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Waiver of Informed Consent: Balancing Protection and Feasibility Roger J. Lewis, MD, PhD Department of Emergency Medicine Harbor-UCLA Medical Center Torrance, California Introduction Experimenting on people who may die, without their consent, is a serious matter.

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waiver of informed consent balancing protection and feasibility

Waiver of Informed Consent: Balancing Protection and Feasibility

Roger J. Lewis, MD, PhD

Department of Emergency Medicine

Harbor-UCLA Medical Center

Torrance, California

  • Experimenting on people who may die, without their consent, is a serious matter.
  • However, if we do not rigorously test new therapies for sudden, life-threatening, and incapacitating illness and injury, we condemn our future patients to receive unproven, possibly ineffective, and potentially harmful therapies.
  • We must strive to balance the risk to individuals’ health and dignity with the risk of not knowing which treatments are effective.
selected provisions of 21 cfr 50 24
Selected Provisions of 21 CFR §50.24
  • Life threatening situation, no proven effective therapy.
  • Prospective informed consent not feasible:
    • Subjects incapacitated by condition;
    • Narrow “therapeutic window” so no time to identify legally authorized representative;
    • Prospective identification/consent not practical.
  • Research holds potential of direct benefit to individual subject, supported by prior studies, and risks are reasonable.
additional protections in 21 cfr 50 24
Additional Protections in 21 CFR §50.24
  • Consultation with representatives of the communities in which the research will be done and from which the subjects will be drawn (“Community Consultation”);
  • Public disclosure to communities prior to study (“Public Disclosure”);
  • Establishment of an independent data safety and monitoring board (DSMB) to oversee study;
  • Procedures to allow family members to “opt out” on subjects’ behalf (or subject to “opt out”); and
  • Public disclosure to communities of study results (“Public Dissemination”).
practical barriers
Practical Barriers
  • In general, investigators, pharmaceutical and device companies, and institutional review boards (IRBs) all have limited knowledge of and experience with these regulations and their requirements:
    • Community consultation;
    • Public disclosure; and
    • Data safety monitoring board (DSMB).
  • This leads to a general reluctance to perform this type of research, decreased efficiency and increased costs.
economic barriers
Economic Barriers
  • Fulfilling requirements of 21 CFR §50.24 may require substantial resources.
  • The development of even potentially highly beneficial therapies may not make economic sense.
  • Especially true if sponsor has limited resources, the incidence of target disease is low, or third party payers are unlikely to cover treatment.
minimally invasive direct cardiac massage mid cm device
Minimally Invasive Direct Cardiac Massage (MID-CM) Device
  • A device developed to be inserted into the chest, to provide direct compression of the heart during cardiopulmonary resuscitation (CPR).
  • Animal and initial human studies suggested increased blood flow with CPR, potentially improving survival rates.
mid cm experience
MID-CM Experience
  • Sponsor made an attempt to initiate multicenter US trial under 21 CFR §50.24.
  • Community consultation and public disclosure predicted to be costly.
  • Most sites had little or no experience with these processes.
  • US trial never initiated.
  • European trial, uncontrolled, performed on 25 subjects in the prehospital setting.
  • Development abandoned, venture capital ran out.
  • Ovine antibody therapy for life-threatening tricyclic antidepressant (TCA) overdose, developed by Protherics, Inc.
  • Phase I/II studies in ten patients demonstrated greatest response in the most severely poisoned patients.
  • More than 90% of severely poisoned patients could not be enrolled in Phase I/II studies since they could not give consent.
  • Impossible to demonstrate efficacy in mildly poisoned patients, since they all do well.
  • After extensive discussions, FDA approved US trial incorporating emergency exception under 21 CFR §50.24.
  • Sponsor declined to proceed, based primarily on economic considerations, including costs of trial and likely market.
  • Product is no longer in development.
dclhb efficacy trial
DCLHb Efficacy Trial
  • Hypotensive adult trauma patients (predicted mortality of 40%).
  • Randomized to (1) receive all standard therapy including blood products or (2) all standard therapy, including blood products, and DCLHb.
  • DCLHb has vasopressor effects, not a true “blood substitute” trial.
  • Planned to enroll 850 patients and allowed a waiver of informed consent.

Baxter's Hemoglobin Therapeutic, HemAssist, First To Reach Advanced Stage Surgery & Trauma Research

First 'Blood Substitute' Cleared by FDA to Begin Phase III Trauma Trial

DEERFIELD, Ill., Nov. 21 /PRNewswire/ -- Baxter Healthcare Corporation reported today that the company's hemoglobin therapeutic, HemAssist(TM)(also known as Diaspirin Cross-linked Hemoglobin or DCLHb), has been cleared by the U.S. Food and Drug Administration (FDA) to enter Phase III clinical testing in patients suffering from blood loss and shock caused by severe trauma. The purpose of this landmark trial is to investigate the effect of HemAssist(TM)(DCLHb) on the survival rates in patients suffering severe trauma.


The trial will be conducted under the new FDA regulation allowing for an exception to the requirement for informed consent in life-threatening emergency circumstances...

dclhb dsmb deliberations
DCLHb DSMB Deliberations
  • Meeting December 8, 1997:
    • Committee informed of apparent imbalance in fatalities under assumption of equal enrollment.
    • DSMB votes to unblind themselves.
    • Action deferred until December 11 pending additional data on mortality and enrollment by treatment group.

Annals Emergency Medicine 2001;38:397-404.

JAMA 1999;282:1857-64.


DCLHb DSMB Deliberations

  • Conference call December 11, 1997:
    • Mortality 8/38 saline;

17/45 DCLHb; p value .098.

    • European data considered.
    • No action.
  • Conference call January 1, 1998:
    • Mortality 9/44 saline;

24/53 DCLHb; p value .010.

    • European data considered.
    • DSMB recommended stopping enrollment.

Annals Emergency Medicine 2001;38:397-404.

JAMA 1999;282:1857-64.


Baxter Ends U.S. Trauma Study of Hemassist (DCLHb)

European Trauma and U.S. surgery Trials Continue on Track

DEERFIELD, Ill., March 31, 1998 - Baxter Healthcare Corporation announced today that it has ended its U.S. Phase III trauma trial investigating the efficacy of its oxygen-carrying solution, HemAssist(DCLHb), for the treatment of severe traumatic hemorraghic shock. Baxter decided to stop the trial, which had enrolled approximately 100 of its expected 850 participants, following an interim data review by the trial’s independent data monitoring committee. The committee found that patients in the treatment group had an increased mortality compared to those in the control group.


“The European trauma trial, where physicians are administering HemAssist(DCLHb) at the trauma site, is continuing on track. Our U.S. Phase III surgery trial moves forward as well.”


Baxter Suspends European Trauma Trial for its Hemoglobin Therapeutic

Decision will Delay Receiving Marketing Clearance

DEERFIELD, Ill., June 2 /PRNewswire/ -- Baxter Healthcare Corporation announced today that it has suspended enrollment in its European clinical trial investigating its oxygen-carrying solution, HemAssist(R)(DCLHb), in patients suffering from severe trauma. Baxter has suspended the trial, which had enrolled 117 patients, to further analyze the data gathered to date and assess if the trial as currently designed can meet the established endpoints for efficacy. Baxter said this decision will delay the company's ability to receive marketing clearance for HemAssist(R)(DCLHb) in the United States or Europe, which it had been expecting by late 1999 or early 2000.



Baxter to Focus on Next-Generation Oxygen-Carrying Therapeutics; Decision Will End Clinical Development of First-Generation Program

Baxter Also Will Incur Special Charges Against Third-Quarter Earnings

DEERFIELD, Ill., Sept. 16 /PRNewswire/ -- Baxter Healthcare Corporation announced today that it has decided to focus its research-and-development efforts in oxygen-carrying therapeutics, or "blood substitutes," on its second-generation program, which is based on genetically engineered hemoglobin molecules. The decision ends the company's clinical development of its first-generation product, called HemAssist(TM) (DCLHb), which is derived from human hemoglobin. The decision will result in a charge of $75 million against third-quarter net earnings.


polyheme trial
PolyHeme Trial
  • “Patients in hemorrhagic shock will begin to receive either saline (salt water, the standard of care) (control) or PolyHeme (investigational treatment) before arrival at the hospital, and continue for a 12 hour post injury period. In the hospital, patients in the control group will receive saline for hydration and blood if necessary. Unlimited doses of each are allowed. Patients in the treatment group will receive saline for hydration and PolyHeme to increase oxygen levels, up to a maximum dose of 6 units during the first 12 hours. Blood will be used thereafter.”


polyheme trial22
PolyHeme Trial
  • Key controversy:
    • Is it ethical to continue randomized therapy in hospital where blood is available?
    • Some IRBs concluded that blood constitutes an “unproven” therapy.
  • My opinion: true nature of uncertainty and motivation for trial couldn’t find the “light of day” in the controversy.
  • More of my opinion: more public DSMB deliberations might have helped
polyheme trial23
PolyHeme Trial
  • Pivotal trial, with over 700 subjects, failed to meet predetermined superiority or non-inferiority criteria (~December 2006)
  • April 26, 2007 (Reuters): - Northfield Laboratories said its CRO informed that the report of the summary data from its pivotal late stage trauma trial of its blood substitute will not be complete until May.
  • Conducting a clinical trial utilizing an exception from informed consent requires:
    • The right therapy, population, setting and study goal;
    • Resources necessary for community consultation, public disclosure, DSMB activities, and other requirements; and
    • A willingness, commitment, and ability to “do the right thing” even if not seemingly the best apparent business strategy.