IT IS a moral dilemma that strikes at the heart of modern biomedical ethics – and it is being played out on the roads and streets of US cities.
Over the next few months, certain victims of serious accidents and trauma injuries in these cities will find themselves enrolled in a trial to test an artificial product designed to mimic human blood. And if patients are unconscious or otherwise unable to provide consent? No matter. Trauma doctors involved in the trial will have the authority to enrol them anyway.
Obtaining consent from patients in clinical trials is the bedrock of modern research ethics. The principle was introduced following the appalling atrocities committed by Nazi scientists in the concentration camps, and many ethicists question whether it can ever be fair to deprive patients of the right to withhold consent. In the US, however, the Food and Drug Administration thinks this can be justified, at least in emergency situations where critically injured victims unable to assent are likely to die without fast treatment – hence the new clinical trial in the US.
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Given the undeniable need to research trauma treatments, such a policy may not be as fundamentally wrong as some claim. But what if the experimental treatment belongs to a class that is known in the past to have had adverse effects? What if certain key safety aspects are hard to assess? These are the questions we need to be asking about the new blood substitute trial.
Made by Northfield Laboratories in Evanston, Illinois, the product, called PolyHeme, is based on haemoglobin, the protein that carries oxygen in blood cells. The trial started in January in Denver, Colorado, and at least five other cities are now participating. Ultimately, 720 trauma victims will be enrolled. Patients in the control group will receive a saline infusion and as much donated blood as they need once they get to the hospital. Those who receive the blood substitute will get real blood only after 12 hours or if they need more than 3 litres of fluid.
If the trial is a success, it will represent a much-awaited triumph. Any product capable of doing the work of natural blood – but without having to be immunologically matched to the patient’s blood group, refrigerated or screened for infections – would be a boon. Its potential global market would run to billions of dollars.
Unfortunately, three other haemoglobin-based blood substitutes have already reached advanced human trials and all have been associated with problems. The most notorious failure came in 1998. When Baxter Healthcare in Deerfield, Illinois, gave its haemoglobin blood substitute to patients in a critical condition, 46 per cent of the patients in the treatment group died, compared to only 17 per cent of the patients given saline.
Now, as then, the company, which no longer develops haemoglobin-based blood substitutes, says it remains unproven that the product caused the extra deaths. However, it did have an undesirable property. As numerous animal and test-tube studies went on to show, the Baxter blood substitute caused vasoconstriction: it tended to close off blood vessels and capillaries, preventing the precious oxygen it carried from getting to the right places.
It turned out that the haemoglobin in the Baxter product could leak into small spaces between blood vessels, causing severe vasoconstriction, by mechanisms still hotly debated. But not all hope was lost. A newer version, which other companies had been working on simultaneously, suddenly looked promising.
These products consisted of haemoglobin molecules linked together into larger units. The extra bulk, researchers reasoned, should reduce leakage. PolyHeme and other products based on the “larger is better” idea entered clinical trials.
But how much better are they? Enough to warrant another series of trials in trauma patients unable to give consent? Some signs do not look encouraging. For example, Canadian blood substitute company Hemosol disclosed last year that a trial of its product had resulted in more heart attacks in the treatment group than in patients given a placebo. The company did not reveal how many more heart attacks there had been, but it halted both this trial and a second study. At the time of going to press, Hemosol had not replied to żěè¶ĚĘÓƵ’s phone or email requests for comment.
Biopure, a company in Cambridge, Massachusetts, has a blood substitute called Hemopure in advanced clinical trials. In several trials, Biopure has reported higher blood pressure in treated patients, a side effect that could be linked to vasoconstriction.
A Biopure spokesman says the rise in blood pressure was not clinically significant and that the product is safe and effective “when used appropriately”. But all is not well at the company. Late last year the US Securities and Exchange Commission began to investigate Biopure over claims that the company misled investors about the progress of its application for an FDA licence for Hemopure. The company revealed the SEC action on the same day it disclosed that the FDA had halted one of its Hemopure trials as a result of concerns about adverse effects. Neither the FDA nor the company specified the nature of the concerns. Several class action suits have followed the SEC announcement.
The blood substitute being rolled out in the new US trial by Northfield is conceptually similar to Biopure’s (one difference is that Northfield’s haemoglobin comes from humans rather than cows). Northfield denies that its product causes vasoconstriction citing a number of studies as evidence.
And the results so far do look encouraging. For example, in a trial of severely injured people, nine of 12 patients who lost blood to levels considered lethal actually survived – a figure otherwise unheard of in the medical literature. But that does not reassure everyone. Northfield’s previous clinical trials may not, it is true, have reported serious side effects, but a closer look reveals that these studies either had small sample sizes (up to 25 patients in the treatment group) or no control group.
What is more, the best way to directly screen for vasoconstriction is with animal tests developed in the past few years in which blood capillaries are observed as the animals receive a treatment. Using these techniques, scientists in Japan and the US showed in 2002 that a linked haemoglobin product of similar size to the Northfield and Biopure substitutes had a moderate vasoconstrictive effect. In the same year Biopure researchers themselves reported indirect evidence of vasoconstriction in their product.
It is unclear exactly how these compounds compare to PolyHeme, but until Northfield conducts and publishes its own versions of these animal tests, the question will be open to debate. Northfield had not clarified whether the company had done these tests as żěè¶ĚĘÓƵ went to press.
So where does all this leave the issue of patient consent? In a less than satisfactory state. At community meetings sponsored by the hospitals involved in the Northfield trial doctors are handing out bracelets that state “I decline the Northfield PolyHeme Study”. The company says that the wording of the federal regulation allowing bypassing of consent specifies that an opt-out must be offered.
Yet not everyone who ends up needing emergency treatment will have attended one of these meetings, and not everyone will get to hear about the troubled history of blood substitutes. In short, not everyone who might want it will get the chance to opt out.
With less troubled treatments, that might be tolerable. But not in this case: ethicists are right to suggest that the trial should be organised on an opt-in rather than opt-out basis. Handing out bracelets reading “I accept the Northfield PolyHeme trial” would ensure that only those who are well informed about the blood substitute would be enrolled.
Persuading enough people to wear opt-in bracelets would be more expensive and time-consuming. But in the light of the concerns about previous blood substitutes and the lack of a definitive answer on vasoconstriction, it would also be fairer.