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Risk, benefit and patient preferences in the treatment of Crohn’s disease
Bruce E. Sands, MD, MSAssociate Professor of Medicine
Harvard Medical SchoolMedical Co-Director, MGH Crohn’s & Colitis Center
Massachusetts General HospitalBoston, USA
Disclosure
• Abbott Immunology• Berlex • BiogenIDEC• Bristol Myers Squibb• Centocor• Elan• Genentech• Millennium Pharmaceuticals• PDL Biopharma• Procter & Gamble• Prometheus Laboratories• Schering Plough• UCB
A question of risks and benefits
• Biologic therapies (indeed, all of the most effective therapies to date) have possible serious adverse effects
• Biologic therapies may also achieve levels of benefit not previously described
• How should risks and benefits be evaluated, and by whom?
Background
• Objective: To estimate the maximum risk of death or disability for specific clinical benefits of biologic therapy that is acceptable to patients with Crohn’s disease
• Conjoint analysis selected as analytical approach• Most valid and reliable technique available for
quantifying patient preferences1,2
1. Johnson FR, et al. Willingness to Pay for Improved Respiratory and Cardiovascular Health: A Multiple-Format Stated-Preference Approach. Health Economics 2000; 9:295–317.
2. Ryan M, et al. Methodological issues in the application of conjoint analysis in health care. Health Economics 1998;7: 373-8.
Conjoint Analysis
• Developed in mathematical psychology, strong theoretical basis
• Gaining widespread use in health care and policy
• Technique based on premises that • any good or service can be described by its
characteristics or attributes, and that• the extent to which an individual values a good or
service depends on these characteristics
• Can be used to• show how people are willing to trade between
characteristics• Estimate relative importance of different characteristics
Ryan and Farrar. BMJ. 2000;320:1530-3.
Questionnaire Content
Designed to approximate treatment decisions that are typical of CD patients
• Demographics
• Elements of the Crohn’s Disease Activity Index (CDAI)
• Short form of Inflammatory Bowel Disease Questionnaire (SIBDQ)
• Description of levels of clinical benefit and treatment attributes
• Description of treatment risks
• Benefit-risk trade-off questions• 10 questions, 6 versions
— 4 questions for internal validity tests— Remaining 6 questions randomized
Treatment Attributes
Attributes Attribute Levels
Serious complications
Prevents all
Reduces some
Has no effect
Time between flare-ups 6 months
2 years
Need to take oral steroids Yes
No
10-year mortality risks due to serious adverse events
• Serious infection
• PML
• Lymphoma
0%
0.5%
2%
5%
Definition of Serious Adverse Events
• Severe InfectionStudies suggest that some medicines for Crohn's disease increase your chance of getting a serious infection. These include sepsis, an infection of the blood system, and tuberculosis and pneumonia, which are infections of the lungs. Despite the availability of the newer antibiotics, infections can and do result in death for some people.
• LymphomaStudies suggest that some medicines for Crohn's disease increase your chance of getting lymphoma, a cancer of the lymph nodes. A person with lymphoma usually becomes aware of a lump in the neck, armpit, or groin. Other symptoms may include fever, night sweats, weight loss, and fatigue. Even with proper treatment lymphoma can result in death.
• PMLStudies suggest that some medicines for CD increase your chance of getting PML (progressive multifocal leukoencephalopathy). PML is a rare brain infection. The symptoms of PML are serious and may include the inability to think clearly, paralysis, blindness, and coma. PML can result in death or serious disability.
Representations of Risk:Absolute Risks
Krupnick A, et al. (2002). Age, health and the willingness to pay for mortality risk reductions: a contingent valuation survey of Ontario residents. Journal of Risk Uncertainty 24(2): 161-86.
Representations of Risk:Comparative Risks
Risk that a 50-year old man will die in 10 years from various causes
Possible risks of serious side effects you will be asked to consider
Accident
CancerHeart Attack All Causes
101,000
51,000
201,000
301,000
401,000
501,000
601,000
701,000
801,000
01,000
0% 0.5% 1% 2% 3% 4% 5% 6% 7% 8%
Risk that a 50-year old man will die in 10 years from various causes
Possible risks of serious side effects you will be asked to consider
Accident
CancerHeart Attack All Causes
101,000
101,000
51,000
51,000
201,000
201,000
301,000
301,000
401,000
401,000
501,000
501,000
601,000
601,000
701,000
701,000
801,000
801,000
01,000
01,000
0% 0.5% 1% 2% 3% 4% 5% 6% 7% 8%
Attributes Treatment A Treatment B
Severity of Crohn's symptoms during treatment
Moderate
• Moderate pain most days or severe pain on some days
• About 8 or more diarrhea stools per day
• Generally feel very poorly
• Considerable problems with work and leisure activities
Remission
• No pain most days
• No more than 1 diarrhea stool per day
• Generally feel well
• No problems with work or leisure activities
Effect on serious complications
(fistulas, abscesses or bowel obstructions)
Prevents some of the serious complications
Time between flare-ups 1 year
Treatment requires taking oral steroids Yes
Chance of dying from a serious infection within 10 years None would die
Chance of dying or having severe disability from PML within 10 years
None would die or have severe disability
20 patients out of 1,000 (2%) would die or have severe disability
Chance of dying from lymphoma within 10 years None would die
Which would you choose if these were the only options available?
Example of a Stated Preference Trade-Off Question
Patients
• Inclusion criteria• Diagnosis of Crohn’s disease• Age > 18• US resident• On-line informed consent
• Patient identification and recruitment• Natalizumab naïve internet panel (n=342)• Natalizumab naïve clinical panel (clinical research and clinical
practice sites) (n=140)• Natalizumab experienced patient panel (clinical research sites)
(n=98)
• Patients required to access survey via the internet• All patients issued web URL and unique password
• IRB review and HIPAA compliant data collection process
Primary Endpoints
• The relative contribution of the treatment efficacy and risk attributes to patient preferences
• The mean maximum acceptable annual risk (MAR) for clinically relevant treatment efficacy attributes
• The percent of patients accepting various levels of risk for clinically relevant treatment efficacy attributes
Results: Relative Importance of Treatment Attributes
0102030405060708090
100
SymptomSeverity
LymphomaRisk
SeriousInfection
Risk
PreventComp.
Time toFlare-up
Natalizumab Naïve Internet PanelNatalizumab Naïve Clinical Panel
Imp
ort
an
ce
0102030405060708090
100
PMLRisk
SteroidUse -
Natalizumab Patient Panel
Imp
ort
an
ce
Results: Maximum Acceptable Risk for Clinically Relevant Benefits
0.00.1
0.20.3
0.40.50.60.7
0.80.91.01.1
Moderate toMild
Moderate toRemission
Severe toModerate
Severe toMild
Severe toRemission
MA
R (
An
nua
l % R
isk)
PMLSerious InfectionLymphoma
EstimatedPML Risk(95 % CI)
4,611Estimated Risk: 3 cases of PML in 3,116 Natalizumab patients treated for 17.9 months (4,648 person years) (Yousri NEJM, 2006)
3= 0.065%
EstimatedPML Risk(95 % CI)
4,611
Results: Maximum Acceptable Risk for Clinically Relevant Benefits
Estimated Risk: 3 cases of PML in 3,116 Natalizumab patients treated for 17.9 months (4,648 person years) (Yousri NEJM, 2006)
3
MA
R (
An
nua
l % R
isk)
0
0.1%
0.2%
0.3%
0.4%
0.5%
0.6%
0.7%
0.8%
Moderate to Mild
Moderate to Remission
Severe to Mild
Severe to Remission
Severe to Moderate
Natalizumab Naïve Internet PanelNatalizumab Naïve Clinical PanelNatalizumab Patient Panel
Moderate to Mild
Moderate to Remission
Severe to Mild
Severe to Remission
Severe to Moderate
= 0.065%
Results: % of Patients Accepting Risk for Clinically Relevant Benefits
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0% 0.2% 0.3% 0.4% 0.5%Percent Risk
Moderate to Remission
Severe to Remission
Pe
rce
nt A
cce
ptin
g R
isk
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0% 0.1%Percent Risk
Severe to MildSevere to Moderate
Moderate to Mild
EstimatedPML Risk(95 % CI)
Discussion• MAR findings are similar across patient panels
• Treatment decisions were primarily driven by the desire for improvements in daily symptom severity
• CD patients are willing to accept significant risks for clinically relevant therapeutic benefits
• Great majority of patients would accept the observed risks in order to achieve clinically relevant therapeutic benefits
Acknowledgements
• RTI• Reed Johnson• Semra Ozdemir
• Elan• Steve Hass• Jeff White• David Miller
• Dartmouth-Hitchcock• Corey Siegel
Treatment AttributesSymptom Severity and Activity Limitations
Remission Mild
CD
Moderate
CD
Severe
CD
No pain most days
Mild pain most days
Moderate pain most days or severe pain some days
Severe pain most days
No more than one loose stool
per day
About 3 diarrhea stools per day
About 8 or more diarrhea stools
per day
More than 12 diarrhea stools
per day
Generally feel well
Generally feel below par
Generally feel poorly
Generally feel terrible
No problems with work or
leisure activities
Some problems with work or
leisure activities
Considerable problems with work or leisure
activities
Unable to engage in work
or leisure activities
Results: Disposition of Patients in Samples
1,007 persons accessed the survey
(8%)
650 patients failed entry criteria or discontinued
(65%)
357 patients completed the questionnaire
(35%)
25 patients failed data quality tests
(4%)
342 patients passed data quality tests
(96%)
31 patients failed entry criteria or discontinued
(11%)
9 patients failed data quality tests
(4%)
98 received Natalizumab in a
clinical trial
278 patients enrolled from clinical practice sites accessed the
survey
247 patients completed
questionnaire(89%)
238 patients passed data quality tests
(96%)
140 patients had not participated in a
clinical trial
Natalizumab Naïve
ClinicalPanel
(N= 130)
Natalizumab Patient
Panel(N= 98)
NatalizumabNaïve Internet
Panel(N= 342)
Results: Patient Characteristics
Variable Natalizumab Naïve Internet Panel
Natalizumab Naïve Clinical
PanelNatalizumab Patient Panel
Sample Size 342 140 98
Age*
mean (SD)45 39 43
Gender*
% Female73 66 53
Years since diagnosis*
mean (SD)
7.2
(3)
6.8
(3)
8.3
(3)
# diarrhea stools in past 7 days
mean (SD)
15
(21)
13
(17)
26
(26)
IBDQ score
mean (SD)
144
(38)
155
(39)
132
(39)
* P < 0.05
Rationale for the Selection of a 10-Year Risk Horizon• The chronic nature of CD and the clinical benefits of its
treatments are easily described in relation to a time horizon of several years
• A 10-year period enhances the plausibility of the risk exposure for a medication taken on a continuing basis for a chronic condition
• Increases the magnitude of risks to a range that patients can evaluate. Previous studies indicate that most people have difficulty conceptualizing probabilities less than 1/1,000 (Krupnick et al., 2002)
• Pretests of the instrument confirmed that 10 years is a reasonable planning horizon for MS patients
Validity Tests in Crohn’s Survey
Validity Test
Natalizumab Naïve
Internet Panel
(n=342)
Natalizumab Naïve
Clinical Panel
(n=140)
Natalizumab Patient
Panel
(n=98)
Stability 93% 89% 93%
Rational Choice 93 95 96
Monotonicity 96 89 84
Transitivity 89 96 95
PERCENT OF PATIENTS WHO PASSED TEST
Distribution of IBDQ Scores: ENACT-1 Baseline Versus Risk-Benefit Study
0
5
10
15
20
25
30
<69 70-94 95-119 120-144 145-169 > 170
ENACT-1 Baseline
CD Internet Patient Panel
Pe
rce
nt
RemissionImproving QOL
•Panel had somewhat better QOL scores than ENACT-1 patients at baseline
Internet Patient Panel CD Treatment Experience
Treatment Current TX Past TX Never Used
5-ASA 51% 44% 5%
Immunomodulators 41% 30% 29%
Infliximab 27% 30% 43%
Oral steroid 14% 74% 12%
Anti-infectives 10% 71% 19%
Budesonide 10% 37% 53%
Adalimumab 3% 2% 95%
Natalizumab 0.4% 3% 97%
Possible Disadvantages of Stated-Choice Approach
• Potential for hypothetical bias• Not same clinical, financial, emotional consequences as
real treatment choices• Realistic treatment options
• Cognitively challenging for subjects• Need for careful subject preparation• Definition of conditions• Probability concepts• Practice with tradeoff task• Internal validity tests
• Requires expertise in • Qualitative and quantitative survey methods• Experimental design• Advanced statistical analysis
Results: Maximum Acceptable Risk by IBDQ Score
IBDQ <= median (146) IBDQ > median (146)
0%
0.2%
0.4%
0.6%
0.8%
Moderate to Mild
Moderate to
Remission
Severe to Mild
Severe to
Remission
Estimated PML Risk
Remission
MA
R (
An
nua
l % R
isk)
0.1%
0.3%
0.5%
0.7%
Multiple Sclerosis StudyMaximum Acceptable Risk Estimates
0%
0.2%
0.4%
0.6%
0.8%
0.1%
0.3%
0.5%
0.7%
MA
R (
An
nua
l % R
isk)
PMLLiver FailureLeukemia
EstimatedPML Risk(95 % CI)
BenefitRelapses: 4 1 during a 5 year period
Progression: 3 yrs 5 yrs
Questionnaire Development
• Questionnaire was designed to:• Approximate treatment decisions that are typical of CD patients• Map the patients’ CD clinical status to standard measures of
severity
• Content drawn from:• Published literature• Established CD instrumentation• Collaboration of gastroenterologists & researchers experienced in
questionnaire design
• Pre-testing:• Assessed the patients’ ability to understand survey content• Assessed their willingness to tradeoff treatment efficacy against
serious side effect risks — Cognitive interviews (n=10)— Pilot data collection (n=51)
Traditional View
Reject
Accept
Minimum acceptable
efficacy
Benefit
Risk
Maximum acceptable
risk
More Realistic View
Risk
Benefit
Maximum acceptable
risk for patients
Minimum acceptable efficacy for
patients
Reject
Accept
Minimum acceptable efficacy for physician
Maximum acceptable
risk for physician