Monday, September 11, 2006

Informed consent under FDA review

The Scientist reports that the FDA is reviewing informed consent rules that would apply when clinical emergency research can be conducted. This on the heels of a Phase III clinical trial by Northfield Laboratories blood substitute PolyHeme that had been widely criticized for allegedly violating emergency research ethics and regulations.

Northfield spokeswoman Sophia Twadell maintained that the trial was ethical and in compliance with federal regulations. The company plans to release topline data from the study by the end of the year and seek FDA marketing clearance under "fast-track" status during the first half of 2007, she told The Scientist.
Several interesting links within and following The Scientist article linked here.

1 comment:

Anonymous said...

Hello, the article is partially false.

Please read

by someone who chaired the board of the Univ of Texas Hospital, who participated in the study.

THIS is an informed opinion.


Letter to the Editor: In Defense of the PolyHeme Trial
by Anne Hamilton Dougherty
2006. The American Journal of Bioethics 6(4):W52

Anne Hamilton Dougherty, University of Texas Medical School, Houston

A lightning rod since its inception, the PolyHeme trial is a randomized evaluation of an investigational oxygen-carrying blood substitute in severely injured trauma victims utilizing waiver of consent. The Boston University Institutional Review Board (IRB) concluded that it did not meet the conditions set forth in 21 CFR 50.24 for exception from informed consent and shared its determination with the Food and Drug Administration (FDA), Northfield Laboratories and with other IRB's reviewing the trial. More recently, Drs. Kipnis, King and Nelson have posted an open letter to participating IRB's imploring them to impose limits on the trial, arguing that waiver of informed consent is unjustified (Kipnis, King and Nelson 2006).

Nonetheless, 32 IRB's have reviewed the protocol and, after thoughtful consideration of its risks and benefits in the context of regulatory requirements, voted approval. The Committee for the Protection of Human Subjects of the University of Texas - Houston, which I chair, was among those. Our decision was preceded by three-and-one-half hours of full committee debate, along with countless hours of subcommittee research, review and negotiation. Community consultation in the Houston metropolitan area included press releases to nine daily newspapers and 41 non-daily newspapers, 16 radio stations, internet postings, 12 advertised community group hearings, and two radio station call-in shows.

How can caring and informed individuals disagree? The primary objection to the trial lies in continued randomization upon hospital arrival where banked blood, the standard of care, is available. Exception from informed consent requires that "human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and obtaining informed consent is not feasible . . ." (21 CFR 50.24). Critics argue that, despite acknowledged limitations of banked blood, its general acceptance in resuscitation is prima facie evidence of its "satisfactory" nature. Once blood is available, they profess, randomization should be reserved for consenting subjects.

Is the efficacy and safety of transfused blood "proven"? Despite its widespread use and acceptance, the performance of banked blood has never been subjected to the level of scrutiny imposed on investigational new drugs. Transfusions fail to improve oxygen consumption in critically ill patients (Fernades et al. 2001). Attendant risks of transfusion reaction and transmission of infection are universally recognized. Few accept transfusion absent life-threatening anemia.

Is the transfusion of banked blood "satisfactory"? Clearly, it is an effective means of immediate resuscitation in hemorrhagic shock, but at what price? Clinical trials have demonstrated that transfusion increases the incidence of multiorgan failure (MOF) and increases mortality (Kao 2000; Johnson et al. 2001). In particular, transfusion of six or more units within the first 12 hours is the primary risk factor for MOF, independent of injury severity (Moore, Moore and Sauaia 1997). MOF is the leading cause of post-injury death, conferring a mortality of 35% and prolonging ICU stays an average of one month with mechanical ventilation and dialysis. The adverse effect on outcomes is not limited to trauma victims, but is particularly pertinent to this population because of the pathophysiology of transfusion-related injury (Corwin et al. 2004; Herbert and Fergusson 2004; Napolitano 2004; Rao et al 2004). Many thoughtful clinicians feel treatment that increases mortality and organ failure is unsatisfactory.

How could blood be bad? It's a universal natural product that serves us well. Banked blood, however, is artificially preserved and gradually degrades with its 42-day storage, releasing from red cell membranes lipid mediators and cytokines. These factors combine with traumatized tissue in a two-step priming of neutrophils and oxygen radical production, each of which is highly correlated with development of MOF (Moore, Moore and Sauaia 1997; Johnson et al. 2001). Transfused units are necessarily the oldest in the blood bank with the highest concentration of toxins. Furthermore, trauma patients requiring massive transfusions first receive unmatched blood. Type-specific blood requires up to 20 additional minutes to deliver and fully cross-matched blood can require 45 minutes. The risk of immunologic complications and medical error increases under the pressure of emergency delivery. Blood's failure to improve oxygen consumption in critically ill patients apparently stems from changes in red cell deformability with storage. Such rheologic changes can produce red cell entrapment, microvascular obstruction and tissue ischemia (Fernandes et al. 2001; Berezina et al. 2002).

By contrast, PolyHeme has a long shelf life and is compatible with all blood types. The risk of viral and bacterial transmission is extremely low. Extensive pre-clinical and earlier clinical studies have shown very few adverse effects. Deleterious vasoconstrictive effects that have plagued earlier blood substitutes are noticeably absent with this product.

A single aborted trial of PolyHeme as adjunct to the practice of acute normovolemic hemodilution (ANH) in elective abdominal aortic aneurysm repair has sparked renewed concern. Ten subjects in the PolyHeme treatment arm experienced myocardial infarction with two fatalities, compared to none in control subjects. The two treatment arms, however, differed more substantially than in the administration of PolyHeme. In this population with established cardiovascular disease, ANH is used to minimize intraoperative blood loss. Phlebotomy (up to 2-3 units, 1.5 liters on average) targets a hemoglobin 9 g/dl and blood volume is replaced with an equivalent amount of preoperative colloid; patient blood is stored for perioperative return. The PolyHeme group in the ANH trial was bled up to six units (2.8 liters on average), and received two units of colloid and four of PolyHeme in an attempt to further enhance the benefit of ANH. Not only was the PolyHeme group bled almost twice as aggressively as the control group, it also received larger volumes of autologous and allogeneic blood in the perioperative return phase. Cardiac events were concentrated in low enrolling centers where fluids were administered more liberally. Massive phlebotomy and fluid shifts in this vulnerable population, rather than the test article, were felt to be responsible for excessive cardiac morbidity and mortality. The trial was curtailed for futility (Northfield Laboratories 2006). Excessive cardiac adverse events have not been observed in any other PolyHeme trials.

Drs. Kipnis, King and Nelson (2006) criticize PolyHeme for its absence of clotting factors. Packed red cells also offer far fewer clotting factors than whole blood. The PolyHeme trial provides for both treatment groups to receive supplemental fresh frozen plasma, replacing clotting factors in both groups. Since transfusion-related toxins are associated with red cell membranes, plasma administration does not appear to participate in the development of MOF.

The twelve-hour clinical phase of the study has also been the subject of suspicion in the press. Some have argued that it is designed to simulate evacuation times under battlefield conditions rather than those in urban areas, speculating that the product is destined strictly for military use; its development in civilian subjects thus would violate the justice principle. In fact, the interval mirrors pre-clinical data on the temporal relationship between injury and neutrophil priming as well as the observation that transfusion of six units or more over the first twelve hours increases risk of MOF, factors as relevant to Houston motor vehicle accident victims as to wounded soldiers.

Finally, some have argued that the trial should reflect an intended use of PolyHeme as a bridge to blood only. In fact, the trial is designed as a superiority trial, testing the hypothesis that the use of PolyHeme as the initial resuscitative fluid in severely injured patients with hemorrhagic shock reduces mortality, compared to the standard of care (crystalloid in the field, then blood when available). That hypothesis cannot be tested if all groups receive blood at the first opportunity.

I support the action of our IRB in approving the PolyHeme trial. In the wake of increasing public criticism we have revisited and affirmed our initial decision. Although some critics feel there is an ethical flaw in trial design, those arguments themselves are flawed and uninformed.

Thoughtful, caring individuals have a right to disagree. Whereas the definition of "unsatisfactory treatment" is imprecise and open to debate, few would argue that allogenic blood transfusion has very significant limitations, its risk being far more complex and ominous than simple immunologic incompatibility or infection transmission.

Our system of human subjects protections depends on the authority of the local IRB system, charged with weighing the risks and benefits of research in the context of community standards, needs and resources. Nowhere is the value of the local review system more evident that in studies requiring waiver of consent which are particularly difficult to orchestrate and demand sincere commitment from the investigative team, the IRB and the community alike. Protocols that may be unsuitable for one medical system may be entirely appropriate for others with different resources. A conscientious local IRB, knowledgeable and passionate about the needs and concerns of the community it serves, is in the best position to review the risk and benefit of proposals in this setting and to interact with the potential subject population in community consultation.


Berezina, T. L., S. B. Zaets, C. Morgan, C.R. Spillert, M. Kamiyama, Z. Spolarics, E.A. Deitch, and G.W. Machiedo. 2002. Influence of storage on red blood cell rheologic properties. Journal of Surgery Research 102: 6-12.

Corwin, H.L., A. Gettinger, R.G. Pearl, M.P. Fink, M.M. Levy, E. Abraham, N.R. MacIntyre, M.M. Shabot, M.S. Duh, and M.J. Shapiro. 2004. The CRIT study: Anemia and blood transfusion in the critically ill-current clinical practice in the United States. Critical Care Medicine 32:39-52.

Fernandes, C. J., Jr., N. Akamine, F. V. De Marco, J.A. De Souza, S. Lagudis, and E. Knobel. 2001. Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients. Critical Care 5: 362-367.

Herbert, P.V., and D.A. Fergusson. 2004. Do transfusions get to the heart of the matter? Journal of the American Medical Association 292(13): 1610-1612.

Johnson, J.L., E.E. Moore, P.J. Offner, D.A. Partrick, D.Y. Tamura, G. Zallen, and C.C. Silliman. 2001. Resuscitation with a blood substitute abrogates pathologic postinjury neutrophil cytoxic function. Journal of Trauma 50:449-56.

Kao, K.J. 2000. Mechanisms and new approaches for the allogeneic blood transfusion-induced immunomodulatory effects. Transfusion Medicine Review 14:12-22.

Kipnis, K., N.M.P. King, and R. M. Nelson. 2006. An open letter to IRBs considering Northfield Laboratories' PolyHeme Trial. American Journal of Bioethics 6(3): 18-21.

Moore, F.A., E.E. Moore, and A. Sauaia. 1997. Blood transfusion: An independent risk factor for postinjury multiple organ failure. Archives of Surgery 132: 620-625.

Napolitano, L.M. 2004. Current status of blood component therapy in surgical critical care. Current Opinion in Critical Care 10: 311-317.

Northfield Laboratories, Inc. 2006. Press release: Northfield Laboratories releases summary observations from its elective surgery trial. March 20, 2006.

Rao, S.V., J.G. Jollis, R.A. Harrington, C.B. Granger, L.K. Newby, P.W. Armstrong, D.J. Moliterno, L. Lindblad, K. Pieper, E.J. Topol, J.S. Stamler, and R.M. Califf. 2004. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. Journal of the American Medical Association 292(13): 1555-1562.

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