E-DRUG: GSK sued over supression of CT results
----------------------------------------------
[An article from today's NY Times, about the State of NY's suit against GSK,
over the latter's suppression of clinical studies which showed one of its
anti-depressants was either ineffective or harmful to children and
adolescents. Also, an important reminder about publication bias, and the
need to get effective Clinical Trial registries working!
Thanks to Sean for spotting this. Copied as fair use. WB]
June 3, 2004
Two Studies, Two Results, and a Debate Over a Drug
By BARRY MEIER
The two drug trials were known
within SmithKline Beecham as Study 329 and Study 377.
Study 329 suggested that the company's popular drug Paxil might help
depressed adolescents. Study 377, completed not long afterward, indicated
that Paxil provided no more benefit than a sugar pill in treating
depressed young people.
But only the favorable study was widely publicized by Paxil's maker. The
company chose not to discuss publicly the trial with negative results, and
those findings came to light only when an outside researcher on the study
team decided to disclose them at a medical conference.
"That particular study would have been buried," said that researcher, Dr.
Robert Milin of the Royal Ottawa Hospital in Canada. "It would have been
buried to the public."
Federal regulators in this country are now scrambling to reassess the
effectiveness and safety of antidepressants like Paxil, after British
regulators touched off a controversy last year by asking drug companies
for unpublished data from antidepressant trials. That data suggested that
several antidepressants, including Paxil, might give rise to suicidal
thoughts in some young users - a potential problem not revealed in any
published studies.
Yesterday, the New York State attorney general, Eliot Spitzer, entered the
fray by taking the unusual step of suing Paxil's maker, which is now
GlaxoSmithKline. Mr. Spitzer's suit accuses the company of consumer fraud
for not disclosing all of its Paxil data.
Officials of GlaxoSmithKline defend their record, saying they provided all
the results of their Paxil clinical trials to the Food and Drug
Administration, as required by law. But the stories of Study 329 and Study
377 provide a window into a far broader issue - the fact that the results
of many human clinical trials of drugs are often never widely publicized
and that, in some cases, doctors may never learn that the trials were even
conducted.
These days, most drug trials are sponsored by pharmaceutical companies.
And for more than a decade, a growing number of medical experts have been
urging drug makers to release more trial data and to create uniform means
of disclosing results through central registries, so that policy makers
and doctors can easily learn the results. Those advocates argue that such
central databases are necessary because drug companies, as well as medical
journals and researchers, tend to spotlight only trials that show positive
results.
Last week, GlaxoSmithKline agreed to make two executives available for
this article to discuss its handling of Studies 329 and 377 and how
information about them was disseminated. But yesterday, a company
spokeswoman, Mary Anne Rhyne, said that in light of Mr. Spitzer's lawsuit
the company had decided not to allow those interviews.
Under F.D.A. rules, a company seeking approval of a new drug must submit
the results of all the clinical trials it runs. But the agency holds that
information in confidence - on the ground that it is proprietary - until
the drug is approved for sale. At that point, summaries and descriptions
of those trials, but not the complete underlying data, are publicly
released.
Somewhat different rules apply to so-called postmarketing tests in which
approved drugs are investigated for new purposes - like prescribing
antidepressants for pediatric use. Safety information from such trials is
supposed to be promptly reported to the F.D.A. But postmarketing data
involving the drug's effectiveness need not be reported until the maker
seeks agency approval for a new claim or use, a process that could take
years.
"We fully understand the desire for access to information and we firmly
believe that consumers should be as well informed as possible," said an
F.D.A. official, who insisted on anonymity. "However, such a listing would
not add the information F.D.A. already receives under current
regulations." For their part, drug industry officials say that it is the
editors of medical journals, not corporate executives, who decide which
trial reports to publish. With a few exceptions, drug makers have resisted
the idea of establishing trial registries. And the industry's trade group,
the Pharmaceutical Research and Manufacturers of America, has never called
for such an initiative. But Dr. Alan Goldhammer, the group's associate
vice president for regulatory affairs, said the group might revisit the
issue in light of the antidepressant controversy.
Currently, a few trial registries exist, like the National Institutes of
Health's database of current trials of drugs for life-threatening
diseases. And in two weeks, policy makers at the American Medical
Association are expected to vote on a proposal that would urge the
government to create a public registry of clinical drug trials. Only a few
companies have responded to the calls by some researchers for public
registries. In 1996, the British unit of Schering, the German drug maker,
agreed to create such a listing. The British company Glaxo Wellcome
decided in 1998 to take a similar step. Two years later the company merged
with SmithKline Beecham, and officials of GlaxoSmithKline said in a brief
statement yesterday that they were now working on an improved version of
the registry.
The drive to create databases of clinical trial results soon sputtered for
lack of industry support, according to people involved in the effort. But
even industry critics acknowledge that drug makers are not the only
roadblocks to the wider dissemination of trial results. Journals also
favor research reports that show strong findings, and researchers say they
have little incentive to push for the publication of a trial without a
conclusive finding.
Those who call for trial registries, however, argue that it is unethical
not to disseminate trial results widely. The participating patients, they
say, typically believe that the findings, whatever the outcome, will
benefit medicine. "We are telling people that they are participating in
research," said Dr. Kevin A. Schulman, a professor of medicine and
business administration at Duke University. "But most of the time what
they are participating in is proprietary marketing research by companies
who have total discretion over whether to publish the results."
It is unclear how, or even if, a database of trial results would change
the practice of medicine. Some researchers say they can often retrieve
unpublished data by asking companies for it or by ferreting out abstracts
of unpublicized findings presented at meetings.
Still, they point out that without a comprehensive trial registry they
cannot tell what they may be missing. Just as important, some experts say,
a system of disclosing trial results would help prevent the type of chaos
now surrounding the use of pediatric antidepressants because the debate
over a drug's efficacy and safety might have already taken place.
The fates of Study 329 and Study 377 appear to underscore that point. Both
tests were conducted during the mid-1990's at various hospitals and
medical centers - Study 329 at facilities in the United States and Study
377 at test centers outside of this country, including Canada, Mexico,
Europe, South Africa and the United Arab Emirates.
Study 329, with its potentially positive findings for Paxil, was completed
first. Its results were presented beginning in 1998 at several meetings of
medical professionals. Meanwhile, a report of the trial, which was led by
Dr. Martin B. Keller, a department chairman at Brown University Medical
School, was submitted to a medical journal for publication, a process that
subjects a study to peer review by scientists not involved in the trial.
Dr. Keller declined to be interviewed for this article. But Dr. Neil Ryan,
a professor at the University of Pittsburgh, who was also involved, said
he believed that the study was rejected by some journals before The
Journal of the Academy of Child and Adolescent Psychiatry accepted it for
publication in 2001.
In the case of Study 377, the one with negative findings, there were no
press releases or publications. And without the action of Dr. Milin and a
Canadian colleague, Dr. Jovan Simeon, the study's findings might have been
seen only by regulators and a few researchers.
Dr. Milin was an unlikely rabble-rouser. In an interview, he said he was a
strong believer in the use of antidepressants like Paxil in adolescents.
He wanted to report the study's findings, he said, mainly because its
negative results might have reflected trial design flaws that he did not
want to see repeated in other studies. "I feel you need to present all the
data even if it is negative," he said.
While drug trials in adults take place at a few sites, Dr. Milin and other
researchers said that one problem with the pediatric antidepressant tests
was that they were dispersed across a dozen or more clinical centers
because each unit often had only a few young patients who qualified. Dr.
Milin said he was spurred to take action after SmithKline officials told
him in 1998 that they did not intend to submit the study for publication.
An internal 1998 SmithKline memorandum, disclosed this year during the
antidepressant controversy, also said the company had "no plans to publish
data from Study 377."
Dr. Milin said that when he told SmithKline executives that he planned to
present the study's finding at a 1999 meeting of the American Academy of
Child and Adolescent Psychiatry, the company did not object. Dr. Milin
said he last heard from GlaxoSmithKline officials about six months ago,
after the controversy erupted over unpublished data from trials like Study
377. Company officials, he said, wanted to make sure that the copy of the
report they had in their file was the same one he had presented five years
earlier.
As for Study 377, Dr. Milin said he assumed that SmithKline officials
would have publicized the trial, any design problems notwithstanding, had
its results been different.
"If they had got a positive outcome," he said, "I would suspect that they
would have pushed to get it published."
--
To send a message to E-Drug, write to: e-drug@healthnet.org
To subscribe or unsubscribe, write to: majordomo@healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: e-drug-help@healthnet.org
Information and archives: http://www.essentialdrugs.org/edrug