PolyHeme®- Signed you up without you knowing

 Blood substitutes would no doubt be a huge benefit to mankind. Outside of hospital it is difficult to store human blood and impossible to find the right blood type. Paramedics are restricted to saline solutions to increase the volume of the blood for patients with severe bleeding. A fluid that mimics the ability of blood to get oxygen to the tissue would provide a huge advantage. Unlike real blood the substitutes would be universally compatible so there would be no need for time-consuming blood testing. Real blood is also in short supply due to lack of donors and expires after only 42 days. An easily manufactured blood substitute could be made quickly so it would never run out and could have a shelf life of up to 12 months. Blood substitutes would also reduce the risk of viruses and other pathogens such as the HIV virus slipping through the net of donor blood testing. As an extra bonus blood substitutes can be made thinner than blood so they can be transfused more quickly in an emergency. PolyHeme manufactured by Northfield Laboratories Inc. was a blood substitute that has come furthest in clinical trials. It was designed to replace blood for a short time until human blood can be given. It was made from expired human blood, which means it could only reduce not remove the need for blood donors.

  Effective blood substitutes are remarkably difficult to make. The main type of blood substitute is called haemoglobin-based oxygen carriers, which use haemoglobin molecules in some form to get blood to the tissues. The problem is that outside cells haemoglobin tends to remain dissociated with oxygen and takes up nitric oxide causing vasoconstriction. The liver also struggles to remove it leading to liver failure. The solution to these problems is to join the haemoglobin molecules together somehow. PolyHeme did this by polymerisation, joining monomers of 4 haemoglobin molecules into a long chain. By controlling the polymerisation the liver problems and vasoconstriction can be ironed out.

 PolyHeme was trialled successfully in a hospital setting before and after surgery and showed clear benefits in those receiving PolyHeme over those not receive blood or blood substitute. However Northfield laboratories Inc. wanted to trial the substitute in an emergency setting where it would be of most use.

 The trouble with trying to research things in an emergency medicine setting is that the patients are usually too busy bleeding everywhere to give informed consent into an experimental trial. To get round this problem of not obtaining consent for its phase III Northfield laboratories Inc. had to agree with certain conditions set by the American FDA (Food and Drug Administration):

1  ) The subject must be suffering from a life-threatening condition necessitating immediate treatment.

2  ) Obtaining informed consent from a legally authorized representative must be infeasible given the time frame in which the subject must be treated.

3  )  Previous clinical evidence must indicate that the investigated therapy will grant a serious benefit to the subject.

4  ) The investigators must make an effort to contact a legally authorized representative during the given therapeutic window.

5  ) An independent committee must review collected data of the ongoing study.

6  ) Available treatments must be “unproven and unsatisfactory”

7) Principal investigators must meet with the communities from which the subjects will be drawn, and publicly disclose pertinent aspects of the study including the risks and benefits.  

 In the phrase III trials involving 32 trauma centres across 19 US states it was the 7^th condition that made it, to put it mildly, ethically dubious. The trial split patients with severe bleeding (car accident victims, victims of violence etc. and patients who were pregnant or suffered serious head injuries or possibly fatal injuries could were excluded) into a control group, who received saline solution before reaching hospital then donated blood at hospital, and the test group, who received PolyHeme before reaching hospital and then PolyHeme afterwards for 12 hours even though more effective donated blood was available.

Signing people up without permission understandably caused a lot of controversy. To avoid some of the criticism the hospitals involved had an opt-out process available. Anyone who did not want to participate in the trial could carry a bracelet with the words: “I decline the PolyHeme trial.’ There are some quite clear flaws with this method. To decline the trial you must first have heard of it and Northfield appeared less than enthusiastic about having to organise community meeting or advertise the trial despite the 7^th condition they agreed on with the FDA. At the community meetings they did organise they were secretive about the exact trial protocol in order to protect its intellectual property (which definitely seems to contradict the agreement that “pertinent aspects of the study including risks and benefits” should be publicly disclosed).

 Northfield Laboratories also came under criticism for targeting minority and low-income neighborhoods for the study. In San Diego, only ambulances working south of Interstate 8, a traditionally bad neighborhood, were equipped with PolyHeme. The company claimed that they wanted to perform the study in neighborhoods with lots of traumatic violence. In this area especially the trial was poorly publicized: ads were supposed to be posted in newspapers and on television indicating the nature of the study and ways to opt out, but never were. Its also appears a little too convenient for the company that the controversial trial was done on people without the money to sue for damages.

 The ethical issues surrounding the PolyHeme trial would have been ignored if it showed a clear benefit over the standard treatment of saline solution. However when the trial results were announced in Nov. 2006 it was revealed that 13.25 of PolyHeme patients died compared with 9.6% of the control group. People fled Northfield Labs like rats from a sinking ship and its share price plummeted. In 2009 the company entered bankruptcy. Various hospitals involved denied they actually ever used the product. The FDA however stood by its decision to approve the trial to the rage of ethical groups. Whilst the human losses from the trial are regrettable the lack of success of blood substitutes is also a shame. New research is looking into the possibility of using stem cells instead for a quick fix of the blood shortage.