Preparation and Characterization of Diaspirin Cross-Linked Hemoglobin Solutions for Preclinical Studies

Nelson, Deanna J.; Azari, Mahmood R.; Brown, RA; Burhop, Kenneth E.; Bush, Stephen H.; Catarello, J.; Chuang, Han-Sheng; Downing, Clive; Estep, Timothy N.; Loewen, A.; McClure, Kelly; McDaniel, A.W.; Michalek, E.; Mozier, N.; Rohn, K.; Spicuzza, J.; Zieske, Paul A.; Zimmerman, Grenith

doi:10.3109/10731199209119662

Cited by 27 publications

(21 citation statements)

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“…The patient qualifies for enrollment in the study as specified in the protocol. 4 to determine how we could best notify patients and their proxies at the earliest possible time that the patient was enrolled in a clinical research protocol. Given that this was the first study using the new regulations for waiver of informed consent, it was incumbent upon investigators to work closely with their institutions and their communities in developing a satisfactory and acceptable consent process.…”

Section: Discussionmentioning

confidence: 99%

“…3 Trauma patients with presumed or proven hemorrhage and persistent hypoperfusion at the time of initial hospital presentation were eligible for enrollment. Approximately 850 patients were to be enrolled and randomized to receive up to 1,000 mL of either the 10% DCLHb solution (a new biological entity of modified tetrameric hemoglobin in a balanced electrolyte solution) 4 or normal saline, in addition to standard therapy.…”

Section: The Dclhb Studymentioning

confidence: 99%

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A Proposed Consent Process in Studies that Use an Exception to Informed Consent

Sloan¹,

Nagy²,

Barrett³

1999

Academic Emergency Medicine

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Abstract. Federal regulations allow an exception to informed consent when it is not feasible to obtain informed consent in certain emergency research circumstances. A multicenter, randomized, singleblinded, normal saline procedure-controlled efficacy trial of diaspirin cross-linked hemoglobin (DCLHb) in acute traumatic hemorrhagic shock was conducted. The study intended to include 850 of the most severely injured trauma patients with hemorrhage and persistent hypoperfusion as demonstrated by vital signs suggestive of vascular collapse or a base deficit that signified prolonged hypoperfusion. It was anticipated that some patients would be unable to provide informed consent, and that identification and availability of some patients' legally authorized representatives (LARs) would be unlikely within the therapeutic window of the intervention. Each participating institution therefore developed a process to implement exception to informed consent. Each hospital's proposed process was reviewed by the institutional review board, the sponsor, the FDA, and the study's data monitoring committee chair. The goal was the development of local implementation processes by which the best interests of patients and their families could be fulfilled using prospective informed consent, the exception to informed consent, and consent to continue in emergency research, as appropriate for each individual patient. This paper describes the proposed implementation method developed for Cook County Hospital. It includes several important features, 1) prospective informed consent by the patient, when feasible; 2) the ability of the patient to decline participation, even when deemed incompetent to provide prospective informed consent; 3) prospective consent by the family/LAR, when feasible; 4) the use of a scripted abbreviated consent by the patient family/ LAR in life-threatening situations when it is possible only to briefly discuss the research being conducted; 5) independent approval for the use of the consent exception by a second physician immediately prior to patient enrollment; 6) the repeated use of consent to continue (both for the family/LAR and by the patient) when an exception to consent has been utilized; and 7) ongoing review of the informed consent process on a case-by-case basis by the institution's scientific review committee. The authors believe this proposed informed consent process maximizes the communication between investigators, patients and their proxies, and the institution's scientific review committee. Multiple mechanisms exist that allow for consent to be provided or declined, both prior to and after enrollment in the research protocol. The ongoing immediate review of the process allows for process enhancements to be made as needed.

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Section: Discussionmentioning

confidence: 99%

Section: The Dclhb Studymentioning

confidence: 99%

A Proposed Consent Process in Studies that Use an Exception to Informed Consent

Sloan¹,

Nagy²,

Barrett³

1999

Academic Emergency Medicine

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“…The new biological entity tested in this study was a 10-g/dL solution of modified tetrameric hemoglobin (DCLHb) in a balanced electrolyte solution. 17 Eligible trauma patients received up to 1,000 mL of either the 10% DCLHb solution or normal saline, in addition to standard therapy.…”

Section: Methodsmentioning

confidence: 99%

The Informed Consent Process and the Use of the Exception to Informed Consent in the Clinical Trial of Diaspirin

Sloan

Koenigsberg

Houghton

et al. 1999

Academic Emergency Medicine

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Abstract. In the clinical trial of diaspirin crosslinked hemoglobin (DCLHb), optimal therapy required the immediate enrollment of patients with severe, uncompensated, traumatic hemorrhagic shock. When it was not feasible to obtain prospective consent, an exception to informed consent was used according to FDA regulation 21 CFR 50.24. Objectives: To examine the informed consent process and the use of the consent exception and consent to continue (CTC), and to describe the patients for whom this process was used. Methods: This was a multicenter, randomized, controlled, single-blinded efficacy trial of DCLHb as an adjunct to standard therapy in the treatment of severe, traumatic hemorrhagic shock. Patients with unstable vital signs or a critical base deficit were treated, with a primary study endpoint of 28-day mortality. Results: During the 11-month study period, 112 patients were randomized in 18 U.S. trauma centers, and data from 98 of the infused patients were analyzed. Prospective consent was obtained from two patients, three family members, and one legally authorized representative (LAR) (6%). Consent to continue was requested for 89 patients (89%), and full participation was granted for 87 of these patients (98%). Consent to continue was provided by 54 (98%) of the 55 patients approached. The mean number of days for family/LAR CTC was 1.1 Ϯ 3.8 days, and 50% of the time it was obtained on the day of study enrollment. Patient CTC was obtained in an average of 13 Ϯ 23 days, with a median of four days. Patients treated in this protocol were more likely to have sustained penetrating trauma than the overall trauma patient population treated in these trauma centers (44% vs 21%, p = 0.002). Conclusions: Informed consent in this study of an emergent therapy most often involved the use of the consent exception and consent to continue, the latter of which occurred in a timely manner. Nearly all of those who were approached for CTC approved full participation in the study, suggesting acceptance of the process outlined in the new regulations. Patients treated in a hemorrhagic shock clinical trial may differ from the general trauma patient population.

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“…The production of αα–Hb has been well documented, both by the US Army [30, 31, 32]and Baxter [33, 34, 35]. Although the same chemical derivative can be produced using bovine [36]or other hemoglobins, the commercial product was made using outdated human blood as raw material.…”

Section: Productionmentioning

confidence: 99%

“…General characteristics of the product were published in descriptions of the process, both by Baxter [33, 34, 37, 44, 53]and LAIR [30, 31, 32, 45, 54]. …”

Section: Characterizationmentioning

confidence: 99%

αα–Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?

Winslow¹

2000

Vox Sanguinis

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In 1998, Baxter Healthcare announced that it was abandoning its product, diaspirin–crosslinked hemoglobin (DCLHb), the first ‘blood substitute’ to complete all phases of human trials. The company announced that the phase III (pivotal) trials in humans had resulted in an unexpectedly high survival in a group of patients serving as controls for those who received their product in a trauma setting. It is not possible to quantitate the time, efforts and money that were expended in the course of developing this product, from 1985 to 1998. It is rumored that the giant healthcare company had expended more than a half billion dollars on this product, not to mention the investment in the same product by the US Army, the National Institutes of Health and many independent university–based scientists. The disappointment was profound and far–reaching. Although the threat of HIV transmission by banked blood has all but disappeared in the developed world, still the bulk of the world’s population faces blood shortages, which this product and its future generations might have helped alleviate. Only Baxter and the Food and Drug Administration may forever know key elements of the history of development of this product. However, because the US Army decided to make its version of the product widely available to scientists, there is a substantial published record, contributed to by both Baxter and independent scientists. Examination of this record leads to the conclusion that there is no single reason for failure. However, it shows that the characteristic hemodynamic response caused by ααHb increased vascular resistance, and probably eliminates its potential as a red cell substitute. Newer solutions that overcome this limitation should fare better in clinical development when this problem is overcome.

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Preparation and Characterization of Diaspirin Cross-Linked Hemoglobin Solutions for Preclinical Studies

Cited by 27 publications

References 1 publication

A Proposed Consent Process in Studies that Use an Exception to Informed Consent

A Proposed Consent Process in Studies that Use an Exception to Informed Consent

The Informed Consent Process and the Use of the Exception to Informed Consent in the Clinical Trial of Diaspirin

αα–Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?

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Preparation and Characterization of Diaspirin Cross-Linked Hemoglobin Solutions for Preclinical Studies

Cited by 27 publications

References 1 publication

A Proposed Consent Process in Studies that Use an Exception to Informed Consent

A Proposed Consent Process in Studies that Use an Exception to Informed Consent

The Informed Consent Process and the Use of the Exception to Informed Consent in the Clinical Trial of Diaspirin

&alpha;&alpha;&ndash;Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?

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αα–Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?