Exception from Informed Consent for Research in Emergency Settings

Marilyn Morris MD, MPH

Susan S. Fish, PharmD, MPH

• 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 isabsolutely essential.”

Helsinki, Finland, 1964 latest revision, 2000

Emergency research is permissible “…only if the condition that prevents obtaining consent is a necessary characteristic of the research population.”

“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

(J. Am. Med. Assoc. 273, 1283–1287;

JAMA April 1995

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 necessary2. Obtaining informed consent is not feasible3. 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

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)

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 ofreasons 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 proceduresa. Window of opportunity/therapeutic windowb. Procedures for attempts at consentc. 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 protocola. Therapeutic windowb. How to attempt consent

3. Write documentsa. Informed consent formb. Information form

INVESTIGATOR RESPONSIBILITIES 21 CFR 50.24 and 45 CFR 46.101(i)

4. Define (in conjunction with IRB)a. Communityb. Methods of community consultationc. 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

Biros 2009

Survey of 1901 people at a “popular public venue”

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?”

10%43%

p < 0.01

Paragraph format

Bullet format

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>

Merriam-Webster.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?”

0

20

40

60

80

Very likely to read Somewhat likely Somewhat unlikely Very unlikely

84%

“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;6:1272-1282. (www.aemj.org)

SUMMARY

• Rare use• Important research• Vulnerable population• Special protections• Respect for persons