Exception from Informed Consent
for Research in Emergency Settings
Marilyn Morris MD, MPH
Susan S. Fish, PharmD, MPH
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Historical Context
Regulations and Responsibilities
Ethical Gaps and Public Perceptions
Defining “community”
EFIC in the inpatient setting
Historical Framework
1949: The Nuremberg Code
“The voluntary consent of the human subject is
absolutely essential.”
Emergency research is
permissible “…only if
the condition that
prevents obtaining
consent is a necessary
characteristic of the
research population.”
Helsinki, Finland, 1964
latest revision, 2000
“Consent to remain in
the research should be
obtained as soon as
possible from the
individual or a legally
authorized surrogate.”
The Belmont Report: 1979
Basic ethical principles
– Respect for Persons
(autonomy)
– Beneficence
– Justice
Minimal risk standard for research without informed
consent
Potential for surrogate consent
January 1981
• Code of Federal Regulations
– Largely based on the Belmont
Report
– Allows a waiver of informed
consent for minimal risk research in
emergency settings
– No specific mechanism for
emergency research posing more
than minimal risk
Deferred Consent
• “Is it ok if I borrow your car yesterday?”
• Brain Resuscitation Clinical Trials
• 1993: Dear Colleague Letter
JAMA April 1995
(J. Am. Med. Assoc. 273, 1283–1287;
THE FINAL RULE, IRB AND INVESTIGATOR
RESPONSIBILITIES
Exception from Informed Consent Requirements
in Emergency Research
21 CFR 50.24 and 45 CFR 46.101(i)
(A) IRB with concurring physician finds and documents
1. Life threatening situation with unproven or unsatisfactory
treatment and research is necessary
2. Obtaining informed consent is not feasible
3. Participation in research has prospect of direct benefit
because:
i. Situation necessitates intervention
ii. Science supports potential of direct benefit
iii. Risks are reasonable compared to medical condition,
risks and benefits of standard therapy, and risks and
benefits of proposed intervention
Exception from Informed Consent Requirements
in Emergency Research
21 CFR 50.24 and 45 CFR 46.101(i)
4. Research could not practicably be done without waiver
5. Potential therapeutic window is short; attempt to contact
subject’s legal representative when possible
6. IRB approves consent procedures and document for
subject or legal representative, if feasible; also approves
procedures and information for family member
Exception from Informed Consent Requirements
in Emergency Research
21 CFR 50.24 and 45 CFR 46.101(i)
7. Additional protections
i. Community consultation
ii. Public disclosure prior to study initiation
iii. Public disclosure after study completion
iv. Independent data monitoring committee
v. Attempt to contact family member when possible
Exception from Informed Consent Requirements
in Emergency Research
21 CFR 50.24 and 45 CFR 46.101(i)
(B) Information provided to subject, legal representative,
and/or family as soon as possible
(C) IRB documentation kept for at least 3 years*
(D) Separate IND/IDE*
(E) If IRB does not approve waiver, documentation of
reasons to be shared with sponsor, FDA, other
researchers, other IRBs *
(*FDA regulations only)
IRB RESPONSIBILITIES
21 CFR 50.24 and 45 CFR 46.101(i)
1. Determine if FDA or HHS regulations apply
2. Know state law - is waiver of consent possible?
3. Find and document that criteria are met
4. Determine consent procedures
a. Window of opportunity/therapeutic window
b. Procedures for attempts at consent
c. Advanced directives policy
5. Assess possibility of prospective consent
(practicability)
IRB RESPONSIBILITIES
21 CFR 50.24 and 45 CFR 46.101(i)
6. Provide opportunity for community consultation; use
results to advise IRB deliberations
7. Assure implementation of public disclosure by
investigator; assess adequacy of efforts
8. Consider advice from DMC
9. Ensure information is given to subject, representative,
family as soon as appropriate
10. Keep records at least 3 years
11. Document and share deliberations if study not
approved
INVESTIGATOR RESPONSIBILITIES
21 CFR 50.24 and 45 CFR 46.101(i)
1. Identify how criteria are met
a. Life threatening situation
b. Clinical equipoise exists
c. This research is needed now (basic science
and animal work are supportive)
d. Consent is not feasible
e. Benefit:Risk assessment
f. Study with consent not practicable
INVESTIGATOR RESPONSIBILITIES
21 CFR 50.24 and 45 CFR 46.101(i)
2.
Document in protocol
a. Therapeutic window
b. How to attempt consent
3.
Write documents
a. Informed consent form
b. Information form
INVESTIGATOR RESPONSIBILITIES
21 CFR 50.24 and 45 CFR 46.101(i)
4. Define (in conjunction with IRB)
a. Community
b. Methods of community consultation
c. Methods of public disclosure
5. Submit/obtain IND/IDE (FDA regulations only)
6. Submit information for continuing review
7. Provide data to DMC
8. Inform subject, representative, family
What do people think of EFIC?
It depends who (and how) you ask.
Nov 15, 1996
“The Return of Joseph Mengele”
“The Food and Drug Administration (FDA)
this month reversed 50 years of medical
ethics by freeing researchers to experiment on
patients without consent. New and improved
life-saving therapies supposedly will result.
But nothing is gained if the most basic of
human rights is the price of progress.”
April 22, 2002
VOICES
• Focus groups, 25 women, 17 men
• Drawn from NYC communities in which the
PAD trial took place
• Resistance to the need for EFIC
• Disconnect between theory and specific
examples.
Richardson 2008
Survey of 1901 people at a “popular public venue”
Biros 2009
Survey of 530 people in ER waiting
room
• 49% believed enrolling patients without prior
consent in an emergency situation would be
acceptable
• 70% would not object to be entered into such
a study without providing prospective
informed consent.
McClure 2003
Survivors of SCD
Dickert 2009
“Would you ask that your
child be excluded?”
Paragraph
format
Bullet
format
p < 0.01
43%
10%
Random Digit Dialing
• Used in proposed hypertonic
resuscitation fluid study
(Bulger
2009)
WHAT IS A COMMUNITY FOR THE PURPOSES OF
EFIC RESEARCH?
Community Consultation
…consultation (including, where appropriate,
consultation carried out by the IRB) with
representatives of the communities in which
the research will be conducted and from
which the subjects will be drawn;
Federal Register: 9/21/95
• The proposed rule recognizes that subjects who are
candidates for emergency research will not meet the
condition of being fully competent. In many cases,
they will be totally incompetent. Such potential
subjects, if they are to be enrolled in research, must
be provided with special additional protections. The
special protections proposed in this rule for subjects
of emergency research include prior FDA and
community consultation on the research, public
disclosure, and careful mandatory oversight of the
welfare of subjects by a data and safety monitoring
board.
com·mu·ni·ty
a unified body of individuals:
a : state, commonwealth
b : the people with common interests living in a particular area;
broadly : the area itself <the problems of a large community>
c : an interacting population of various kinds of individuals (as
species) in a common location
d : a group of people with a common characteristic or interest living
together within a larger society <a community of retired persons>
e : a group linked by a common policy
f : a body of persons or nations having a common history or
common social, economic, and political interests <the international
community>
g : a body of persons of common and especially professional
interests scattered through a larger society <the academic
community>
MerriamWebster.com
Merchant RM, Rubright JD, Pryor HP, Karlawish
JHT.
EFIC in the inpatient setting
EFIC in the inpatient setting
• What constitutes impracticability?
– To what extent is prospective consent possible?
• Who comprises the community?
– Setting specific rather than geographic?
– Who are the community leaders?
Themes from an inpatient
community consultation
• Pre-consent
– Burden on families
– Validity of consent
• Need for some communication
• Importance of verbal over written
communication
• Discomfort with randomization
• Discomfort with “control” arm
The inpatient community
• Parents of children hospitalized in an intensive
care unit
– 91/91 reported that parents of critically ill children
represent the most important community
– 75/91 (82%) felt that the inpatient community
represents the entire relevant community
Morris 2006
Trial of a brochure to inform parents of
an ongoing EFIC trial
“Is this a good way to
communicate with parents about a
research study?”
“Would you have read this if someone
gave it to you when your child was
admitted?”
80
84%
60
40
20
0
Very likely to read
Somewhat likely Somewhat unlikely
Very unlikely
“Do you think this study should take
place?”
Evaluation of Public Disclosure
• 75/93 parents interviewed were aware of the
study
• 76/93 remembered seeing the brochure
– 26% did not read,
– 39% read quickly, and
– 35% read carefully
• 37/93 remembered seeing the poster
– 51% did not read,
– 32% read quickly, and
– 17% read carefully
Evaluation of Public Disclosure
• Would you want your child to participate in
the study?
– 67% yes
– 9% no
– 24% undecided.
• Of the 7 parents who did not want to
participate, 3 had opted out and 4 were
unaware that they could opt out.
“Let us not forget that progress is an optional goal,
not an unconditional commitment. ... Let us also
remember that a slower progress in the conquest of
disease would not threaten society, grievous as it is to
those who have to deplore that their particular disease
be not conquered, but that society would indeed be
threatened by the erosion of those moral values
whose loss, possibly caused by too ruthless a pursuit
of scientific progress, would make its most dazzling
triumphs not worth having.”
-Hans Jonas
RESOURCES
• REGULATIONS: www.fda.gov
• GUIDANCE: www.fda.gov
• IMPLEMENTATION: Biros MH, Fish SS,
Lewis RJ. Acad Emerg Med 1999;6:12721282. (www.aemj.org)
SUMMARY
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Rare use
Important research
Vulnerable population
Special protections
Respect for persons