Hemoglobin-Based Oxygen Carriers: Compassionate Use and Compassionate Clinical Trials (2010)

In this issue of Anesthesia & Analgesia, Mackenzie et al.1 supply information gathered from patients given a bovine-derived glutaraldehyde cross-linked and polymerized hemoglobin-based oxygen carrier (HBOC), hemoglobin (glutamer-250, HBOC-201, Hemopure®, Biopure Corporation, Cambridge, MA) in a “compassionate use” program. The official United States (US) Food and Drug Administration (FDA) term for use of nonapproved pharmaceuticals and devices is the “Expanded Access” program. This program was revised in August 20092 to clarify previous regulations, capture and formalize previous informal programs, and allow for new types of expanded access for treatment use. To participate in this program, a patient must have a serious or immediately life-threatening disease or condition for which there is no comparable or satisfactory alternative therapy; the potential benefit to the patient must outweigh the potential risks of the treatment; and treatment with the investigational drug cannot interfere with a clinical investigation(s) that could support approval of the drug. For treatment of a single individual (rather than intermediate-size populations and more widespread treatment), the FDA must determine that the patient cannot obtain the drug under another investigational new drug (IND) or protocol. The FDA may approve individual emergency use by telephone, with supporting documentation submitted within 15 days,2 and, as provided by the regulation covering IRBs and informed consent, if there is insufficient time for an IRB to meet, a drug or biologic may be administered, or a device used, without IRB approval a priori.3 Notification of the IRB is required within 5 days. Biopure is to be commended for having maintained a program for making their HBOC available for individual use, as these programs entail potential and real difficulties. There may be limited supply of a drug/biologic, there may be competition between expanded access programs and the regulatory programs (for patients or internal resources, or both), the physician might not have been trained appropriately in the use of the drug, and, importantly, such use in an uncontrolled setting in patients with life-threatening advanced disease may result in adverse events that “might raise difficult to resolve but spurious safety concerns about the drug.”* The latter issue is of substantial concern to pharmaceutical firms because they may be fearful that such events might delay or derail regulatory approval. Thus, a single patient program is frequently perceived to represent unnecessary risk to a return on a substantial investment. (It has been estimated that the pharmaceutical industry has invested approximately $2 billion for HBOC development.) In addition, such use resembles neither a carefully controlled trial nor clinical practice, because frequently there is substantial delay between the desire to use the drug and its administration. As little is learned from individual patient use,* and as such sparse data do not fulfill the criteria for product registration, companies with these programs are to be applauded for accepting these risks in the absence of significant potential corporate benefit (although some public goodwill may accrue) but of potential benefit for the individual patient. What is learned by the treatment of a single patient with an investigational drug or biologic is only somewhat enhanced by the cumulative information from several such patients. Examination of both efficacy and safety is limited by the absence of (a) a contemporaneous randomly allocated control group; (b) a homogeneous population; (c) a treatment protocol, thus resulting in nonuniformity of dosage and timing of administration; (d) mandated collection of efficacy or safety data, thus resulting in variable and frequent absence of important information; and (e) verification of data collected. Thus, it is not possible to draw conclusions about efficacy or safety from collection of individual IND data, despite the temptation to do so. The information reported by Mackenzie et al.1 is affected by all of the above limitations, and another, as well. It is not clear what criteria could be used to determine whether observed ischemic events were induced by the patient's anemia or by the administered HBOC. Comparison of their survival data with patients for whom they obtained FDA approval, but who were not infused with HBOC-201, is not scientifically valid nor is comparison with historical series, because the groups are not likely comparable and disease management has varied with time. Nevertheless, perhaps surprisingly, the mortality rate that they reported for those given the HBOC, 58%, is not less than that for those patients for whom FDA approval was obtained but were not given the HBOC (50% after some exclusions, as described) or that of previous reports of untransfused patients with similarly severe acute anemia.4–6 In a comprehensive review of reported cases and series of untransfused Jehovah's Witnesses from 1970 to 1993, Viele and Weiskopf4 noted no mortality when hemoglobin was >5 g/dL, and 44% mortality when the hemoglobin concentration was less than that value. In a retrospective review of surgical patients who declined transfusion, when perioperative hemoglobin concentration was <6 g/dL, Carson et al.6 found a mortality rate of 62% (8 of 13) and in a subsequent larger review, a mortality rate of 33% (12 of 36) for a similar group.5 The lack of what should be lower mortality when augmenting oxygen-carrying capacity and delivery for extreme anemia by treatment with an HBOC draws attention to the peril of forming conclusions from uncontrolled data, or conversely, perhaps to important safety issues. Mackenzie et al. sought to test the hypothesis that survivors had a lesser oxygen debt (a well-recognized consequence of inadequate tissue oxygenation) than did nonsurvivors. However, their comparison of survivors and nonsurvivors by use of a post hoc construct, hemoglobin concentration <8 g/dL times duration, is wanting, because there is scant physiologic evidence that hemoglobin concentrations of 7 to 8 g/dL produce oxygen deficit in the absence of severe cardiovascular disease (an exclusion criterion for treatment under their emergency INDs). Use of a lesser hemoglobin threshold for this analysis could have been more instructive. Although HBOCs clearly carry oxygen, and nearly all off-load oxygen, and have demonstrated efficacy in a variety of animal models, proof of efficacy in clinical trials has been less consistent. In part, this is attributable to a limited intravascular half-life, generally <1 day, making for challenging trial design and necessitating either continued therapy or replacement with erythrocytes simultaneous with disappearance of intravascular HBOC. This only postpones, rather than avoids, transfusion, as was demonstrated in a clinical trial with a fluorocarbon of similar intravascular half-life.7 To obviate this problem, trials have been conducted in cardiac surgery,8–10 where hemodilution resolves during the postoperative period, thus maintaining hemoglobin concentration as the intravascular HBOC concentration decreases; or in trauma. In trauma, the HBOC has been administered either in the emergency room11 or earlier, before hospitalization when blood is not available,12 and in that latter circumstance, the clinical comparison is against something other than standard transfusion. Trials in trauma are very difficult and expensive to plan and implement. Inasmuch as victims of trauma sufficiently severe to require transfusion or administration of a hemostatic agent are frequently unable to provide informed consent, adequate enrollment of these patients requires that these trials be performed under the regulation allowing their conduct without such consent.13 The FDA has determined that such trials for HBOCs and other compounds, performed under this regulation, without patient informed consent, must have mortality as the efficacy end point. Furthermore, the FDA has imposed 30-day mortality as a “durable” end point, with a view that improving mortality for a lesser period, such as 24 or 48 hours is of little import if there is no difference at 30 days. This presents 2 problems. First, not all clinically important and appropriate therapies are designed to decrease mortality. Second, the 30-day period is arbitrary and essentially converts a usual safety end point to one of efficacy. Doing so, in some instances, produces an efficacy end point so distant from the timing and mechanism of action as to be physiologically and pharmacologically irrational. Although some would regard an improved 24- or 48-hour mortality as problematic if it were not carried through for 28 or 30 days, I suggest that the longer period is an appropriate safety issue that should be properly balanced against a rational end point and period for efficacy. Development of artificial oxygen carriers has had a long, tortuous, and difficult road. Baxter terminated the program of their HBOC (DCLHb; diaspirin cross-linked hemoglobin) after 20 years of development and substantial cost after a clinical trauma trial that resulted in higher mortality of the patients treated with HBOC than those not so treated11 and terminated the clinical program of the recombinant hemoglobin products (rHb1.1, Optro®; and rHb2.0) that had been developed by Somatogen.14–17 That trauma trial was the first to be approved under the provisions of 21CFR50.24,13 exception from informed consent, and thus produced considerable consternation. Earlier this year, Northfield Laboratories announced that it would “wind down its business operations”** after their large phase III clinical trial of its HBOC, PolyHeme®, in a setting of prehospital and initial 12 hours of hospitalization, administered to patients with major trauma failed to successfully achieve its dual primary end point of superiority/noninferiority of mortality (compared with expected mortality in a rural setting with longer transit times to hospital and availability of blood).12 Northfield Laboratories reported that this resulted in the FDA determining that the failure to “meet the prespecified primary efficacy end point” in the phase III clinical trial together with “the safety data of all controlled studies reveal that the administration of PolyHeme places the patients at a higher risk of significant adverse events,” and that “therefore, in the absence of clinical benefit, the risk:benefit assessment of the product in trauma is unfavorable.”† In a similar action, Biopure filed for bankruptcy protection on July 16, 2009‡ likely owing to their HBOC having been on prolonged “clinical hold” with no clear path for continued development, because of concerns by the FDA regarding the product's safety.§ The company's assets have been sold and, as of the date of this writing (July 30, 2009), there has been no announcement suggesting a continuation of the clinical program, although further attempts at development remain possible. Other HBOCs have had similar fates. For example, Hemosol (Mississauga, ON, Canada) halted clinical development of their HBOC, Hemolink®, because of a higher incidence of myocardial damage in patients given their HBOC than in those not given their HBOC in a phase III randomized trial of patients undergoing cardiopulmonary bypass for cardiac surgery.∥ Sangart continues to develop its HBOC, Hemospan®, in Europe for an apparently different indication(s).18 Myocardial injury has been a major concern for HBOCs, and a central topic at a recently held National Institutes of Health–FDA workshop regarding HBOC safety.19,20 At least 4 HBOCs have had adverse cardiac issues in clinical trials, and it is believed that this might be an effect of this class of compounds.19–21 This has led some to suggest that HBOCs require fundamental redesign and further preclinical testing before additional clinical trials are undertaken.19,20 Many of the adverse actions of HBOCs, including myocardial damage,22 systemic23–25 and pulmonary hypertension,14 gastrointestinal symptoms,15 circulation and function,25–28 and hepatocellular injury,19,20 have been attributed to its ability to scavenge nitric oxide (NO),19,20 although other potential sources of toxicity (free heme; oxidative reactions by hemoglobin; and excessive oxygen delivery) are also being investigated. The focus of attention has been NO-reduced vasoconstriction. I have previously speculated that it is possible that the effect of NO scavenging on platelet function and coagulation might be an important effect of HBOC products, and that this interaction could be related to the effects of HBOCs on myocardial ischemia and infarction.19,20 Cell-free hemoglobin stimulates platelets and blocks the inhibitory effects of a NO donor in vitro, and, in patients with sickle-cell disease and markers of hemolysis, a NO donor reduces platelet activation in vivo.29 Returning to “compassionate use,” the definition of “compassion” includes the desire to help. Thus, in a sense, all clinical trials are “compassionate.” This thought was echoed in the testimony before Congress of Robert Temple, Associate Director of the Center for Drug Evaluation and Research/FDA.* The FDA is mandated to ensure that drugs and biologics are effective and safe.30 However, nearly always that means balancing the two because pharmaceuticals are rarely completely absent of safety concerns. This task is difficult enough in many circumstances but is extraordinarily difficult for studies related to serious trauma. Embedded in this judgment is the definition of the end point for determination of efficacy. At least 2 major clinical trials with HBOCs have been performed in the US under the provisions of 21CFR50.24, an exception to informed consent. There is an appropriate strong culture and belief in the US of the need for informed consent for human participation in research. In the proposal31 and notification32 of the final rule, the FDA made reference to the Belmont report of 1978,33 an outgrowth to a certain extent of the Helsinki Declaration of 196434 (revised several times since), which itself was a compromise35 between those wishing to implement in full the Nuremberg Code of 194936 and those wishing no regulations. The military has a clear interest in having an oxygen-carrying therapeutic for use where blood is not available, but the ethics of conducting a randomized trial in a battlefield setting have not been resolved. The execution of such a trial under these conditions and the resulting data are likely to be problematic. The regulation permitting clinical research without informed consent, while recognizing the fervent US commitment to informed consent and providing substantial protection for individuals, represents to a certain degree an emphasis of the concepts of beneficence and utilitarianism37 (maximization of total societal “good”) over that of “autonomy” (individual rights): i.e., that potential benefit for the many outweighs the rights of an individual (in this case, that of individual informed consent). Without adequate checks and protection, this can lead to a tyranny of the majority with unreasonable abrogation of individual rights. The argument, made at times, that if a person were competent, she or he would agree to participate,31,32 is clearly not universally applicable as not rarely do competent patients refuse treatments, even for a potentially lethal condition. In addition to the protection that the research offers, “the prospect of direct benefit to the subjects,”13 one of the justifications for allowing research in the absence of informed consent is that for the specific circumstance it is “necessary to collect valid scientific evidence to determine the safety and effectiveness of the intervention . . . that has likelihood to result in advancement of knowledge and improvement of therapies.”31,32 This justification implies that such information will be aired publicly and fully. Although data resulting from trials that have been conducted under this regulation have been published,11,12 they have been incompletely so. The FDA cannot release proprietary information or data without approval of the owner of those data. It should be incumbent on the FDA that a condition for granting permission to conduct a clinical trial under 21CFR50.24 be that all significant data related to efficacy and safety be made fully available and evaluated in the public domain. Forfeiture of individual rights demands no less. There is potential for much to be learned from these data, and they could be instructive for improvement of future research efforts. HBOC development has been hampered by our inadequate understanding of the data already gathered. Research efforts with potential for benefit of many may be furthered substantially if the full data sets are made public and scientifically assessed.