FARMAKOEKONOMI

MODELING
Dr. Dwi Endarti, M.Sc, Apt
Lab Manajemen Farmasi dan Farmasi Masyarakat
Departemen Farmasetika – Fakultas Farmasi UGM

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Pendekatan studi Farmakoekonomi berdasarkan cara pengumpulan
data
Farmakoekonomi berbasis studi klinik
(“piggyback pharmacoeconomic study”/”pharmacoeconomic
study alongside clinical trial”)

Farmakoekonomi berbasis studi observasional

(“real world data/real life data/naturalistic pharmacoeconomic
study”)

Farmakoekonomi berbasis modeling

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 Farmakoekonomi berbasis studi klinik
Economic Evaluation Alongside Clinical Trials (EEACTs) is direct observation of the impact
of a therapy on costs and effect

Data are directy observed over the trial period:

Phase III: Phase IV: post-
Phase I: Phase II:
confirm findings marketing
checking for checking for
in large patient surveillance
safety eficacy
population studies

Cost of Illness study Observational data to evaluate

EEACTs
(prevalence/incidence-based CoI) costs, effectiveness,
and adverse drug reaction
Provides economic data for
Provides economic
registration, pricing
evidence for 3

reimbursement
 Farmakoekonomi berbasis studi observasional
“real world data” are observations of effects based on what happens after a prescriptive
(treatment) decision is made where the researcher does not or cannot control who gets
what treatment and does not or cannot control the medical management of the patient beyond
observing outcomes”

Data derived from:

 Prospective observational studies  Non-interventional observations
 Database studies  Prospective registries; Retrospective databases
 Medical records  Data abstraction

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 Farmakoekonomi berbasis modeling

Modeling  Data input diekstrapolasikan menggunakan logika dan persamaan matematika

sehingga menghasilkan suatu kesimpulan studi (biaya, outcome, dan rasio biaya-outcome)

Data derived from:

 Data hasil uji klinis
 Data hasil studi observasional dan lainnya
 Estimasi, asumsi

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 Types of models commonly used
 Decision tree
 Markov model
 Discrete event simulation
 System dynamic model
 Agent-based model/individual-based model

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 Decision trees
 Earliest and most widely used
 Structurally simplest
 Simple directed graph without recursion
 Pictorial representation of a decision situation
 A chronological representation of the decision process
 Present a sequence of decisions and chance events over time
 Static model take a snapshot of a situation
 Well suited to modeling outcomes that occur in the short-term and have a definite conclusion

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 Decision tree components
 A network of three types of nodes:
 Decision (choice) nodes
 Chance (states of nature) nodes
 Outcome (terminal or end) node
 Probability
 Each chance event is assigned a probability
 Sum of alternatives =1 (100%)
 Outcomes value

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 Example of a Decision Tree
Succes

Value_1

Medication A

Failure

Value_2

Disease X

Succes Value_3

Medication B
DECISION NODE

Failure

Value_4
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CHANCE NODE TERMINAL NODE
 Steps in decision tree analysis
1. Identify the decision
2. Structure the decision
3. Specify:
 Consequences of each decision option over time
 Probability that each consequence will occur
4. Determine the value of each outcome ($, LE, QALY)
5. Select the option with the highest expected outcome

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 Step 1: identify the decision
 Who will be the decision maker?
 What perspective will be considered?
 What is the decision and what options will be considered?
 Over what time span will the consequences be analyzed? (how long will study for the
decision?)
 Example: consider a patient with signs and symptoms suggesting a disease X, there will be two
options:
 Treatment with medication A or medication B

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 Step 2: structure the decision
Succes

Medication A

Failure

Disease X

Succes

Medication B

Failure

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 Step 3: specify probabilities of consequences for each options
Succes

p1=0.7
Medication A

Failure

Disease X p2=0.3

Succes

p3=0.8
Medication B

Failure

p4=0.2 13
 Probability for each arm
1++ High-quality meta-analyses, systematic reviews of RCTs, or RCTs
More Reliability
with a very low risk of bias.
1+ Well-conducted meta-analyses, systematic reviews of RCTs, or
RCTs with a low risk of bias.
1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high
risk of bias.
2++ High-quality systematic reviews of case control or cohort
studies. High-quality case control or cohort studies with a very
low risk of confounding, bias, or chance and a high probability
that the relationship is causal.
2+ Well-conducted case control or cohort studies with a low risk of
confounding, bias, or chance and a moderate probability that the
relationship is causal.
2- Case control or cohort studies with a high risk of confounding,
bias, or chance and a significant risk that the relationship is not
causal.
3 Non-analytic studies: for example, case reports, case series.
4 Expert opinion.
Less Reliability 14
Source: Based on Sackett and others (Canadian Task Force on the Periodic Health Examination)
 Step 4: determine the value of each outcome (cost, LE, QALY)
Succes
u1
Medication A
p1

Failure

Disease X u2
p2
Succes
u3
Medication B
p3

Failure
u4
p4 15
 Calculate the outcome values for each alternative

u1
Medication A
p1
p1u1 + p2u2
p2
Disease X u2

u3
p3
MedicationB
p3u3 + p4u4
p4
u4 16
 Step 5: select the option with the highest expected outcome

 If the outcome is cost: the cheaper is most effective

 If the outcome is LE/LY/QALY: the higher is most effective

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 Decision Tree Example
 Illustrative example: Heparin for the prevention of deep vein thrombosis
(DVT) in hip replacement patients
 Patients are at risk of DVT (and pulmonary embolism) post-surgery
 Heparin can be injected pre-surgery and for 7-10 days post-surgery to try
and prevent clots
 However, there are risks of bleeding
 The research question:
 ‘Which is the more cost-effective treatment for hip replacement patients, heparin
or conventional treatment?’
Decision tree for heparin
Bleed
DVT
No bleed
LMW heparin
Bleed
No DVT
No bleed
Hip replacement patients
Bleed
DVT
No bleed
Conventional treatment
Bleed
No DVT
No bleed
Entering probabilities
Bleed
DVT 0.1
0.14 No bleed
LMW heparin 0.9
Bleed
No DVT 0.1
0.86 No bleed
Hip replacement patients 0.9
Bleed
DVT 0.01
0.25 No bleed
Conventional treatment 0.99
Bleed
No DVT 0.01
0.75 No bleed
0.99
 Costs and Utilities
 Costs assumed:  Utilities assumed:
 Cost of heparin - £300  DVT – 0.70
 Cost of conventional treatment - £50  Bleed – 0.95
 Cost of deep vein thrombosis event -  DVT & bleed – 0.65
£2000  No event – 1.00
 Cost of bleed - £500
Entering outcomes (QALYs) QALY

Bleed
0.65
DVT 0.1
0.14 No bleed
0.7
LMW heparin 0.9
Bleed
0.95
No DVT 0.1
0.86 No bleed
1.00
Hip replacement patients 0.9
Bleed
0.65
DVT 0.01
0.25 No bleed
0.7
Conventional treatment 0.99
Bleed
0.95
No DVT 0.01
0.75 No bleed
1.00
0.99

Assume timeframe is one year

Entering outcomes (Costs) Cost £

Bleed
2800
DVT 0.1
0.14 No bleed
2300
LMW heparin 0.9
Bleed
800
No DVT 0.1
0.86 No bleed
300
Hip replacement patients 0.9
Bleed
2550
DVT 0.01
0.25 No bleed
2050
Conventional treatment 0.99
Bleed
550
No DVT 0.01
0.75 No bleed
50
0.99
 Full structure of cost-effectiveness analysis

Bleed
2800 / 0.65
DVT 0.1
0.14 No bleed
2300 / 0.7
LMW heparin 0.9
Bleed
800 / 0.95
No DVT 0.1
0.86 No bleed
300 / 1.00
Hip replacement patients 0.9
Bleed
2450 / 0.65
DVT 0.01
0.25 No bleed
2050 / 0.7
Conventional treatment 0.99
Bleed
550 / 0.95
No DVT 0.01
0.75 No bleed
50 / 1.00
0.99
 Example: analysing the tree (output as QALYs)
Bleed
0.65
DVT 0.1 A
No bleed
A
0.14
0.7
LMW heparin 0.9
0.95 QALYs C
Bleed
0.95
No DVT 0.1 B
No bleed B
0.86
1.00
Hip replacement patients 0.9
LMW heparin : 0.95 QALYs
Bleed
0.65
DVT 0.01
No bleed
DD
0.25
0.7
Conventional treatment 0.99
0.92 QALYs FF Bleed
0.95
No DVT 0.01
EE
0.75 No bleed
1.00
0.99
 Rollback Calculations
 Work from terminal nodes towards decision nodes

 QALYs of conventional treatment arm is

 QALYs of heparin arm is

Point D = (0.65*0.01) + (0.70*0.99) = 0.6995

Point A = (0.65*0.1) + (0.70*0.9) = 0.695
Point E = (0.95*0.01) + (1.0*0.99) = 0.9995
Point B = (0.95*0.1) + (1.0*0.9) = 0.995
Point F = (0.6995*0.25) + (0.9995*0.75) = 0.9245
Point C = (0.695*0.14) + (0.995*0.86) = 0.953
Example: analysing the tree (output as costs)
Bleed
2800
DVT 0.1
A
0.14 No bleed
2300
LMW heparin 0.9
£ 630 C
Bleed
800
No DVT 0.1 B
0.86 No bleed
300
Hip replacement patients 0.9
Conventional treatment : £ 555
Bleed
2550
DVT 0.01 D
0.25 No bleed
2050
Conventional treatment 0.99
£ 555 F
Bleed
550
No DVT 0.01
E
0.75 No bleed
50
0.99
 Rollback Calculations
 Work from terminal nodes towards decision nodes

 Costs of conventional treatment arm is

 Costs of heparin arm is

Point D = (2,550*0.01) + (2,050*0.99) = 2,055

Point A = (2,800*0.1) + (2,300*0.9) = 2,350
Point E = (550*0.01) + (50*0.99) = 55
Point B = (800*0.1) + (300*0.9) = 350
Point F = (2,055*0.25) + (55*0.75) = 555
Point C = (2,350*0.14) + (350*0.86) = 630
Example: Result from analysing the tree (CEA)

Strategy Cost Incremental QALY Incremental ICER

Cost QALY (£ per
QALY)
Conventional £555 0.92
Treatment
LMW heparin £630 £75 0.95 0.03 £2500

ICER = 630 – 555 = 75 = £2500 per QALY

0.95 - 0.92 0.03
 Markov Model
 A recursive model, allowing movement back and forth between points in
a model
 Used to
 Chronic disease
 Long-term outcome
 Markov model compile outcomes (cost, survival, QALY based on the
progression over time of subject into the various Markov health states
and their experience in term of accumulated cost, survival, and QALY)
 Markov model simplifies reality (in our case = disease processes) by
representing it as a series of successive “Health States”
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 Components of Markov model
 Structure
 List of states with the transitions specified for each state (health state)
 Probabilities (transitional probabilities)
 Initial set of probabilities describing the initial distribution of Markov cohort among the states
immediately before the process begins
 Rewards
 Payoffs : cost, outcome (LY, QALY)
 Termination condition
 Absorbing state (stopping rule)

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Markov Model Transient or
Recurrent state: can
leave, stay, or return

Absorbing state:
individuals who enter
that state cannot
transition out of it

Temporary state: state that allowed transition

only to other states. Thus, it is impossible to
remain in a temporary state for more than
one cycle

Inadomi JM. Eur J Gastroenterol Hepatol. 2004, 16:535–542.

 Steps to develop Markov model
1. Identify Markov health states
2. Identify cycle length
3. Identify allowable transitions
4. Identify transition probabilities
5. Identify outcome values (cost and QALY)
6. Program the model and Run the simulation
7. Interpret results

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 1. Identify Markov health states
 Use the literature and expert opinions to identify health states
 It may be better to define health state according to what makes sense from a
disease progression perspective
 Definition of states must match cycle length
 Different types of states:
 Absorbing states: subjects remain there (“death”)
 Non-absorbing states: subjects can exit state by getting worse or better

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 2. Identify cycle length
 Cycle length must match the definition of the health states
 To ensure that the length of the cycle reflects:
 The nature of the disease and the timing of outcomes:
 Acute disease require short cycles
 When events can repeat frequently, a short cycle is also appropriate
 Chronic disease may require longer cycles
 Normally, the longest of cycle is 1 year

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 3. Identify allowable transitions
 Focus is on:
 Structure of the model
 Relationships between model states
 The best approach may be to:
 Develop comprehensively the entire
clinical pathway from the initial to the
final states
 Create synthetic summary and
representation of the model
Death  Death (absorbing state)
 Example of defining allowable transitions:
Asymptomatic disease 
Asymptomatic disease
Asymptomatic disease  Progressive
disease
Asymptomatic disease  Death
Progressive disease  Progressive
disease
Progressive disease  Death
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 4. Identify transition probabilities
 Transitional probabilities can be estimated from primary or secondary data sources:
 Mortality: life tables and actuarial databases
 Clinical trials, registries, retrospective databases
 Literature
 Subjective opinions from experts
 Pure assumptions
 Transitional probabilities:
 Probability that of going from state A to state B in one cycle
 Likelihood that an event will occur in a given time period (between 0 – 1)
 Unitless

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Example of transition probabilities

Transition from To Total

Asymptomatic Progressive Death
Asymptomatic 1 – p[Prog] – p[Dn] p[Prog] p[Dn] 1
Progressive 0 1 – p[Dp] p[Dp] 1
Death 0 0 1 1

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 5. Identify outcomes value
 Outcomes value = payoffs associated with the state:
 Survival (Life expectancy)
 QALY
 Costs

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 6. Program the model and run the simulation
 There is 2 approach can be used to program Markov model:
 Markov cohort simulation:
determines the prognosis of an entire cohort of patient all at once, by splitting the initial cohort into all the
different states of the model
 First order Monte-Carlo simulation:
Follows a large number of patients individually through the model; using random numbers and probability to
solve problems

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 7. Interpreting and Presenting the results
 Average life expectancy for the cohort of patient simulated
= Sum of all person-years across all cycles and patients
Number of patients entering the simulation

 Total cost/QALY incurred by the entire cohort of state

= Each person-year in each particular state x Annual cost/QALY

 Lifetime cost/QALY
= Total cost/QALY
Number of patients entering the simulation

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Illustration: markov cohort simulation

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 State-Transition Diagram for Atrial Fibrillation
State of Next Cycle
State of Well Post- Dead
Current Cycle Stroke
p11=0.7
Well 0.7 0.2 0.1

Well Post- 0.0 0.9 0.1

Stroke
p12=0.2 p13=0.1 Dead 0.0 0.0 1.0

p22=0.9

Post- Dead
Stroke p23=0.1
p33=1.0

The probabilities for all paths out of a state must sum to 1.0.
 Evaluating Markov Models:
Cohort Simulation
State
Cycl Well Post- Dead Sum of Survival Check
e Stroke Years
Lived
0 10,000 0 0 10,000
1 7,000 2,000 1,000 9,000 0.9000 10,000
2 4,900 3,200 1,900 8,100 0.8100 10,000
3 3,430 3,860 2,710 7,290 0.7290 10,000
4 2,401 4,160 3,439 6,561 0.6561 10,000
5 1,681 4,224 4,095 5,905 0.5905 10,000
6 1,176 4,138 4,686 5,314 0.5314 10,000
7 824 3,959 5,217 4,783 0.4783 10,000
93 0 1 9,999 1 0.0001 10,000
94 0 0 10,000 0 0.0000 10,000
 State
Cycle Well Post-Stroke Dead Sum of Years Survival Check
Lived
0 10,000 0 0 10,000

0.7*10,000 0.2*2000 0.1*10,000

1 7,000 2,000 1,000 9,000 0.9000 10,000

1,000+(0.1*7,000)
(0.2*7,000)+ +(0.1*2,000)
0.7*7,000
(2,000-0.1*2,000)

2 4,900 3,200 1,900 8,100 0.8100 10,000

94 0 0 10,000 0 0.0000 10,000

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TERIMA KASIH

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