Experts call for caution in clinical trials

Oxygen-carrying blood substitutes currently in clinical trials are associated with a much higher likelihood of serious adverse events such as heart attack and death.

This conclusion, stemming from a meta-analysis of previous research trials that was published this week [1], has prompted experts to call for greater caution before continuing with further human trails of blood substitutes.

Synthetic alternatives to blood that specifically act as oxygen carriers have been  in development for decades. Early successes were seen with perfluorinated liquids such as Fluosol, which won US Food and Drug Agency (FDA) approval in 1989. But it was withdrawn just five years later, due to its side effects and storage problems.

A new generation of haemoglobin-based oxygen carriers, or HBOCs, has shown much more promise. For example, Northfield Laboratories of Evanston, Illinois, is currently seeking FDA approval to use its red cell substitute, known as PolyHeme, for emergency transfusions.

But at a blood substitute workshop co-sponsored by the US National Institutes of Health (NIH) and the FDA on 30 April in Bethesda, Maryland, US, Charles Natanson, a senior scientist at the NIH, sounded a note of caution.

There won’t be blood

Natanson’s team conducted a meta-analysis of 16 trials of 5 HBCO products used on over 3500 patients. His group found an increase in deaths of more than 30 per cent for the patients who were treated with HBCOs, compared with those in the control group. Even more striking, their data revealed a three-fold increase in risk of heart attacks among those who received HBCOs. Natanson argues that these products are so dangerous that they should only be studied in patients with no hope of survival.

A separate evaluation of HBOCs by FDA has also found that the products are linked with health problems including cardiac toxicity, neurotoxicity, and myocardial ischemia, which is typically associated with a reduction in blood flow to heart tissue. 

Despite the data, some experts at the workshop suggested that FDA should still approve the use of investigational HBOC products for use in, for example, patients with life-threatening anaemia who do not have the option of a blood transfusion.

And Steven Gould, chairman and CEO of Northfield Laboratories, stressed that their product should be judged by specific clinical trials, and not by meta-analyses. ’We believe our studies demonstrate that PolyHeme offers a survival benefit in cases of life-threatening red blood cell haemoglobin levels and has an acceptable safety profile and favourable benefit-to-risk ratio when red blood cells are not available,’ he says.

Biopure, a company developing a candidate HBOC called Hemopure, adds that exposure to its product does not result in an unreasonable risk of injury. The company claims that many or all of the serious adverse events reported in its studies do not appear to be linked to the product.

However, experts at the Bethesda workshop acknowledged that a lack of freely-available clinical data is posing a major problem for the field. Some is proprietary data owned by companies developing the products, while other studies simply remain unpublished.  The proceedings of the NIH/FDA workshop will be developed for the agencies in the coming weeks to inform their decision-making.

Rebecca Trager, US correspondent for Research Day USA