A Medical Researcher Pays For Doubting Industry Claim Suggests Parallels to Vaccine Controversy

      [This disturbing article illustrates how potentially harmful medicines
(and perhaps vaccines as well) are finding their poorly-tested way into our
children's bodies for profit.  By Cynthia Crossen cynthia.crossen@wsj.com in
the WALL STREET JOURNAL, January 3, 2001.  Thanks to Kenvian Moravec and
Paula Stepankowsky.]

      When Erdem Cantekin declared a war of ethics on the University of
Pittsburgh Medical Center, he was an ambitious 42-year-old biomedical
engineer with a future full of promise. He was a tenured professor, he and
his wife, who was pregnant, were preparing to buy their first house, and he
was director of research at a respected institute at the university.
      Fifteen years later, Dr. Cantekin is broke, his career is in shambles,
and he is widely known in his field as a "troublemaking whistle-blower," as
he puts it. He is deep in debt to his lawyers and unable to afford a car,
let alone the house he and his wife had once chosen for themselves. When he
walks around the Pittsburgh campus, people who recognize him avert their
      "I don't have any life left in this town," Dr. Cantekin says. "I am in
the gulag."
      Dr. Cantekin might have been nothing more than a brief sideshow in the
annals of medical research, except that he is self-righteously persistent,
and more important, his cause is at the center of a $3 billion-a-year
industry: antibiotics for children's ear infections. Dr. Cantekin believes
that in 1986, a fellow researcher at Pittsburgh, Charles Bluestone,
manipulated the results of a study on children's antibiotics to benefit drug
companies whose grants and honoraria he had accepted.
      "It was a fraudulent study," says Dr. Cantekin, who was Dr.
Bluestone's co-investigator on the project. "This isn't a question of
scientific interpretation. They made certain changes to make the drugs look
      Partly as a result of this compromised research, he argues, millions
of children have been taking antibiotics unnecessarily, spawning a
population of antibiotic-resistant "superbugs" that threaten everyone.
      Dr. Bluestone, a widely respected pediatric ear specialist, believed
antibiotics were useful for the condition called otitis media with effusion,
which is an accumulation of fluid in the middle ear. Lawyers for Dr.
Bluestone and officials of the University of Pittsburgh, citing continuing
litigation, declined to comment for this article. But in legal documents,
they have repeatedly denied any impropriety in the research. At the time,
there were no university or government regulations regarding private funding
for research. Dr. Bluestone's paper on his research was peer-reviewed and
accepted for publication by the New England Journal of Medicine. Dr.
Cantekin, university officials have maintained, was making his allegations
out of "malice" because his point of view on the study had been overridden.
      In the years since the two doctors split over their research, Dr.
Cantekin's allegations against Dr. Bluestone have been weighed by three
University of Pittsburgh committees, three panels of the National Institutes
of Health, a congressional subcommittee, a federal district court and the
U.S. Court of Appeals. The government, the university and Dr. Cantekin have
spent thousands of hours and millions of dollars trying to sort out what
happened in that Pittsburgh medical laboratory in the mid-1980s. And it
isn't over yet: Dr. Cantekin has brought a whistle-blower lawsuit against
his adversaries, and a trial looms.
      Deadly Consequences
      But as the dispute has moved slowly through these tribunals, medical
science has gradually come to its own conclusions about antibiotics and ear
infections -- and they are in line with Dr. Cantekin's. Although more
antibiotics are prescribed today for children's ear infections -- and for
longer periods of time -- in the U.S. than anywhere in the world, several
recent, independently financed studies have found that for the vast majority
of ear infections, antibiotics are little more effective than no treatment
at all. Worse, physicians are now seeing in their own practices the
potentially deadly consequences of too many children taking too many
antibiotics -- drug-resistant strains of bacteria. In the past few years,
some pediatricians have begun to prescribe shorter courses of antibiotics,
or even to take a different tack entirely: so-called watchful waiting. If
the infection doesn't clear up in a few days, then antibiotics are used.
      This approach would have been anathema to the pediatricians of the
1960s and '70s, for whom antibiotics were a miracle drug. In the 1940s and
'50s, it was unusual for a child to see a doctor for a simple earache --
there was little that could be done for them, and they usually cleared up
anyway. But the consequences of untreated ear infections were well-known and
occasionally dire. Some children suffered mastoiditis, meningitis, hearing
loss and even death. Doctors and researchers suspected that antibiotics
could help prevent some of these catastrophes, but there was no scientific
      That was the issue Dr. Cantekin and his then-mentor, Dr. Bluestone,
decided to tackle in the early 1980s. The two men had met in Boston several
years earlier. Dr. Bluestone, a graduate of the University of Pittsburgh and
its medical school, was fast making a name for himself in pediatric
otolaryngology. He has written more than 300 articles on the subject, as
well as serving on government advisory boards. Dr. Cantekin, who was born
and raised in Turkey, where his father was a middle-class public servant,
had come to the U.S. to study at the Carnegie Institute of Technology in
Pittsburgh, where he received a doctorate in biomedical engineering. In
1973, he was introduced to Dr. Bluestone, who was then working at Boston
City Hospital. Dr. Bluestone hired Dr. Cantekin to help design and carry out
research on children's ear infections.
      In 1976, Dr. Bluestone invited Dr. Cantekin to come to Pittsburgh with
him to set up the new Otitis Media Research Center. A few years later, the
two men designed a large, randomized, double-blinded clinical trial -- the
gold standard of biomedical research. Over five years, they would compare
antibiotic treatment -- specifically, a generic drug called amoxicillin --
with no treatment at all on ear infections. Their research received a hefty
$17.4 million in grants from the National Institutes of Health.
      The first sign of trouble between the two investigators came in 1984,
about halfway through the trial. The Otitis Media Research Center, of which
Dr. Bluestone was the overall director, was then grappling with an
accumulated deficit of about $300,000. Dr. Bluestone wrote letters to three
pharmaceutical companies that made antibiotics for children, asking if they
were interested in having their products tested alongside amoxicillin.
      Eventually, several companies, including Eli Lilly & Co., Ross
Laboratories (now part of Abbott Laboratories) and Beecham Group (now part
of GlaxoSmithKline PLC), contributed about $3.4 million to support trials of
antibiotics for ear infections. "If we didn't have the support of non-NIH
funding, such as from pharmaceutical companies, we would not be able to
complete our clinical trials," Dr. Bluestone said later in a letter to the
NIH. In addition, between 1983 and 1988, Dr. Bluestone received $262,000 in
honoraria and travel expenses from pharmaceutical companies whose drugs he
was testing.
      After adding new sponsors, Dr. Bluestone made some changes to the
original study design. Looking at interim data, he concluded that
amoxicillin was effective, compared with a placebo, and he created new arms
of the study to compare two "boutique" antibiotics, Lilly's Ceclor and
Ross's Pediazole, to amoxicillin. The newer antibiotics can cost between $30
and $70 for a course of treatment, compared with about $6 for amoxicillin.
      Points of Disagreement
      Dr. Bluestone's changes disturbed Dr. Cantekin, who wasn't convinced
that amoxicillin had been proven superior to a placebo. The two disagreed on
several items, including the study's primary end point -- the time at which
the drug's effect is assessed. Dr. Bluestone thought it should be four
      Dr. Cantekin, arguing that ear infections often recur, decided on
eight. The data showed that after four weeks, a small percentage of children
taking antibiotics had healthier ears than those on a placebo. But at eight
weeks, the two groups had equal numbers of cures. In terms of scientific
protocol, both researchers' choices were justifiable. Indeed, a panel of
experts that reviewed Dr. Bluestone's research for the federal Office of
Scientific Integrity found "no substantial evidence indicating willful
misrepresentation or a serious deviation from commonly accepted practices."
      Dr. Cantekin, however, believed that amoxicillin's efficacy was still
open to question, and that the new arms of the study were therefore useless.
"Every new drug has been compared with amoxicillin," he says. "If the
benchmark is only as good as a placebo, the whole thing is a house of
cards." Although he himself had accepted funding from drug companies in the
past, Dr. Cantekin decided to stop. He told the chairman of his department
that he no longer wished to work on privately funded research.
      Even then, Dr. Cantekin was one of only a handful of biomedical
researchers who shunned industry funds. Since the early 1980s, connections
in biomedicine between academics and drug companies have become so pervasive
that a recent footnote to an article on antidepressants in the New England
Journal of Medicine disclosed more than 350 financial ties between the
authors of the article and pharmaceutical companies that sell
      Many members of the medical establishment say cooperation between
universities and industry is crucial, given rising research costs and the
desire to attack disease swiftly and systematically. "Not to have a
[public-private partnership] to study and bring to market new drugs would be
a terrible thing," says Steve Berman, president of the American Academy of
Pediatrics. "The industry budget far outweighs the government budget for
some kinds of research. It's absolutely essential that industry be
      But such connections may have other, less visible consequences. The
interlocking interests tend to protect the status quo by suppressing dissent
and give the false impression that there is no doubt, disagreement or error
in biomedical research. "In an environment where there seems to be a lot of
uncertainty, you may not get the level of funding you want," says Edward
Dangel of the Boston law firm of Dangel & Fine, one of Dr. Cantekin's
lawyers. "You don't want to look disorganized."
      At Pittsburgh, as at most other research universities, industry money
has helped to step up the pace and rewards of innovation. For the fiscal
year ended June 30, 1999, Pittsburgh received more than $36.3 million in
corporate grants, about 11% of overall research funding.
      While Pittsburgh was encouraging private industry to fund biomedical
research, the National Institutes of Health was also unfazed by researchers
commingling government and industry money. In the early 1980s, neither the
NIH nor most research universities had formal conflict-of-interest
guidelines. Scientists were assumed to be impervious to financial
temptations, and while disclosure of private funding was required on grant
applications, it wasn't considered relevant to a project's merit.
      "It was common knowledge that [Dr. Bluestone] was partially supported
by drug company money," said Ralph Naunton, a former official of the
National Institute on Deafness and Other Communication Disorders, in a
deposition. "We had Dr. Bluestone's verbal assurance that there was no
conflict." (Dr. Naunton has since retired and couldn't be reached for
comment.) In 1985, with their data complete, Dr. Cantekin and Dr. Bluestone
found themselves in an unusual position: Using the same statistics, Dr.
Bluestone judged antibiotics useful for ear infections, while Dr. Cantekin
declared the opposite. Dr. Cantekin tried to persuade other members of the
research team that he was right and Dr. Bluestone wrong. Dr. Cantekin "was
rigid," Dr. Bluestone told the Office of Scientific Integrity in 1989. "He
only wanted it presented his way. He did not listen to anybody else. His
co-authors had other opinions, and I felt their opinion was the best." So
Dr. Bluestone, the study's senior investigator, wrote the official paper,
and in the summer of 1986 submitted it to the New England Journal of
      Academia has conventions for scientific disagreements, but Dr.
Cantekin, whose grandfathers were revolutionaries who helped overthrow the
Ottoman empire, isn't a conventional man. Rather than writing a dissenting
letter to the editor, he took the step that would destroy his career: He
drafted a separate report of the study with his own conclusions and
submitted it to the New England Journal of Medicine. Now holding two reports
on the same study, the medical journal asked officials at Pittsburgh to
choose one paper for publication. University officials responded by saying
that only Dr. Bluestone was authorized to publish the data.
      For the next five years, Dr. Cantekin's accusations were considered --
and mostly rejected -- by several panels. All three university committees
exonerated Dr. Bluestone. One NIH inquiry found that while Dr. Bluestone
should have been more forthright about his acceptance of private-sector
funds when applying for NIH grants, his conduct was excusable. Another NIH
report, however, recommended that Dr. Bluestone be placed on five years of
administrative oversight for "having analyzed the data from NIH-funded
research in a manner biased toward the effectiveness of the antibiotics he
had evaluated with public monies."
      Meanwhile, in 1989, the NIH issued its first draft of
conflict-of-interest guidelines for researchers, which would have been
voluntary. The proposal resulted in a storm of protest from universities and
industry. Officials predicted that the requirement for scientists to divulge
their financial holdings and divest themselves of stock in companies whose
products they tested would cause "the U.S. biomedical industry to languish
in a second-rate position," as one chief executive of a biotech company
wrote to the NIH. It took six more years before the NIH produced a final
      In 1990, the congressional subcommittee on Human Resources and
Intergovernmental Relations, which was holding hearings on misconduct in
scientific research that posed public risks, excoriated both the university
and the NIH for their handling of Dr. Cantekin's claims. Most troubling, the
subcommittee reported, was that Dr. Cantekin's dissenting report had been,
for all practical purposes, censored. "Evidence of the ineffectiveness of
antibiotics would have been available to physicians and the public several
years ago, if the medical school had not prevented Dr. Cantekin from
publishing them," the panel noted.
      But not even a congressional endorsement could rescue Dr. Cantekin
from his exile in Pittsburgh, where he was still officially a member of the
faculty, though his salary remained frozen at its 1986 level. He had no
research projects, and he hasn't spoken to an official of the medical school
for 15 years. Five times since 1986, Dr. Cantekin has arrived at his office
to find a note on his door saying that his belongings had been moved
somewhere else.
      Now he doesn't even bother to unpack his few boxes of books and
papers. Nor will he turn on his office computer, which appeared mysteriously
on his desk several months ago, in case his activities are being monitored.
He brings his frustration home to his wife, a psychologist, and daughter,
who has come to hate hearing her father talk about earaches. "My potential
has been stolen from me," Dr. Cantekin says. "No one's going to hire me
unless there's a revolution in the medical profession."
      In April 1991, five years after the war had begun, two big events in
the long-running dispute coincided. One was the publication by Dr.
Bluestone's research team of another paper based on data collected during
the clinical trials of 1981 to 1985. Again the team concluded that children
with ear infections -- in this case, acute otitis media, or painful and
inflamed ears -- "should routinely be treated with amoxicillin (or an
equivalent antimicrobial drug)." A close reading of the data showed that
children who hadn't received medication had a cure rate of 92.5%, compared
with 96% of those who were treated.
      Published in the journal of the American Academy of Pediatrics, the
study became one piece of evidence for a federal panel then drawing up
recommendations for the treatment of otitis media. The panel's Clinical
Practice Guideline for parents stated that antibiotics "may increase chance
(by about 14%) and speed of middle ear fluid going away." The panel cited
the Bluestone group's study in six of eight footnotes to a chart
illustrating the efficacy of antibiotic treatment. "If a government agency
advises you that antibiotics are good for children's ear infections, you
don't think, 'Drug companies are behind that.' But in this case, they were,"
says Danielle Brian, executive director of the Project on Government
Oversight in Washington, D.C.
      The second big event of April 1991 was that Dr. Cantekin filed a
lawsuit against Dr. Bluestone and Pittsburgh in U.S. District Court in
      Until then, Dr. Cantekin had avoided the legal system or any
consideration of a financial settlement with the university. "The first
thing Pittsburgh did when they found out [Dr. Cantekin] had retained me was
to dispatch a lawyer to my office with a checkbook," says Robert Potter, a
partner in the Pittsburgh law firm of Strassburger, McKenna, Gutnick &
Potter in Pittsburgh.
      "The lawyer closed the door and asked, 'What does he want?' But for
[Dr. Cantekin], it wasn't a question of money. You couldn't settle with him
because you couldn't settle the scientific issue."
      As his cause began to fade from public view, and antibiotic
prescriptions continued to rise, Dr. Cantekin invoked the federal False
Claims Act, which allows an individual to sue on the government's behalf for
damages caused by another person's false claims. Enacted in 1863, the law
has been used almost exclusively against defense contractors. But recently,
it has also become an appeals court for academicians alleging scientific
fraud against universities and scientists. If the whistle-blower's case is
proved, he or she may collect as much as three times the amount of research
grants that involved fraudulent claims. In his suit, Dr. Cantekin charged
that Dr. Bluestone had fraudulently not disclosed his private financing in
grant applications to the NIH. If the NIH had known of this drug company
money, Dr. Cantekin asserted, Dr. Bluestone wouldn't have received his
federal funding.
      Dr. Bluestone and the university won the first legal round in 1998,
when the district court issued a summary judgment in their favor. The judge,
Donald E. Ziegler, noted that in June 1987, Dr. Bluestone had sent a letter
to the NIH disclosing his private funding -- "a cost-sharing arrangement was
implemented," Dr. Bluestone had written, adding, "but it was not explained
fully." That letter nullified the claim that Dr. Bluestone hadn't told the
government about his private funding, the court said. Even if Dr. Bluestone
had notified the NIH on his grant applications, as he was supposed to do,
there was no evidence that his NIH funding would have been jeopardized, the
judge decided.
      Dr. Cantekin appealed to the United States Court of Appeals for the
Third Circuit, and in September 1999, he won his first major victory in the
long war. "One can easily infer," the appeals court said, that Dr.
Bluestone's letter, which was sent after Dr. Cantekin had lodged his
complaint to the NIH, "was not an expression of an honest oversight, but an
attempt to cover up prior misconduct and limit its damage."
      'Material and Negative'
      Furthermore, two of the five members of the NIH panel that had
approved Dr. Bluestone's grants said in affidavits that they hadn't known
about his private funding. That information would have had a "material and
negative" impact on their funding decisions, both said. Finally, the
appellate court found it unlikely that Dr. Bluestone may simply have misread
the instructions on the application, which asked for a list of "all research
support." The court noted that for a scientist, the best of both worlds is
to enjoy the munificence of private industry and a government imprimatur on
their studies.
      "In investigating treatments that have a disputed efficacy and a high
aggregate cost," the court said, "[Dr.] Bluestone can be reasonably expected
to know of the government's heightened interest in avoiding bias." The
appellate sent the suit back to the district court for trial, which hasn't
been scheduled yet.
      Conflicts of interest remain a contentious issue in biomedical
research, particularly after the 1999 death of a young man undergoing gene
therapy at an academic center whose director had a financial stake in the
outcome of the procedure. But no one suggests that private industry,
academia and the government should, or even could, disentangle themselves.
As the saying goes, the only people without conflicts of interest are those
who know nothing at all about the subject.
      Erdem Cantekin wouldn't agree. But 15 years after having blown the
whistle on what he believed was biased medical research, he has the
whistle-blower's greatest regret. "If I had known the consequences would be
so abrupt and severe," he says, "I wouldn't have done it."