Technology Assessment Report commissioned by the NHS R&D HTA Programme on behalf of the National Institute for Health and Clinical Excellence

Reference No. 05/22 11th

Final version: 5th June 2006

1. Title of the project:

Ezetimibe for the treatment of hypercholesterolaemia

2. TAR team

School of Health and Related Research (ScHARR) Technology Assessment Group, The University of Sheffield.

Lead: Roberta Ara, Operational Research Analyst ScHARR, University of Sheffield, 30 Regent Court, Sheffield S1 4DA Tel: 0114 222 0788 Fax: 0114 272 4095 E-mail: [email protected]

3. Plain English Summary The UK population has one of the highest average serum cholesterol levels in the world,[1] with about 27% and 70% of people having a serum cholesterol level ≥ 6.5 mmol/L and ≥ 5.0 mmol/L, respectively.[2] High levels of cholesterol in the blood (hypercholesterolaemia) are associated with an increased risk of coronary heart disease (CHD) and stroke.[3] Serum cholesterol is an important determinant of cardiovascular risk. The increased risk is due mainly to raised low-density lipoprotein cholesterol (LDL-C). Lowering concentration of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), and raising high-density lipoprotein cholesterol (HDL-C) can reduce the risk of cardiovascular events, and in high risk patients, the cardiovascular morbidity and mortality. More importantly, the absolute risk for an individual also depends on other cardiovascular risk factors such as smoking, diabetes and hypertension, and treatment decisions are generally based on overall risk.

Primary hypercholesterolaemia is associated with an underlying genetic defect; this can be due to a single genetic defect, or, much more commonly, to the interaction of a number of genes with dietary and other factors.[4] Secondary hypercholesterolaemia is caused by another disease state or by drug therapy. The majority of people with hypercholesterolaemia have plasma-cholesterol concentrations that are only mildly or moderately elevated, and they exhibit no clinical symptoms. At the other end of the spectrum, severe hypercholesterolaemia can cause xanthomas (lesions on the skin containing cholesterol and fats) and arcus corneae (cholesterol deposits in the eyes). In people with very severe forms of the condition, such as heterozygous familial hypercholesterolaemia (affects about one in every 500 people.), onset of CHD is not uncommon during the second and third decade of life. Men are at greater risk than women, and if untreated, 50-75% will have a heart attack (myocardial infarction) by the age of 60 years.[1]

Factors which influence the degree of disease in people with hypercholesterolaemia include diet, obesity, smoking and lack of physical activity. Dietary and lifestyle changes are therefore important components in the management of the condition. Lipid regulating drugs may also be indicated and statins are the first choice drugs.[5] However, lipid goals are frequently not achieved due to the initiation of low doses of lipid-lowering medications, inadequate response to therapy, non-adherence to drug treatment and adverse effects.[6;7]

Ezetimibe is a novel, orally active selective inhibitor of intestinal absorption of cholesterol and related plant sterols. Its mechanism of action differs from that of other classes of cholesterol lowering drugs in that ezetimibe selectively inhibits the absorption of dietary and biliary cholesterol and related plant sterols. It does not affect the absorption of fat soluble vitamins or triglycerides in the intestine.[8]

The aim of this review is to systematically evaluate and appraise the clinical and cost effectiveness of ezetimibe (in its licensed indication) as combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK.

4. Decision problem

4.1. Purpose of the assessment The assessment will address the question “What is the clinical and cost effectiveness of ezetimibe (in its licensed indications) as combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in adults”.

4.2. Clear definition of the interventions Ezetimibe is a unique cholesterol absorption inhibitor that blocks the intestinal absorption of dietary and biliary cholesterol and related plant sterols without affecting the uptake of triglycerides or fat soluble vitamins.

Ezetimibe monotherapy (Ezetrol, MSD-Schering-Plough Ltd) is licensed as an adjunctive therapy to diet for:

ƒ Primary (heterozygous familial and non-familial) hypercholesterolaemia in patients in whom a statin is considered inappropriate or is not tolerated

ƒ Primary (heterozygous familial and non-familial) hypercholesterolaemia, co- administered with a statin, in patients who are not appropriately controlled with a statin alone

ƒ Homozygous familial hypercholesterolaemia, co-administered with a statin. Patients may also receive adjunctive treatments such as LDL-C apheresis)

ƒ Homozygous familial sitosterolaemia

A fixed dose combination tablet containing ezetimibe and simvastatin (Inegy, MSD- Schering-Plough Ltd) is also licensed as an adjunctive therapy to diet for use in:

ƒ Primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate: patients not appropriately controlled with a statin alone or patients already treated with a statin and ezetimibe

ƒ Homozygous familial hypercholesterolaemia. Patients may also receive adjunctive treatments such as LDL-C apheresis

4.3. Place of intervention in the treatment pathway The review will focus on the use of ezetimibe (in its licensed indication) as combination therapy or monotherapy in adults for the treatment of primary hypercholesterolaemia in the UK.

The National Service Framework for CHD[9] recommends that patients with clinical evidence of CHD or those with a 10 year risk greater than 30% should be prescribed lipid lowering therapy (combined with advice on diet and lifestyle) with the aim of reducing serum TC to less than 5 mmol/L (or a reduction of 20-25% if that produces a lower concentration) and LDL-C to below 3 mmol/L (or a reduction of about 30% if that produces a lower concentration). More recent guidance from six joint British Societies[3] advocate lower treatment thresholds (e.g. TC less than 4.0 mmol/L and LDL-C below 2.0 mmol/L in all people with CVD or at high risk of CVD, defined as a total CVD risk ≥ 20% over 10 years).

The recent technology appraisal on statins for the prevention of cardiovascular events recommends initiation of statin treatment in patients with 20% or greater 10 year CVD risk.[10] Statins are the most effective drug for lowering LDL-C, in comparison to other classes of drugs, and reduce coronary events, all cardiovascular events and total mortality.[5] However, lipid goals are frequently not achieved due to the initiation of low doses of lipid-lowering medications, inadequate response to therapy, non- adherence to drug therapy and adverse effects.[6;7]

The current review will not consider the use of ezetimibe in people with homozygous familial hypercholesterolaemia or homozygous sitosterolaemia.

4.4. Relevant comparators For patients whose condition is not adequately controlled with a statin alone (defined as failure to achieve a target lipid level) the relevant comparator is:

ƒ Optimal statin therapy

ƒ Treatment with a statin in combination with other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates

For patients in whom a statin is considered inappropriate, or is not tolerated, the relevant comparators are:

ƒ Other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates

4.5. Population and relevant subgroups The population for the assessment will include adults (aged 18 years and over) with primary (heterozygous familial and non-familial) hypercholesterolaemia who are candidates for treatment with statins on the basis of their CVD status or risk and whose condition is not appropriately controlled with a statin alone, or in whom a statin is considered inappropriate or is not tolerated. The identification of subgroups of patients for whom ezetimibe is particularly appropriate or inappropriate will be governed by the available evidence. However, on a priori grounds, information will be sought for people with or without existing ischaemic heart disease or other vascular disease, people with or without diabetes and different ethnic groups.

4.6. Key factors to be addressed The review will aim to evaluate the following objectives:

ƒ Evaluate the clinical effectiveness of ezetimibe as combination therapy or monotherapy in terms of mortality and cardiovascular morbidity. Surrogate end-points (such as total, LDL and HDL cholesterol) will be utilised where information on clinical endpoints is unavailable

ƒ Evaluate the adverse effect profile and toxicity

ƒ Evaluate the cost-effectiveness of ezetimibe in terms of incremental cost per quality-adjusted life years

ƒ Advise on the patient groups for whom ezetimibe might be particularly appropriate

ƒ Estimate the possible overall cost in England and Wales

5. Report methods for synthesis of evidence of clinical effectiveness A review of the evidence for clinical effectiveness will be undertaken systematically following the general principles recommended in the QUOROM statement.[11]

5.1. Population 5.1.1. Inclusion criteria Adults (defined as > 18 years of age) with primary (heterozygous familial and non- familial) hypercholesterolaemia

5.1.2. Exclusion criteria Adults with homozygous familial hypercholesterolaemia or homozygous sitosterolaemia

5.2. Interventions

ƒ For patients whose condition is not adequately controlled with a statin alone the intervention is ezetemibe plus statin combination therapy

ƒ For patients in whom a statin is considered inappropriate, or is not tolerated the intervention is ezetemibe monotherapy

5.3. Comparators

ƒ For patients whose condition is not adequately controlled with a statin alone the comparator is optimal statin monotherapy or treatment with a statin in combination with other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates

ƒ For patients in whom a statin is considered inappropriate, or is not tolerated, the comparator is an alternative lipid lowering agent such as nicotinic acid/ acipimox, bile acid resins and fibrates

5.4. Setting

ƒ Primary and secondary care

5.5. Outcomes

ƒ Survival ƒ Fatal and non-fatal cardiovascular events ƒ Adverse effects of treatment ƒ Health-related quality of life

Where information on clinical end-points is unavailable, consideration will be given to surrogate end-points, such as TC, LDL-C and HDL-C.

5.6. Search strategy A comprehensive search will be undertaken to systematically identify clinical and cost- effectiveness literature pertaining to ezetimibe for primary hypercholesterolaemia. The search strategy will comprise the following main elements: ƒ Searching of electronic databases ƒ Contact with experts in the field ƒ Scrutiny of bibliographies of retrieved papers

5.6.1. Electronic searches Search strategies will be used to identify relevant trials (as specified under the inclusion criteria, below) and systematic reviews/meta-analyses (for identification of additional trials). Searches will not be restricted by language or publication date. An example of the Medline search strategy is shown in Appendix 1.

5.6.2. Databases The following electronic databases will be searched from inception: MEDLINE (Ovid); CINAHL; EMBASE; The Cochrane Library including the Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register (CENTRAL), DARE, NHS EED and HTA databases; Science Citation Index (SCI); National Research Register (NRR); Current Controlled Trials; Clinical Trials.gov.; BIOSIS; OHE HEED.

5.7. Inclusion criteria The following study types will be included: • Systematic reviews • Randomised controlled trials • Economic evaluations.

Trials of less than twelve weeks duration are unlikely to inform on survival, CVD events, adverse events or HRQoL due to lipid lowering treatments. Where information on clinical end-points is unavailable, data from trials of sufficient duration (i.e. at least 12 weeks) for surrogate endpoints (such as TC, LDL-C and HDL-C) will be included. This criterion will be relaxed for consideration of adverse events, for which observational studies may be included. Titles and abstracts will be examined for inclusion by one/two reviewers independently. Disagreement will be resolved by consensus.

5.8. Exclusion criteria Reviews of primary studies will not be included in the analysis, but will be retained for discussion and identification of additional trials. Studies which are considered methodologically unsound will be excluded from the review as well as the following publication types: non-randomised studies (except for adverse events); animal models; preclinical and biological studies; narrative reviews, editorials, opinions; non-English language papers and reports where insufficient methodological details are reported to allow critical appraisal of study quality.

5.9. Data extraction strategy Data will be extracted independently by one reviewer using a standardised data extraction form and checked by another. Discrepancies will be resolved by discussion, with involvement of a third reviewer when necessary. Where multiple publications of the same study are identified, data will be extracted and reported as a single study.

5.10. Quality assessment strategy The quality of randomised controlled trials will be assessed according to criteria based on those proposed by the NHS Centre for Reviews and Dissemination[12] (see Appendix 2). The purpose of such quality assessment is to provide a narrative account of trial quality.

5.11. Methods of analysis/synthesis Data will be tabulated and discussed in a narrative review. Where appropriate (i.e. populations, interventions and outcomes are comparable), meta-analysis will be employed to estimate a summary measure of effect on relevant outcomes based on intention to treat analyses.

Meta-analysis will be carried out using fixed and random effect models, using RevMan software. Heterogeneity will be explored through consideration of the study populations, methods and interventions, by visualization of the results and, in statistical terms, by χ2 test for homogeneity and the I2 statistic.

5.12. Methods for estimating qualify of life Ideally, evidence on the impact of ezetimibe on HRQoL will be available directly from the trials included in the review. In the absence of such evidence, literature searches will be conducted to identify alternative sources. The quality of life data will be reviewed and used to generate quality adjustment weights for the different health states in the model.

6. Report methods for synthesising evidence of cost-effectiveness The sources detailed in section 5 will be used to identify appropriate published cost- effectiveness and cost-utility studies. These will reviewed and possibly used to inform suitable methodologies for the ezetimibe economic model. Stand alone cost analyses based in the UK NHS will also be sought.

The quality of economic studies will be assessed using a combination of key components of the British Medical Journal checklist for economic evaluations[13] together with the Eddy checklist on mathematical models employed in technology assessments[14] (Appendix 3); as used in the recent statin Technology Appraisal Report.[10]

An economic evaluation will be carried out from the perspective of the UK NHS. The model structure will be determined in consultation with clinical experts. The costs and benefits associated with ezetimibe in combination with a statin will be compared with optimal statin monotherapy or treatment with a statin in combination with other lipid regulating drugs, such as nicotinic acid/acipimox, bile acid resins and fibrates. For people whom a statin is considered inappropriate or not tolerated, ezetimibe monotherapy will be compared with an alternative lipid regulating drug such as nicotinic acid/acipimox, bile acid resins and/or fibrates. In order to reflect the chronic nature of the disease, the time horizon of the analysis will be a patient’s lifetime. However, the model will be constructed to facilitate the use of shorter horizons.

Costs will include the direct cost of treatments and costs associated with cardiovascular events. Ideally costs will be derived from the source of clinical effectiveness. If unavailable, costs for the differing health states will be identified through literature searches. If appropriate, costs of monitoring patients and adverse events will also be considered.

The final outcome measures will depend on the available evidence, but are likely to include:

cost per life year gained, and/or cost per quality adjusted life year gained (QALY)

Sensitivity analysis will be undertaken to identify key parameters that determine the cost-effectiveness of the intervention with the objective of identifying how secure the results of the economic analyses are, given the available evidence. In addition, uncertainty with respect to model parameters will be explored with a probabilistic sensitivity analysis (PSA), where uncertainty of all input variables is modelled with probability distribution of their value. In addition, where information is available, consideration will be given to concordance with treatment and its impact on effectiveness.

7. Handling the company submission(s) Any 'commercial in confidence' data taken from the company submission will be underlined and highlighted in the assessment report. The industry dossiers will be used to identify any RCTs or cost-effectiveness studies omitted from the systematic review. Economic models included within the sponsor submissions, will be critically appraised by the review team with respect to strengths, weaknesses and assumptions. It is anticipated that we will develop our own economic model to estimate cost- effectiveness/cost-utility. A comparison will be made of the sponsor and the review team models. If large differences exist in pivotal results the discrepancies will be analyzed.

8. Competing interests of authors

None of the authors have financial interest in the companies who manufacture the drugs included in this review.

Dr Wilf Yeo has received speaker fees for talks to GPs and prescribing advisors on the National Service Framework for CHD, which includes the use of statins by the following companies: Novartis, Pfizer, MSD and AstraZeneca.

Professor P Durrington was until 2005 an International Advisory Board member to Merck Sharp & Dohme/Schering Plough and advised the same companies nationally until the beginning of 2006. Received remuneration for advice. Resigned advisory roles to these and other companies when joined an advisory group to the Commission on Human Medicines earlier this year. Thus had already done so when approached by ScHARR to assist in the HTA on Ezetimibe.

11. Appendices

Appendix 1: Draft search strategy Search strategy for Medline to identify RCT’s

1 ezetimibe.tw. 2 ezetrol.tw. 3 zetia.tw. 4 vytorin.tw. 5 inegy.tw. 6 or/1-5 7 randomized controlled trial.pt. 8 controlled clinical trial.pt. 9 randomized controlled trials/ 10 random allocation/ 11 double blind method/ 12 single blind method/ 13 or/7-12 14 clinical trial.pt. 15 exp clinical trials/ 16 (clin$ adj25 trial$).tw. 17 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).tw. 18 placebos/ 19 placebo$.tw. 20 random$.tw. 21 research design/ 22 or/14-21 23 "comparative study"/ 24 exp evaluation studies/ 25 follow-up studies/ 26 prospective studies/ 27 (control$ or prospectiv$ or volunteer$).tw. 28 or/23-27 29 13 or 22 or 28 30 "animal"/ 31 "human"/ 32 30 not 31 33 29 not 32 34 33 and 6 35 hypercholesterolemia.af. 36 hypercholesterolaemia.af. 37 34 and (35 or 36) 38 "163222-33-1.".rn. 39 6 or 38 40 39 and 33 and (35 or 36)

Appendix 2: Draft quality assessment scale

Was the method used to assign participants to the treatment groups really random?

What method of assignment was used?

Was the allocation of treatment concealed?

What method was used to conceal treatment allocation?

Was the number of participants who were randomised stated?

Were details of baseline comparability presented?

Was baseline comparability achieved?

Were the eligibility criteria for study entry specified?

Were any co-interventions identified that may influence the outcomes for each group?

Were the outcome assessors blinded to the treatment allocations?

Were the individuals who administered the intervention blinded to the treatment allocation?

Were the participants who received the intervention blinded to the treatment allocation?

Was the success of the blinding procedure assessed?

Were at least 80% of the participants originally included in the randomised process followed up in the final analysis?

Were the reasons for withdrawal stated?

Was an intention-to-treat analysis included?

Y – item addressed; N – no; ? – not enough information or not clear; NA –not applicable Appendix 3: Critical appraisal checklist for economic evaluations using key components of the British Medical Journal checklist for economic evaluations[13] together with the Eddy checklist on mathematical models employed in technology assessments.[14]

Reference ID Title Authors Year Modelling assessments should include: Yes/No 1 A statement of the problem; 2 A discussion of the need for modelling vs. alternative methodologies

3 A description of the relevant factors and outcomes; 4 A description of the model including reasons for this type of model and a specification of the scope including; time frame, perspective, comparators and setting. Note: n=number of health states within sub- model

5 A description of data sources (including subjective estimates), with a description of the strengths and weaknesses of each source, with reference to a specific classification or hierarchy of evidence;

6 A list of assumptions pertaining to: the structure of the model (e.g. factors included, relationships, and distributions) and the data;

7 A list of parameter values that will be used for a base case analysis, and a list of the ranges in those values that represent appropriate confidence limits and that will be used in a sensitivity analysis;

8 The results derived from applying the model for the base case;

9 The results of the sensitivity analyses; unidimensional; best/worst case; multidimensional (Monte Carlo/parametric); threshold. 10 A discussion of how the modelling assumptions might affect the results, indicating both the direction of the bias and the approximate magnitude of the effect; 11 A description of the validation undertaken including; concurrence of experts; internal consistency; external consistency; predictive validity.

12 A description of the settings to which the results of the analysis can be applied and a list of factors that could limit the applicability of the results; 13 A description of research in progress that could yield new data that could alter the results of the analysis

References

1. Prodigy Guidance –Hyperlipidaemia. Available at: http://www.prodigy.nhs.uk/ProdigyKnowledge/Guidance/WholeGuidanceView.a spx?GuidanceId=37387# (accessed on 26/04/2006)

2. Primatesta P, Poulter NR. Levels of dyslipidaemia and improvement in its management in England: results from the Health Survey for England 2003. Clin Endocrinol (Oxf) 2006; 64 292-8

3. British Cardiac Society; British Hypertension Society; Diabetes UK; HEART UK; Primary Care Cardiovascular Society; Stroke Association. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 Suppl 5: v1-52.

4. Pullinger CR, Kane JP, Malloy MJ. Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders. Expert Review of Cardiovascular Therapy 2003, 1 107-119

5. Joint Formulary Committee. British National Formulary. [51] ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2006

6. Hippisley-Cox, J., Cater, R., Pringle, M. and Coupland, C. Cross-sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices. BMJ 2003; 326 689-693.

7. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment (L- TAP) Project: A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160 459-467.

8. MSD-SP Limited. Ezetimibe - Summary of Products Characteristics. electronic Medicines Compendium MSD-SP Limited; 2006

9. Department of Health. National Service Framework for Coronary Heart Disease- Modern Standards & Service Models. Department of Health; 2000

10. National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events - Technology appraisal 94. London, NICE; 2006

11. CONSORT. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement flow diagram. Available at: http://www.consort-statement.org/QUOROM.pdf (accessed on 26/04/2006)

12. NHS Centre for reviews and Dissemination. Report 4: Undertaking systematic reviews of research on effectiveness; CRD's guidance for those carrying out or commissioning reviews. York: University of York; 2001

13. Drummond, M. and Jefferson, T. O. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ 1996; 313 275-283

14. Eddy, DM Technology assessment: The role of mathematical modelling. In Assessing medical technology. Washington DC: National Academy Press; 1985: p144-154

Reference List

(1) Prodigy Guidance. Hyperlipidaemia. Available at: http://www prodigy nhs uk/ProdigyKnowledge/Guidance/WholeGuidanceView aspx?GuidanceId=37387# (accessed on 26/04/2006) 2006

(2) Primatesta P, Poulter NR. Levels of dyslipidaemia and improvement in its management in England: results from the Health Survey for England 2003. Clin Endocrinol (Oxf) 64[3], 292-298. 2006. Ref Type: Journal (Full)

(3) British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, Stroke Association. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 91 ()[Suppl. 5], v1-52. 2005. Ref Type: Journal (Full)

(4) Pullinger CR, Kane JP, Malloy MJ. Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders. Expert Review of Cardiovascular Therapy 1[1], 107-119. 2003. Ref Type: Journal (Full)

(5) Joint Formulary Committee, . British National Formulary. [51] ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2006.

(6) Hippisley-Cox J, Cater R, Pringle M, Coupland C. Cross-sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices. BMJ 326[7391], 689-693. 2003. Ref Type: Journal (Full)

(7) Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment (L- TAP) Project: A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 160, 459-467. 2000. Ref Type: Journal (Full)

(8) MSD-SP Limited. Ezetimibe - Summary of Products Characteristics. electronic Medicines Compendium 2006 MSD-SP Limited 2006 2006 (9) Department of Health. National Service Framework for Coronary Heart Disease- Modern Standards & Service Models. London, Department of Health; 2000.

(10) National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events - Technology appraisal 94. 2006. London, NICE. Ref Type: Pamphlet

(11) CONSORT. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement flow diagram. Available at: http://www consort-statement org/QUOROM pdf (accessed on 26/04/2006) 2006

(12) NHS Centre for reviews and Dissemination. Report 4: Undertaking systematic reviews of research on effectiveness; CRD's guidance for those carrying out or commissioning reviews. York: University of York; 2001.

(13) Drummond M, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ 313, 275-283. 1996. Ref Type: Journal (Full)

(14) Eddy DM, . Technology assessment: The role of mathematical modeling. in Assessing medical technology. Washington DC: National Academy Press; 1985.