Enhancing Informed Consent: Enhancing Informed Consent: Lessons from Studies in Lessons from Studies in

Childhood CancerChildhood Cancer

Eric Kodish, MD

Department of Bioethics

Lerner College of Medicine

Cleveland Clinic

SACHRP

October 28, 2009

Pediatric EthicsPediatric Ethics“A branch of bioethics that analyzes moral aspects of decisions made relating to the health care of children.”

Lyren and Kodish

Encyclopedia of Bioethics

3rd Edition

Informed Consent Informed Consent

in Pediatricsin Pediatrics = = Parental PermissionParental Permission

+ Assent of the + Assent of the ChildChild

A Misnomer

The Beginning: Questions about Informed Consent

What is better informed consent?

A higher consent rate / better accrual numbers? A lower consent rate suggesting freedom to decline? Enhanced compliance with federal regulations? Improved understanding of the study by subjects? Empowered participants in control of the research decision?

Project on Informed Consent (PIC):Research Strategy, 1999-2002

1. Describe current practice using direct observation methodology2. Learn from parents of children with cancer and collaborate to improve

the consent process.

Two Sources of Information

1. Direct Observation of Informed Consent Conferences (ICCs) and Parent Interviews

PIC is the 1st informed consent study to include direct observation

2. Parental Recommendations for Improving Informed Consent Focus Groups and the Parent Advisory Group on Informed Consent

(PAGIC)

DIRECT OBSERVATION

FOCUS GROUPS

PAGICN = 9

N = 72

N = 140Year 1- 2

Year 3

Year 4

Project on Informed Consent:Research History

The Informed Consent ProcessThe Informed Consent Process

Diagnosis Treatment End

Observed/taped conference(s) andinterviews

Telephone Interviews

Focus Groups PAGIC

Clinical Event

Research Event

Treatment at 4-6 months

Notification

Disclosure and consent conferences

Results: Randomization was explained by physicians in 83% of cases and consent document was presented during the conference in 95% of cases. Interviews after the conference demonstrated that 68 (50%) of 137 parents did not understand randomization. Parents of racial minority and lower socioeconomic status were less likely to understand randomization (P<.001 for each). Discussion of specific clinical trial details and the presence of a nurse during the conference were associated with understanding. Eighty-four percent of children were enrolled in a leukemia trial.

Conclusions: Despite oral and written explanation, half of the parents in this study did not understand randomization for childhood leukemia trials. To make informed consent more effective, future research must seek to improve communication during this critical interchange.JAMA, 2004;291:470-475 www.jama.com

Parental Understanding: Parental Understanding: ChoiceChoice

On a conceptual level, understanding choice is more than just On a conceptual level, understanding choice is more than just

understanding that trial participation is voluntary.understanding that trial participation is voluntary.

Understanding choice requires that parents/patients have a clear Understanding choice requires that parents/patients have a clear appreciation of the alternative(s) to study participation.appreciation of the alternative(s) to study participation.

33% of parents did 33% of parents did notnot understand that understand that they had a choice between participation they had a choice between participation in the RCT and off-study therapy.in the RCT and off-study therapy.

Hiatus of Informed Consent, Hiatus of Informed Consent, PIC StudyPIC Study

Explained UnderstoodExplained Understood

by Cliniciansby Clinicians by Parentsby Parents

Choice: Choice: 89%89% 67%67%

Randomization:Randomization: 83%83% 49%49%

Deficits in Parental UnderstandingDeficits in Parental Understanding

Source/cause of deficits in parental understanding is Source/cause of deficits in parental understanding is not clearnot clear

Whatever the cause, this evidence suggests that Whatever the cause, this evidence suggests that data driven interventionsdata driven interventions to improve the process of to improve the process of communication and information exchange can communication and information exchange can positively affect:positively affect:

Parental comfort levelParental comfort level Parental understandingParental understanding Parental involvementParental involvement

Learning from Parents: The PAGIC ModelLearning from Parents: The PAGIC ModelWhat is Leukemia?

Current Treatment

Randomized Clinical Trial

Understand?

Yes

Understand?

Yes

No

No

Decision

Understand?No Yes

1st Meeting

2nd Meeting

1st or 2nd Meeting

Depending Upon Parents

Why is interactivity important?Why is interactivity important?1) c/w conceptual ideal (bidirectional ICP)1) c/w conceptual ideal (bidirectional ICP)

2) Data from PIC show question asking a/w better parental 2) Data from PIC show question asking a/w better parental understandingunderstanding

IncreasedInteractivity

BetterUnderstanding

Intervention

The MUlti-Site Intervention Study to Improve Consent

(MUISIC) 2003-2007

Intervention phase of MUISIC builds on accomplishments of the PIC study

Previous research identified deficits in informedconsent. MUISIC tests 2 (subsequently 3)

rationally-designed interventions that may improve outcomes for informed consent

Specific Aims of MUISIC

1) To utilize our scientific understanding of the informed consent process in childhood leukemia trials to further develop, test and implement three data-based interventions to improve informed consent:

Physician-directed – teaching improved management of the informed consent conference

Parent-directed – delivered by nurse educators and based on the model of anticipatory guidance for informed consent

Parent-directed – delivered via DVD and based on the model of anticipatory guidance for informed consent

Specific Aims of MUISIC, cont.

2) To conduct a clinical trial to test the effect of each intervention on three specific outcomes:

a. Parental comprehension of choice and alternative to clinical trial participation

b. Parental understanding of randomization

c. Parental participation during the informed consent process as measured by the number and quality of questions asked by parents

3) To determine if any one intervention is superior to a control group, and how the three interventions compare to one another.

Study DesignStudy Design

MUISIC

Physician-DirectedIntervention

Control/No Intervention

Philadelphia

Washington, D.C.

Cleveland

Oakland

Atlanta (SR)

Los Angeles

Atlanta (Eg)

Parent-DirectedIntervention

(Nurse)

Parent-DirectedIntervention

(DVD) Pittsburgh

Description of Intervention Models – Parent-Directed Nurse Intervention

Target of Target of Content of InterventionTraining Intervention Intervention Outcome

Nurse Parents Improved understanding of consent (parents);enhancedinvolvementof parents in theconsent process,relative to controls

Support and anticipatoryguidanceregarding informed consent conference

Description of Intervention Models – Parent-Directed DVD Intervention

Target of Target of Content of InterventionTraining Intervention Intervention Outcome

DVD Parents Support andanticipatoryguidanceregardinginformed consentconference

Improvedunderstanding ofconsent (parents);enhancedinvolvementof parents in theconsent process,relative to controls

Description of Intervention Models – Physician-Directed Intervention

Target of Target of Content of InterventionTraining Intervention Intervention Outcome

Physician Physicians Communication;listening skills;management ofconsent conference

Improvedunderstanding ofconsent (parents);enhanced involvementof parents in theconsent process,relative to controls

Study DesignStudy Design

MUISIC

Physician-DirectedIntervention

Control/No Intervention

Philadelphia

Washington, D.C.

Cleveland

Oakland

Atlanta (SR)

Los Angeles

Atlanta (Eg)

Parent-DirectedIntervention

(Nurse)

Parent-DirectedIntervention

(DVD)Pittsburgh

Distribution by Site

Parent (Nurse Delivered) Intervention SitesCL14LA10AI12

Parent (DVD Delivered) Intervention SitePI12

Physician Intervention SitesPH36DC22

Control SitesAT33OA 7

--------------------------------------------Total N = 146

Demographics For All CasesDemographics For All Cases

DEMOGRAPHIC DEMOGRAPHIC CHARACTERISTICSCHARACTERISTICS

[MEAN (RANGE) / %][MEAN (RANGE) / %]

All Sites All Sites NN=134=134

Physician-Physician-Directed Directed

Intervention Intervention Site Site

NN=58=58

Parent-Parent-Directed Directed

Intervention Intervention Site Site

NN=36=36

Control Control SiteSiteNN=40=40

Parent AgeParent Age 35.2735.27(19-54)(19-54)

37.437.4(23-54)(23-54)

33.533.5(19-49)(19-49)

33.933.9(19-49)(19-49)

Patient AgePatient Age6.26.2

(0.4-18)(0.4-18)5.65.6

(1-8)(1-8)6.86.8

(1-18)(1-18)6.46.4

(0.4-18)(0.4-18)

Parent GenderParent Gender

(% Female)(% Female)75%75% 71%71% 81%81% 78%78%

Patient GenderPatient Gender(% Female)(% Female) 44%44% 40%40% 50%50% 45%45%

Parent EthnicityParent Ethnicity(% Minority)(% Minority) 45%45% 35%35% 61%61% 45%45%

ISPISP

1-21-2 36%36% 45%45% 31%31% 28%28%

33 22%22% 28%28% 17%17% 20%20%

4-54-5 42%42% 28%28% 53%53% 53%53%

Features of the ICC – MUISIC StudyFeatures of the ICC – MUISIC Study

ICC FeatureICC Feature MeanMean RangeRange

LengthLength 80.13 min80.13 min 23-244 min23-244 min

# of participants# of participants 6.56.5 2-142-14

Feature N=134 [#, (%)]

Attending physician led ICC

100 (75%)

Fellow led ICC 34 (25%)

Communicating Prognosis in the ICCCommunicating Prognosis in the ICC

Diagnosis

DiagnosisN=134[#, (%)]

Standard Risk ALL 62 (46%)

High Risk ALL 46 (34%)

AML 26 (19%)

COMMUNICATING PROGNOSISN=134[#, (%)]

Frames in terms of survival/cure 119 (89%)

Frames in terms of mortality 71 (53%)

Specific number info 98 (73%)

Physician Training Seminars: Physician Training Seminars: Participant Numbers*Participant Numbers*

Physician-Directed Intervention Sites

Seminar 1(Dates of seminar)

Seminar 2(Dates of seminar)

Seminar 3(Dates of seminar)

Total trained physicians*

Washington, DC (CNMC)

4(2/12/2004)

5(9/9/2004)

5(7/7/2005) 14

Philadelphia, PA (CHOP)

13(3/12/2004)

9(10/21/2004)

7(9/13/2005) 29

*Seven physicians at CNMC and thirteen from CHOP attended booster seminars conducted after these full day seminars.

102 total cases

60 physician- directed

intervention42 control

44 cases

2 excluded for missed ICC

40 cases

11 excluded for no offer of trial

14 excluded for no offer of trial

33 total physician-directed cases

26 total control cases

2 excluded for missed ICC

14 excluded for not attending

training seminar

Enrollment and group assignmentEnrollment and group assignment

Observed Features of ICCObserved Features of ICC

ICC FeatureICC Feature[# (%)][# (%)]

Physician-Physician-DirectedDirectedInt. Site:Int. Site:TrainedTrained

NN=33=33

Parent-Parent-DirectedDirectedInt. SiteInt. Site

NN=21=21

Control SiteControl Site

NN=26=26

Right to withdrawRight to withdraw 26 (79%)26 (79%) 15 (71%)15 (71%) 21 (81%)21 (81%)

Described as Described as voluntaryvoluntary 29 (88%)29 (88%) 19 (91%)19 (91%) 19 (73%)19 (73%)

Observed Features of ICCObserved Features of ICC

ICC FeatureICC Feature[# (%)][# (%)]

Physician-Physician-DirectedDirectedInt. Site:Int. Site:TrainedTrained

NN=33=33

Parent-Parent-DirectedDirectedInt. SiteInt. Site

NN=21=21

Control SiteControl Site

NN=26=26

Randomization Randomization explainedexplained 27 (82%)27 (82%) 21 (100%)21 (100%) 20 (77%)20 (77%)

Explains difference Explains difference between RCT and between RCT and non-RCTnon-RCT

32 (97%)32 (97%) 16 (76%)16 (76%) 21 (81%)21 (81%)

Parent Interviews: Parent Interviews: Understanding by ParentsUnderstanding by Parents

Parent FeatureParent Feature[# / [# / NN (%)] (%)]

Physician-Physician-DirectedDirectedInt. Site:Int. Site:TrainedTrained

NN=33=33

Control SiteControl Site

NN=26=26

P valueP value

Understands Understands RandomizationRandomization**

20/26 (77%)20/26 (77%) 14/18 (78%)14/18 (78%) 0.9470.947

Distinguishes - Distinguishes - ChoiceChoice 28/33 (85%)28/33 (85%) 16/26 (62%)16/26 (62%) 0.0410.041

* Excludes participants offered non-randomized trials

MUISIC vs. PIC:MUISIC vs. PIC:Understanding RandomizationUnderstanding Randomization

Comparing PIC study with MUISIC study Comparing PIC study with MUISIC study control group:control group:

Understanding randomization was only Understanding randomization was only 50%50% in PIC in PIC study with the larger group size of study with the larger group size of NN=140=140. .

Understanding randomization was Understanding randomization was 78%78% in MUISIC in MUISIC study for the smaller control group sample size of study for the smaller control group sample size of N=26N=26..

Learning from Parents: The PAGIC ModelLearning from Parents: The PAGIC ModelWhat is Leukemia?

Current Treatment

Randomized Clinical Trial

Understand?

Yes

Understand?

Yes

No

No

Decision

Understand?No Yes

1st Meeting

2nd Meeting

1st or 2nd Meeting

Depending Upon Parents

Sequence AnalysisSequence Analysis

* The first six coded variables were * The first six coded variables were considered to be part of “What is considered to be part of “What is leukemia?” and were noted as discussed leukemia?” and were noted as discussed during the ICC prior to discussion of during the ICC prior to discussion of current therapy more often in the PDI than current therapy more often in the PDI than control group cases.control group cases.

† † Side effects of therapy, outline treatment Side effects of therapy, outline treatment plan and length of treatment were items plan and length of treatment were items coded if they were discussed prior to coded if they were discussed prior to description RCT description RCT

Fidelity to PAGIC ModelFidelity to PAGIC Model

Coded Variable

Physician-intervention cases(N=33)

Control cases(N=26) Probability

p Effect size

(ES)

Yes Yes

* Diagnosis discussion

93.9% 76.9% 0.058 17%

Discussion of prognosis

87.9% 57.7% 0.008 30%

Prognostic characteristic

78.8% 42.3% 0.004 37%

Definition of leukemia

78.8% 30.8% 0.000 48%

Review test results 72.7% 19.2% 0.000 54%

Definition of remission

75.8% 34.6% 0.001 41%

† Side effects of therapy

84.8% 38.5% 0.000 46%

Outline treatment plan

81.8% 61.5% 0.082 20%

Discuss length of treatment

81.8% 57.7% 0.042 24%

Question asking by ParentsQuestion asking by Parents

Questions Sites NMean

(questions per 10 minutes)Probability

p

Research related PDI 33 1.5 (SD = 1.1)

0.2Control 26 1.1 (SD = 1.2)

Non-research related PDI 33 5.5 (SD = 3.3)

0.003Control 26 3.2 (SD = 2.3)

Total questions PDI 33 7.0 (SD = 4.0)

0.007Control 26 4.0 (SD = 3.3)

Parent Interview Data: Parent Interview Data: Understanding by ParentsUnderstanding by Parents

Parent FeatureParent Feature[# / [# / NN (%)] (%)]

Physician-Physician-DirectedDirectedInt. Site:Int. Site:TrainedTrained

NN=33=33

Parent-Parent-DirectedDirectedInt. SiteInt. Site

NN=21=21

Control SiteControl Site

NN=26=26

Understands Understands RandomizationRandomization**

20/26 (77%)20/26 (77%) 12/19 (63%)12/19 (63%) 14/18 (78%)14/18 (78%)

Distinguishes - Distinguishes - ChoiceChoice 28/33 (85%)28/33 (85%) 17/21 (81%)17/21 (81%) 16/26 (62%)16/26 (62%)

* Excludes participants offered non-randomized trials

Data on Parental Understanding OutcomesData on Parental Understanding Outcomes

Parental Understanding: Choice 85% of parents at physician-directed intervention sites (trained physician) and 81% of parents at parent-directed intervention sites understood that they had a choice between RCT and off-study therapy

Only 62% of parents at control sites understood that they had a choice

between RCT participation and off-study therapy

Parental Understanding: Randomization 77% of parents at physician-directed intervention sites (trained physician) and 63% of parents at parent-directed intervention sites understood that their child would be randomly assigned to one of RCT multiple arms

78% of parents at control sites understood that their child would be randomly assigned (remember this was 50% in PIC, with larger sample)

Key Summary PointsKey Summary Points With attention to sequence, With attention to sequence,

choreography and communication choreography and communication science, we can improve the informed science, we can improve the informed consent process.consent process.

The lessons we have learned may not The lessons we have learned may not apply to other contexts.apply to other contexts.

More research is needed.More research is needed.

Support from NIH R01 CA 083267Support from NIH R01 CA 083267