U.S. and Canadian regulatory rules allowed companies to conduct "secret science" that jeopardized the lives and health of hundreds of people who took part in clinical trials for a human blood substitute, even though earlier tests had shown the existing products were dangerous, researchers reported Monday.

A review of data from 16 clinical trials showed people who got blood substitutes were 30 per cent more likely to die than those who did not. And the risk of heart attack in patients who received the products was nearly three times higher, according to the study.

The authors and others suggested rules should be changed to require companies to publish study data promptly, especially negative findings that might red flag future such studies by other groups. And if they won't do so, critics say, regulatory agencies like the U.S. Food and Drug Administration or Health Canada should.

"If the research isn't published or otherwise made public, someone knows that the proposed therapy may be harmful, but that somebody won't tell anybody else," said Dr. Joel Lexchin, a York University researcher who closely monitors regulation of the pharmaceutical industry.

"So you have research ethics boards approving studies where the therapy may be dangerous. You have patients enrolling. You have the doctors who are running the trials undertaking them. . . . You've got all these people participating in something which is inherently unethical."

Both the FDA and Health Canada said data provided to them by drug makers is proprietary information and cannot be released without the consent of the submitting company.

"There are very distinct limitations to the FDA's ability to share information which is identified as confidential or trade secret," Dr. Jay Epstein, director of the office of blood research and review, said in a briefing for journalists.

"And that sort of information would not be made public under current laws and regulations."

A spokesperson for Health Canada said the drug regulator is looking at ways to try to increase transparency of clinical trials.

"Health Canada is currently exploring the development of a regulatory requirement for the registration of clinical trials and disclosure of results," Stephane Shank said via e-mail.

"While this work proceeds, Health Canada encourages sponsors and manufacturers to register their clinical trials of therapeutic products within 21 days of the trial's onset" in one of two international clinical trial registries.

The study was published Monday by the Journal of the American Medical Association in advance of a two-day FDA hearing on blood substitutes that will be held in Bethesda, Md., beginning Tuesday.

A safe substitute for human blood would be enormously useful, especially in theatres of war and in remote settings.

Researchers in the U.S. military and a number of biotech companies have been working for years to devise such products, aiming for something that would have a long shelf-life, wouldn't require refrigeration, would eliminate the risk of transmission of HIV or other blood-borne infections and could be given to anyone, regardless of their blood type.

But the products devised so far - called hemoglobin-based oxygen carriers or HBOCs - have been a disappointment. Despite numerous trials in a variety of different patient populations, they have failed to show benefit and, this new study reveals, have shown significant risk. Only one country, South Africa, has approved a blood substitute product.

The researchers, from the U.S. National Institutes of Health and the Washington-based consumer advocacy group Public Citizen, pooled data from 13 published studies, and three more for which results were either disclosed in a press release or in an FDA review. They made several attempts to get additional data from companies that had conducted studies but the requests were either ignored or rebuffed.

The authors were critical of the FDA for not requiring the companies to publish their findings, and for allowing additional trials to be conducted after the risk should have been apparent.

"At some point, somebody should have realized that we've tried it in trauma patients, we've tried it in surgical patients, we've tried it in stroke patients, we've tried many different formulations and we keep finding the same result," said Dr. Charles Natanson, lead author of the meta-analysis, a technique in which data from a number of trials are combined and re-analyzed.

"At some point, and we sort of argue in the paper that may have been the year 2000 . . . it was time to put a halt" to additional trials, Natanson said.

Canadian patients were also exposed to the risks in clinical trials of a product called Hemolink, which was made by a now defunct company called Hemosol Inc. The company conducted at least three trials of the product, though data from only two were included in the JAMA analysis.

Natanson, who is an advocate for patient safety in clinical trials, was paid $10,000 to review the data from a third trial when Hemosol was trying to decide whether to push on with the research. The company later went into receivership.

The company never published the findings and Natanson cannot comment on what he saw or recommended.

An editorial accompanying the review points out further studies of these products are underway or planned in a number of countries around the globe.

The authors, from the Ottawa Health Research Institute, argue future work on blood substitute products should not be allowed in humans until it's clear from animal studies that the products are likely to be safer.

Lead author Dean Fergusson, a clinical trials expert, said the withholding of the negative results meant ethics boards and trial participants could not accurately weigh the risks and benefits of the research.

"How can patients or their decision makers make truly involved consent without all this information? I think that's a huge message," said Fergusson, who reported he was paid a one-time fee of $500 for attending a Hemosol advisory board meeting.

The lack of disclosure suggests company stock prices were placed at a higher priority than the safety of people being asked to go into clinical trials, experts suggest.

"They didn't think beyond the four walls of their corporation, I think, quite frankly," Fergusson said of the companies.

Lexchin was more critical of Health Canada for treating unpublished studies as confidential information. "They're calling this business information, not health information," he said.

Epstein said the FDA's own analysis of the accumulating experience with the blood substitutes led it to conclude there were safety risks associated with the entire class of drugs. "It's because of FDA's safety concerns that there currently are no ongoing studies of HBOCs in the United States trials and no approved HBOC products."

But he challenged the Natanson article's contention that the risk should have been apparent by 2000, saying the FDA had access to information Natanson and his colleagues have not seen that suggested there might be benefits in some situations.

"Basically even though aware of certain safety signals, our reviewers determined that there were enough differences between products and their intended uses to support a careful weighing of individual clinical trial proposals, only some of which were allowed to proceed," Epstein said.