HTA Agencies Facing Model Biases: The Case of Type 2 Diabetes

Abstract

When evaluating new drugs or treatments eligible for reimbursement, health technology assessment (HTA) agencies are repeatedly faced with cost-effectiveness analyses that evidence lack of adequate data and modeling biases. The case of type 2 diabetes illustrates this difficulty. In spite of its high disease burden, type 2 diabetes is poorly documented through existing cost-effectiveness analyses. We support this statement by an exhaustive literature review that enables us to precisely pinpoint the limitations of models used for the assessment of newly marketed (and expensive) drugs. We find that models are mostly restricted to surrogate endpoints and based on non-inferiority clinical trial data; they also show biases in the choice of comparators and inclusion criteria. Such limitations undermine the scope and applicability of HTA practice guidelines based on cost-effectiveness evidence. Nevertheless, cost-effectiveness models remain an opportunity to better inform decision makers and to reduce the uncertainty surrounding their decisions. HTA agencies are best placed to provide incentives for companies to improve the quality of the cost-effectiveness studies submitted for pricing and reimbursement decisions. One such incentive is to include stages of discussion between the company and the health authority during the evaluation process.

Appendices

Appendix 1: Literature Search Strategy

1.1 Method

The global search concerns the publications in English and French and was conducted from December 2008 to May 2012. An additional search was conducted on cost-effectiveness studies only with Medline from May 2012 to April 2014.

The following sources were consulted:

• For international literature: Medline, Embase, NHS-EED and Cinahl databases;

• For French-written literature: Pascal database and the Banque de Données en Santé Publique;

• The Cochrane Library;

• Websites publishing guidelines and HTA reports;

• Websites of diabetes organizations.

In the evaluation of the drug’s efficacy, the selection criteria were:

• Randomized controlled studies,

• Minimum length of 12 weeks,

• Minimum number of patients of 100 (unless there are no larger studies).

Studies only based on thiazolidinediones comparisons were excluded are these drugs are not marketed any more in France.

1.2 Results of the Global Search

• Number of identified references: 3,567

• Number of analyzed publications: 1,304

• Number of selected publications: 312

1.2.1 References Database

The search strategy in references databases is built on thesaurus key words or free words in title or abstract, combined with type of studies key-word.

The table describes the search strategy in Medline, Embase and Cinahl databases (without suppression of double counts).

Search strategy in Medline, Embase and Cinahl databases (from HAS, 2013 [2])

Type of study/subject		Number of references
	Key-words
Glucagon-like peptide-1 analogs (exénatide, liraglutide)
– Guidelines		M/E: 44
Step 1	Glucagon-Like-Peptide-1/de OR (Glucagon-Like-Peptide-1 OR GLP-1)/ti,ab OR (exenatide OR liraglutide)/ti,ab,nom de molécule
AND
Step 2	(Non-Insulin-Dependent-Diabetes-Mellitus OR “Diabetes Mellitus, Non-Insulin-Dependent” OR Diabetes-Mellitus-Type-2)/de OR (type-2 AND diabetes)/ti,ab
AND
Step 3	(guideline OR practice-guideline OR consensus-development-conference OR consensus-development-conference-nih)/Type de publication OR (Health-Planning-Guidelines OR Practice-Guideline OR Consensus-Development)/der OR (guideline* OR recommendation* OR guidance* OR policy-statement OR position-paper)/ti OR (consensus conference* OR consensus statement*)/ti,ab
– Meta-analyses and systematic reviews		M/E: 22
Step 1 AND Step 2
AND
Step 4	(Meta-Analysis OR Systematic-Review)/der OR meta-analysis/Type de publication OR (meta-analys* OR metaanalys*)/ti OR (systematic-review* OR systematic-overview* OR systematic-literature-review*)/ti,ab OR cochrane-database-syst-rev/Source
– Randomized controlled trials		M/E: 152
Step 1 AND Step 2
AND
Step 5	(Randomization OR Single-Blind-Procedure OR Double-Blind-Procedure OR Crossover-Procedure OR Randomized-Controlled-Trial OR Double-Blind-Method OR Single-Blind-Method OR Random-Allocation OR Cross-Over-Studies)/de OR randomized-controlled-trial/Type de publication OR random*/ti
– Adverse events		M/E: 287
(Step 1 AND Step 2
AND
Step 6)	(risk OR safety OR adverse OR harm OR pharmacovigilance OR side-effect* OR precaution* OR warning* OR contraindication* OR contra-indication*)/ti,ab
OR
Step 7	(Glucagon-Like-Peptide-1/adverse effects OR Exendin-4/adverse effects OR Liraglutide/adverse effects)/de
– Acceptability		M: 43
(Step 1 AND Step 2
AND
Step 8)	(acceptability OR acceptance OR participation OR preference* OR choice* OR attitude* OR adhesion OR complian* OR cooper*)/ti,ab OR view/ti OR (patient participation OR consumer satisfaction OR patient acceptance of health care OR attitude to health OR refusal to participate OR mandatory programs OR voluntary programs OR informed consent OR emotions OR choice behavior OR “Patient Satisfaction”)/de
– Social		M: 19
(Step 1 AND Step 2
AND
Step 9)	(Social-disorder* OR social-impairment* OR social-group* OR social-interaction* OR social-contact* OR loneliness OR quality-of-life OR absenteeism OR productivity OR disability OR disable* OR eq5d OR eq-5d OR euro-qol OR euroqol OR sf-36 OR sf36 OR hrql OR hrqol OR well-being OR well-being OR qaly)/ti,ab OR qol/ti OR (social environment OR social change OR social behavior disorders OR social behavior OR interpersonal relations OR family relations OR socialization OR social adjustment OR social isolation OR loneliness OR quality of life OR quality-adjusted life years OR activities of daily living OR sickness impact profile OR employment OR absenteeism OR work capacity evaluation OR occupations OR job satisfaction OR disability evaluation OR disabled persons OR social support OR self-help groups OR self-care OR “Health Status”)/de
– Models		M: 8
(Step 1 AND Step 2
AND
Step 10)	model*/ti OR (“Markov Chains” OR “Models, Economic” OR “Models, Econometric” OR “Decision Trees” OR “Models, Theoretical” OR “Models, Statistical” OR “Economics, Hospital” OR “Economics, Pharmaceutical”)/de
– Economic		M: 10
(Step 1 AND Step 2
AND
Step 11)	(economic* OR “cost of illness” OR “burden of disease” OR cost-effectiveness OR pharmacoeconomic* OR pharmaco-economic*)/ti,ab OR budgets[mh] OR (cost* OR costs)/ti OR (costs and cost analysis OR economics, medical OR financing, government OR health care sector OR insurance, health OR social security)/de
OR
(Step 1 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Glucagon-Like Peptide 1/economics”/de)
dipeptidylpeptidase-4 inhibitors
– Guidelines		M/E: 40
Step 2 AND Step 3
AND
Step 12	(Dipeptidyl-Peptidase-Iv-Inhibitors OR Dipeptidyl-Peptidase-Iv-Inhibitor OR Saxagliptin OR Sitagliptin OR Vildagliptin)/de OR (dipeptidyl-peptidase-4-inhibitor* OR dipeptidyl-peptidase-IV-inhibitor* OR Dpp-iv-inhibitor* OR DPP-4-inhibitor* OR vildagliptin OR sitagliptin OR saxagliptin)/ti,ab,nom de molécule
– Meta-analyses and systematic reviews		M/E: 29
Step 2 AND Step 4 AND Step 12
– Randomized controlled trials		M/E: 136
Step 2 AND Step 5 AND Step 12
– Adverse events		M/E: 121
(Step 2 AND Step 6 AND Step 12)
OR
Step 13	(Dipeptidyl-Peptidase-Iv-Inhibitors/adverse effects OR Dipeptidyl-Peptidase-Iv-Inhibitor/adverse effects OR Saxagliptin/adverse effects OR Sitagliptin/adverse effects OR Vildagliptin/adverse effects)/de
– Acceptability		M: 9
Step 12 AND Step 2 AND Step 8
– Social aspects		M: 4
Step 12 AND Step 2 AND Step 9
– Models		M: 4
Step 12 AND Step 2 AND Step 10
– Economic		M: 2
(Step 12 AND Step 2 AND Step 11)
OR
(Step Step 12 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Dipeptidyl-Peptidase IV Inhibitors/economics”/de)
Long acting insulin analogs
– Guidelines		M/E: 24
Step 2 AND Step 3
AND
Step 14	(glargine or detemir)/ti,ab,nom de molécule OR (“Insulin, Long-Acting” OR glargine OR “insulin detemir”)/de
– Meta-analyses and systematic reviews		M/E: 24
Step 2 AND Step 4 AND Step 14
– Randomized controlled trials		M/E: 111
Step 2 AND Step 5 AND Step 14
– Adverse events		M/E: 67
(Step 2 AND Step 6 AND Step 14)
OR
Step 15	(Insulin-Glargine/adverse effects OR Insulin-Detemir/adverse effects)/de
– Acceptability		M: 20
Step 14 AND Step 2 AND Step 8
– Social		M: 18
Step 14 AND Step 2 AND Step 9
– Models		M: 1
Step 14 AND Step 2 AND Step 10
– Economic		M: 10
(Step 14 AND Step 2 AND Step 11)
OR
(Step 14 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Insulin, Long-Acting/economics”/de)
Thiazolidinediones
– Guidelines		M/E: 32
Step 2 AND Step 3
AND
Step 16	Thiazolidinediones/de OR 2-4-Thiazolidinedione-Derivative/de OR pioglitazone/ti,ab,nom de molécule OR Pioglitazone/de
– Meta-analyses and systematic reviews		M/E: 42
Step 2 AND Step 4 AND Step 16
– Randomized controlled trials		M/E: 192
Step 2 AND Step 5 AND Step 16
– Adverse events		M/E: 214
(Step 2 AND Step 6 AND Step 16)
OR
Step 17	(Thiazolidinediones/adverse effects OR 2-4-Thiazolidinedione-Derivative/adverse effects OR Pioglitazone/adverse effects)/de
– Acceptability		M: 32
Step 16 AND Step 2 AND Step 8
– Social		M: 8
Step 16 AND Step 2 AND Step 9
– Models		M: 7
Step 16 AND Step 2 AND Step 10
– Economic		M: 9
(Step 16 AND Step 2 AND Step 11)
OR
(Step 16 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Thiazolidinediones/economics”/de)
Glinides
– Guidelines		M/E: 0
Step 2 AND Step 3
AND
Step 18	(Repaglinide OR Mitiglinide OR Nateglinide)/de OR (Repaglinide OR Mitiglinide OR Nateglinide OR glinid*)/ti,ab,nom de molécule
– Meta-analyses and systematic reviews		M/E: 1
Step 2 AND Step 4 AND Step 18
– Randomized controlled trials		M/E: 27
Step 2 AND Step 5 AND Step 18
– Adverse events		M/E: 14
(Step 2 AND Step 6 AND Step 18)
OR
Step 19	(Repaglinide OR Mitiglinide OR Nateglinide)/adverse effects/der OR (Piperidines/adverse effects/de AND (Repaglinide OR Mitiglinide OR Nateglinide)/Nom de molécule)
– Acceptability		M: 5
Step 18 AND Step 2 AND Step 8
– Social		M: 2
Step 18 AND Step 2 AND Step 9
– Models		M: 0
Step 18 AND Step 2 AND Step 10
– Economic		M: 0
(Step 18 AND Step 2 AND Step 11)
OR
(Step 18 AND “Diabetes Mellitus, Type 2/economics”/de)
Alpha glucosidases inhibitors
– Guidelines		M/E: 4
Step 2 AND Step 3
AND
Step 20	(Acarbose OR Miglitol OR “alpha-Glucosidases/antagonists and inhibitors” OR Alpha-Glucosidase-Inhibitor)/de OR (Acarbose OR Miglitol OR (Inhibitor* NEAR (Alpha ADJ Glucosidase*)))/ti,ab
– Meta-analyses and systematic reviews		M/E: 0
Step 2 AND Step 4 AND Step 20
– Randomized controlled trials		M/E: 22
Step 2 AND Step 5 AND Step 20
– Adverse events		M/E: 16
(Step 2 AND Step 6 AND Step 20)
OR
Step 21	(Acarbose OR Miglitol OR Alpha-Glucosidase-Inhibitor)/adverse effects/de OR (Miglitol/Nom de molécule AND 1-Deoxynojirimycin/adverse effects/de)
– Acceptability		M: 0
Step 20 AND Step 2 AND Step 8
– Social		M: 1
Step 20 AND Step 2 AND Step 9
– Models		M: 1
Step 20 AND Step 2 AND Step 10
– Economic		M: 1
(Step 20 AND Step 2 AND Step 11)
OR
(Step 20 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Acarbose/economics”/de)
Glucose lowering sulfonylurea
– Guidelines		M/E: 3
Step 2 AND Step 3
AND
Step 22	(Sulfonylurea-Compounds OR Carbutamide OR Chlorpropamide OR Glibenclamide OR Gliclazide OR Glimepiride OR Glipizide OR Tolbutamide OR Tolazamide OR Sulfonylurea-Derivative)/de OR (Carbutamide OR Chlorpropamide OR Glibenclamide OR Glyburide OR Gliclazide OR Glimepiride OR Glipizide OR Tolbutamide OR Tolazamide OR (hypoglycaemic NEAR sulfamide*) OR (hypoglycemic NEAR sulfamide*) OR (sulfonurea NEXT (derivative* OR compound*)))/ti,ab
– Meta-analyses and systematic reviews		M/E: 3
Step 2 AND Step 4 AND Step 22
– Randomized controlled trials		M/E: 52
Step 2 AND Step 5 AND Step 22
– Adverse events		M/E: 59
(Step 2 AND Step 6 AND Step 22)
OR
Step 23	(Sulfonylurea-Compounds OR Carbutamide OR Chlorpropamide OR Glibenclamide OR Gliclazide OR Glimepiride OR Glipizide OR Tolbutamide OR Tolazamide OR Sulfonylurea-Derivative)/adverse effects/de
– Acceptability		M: 6
Step 22 AND Step 2 AND Step 8
– Social		M: 5
Step 22 AND Step 2 AND Step 9
– Models		M: 0
Step 22 AND Step 2 AND Step 10
– Economic		M: 1
(Step 22 AND Step 2 AND Step 11)
OR
(Step 22 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Sulfonylurea Compounds/economics”/de)
Metformin
– Guidelines		M/E: 20
Step 2 AND Step 3
AND
Step 24	(Metformin OR Biguanides)/de OR (Glucophage OR Biguanide* OR Metformin*)/ti,ab
– Meta-analyses and systematic reviews		M/E: 15
Step 2 AND Step 4 AND Step 24
– Randomized controlled trials		M/E: 74
Step 2 AND Step 5 AND Step 24
– Adverse events		M/E: 124
(Step 2 AND Step 6 AND Step 24)
OR
Step 25	(Metformin OR Biguanide*)/adverse effects/de
– Acceptability		M: 33
Step 24 AND Step 2 AND Step 8
– Social		M: 15
Step 24 AND Step 2 AND Step 9
– Models		M: 5
Step 24 AND Step 2 AND Step 10
– Economic		M: 10
(Step 24 AND Step 2 AND Step 11)
OR
(Step 24 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND (“Metformin/economics” OR “Biguanides/economics”)/de)
Insulin
– Guidelines		M/E: 27
Step 2 AND Step 3
AND
Step 26	Insulin/de OR Insulin*/ti
– Meta-analyses and systematic reviews		M/E: 23
Step 2 AND Step 4 AND Step 26
– Randomized controlled trials		M/E: 115
Step 2 AND Step 5 AND Step 26
– Adverse events		M/E: 137
(Step 2 AND Step 6 AND Step 26)
OR
Step 27	Insulin/adverse effects/de
– Acceptability		M: 123
Step 26 AND Step 2 AND Step 8
– Social		M: 24
Step 26 AND Step 2 AND Step 9
– Models		M: 29
Step 26 AND Step 2 AND Step 10
– Economic		M: 14
(Step 26 AND Step 2 AND Step 11)
OR
(Step 26 AND “Diabetes Mellitus, Type 2/economics”/de)
OR
(Step 2 AND “Insulin/economics”/de)

ab abstract, de descriptor, M MEDLINE, M/C MEDLINE + Cinahl, M/E MEDLINE + Embase, ti title

Appendix 2: Consulted Websites

• Assemblée Nationale

• Association de Langue Française pour l’Etude du Diabète et des maladies Métaboliques, ALFEDIAM/SFD

• Bibliothèque médicale Lemanissier

• Bibliothèque Interuniversitaire de Médecine, BIUM

• Catalogue et index des sites médicaux francophones, CISMeF

• Comité d’Evaluation et de Diffusion des Innovations Technologiques, CEDIT

• Conseil économique et social

• Evaluation des technologies de santé pour l’aide à la décision (Fédération hospitalière de France), ETSAD

• Expertise collective INSERM

• Institut de Recherche et Documentation en Economie de la Santé, IRDES

• Institut de Veille Sanitaire, INVS

• Institut national de prévention et d’éducation pour la santé, INPES

• La Documentation française

• Ministère de la Santé, de la Jeunesse et des Sports

• Réseau d’évaluation en économie de la santé, REES

• Société Française d’Endocrinologie, SFE

• Societe Francaise de Cardiologie, SFC

• Société Francophone du Diabète, SFD

• Société Française de Médecine Générale, SFMG

• Adelaide Health Technology Assessment, AHTA

• Agence d’Evaluation des Technologies et des Modes d’Intervention en Santé, AETMIS

• Agency for Healthcare Research and Quality, AHRQ

• Alberta Medical Association

• American Academy of Pediatrics, AAP

• American Association for Clinical Chemistry, AACC

• American Association of Clinical Endocrinologists, AACE

• American College of Cardiology, ACC

• American College of Foot and Ankle Surgeons, ACFAS

• American College of Physicians, ACP

• American Heart Association, AHA

• Association Suisse du Diabète, ASD

• Australian Safety and Efficacy Register of New Interventional Procedures, Surgical, ASERNIP

• Blue Cross Blue Shield Association, Technology Evaluation Center, BCBS

• BMJ Clinical Evidence, BMJ CE

• California Technology Assessment Forum, CTAF

• Canadian Agency for Drugs and Technologies in Health, CADTH

• Canadian Diabetes Association

• Canadian Task Force on Preventive Health Care, CTFPHC

• CDC Infection Control Guidelines, CDC

• Centre for Reviews and Dissemination databases, CRD

• Centre Belge d’Information Pharmacothérapeutique, CBIP

• Centre fédéral d’expertise des soins de santé, KCE

• Centre for Clinical Effectiveness, CCE

• Clinical Knowledge Summaries, CKS

• CMA Infobase

• Cochrane Library

• College of Physicians and Surgeons of Alberta, CPSA

• Conseil Supérieur de la Santé (Belgique), CSS

• Department of Health, DH

• Diabetes Research and Wellness Foundation

• Diabetes UK

• European Association for the Study of Diabetes, EASD

• European Core Indicators in Diabetes, EUCID

• European Medicines Agency, EMEA

• European Society of Cardiology

• Euroscan

• GIN (Guidelines International Network), GIN

• Groupe de Recherche Interdisciplinaire en Santé, GRIS

• Guideline Advisory Committee, GAC

• Guidelines and Protocols Advisory Committee, GPAC

• Guidelines Finder (National Library for Health)

• Health Economics Resource Centre, University of York, HERC

• Health Services Technology Assessment Text, HSTAT

• Horizon Sanning, HS

• IDEAS Economics and Finance Research, Base REPEC, REPEC

• Institute for Clinical Evaluative Sciences, ICES

• Institute for Clinical Systems Improvement, ICSI

• Institute for Health Economics Alberta, IHE

• International Diabetes Federation, IDF

• International Society for Pediatric and Adolescent Diabetes, ISPAD

• International Society for Pharmacoeconomics and Outcomes Research, IPSOR

• Intute Health & Life Sciences, INTUTE

• Joslin Diabetes Center

• Medical Services Advisory Committee, MSAC

• Minnesota Department of Health, Health Technology Advisory Committee (up to 2002), HTAC

• National Coordinating Centre for Health Technology Assessment, NCCHTA

• National Guideline Clearinghouse, NGC

• National Health and Medical Research Council, NHMRC

• National Horizon Scanning Centre, NHSC

• National Institute for Health and Clinical Excellence, NICE

• National Institute of Diabetes, Digestive and Kidney Diseases, NIDDK

• National Institutes of Health, NIH

• National Kidney Foundation, NKF

• National Prescribing Centre, NPC

• New Zealand Guidelines Group, NZGG

• New Zealand Health Technology Assessment, NZHTA

• NHS Map of Medicine

• Ontario Health Technology Advisory Committee, OHTAC

• Public Health Agency of Canada, Diseases Prevention and Control Guidelines, PHAC

• Royal College of Nursing, RCN

• Santé Canada

• Scottish Intercollegiate Guidelines Network, SIGN

• Singapore Ministry of Health, MOH

• The Endocrine Society

• Tripdatabase

• U.S. Preventive Services Task Force, USPSTF

• Veterans Affairs Technology Assessment Program

• Veterans’ affairs, Dep. Of Defense Clinical practice guidelines

• West Midlands Health Technology Assessment Collaboration, WMHTA