Template farmaco-economisch dossier

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Template Pharmacoeconomic

dossier

(Concerning a reimbursement

application for a “GVS geneesmiddel”

or “medisch specialistisch

geneesmiddel”)

National Health Care Institute

Zorginstituut Nederland (ZIN)

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General Instructions

This is the template for a pharmacoeconomic dossier as part of a reimbursement application (concerning a “GVS geneesmiddel” or a “medisch specialistisch geneesmiddel”) addressed to the National Health Care Institute (ZIN). This reporting guideline is designed to obtain all relevant information for a pharmacoeconomic assessment in a complete and structured manner.

All pharmacoeconomic evaluations submitted in order to support a reimbursement application need to be performed according to the current guidelines for economic evaluations in health care. The documents “Guideline for Economic Evaluations in Healthcare” and the “Manual for Costing Research” are available on the ZIN website (www.zorginstituutnederland.nl).

In the Guideline a reference case is introduced which all economic evaluations should comply with at minimum. Please check if your economic evaluation is in line with the reference case as presented in the table below.

Part Reference case See

Guideline/p aragraph

Perspective Societal perspective 1.2 PICOT P: (Patient) population in the Netherlands 1.3

C: Standard of care or usual care in the Netherlands

T: Lifetime

Scoping beforehand with relevant stakeholders 1.4 Economic

evaluation type Cost-utility analysis (CUA) 2.1.1 Discounting Costs 4% and effects 1.5% 2.2 Uncertainty and

sensitivity analysis

Univariate, probabilistic sensitivity analysis and

scenario analysis 2.3

Effectiveness Systematic review 3.1 Costs All costs inside the healthcare sector, patient and

family and other sectors. Productivity losses: friction cost method. For reference prices use wherever possible the ‘costing guidance’ module

3.2

Effects Expressed in QALYs, a least the EQ-5D-5L with Dutch valuation and whenever relevant also life years gained

3.3

Results

reporting Total costs and effects, incremental costs and effects, incremental cost-effectiveness ratio 4.2 Univariate sensitivity analysis: Tornado diagram

and table

Scenario analysis: table

Probabilistic sensitivity analysis: CE-plane and CEAC

4.3

Using the underlying template is mandatory; therefore please comply with the instructions in this form. Deviations will be accepted on occasion, yet only in case the deviation is well justified. Please mark any sections that you do not consider to be relevant with ‘N/A’ and provide an explicit justification for doing so. A submission of 50 pages maximum (except attachments and references) is recommended. The submission must be in Dutch or in English. For model-based economic evaluations, please submit a transparent and fully executable (without password protection) electronic copy of the model. Please provide full access to the programming code, in such a way that ZIN employees will be able to execute the model, and thus replicate the results of the report. In addition, please ensure that the submitted versions of the model program and the content (methods, results) of the report match. The model should

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be constructed using standard software, i.e. Excel. Please discuss the choice of software with ZIN at your earliest convenience before submitting your application.

Submission criteria:

 Dutch or English language is permitted.

 All specified sections have to be completed. On occasion, marks with ‘N/A’ are acceptable if a section cannot be completed and an explicit and thorough justification is provided.  Removing sections is NOT allowed.

 Adding fields, flow-charts, tables and figures is allowed. Tables can be adjusted, added or removed. Figures and tables can be placed between the text frames.

 Please number all references in the text and include them in a reference list using the Vancouver rules (see: http://www.icmje.org). It is preferable that the references are numbered throughout the whole dossier.

 Please include all references.

 Please include technical documentation, such as the mathematical formulas of the model, detailed statistical techniques, descriptions of the validation methods and results and a detailed explanation of the electronic model.

Submission will not be considered by ZIN if these criteria are not met. Please use the

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Submission checklist

Please verify the completion of the following:

Submission checklist _{Accepted by ZIN} Title page

Header and footer Table of contents Summary

Introduction

- Registered indication - Type of disease/disorder - Dutch epidemiological data

-

Applications and reimbursement in other countries - Research question/Objective Methods - Patient population

- New treatment (intervention) - Comparative treatment (same

as in effectiveness application) - Clinical outcomes

- Lifetime horizon

- Analytical technique: cost-utility analysis is performed - Societal perspective is used

(including health care costs, patient and family costs and costs in other sectors) - Literature study: cost-effectiveness models - Literature study: systematic

review and meta-analysis of effectiveness

- Model structure - Transition probabilities

-

Utilities: EQ-5D-5L with Dutch valuation

- Dutch costs

- Friction cost method for productivity losses

-

Differential discounting (4% costs 1.5% effects) - Assumptions - Internal validation - External validation - Scenario analyses

-

Sensitivity analyses

-

Value of information analysis (if applicable)

Results

- Burden of disease

- Incremental and total effects - Incremental and total costs - ICER

- Scenario analyses

-

Sensitivity analyses

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(optional)

General Discussion and Conclusion Discussion in case of initial submission intramural drug (if applicable)

Discussion in case of resubmission intramural drug at t=x (if applicable) All references are correct

All references are included All appendices are included

The electronic model is unlocked and included in the submission

Technical documentation including all of the following

-

Mathematical formulas as used in the model

-

Detailed statistical techniques as used in the model

- Description of the methods and results of the internal

validation

- Description of the methods and results of the external

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Pharmacoeconomic dossier

for

Generic name (Brand name®)

for the treatment of:

disease/disorder

Dossier status:

Preliminary dossier / Final dossier

Date:

Details manufacturer:

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Pharmacoeconomic dossier for Generic name (Brand name®)

Abbreviations

8 Summary

9 1. Introduction

10

1.1 Registered indication of the drug 10

1.2 Type of disease/disorder 10

1.3 Epidemiology 10

1.4 Applications and reimbursement in other countries 10

1.5 Research question / objective 10

2. Methods

11

2.1 Patient population 11

2.2 New treatment (intervention) 11

2.3 Comparative treatment 11 2.4 Clinical Outcomes 11 2.5 Time horizon 11 2.6 Analytical technique 12 2.7 Literature study 12 2.7.1. Economic models 12

2.7.2. Systematic review and Meta-analysis of effectiveness 12

2.8 Economic Model and input parameters 12

2.8.1. Model structure 13

2.8.2. Model input parameters 13

2.8.3. Assumptions 14

2.9 Validation 15

2.10 Sensitivity & scenario analyses 15

3. Results

17

3.1 Burden of disease 17

3.2 Incremental and total effects 17

3.3 Incremental and total costs 17

3.4 Incremental cost-effectiveness ratio (ICER) 18

3.5 Sensitivity analyses 18

4. Discussion and conclusion

20

4.1 General discussion and conclusion 20

4.2. Discussion in case of initial submission for intramural drug (if applicable) 20 4.3. Discussion in case of resubmission for intramural drug at t=x (if applicable) 20

References

21 Appendices

22

Preliminary dossier/Final dossier: XX/XX/20XX

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Abbreviations

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Summary

Please add a summary of the findings with a maximum of 750 words, without the use of tables or figures

Research question

Clearly state the research question of the pharmacoeconomic evaluation.

Methods

Briefly, describe the study perspective, patient population, comparative treatment, analytical technique and study design.

Results

Describe the study results in terms of costs, effects and the incremental cost-effectiveness ratio.

Conclusion

Describe the conclusion of the pharmacoeconomic evaluation.

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1. Introduction

1.1 Registered indication of the drug

Please provide brief information on the drug, including the registered indication and the indication for which reimbursement is requested. Also include for which indications the substance is currently reimbursed.

1.2 Type of disease/disorder

Please provide information regarding the type of disease and/or indication addressed in the economic evaluation. Please provide the characteristics of current Dutch patients with regard to age, weight (if applicable), co-morbidities, and mortality rates. Please describe the current treatment options for Dutch patients according to (preferably Dutch) clinical guidelines.

1.3 Epidemiology

Please present Dutch data regarding prevalence and incidence. If no Dutch data are available, European or global epidemiological data may be presented. Please clearly justify and

substantiate why these data are representative for the Dutch population.

1.3.1 Dutch epidemiological data of subgroups

If effectiveness data show significant differences between subgroups or if it can be expected that cost-effectiveness will be different between subgroups, provide Dutch data on prevalence and incidence (and if applicable mortality) rates on subgroups of interest.

1.4 Applications and reimbursement in other countries

Indicate whether the evaluation of the drug is currently ongoing in other European countries, the USA, Canada, or Australia or whether it is finalized. If finalized, please describe the cost-effectiveness results in those countries and the outcome of the reimbursement decision that followed.

1.5 Research question / objective

Please clearly state the research question and include the claim of the applicant regarding the cost-effectiveness of the drug of interest.

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2. Methods

In paragraphs 2.1 until 2.5 the PICOT should be described.

2.1 Patient population

Please describe the patient population included in the pharmacoeconomic analysis. Please ensure that the study population included in the clinical registration trials and the electronic model correspond to the registered indication of the drug. The economic evaluation must be performed on the entire study population and also on subgroups that have been identified on the basis of possible differences in effectiveness, costs and/or other arguments. Please fill in tables 1 and 2 in the appendix.

Furthermore, please provide a table comparing the actually modelled population with the populations in the clinical studies. Please indicate age, sex, earlier treatment, co-morbidities, race, etc. per modelled group. If a meta-analysis has been performed, please show which studies were included.

2.2 New treatment (intervention)

Please describe the intervention/combination of interventions being considered.

2.3 Comparative treatment

Please compare the new treatment with the standard treatment or treatment combination, or if that does not exist, the usual treatment. Also please provide support for the choice of the comparative treatment. The comparative treatment should be the same as used in the pharmacotherapeutic assessment.

2.4 Clinical Outcomes

Please describe the clinical outcomes used in the model per modelled cohort. Please describe and provide support for each outcome measure on how effects were measured. If effects are extrapolated for the model, please clearly describe and provide support for the methods used. Please fill in tables 3 and 4 in the appendix.

If certain relevant outcome measures have been excluded from the economic evaluation please justify this decision.

2.5 Time horizon

The preferred time horizon of a pharmacoeconomic evaluation is lifetime. Please substantiate that the chosen time horizon is lifelong. If a different time horizon is chosen, please justify this choice. Additionally, please indicate and justify the length of the clinical studies used to extrapolate the data in time.

2.6 Analytical technique

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In accordance with the Dutch guideline for economic evaluations in health care, accost-utility analysis and societal perspective should be used. A societal perspective includes all costs and benefits, irrespective of who actually bears the costs or receives the benefits, including productivity costs, travel costs and costs associated with care given by informal caregivers. Please confirm that the following is used:

- Cost-utility analysis

- Societal perspective (including all above mentioned cost categories)

- Differential discounting (4% costs, 1.5% effects)

2.7 Literature study

2.7.1. Economic models

Describe the search strategy: to

 Describe the models found and the usefulness of those published models for this dossier.  Provide the results per treatment, indication, cost-effectiveness, costs/QALY, quality of

life and its combinations.

 Please discuss briefly which information from these publications is used for this economic evaluation.

2.7.2. Systematic review and Meta-analysis of effectiveness

If the effectiveness input of an economic evaluation is based on a review of a number of effectiveness studies, then please provide details of the method of synthesis or meta-analysis of evidence per cohort and per outcome modelled. Please also indicate which studies have been excluded and why. Please include a flow-chart of the study selection.

Search strategy: Inclusion criteria:

Results of search strategy: Excluded studies:

Analytical technique: Results:

2.8 Economic Model and input parameters

Modelling is obligatory, and should be in line with the outcome of the pharmacotherapeutic analysis of the clinical studies (preferably ones that have already been published). To ensure transparency please describe clearly the following aspects in paragraph 2.8.1: the type of model used, the rationale for the model, the cycle length, the size of the cohort followed and the moment of entry in the model.

Describe the input parameters used and their values in paragraph 2.8.2. Please verify that the transition probabilities, background mortality rates, utilities, resource use and costs are incorporated correctly into the model. The clinical effect parameters do not need to be described here, because they have already been explained in paragraph 2.4.

Please ensure that the ZIN assessor will be able to change input data to verify the model.

2.8.1. Model structure

 Describe the model structure (Markov, decision tree, etc.) and software that is used.

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 Please motivate that this modelstructure simulates the disease in the Netherlands correctly  Describe the health states that are used in the model.

 Please depict the model in a figure.  Describe the cycle length.

 Describe the size of the cohort followed.  Describe the moment of entry in the model. Model structure:

Health states: Cycle length: Size of the cohort: Moment of model entry:

Figure: Schematic structure of the model

2.8.2. Model input parameters

2.8.2.1. Transition probabilities

Transition probabilities (general description and substantiation of the transition probabilities as used in the model): Please fill in the table below.

(Even if no transition probabilities have been employed, please include the statistical substantiation of the relevant key parameters)

Table..

. Transition probabilities

Transition probability Value Substantiation (including source) Health state A to health state B 0.657 Primary outcome measure clinical

trial2

2.8.2.2. Utilities

Please describe the sources for utilities. Please be advised that the Dutch guideline specifies that the EQ-5D-5L with Dutch tariffs should be used. In case this information is not available, please describe the type of valuation used, nationality of the respondents, and the valuation perspective (patient or societal).

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2.8.2.3. Costs

Please consult the National Health Care Institute Cost Research Manual for the identification, measurement and evaluation of costs. Describe this as follows:

 Cost identification: Please specify the cost categories taken into account and the studies

they were derived from. Please fill in tables 5.a and 5.b in the appendix. The

following cost categories should be identified:

- Healthcare costs: 1) all direct costs related to the intervention, 2) all disease related healthcare costs made until death.

- Costs made by patients and family (including e.g. travelling expenses, compensation for informal care).

- Costs in other sectors (for example in education, volunteer work, or by

municipalities and productivity costs: costs due to absence from work or lower productivity when present (presenteeism), and in unpaid work).

- The above mentioned costs should be included in the base case analysis. The inclusion of healthcare costs of unrelated illness should be explored in a scenario analysis (however only if the intervention is life extending).

 Motivation for excluding cost items: If certain relevant cost items have been excluded

from the economic evaluation please justify this decision and describe the potential consequences of excluding these costs.

 Cost measurement and valuation: After identifying the types of costs that need to be

included in the analysis, the costs are measured. This measurement comprises an inventory of the deployment of people and resources during treatment. Please describe and justify how all costs were measured. The identified and measured cost units subsequently need to be assessed in monetary units using the National Health Care Institute Cost Research Manual for the inputs. If no standard cost inputs are available, please describe and provide support for the identified and measured cost units.

Costs were determined for the year:

Table… Dutch unit costs (€) for resources used

Resources Description of measurement

(including sources) (including sources)Unit cost

GP visit GP visits were measured using Case report Forms (see appendix 1). Participating physicians filled in these forms on a weekly basis and were checked by a GP assistant.

€ 30 (Dutch Cost

Research Manual)

2.8.3. Assumptions

Please describe and substantiate the assumptions as used in the model. Please fill in the table below. Table... Assumptions Assumption Source 1. 2. 3. 4. 5. 6. 7. 8.

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2.9 Validation

Please validate the model internally and externally. Please provide the results of theinternal validation, specifying who performed the validation and the errors that occurred.

Please also include a face validation (i.e. whether the outcomes of the model correspond to the outcomes found in the clinical studies and/or clinical practice) and a technical validation. Please describe the validation process and include a written report as an attachment. If no cost studies have been performed in the Netherlands, it is required that the resource consumption is validated for the Dutch situation by medical specialists.

2.10 Sensitivity & scenario analyses

Sensitivity analyses must be used to show how the results depend on the assumptions made. The methods used for sensitivity analyses, the choice of parameters and the range of these parameters all need to be stated and justified. If relevant, please include a scenario with unrelated medical costs.

2.10.1 Univariate sensitivity analyses

Description of the method used for the univariate sensitivity analyses: The following parameters were analysed (include motivation):

 



Table… Parameter limits used in the univariate sensitivity analyse

s

Parameter Base case

analysis Lower limit Upper limit Source

2.10.2 Probabilistic sensitivity analysis

Description of the methods used for the probabilistic sensitivity analysis: The following parameters were analysed (include motivation):

  

Table… Distribution and parameter limits used in the probabilistic sensitivity analysis

Parameter Distribution Base case

analysis Lower limit Upper limit Source

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2.10.3 Scenario analyses

The following scenarios were analysed:

 Inclusion of healthcare costs of unrelated illness (only if the intervention is life extending).



2.10.4 Value of information analysis (optional)

A value of information (VOI) analysis is based on the results of the probabilistic sensitivity analysis. The expected value of perfect information (EVPI) initially quantifies all consequences of the uncertainty around the parameters. In all model-based economic evaluations where decision uncertainty is found (when the probability that the intervention is cost-effective is lower than 100% at the applicable reference value but still higher than 0%) an EVPI should be calculated.

Supplementary VOI analyses can answer the question whether, and what kind of additional study is efficient. Additionally, they can indicate whether the definitive decision should be postponed while awaiting the results of additional studies. These analyses are relevant if additional study and/or postponement of the decision is a viable policy option. This is only the case in initial submissions of intramural medicines and/or candidates for conditional

reimbursement (“voorwaardelijke toelating”). If a value of information analysis is relevant, the method used and the selection of parameters that were included in the Expected Value of Partial Perfect Information analyses should be described (see the appendix of the Guideline).

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3. Results

3.1 Burden of disease

The burden of disease provides insight into the loss of health and wellbeing of patients due to premature mortality, disability and other non-fatal events. Burden of disease data are

necessary because in the conclusion and discussion chapter these data are related to the cost-effectiveness results using reference values (for more information see the ZIN report:

“Kosteneffectiviteit in de praktijk”).

The burden of disease in the context of a reimbursement application is a quantitative assessment of the number of QALYs lost due to the disease, compared to the QALYs without the disease. It is quantified using the proportional shortfall method, using the following formula: 1-(remaining QALYs with the disease/remaining QALYs without the disease). The number of QALYs with the disease but without treatment can be gathered from the control condition by using the pharmacoeconomic model. This is compared with the number of QALYs in a situation without the disease. The parts of the model regarding the utilities and mortality prediction sections have to be acceptable.

Please perform a quantitative burden of disease assessment as mentioned above and using ‘het stappenplan’ as mentioned in appendix 3 of the ZIN report: Pakketbeheer in de praktijk deel 3.* Please describe the quantitative results of the burden of disease for all subgroups included in the model/analysis.

Please provide Dutch (preferred) or international data form the literature on the burden of disease if available and discuss the validity of the estimated burden of disease compared to these published data.

* ZIN will publish a report on burden of disease in the near future. For the time being the instructions as mentioned in “Pakketbeheer in de Praktijk deel 3” should be used to estimate the burden of disease.

3.2 Incremental and total effects

Please describe the discounted and undiscounted incremental and total effects of the drug and the comparative treatment(s). Additionally, please attach a table with all the results following the example below.

Table…

Discounted and undiscounted incremental and total effects

Discount rate 1,5%

Intervention Comparator Difference Life expectancy (in

years) QALYs

3.3 Incremental and total costs

Please describe the discounted and undiscounted incremental and total costs of the drug and the comparative treatment(s). Also indicate which parameters are cost-drivers in the model. Also please attach a table with all the results following the example below.

Table... Discounted and undiscounted incremental and total costs Preliminary dossier/Final dossier: XX/XX/20XX

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Cost categories Discount rate 4%

Intervention Comparator Difference

Healthcare cost € € €

- € € €

€ € €

Patient and family costs € € €

- Informal care costs € € €

Other costs

Total cost € € €

3.4 Incremental cost-effectiveness ratio (ICER)

Please report the incremental cost-effectiveness ratio (ICER) per patient and per subgroup if applicable. Additionally, please attach a table with all the results following the example below.

Table..

. Discounted and undiscounted ICER’s

ICER

Incremental cost per QALY (discounted) € Incremental cost per life year gained (discounted) € Incremental cost per QALY (undiscounted) € Incremental cost per life year gained (undiscounted) €

3.5 Sensitivity analyses

In order to show the impact of parameter uncertainty on the outcome please present the results of unvariate sensitivity analyses in a tornado diagram. The results of the probabilistic sensitivity analysis should be presented using a effectiveness plane and

cost-effectiveness acceptability curve. Additionally, please analyse the impact of the assumptions made in scenario analyses. Please describe the results of all sensitivity and scenario analyses performed as mentioned in section 2.10. Please fill in the table and figures below. If applicable also describe the results of the VOI analysis here.

Tabel… Results of univariate and multivariate sensitivity analyses

Subject ICER (€/LYG) ICER (€/QALY)

lower upper _lower _upper _lower _upper

Base case 6853 7965

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Figure… Tornado diagram from the univariate sensitivity

analyses

Tabel… Results of scenario

analyses

Subject ICER (€/LYG) ICER (€/QALY)

Base case 6853 7965

Inclusion of healthcare costs of unrelated illness

Figure... CE plane from the probabilistic sensitivity analysis

Figure … Cost-effectiveness acceptability curve (CEAC)

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4. Discussion and conclusion

4.1 General discussion and conclusion

In this paragraph the following issues should be addressed:

- Briefly summarize the results of the cost-effectiveness analyses as performed

- All crucial assumptions are to be addressed, and their impact on the results should be discussed

- Discuss the results of the univariate sensitivity analyses and highlight the parameters with the highest impact.

- Formulate the cost effectiveness conclusion by using both the estimated burden of disease and the accompanying reference value (see the ZIN report “Kosteneffectiviteit in de Praktijk” for information about the reference values) and describe the chance that the intervention is cost-effective (as resulting from the probabilistic sensitivity analysis)

- Please compare the results with economic evaluation studies of the same drug (if available) in other countries or in the literature.

- Please make sure that the conclusion is supported by the results presented.

We conclude that the chance that [medicine] is a cost-effective treatment for patients with [disease] compared to [comparative treatment] is, ..% , assuming a relevant reference value of [€20,000, €50,000 or €80,000 per QALY] for this disease.

4.2. Discussion in case of initial submission for intramural drug

(if applicable)

In case the dossier concerns an initial submission of an intramural drug please discuss the results of the value of information analysis here, if performed. Additionally, please provide recommendations for further research.

4.3. Discussion in case of resubmission for intramural drug at

t=x (if applicable)

In case the dossier concerns a resubmission of an intramural drug at t=x, please discuss the results of this resubmission here and compare these with the results and recommendations as mentioned in the initial submission.

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References

Please number the references and display according to the Vancouver rules: Name Initials. Title.Source Year; vol: pag-pag. Limit the number of authors to three.

Example:

Magill AJ, Abraham FG, Boekes MA, et al. Fever in the returned traveler. Infect Dis Clin North Am 1998; 12: 445-69.

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Appendices

Table 1. Description studies (registry, subgroups, clinical

studies)

study name/

subgroup research design (level of evidence)

patients intervention

& comparator followup primary outcome measures number characteristics

Table 2. Patient characteristics of treatment and comparator

(please also include these data for subgroups)

[Intervention]

n (%) [Comparator]n (%) p age (mean, range)

gender comorbidities

age at diagnosis (mean) time since diagnosis (mean) co-medication

Table 3 Effectiveness of treatment and comparator

[Intervention]

n (%) [Comparator]n (%) p

Primary outcome measure

baseline values (range) values after....time (range) Secundary outcome measures

Table 4: Summary of the utilities applied in the model

utility source baseline utility value 95% CI

Table 5.a Dutch unit costs (€) for resources used

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Pharmacoeconomic dossier for Generic name (Brand name®) Resources Description of measurement

(including sources) (including sources)Unit cost

GP visit GP visits were measured using Case report Forms

(see appendix 1). Participating physicians filled in these forms on a weekly basis and were checked by a GP assistant.

€ 30 (Dutch costing manual)

Table 5.b: Identification and valuation of costs

Identification (items) average total costs

(in year €) Minimal to maximum values Source Medication

-Costs related to side-effects

-Other costs (per item)

-Preliminary dossier/Final dossier: XX/XX/20XX

Template farmaco-economisch dossier

Template Pharmacoeconomic

dossier

(Concerning a reimbursement

application for a “GVS geneesmiddel”

or “medisch specialistisch

geneesmiddel”)

National Health Care Institute

Zorginstituut Nederland (ZIN)

General Instructions

Submission criteria:

Submission checklist

-

-

-

-

-

-

-

-

Pharmacoeconomic dossier

for

Generic name (Brand name®)

for the treatment of:

disease/disorder

Dossier status:

Preliminary dossier / Final dossier

Date:

Contents

Abbreviations

8

Summary

9

1. Introduction

10

2. Methods

11

3. Results

17

4. Discussion and conclusion

20

References

21

Appendices

22

Abbreviations

Summary

Research question

Methods

Results

Conclusion

Describe the conclusion of the pharmacoeconomic evaluation.

1. Introduction

1.1 Registered indication of the drug

1.2 Type of disease/disorder

1.3 Epidemiology

1.3.1 Dutch epidemiological data of subgroups

1.4 Applications and reimbursement in other countries

1.5 Research question / objective

2. Methods

2.1 Patient population

2.2 New treatment (intervention)

2.3 Comparative treatment

2.4 Clinical Outcomes

2.5 Time horizon

2.6 Analytical technique

2.7 Literature study

2.7.1. Economic models

2.7.2. Systematic review and Meta-analysis of effectiveness

2.8 Economic Model and input parameters

2.8.1. Model structure

Figure: Schematic structure of the model

2.8.2. Model input parameters

2.8.2.1. Transition probabilities

. Transition probabilities

2.8.2.2. Utilities

2.8.2.3. Costs

2.8.3. Assumptions

2.9 Validation

2.10 Sensitivity & scenario analyses