A prescription for full disclosure: The results of clinical trials of many drugs are going unreported or unnoticed, which flies in the fact of science and may even harm patients

Irving News Comments
Reproduced with Permission

[Note: #1 -- Why isn't the very same demand for scientific integrity and the very same anger over the use of false scientific data made for researchers and drug companies involved in human embryology and human genetic engineering research -- both basic and clinical?

#2 -- For over 15 years bench researchers have confided to me the deep stress they are under from various pharmaceutical companies whose drugs they are simultaneously testing; the drug companies pressure these researchers to falsify their data to make their own company's drugs fare better in research protocols. If the researchers don't comply, they loose their grants.

#3 -- In both cases above, sooner or later this false data is applied to "wanted" children, to pregnant and older mothers, and to the population in general. The issue is scientific integrity per se, not selectively which scientific field it is or is not OK to falsify. (See Irving, "The impact of scientific 'misinformation' on other fields: Philosophy, theology, biomedical ethics and public policy", Accountability in Research April 1993, 2(4):243-272, at: http://www.all.org/abac/dni009.htm. -- DNI]

Promoting openness and full disclosure http://www.ahrp.org


The systemic problems undermining the scientific integrity of clinical trial reports, is now being acknowledged by Dummond Rennie, deputy editor at the Journal of the American Medical Association:

"Only a legally binding obligation to disclose all trials will force all critical medical and drug data out into the open, and keep it that way even when the heat is off."

Given the harmful, but preventable consequences caused by physicians who prescribe drugs without fully knowing the potential hazards--because drug manufacturers and the FDA have kept such vital information from physicians--it is no longer tolerable to give drug companies an option to disclose or withhold data!

The medical scientific community has failed to self-regulate. Those who conduct clinical trials have become subservient to the drug companies that pay them. The scientific community and drug manufacturers must be held legally responsible. They must disclose the entire clinical trial data set--not just selectively report positive findings.

Congress needs to act to stop the flow of misinformation about prescription drugs--concealment of data results in preventable injury and death.

Contact: Vera Hassner Sharav
Tel: 212-595-8974
e-mail: veracare@ahrp.org

Philadelphia Inquirer
Posted on Sun, Aug. 15, 2004

A prescription for full disclosure: The results of clinical trials of many drugs are going unreported or unnoticed, which flies in the fact of science and may even harm patients.

By Faye Flam

(emphasis added)

In criminal proceedings in the United States, the prosecution is legally required to provide the defense with any information that might be beneficial to the defendant - even if it may hurt the prosecution's case. Scientists are bound to a similar type of disclosure through an unwritten code of ethics. It's part of what separates real science from pseudo-science or folk wisdom.

Real science requires "a kind of utter honesty," the late physicist Richard Feynman said in a 1974 address titled "Cargo Cult Science." "The idea is to try to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgment in one particular direction or another."

Society expects the research backing the drugs we take and the medical procedures we undergo to abide by such high scientific standards and ethics.

But a number of critics say that, in the world of medical research, important results are going unnoticed or unpublished - especially results of clinical trials where drugs don't perform as hoped or expected.

Two cases have brought the issue to light recently. First, New York Attorney General Eliot Spitzer filed a civil suit against giant GlaxoSmithKline for failing to adequately publicize studies indicating that the antidepressant Paxil may lead to severe emotional problems and possibly suicide when given to children. Then the New York Times and other publications exposed a clinical trial that was never published, showing that a similar drug, called Celexa, worked no better than a placebo for relieving depression in adolescents, while a much-publicized trial reached the opposite conclusion.

These are not isolated cases, said Kay Dickerson, a professor at Brown University's Center for Clinical Trials and Evidence-Based Healthcare. Over the years, she has collected data that she says illustrate a systematic bias in the medical literature. Studies showing that drugs work are three times as likely to be published as those showing they don't work or do more harm than good, she said.

That doesn't mean there's no safety net out there to protect society from bad drugs. The Food and Drug Administration still won't approve a new prescription drug until the manufacturers demonstrate its safety and efficacy in specified applications in a regimented series of experimental trials. But in recent years, the rules have been relaxed and the number of required trials decreased in an attempt to speed drug approvals. "I wish consumers knew about this," Dickerson said.

And once a drug is approved, the law doesn't stop doctors from prescribing it for other "off-label" uses or, in the case of antidepressants, for children and teenagers when the drugs were approved for adults. Yet negative results of trials related to those additional uses of a drug may not have been available to prescribing doctors or follow-up researchers because they were never published. The result is that decisions are made based on incomplete information.

In many cases, it's not that the journals refuse to publish negative results, Dickerson said, but that researchers never write them up or send them to the journals.

Sometimes, when researchers try to publish their results, the companies that sponsor them try to intervene. That happened in 2000 when Immune Response Corp. sued James Kahn, a University of California San Francisco AIDS researcher, for defamation after Khan and a colleague published results showing that the company's experimental AIDS treatment did not help stave off AIDS symptoms or bolster the immune systems of the subjects. The company argued that Kahn's team failed to highlight some positive effects seen in a few of the research subjects. The lawsuit was later dropped.

Private companies have a tradition of keeping trade secrets, and for drug companies, some secrecy may be essential to compete in the marketplace. But critics say secrecy is inappropriate when drugs are being tested in human volunteers or the information withheld could have helped patients or doctors make better decisions.

Brown's Dickerson decided to trace all the drug trials conducted at Johns Hopkins University as well as those conducted by the National Institutes of Health. Many of the ones that reflected badly on some new drug or treatment were left unpublished, she said, though the science was sound.

That bias can become amplified when researchers comb through the published literature and combine known studies in a so-called meta-analysis. These collections of studies often try to reexamine the risks and benefits of common health measures - whether hormone replacement or cholesterol drugs or vitamin pills.

"If you only publish good news, the whole system breaks down," said Drummond Rennie, a deputy editor at the Journal of the American Medical Association. "I've been fighting for this for decades." He attributed the shortage of negative results to researchers either bowing to pressure from the drug companies that fund them or trying too hard to please their sponsors.

That can lead to such situations as that recently seen with hormone-replacement therapy, Dickerson said. It was approved for hot flashes and other symptoms but was being prescribed for thousands of women under the assumption that it prevented heart disease and other chronic illnesses.

In the mid 1990s a group of European researchers did a meta-analysis that included unpublished work and found that, for many women, hormone replacement's risks may outweigh its potential benefits. Several years later a large clinical trial came to the same conclusion.

Why would different trials of the same drug give different results? Don't drugs either work or not?

It used to be that drugs that worked had a clear and powerful effect - penicillin clearly killed bacteria and insulin clearly helped diabetics control their blood sugar. Today, even a blockbuster drug may ease pain or depression only a little better than a placebo and may not work at all in some patients.

And drugs that don't work can easily appear to do otherwise, Rennie said. Say you have two identical pills and you call them A and B. In theory, both should be equally effective because they are identical. But given enough trials, he said, a few will by chance show that A is better than B, and a few will show that B is better than A. If researchers want to sell B, they could publish only the results that make it look superior, ignoring the ones in which A comes out ahead.

No one is asking the drug companies to publish every scrap of information on every chemical they test for drug action. But a number of groups have begun to propose ways to ensure that all clinical trials are made public.

GlaxoSmithKline volunteered last spring to post all clinical trial results on the company Web site. The trade group Pharmaceutical Research and Manufacturers of America recently published "principles of conduct" for clinical trials that encourage full disclosure of important results.

Critics such as Rennie argue that such voluntary measures won't go far enough. Companies retain the power to stop posting all results once the current controversy dies down.

He is in agreement with the American Medical Association, which, in June, urged the federal government to create a registry of all clinical-trials and their results. Around the same time a group of twelve editors from major journals proposed requiring all trials to go into a publicly accessible database from the start in order to be considered for publication.

Only a legally binding obligation to disclose all trials will force all critical medical and drug data out into the open, he said, and keep it that way even when the heat is off.

Contact staff writer Faye Flam at 215-854-4977 or fflam@phillynews.com.
Faye Flam covers science for The Inquirer. Beginning next month, she will be a Knight-Wallace Fellow at the University of Michigan.

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