drug studies

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June 3, 2004

Two Studies, Two Results, and a Debate Over a Drug

By BARRY MEIER

he two drug trials were known within Kline 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. 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companies for unpublished data from antidepressant trials.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 GlaxoKline. Mr. Spitzer's suit accuses the company

of consumer fraud for not disclosing all of its Paxil data.

Officials of GlaxoKline 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, GlaxoKline 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, 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 Kline Beecham, and officials of

GlaxoKline 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. 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. 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

, 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 Kline officials told him in 1998 that they did not intend

to submit the study for publication. An internal 1998 Kline

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 Kline 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 GlaxoKline

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 Kline 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. "

the new york times