{If researchers can't obtain all relevant data from FDA then all
scientific/medical conclusions are illusion.}

"The FDA gave a legal rationale for its silence: Some clinical trial
data are considered "trade secrets," or commercially protected
information, and thus are exempted from release under the Freedom of
Information Act. Since the FDA doesn't routinely perform comprehensive
reviews of drugs once they are on the market, when uncommon but deadly
side effects tend to be picked up, independent researchers are often
the only hope of catching such flaws. But the trade-secrets rule can
leave researchers in the dark about the most worrisome data-negative
results that support a failed application to market a drug."

Drug Secrets
What the FDA isn't telling.
By Jeanne Lenzer
Posted Tuesday, Sept. 27, 2005, at 3:38 AM PT

Traci Johnson's body was discovered on Feb. 7, 2004, hanging by a scarf
from a shower rod in an Indianapolis laboratory run by the drug company
Eli Lilly. The 19-year-old college student had been serving as a test
subject in a clinical trial of the experimental antidepressant
duloxetine. Investigators from the Food and Drug Administration rushed
to Indianapolis to determine whether the experimental drug was related
to her death. The probe was inconclusive.

This left researchers in a quandary: Was the drug safe or not? Could
duloxetine trigger suicide, as some experts suggested? Or was Johnson's
death an "isolated tragedy," as Eli Lilly claimed? When drug
manufacturers fail to publish negative study results, as studies show
is often the case, the best source of information about these questions
is the FDA. The agency-which was rocked last week by the sudden
resignation of Commissioner Lester Crawford-requires companies
seeking approval for a drug to provide data from randomized controlled
trials, studies in which some patients are given the drug and others
are given a placebo. But when researchers and the press started asking
about duloxetine, the FDA didn't scour its database and go public. It
kept quiet.

The FDA gave a legal rationale for its silence: Some clinical trial
data are considered "trade secrets," or commercially protected
information, and thus are exempted from release under the Freedom of
Information Act. Since the FDA doesn't routinely perform comprehensive
reviews of drugs once they are on the market, when uncommon but deadly
side effects tend to be picked up, independent researchers are often
the only hope of catching such flaws. But the trade-secrets rule can
leave researchers in the dark about the most worrisome data-negative
results that support a failed application to market a drug.

The argument for secrecy is that failed efforts at drug development
need protection lest entrepreneurs suffer a competitive disadvantage
when other companies aren't forced to expend the same time and money
exploring dead ends. And at first blush, there would appear to be
little need for clinical data on a drug that isn't in use. The problem
is that many drugs have multiple uses. Duloxetine, for example, is
marketed under the brand name Cymbalta to treat depression. Traci
Johnson committed suicide while taking duloxetine during tests for
selling the drug to treat stress urinary incontence, under the brand
name Yentreve. If a drug is on the market for one use and studies about
another use suggest disquieting risks-as the death of Traci Johnson
may-do the benefits of keeping the study data secret outweigh the
costs?

The FDA approved Cymbalta to treat depression in August 2004. By the
end of that year, Cymbalta sales topped $61.3 million. At some
point-the date is undisclosed-Eli Lilly began testing Yentreve. In
January 2005, as Cymbalta sales climbed to $106.8 million for the first
quarter, Lilly announced that it was withdrawing its application for
Yentreve. Then it cited the trade-secret rule in refusing to disclose
why the drug did not win approval. Perhaps the rationale was
harmless-the drug didn't work for incontinence. But duloxetine has
been approved as a treatment for incontinence in Europe since August
2004.

Over four months beginning in January, I filed several Freedom of
Information Act requests on behalf of the Independent on Sunday, a
British newspaper, for all safety data related to Cymbalta and
Yentreve. I received a database that included 41 deaths and 13 suicides
among patients taking Cymbalta. Missing from the database was any
record of Johnson, or at least four other volunteers known to have
committed suicide while taking Cymbalta for depression.

When I asked the about the missing results, FDA officials cited a
federal regulation that they said prohibited the agency from releasing
study data-or acknowledging the existence of an application-for a
drug that fails to win FDA approval. Since the FDA never approved
Yentreve, all the data about it were off limits. The agency may have
used a similar rationale in failing to release safety data about the
pain reliever Bextra, which Pfizer, its manufacturer, withdrew from the
market in April for fear of links to an increased rate of heart attack.

In its Web-site database, Eli Lilly initially listed no suicides and
two deaths among patients enrolled in seven clinical trials of Cymbalta
for depression. (Lilly's database won the company praise in a May New
York Times article for being "the company that has gone furthest in
disclosing results.") Today the Web site lists 10 clinical trials of
Cymbalta and five of Yentreve, with one suicide and five deaths
combined. Based on the dates of the trials and the circumstances of the
deaths, it's clear that the Web-site numbers do not include any of the
five suicides missing from the FDA database. Lilly admits that it has
never made public at least two of those deaths. Lilly spokesman David
Shaffer said that data was unavailable because some of the studies were
still in progress. He also said that two of the suicides "took place in
depression studies run by another company," and that "the decision
about how and when to disclose such information rests with that
company." Shaffer was referring to the Japanese firm Shionogi & Co.,
which partners with Lilly to market duloxetine in Japan.

Meanwhile, my sources (sorry, they're gun-shy and anonymous) were
telling me that duloxetine caused suicidal tendencies in patients who
took the drug for incontinence-and who were not depressed. That news
was potentially explosive. In the face of questions about a link
between antidepressants and suicide, industry experts have long
insisted that it's depression, not the drugs used to treat it, that
causes patients to kill themselves. Johnson's death appeared to call
that claim into question. She entered the clinical trial as a healthy,
nondepressed volunteer in order to help pay her college tuition. And
she was only approved for the study after undergoing thorough medical
testing to screen out depression or suicidal tendencies.

Because one patient's reaction can't prove anything one way or the
other, it was critical for researchers to analyze the results of all
the patients in Lilly's duloxetine studies. Instead, the FDA's
interpretation of the trade-secrets rule left only the positive data
from the Cymbalta trials available for review.

In June, after the Independent article, the FDA (without issuing a
press release) noted on its Web site that one suicide "was reported in
a Cymbalta clinical pharmacology study in a healthy female volunteer."
The agency added that new data from stress urinary incontinence trials
showed that middle-aged women taking duloxetine had a suicide attempt
rate of 400 per 100,000 person-years, more than double the rate of
about 160 per 100,000 person-years among other women of a similar age.
These findings had been withheld from the public, and the researchers
asking for them, for five months after the FDA had reviewed data
showing the increased risk.

The FDA claims it has no choice but to resist releasing information
about drugs it doesn't approve. "My hands are tied," said Dr. Robert
Temple, FDA's director of medical policy. "This is something only
Congress can change." That may be as much a matter of the FDA's
interpretation as it is of the law, however. Experts disagree about
whether congressional action or a federal court ruling is needed to
make data like Johnson's death available, or whether the FDA could
choose to disclose more itself.

The voluntary guidelines promoted by the drug industry, however, are
not a solution. These guidelines encourage companies to list every
clinical trial they initiate. Registration would be helpful. But it
would not compel companies to release the data from, or even the
outcomes of, their trials, as long as they companies can argue that
this information is "commercially protected."

The use of trade-secret laws to conceal deaths and serious side effects
linked to drugs has the obvious flaw of putting profits before public
health. It also subverts the covenant between researchers and study
volunteers. Subjects like Traci Johnson are told that even if they do
not personally benefit from a new drug, the scientific knowledge gained
from the study in which they've participated will benefit others. The
volunteers should be told instead that scientists will learn about
their experience only if it's good news for the drug they're helping to
test.

sidebar

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Stress urinary incontinence is a condition in which women leak urine
with they laugh or sneeze.

sidebar

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In the wake of revelations that the COX-2 inhibitor Vioxx caused a
dramatic increase in heart attacks, doctors began switching patients to
the pain reliever Bextra, believing it was safer. Bextra sales rose 57
percent after Vioxx was withdrawn from the market in September 2004.
Dr. Peter Jüni, a senior research fellow in clinical epidemiology at
the University of Berne, filed a FOIA request with the FDA for its
safety data on Bextra. The FDA released a clinical trial report so
heavily censored that it looks like a top-secret document. The stamp on
the report reads: "28 page(s) are redacted because it [sic] contains
trade secret and/or confidential information that is not disclosable."

Acting on a tip, Dr. Curt Furberg, an FDA advisory panelist, obtained
unpublished safety data on Bextra from its manufacturer, Pfizer. His
analysis showed that Bextra was no safer than Vioxx. After Furberg told
the New York Times last November that Bextra was unsafe, the FDA
removed him from its advisory panel. Furberg's study was published in
the journal Circulation. In February 2005 the FDA asked Pfizer to
withdraw Bextra from the market. Pfizer did so in April.

Total known    FDA database    Lilly clinical trials Web site

Deaths 46         41                 5

Suicides 16       11                 1

"(Lilly's database won the company praise in a May New York Times
article for being "the company that has gone furthest in disclosing
results."

Jeanne Lenzer is a freelancer whose work appears regularly in the
medical journal BMJ. Her e-mail address is jeanne.lenzer@gmail.com.
Article URL: http://www.slate.com/id/2126918/

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