| In yet another example of pharmaceutical hubris, | | | | blood). These were patients whose condition was not |
| Biopure has ballyhooed a study it financed, claiming it | | | | being adequately helped by HBOC. Thus, the goal of |
| shows that their product is successful and safe. | | | | the study was to limit the percentage of cases in |
| Reading the study itself, though, shows a completely | | | | which PRBC was required. Success was defined as |
| different result: | | | | avoiding PRBC infusion in 35% of subjects. The study |
| - The death rate was 1-2/3 times higher in those | | | | reports that over 50% of the HBOC group were able |
| who received artificial blood. | | | | to avoid PRBC infusions. This is the basis of the claim |
| - Adverse events were 1-1/2 times higher in those | | | | for success. |
| who received artificial blood. | | | | Subjects deemed to require a transfusion were given |
| - Serious adverse events were 1-2/5 times higher in | | | | either HBOC or PRBC by randomization. Some |
| those who received artificial blood. | | | | patients who were started on HBOC were later |
| - Double the number of heart attacks occurred in | | | | switched to PRBC "based on the investigator's |
| those who received artificial blood. | | | | assessment of clinical need," according to the study. |
| The number of strokes cannot be given a statistical | | | | How this determination was made was not discussed, |
| outcome, because six people who received artificial | | | | though it was claimed that "contemporary transfusion |
| blood had strokes, while there were no strokes in | | | | process" was adhered to. |
| the control group. Are your eyes spinning? Is your | | | | Each of the two groups of subjects were divided |
| mouth hanging open in shock? Do you think there | | | | into two more groups. Those who were given HBOC |
| must have been a misprint? Is it possible that 1-2/3 | | | | (artificial blood) were divided according to whether |
| more deaths, double the number of heart attacks, an | | | | they were switched to PRBC. Those who were |
| infinitely higher rate of strokes, and more adverse | | | | given PRBC only were divided according to whether |
| events can be considered successful? | | | | they were given two or fewer units of blood or |
| The answer, when you're a pharmaceutical | | | | three or more units. |
| corporation trying to make profits, is an unequivocal | | | | Subjects who were started on HBOC and never |
| yes. Biopure is trying to get Hemopure, a | | | | received PRBC were considered moderate risk. |
| hemoglobin-based oxygen carrier (HBOC) intended to | | | | Those who were started on PRBC and received |
| replace blood in transfusions, approved for sale. To | | | | fewer than three units were also considered |
| this end, on June 10th, it produced a press release | | | | moderate risk. Those who were started on HBOC |
| quoting the company's medical vice president, Dr. A. | | | | and switched to PRBC were considered high risk. |
| Gerson Greenburg, as saying, "It is gratifying to have | | | | Those who were started on PRBC and received |
| experts cull through the complex data repeatedly until | | | | three or more units were considered high risk. |
| insight into our product emerged." | | | | Several markers for health were tracked in the |
| If you translate that statement, what you have is a | | | | subjects. These include creatinine, hemoglobin levels, |
| claim that even the worst results can be ignored in | | | | systolic blood pressure, lipase, and liver function tests. |
| favor of a carefully defined definition of success that | | | | There was discussion about whether adverse events |
| fits a small portion of the data. | | | | were associated with various test results. HBOC had |
| Metastudy of Artificial Blood | | | | a negative impact on all these markers. Positive or |
| Charles Natanson of the National Institutes of Health | | | | negative, they do not have any bearing on the claim |
| led a metastudy documenting increased deaths from | | | | of efficacy for Biopure's artificial blood, though they |
| all artificial blood products. Biopure complained, claiming | | | | may be indicative of why there were so many more |
| that it was a "poorly constructed meta-analysis | | | | adverse events with it. |
| predicated on the hypothesis of an increased | | | | Results |
| mortality". | | | | Results from the four groups were discussed |
| The author, A. Gerson Greenburg, MD, Vice President | | | | extensively in the study report. The study stated |
| of Medical Affairs, further stated, "In my opinion, it | | | | that nearly all of the negative results were in the high |
| would be in the best interest of science and the field | | | | risk groups. This is hardly surprising, especially in light |
| that both publications be formally retracted from the | | | | of the fact that the results of the study determined |
| literature and an apology issued for being inaccurate, | | | | which subjects were classed as high risk. |
| erroneous, incorrect, improper and unjust." Strong | | | | Being switched from HBOC to PRBC, or being given |
| words! | | | | more than two transfusions in those started on |
| Biopure sent out notices of a new trial of their | | | | PRBC, were the only determinants of high risk |
| artificial blood product, Hemopure. They quickly | | | | classification. There is no way to identify high risk, |
| blanketed the online finance world with notifications | | | | other than by treatment. Thus, this separation into |
| of it and claims of both its efficacy and safety. The | | | | smaller groups accomplishes nothing but obfuscation. |
| same article, word-for-word, appeared on sites all | | | | The authors identified those at greatest risk as being |
| over the 'net. | | | | over age 80. They make this claim based on 43% of |
| I read and carefully reviewed the study itself. | | | | cardiac severe adverse events and half of the |
| Biopure's claims and the study's results are wildly | | | | deaths being in this group, though they are only 9% |
| different. | | | | of the total number of subjects. While this is |
| Conflicts of Interest | | | | interesting, it does not include all adverse events. |
| The study, "HBOC-201 as an Alternative to Blood | | | | Were those who suffered strokes the same age, or |
| Transfusion: Efficacy and Safety Evaluation in a | | | | were they, perhaps, two decades younger? That |
| Multicenter Phase III Trial in Elective Orthopedic | | | | information is not provided. So, very little can be |
| Surgery" was published in the June issue of the | | | | concluded about the relative risk of artificial blood |
| Journal of Trauma. (HBOC is an acronym for | | | | based on age. |
| hemoglobin based oxygen carrier.) | | | | Yes, it's interesting that 43% of severe cardiac |
| One of the authors is Greenburg, Biopure's medical | | | | events were among people over age 80. However, |
| vice president. The lead author is Jonathan S. Jahr, | | | | the ages of the rest of the subjects who suffered |
| MD. As a stockholder in Biopure, Jahr has a financial | | | | from cardiac events is not noted. Neither are the |
| interest in the results of the study. He has previously | | | | ages of the stroke victims given. Nor the ages |
| published a study that withheld data showing | | | | associated with any other adverse events. In fact, |
| negative results. | | | | what is most notable here is the lack of information |
| In 2004, a lawsuit was filed against Biopure for | | | | provided. |
| misleading investors for misrepresenting Hemopure's | | | | The authors state: |
| safety after it knew that the FDA had misgivings | | | | "There are a number of physiologic effects of |
| about it. They settled out of court. Several other | | | | HBOC-201 that are known and expected for this |
| class action suits have been filed against Biopure. | | | | class of drugs...removal of these expected AEs |
| How can results like these be reported as successful? | | | | [adverse events] reduced the difference between |
| Different techniques were used to obfuscate the | | | | matching groups...and clearly accounted for the |
| recent trial's results: | | | | majority of the differences between groups." |
| - Implying that, because it was already known that | | | | From a patient's point of view--and, one would hope, |
| the product causes certain adverse events, then | | | | that of a doctor--the fact that adverse events are |
| those particular effects could be ignored as not | | | | known to occur in a class of drugs does not eliminate |
| relevant. | | | | them from concern. |
| - Specifying success as avoidance of real blood | | | | The authors blame over and under treatment for a |
| transfusion in a certain percentage of cases, ignoring | | | | large portion of adverse events. What determines |
| negative results in patients. | | | | whether a patient has been over or under treated is |
| - Identifying the subset of patients with the worst | | | | not defined, making it a questionable piece of |
| results and placing the blame on their characteristics. | | | | information. |
| Study Methodology | | | | The authors show a significant decrease in the use |
| The Subjects | | | | of their artificial blood product. They don't, though, |
| Orthopedic patients having a wide range of surgeries | | | | state what basis, other than "contemporary |
| were used in the study of Biopure's HBOC were the | | | | transfusion process" was used to determine when or |
| subjects. There were 693 subjects in 46 locations | | | | why real blood needed to be used instead. |
| around the world, including the US, Europe, Canada, | | | | Implications |
| and South Africa. 350 were in the HBOC (artificial | | | | If those who are at high risk could be identified |
| blood) group, and 338 were in the packed red blood | | | | before being subjected to artificial blood, then the |
| cell (PRBC) control group. Types of surgery were all | | | | study might be considered successful. However, the |
| related to the skeletal joint system. 304 of the HBOC | | | | only determinants for high risk were the results of |
| group and 282 of the PRBC group underwent | | | | the study -- those who required a switch from HBOC |
| nonback surgery. 46 of the HBOC group and 48 of | | | | to PRBC or those who required three or more units |
| the PRBC group underwent back surgery. | | | | of PRBC. So, the bottom line for any potential patient |
| The trial ran for six weeks. There was no long term | | | | is whether there is greater risk from artificial blood |
| follow-up. | | | | than real blood. The answer to that was quite clearly |
| Reasons for doing HBOC or PRBC infusions included: | | | | delineated by the study. Yes, severe risks, including |
| Heart rate over 100 beats per minute | | | | death, are greatly increased by Biopure's product, |
| - Low systolic blood pressure | | | | Hemopure. |
| - Evidence of myocardial ischemia in an ECG | | | | No amount of obfuscation or discussion of whether a |
| - Acidosis | | | | patient was medium or high risk changes that fact. |
| - Blood loss over 7 milliliters/kilogram | | | | From the point of view of most patients, success is |
| - Diminished urine output less than 0.5 milliliters | | | | not measured by whether real blood transfusions are |
| kilogram/hour Weakness or dizziness | | | | avoided. What counts is the likelihood of encountering |
| The Study | | | | an adverse event, like heart attack or stroke, or |
| If certain criteria were met, those who had been | | | | dying. If that risk is greater with Biopure's product, |
| given HBOC (artificial blood) were given PRBC (real | | | | then most patients will not want it used. |