ enormous financial incentive to cheat. The case of Dr. Fiddes\ underscores the ease with which such a system can be deceived -- a\ situation that has not been remedied since the discovery of his\ crimes.\ \ The story of the corruption at the Southern California Research\ Institute was pieced together from memos and other internal documents,\ investigators\' notes, drug company and court records, personal diaries\ and affidavits of participants, as well as interviews with Government\ officials, lawyers and the former employees and consultants at the\ company, which is now defunct.\ \ The picture that emerges from these documents and interviews is of a\ research office ruled by a doctor driven by greed. Few employees other\ than the study coordinators -- mostly women of limited financial means\ -- were aware of the magnitude of the swindle. Those bothered by it\ were repeatedly assured that this was the way the drug industry\ worked. Faced with that perception, there seemed little they could do\ without risking their livelihood to stop the influential Dr. Fiddes, a\ man who believed that the system of monitoring was too poorly designed\ to ever catch him.\ \ \"I don\'t think he thought he could be touched,\" said Kathryn Davis, a\ medical transcriber at the research center. \"We just didn\'t understand\ why it had to go down the way it did. Maybe he just wanted too much\ too fast.\"\ \ Through his lawyer, Dr. Fiddes -- who is now serving a 15-month\ sentence for fraud in the Metropolitan Detention Center in Los Angeles\ -- refused repeated requests for an interview. But in interviews with\ the Government after he agreed to plead guilty, Dr. Fiddes portrayed\ himself as a man trapped by the dishonesty of others. He maintained\ that most researchers are forced to cheat because drug companies issue\ requirements for test subjects that sound good in marketing material,\ but are impossible to meet in the real world. He said -- with no\ evidence to back up his claim -- that anyone successful in the\ business was skirting the rules.\ \ Still, at his own research center, Dr. Fiddes laid much of the blame\ for everything that happened on his study coordinators -- again,\ without providing evidence to support the assertion. While he was the\ beneficiary of the illegal activity, he maintained that it was the\ salaried employees working for him who devised the frauds, often\ without his knowledge. The information provided by Dr. Fiddes has not\ resulted in any additional investigations.\ \ Despite his refusal to accept the blame, Dr. Fiddes was anguished at\ being labeled a criminal. In a letter pleading for mercy that he sent\ last year to Federal District Judge Robert M. Takasugi, he described\ his torment. \"My family has had to endure the humiliation of seeing a\ husband and father sink from being a widely respected community member\ to now being visualized as nothing more than a common crook,\" Dr.\ Fiddes wrote. \"My mother often said, \'The only thing in life that is\ important is to be able to hold your head up high.\' I now know what\ that means.\"\ \ The Career\ From Family Doctor To Drug Researcher\ \ Robert Fiddes always wanted to be a skater. As a teen-ager in his\ native Vancouver, British Columbia, he rose most mornings before dawn,\ walking to a chilly ice arena for his 5 A.M. practice. The hard work\ paid off; he often told of winning Canada\'s junior figure skating\ championship, a victory that set him on the path to going\ professional.\ \ But when the time came to choose between a career as a figure skater\ or enrolling in a university, young Robert Fiddes took the academic\ path. And there he showed that same drive, gaining acceptance to\ medical school at the University of British Columbia after just three\ years in college, according to his curriculum vitae.\ \ In 1970, at 25, Dr. Fiddes earned his medical degree and, with his new\ wife, Rebecca, came to Long Beach, Calif., for a job as a hospital\ intern. He went on to join a medical partnership, but in 1981 opened\ his own practice in Whittier with a medical assistant, LaVerne\ Charpentier, in a converted house with an awning and flower garden. It\ was the perfect image for an old-time family doctor, and the practice\ blossomed.\ \ Dr. Fiddes\'s wife would later write of those early days in a letter to\ the judge who sentenced her husband. \"His patients adored them and\ showered the office with everything from home-baked cookies to\ hand-crocheted dolls,\" she wrote. \"Both Rob and Laverne worked long\ and hard to provide his patients with the best care.\"\ \ Eventually, Dr. Fiddes formed a group made up of several family\ doctors in the area. But by the late 1980\'s, an obstacle emerged that\ Dr. Fiddes was unable to sidestep. Managed care was sweeping\ California, and Dr. Fiddes chafed at the new rules. \"He felt his hands\ were tied in performing whatever tests were necessary to assist in the\ proper diagnosis of the patient,\" Mrs. Fiddes wrote in her letter.\ Patients \"felt equally frustrated with the new system.\"\ \ Growing restless, he decided to pursue a law degree, attending night\ school. In 1987, he passed the California state bar exam.\ \ But by then, the medical profession had changed so radically that an\ entirely new specialty presented itself: Doctors were testing the\ safety and effectiveness of new drugs for pharmaceutical companies,\ using their patients as subjects. Recognizing the opportunity to get\ away from managed care, Dr. Fiddes jumped at the chance.\ \ His new clinical-trials business grew rapidly. Dr. Fiddes appointed\ Ms. Charpentier as his first full-time study coordinator, and raided a\ private research firm in the area, California Clinical Trials, to\ build his staff. He began to dream of eclipsing his biggest rivals and\ taking his new enterprise public, at times doodling his ideas for a\ corporate logo onto pads of paper.\ \ As the business grew, former employees said, a pattern soon emerged.\ Dr. Fiddes would meet with patients in his first-floor office, then\ refer them to the study coordinators on the second floor. Often, the\ patients who arrived there felt reluctant to take part in the trials.\ \ \"They were pushed to go up there,\" said Susan Lester, the former study\ coordinator who blew the whistle on Dr. Fiddes. \"They often would say,\ \'I don\'t want to participate in this, but I don\'t want to make him\ mad.\' \"\ \ In the early days, Ms. Lester and other coordinators would tell\ wavering patients to take their time, perhaps by sleeping on the idea,\ before signing an agreement to participate. But Dr. Fiddes and Ms.\ Charpentier, who also declined interview requests, quickly put an end\ to such solicitousness.\ \ \"I was told that it was a big mistake to let them think about\ joining,\" Ms. Lester said. \"They said, \'You don\'t tell them they have\ any choice about it. You put them in.\' \"\ \ The Fraud\ Falsifying Records, Endangering Patients\ \ Kimberly Carlon\'s interviews for a job at the Southern California\ Research Institute had been going well. She had only one more hurdle\ to clear: speaking to Dr. Fiddes himself. If he approved of her, Ms.\ Carlon, a certified respiratory therapist, would become the research\ site\'s latest study coordinator. Sitting in front of Dr. Fiddes\'s desk\ in early 1996, she listened as he described a hypothetical situation.\ Suppose, he said, that a patient was available for a study, but was\ taking medication prohibited by the study protocol. The answer seemed\ obvious, Ms. Carlon replied: she would send the patient on his way.\ \ Well, Dr. Fiddes told her, that was not the way he did things. At the\ Southern California Research Institute, he said, the patient would be\ entered into the trial; that would require the center to falsify\ records so that the violation of study rules could be hidden.\ \ Ms. Carlon got the job. But she would later describe her discussion\ with Dr. Fiddes as the first moment she should have realized something\ was wrong.\ \ Like every other study coordinator who passed through Dr. Fiddes\'s\ research center, Ms. Carlon found herself being pushed to break the\ rules. When she ran a 1996 study for a new asthma inhaler sponsored by\ Fisons, a British drug maker, she found a patient who had been\ enrolled even though she had an incurable lung disease that should\ have disqualified her. When a monitor hired by Fisons asked to see the\ patient\'s medical chart, Ms. Carlon approached Delfina Hernandez, a\ more senior employee, and asked what to do.\ \ Ms. Hernandez quickly fetched the patient\'s medical chart, and pulled\ out every page that made reference to the lung disease. Then,\ according to investigative documents, she turned the remaining records\ over to the monitor. The violation went undetected.\ \ Ms. Hernandez, who later pleaded guilty to fraud, declined to comment.\ \ Again and again, study coordinators were instructed by Dr. Fiddes and\ his top aide, Ms. Charpentier, to ignore the requirements of the drug\ studies. The rules called for excluding smokers from an asthma study?\ The coordinators were told to put the smokers in anyway, and not\ mention their habit in the medical records. A certain blood pressure\ was required for patients to participate in a hypertension study? Then\ the coordinators were expected to write that level into the chart,\ regardless of the truth. Patients\' medical records contained health\ histories that precluded them from participating in a test? Then the\ offending pages were ripped out and destroyed, and the patients placed\ on the experimental medication despite the dangers.\ \ Over time, the frauds orchestrated by Dr. Fiddes grew ever more\ audacious. Eventually, according to Government documents, it was not\ just the records that were being falsified. Instead, medical tests\ were rigged -- and at times, patients simply invented. Outside\ monitors reviewed the documentation, but since there were real lab\ records for the rigged tests, they had no clue that they were being\ deceived.\ \ The office refrigerator became the source of human bodily fluids that\ met the requirements of various studies. A jug of urine was often\ found there on Monday mornings, provided by Carol Rose, an employee.\ Ms. Rose\'s urine contained high levels of protein -- just the trait\ patients needed to qualify for certain studies. Dr. Fiddes paid Ms.\ Rose \$25 each time she collected her urine and brought it to the\ office, where over time it was divvied up among specimen cups labeled\ with other people\'s names and presented for testing.\ \ The refrigerator also proved useful when the research center was\ conducting studies on hormone replacement therapy for menopausal\ women. The studies required women with blood serums that showed low\ levels of estrogen and high levels of follicle-stimulating hormone --\ signs that a woman is going through menopause. To make sure that the\ patients\' tests qualified, Dr. Fiddes sent out a memo specifying the\ hormone levels required for the study. \"We need some serum that scores\ these numbers in the frig at all times,\" he wrote.\ \ Another study on an antibiotic required that patients have a certain\ type of bacteria growing in their ear. No problem for Dr. Fiddes. He\ bought the bacteria from a commercial supplier and shipped them to\ testing labs, saying they had come from his patients\' ears.\ \ Dr. Fiddes\'s coordinators, paid bonuses for recruiting patients into\ studies, soon began improperly enrolling themselves and members of\ their families. Often, names were changed to avoid detection by drug\ company monitors. At times, family members took part in several\ studies at once -- a violation of the rules because studies require\ that participants not be taking other medications, so that the data\ obtained relate only to the drug under study.\ \ Employees \"were running around doing E.K.G.\'s on each other, if the\ patient couldn\'t pass,\" said Sloan A. Bergman, a former study\ coordinator who quit working for Dr. Fiddes after less than a year\ because of ethical concerns. \"I wasn\'t happy, but I needed a job.\"\ \ Yet all the while, there were constant reminders that the true cost of\ the frenzied drug testing was being borne by sick and vulnerable\ patients.\ \ In the summer of 1995, the research institute began work on a study of\ Cozaar, a hypertension medication sponsored by Merck & Company. Among\ the patients enrolled by Dr. Fiddes was Arlene Roberts, a 70-year-old\ woman with high blood pressure. Instead of dropping, her blood\ pressure rose dangerously when she took the drug. Dawn Simons, the\ study coordinator, became alarmed and sent Ms. Roberts to see Dr.\ Fiddes. Rather than taking her out of the study, Dr. Fiddes prescribed\ two other hypertension drugs. The triple dosage not only violated the\ study rules, it made it impossible to gauge the effect of Cozaar.\ \ A few days later, Ms. Roberts returned. Her face was bruised, her\ speech was slurred and she had trouble walking. She told Ms. Simons\ that she had passed out over the weekend while bathing. Ms. Simons\ took her pulse and found that her heart was barely beating -- a\ result, the coordinator thought, of bombarding her body with\ hypertensive drugs. Worried that Ms. Roberts was headed toward cardiac\ arrest, Ms. Simons asked Ms. Lester, her fellow study coordinator, for\ assistance. The two helped Ms. Roberts, who by then could barely walk,\ to Dr. Fiddes\'s office.\ \ \"He said, \'It\'s no big deal. She\'s probably making more of it than it\ really is,\' \" Ms. Lester recalled in a recent interview.\ \ Ms. Simons, dismayed at what was happening, thought Ms. Roberts should\ be dropped from the study. But Dr. Fiddes refused, keeping her on the\ medications for several more weeks. Ms. Roberts was soon seeing\ another doctor in a hospital for the problems that emerged during the\ study. Ms. Simons, the study coordinator, resigned from her job, but\ not before surreptitiously copying all the medical records and turning\ them over to Ms. Roberts in case she wanted to bring a lawsuit. Ms.\ Roberts, who recovered at the hospital, never sued.\ \ Dr. Fiddes received payment in full from Merck -- his reward for\ keeping Ms. Roberts in the study through its completion.\ \ Avoiding Detection\ The F.D.A. Ignores An Early Warning\ \ Ilse Beverly finally decided that Dr. Fiddes had to be stopped. While\ working for him for five years handling laboratory tests like blood\ work, Ms. Beverly had seen signs of his willingness to cheat on drug\ studies. And so in January 1995, almost immediately after leaving her\ job, Ms. Beverly telephoned investigators with the Food and Drug\ Administration.\ \ She reported her own experiences, such as the time in 1990 that Dr.\ Fiddes had asked her -- without explaining why -- to find a way to\ alter lab values in urine tests. She also provided the names of study\ coordinators who knew that testing data were being manipulated to\ enroll larger numbers of patients. With her revelations, the\ Government had its first solid lead on what was happening in Dr.\ Fiddes\'s office fully 17 months before Ms. Del Valle exposed his\ crimes to an F.D.A. auditor. Investigators wrote memos about Ms.\ Beverly\'s allegations, and forwarded them from Los Angeles to the\ clinical investigations branch of the F.D.A.\ \ There, the memos were filed away. No investigation was begun.\ \ Brad Stone, a spokesman for the F.D.A., said that, because aspects of\ the case have not been finished, the agency could not comment at this\ time.\ \ Dr. Fiddes had always found it easy to elude detection by the crews of\ company monitors and Government auditors that visited his offices,\ even when his employees spelled out their suspicions about what was\ happening. It was not that he was particularly adept at dodging their\ questions; rather, they seemed reluctant to challenge such a prominent\ figure in the drug-testing business. \"This business can be run on\ words, and I have learned the words,\" Dr. Fiddes wrote in a 1995 memo.\ \" \'We have no problems\' is our motto, and tell this to every monitor.\"\ \ When Dr. Fiddes\'s efforts to enroll patients were thwarted by system\ safeguards intended to insure accurate test data, he often found ways\ around the problem.\ \ In a 1995 study of an experimental pain reliever for arthritis called\ PHZ 136 that was sponsored by the Zambon Corporation, Dr. Fiddes faced\ a particularly difficult impediment. The patients were supposed to\ have arthritis of the knee, as verified by X-rays.\ \ Dr. Fiddes tried to recruit patients. Again and again, he sent their\ X-rays to an independent radiologist for review. And almost every time\ the answer came back the same: The patient did not have arthritis, and\ so did not qualify for the study. Frustrated, Dr. Fiddes told the\ coordinator of the study, Ms. Lester, to look through his medical\ files for patients with arthritis of the knee. Then, he said, she\ should offer each of those patients \$25 to come in and get multiple\ X-rays, which he could substitute for the X-rays of patients who did\ not qualify. But Ms. Lester drew the line, and refused.\ \ The ever-resourceful Dr. Fiddes found a way around that obstacle,\ however. Through his staff, he got in touch with the project manager\ at Pharmaceutical Product Development Inc., which was managing the\ study for Zambon, and asked a question: Because he was a doctor,\ couldn\'t he just interpret his patients\' X-rays himself, rather than\ send them to a certified radiologist?\ \ The company was happy to oblige. Researchers \"may interpret knee X-ray\ films obtained on candidates,\" Julia Dixon, the project manager, wrote\ in a letter to Dr. Fiddes. \"There is no need for a radiological\ consult.\"\ \ From that moment on, Dr. Fiddes had no trouble finding patients who\ qualified for the study. \"That kind of opened it up for him right\ there and then,\" Ms. Lester said. \"Everyone understood that if he was\ going to read the X-ray, he was going to lie.\"\ \ Not long afterward, Dr. Fiddes received a letter from one of the\ testing company\'s study monitors. \"CONGRATULATIONS on meeting your\ enrollment deadline!\" the monitor, Cheryl Grant, wrote in a letter\ dated Feb. 19, 1996. \"I performed a 100 percent source document\ verification, and found no outstanding issues.\"\ \ Through Pharmaceutical Product Development, a testing company, Dr.\ Fiddes was paid \$45,268 for his effort in the Zambon study. The\ company never detected his fraud. Zambon declined to comment, citing\ confidentiality of the study, as did Pharmaceutical Product\ Development. But Nancy Zeleniak, a spokeswoman for the testing\ company, said its monitoring was of the highest quality. \"We have\ standard operating procedures for detecting fraudulent or fabricated\ data,\" she said. \"We are helping to set standards in the industry.\"\ \ Another company came closer to putting him on the spot. Several former\ coordinators for Dr. Fiddes said they had reported his unethical\ conduct to Pat Pryor, an independent study monitor working with Pfizer\ Inc. Tipped off to the discrepancies, Ms. Pryor sharply challenged Dr.\ Fiddes and his staff in her reviews of their paperwork.\ \ Dr. Fiddes chafed at the challenges, feigning outrage. \"Our integrity\ and reputation for performing high-quality clinical trial work has\ been injured, and we are justifiably upset,\" Dr. Fiddes wrote in a\ July 1995 letter to Pfizer, complaining about Ms. Pryor\'s demands. He\ insisted Pfizer \"have a new monitor assigned to our site immediately.\"\ \ Not long afterward, Dr. Fiddes announced the news at a staff meeting:\ Pat Pryor would not be returning to monitor the Southern California\ Research Institute.\ \ Pfizer said that the company replaced monitors if there seemed to be a\ conflict. \"In order to insure the most objective and best monitoring,\ we generally recommend that if there is personal conflict, and no\ certainty of irregularities, that a new neutral person is assigned to\ review all of the data,\" said Betsy Raymond, a spokeswoman for Pfizer.\ \ But in the Fiddes case, that policy did not improve the monitoring.\ \"We have an extensive system of checks and balances,\" Ms. Raymond\ said. \"Even with all of that, we didn\'t uncover the fraud.\"\ \ Why was Dr. Fiddes able to fool the monitors so easily? Because the\ oversight system is mostly designed to catch errors, not fraud. To\ protect patient confidentiality, monitors are forbidden even to know\ the names of test subjects, meaning that no spot-checks are ever\ performed by the companies to make sure that researchers are not\ making up lab values or inventing patients.\ \ But Dr. Fiddes\'s luck in avoiding detection would not hold. By May\ 1996, more than half a dozen study coordinators -- including Ms.\ Simons and Ms. Bergman -- resigned, fearful that the fraud would cost\ them their nursing licenses or certifications. Ms. Lester likewise\ decided she could take no more, and wrote a letter to Dr. Fiddes\ declaring that she would no longer participate in fraudulent,\ unethical work.\ \ A response came quickly. Ms. Lester was ordered to clean out her desk\ immediately, and was escorted from the building. On her way out the\ door, she bumped into Kathryn Davis, another Fiddes employee. With\ tears in her eyes, Ms. Lester made Ms. Davis a promise.\ \ \"She told me before she left that she was going to bring Dr. Fiddes to\ his knees,\" said Ms. Davis, a former employee. \"I had no idea that she\ meant it seriously.\"\ \ The Cover-Up\ \'You MUST Be Able To Dump Your Files\'\ \ Alan Knox, the chief financial officer of the research center, was\ working in his office in the summer of 1996 when its chief operating\ officer burst in. The officer, Elaine Lai, demanded that Mr. Knox pull\ a series of invoices documenting payments to an employee, Carol Rose.\ \ Mr. Knox fished the invoices from a filing cabinet. As he read them,\ he grew concerned. Written clearly across the \$25 invoices were the\ words \"urine sample.\" For the first time, he was seeing the evidence\ that Ms. Rose was being paid to substitute her own urine for that of\ patients.\ \ Wary of what was happening, Mr. Knox copied the invoices, and kept the\ originals. As he handed the copies to Ms. Lai, he asked her and Ms.\ Hernandez, the longtime senior employee of Dr. Fiddes, what was going\ on. Well, came back the response, apparently Susan Lester had gone to\ the F.D.A., and worse, was contacting other former coordinators and\ trying to persuade them to talk to the Government about the way Dr.\ Fiddes conducted his research.\ \ \"I remember inquiring with Delfina and Elaine and saying, \'What\'s the\ big deal?\' \" Mr. Knox said in a recent interview. \"They looked at me,\ they looked at each other and said, \'We have to tell him the truth.\' \"\ As he listened to them recount the trickery that had taken place at\ the institute, he said, \"I was just taken aback by the level of\ fraud.\"\ \ His first thought, he said, was that Dr. Fiddes and his top aides\ should confess everything to the F.D.A. But unknown to him, they were\ at that very moment planning a cover-up that would involve destroying\ incriminating documents and manufacturing new ones that might place\ the blame for any problems on Ms. Lester.\ \ Dr. Fiddes was most concerned about the urine substitution, out of\ fear that Ms. Rose would talk, according to notes of investigator\ interviews. So, in August 1996, he called a meeting at the Hilton\ Hotel in Whittier with Ms. Lai, Ms. Hernandez and his longtime\ assistant, Ms. Charpentier.\ \ To solve the Carol Rose problem, Dr. Fiddes told the group, he would\ create a bogus medical chart and false patient history for her. If\ asked, he would say that urine had been collected as part of her\ medical treatment.\ \ The following Saturday, Ms. Lai called a meeting for what she called\ \"chart review.\" The actual mission was to go through the medical\ charts and destroy any evidence of wrongdoing.\ \ Days later, on Aug. 21, Ms. Lai called for another meeting for\ strategic planning. In a memo to Dr. Fiddes, Ms. Charpentier and Ms.\ Hernandez, she made clear the need to move quickly.\ \ \"F.D.A. is busting down our door on Monday,\" Ms. Lai wrote. \"You MUST\ be able to dump your files to your car when F.D.A. knocks.\"\ \ Ms. Lai added in the letter that they had to agree to scripted\ responses to all questions the Government might ask.\ \ As Dr. Fiddes and his allies were secretly working on their cover-up,\ Mr. Knox was reaching out to regulatory experts who he thought could\ help the company in its talks with the F.D.A. He got in touch with\ Gretchen McKelvey, a quality assurance consultant for clinical trials,\ who was quickly hired to help out. Ms. McKelvey was stunned by the\ magnitude of the fraud she discovered at Dr. Fiddes\'s office. But even\ more incomprehensible was the blase attitude Dr. Fiddes demonstrated\ as he calmly informed her of his cover-up plans.\ \ \"I explained to him that what had happened here was considered\ criminal, and that he could be prosecuted for conspiracy and fraud,\"\ Ms. McKelvey said in an interview. \"Dr. Fiddes replied that they were\ going to blame Susan Lester for all of the problems, and he was going\ to say he had no knowledge of what was going on.\"\ \ About that time, Ms. McKelvey learned that Dr. Fiddes had moved all of\ the patient records off site. When she asked where they were, she\ said, he replied that they were in storage. Days later, when she\ pressed for them again, Dr. Fiddes told her the records had been lost.\ \ \"I was starting to get really scared,\" she said. \"I don\'t like to be\ messed with.\"\ \ As the situation deteriorated, Ms. McKelvey decided the situation was\ too big to handle alone, and required someone with more expertise in\ dealing with the Government. She sought advice from Michael Hamrell, a\ consultant who specialized in the F.D.A. Mr. Hamrell arrived at the\ research site for a briefing from the company\'s top executives,\ including Dr. Fiddes and Mr. Knox. They made no bones about all the\ protocol violations they had committed. Why would Dr. Fiddes be so\ open? Because, as Mr. Hamrell learned quickly, he still believed that\ he could outsmart the system.\ \ \"He told me that he knew the law better than the F.D.A., and that the\ F.D.A. couldn\'t touch him,\" Mr. Hamrell said. \"He told me he was a\ lawyer, and he wasn\'t responsible.\"\ \ Many of those who worked for him, like Mr. Knox and Ms. McKelvey, saw\ the writing on the wall and resigned soon after being hired. But\ others who for years had accepted Dr. Fiddes\'s repeated assurances\ that everyone in the industry did the same things were shaken and\ agonized about whether to confess.\ \ \"I want to spill my guts, but what is going to happen to me and my\ future?\" Delfina Hernandez, one of Dr. Fiddes\'s top aides, wrote in\ her diary as investigators closed in. \"God forgive me if you think I\ did wrong, and punish me if I did anything to hurt these patients.\"\ \ She soon found out what would happen to her future. On Feb. 16, 1997,\ teams of Federal agents swarmed into the Southern California Research\ Institute\'s office. The entire staff was ordered to move to the front\ of the building, as the agents seized box after box of documents. One\ agent with a video camera filmed every employee\'s face for use in\ future identifications.\ \ With employees facing such intimidating law enforcement tactics,\ cracks began to emerge in the conspiracy to lie to investigators. Ms.\ Hernandez was the first to decide to provide evidence to the\ Government, and the other dominoes quickly fell. By September 1997,\ Dr. Fiddes, Ms. Hernandez and Ms. Charpentier agreed to plead guilty.\ Ms. Lai pleaded guilty soon afterward.\ \ Now, with Dr. Fiddes compelled to cooperate as part of his plea\ agreement, the Government hoped to learn more from him that would help\ in the battle against research fraud. On Oct. 10, at 10:30 A.M., Dr.\ Fiddes met for an interview with William Leitner and Hetal Sutaria of\ the F.D.A.\ \ For five hours, the agents grilled Dr. Fiddes. He told them that fraud\ was rampant in the research industry. He named names of doctors he\ suspected of engaging in practices similar to his own. And he\ described some telltale signs that should raise suspicions of possible\ fraud.\ \ But, the investigators asked, what evidence of fraud is there in the\ records reviewed by monitors and the Government? What could the\ watchdogs have seen that would have allowed them to detect his fraud?\ \ Nothing, Dr. Fiddes replied. Had it not been for a disgruntled former\ employee, he would have still been in business.\ \ STOPGAP MEDICINE: A special report. For the Uninsured, Drug Trials Are\ Health Care\ New York Times, The (NY) - Tuesday, June 22, 1999\ Author: GINA KOLATA and KURT EICHENWALD\ Abstract: Special report, Stopgap Medicine, on growing number of\ uninsured drug-trial nomads who rely on clinical trials and primary\ doctors as their primary source of medical care; in recent years, need\ for test subjects has exploded as industry has brought to market ever\ increasing number of new products; drug companies have developed new\ methods of finding participants for trials by turning to\ private-practice doctors who recruit from their lists of patients, but\ even so, influx of participants has not been enough to satisfy demand;\ filling gap are chronically ill with limited or no health insurance,\ for whom experiments have become treatments and clinical investigators\ their specialists; while system provides patients with critical\ service they cannot obtain otherwise, medical experts say benefit can\ be fleeting or nonexistent; say chronically ill patients with no other\ options can be treated with experimental medication that does not\ work, or that worsens their condition, or can end up with placebo\ rather than medication itself; note once study is over they are left\ to their own devices and can be barred by rules of one clinical trial\ from participating in another study for months--forcing them to rely\ on samples of medications provided by drug companies or go without\ treatment altogether; photos; charts (M)\ Carole Danforth\'s asthma had gotten the best of her. No longer did she\ have the energy for activities she loved, like playing with her\ grandchildren or doing yardwork. Some days, her breathing was so\ labored she could not get up from the couch. And there seemed little\ she could do about it: Ms. Danforth, a 51-year-old housecleaner in\ Taunton, Mass., had no insurance and little money for doctors or the\ inhalers she needed when her condition was at its worst.\ \ Then, two years ago, her life changed. Friends told her of a doctor\ who was offering free examinations and drugs as part of a study of an\ experimental asthma medication. Perhaps, the friends suggested, the\ doctor could help her.\ \ The doctor, Michael Lawrence, was soon providing Ms. Danforth with\ free diagnostic tests -- including a chest X-ray she could never have\ afforded -- to determine if she was eligible. Ms. Danforth was\ accepted for the study and within days Dr. Lawrence gave her a free,\ but unapproved, medication for asthma. Her breathing returned to\ normal.\ \ Ms. Danforth had finally found her access to health care -- albeit one\ where a medicine she finds effective lasts only as long as the study.\ As a result, she has become one of a growing number of drug-trial\ nomads, wandering from study to study as they become available.\ \ \"I can\'t keep track of them all,\" Ms. Danforth said of the drug\ studies in which she has participated. \"But I haven\'t felt this good\ in a long time.\"\ \ In recent years, the need for test subjects in experimental drug\ trials has exploded as the industry has brought to market an\ ever-increasing number of new products. In response, drug companies\ have developed new methods of finding participants for the trials by\ turning to private-practice doctors who recruit from their lists of\ patients. But even that influx of participants has not been enough to\ satisfy the demand.\ \ Filling the gap, according to industry officials and researchers, are\ people like Ms. Danforth: chronically ill with limited or no health\ insurance, relying on clinical trials by private doctors as their\ primary source of medical care. For these people, experiments have\ become treatments; clinical investigators are their specialists.\ \ Medical experts recognize the shortcomings of this system. On the one\ hand, the doctors are white knights, providing a critical service that\ such patients cannot obtain any other way. Patients \"are better off\ getting experimental therapy than no therapy at all,\" Paul Menzel, a\ philosophy professor at Pacific Lutheran University in Tacoma, Wash.,\ said.\ \ But the benefit can be fleeting or nonexistent. Chronically ill\ patients with no other options can be treated with an experimental\ medication that does not work or that even worsens their condition. Or\ they can end up with a placebo -- a dummy pill or treatment -- rather\ than the medication itself. And once the study is over, usually in a\ matter of weeks, they are left to their own devices. They can be\ barred by the rules of one clinical trial from participating in\ another study for months, forcing them to rely on samples of\ medications provided by drug companies or to go without treatment\ altogether.\ \ That leaves many patients in a sad position: Having tasted, for a\ moment, how good life can be when their conditions are controlled,\ they are plunged back into a life of disabling symptoms.\ \ \"Studies are becoming like a stopgap\" with the private doctors, said\ Dr. Richard A. Friedman, director of the psychopharmacology clinic at\ New York Hospital-Cornell Medical Center in Manhattan. \"And that\'s\ pretty bad, taking from them what they need and then tossing them\ back.\"\ \ That description underscores a hard fact of medical research: The\ subjects of drug trials are not, technically speaking, being treated\ for a disease. Rather, they are participating in an experiment.\ \ \"One will often hear from physicians and economists that there is\ always a way for them to get medical care, so this must be one of the\ ways,\" said Norman Daniels, a professor of philosophy at Tufts\ University who specializes in ethics and health policy. \"In my view,\ it does not count as medical care.\"\ \ The Trend\ Uninsured Pursue Unaffordable Care\ \ Nobody tracks how many uninsured people seek health care from clinical\ studies, but researchers agree that they number in the thousands and\ that their ranks are growing.\ \ The result is that researchers in areas with many poor people often\ have the best chance of attracting research subjects. \"That\'s one of\ the reasons that we have been so successful,\" Dr. Paul Chervinsky,\ medical director at New England Clinical Studies in New Bedford,\ Mass., said. \"New Bedford has always been an economically deprived\ area.\"\ \ Even people with insurance plans that impose significant restrictions\ -- like managed care programs that require pre-approval to visit a\ specialist -- are circumventing the gatekeepers by seeking out\ clinical trials, researchers said.\ \ \"A lot of patients tell me that they feel frustrated with the care\ that they receive from the H.M.O.,\" said Dr. Norman Zinner, a Los\ Angeles doctor who heads Affiliated Research Centers, an organization\ of private-practice urologists who do drug studies. \"They want to know\ if they might be eligible for a drug study so that they could get\ relief.\"\ \ Of course, the poor have long been participants in drug studies,\ usually through university medical centers. But once a study is\ completed those institutions often direct the patients to other\ university programs that provide health care to the poor -- programs\ that private doctors who normally see only paying patients have few\ dealings with.\ \ The benefits for test subjects are obvious. For many, a clinical trial\ offers a rare opportunity for a full diagnostic workup by a medical\ specialist as well as access, at no charge, to the latest treatments.\ \ \"Arkansas is not a wealthy state, and most of the drug studies that we\ do provide the patient with free medication,\" said Lin Richardson,\ director of practice management at Baptist Health Systems, which\ operates a network of private practices in Little Rock that conduct\ drug studies involving a large number of uninsured patients. \"It is\ amazing what I have seen happen for some of our patients.\"\ \ The Ethics\ Right and Wrong On the Frontier\ \ Ethical qualms arise from the fact that clinical trials are not\ intended to be medical care. In this context, the doctors are\ investigators, not personal physicians. The drugs are often\ experimental, and no one knows for sure whether they work. On top of\ that, because many clinical trials compare an active drug with a\ placebo, the patients often stand as good a chance of receiving no\ treatment.\ \ Clinical trials also raise a problem never experienced in true patient\ care: Even if a test medication improves the health of a chronically\ ill person, the drugs will no longer be supplied once the study ends.\ \ Some researchers and study co-ordinators strive to avoid that outcome.\ \"I believe it\'s a violation of human rights\" to keep patients dangling\ untreated between studies, said Maria Lopez, a study coordinator for\ Dr. Herbert Rubin, a gastroenterologist in Beverly Hills, Calif. Dr.\ Rubin provides his uninsured test subjects with drug company samples\ between tests, a practice that Ms. Lopez said was frowned upon by the\ companies.\ \ \"Drug company representatives will be like: \'Remember, you have to\ give these to patients who will actually buy,\' \" Ms. Lopez said.\ \ Other researchers refuse to allow the uninsured to use drug studies\ for medical care.\ \ \"It\'s not right that some people would give the patient the false\ impression that they are getting full medical care when they are not,\"\ said Dr. Thomas Littlejohn, who directs Piedmont Medical Group in\ Winston-Salem, N.C.\ \ Told of the trend, medical ethicists were divided. Some expressed\ concern, saying that vulnerable patients were being coerced through\ the lure of medical care to put their bodies on the line.\ \ \"It becomes a further exploitation of the poor,\" John Paris, an ethics\ professor at Boston College, said.\ \ But others were less certain, noting that the trend presented new\ options for getting care to people whose choices were limited.\ \ \"It is a nasty dilemma,\" Professor Menzel said. \"There is no way you\ can win on this one.\"\ \ The Patients\ A Roller Coaster Without Relief\ \ When Victor Miranda saw Dr. Rubin\'s ad in La Opinion, a Spanish\ language newspaper in Los Angeles, he did not even call ahead for an\ appointment.\ \ Instead, Mr. Miranda, a 37-year-old house painter from Guatemala,\ hopped on a bus in the morning and traveled an hour and a half to Dr.\ Rubin\'s office. He said through a translator that he had suffered from\ heartburn and agonizing stomach pain for two years but had not seen a\ doctor because he could not pay for it.\ \ Dr. Rubin determined that he had an inflamed esophagus, an easily\ treatable condition, and enrolled Mr. Miranda in a study comparing\ drugs developed by Astra Pharmaceuticals.\ \ The paradoxes of such experiences are not lost on patients. While most\ praise the doctors who conduct the research, many also resent the\ compromises they have to make.\ \ \"The health care they give you is really specific for what they\'re\ testing for,\" said Elizabeth Elder, a 52-year-old uninsured woman in\ Albuquerque, N.M., who has participated in a number of studies, \"so it\ isn\'t really health care.\"\ \ Others are simply grateful for whatever medical attention they can get.\ \ In Lemoyne, Ohio, Roland and Linda Gladieux were looking for drug\ studies to get relief from a host of medical problems. They could not\ afford insurance; the cheapest policy they could find cost \$500 a\ month with a \$2,500 deductible and paid only 70 percent of medical\ costs above that.\ \ Mr. Gladieux, a burly 51-year-old who manages a car-repair shop, has a\ chronic wheezing cough. He had gone to a doctor who wanted to test him\ for emphysema, but Mr. Gladieux declined, unable to afford the tests.\ So when he saw an advertisement on television late last year seeking\ people with chronic bronchitis, he jumped at the chance.\ \ The ad was placed by Dr. John Winder, an asthma and allergy specialist\ in Sylvania, Ohio, who does drug studies alongside his private\ practice. The bronchitis study was already fully enrolled when Mr.\ Gladieux called. But Dr. Winder\'s recruiters told him of studies for\ other ailments. Learning that a heartburn study was opening, Mr.\ Gladieux offered his wife, who has had severe heartburn for 20 years.\ She got into the study.\ \ \"It was a godsend,\" Mrs. Gladieux said. The experimental medication\ cleared up her heartburn and for the first time in years she could eat\ foods like lasagna without suffering.\ \ Now the heartburn study is over and the Gladieuxes are looking for\ other drug studies to join -- bronchitis for him, heartburn for her.\ Or almost anything.\ \ \"I have arthritis real bad,\" Mrs. Gladieux said. When she saw Dr.\ Winder for her last visit in the heartburn study she asked him to keep\ her in mind. \"I told him if anything comes up, give me a call,\" she\ said.\ \ The financial difficulties that lead patients to choose experiments\ for their health care are not limited to people with little or no\ insurance. Adriana Medina, a 24-year-old medical assistant in Tucson,\ Ariz., has health insurance through a health maintenance organization.\ The plan paid for her 8-year-old daughter, Gabriela Garcia, to see a\ pediatrician for her asthma. But when that failed to help, the plan\ would not pick up the cost of a specialist.\ \ \"She was on so many medications, and she was constantly sucking on the\ breathing machine,\" Ms. Medina said. \"It was just a roller coaster\ ride. She was never well.\"\ \ Unable to afford the specialist, Ms. Medina enrolled Gabriela in a\ drug study conducted by a local asthma expert, Dr. Jay Grossman. \"Just\ hearing that it was an asthma specialist I said, \'Hey, what do I have\ to lose?\' \" she said.\ \ The experimental asthma drug changed Gabriela\'s life. The trial \"is\ allowing her to have a normal childhood,\" Ms. Medina said.\ \ \"My only worry,\" she added, \"is that the study will be over and she\'ll\ be back where she started from.\"\ \ The completion of a study can be a poignant moment, several doctors\ said, especially when the subjects, like Gabriela Garcia, finally\ received medical help that had eluded them. The subjects spent weeks\ or months sitting in waiting rooms with private patients, filling out\ the same forms and looking through the same magazines as everyone\ else. Their diagnostic tests were done in the usual exam rooms, and\ they received drugs just like private patients. Then the study ended\ and the subjects had to leave.\ \ \"They have had more medical care from me than they have had from\ anybody for years,\" Dr. Winder said. \"It is hard for them to\ understand that they are not my patients.\"\ \ In the end, if no new clinical trials are available to them, that\ reality can leave patients feeling frightened and abandoned. Josette\ Good, a 60-year-old widow, used to count on Dr. Winder to keep her\ enrolled in study after study for asthma. But last year, she moved to\ Lake Milton, Ohio, near her children but 200 miles from Dr. Winder\'s\ office.\ \ Now, medical care has become an issue; adequate health insurance is\ beyond her budget, and Dr. Winder could not help her find a study in\ her area. She has only one inhaler left, from the last study she\ participated in, so she uses it sparingly, at times borrowing another\ from a friend. Hoping to make her inhaler last through the summer, she\ limits her activities, avoiding yardwork and even short walks.\ \ \"It\'s just so tough,\" Mrs. Good said. \"I pray nothing happens.\"\ \ DRUG TESTERS SEEK UNINSURED\ Times Union, The (Albany, NY) - Tuesday, June 22, 1999\ Author: GINA KOLATA and KURT EICHENWALD New York Times\ The need for test subjects in experimental drug trials in the United\ States has exploded as the industry has brought to market an\ ever-increasing number of new products.\ \ In response, drug companies have developed new methods of finding\ patients for the trials by turning to private-practice doctors, who\ recruit from their lists of patients. But even that influx of\ participants has not been enough to satisfy the demand.\ \ Filling the gap, according to industry officials and researchers, are\ chronically ill patients with limited or no health insurance. For\ these people, experiments have become treatments; clinical\ investigators are their specialists.\ \ Medical experts recognize the shortcomings of this system.\ \ On the one hand, the doctors are white knights, providing a critical\ service that such patients cannot obtain any other way. Patients ``are\ better off getting experimental therapy than no therapy at all,\'\' said\ Paul Menzel, a philosophy professor at Pacific Lutheran University in\ Tacoma, Wash.\ \ But the benefit can be fleeting or nonexistent. Chronically ill\ patients with no other options could be treated with an experimental\ medication that does not work or that even worsens their condition. Or\ they could end up with a placebo rather than the medication itself.\ And once the study ends, usually after weeks, they are left to their\ own devices.\ \ They can be barred by the rules of one clinical trial from\ participating in another study for months, forcing them to rely on\ samples of medications provided by drug companies or to go without\ treatment.\ \ ``Studies are becoming like a stopgap\'\' with the private doctors, said\ Dr. Richard A. Friedman, director of the psychopharmacology clinic at\ New York Hospital-Cornell Medical Center in New York City. ``And\ that\'s pretty bad, taking from them what they need and then tossing\ them back.\'\'\ \ That description underscores a hard fact of medical research: The\ subjects of drug trials are not, technically speaking, being treated\ for a disease. Rather, they are participating in an experiment.\ \ ``One will often hear from physicians and economists that there is\ always a way for them to get medical care, so this must be one of the\ ways,\'\' said Norman Daniels, a professor of philosophy at Tufts\ University who specializes in ethics and health policy. ``In my view,\ it does not count as medical care.\'\'\ \ Nobody keeps track of how many uninsured people seek health care from\ clinical studies; but researchers agree that they number in the\ thousands and that their ranks are growing.\ \ One such person is Carole Danforth, whose asthma in recent years had\ gotten the best of her. No longer did she have the energy for\ activities she loved, like playing with her grandchildren or doing\ yardwork.\ \ Some days, her breathing was so labored she could not get up from the\ couch. And there seemed little she could do about it: Danforth, a\ 51-year-old housecleaner in Taunton, Mass., had no insurance and\ little money for doctors or the inhalers she needed when her condition\ was at its worst.\ \ Then, two years ago, her life changed. Friends told her about a local\ doctor who was offering free examinations and drugs as part of a study\ of an experimental asthma medication.\ \ The doctor, Michael Lawrence, was soon providing Danforth with free\ diagnostic tests -- including a chest X-ray she could never have\ afforded -- to determine if she was eligible. Danforth was accepted\ for the study and within days Lawrence gave her a free, but\ unapproved, medication for asthma. Her breathing returned to normal.\ \ Danforth had finally found her access to health care -- albeit one\ where a medicine she finds effective lasts only as long as the study.\ As a result, she has become one of a growing number of drug-trial\ nomads, wandering from study to study.\ \ In Pediatrics, a Lesson in Making Use of Experimental Procedures\ New York Times, The (NY) - Sunday, October 3, 1999\ Author: GINA KOLATA and KURT EICHENWALD\ Abstract: Pediatric cancer world offers model for effective way to\ handle experimental procedures; most doctors refuse to offer pediatric\ treatments outside clinical trials, insurance companies usually pay\ bills and experimental procedures are tested rapidly, before they\ reach marketplace; pediatric oncologists have organized selves into\ two major consortiums that enroll virtually every child in clinical\ trial (M)\ If there is a model for an effective way to handle experimental\ procedures, it is the world of pediatric cancer.\ \ In that arena, most doctors refuse to offer such treatments outside\ clinical trials, insurance companies usually pick up the tab and\ experimental procedures are tested quickly, before they reach the\ marketplace. The result is that the procedures that work are adopted\ widely; those that do not are quickly abandoned.\ \ Why the difference from adult medicine? The credit, in large part,\ goes to pediatric oncologists. They have organized themselves into two\ major consortiums that enroll virtually every child in a clinical\ trial.\ \ The two groups agreed to sponsor only credible studies that truly\ advanced knowledge of the field -- quashing the \"me-too\" phase 2\ research that proliferates in other medical specialties. With such\ quality control in place, the pediatricians were able to successfully\ lobby health insurance companies to pay for medical care in clinical\ trials. The companies generally refuse to pay for experimental\ procedures offered outside trials.\ \ The pediatricians have good reason to unite behind clinical trials.\ With comparatively few children getting cancer, the number of\ available test subjects was already severely limited. Doctors\ convinced each other that it was better for the children to test\ treatments promptly than to provide them, untested, to every comer.\ \ The results are heartening. While just one percent of adult cancer\ patients enroll in clinical trials, 60 percent of pediatric cancer\ patients do. Cancer specialists maintain that the consequences are\ clear: Progress is much faster in pediatric cancer than it is in\ cancer that strikes adults.\ \ \"I can\'t imagine why adult oncologists don\'t follow the same route,\"\ said Dr. Kenneth Lazarus, a pediatric cancer specialist in San\ Antonio. \"If you take all the cancers that were incurable in the late\ 1960\'s, nearly all are curable now. It\'s dramatic what\'s happened.\"\ \ In the pediatric world, even bone marrow transplants were tested\ promptly. In the late 1980\'s and early 1990\'s, at the very time the\ procedure was being widely sold for adult cancer patients, pediatric\ oncologists began giving it to children with neuroblastoma, a cancer\ of the nervous system. The cancer appears in just 500 children each\ year. But its effects can be devastating, striking toddlers from 2 1/2\ to 4 years old and often spreading to the bones, where it can cause\ excruciating pain before killing the child.\ \ As soon as transplants appeared as a possibility, the Children\'s\ Cancer Group, one of the national consortiums of pediatric cancer\ specialists, began a randomized clinical trial. The group began the\ trial in January 1991; within five years, it had reached the\ enrollment goal of 545 children. And even though there was a belief\ among some pediatric cancer specialists that bone marrow transplants\ would be more effective than standard chemotherapy for these children,\ there was virtually no market for the procedure outside the clinical\ trial.\ \ \"We didn\'t have trouble finding children to enroll,\" said Dr. Archie\ Bleyer, the chairman of the Children\'s Cancer Group. In fact, he said,\ \"the trial was actually completed ahead of schedule.\"\ \ It is now finished, and the results show what the doctors had hoped --\ that bone marrow transplants do improve survival for children with\ neuroblastoma.\ \ The extraordinary success of clinical trials in pediatric cancer would\ not have been possible without the cooperation of health insurance\ companies, cancer specialists say. Unlike the situation in adult\ cancer, where companies have refused to pay for patients receiving\ experimental procedures in clinical trials, the same companies\ routinely pay for children in clinical trials.\ \ Susan Radtky, stem cell transplant coordinator at Riley Hospital for\ Children in Indianapolis, said that the insurance companies were\ usually cooperative. \"In five years and 200 patients, by and large, I\ have had 5 percent really problem cases, with insurance companies\ denying it,\" she said.\ \ Some insurance companies even go as far as to use the reimbursement\ structure to push children into studies.\ \ \"I have seen contracts that said that if it is not a qualified trial\ being offered at a qualified center, then it is not covered,\" said Dr.\ Andrew Kelahan, the chief operating officer of the Coalition of\ National Cancer Cooperative Groups, which represents the major groups\ of medical institutions that conduct cancer clinical trials.\ \ One way to encourage the testing of experimental procedures for adults\ might be for insurance companies to institute a similar system, some\ academic doctors say.\ \ But insurance companies alone are unlikely to change the system of\ marketing untested procedures to adults.\ \ Last fall, working with the Coalition of National Cooperative Groups,\ United Healthcare, which provides health insurance for 13 million\ Americans, worked out an arrangement to nudge adults into clinical\ trials. Dr. Lee Newcomer, a senior vice president for health policy at\ United Healthcare, explained: \"If there was a new treatment out, we\ would pay for it under the trial scenario. But if someone said they\ wanted to give it off of the trial we would say no.\"\ \ But by a year later, nothing had changed. \"It\'s not working,\" Dr.\ Newcomer said. So far, only a dozen patients have entered clinical\ trials. Moreover, he added, most of those patients were never even\ told by their doctors that a clinical trial was an option. They found\ out about the trials and enrolled despite, not because of, their\ doctor\'s advice, he said.\ \ Now, Dr. Newcomer said, \"the onus is on the physician community.\"\ Doctors, he said, may say they believe in putting patients in trials,\ but when offered an incentive and an opportunity, \"it doesn\'t happen.\"\ \ HOPE FOR SALE: A special report. Business Thrives on Unproven Care,\ Leaving Science Behind\ New York Times, The (NY) - Sunday, October 3, 1999\ Author: GINA KOLATA and KURT EICHENWALD\ Abstract: Special report, Hope for Sale, on multimillion-dollar\ industry that sells unproven experimental treatments; focuses on bone\ marrow transplants for solid tumor cancers like breast cancer; notes\ wide availability of unproven procedure at university medical centers\ and community hospitals and even from publicly traded companies sops\ up vast majority of potential test subjects, making it hard to conduct\ clinical trials; graph of rising number of transplants; photos (L)\ For years, Dr. Larry Norton tried to conduct a medical study to\ determine, once and for all, whether bone marrow transplants could\ really save the lives of women desperately ill with breast cancer.\ \ His efforts -- and those of dozens of other doctors -- were largely\ futile. Year after year, few women were willing to participate in the\ clinical tests, which, to be scientifically valid, required patients\ to be randomly assigned to either the experimental treatment or\ standard chemotherapy.\ \ Many believed the experimental treatment was their only hope, and were\ unwilling to leave anything to chance. So most chose to get\ transplants from a growing number of hospitals and cancer centers that\ are part of a multimillion-dollar industry that sells experimental\ treatments. There, for more than a decade, many women were told that\ the procedure was the only thing that could save their lives -- when,\ in fact, no one knew for sure whether it was better or worse than the\ standard treatment.\ \ \"I got so angry,\" Dr. Norton said. \"Fifty years from now, we will look\ at this period with horror and say \'How could this have happened.\' \"\ \ But Dr. Norton, head of the division of solid tumor oncology at\ Memorial Sloan-Kettering Cancer Center in New York, said he understood\ why the women refused to join the study: Few patients, faced with\ advanced and likely fatal disease, would risk passing up a supposedly\ cutting-edge treatment simply to advance scientific knowledge.\ \ Experts say that tens of thousands of such personal decisions, made\ under enormous emotional strain, are significantly slowing the search\ for cures for dire diseases like cancer. The wide availability of\ unproven procedures sops up the vast majority of potential test\ subjects, they say, making it difficult, or impossible, to assess\ which treatments work and which do not.\ \ An increasing number of untested treatments are being sold to\ desperate patients with ailments like cancer, heart failure and\ Parkinson\'s disease. Today, experimental procedures can be purchased\ outright from community hospitals, university medical centers and even\ from publicly traded companies.\ \ To better understand the workings of this system, The New York Times\ examined one of the most widely offered procedures -- bone marrow\ transplants for solid tumor cancers like breast cancer. The\ examination found that this procedure entered the medical marketplace\ in the 1980\'s before studies to test its effectiveness had even begun.\ By the time testing was under way, the business had taken on a life of\ its own. Patients were unavailable and tests were delayed for years or\ had to be abandoned.\ \ The issue arises because medical procedures, like the bone marrow\ transplants or new surgical techniques, are not regulated, reflecting\ the Government\'s usual reluctance to interfere with doctors\' practice\ of medicine. By contrast, Federal rules require that new drugs or\ devices like a heart valve be proven safe and effective before being\ sold to the public.\ \ Doctors, of course, can voluntarily regulate themselves and those in\ one tiny specialty, pediatric cancer, have done so. These doctors have\ agreed to provide experimental procedures only to patients who\ participate in valid research. In that specialty, the availability of\ a pool of test subjects assures that new ideas for treatments are\ rapidly tested, allowing them to be adopted nationwide if they work,\ or tossed aside if they prove useless. As a result, the advances in\ this field have been phenomenal, far outracing anything seen in adult\ medicine.\ \ \"Too often people have access to therapies that are not proven,\" said\ Fran Visco, president of the National Breast Cancer Coalition, a\ patient group. \"As a result, we don\'t get enough individuals to\ participate in the clinical trials, so it takes a long time to get\ answers, or we never get answers.\"\ \ In breast cancer, testing of bone marrow transplants took twice as\ long as anyone expected. Throughout the 1990\'s, doctors and hospitals\ reported to a national registry that about 15,000 women had purchased\ bone marrow transplants for treatment of breast cancer. Medical\ experts said that the voluntary reporting system missed about half of\ the women who actually received the procedure. Yet, while as many as\ 30,000 women had bone marrow transplants for breast cancer, only 1,000\ participated in the scientific studies.\ \ In ovarian cancer, it proved impossible to even conduct a trial of\ bone marrow transplants. Doctors at more than 100 medical institutions\ nationwide spent two and a half years seeking 285 women who would\ participate. They enlisted just 25. Last April, researchers admitted\ defeat. The ovarian cancer trials collapsed.\ \ Many doctors, like Dr. Maurie Markman, director of the Taussig Cancer\ Center at the Cleveland Clinic, were unable to enroll a single patient\ despite monumental efforts.\ \ \"It\'s a tragedy that we can\'t do a randomized trial in the United\ States to answer this,\" Dr. Markman said. \"Unfortunately, if someone\ says they can cure you and I say I can\'t, it is very logical that\ people will drift to those who can give you hope.\"\ \ Those who sell experimental procedures have a different view. They say\ they are helping patients who have run out of options and that\ researchers who are only focused on determining whether a treatment\ works are out of touch with the needs of patients suffering with a\ disease now.\ \ \"These are not guinea pigs, this is not a fascist society,\" said Dr.\ William H. West, chairman of Response Oncology, a publicly traded,\ for-profit company that sells the procedure. \"We are an open\ marketplace, and that\'s true in clinical trials.\"\ \ But other experts point out that the same arguments could be made\ about drugs and medical devices. In those cases, the Government has\ decided that treatments must be proven safe and effective before they\ are offered on a large scale. Abandoning that standard for procedures,\ these experts said, is perilous.\ \ \"Physicians must demand the same high standards of science for new\ procedures as we do for new medicines,\' said Dr. C. Warren Olanow,\ professor and chairman of the department of neurology at the Mount\ Sinai School of Medicine in New York. \"The alternative is uncontrolled\ human experimentation.\"\ \ Today, in bone marrow transplants, the uncertainty lives on, tearing\ at women as they face the decision of whether to undergo this\ difficult procedure. With so many years having passed since the idea\ of bone marrow transplants first emerged, they struggle to understand\ how a medical system so advanced could not yet answer a question so\ basic: does the treatment work?\ \ Catherine Porter, 44, who has breast cancer that has spread to other\ parts of her body, is among those wondering. Seven years ago, Mrs.\ Porter, of Imlay City, Mich., had a breast removed to combat her\ cancer. She felt certain she had been cured. Then, recently she\ learned the cancer was back, worse than ever. Figuring she would take\ a gamble, she elected to have a bone marrow transplant two weeks ago\ at the Barbara Ann Karmanos Cancer Institute in Detroit.\ \ Last week, she arrived home. Now, she waits, wondering if the\ experimental treatment she received will help her, and why medical\ science still cannot answer that question for so many thousands of\ women.\ \ \"Something has got to be done,\" she said, \"So we don\'t have to keep\ doing this.\"\ \ The Procedure\ Early Success Leads to Competition\ \ Dr. Gabriel Hortobagyi was something of a rebel.\ \ In 1979, when the options for treating breast cancer were limited, Dr.\ Hortobagyi was one of a handful who ventured into uncharted territory:\ treating the cancer with a bone marrow transplant. When the first\ patient appeared to do well, Dr. Hortobagyi offered the procedure to\ another woman, and another.\ \ It was not an easy procedure. Known within the field as high-dose\ chemotherapy followed by bone marrow transplant or stem cell rescue,\ the experimental treatment is based on a simple concept: if a little\ chemotherapy killed some of the cancerous cells in a woman\'s body, a\ lot might kill them all.\ \ So doctors remove some bone marrow or red blood cells from the\ patient, then load her with huge amounts of toxic drugs, quantities\ that destroy the bone marrow. The hope is that the high doses will\ eliminate the cancer and that the saved bone marrow, when returned to\ the body, will grow back quickly enough so that the patient does not\ die from infection. A version of the procedure, using donations of\ bone marrow, had long been established as effective for blood cancer,\ but solely because the cancer was in the marrow that was being\ replaced. The use of the treatment for breast cancer involved a\ completely different -- and untested -- reasoning.\ \ Even though Dr. Hortobagyi and a handful of other pioneers at academic\ centers selected patients who were young and otherwise healthy, they\ could not save some from the terrible effects of the powerful\ anticancer drugs. Fifteen to 20 percent of the women in those early\ days died from the harsh drugs alone; others had permanent injuries,\ including hearing loss, nerve damage and heart damage.\ \ The outlaws became heroes by the late 1980\'s, when they began\ announcing what looked like amazing outcomes. The data were not\ scientifically valid proof that the treatment worked -- each medical\ center looked at less than a few dozen patients and had to infer how\ they would have fared without a transplant.\ \ But the data appeared to make a startling point. Women with advanced\ breast cancer who had had transplants experienced remission rates of\ 50 to 60 percent. The general population of women with advanced breast\ cancer who had received conventional chemotherapy had remission rates\ of just 10 to 15 percent.\ \ \"Those of us who were involved got very very excited,\" Dr. Hortobagyi\ said. \"We told our patients, \'Look at the results we\'re getting.\' \"\ \ The patients were not the only ones who looked. With the apparent\ success of the bone marrow transplants, a new business had been born.\ \ \"It seemed so logical,\" Dr. Norton said. \"It started getting accepted\ without clinical trials.\"\ \ Data from a voluntary registry, the Autologous Blood and Bone Marrow\ Transplant Registry of North America, show the growth in the\ popularity of this procedure. The registry, which records about half\ of the bone marrow transplants in the United States, found that 271\ women with breast cancer had transplants in 1989. Two years later the\ number had jumped to 749. By 1997 there were 2,853 bone marrow\ transplants for breast cancer reported.\ \ For-profit corporations offering bone marrow transplants emerged by\ the late 1980\'s. Response Oncology, one of the first, started offering\ the procedure in 1989 as part of what it called a \"clinical trials\ program.\"\ \ That program involved only trials that gave everybody the procedure\ and watched how they fared. These studies cannot be used to\ demonstrate whether the procedure is any better than the standard\ treatment, because there is no comparison group of similar patients.\ Therefore, there is no way of knowing how the patients would have\ fared with conventional treatment.\ \ But the trials did help Response Oncology earn profits. Dr. West, the\ chairman of the company, said the profit margin from bone marrow\ transplants is 15 percent. All told, Response Oncology brought in \$128\ million in revenue in 1998, largely from its cancer centers providing\ bone marrow transplants.\ \ In large part, the company, based in Memphis, approached the sale of\ the experimental procedure like any other business. It undercut\ potential competitors on price, charging \$80,000 per transplant at a\ time when others were charging \$200,000.\ \ \"We\'ve been a very competitive force,\" Dr. West said. \"What happened\ was a battle over the franchise -- who owns high-dose chemotherapy?\"\ \ Private hospitals also joined the fray. Institutions like a hospital\ in Zion, Ill., owned by Cancer Treatment Centers of America advertise\ heavily for patients and even pay for patients to travel there for the\ procedure. Hospitals associated with giant for-profit chains,\ including the Columbia/HCA Healthcare Corporation and Tenet\ Healthcare, opened bone marrow transplant programs that offered the\ treatment to women with breast cancer.\ \ But the academic medical centers -- even those trying to recruit\ patients for clinical trials -- did not stand aside and let all the\ profits go elsewhere. By the early 1990\'s virtually every major\ medical center was offering bone marrow transplants for breast cancer\ patients and a growing number of community hospitals were offering\ them as well.\ \ At academic centers, bone marrow transplant programs quickly became\ \"the cash cow for the cancer service,\" said Dr. William McGuire, an\ ovarian cancer specialist at Mercy Medical Center in Baltimore.\ \ The doctors who provided transplants were rewarded with money and prestige.\ \ \"Bone marrow transplanters are kings,\" said Dr. I. Craig Henderson, a\ breast cancer expert at the University of California at San Francisco.\ \"They usually get a higher salary, they usually get more money. And\ more important, they have security and power.\"\ \ Every entity offering the experimental procedure tried a different\ sales pitch. Some promoted the prestige of their institutions, others\ the convenience of their locations, others their caring attitudes and\ patient support, and others, like Response Oncology, their lower\ prices.\ \ Soon, with competition red hot, a new business spinoff emerged:\ Doctors, hospitals and companies began selling bone marrow transplants\ to patients with other types of tumors, like ovarian and brain\ cancers. But if the breast cancer treatments were based on a theory,\ these new uses were theories on a theory.\ \ \"It is a technology based on a hypothesis,\" Dr. McGuire said.\ \ Paying for the procedures turned out not to be a problem for many\ patients: Their insurance companies ended up footing the bill. The\ insurers at first refused, pointing out clauses in their policies\ saying they would not pay for experimental procedures. But under\ pressure from patients, doctors, lawyers and lawmakers, most insurance\ companies gave in.\ \ Take the case of Rita Hartmann, a 60-year-old elementary school\ teacher from Wooster, Ohio. When her ovarian cancer recurred, Mrs.\ Hartmann and her husband agonized over what to do. Cancer Treatment\ Centers of America told her she had a 30 percent chance of a cure if\ she had a transplant, but her insurance company said it would not pay.\ Mrs. Hartmann\'s husband wanted to mortgage their house, sell all they\ owned to raise the money. But Mrs. Hartmann held back. \"I said,\ \'That\'s too traumatic,\' \" she said.\ \ Instead, she called a staff aide for her Senator, Mike DeWine, a\ Republican. The aide in turn reached Mrs. Hartmann\'s insurance\ company. In addition, Mrs. Hartmann and 20 of her friends wrote\ pleading letters to her insurer. Three months later, on Valentine\'s\ Day last year, the company agreed to pay. Mrs. Hartmann had her\ transplant.\ \ Her cancer returned within nine months.\ \ Under pressure from doctors and patient groups, Congress even mandated\ in 1994 that insurers for Federal employees pay for bone marrow\ transplants for women with breast or ovarian cancer. Soon, lobbied by\ doctors, hospitals and patient groups, about a dozen states adopted\ their own mandates that the experimental procedure be covered.\ \ Lost in the rush to offer the treatment to more cancer patients with\ solid tumors was the fact that the procedure still had not been shown\ to work even for breast cancer, where it got its start.\ \ \"It evolved into a standard of care,\" said Dr. John Glick, director of\ the Cancer Center at the University of Pennsylvania. \"It isn\'t.\"\ \ The Patients\ Rejecting Trials In Quest for a Cure\ \ The poison seeped through the catheter implanted in Deborah Holmes\'s\ chest, slowly destroying cells throughout her body. The bone marrow\ transplant was painful and experimental, but Ms. Holmes believed it\ her only real hope of beating her ovarian cancer. With it, the doctors\ performing the procedure assured her, she had a 30 percent chance of\ wiping out the malignancy; without it, they said, she would probably\ die.\ \ After being assured that her insurance company would pick up the\ \$150,000 bill, Ms. Holmes traveled halfway across the country for the\ treatment, from her home in Hamden, Conn., to the hospital in Zion,\ Ill., operated by Cancer Treatment Centers of America. To Ms. Holmes,\ it was worth the trip. \"There was so much hope there, so much positive\ energy down to the nurses and the doctors,\" Ms. Holmes said.\ \ At Brown University in Rhode Island, a 90-minute drive from Ms.\ Holmes\'s home, the mood was far less positive. Despite the happy\ assurances of 30 percent cure rates at places like Cancer Treatment\ Centers, researchers at the university knew the truth: No one could\ say whether this procedure worked for ovarian cancer patients like Ms.\ Holmes.\ \ Brown was part of a consortium of institutions scouring the nation for\ just 285 women with ovarian cancer to participate in research to\ determine whether bone marrow transplants prolonged lives. But with so\ many desperate patients like Ms. Holmes flying anywhere to get the\ experimental treatment, finding test subjects was almost impossible.\ On April 25, after two years of trying to enroll women, researchers\ admitted defeat.\ \ Ms. Holmes, unaware of the national clinical trial, believed what\ Cancer Treatment Centers of America had told her -- that transplants\ could cure women like herself. When her cancer returned last November,\ five months after her transplant, Ms. Holmes said she guessed she was\ just one of the unlucky ones.\ \ She died on Aug. 14.\ \ The collapse of the ovarian cancer trials underscores the problems\ with the current system for selling unproven medical procedures. Even\ though there may be plenty of patients eligible to join such studies,\ they may be unwilling to participate when they can obtain the\ procedure elsewhere.\ \ Breast cancer clinical trials had begun several years before, in 1990,\ but struggled to find patients. There were two national trials: one\ for women whose breast cancer had spread throughout their bodies and\ another for women whose cancer had spread to at least 10 of the lymph\ nodes under their arms. Researchers expected it would take about three\ years to enroll about 1,000 women in the two studies. Instead it took\ seven years. For every 10 women who could have been in a clinical\ trial, 1 actually enrolled, Dr. Norton said.\ \ That is not so surprising, Dr. Henderson said. Patients in the\ clinical trials must sign a consent form spelling out their grim\ prognosis and stating that there is no evidence that bone marrow\ transplants are any better than the standard therapies.\ \ To enter the trial, he said, \"you have to face these realities, which\ is never easy.\"\ \ But if the patient has a transplant outside a trial with a control\ group of patients, known as a randomized trial, enthusiastic doctors\ may tell her that a transplant could save her life. Although patients\ \"have a right to the truth,\" Dr. Henderson said, they understandably\ \"are not going to go to doctors who take away hope\"\ \ Medical centers had to make a choice: Offer only the randomized\ clinical trials -- and watch patients leave in droves -- or offer bone\ marrow transplants outside the randomized trials for those who would\ not participate in the research studies.\ \ Dr. Andrew L. Pecora, chief of the adult blood and marrow stem cell\ transplant program at Hackensack University Medical Center in New\ Jersey, gave women an option of having a transplant outside a\ randomized trial. \"I offered the clinical trial to every patient,\" he\ said. \"But I did not force them to do it.\" Few entered the trial, he\ said.\ \ Dr. Norton refused to provide transplants outside the trial. His\ patients went elsewhere. \"I was disheartened but I wasn\'t surprised,\"\ he said.\ \ As the business was booming and the trials staggering, Dr. Hortobagyi,\ one of the pioneers who had helped get transplants started, was having\ second thoughts. Those initial stunning results he and others had\ reported were with carefully selected patients younger than 60 and\ otherwise healthy -- no heart disease, no emphysema, nothing that\ might make the high doses of drugs even more risky.\ \ The researchers had compared their outcomes with the outcomes with\ conventional chemotherapy for all women with advanced breast cancer,\ even though most breast cancer patients were older and sicker than\ those who had transplants. Dr. Hortobagyi decided to go back and\ compare the outcomes in the women who had transplants with those of\ women who were just as young and healthy but who had conventional\ chemotherapy.\ \ The women, he discovered, did just as well when they had conventional\ chemotherapy. The women he had provided with transplants did not\ survive in greater numbers because of the procedure. They survived\ because they were healthier to begin with.\ \ It was a hard fact to face.\ \ In promoting transplants, \"we deceived ourselves and we deceived our\ patients,\" Dr. Hortobagyi said. \"We oversold it.\"\ \ But that realization came too late.\ \ The Future\ Dismay as Results Prove Disappointing\ \ Last May 17 a crowd of breast cancer specialists filled a conference\ room half the size of a football field at the Georgia World Congress\ Center in Atlanta. Those who came too late to get seats spilled into\ two smaller rooms nearby with closed circuit television screens. Few\ at the annual meeting of the American Society of Clinical Oncology\ wanted to miss this moment when the leaders in their field would\ present the long-awaited data from clinical trials of bone marrow\ transplants for women with advanced breast cancer.\ \ Five studies had been completed -- two large clinical trials from the\ United States, two large trials from Europe, and a small one involving\ 154 women from South Africa. In all, about 2,000 women had been\ randomly assigned to have the experimental procedure or conventional\ chemotherapy and enough time had elapsed to ask if the women who had\ transplants lived longer than those who did not have them.\ \ The results were not the triumph that many had hoped for.\ \ In four of the five clinical trials, there was no difference in\ survival between women who had transplants and those who had\ conventional therapy.\ \ Only in the South African study did the women who received bone marrow\ transplants outlive the patients in the group who received standard\ therapy. But on closer inspection of the data, even that success\ seemed suspect: the women who had transplants lived about as long as\ the women in the other studies. But the women who had conventional\ chemotherapy in the South African study did far worse. The results did\ not indicate that transplants improved survival, but that the outcomes\ for the control group were poor.\ \ No one on the podium that day claimed that the studies showed that\ transplants were a triumph. Indeed, the trials\' failure to show the\ expected benefits of transplants gave rise to a troubling question:\ When the best available data provided no evidence that bone marrow\ transplants were any better than conventional chemotherapy, should\ transplants continue to be promoted and sold?\ \ For the National Breast Cancer Coalition, which represents cancer\ patients, the data spoke for themselves: Bone marrow transplants had\ been tested and had failed.\ \ \"How can anybody look at these data and think this is something we\ should continue doing or that they are inconclusive?\" asked Ms. Visco,\ the coalition\'s president. The group put out a news release saying,\ \"It is time to move beyond the infrastructure\" created around\ transplants.\ \ But cancer specialists were less definitive. Many said they still saw\ promise in transplants, arguing that it was too soon to say for sure\ that the procedure offered no benefits. They urged that nothing change\ for the time being while the women in the studies were followed for\ longer periods to see if those who had transplants eventually did\ better. They also said that chemotherapy had improved over the last\ decade and because the studies used older drugs, it remained possible\ that bone marrow transplants with new drugs might be better than\ conventional chemotherapy.\ \ Reflecting these views, the American Society of Clinical Oncologists\ put out a news release saying that the papers presented at the meeting\ \"report mixed early results\" and that more years of study are needed.\ \ Dr. Allen S. Lichter, the departing president of the society and dean\ of the University of Michigan Medical School, urged that nothing\ change for the time being while new studies get under way and the\ women in the initial studies continue to be followed.\ \ \"As a nontransplanter and a keen observer of this research, I don\'t\ think there is enough information to say it should die,\" Dr. Lichter\ said. He also said that because not every woman is eligible for a\ clinical trial or has ready access to one, transplants should still be\ available outside trials. \"I for one am not ready to say that this\ should only be done in a clinical trial,\" Dr. Lichter said.\ \ Dr. West of Response Oncology said his company intended to keep\ selling transplants. Calls to stop offering them are \"an\ oversimplification,\" he said, because the trials were not definitive.\ More trials and years of further study are needed, he said.\ \ At bottom, he said, critics are missing the point. What matters, he\ said, is not whether the treatment has been shown to work but whether\ studies are producing more knowledge.\ \ \"You could say there was only one important question and you didn\'t\ answer that one,\" Dr. West said. \"I know you want to think of it as a\ drug that either works or doesn\'t. I think of it more as a platform\ that needs to be modified and studied.\"\ \ So now oncologists and companies say they will press ahead, continuing\ to sell a painful, expensive procedure that the best available science\ says is no improvement over standard care, which is less traumatic.\ Some patient advocates and doctors find this a troubling abandonment\ of the rigors of science.\ \ \"I don\'t have a problem with oncologists who say, \'We really have to\ do something for these patients, they are facing a terribly short\ future,\' \" said Dr. Alan Garber, a professor of medicine at Stanford\ University. \"The problem is when they start to do things that have\ been tested and have not proven effective. Then you are leaving the\ arena of science and going into blind faith.\"