What You Don't Know About a Drug Can Hurt You
- From: Jim Higgins <gordian238@xxxxxxxxxxx>
- Date: Fri, 12 Dec 2008 18:43:32 -0800 (PST)
What You Don't Know About a Drug Can Hurt You
http://online.wsj.com/article/SB122903390105599607.html
Untold Numbers of Clinical-Trial Results Go Unpublished; Those That
Are Made Public Can't Always Be Believed
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By ROBERT LEE HOTZ
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There's a common assumption that when a drug makes it to market, it
has run a rigorous gantlet of testing and proper disclosure. Testing,
yes. Disclosure -- not necessarily.
Findings from many clinical studies assessing prescription drugs never
see light of day. That skews the basic scientific record that every
patient, physician and researcher needs to judge whether treatments
cause more harm than good. There is no easy way to discover how much
knowledge we've been missing, raising the possibility that we may be
taking medications that are less effective than we've been led to
believe or may have undisclosed side effects.
Forum
Discuss: Do you trust prescription drugs? Do you think pharmaceutical
research is over-regulated or under-regulated?
"There is data that you are not seeing," says Deborah Zarin, director
of the National Library of Medicine's online clinical trials registry.
"There is a huge problem here if an unknown amount of the information
is censored and you don't even know it is censored."
All told, about $58 billion in privately funded drug research is
currently underway -- twice the basic federal medical research budget
-- encompassing an estimated 50,000 clinical trials among 2.3 million
patients. Even under the best of circumstances, though, the sheer
volume of clinical testing has overwhelmed medicine's ability to
independently assess these commercial trials and make all their
results public, medical research analysts have concluded.
For a decade or more, researchers, federal regulators, pharmaceutical
companies and medical journal editors have sought a balance between
commercial secrecy, scientific openness and the public health.
Incomplete test results can lull doctors into believing that drugs
they prescribe are better than a placebo, and mislead scientists
conducting follow-up studies.
Since 2004, prescription drug scandals over deceptive marketing,
unreported side effects and hidden payments to medical researchers
have highlighted the gap between the number of clinical trials
conducted and the number published. That has prompted reforms in how
commercial medical data is handled. The Pharmaceutical Research and
Manufacturers Association of America, for example, created an online
data base that summarizes clinical study results involving hundreds of
prescription medicines.
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What You Don't Know About a Drug Can Hurt You
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Findings from many clinical studies assessing prescription drugs never
see light of day.
What You Don't Know About a Drug Can Hurt You
What You Don't Know About a Drug Can Hurt You
By law, comprehensive clinical data must be filed at the U.S. Food and
Drug Administration, to make the case for market approval of a new
drug and form the basis for safety information that accompanies every
prescription. All the critical information that a doctor or patient
needs is summarized on the FDA-approved drug label, says Ken Johnson,
senior vice president of the pharmaceutical research trade
association, "including important drug safety information that may not
be included in a published paper." Such information is updated
regularly as new findings become available, industry experts say. "It
is important for people to know that the FDA sees all of the data,"
says Jeffrey Francer, the trade association's assistant general
counsel.
After years of congressional debate, however, the FDA now has imposed
more stringent reporting requirements to ensure the complete
scientific record of clinical drug experiments is readily available.
Under a new federal law, researchers for the first time will have to
post their basic results publicly on the federal online registry
maintained by the National Library of Medicine.
Since it was established nine years ago as a voluntary patient guide,
the federal registry at www.ClinicalTrials.gov has logged 65,000
studies. Prodded by medical journal editors and settlements in five
major lawsuits, researchers have gone from registering 25 new studies
a week to about 350 every week. Until this past September, though,
researchers only had to report the start of a clinical trial. They had
no federal obligation to report the outcome in the registry or in a
peer-reviewed journal.
Several recent surveys of the medical literature offer a glimpse of
how much data about drugs already on the market never made it into the
published record.
Last month, analysts led by health research expert Lisa Bero at the
University of California in San Francisco checked 164 clinical trials
testing 33 different drugs submitted for FDA approval from 2001 to
2002 and found that one in four had yet to be published. Almost all of
the unpublished findings made the drug in question look bad.
Recommended Reading
Under a new federal law, researchers conducting clinical trials must
post their findings publicly at an online federal clinical trials
registry maintained by the National Library of Medicine. The
Pharmaceutical Research and Manufacturers Association of America also
maintains summaries of clinical study results in an online data base.
Normally, clinical trials involving safety and effectiveness of new
drugs are reported to the U.S. Food and Drug Administration but are
not always published in peer-reviewed medical literature, University
of California at San Francisco medical analysts reported in "Reporting
Bias in Drug Trials Submitted to the Food and Drug Administration:
Review of Publication and Presentation," published in the journal PLoS
Medicine. Medical informatics experts at UCSF found that more than
half of all supporting trials for FDA-approved drugs remained
unpublished in "Publication of Clinical Trials Supporting Successful
New Drug Applications: A Literature Analysis," in PLoS Medicine.
Writing in The Oncologist, researchers reported that many clinical
trials of cancer chemotherapy drugs are not published, in "Practicing
on the Tip of an Information Iceberg? Evidence of Underpublication of
Registered Clinical Trials in Oncology."
In Drugs: From Discovery to Approval, author Rick Ng offers a step-by-
step introduction to all the key processes involved in bringing a drug
to the market, including the performance of pre-clinical studies, the
conduct of human clinical trials, and regulatory controls.
In The Truth About the Drug Companies: How They Deceive Us and What to
Do About It, former New England Journal of Medicine Editor Marcia
Angell explains how much of the revenue generated by "Big Pharma" goes
into aggressive marketing campaigns.
In Understanding Pharma: The First, Practical Guide on How
Pharmaceutical and Biotech Companies Really Work, John Campbell covers
pharmaceutical research and discovery, clinical development,
marketing, sales, and business development.
In September, medical informatics expert Ida Sim at UCSF and her
colleagues reviewed 900 FDA filings involving 90 new drugs and
reported that more than half of the clinical trials were still
unpublished 5 years after the drugs had been approved.
Only one in five cancer clinical trials ever is disclosed in a medical
journal, doctors at the University of Washington reported in the
journal Oncology earlier this year.
"What's happening in oncology is happening in all other fields of
medicine," says study co-author health economist Scott Ramsey at the
Fred Hutchinson Cancer Research Center in Seattle, who checked more
than 2,000 chemotherapy trials recorded in the federal registry. "You
may not get a full picture of whether a drug is effective or not. With
the stakes being what they are in terms of money and human lives, this
is a big problem in my view."
Moreover, when clinical data is published in one of 5,200 peer-
reviewed biomedical journals, the information on health risks and
benefits may be biased by spin and selective reporting, medical
analysts said.
For example, researchers who reviewed the FDA's regulatory paperwork
for dozens of recently approved drugs found that in some clinical
trials submitted for publication, conclusions had been changed,
statistics revised, and outcomes altered to make treatments look more
effective. Among 43 outcomes reported in the FDA filings that did not
favor a drug, 20 were never published. In four out of five instances
in which the statistical significance of findings was changed from the
FDA filing, the published version was more favorable.
"We saw a lot of changes," Dr. Bero says. "All the changes that
occurred made the drug look more favorable."
That reflected a broader pattern of medical research documented by Dr.
Bero and other analysts. A study showcasing the promise of a new drug
was more likely to be submitted for publication than one reporting
negative findings. "It was not that journals are suppressing the
information," Dr. Bero says. "People were not submitting the data."
Earlier this fall, researchers at the State University of New York
reviewed 1,835 clinical research articles from four leading
otolaryngology journals and reported that a third of them failed to
mention any side effects at all. In half of those studies that did
mention harmful effects, researchers failed to describe them.
"The evidence from clinical trials conducted by the companies that
produce the drugs is really the only source of evidence for whether a
drug works or not," Dr. Sim says. "The public deserves a fair
representation of the evidence for and against expensive new drugs."
No one knows why so much test data was suppressed, overlooked or
discarded. In the competitive hustle of academia and commerce, the
public interest can just take second place to other considerations.
"Journals want to sell journals; companies want to increase profits;
and researchers would like to advance their careers," says Dr. An-Wen
Chan, a medical policy analyst at the Mayo Clinic in Rochester. "They
can conflict. Sometimes, decisions are not made in the best interest
of the patients."
As of September, failure to report basic data about clinical test
results on the federal public registry in a timely way can open
researchers to fines of $10,000 a day and loss of their federal
research funding. Scientists now are reporting their findings at a
rate expected soon to reach 200 new studies every week. "From our
perspective, it is very hard to argue now that there is not
transparency," says the pharmaceutical association's Mr. Francer.
Even so, the new registry regulation only covers new tests. Registry
reports of serious side effects won't be required until next year. The
findings also won't be formally verified.
It will be at least another two years before all the new mandatory
reporting requirements are in place and it may be a decade before
anyone will know whether so much data disclosure actually improves
patient well-being and the quality of care.
"The companies are still fighting every step of the way," Dr. Zarin
says. "But they have realized there is a public relations advantage in
appearing more transparent."
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