Unpublished Data Shows Clinical Trial Deaths Posted by Rob at 02/22/06 11:33 AM

A story in today's Wall Street Journal, "Amid Alarm Bells, A Blood Substitute Keeps Pumping," is the latest in a long string of examples of companies downplaying potentially deadly side effects from prescription drugs and medical devices.

The story in the February 22, 2006, Wall Street Journal begins:

Several years ago a clinical trial of a blood substitute called PolyHeme finished with worrisome results. Ten of 81 patients who received the fake blood suffered a heart attack within seven days, and two of those died. None of the 71 patients in the trial who received real blood were found to have had a heart attack.

PolyHeme's maker, Northfield Laboratories Inc., quietly shut down the trial and didn't publicly disclose the results, which are described in internal documents viewed by The Wall Street Journal. It decided the heart attacks might have been due to doctor inexperience in using PolyHeme, not a problem with the product itself.

The story cites all kinds of problems developing blood substitutes, for example that hemoglobin molecules

are known to be dangerous if they aren't held within red blood cells. The molecules tend to seep into the walls of blood vessels and cause inflammation. Most relevant to heart attacks, they can constrict blood vessels and cause clotting.

The importance of the story is the lack of disclosure of the deaths and other negative side effects associated with earlier clinical trials. Now the drug company is pushing forward with additional trials for the product.

Some veteran doctors are concerned about the push by Northfield, of Evanston, Ill., to test its product without publicly disclosing earlier results. Ronald M. Fairman, chief of vascular surgery at the Hospital of the University of Pennsylvania, says he repeatedly urged the company to publish the data but got nowhere. "Even now, it remains frustrating the multicenter results were not disclosed," he says.

The company defends its action:

Northfield's chief executive, Steven A. Gould, argues the heart attacks could well have been caused by doctors pumping too much total fluid -- PolyHeme plus real blood -- into patients. He says PolyHeme could help many people, such as those in an ambulance who don't have access to human blood. "Our experience suggests the risk-benefit balance is in the patient's favor," Dr. Gould says.

In a statement, Northfield denies it "resisted publication" but says: "We did not allocate resources to publication. In retrospect, reporting the full study results earlier would have been better."

The company did inform the FDA of the trial results, and now the company says they plan to make a medical abstract of the study public in April. It is not only the deaths but other adverse effects that cause concern:

Besides the heart attacks and deaths in those taking PolyHeme, the trial suggested the product was linked with other serious adverse events such as heart rhythm aberrations and pneumonia. These events occurred in 54% of the PolyHeme patients versus 28% in the control group, according to Northfield's internal documents. The higher rate of heart attacks and serious events was considered statistically significant, meaning there is minimal likelihood they happened by chance. Overall, eight PolyHeme patients died versus four on conventional therapy, a difference that wasn't found to be statistically significant.

The FDA, while concerned, has agreed to let the company conduct further clinical trials:

The FDA's Dr. Epstein, who is director of the agency's blood-products office, sides with Dr. Gould, calling Northfield's theory a plausible one. "Of course it's alarming there were excess deaths in the treatment group," he says. "We are highly mindful of the adverse events." But, he goes on, "the adverse-event profile in the aneurysm trial, while significant, was not a show-stopper." The FDA's review suggested that "volume overload" rather than "any intrinsic toxicity of the product" was responsible for the cardiac events, he says.

Putting aside the question of whether the results from the first test should preclude further clinical trials on unwitting human subjects. . .

Because Northfield needs only about 120 more people to complete its study, any individual's chance of being enrolled is low. However, those who are still worried can get the blue plastic wristband from the company to signal that they refuse to take part.

[To get the blue plastic wristband indicating you don't want to be part of the clinical trial contact the company.]
. . . what is the FDA -- and what is Congress -- doing with this latest example of drug companies failing to disclose potentially deadly side effects from the drugs they make?
Drug companies point to voluntary disclosure as the solution to a lack of complete information about potential side effects of prescription medicines. The WSJ article points out, for the umpteenth time, that we are foolish to rely on drug companies to voluntarily disclose information that they perceive may negatively impact their bottom line.

The reason we have laws is to provide a strong incentive to companies to do what is in the public's interest, even if the companies don't believe it to be in their financial interest. Until we have a law requiring disclosure of clinical trial results we can expect stories like these on a regular basis.

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