Waiver of Informed Consent: Balancing Protection and Feasibility

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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

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Introduction

• 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.

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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.

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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).

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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.

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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.

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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.

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MID-CM Device by TheraCardia
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MID-CM Device by TheraCardia
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MID-CM Device by TheraCardia
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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.

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TriTAb

• 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.

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TriTAb

• 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.

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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.

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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...
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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 200138397-404. JAMA
19992821857-64.
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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 200138397-404. JAMA
19992821857-64.
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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 trials 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.
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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. ...
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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. ...
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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.
• http//www.northfieldlabs.com/amb_trial_des.html

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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 couldnt find the light of
  day in the controversy.
• More of my opinion more public DSMB
  deliberations might have helped

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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.

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PolyHeme Trial
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Conclusions

• 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.

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