CER
MCO Principles and
Natalizumab case study
AcademyHealth, Boston MA
Tuesday June 29th, 2010
Fadia T. Shaya, PhD, MPH
Center on Drugs and Public Policy
University of Maryland School of Pharmacy
fshaya@rx.umaryland.edu
Objectives

Payers’ considerations in CER

CASE STUDY:

Multiple Sclerosis / Crohn’s Disease clinical overview

Health Related Quality of Life

Cost-Effectiveness Analysis

Formularyy Recommendations

MCO survey
Planning your OR study






Adopt a perspective
S
Specify
if the
th disease
di
or condition
diti
Select relevant alternatives for comparison
Define specific population
Determine time horizon
List all consequences related to the
treatment alternatives for the patient
populations of interest
ECHO model

Consequences: any effect related to the alternatives modeled

Clinical intermediary: Measurements of a patient’s physical or biomedical status
used
d as a surrogate
t for
f or to
t infer
i f the
th degree
d
off disease
di
(BP,
(BP FEV)
Clinical outcomes: Medical events that occur as a result of disease or treatment
(stroke, disability, hospitalization)



Humanistic intermediary: Factors that affect the formation of patients’ opinions
about the effects of disease or treatment on their lives and wellbeing (perceptions)
Humanistic outcomes: Patient self-assessment of the impact of disease or
treatment on their lives and well-being
g ((HRQoL,, PROs))

Costs: Direct medical, direct nonmedical, and indirect costs related to treatments

Economic outcomes: Direct and indirect costs compared to consequences of
medical treatment alternatives (CBA, CEA, CMA)

Treatment modifiers: Factors that may alter intermediaries or outcomes associated
with
ith treatment
t t
t alternatives
lt
ti
(side
( id effects,
ff t compliance)
li
)
Factors that Affect Insurer
D i i
Decisions
Consumer
Co su e e
expectations
pectat o s
DTC advertising
Politics and public image
Safety
Efficacy
Productivity,
y satisfaction and QOL
Effectiveness
Acquisition cost
Physician support
FORMULARY
DECISION
Cost--effectiveness
Cost
HEDIS and NCQA
Regulatory Issues
Disease management programs
Budget Impact
PBM, physician and
pharmacist contracts
Discounts and Rebates
BCBS: an Example
Conduct ~20 to 25 new assessments of drugs,
devices/ other technologies each year
Generally
y focus on clinical effectiveness rather than
cost-effectiveness
Have own criteria to evaluate drugs, devices,
procedures and biological
p
g
p
products to improve
p
health outcomes
Five Criteria by BCBS





The technology must have final approval from
the appropriate governmental regulatory bodies
The scientific evidence must permit
conclusions concerning the effect of the
t h l
technology
on h
health
lth outcomes
t
The technology must improve net health
The technology must be as beneficial as any
established alternative
The improvement must be attainable outside
investigational settings
Tysabri (natalizumab)
Indication
MS: A monotherapy treatment for patients with
relapsing forms of multiple sclerosis who have had
an inadequate response to or are unable to tolerate
alternative therapies.
Dosage:
300 mg/15 mL
(20 mg/mL)
IV every 4 weeks
CD:
CD: Inducing and maintaining clinical response
and remission in adult patients with moderately to
severely active Crohn’s disease with evidence of
inflammation who have had an inadequate
response to, or are unable to tolerate, conventional
therapies and inhibitors of TNF-α.
Safety
Contraindications
Tysabri is contraindicated in
patients
ti t allergic
ll i to
t natalizumab
t li
b or
murine proteins.
Precautions
Tysabri® induces increases in
circulating lymphocytes,
monocytes, eosinophils, basophils,
and nucleated red blood cells
cells.
These effects are reversible,
usually within 16 weeks after the
y
induces mild
last dose. Tysabri®
decreases in hemoglobin levels
that are frequently transient.
Drug Interactions
Concurrent use with
i
immunomodulators,
d l t
immunosuppressants, and
antineoplastics may further
increase the risk of PML and
other opportunistic infections,
and should not ordinarily be
treated with Tysabri®.
Adverse Events
Headache
Pain in extremity
Fatigue
Rash
UTI
Abdominal
Abdominal
Depression
discomfort
Arthralgia
Gastorenteritis
Lower Respiratory Tract Infection
Vaginitis
Diarrhea
Di h
TOUCH Prescribing Program

Due to Tysabri’s® risk of PML, distribution is tightly
regulated by Biogen Idec’s Tysabri® Outreach: Unified
Commitment to Health (TOUCH™) Prescribing Program
Program.
The TOUCH™ program requires prescribers to:
 Educate patients on the risks and benefits before beginning
treatment.
treatment
 Report serious opportunistic and atypical infections.
 Evaluate the patient 3 months after the first infusion, 6
months after the first infusion
infusion, and 6 months thereafter
thereafter.
 Determine every 6 months whether treatment should be
continued and if so reauthorize treatment.
 Submit it Biogen Idec the Reauthorization questionnaire and
Tysabri Patient Status Report every 6 months.
Multiple Sclerosis (MS)
 Multiple Sclerosis is an autoimmune disease
affecting the autoimmune system.
 Prevalence: 2-150 p
per 100,000
,
 Multiple Sclerosis is not a curable disease
 Only can delay disability progress, prevent new attacks
T
Tysabri
b i iis only
l iindicated
di t d ffor R
Relapsing/Remitting
l
i /R itti
Multiple Sclerosis (RRMS)
AFFIRM
Drug
Regimen
n/Demographics
Design
End Points
Results/Comments
1.NAT 300
mg IV
every 4
weeks
NAT 627
Placebo: 315
RCT,
DB, PC,
PG, MC
Primary:
-Cumulative
probability of
sustained
disability
progression
(EDSS)
_____
Placebo NAT 300
Cumulative
probabilty
0.77
0.43
Secondary:
-Annualized
relapse rate at 2
years
-New/growing
lesions
- Adverse events
- Progression of
disability after 2
years (MSFC)
Adverse
Events
2. Placebo
Duration:
116
weeks
Inclusion:
-Age: 18-50
-RMS
-EDSS ≤ 5
- 1 relapse previous
12 months
Exclusion:
-Progressive MS
-Unstabilized relapse
-Recent treatment
with
ith mostt other
th
therapies
Probability
of relapse
56%
28%
MSFC
-0.04
0.09
Lesions
T2
Gd+
T1
Insignificant
difference
6.1
1.2
-
1.2
0.1
76%
reduction
All results p<0
p<0.001
001 except MSFC
MSFC,
p≤0.005
NAT = natalizumab, IV = intravenous, RMS = relapsing multiple sclerosis, EDSS = expanded disability status scale, MS =
multiple
lti l sclerosis,
l
i MSFC = multiple
lti l sclerosis
l
i functional
f
ti
l composite,
it RCT = randomized
d i d controlled
t ll d ttrial,
i l DB = d
double-blind,
bl bli d PC
= placebo-controlled, PG = parallel-group, MC = multicentered, p = probability value, Gd+ = gadolinium enhanced
Polman CH, O’Conner PW, Hardova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910
Safety Evaluation Study
Drug
Regimen
n/Demographics
Design
Results/Comments
1.NAT 300
mg IV
n = 3116
Safety
evaluation
-No new cases of PML confirmed
-44 cases referred to IAC
-43 cases ruled out
-1 case indeterminate due to lack off follow-up
f
-3 previous cases of PML (2 in MS), fulfilled
diagnostic criteria for PML
-Estimated incidence of PML with NAT:
1 case per 1
1,000
000 patients
i
(95% CI
CI: 0
0.2,
2 2
2.8
8 per
1000) with a mean of 17.9 monthly doses
2. Placebo
Duration:
Mean of
17.9
months
th
Inclusion:
-Patients who were
previously in a NAT
clinical trial
(including placebo)
Exclusion:
- Patients who had a
remote exposure to
NAT.
NAT = natalizumab, IV = intravenous, PML = progressive multifocal encephalopathy, IAC = Industry Advisory Council, MS =
Multiple Sclerosis,
Sclerosis CI = Confidence Interval
Yousry TA, Habil M, Major EO, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9):924-933.
Clinical Trials Summary - MS




Probability of disease progression
decreased with natalizumab
Decreased relapse rate with natalizumab
Decreased development and growth of
lesions with natalizumab
Comparable adverse events
 Risk of PML exists with natalizumab, but can
be limited by TOUCH Prescribing Program
Crohn’s Disease (CD)

Crohn’s Disease is an inflammatory disease of
the digestive system
system.
 Autoimmune

Affects 400,000-600,000 people in North America

Tysabri is indicated for inducing/maintaining clinical
response and remission in adult patients with
moderately to severely active Crohn’s disease.
Decision Tree – Crohn’s Disease
ENABLE (CD1)
Drug
Regimen
n/Demographics
Design
End Points
Results/Comments
1.NAT 300
mg IV
every 4
weeks
(0,4,8,
followed
at 12)
NAT 724
Placebo: 181
RCT,
DB, PC
Primary:
- ≥70 point
decrease in
C
CDAI
score at
week 10
_____
Primary*
2. Placebo
Exclusion:
-Various bowel
conditions
-TNF
TNF iinhibitor
hibi therapy
h
within 12 weeks
Duration:
12
weeks
Inclusion:
-Age ≥ 18
-6 month history of CD
-Moderate/severe CDAI
(score ≥220 and ≤450)
Placebo
49%
S
Secondary**
**
30%
%
NAT 300
56%
37%
%
Secondary:
- <150
150 CDAI
score (disease
remission)
*p = 0.05
**p = 0.12
NAT = natalizumab, IV = intravenous, CD = Crohn’s Disease, CDAI = Crohn’s Disease Activity Index, TNF = tumor necrosis
f t RCT = randomized
factor,
d i d controlled
t ll d ttrial,
i l DB = d
double-blind,
bl bli d PC = placebo-controlled,
l
b
t ll d p = probability
b bilit value
l
Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912-1925.
ENABLE (CD3)
Drug
Regimen
n/Demographics
Design
End Points
Results/Comments
1.NAT 300
mg IV
every 4
weeks
(12-56,
followed
at 60)
NAT: 168
Placebo: 171
RCT,
DB, PC
Primary:
- Clinical
response in
study CD1
C
sustained
through week 36
_____
Primary*
2. Placebo
Duration:
48
weeks
Inclusion:
- ≥70 point decrease
in CDAI score at
week 10 in CD1
Exclusion:
- N/A
Placebo
28%
S
Secondary**
**
26%
%
NAT 300
61%
44%
%
Secondary:
S
d
- <150 CDAI
score (disease
remission)
*p < 0.001
**p = 0.003
NAT = natalizumab, IV = intravenous, CDAI = Crohn’s Disease Activity Index, CD = Crohn’s Disease, RCT
= randomized controlled trial, DB = double-blind, PC = placebo-controlled, p = probability value
Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912-1925.
ENABLE Extension (CD2)
Drug
Regimen
n/Demographics
Design
End Points
Results/Comments
1.NAT 300
mg IV
every 4
weeks
(0,4,8,12)
NAT: 259
Placebo: 250
RCT,
DB, PC,
PG, MC
Primary:
- ≥70 point
decrease in
C
CDAI
score at
weeks 8 and 12
_____
Primary*
2. Placebo
Duration:
12
weeks
Inclusion:
-Age ≥ 18
-6 month history of CD
-Moderate/severe
CDAI (score ≥220 and
≤450)
-Elevated CRP (>2.87
mg/mL)
Placebo
32%
S
Secondary**
**
16%
%
Secondary:
-<150
150 CDAI
score (disease
remission) at
weeks 8 and 12
NAT 300
48%
26%
%
Exclusion:
- Various bowel
*p < 0.001
conditions
- TNF inhibitor therapy
**p = 0.002
within 12 weeks
NAT = natalizumab
natalizumab, IV = intravenous
intravenous, CD = Crohn’s
Crohn s Disease
Disease, CDAI = Crohn’s
Crohn s Disease Activity Index
Index, CRP = C
C-reactive
reactive
protein, TNF = tumor necrosis factor, RCT = randomized controlled trial, DB = double-blind, PC = placebo-controlled, PG =
parallel-group, MC = multicentered, p = probability value
Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology 2007;132(5):1672-1683.
Clinical Trials Summary - CD



Natalizumab not effective vs placebo
d i fi
during
firstt 10 weeks
k off ttreatment
t
t
Effective beyond
y
10 weeks
Natalizumab effective during first 10
weeks of treatment when CRP is
elevated
Importance of HRQoL



Patients with CD and MS often have
lower QoL than the general population
population.
Available therapeutic options are costly.
Evidence for humanistic outcomes is of
interest because it shows additional
value that clinical outcomes do not
provide.
Health
H
lth Quality
Q lit off Life
Lif for
f C
Crohn’s
h ’
Disease



Feagan et al. used disease-specific (IBDQ)
and generic health (SF-36
(SF 36, EQ-5D
EQ 5D, Subject
Global Assessment) quality of life assessments
to determine natalizumab's humanistic value in
CD.
The variety of assessments utilized offset the
modest patient enrollment.
Key finding: substantial improvements on
HRQ L for
HRQoL
f patients
ti t who
h responded
d d to
t initial
i iti l
induction therapy and continued therapy for an
additional 48 weeks of treatment
treatment.
Health
H
lth Quality
Q lit off Life
Lif for
f M
Multiple
lti l
Sclerosis



Rudick et al. lacked variety in their
assessmentt tools.
t l
High
g p
patient enrollment strengthened
g
the
applicability of the results to clinical
practice.
Key finding: natalizumab treatment was
shown
h
tto greatly
tl iimprove th
the HRQ
HRQoL
L ffor
MS patients.
COST-EFFECTIVENESS ANALYSIS
HEALTH ECONOMIC MODEL(MS)
from Managed Care Dossier: TYSABRI. New York, NY: Biogen Idec, 2008.
COST-EFFECTIVENESS
COST
EFFECTIVENESS
ANALYSIS(MS)
Results in ICER Ratios
$48,921
Managed Care and CER
A Pilot Survey of MCOs
How familiar are you with the concept
i
Eff
i
off C
Comparative
Effectiveness
Research (CER)?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
How often do y
you use CER to assess
health outcomes?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Occasionally
(3) Sometimes
(4) Often
(5) Always
T what
h extent d
d CER for
f
To
do you need
your decision making?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
How does CER impact
your
decision on
p
y
formulary lists?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
D you use CER iin your decisions
d i i
Do
on
formulary lists?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
In which of the following areas do you
d CER most relevant
l
regard
to your
decision-making?
50.00
45 00
45.00
40.00
35.00
30.00
25.00
20 00
20.00
15.00
10.00
5.00
0.00
(1) Prescription drugs
(2) Specialty drugs
(3) Medical devices
(4) Others
Do you conduct your own CER?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
D you consider
id using
i
i ValueV l
Do
CER in
Based Benefit Design?
60.00
50.00
40.00
30.00
20.00
10.00
0.00
(1) Not at all
(2) Minimal
(3) Somewhat
(4) Moderate
(5) Very much
H
i i
d
How
many participants
are covered
under a plan of your company?
45.00
40.00
35.00
30.00
25.00
20.00
15.00
10.00
5 00
5.00
0.00
(1) Less than 500,000
(2) 500,0001,000,000
(3) 1,000,0003,000,000
(4) 3,000,0005,000,000
(5) more than
5,000,000
References





Tysabri® (natalizumab) [package insert]. Cambridge, MA:
Biogen Idec, Inc; 2008.
Managed Care Dossier: Tysabri® (Multiple Sclerosis)
Sclerosis).
Wellesley, MA: Biogen Idec, Inc., 2008.
Managed Care Dossier: Tysabri® (Crohn’s Disease).
Wellesley MA: Biogen Idec
Wellesley,
Idec, Inc
Inc., 2008
2008.
Kobelt G, Berg J, Lindgren et al. Modeling the costeffectiveness of a new treatment for MS ( natalizumab)
compared
p
with current standard p
practice in Sweden,, Multiple
p
Sclerosis: 2008; 14:679-690.
Rudick RA, Miller D, Hass S, Hutchinson M, Calabresi PA, et
al. Health-related Quality of Life in Multiple Sclerosis: Effects of
N t li
Natalizumab.
b Ann
A Neurol.
N
l 2007 O
Oct;62(4):335-46.
t 62(4) 335 46