Testimony of Sidney Wolfe, M.D.
Public Citizen’s Health Research Group
Before the FDA Blood Products Advisory Committee
Concerning the Protocol for Biopure’s Blood Substitute HBOC-201
We strongly oppose the approval of the proposed experiment involving unconscious trauma victims being given the blood substitute, HBOC-201, for the following reasons:
- Previous clinical data demonstrate large increases in risk.
- The animal models the Navy and Biopure rely upon are much less relevant and therefore do not trump the previous clinical data.
- The study design is not relevant to either people in rural areas or in military settings, in both of which pre-hospital intervals are much longer.
- The absence of informed consent in light of the above would be unconscionable, but—–
- Even with informed consent, this trial can not seriously be said to be at equipoise and is thus unethical.
Previous clinical data demonstrate large increases in risk. The following charts are taken from FDA’s analysis of human study data from earlier, now-abandoned attempts to approve HBOC-201 for elective surgery such as orthopedic procedures. It can be seen that there is a substantial risk, compared with the use of either blood or standard non-blood IV fluids.
The chart above shows that in the group of people younger than 70 getting either human blood or standard IV solutions, there were three deaths, a total of 16 serious cardiovascular events and a total of 28 serious adverse events out of 422 patients randomized to get these therapies. By contrast, in the groups randomized to get HBOC-201, there were nine deaths, a total of 41 serious cardiovascular events and a total of 76 serious adverse events out of 476 patients.
The chart above compares all patients of all ages who got HBOC-201 with those who were given non-blood IV solutions. In the latter group, there was one death, a total of 11 serious cardiovascular events and a total of 15 serious adverse events out of 131 patients randomized to get these therapies. By contrast, in the groups randomized to get HBOC-201, there were four deaths, a total of 24 serious cardiovascular events and a total of 40 serious adverse events out of 177 patients.
In the previous human studies, HBOC-201 is clearly more dangerous than either blood or IV solutions.
The animal models the Navy and Biopure rely upon are much less relevant and therefore do not trump the previous clinical data. As pointed out in the many of the internal FDA or outside reviews, the controlled nature of the animal studies does not overcome the actual human data from the trials mentioned above.
The comments of several FDA or outside reviewers highlight the shortcomings and dangers of this proposed study:
“In the real world of trauma care, the fraction of patients that will benefit from such treatment is probably small, a few percent at best. However, the presence of injury and hypovolemia [decreased blood volume] will raise the fraction of patients having bad reactions to the HBOC by creating unusual patterns of altered perfusion, bacteremia, endotoxemia, and inflammation…
Thus, the [animal] model probably overestimates benefit and previous clinical experience almost certainly underestimates the toxicity of these products.” (FDA reviewer #3)
Similarly, on page 15 of FDA’s “Issue Summary”, The FDA’s discussion of “Heterogeneity in the expected mortality of individual subjects” raised a “major concern…Many subjects who ordinarily would survive and do well without HBOC-201 will be exposed to its risks. This is a central concern for a trial performed with waiver from informed consent where there must be a likelihood of benefit to individual subjects.”
FDA reviewer # 6 stated that:“It would appear that HBOC-201 has a significant risk for hypertension….The real question is whether the oxygen carrying capacity of the Hgb solution is of enough benefit to offset the risk of hypertension, myocardial infarct, cerebral vascular accidents and renal complications. Based on previous analysis by the FDA and Table V, I would say the benefit to risk has not been achieved.”
The study design is not relevant to either people in rural areas or in military settings, in both of which pre-hospital intervals are much longer. The almost certain, urban location of most trauma victims who participate in this study all but guarantees that the transit time to the hospital, where human blood is available, will be far less than in rural areas or in military situations, the latter being the special interest driving the Navy’s participation in these trials. Thus, whatever answers might derive from the study, were it to be allowed to go forward, would not be very useful for these different situations.
The absence of informed consent in light of the above would be unconscionable, but—–Even with informed consent, this trial can not seriously be said to be at equipoise and is thus unethical.
In summary, none of the FDA’s requirements for allowing RESUS to proceed are met:
- Human subjects be exposed to an unreasonable and significant risk.
- Participation does not hold out the prospect of a direct benefit because many of the lesser severity patients might well survive better with standard IV (Ringer’s) therapy than with HBOC-201.
- The previously stated FDA reasons for disallowing the study to begin are still quite valid.