Role of centralized review processes for making reimbursement decisions on new health technologies in Europe

Abstract

Background:

The purpose of this study was to compare centralized reimbursement/coverage decision-making processes for health technologies in 23 European countries, according to: mandate, authority, structure, and policy options; mechanisms for identifying, selecting, and evaluating technologies; clinical and economic evidence expectations; committee composition, procedures, and factors considered; available conditional reimbursement options for promising new technologies; and the manufacturers’ roles in the process.

Methods:

A comprehensive review of publicly available information from peer-reviewed literature (using a variety of bibliographic databases) and gray literature (eg, working papers, committee reports, presentations, and government documents) was conducted. Policy experts in each of the 23 countries were also contacted. All information collected was reviewed by two independent researchers.

Results:

Most European countries have established centralized reimbursement systems for making decisions on health technologies. However, the scope of technologies considered, as well as processes for identifying, selecting, and reviewing them varies. All systems include an assessment of clinical evidence, compiled in accordance with their own guidelines or internationally recognized published ones. In addition, most systems require an economic evaluation. The quality of such information is typically assessed by content and methodological experts. Committees responsible for formulating recommendations or decisions are multidisciplinary. While criteria used by committees appear transparent, how they are operationalized during deliberations remains unclear. Increasingly, reimbursement systems are expressing interest in and/or implementing reimbursement policy options that extend beyond the traditional “yes,” “no,” or “yes with restrictions” options. Such options typically require greater involvement of manufacturers which, to date, has been limited.

Conclusion:

Centralized reimbursement systems have become an important policy tool in many European countries. Nevertheless, there remains a lack of transparency around critical elements, such as how multiple factors or criteria are weighed during committee deliberations.

Keywords:

• reimbursement
• centralized review
• health technologies
• Europe

Introduction

The past decade has seen unprecedented growth in the number of new, often high-cost, health technologies and consumer demand for access to them. It has also seen increased public awareness and scrutiny of decisions about which technologies to include in the basket of publicly insured services.^1–3 To improve the legitimacy of such decisions and optimize health outcomes through the effective use of increasingly strained health care resources, many payers, particularly those in Europe, have established centralized systems for determining the reimbursement status of new health technologies.^4,5 In this invited review, we compare these systems across selected countries in Northern, Southern, Western, Eastern, and Central Europe, examining:

• Their mandate, authority, organizational structure, and policy options

• Mechanisms for identifying, selecting, and evaluating technologies

• Clinical and economic evidence expectations

• Review committee composition, procedures, and key factors considered during deliberations

• Use of conditional reimbursement options for enabling access to promising new technologies around which considerable uncertainty related to clinical and/or economic value exists

• The role of manufacturers in steps comprising the reimbursement review process.

Methods

This review is based upon findings from a comprehensive search for publicly available information on centralized reimbursement systems in selected European countries. Peer-reviewed literature published in English over the past decade (ending in January 2011) was located using a structured search strategy that combined relevant controlled vocabulary terms, ie, MeSH and EMTREE (eg, “technology, medical,” “reimbursement mechanisms,” “decision-making,” “technology assessment,” “health policy”) and free text terms (eg, “pharmaceuticals,” “medical devices,” “coverage,” “funding,” “centralized review,” “health technology assessment,” and “reimbursement,” the full search strategy being available from the authors). Such terms were identified through an analysis of words used to index references familiar to the authors. The strategy was applied to several health-related electronic bibliographic databases, including PubMed, MEDLINE, EMBASE, HealthSTAR, CINAHL, EconLit, PASCAL, SCOPUS, International Pharmaceutical Abstracts, Web of Science, and the UK Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, and Health Technology Assessment). For comprehensiveness, reference lists of retrieved papers and the most recent issues of health policy-related journals were hand-searched.

A search for gray (unpublished) literature (eg, working papers, conference abstracts, reports, presentations, government documents) was also performed using the Google^® search engine and terms from the main search strategy. In addition, the following dedicated gray literature databases were scanned: the New York Academy of Medicine’s Gray Literature database, Knowledge Utilization database, Systematic Reviews for Management and Policy Making, and National Health Service Evidence in Health and Social Care. Separate searches for information on centralized reimbursement processes within health care systems of the top 30 European countries ranked according to gross domestic product per capita by the World Bank were also conducted. This number was considered sufficient to capture the full spectrum of such processes. For each country, the websites of relevant ministries (eg, health, social affairs, economics), translated into English with Google Translate^®, were scanned for documents describing legislation and other policies and processes for making reimbursement decisions on new health technologies, including pharmaceuticals, medical devices, diagnostic tests, and procedures.

Documents retrieved from the various searches were reviewed independently by two of the authors. Published papers unrelated to the introduction of individual health technologies (eg, those on macrolevel priority setting) were excluded. Because the purpose of this review was to examine current actual processes, papers proposing specific decision-making tools or discussing one component of decision-making were also excluded. Information on process-related characteristics of the centralized reimbursement systems, including perceived strengths and weaknesses, was extracted using a standardized, pretested data abstraction form. To ensure it reflected the current policy environment, the following individuals were consulted: corresponding authors of published papers, contacts listed on organizations’ websites, and European policy experts with whom the authors were already acquainted.

Extracted information was tabulated to facilitate the identification of patterns or trends across country-specific reimbursement processes, and subsequently analyzed qualitatively using content analysis and constant comparison techniques.

Results

Of the 30 European countries initially identified for the review, information on centralized reimbursement processes could only be found for 23. Therefore, the review included the following 23 countries: Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Norway, Poland, Portugal, Scotland, Slovakia, Spain, Sweden, Switzerland, the Netherlands, the United Kingdom, and Wales.

Mandate of centralized reimbursement systems

The majority (18/23) of countries have established centralized reimbursement processes to support coverage decision-making for either pharmaceuticals or pharmaceuticals and devices needed for their delivery. In general, eligible pharmaceuticals comprise those requiring a prescription. Two-thirds of such processes review both inpatient and outpatient pharmaceuticals (12/18), while one-third (6/18) considers those administered in outpatient settings only (Table 1). The remaining five countries have invested in centralized reimbursement systems that span medical devices, procedures, and pharmaceuticals (Table 1). Despite differences in the scope of technologies included, such processes share a similar mandate to determine the reimbursement status of new technologies. In most of the countries, this amounts to a decision on whether to add the technology to a “positive list” (ie, list of insured services). However, a small proportion of the countries also maintain a “negative list” (ie, a list of nonreimbursable services), broadening the mandate of their centralized reimbursement systems to include decisions resulting in active exclusion of some technologies from the benefit plan (Table 1). In legislation governing most systems (13/23), decisions are authoritative (ie, must be implemented), rather than advisory (ie, recommendations). Given that the price of a technology can significantly influence assessments of value for money and affordability, many of the countries have also incorporated pricing into the mandates of such systems (discussed in detail later). Finally, all consider at least three funding decision options, ie, provide, do not provide, and provide with restrictions or conditions (ie, restrict use to specific providers or patients meeting certain criteria, Table 1). In addition, approximately one-third have introduced a fourth option, ie, provide while additional evidence is collected. The latter comprises a provisional funding arrangement in which the technology is reimbursed in the interim while information needed to reduce uncertainties in existing evidence is collected to support a definitive decision.

Table 1 Centralized reimbursement system and mandate

Country	Centralized reimbursement review/decision-making body (role)	Technology scope	Decision problem	Decision “scope”		Available decision options
				Reimbursement	Linkage to pricing	Provide	Do not provide	Provide with restrictions	Provide while additional evidence is collected
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board/Austrian Medicines Evaluation Commission (recommendations)^Citation21,Citation56^–^Citation58	Pharmaceuticals – Outpatient^Citation55	Provide as publicly insured service (reimbursable)^Citation55 Do not provide as publicly insured service (nonreimbursable)^Citation55	Yes^Citation56,Citation59	Yes^Citation21,Citation56,Citation59	Yes^Citation56	Yes^Citation56	Yes^Citation56	Not specified
Belgium	Minister of Social Affairs (decisions) Commission on reimbursement of medicines/Drug Reimbursement Committee (recommendations)^Citation9,Citation60^–^Citation63	Pharmaceuticals – Outpatient – Inpatient^Citation21,Citation64	Provide as publicly insured service (reimbursable)^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21
Czech Republic	State Institute for Drug Control (decisions)^Citation65^–^Citation67	Pharmaceuticals – Outpatient^Citation65	Provide as publicly insured service (reimbursable)^Citation65	Yes^Citation67	Yes^Citation67	Yes^Citation65	Yes^Citation65	Yes^Citation65	Not specified
Denmark	Danish Medicines Agency (decisions).^Citation68^–^Citation70 Reimbursement Committee (recommendations)^Citation68,Citation70	Pharmaceuticals – Outpatient^Citation71	Provide as publicly insured service^Citation38,Citation46,Citation69,Citation71	Yes^Citation68	No^Citation68	Yes^Citation38,Citation69	Yes^Citation38,Citation69	Yes^Citation38,Citation69	Not specified
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	Pharmaceuticals – Outpatient^Citation72	Provide as publicly insured service (reimbursable)^Citation72	Yes^Citation72	Yes^Citation72	Yes^Citation72	Yes^Citation72	Yes^Citation72	No^Citation67
Finland	Pharmaceuticals Pricing Board (decisions)^Citation64,Citation73,Citation74 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Pharmaceuticals – Outpatient^Citation76	Provide as publicly insured service (reimbursable)^Citation76 Do not provide as publicly funded service (nonreimbursable)^Citation76	Yes^Citation76	Yes^Citation76	Yes^Citation77	Yes^Citation73	Yes^Citation73	No^Citation74
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	Pharmaceuticals – Outpatient – Inpatient^Citation79 Devices^Citation79 Procedures^Citation79	Provide as publicly insured service (reimbursable)^Citation80	Yes^Citation16,Citation20,Citation22,Citation78	Yes^Citation16,Citation20,Citation22,Citation78	Yes^Citation20	Yes^Citation20	Yes^Citation20	Yes^Citation16,Citation20
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19	Pharmaceuticals – Outpatient – Inpatient^Citation81,Citation82 Devices^Citation18 Procedures^Citation83	Provide as publicly insured service (reimbursable)^Citation55 Do not provide as publicly funded service (nonreimbursable)^Citation55 Note: Must not exclude technologies for which there is no alternative^Citation18,Citation81	Yes^Citation19	Yes^Citation82,Citation84	Yes^Citation19	Yes^Citation19	Yes^Citation19	Yes^Citation19
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85,Citation86	Pharmaceuticals – Outpatient^Citation85	Classify pharmaceutical into therapeutic category^Citation85	Yes^Citation85	Yes^Citation87	N/A	N/A	N/A	N/A
Hungary	Ministers of Health and Finance (decisions) National Health Insurance Fund Administration Health Technology Assessment Committee (recommendations)^Citation88,Citation89	Pharmaceuticals – Outpatient – Inpatient^Citation90	Provide as publicly insured service^Citation88 Do not provide as publicly funded service (nonreimbursable)^Citation26	Yes^Citation88	Not specified	Yes^Citation90	Yes^Citation90	Yes^Citation90	Not specified
Ireland	Health Service Executive (decisions)^Citation91,Citation92	Pharmaceuticals – Outpatient – Inpatient Devices Procedures^Citation91,Citation92	Provide as publicly insured service (reimbursable)^Citation92	Yes^Citation91	No^Citation91	Yes^Citation91	Yes^Citation91	Yes^Citation91	No^Citation93
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Pharmaceuticals – Outpatient – Inpatient^Citation21	Provide as publicly insured service (reimbursable)^Citation21	Yes^Citation96,Citation97	Yes^Citation96,Citation97	Yes^Citation96	Yes^Citation96	Yes^Citation96	Yes^Citation96
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmacoeconomics (recommendations)^Citation98	Pharmaceuticals – Outpatient – Inpatient^Citation34	Provide as publicly insured service (reimbursable)^Citation98	Yes^Citation98	Yes^Citation98	Yes^Citation98	Yes^Citation98	Yes^Citation98	Not specified
Poland	Ministry of Health (decisions)^Citation99	Pharmaceuticals – Outpatient – Inpatient^Citation100	Provide as publicly insured service (reimbursable)^Citation100	Yes^Citation100	Yes^Citation100	Yes^Citation100	Yes^Citation100	Yes^Citation100	Not specified
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation44,Citation101	Pharmaceuticals – Outpatient – Inpatient^Citation102	Provide as publicly insured service (reimbursable)^Citation44	Yes^Citation103	Yes^Citation99	Yes^Citation99	Yes^Citation99	Yes^Citation99	No^Citation99
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Pharmaceuticals – Outpatient – Inpatient^Citation30	Provide as publicly insured service (reimbursable)^Citation30	Yes^Citation104	No^Citation104	Yes^Citation104	Yes^Citation104	Yes^Citation99	No^Citation99
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105^–^Citation107	Pharmaceuticals – Outpatient – Inpatient^Citation102	Provide as publicly insured service (reimbursable)^Citation102 Do not provide as publicly funded service (nonreimbursable)^Citation102	Yes^Citation106	Yes^Citation106	Yes^Citation102	Yes^Citation102	Yes^Citation102	Not specified
Spain	Ministry of Health Directorate General of Pharmacy and Health Products (decisions)^Citation21,Citation108	Pharmaceuticals – Outpatient – Inpatient^Citation108	Provide as publicly funded service (reimbursable)^Citation108 Do not provide as publicly funded service (non-reimbursable)^Citation108	Yes^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21	Yes^Citation21	No^Citation21
Sweden	Dental and Pharmaceutical Benefits Board (decisions)^Citation15,Citation109,Citation110	Pharmaceuticals – Outpatient Devices (for administration of pharmaceuticals)^Citation15,Citation21,Citation33,Citation109	Provide as publicly funded service (reimbursable)^Citation15	Yes^Citation111	Yes^Citation112	Yes^Citation109	Yes^Citation109	Yes^Citation109	Yes^Citation109
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113^–^Citation115	Pharmaceuticals – Outpatient – Inpatient^Citation113	Provide as publicly funded service (reimbursable)^Citation113	Yes^Citation113,Citation114	Yes^Citation113,Citation114	Yes^Citation113,Citation114	Yes^Citation113,Citation114	Yes^Citation113,Citation114	Not specified
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Medicinal Products Reimbursement Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation116	Pharmaceuticals – Outpatient – High cost Inpatient^Citation49 Procedures^Citation117	Provide as publicly funded service (reimbursable)^Citation49	Yes^Citation117,Citation118	No^Citation31	Yes^Citation31	Yes^Citation31	Yes^Citation119	Yes^Citation119
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Pharmaceuticals – Outpatient – Inpatient^Citation7 Devices^Citation7 Procedures^Citation7	Provide as publicly funded service (reimbursable)^Citation7	Yes^Citation7	No^Citation7	Yes^Citation7	Yes^Citation7	Yes^Citation7	Yes^Citation7
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation120	Pharmaceuticals – Outpatient – Inpatient^Citation120	Provide as publicly funded service (reimbursable)^Citation120	Yes^Citation120	No^Citation120	Yes^Citation120	Yes^Citation120	Yes^Citation120	Yes^Citation120

Assessment of health technologies in centralized reimbursement systems

Approaches to the identification of technologies for review by centralized reimbursement systems vary across countries (Table 2). Broadly, there are three strategies: technologies may be submitted by manufacturers seeking coverage for newly licensed pharmaceuticals (13/23); they may be referred by potential payers (eg, government, sickness funds) or users (eg, hospitals, providers, patients), as well as manufacturers (8/23); or they may be identified by payers or users only (2/23). Systems limited to consideration of reimbursement applications from manufacturers alone typically review submissions in order of receipt, unless a technology is eligible for “fast tracking,” which moves it to the front of the queue. In countries with such mechanisms (eg, the Netherlands), eligibility criteria include technologies (mainly pharmaceuticals) used to treat rare or life-threatening conditions for which no alternatives beyond best supportive care exist. Some countries (eg, Scotland and Norway) have more closely linked centralized regulatory and reimbursement processes in order to reduce overall inefficiencies in technology policy. Specifically, pharmaceuticals are automatically sent to the centralized reimbursement system for review upon market approval. In systems that accept referrals from multiple stakeholders, technology selection and/or prioritization criteria have been established. For example, Germany’s Federal Joint Committee, which determines which technologies to review, takes into account clinical relevance, cost implications, and potential “risks” related to the technology and its introduction into the health care system.⁶ In the UK, the topic selection panel of the National Institute of Health and Clinical Excellence, whose members include health care providers and patient representatives, formulate recommendations following consideration of: the burden of disease for which the technology targets; anticipated clinical impact (ie, whether the technology represents a significant medical advance that could yield substantial health benefits); potential impact on National Health Service costs and resources; alignment of the technology with broader government priority areas; concerns over appropriateness of use in practice; and potential for national guidance to add value.⁷ Recommendations are forwarded to the Department of Health, which makes the final decision.

Table 2 Comparison of processes for identifying, selecting, and assessing technologies

Country	Centralized reimbursement review/decision-making body (role)	Technologies to be considered for review		Health technology assessment
		Technology identification	Technology selection	Synthesis and analysis of evidence (assessment report)	Evaluation of evidence provided (evaluation report)
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation58	Typically considered in order received^Citation58	Manufacturer through submission requirements^Citation55 Methods should comply with internationally recognized systematic review and economic guidelines^Citation55	Technical staff within Association of Austrian Social Security Institutions (Department of Pharmaceutical Affairs – pharmacological and medical-therapeutic assessment; Health Economics Team – economic assessment)^Citation55
Belgium	Minister of Social Affairs (decisions) Commission on reimbursement of medicines/Drug Reimbursement Committee (CRM) (recommendations)^Citation9	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation17	Typically considered in order received^Citation17	Manufacturer through submission requirements^Citation9 Methods should comply with internationally recognized systematic review guidelines^Citation9	Technical staff within CRM supported by external experts^Citation9
Czech Republic	State Institute for Drug Control (decisions)^Citation65	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation66	Typically considered in order received^Citation65	Manufacturer through submission requirements^Citation66	Technical staff within State Institute for Drug Control^Citation65
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation84	Typically considered in order received^Citation84	Manufacturer through submission requirements^Citation68 Methods must comply with “Danish guidelines for the socioeconomic analysis of medicines”^Citation68	Technical staff within Danish Medicines Agency supported by external experts, if necessary^Citation68
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation72	Not specified	Manufacturer through submission requirements^Citation72	Technical staff within Estonian Health Insurance Fund and State Agency of Medicines^Citation72
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation76	Typically considered in order received^Citation73	Manufacturer through submission requirements^Citation122 Methods must comply with guidelines of the Ministry of Social Affairs and Health^Citation122	Technical staff within Pharmaceuticals Pricing Board supported by external experts^Citation122
France	Ministry for Health and Social Security (decisions)^Citation21,Citation78 French National Authority for Health (recommendations)^Citation78	Depends on type of appraisal1^Citation6,Citation20 Single technology appraisal Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals and devices Health care professional associations seeking reimbursement for procedures Multiple technology appraisals Typically classes of pharmaceuticals or categories of devices Referred by: Health care professional associations Ministry of Health National Union of Health Insurance Funds Patient and/or carer organizations^Citation120	Single technology appraisals Typically considered in order received^Citation16 Multiple technology appraisals Selection criteria not specified	Single technology appraisals Manufacturer through submission requirements^Citation20 Multiple technology appraisals Technical staff within Health and Social Security supported by external experts^Citation20 Methods should comply with internationally recognized systematic review and economic guidelines^Citation20	Single technology appraisals Technical staff within Health and Social Security supported by external experts^Citation20 Multiple technology appraisals Technical staff within Health and Social Security or independent academic group^Citation20
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19	Referred by: Associations represented by Federal Joint Committee Ministry of Health Institute for Quality and Efficiency in Health Care Federal commissioner of patient affairs Patient and/or carer organizations^Citation18	Determined by Federal Joint Committee Selection criteria: Clinical relevance Cost implications “Risks”^Citation6	Technical staff within Institute for Quality and Efficiency in Health Care supported by external experts^Citation123,Citation124 Methods must comply with Institute for Quality and Efficiency in Health Care systematic review and economic guidelines^Citation124	Technical staff within Institute for Quality and Efficiency in Health Care supported by external experts^Citation123,Citation124
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation85	Not specified	Manufacturer through submission requirements^Citation85	Technical staff within Transparency Committee in the Reimbursement and Medicinal Products^Citation85
Hungary	Ministers of Health and Finance (decisions) National Health Insurance Fund Administration (recommendations)^Citation88,Citation89	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals National Health Insurance Fund Administration^Citation88	Not specified	Technical staff within National Technology Assessment Office of the National Institute for Strategic Health Research^Citation90	Technical staff within National Technology Assessment Office of the National Institute for Strategic Health Research^Citation90
Ireland	Health Service Executive (decisions)^Citation91,Citation92	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation91 Referred by: Department of Health and Children of the Health Services Executive for new and existing devices and diagnostic tests that might “incur a high cost or have a significant budget impact”^Citation91	Not specified	Manufacturer through submission requirements^Citation93,Citation125 Methods must comply with Irish Health Technology Assessment Guidelines^Citation93	Technical staff within National Centre for Pharmacoeconomics, supported by external clinical experts^Citation93
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation27	Typically considered in order received^Citation27	Manufacturer through submission requirements^Citation126 Methods must comply with Italian submission guidelines^Citation27	Members of Technical Scientific Committee^Citation126
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmacoeconomics (recommendations)^Citation98	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation34	Not specified	Manufacturer through submission requirements^Citation34 Methods should comply with internationally recognized systematic review guidelines^Citation34	Technical staff within Norwegian Medicines Agency and Department of Pharmacoeconomics^Citation98
Poland	Ministry of Health (decisions)^Citation99	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation99	Not specified	Manufacturer through submission requirements^Citation99	Technical staff within Ministry of Health^Citation99 Agency for Health Technology Assessment^Citation127
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation36,Citation45	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation36	Not specified	Manufacturer through submission requirements^Citation36	Technical staff within INFARMED supported by external experts^Citation36
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation104 Automatic within 12 weeks of market launch^Citation104	Exclusion criteria: Already appraised by National Institute of Health and Clinical Excellence through its multiple technologies appraisal process^Citation104	Manufacturer through submission requirements^Citation128 Methods must comply with Scottish Medicines Consortium systematic review and economic guidelines^Citation34	Technical staff within Scottish Medicines Consortium supported by external experts^Citation128
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation107,Citation129,Citation106	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation104	Not specified	Manufacturer through submission requirements^Citation131	Working group for pharmacoeconomics and outcomes research^Citation131
Spain	Ministry of Health Directorate General of Pharmacy and Health Products Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	Referred by: Ministry of Health (newly approved pharmaceuticals)^Citation108	Not specified	Manufacturer through invitation to submit information to Inter-Ministerial Pricing Commission^Citation21 Technical staff within Ministry of Health^Citation132	Inter-Ministerial Pricing Commission^Citation21
Sweden	Dental and Pharmaceutical Benefits Board (decisions)^Citation15,Citation109,Citation110	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation104 Dental and Pharmaceutical Benefits Board (for pharmaceuticals approved prior to 2002)^Citation133,Citation134	For new pharmaceuticals: typically considered in order received For older pharmaceuticals: Overall sales volume^Citation134,Citation135	For new pharmaceuticals: Manufacturer through submission requirements^Citation136 For older pharmaceuticals: Technical staff within Dental and Pharmaceutical Benefits Board supported by external experts^Citation136 Methods must comply with Dental and Pharmaceutical Benefits Board systematic review and economic guidelines^Citation10	For new pharmaceuticals: Technical staff within Dental and Pharmaceutical Benefits Board^Citation136 For older pharmaceuticals: Technical staff within Dental and Pharmaceutical Benefits Board supported by external experts^Citation136
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation114,Citation115	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation114 Patients and carers Hospitals and hospital groups Health care professional associations Federal Office of Public Health^Citation114,Citation137	Not specified	Manufacturer through submission requirements^Citation113	Federal Drug Commission^Citation114
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Medicinal Products Reimbursement Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation116	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation31 University hospital federations, health care professional associations, and Dutch Healthcare Insurance Board for high-cost inpatient pharmaceuticals	Not specified	Manufacturer through submission requirements^Citation31 Technical staff within Dutch Healthcare Insurance Board^Citation117 Methods must comply with internationally recognize systematic review guidelines and Dutch Healthcare Insurance Board economic guidelines^Citation117	Technical staff within Dutch Healthcare Insurance Board^Citation117
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals Patients and carers Health care providers Health care professional associations General Public National Horizon Scanning Centre^Citation120	Selection criteria: Burden of disease (population affected, mortality, and morbidity) Resource impact (on National Health Service costs and resources) Clinical importance Policy importance (alignment with government priority areas) Inappropriate variations in practice Likelihood of national guidance adding value^Citation7 Technology selection panel composition: Health care providers (specialists, general practitioners, and public health professionals) Patient representatives Technology selection panel makes recommendations. Final decisions made by Department of Health^Citation7	Single technology appraisals Manufacturer through submission requirements^Citation120 Multiple technology appraisals Independent academic group^Citation120 Methods must comply with National Institute for Health and Clinical Excellence systematic review and economic guidelines^Citation120	Single technology appraisals Independent academic group^Citation120 Multiple technology appraisals Independent academic group^Citation120
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation28	Referred by: Manufacturers seeking reimbursement for newly approved pharmaceuticals^Citation28 Welsh Medicines Partnership horizon scanning process for identifying pharmaceuticals expected to receive market approval within 18 months^Citation28	Typically considered in order received^Citation28	Manufacturer through submission requirements^Citation28 Welsh Medicines Partnership^Citation28 Methods must comply with All Wales Medicines Strategy Group systematic review and economic guidelines^Citation28	Welsh Medicines Partnership^Citation28

Across centralized reimbursement systems, technology identification and selection is followed by some form of health technology assessment (Table 2). This involves collection and synthesis of evidence (clinical and, in most cases, economic), the findings of which are presented in an assessment report, and critical appraisal of the relevance, quality, and generalizability of that evidence. The results of the latter are summarized in an evaluation report. Responsibility for the preparation of these reports varies. In systems where a manufacturer’s submission initiates the reimbursement review process, the assessment report is part of the submission (Table 2). Therefore, its preparation rests with the manufacturer. Most systems have developed a standard template/structure for the report and submission guidelines to which manufacturers must adhere. These guidelines largely include content/information requirements and internationally accepted methods for synthesizing and analyzing evidence. In two of the countries, responsibility for the assessment depends upon the type of review (“appraisal”). Both France and the UK have created “single technology appraisal” and “multiple technology appraisal” processes. “Single technology appraisals” compare the candidate technology with a limited number of alternatives for a specific, well-defined indication (eg, disease stage). Their scope most closely resembles processes based upon manufacturers’ submissions. “Multiple technology appraisals” consider either several indications for a candidate technology or several technologies (along with the candidate technology) for a condition at one or more points in its course, taking a disease management approach. The assessment report for a single technology appraisal is prepared by the manufacturer. For a multiple technology appraisal, the report is drafted either internally with support from external content and methodological experts (France) or by an independent academic group (the UK). Finally, in some countries, technical staff of a dedicated health technology assessment body or the centralized reimbursement system itself undertake the assessment report, regardless of the scope (eg, Germany).

With one exception (the UK), responsibility for preparing the evaluation report that accompanies each assessment also lies with technical staff and, if necessary, external experts. The National Institute of Health and Clinical Excellence commissions independent academic groups to evaluate assessments submitted by manufacturers as part of its single technology appraisal process.

Clinical and economic evidence expectations of centralized reimbursement systems

Centralized reimbursement systems have issued their own guidelines or endorsed internationally recognized published ones specifying clinical and economic evidence requirements for assessment reports (Tables 3 and 4). These guidelines state topics to be addressed and the types of information accepted for addressing them. In most cases (16/23), specified clinically-related topics are similar and include: burden of illness and/or characteristics of the target patient population; therapeutic claim of the candidate technology; safety; efficacy; and effectiveness (preferably comparative effectiveness) across relevant patient subgroups (Table 3). Additionally, several require information on current management or the place of the candidate technology within existing treatment pathways (eg, France and the UK), and its proposed frequency and duration of use (eg, Austria). Across systems and where reported, there is a shared preference for information on health outcomes that represent final clinical endpoints related to mortality, morbidity, and quality of life. Less frequently, information on adverse events/complications is also required. This may be explained by the fact that a prerequisite for reimbursement review is typically regulatory approval. Therefore, systems may view reconsideration of adverse events, which relate to the safety of a technology, unnecessary. In systems proposing or stipulating the use of quality-adjusted life-years (7/23), change in health-related quality of life is to be measured in patients and then valued in the public or general population (eg, the UK). Surrogate outcomes are discouraged or not accepted unless well validated (eg, Germany). Lastly, some systems elicit the views of patients and or carers in identifying topic specific outcomes and their relative importance (eg, Germany).

Table 3 Comparison of clinical evidence requirements

Country	Centralized reimbursement review/decision-making body (role)	Clinical evidence requirements
		Topic	Preferred clinical outcomes	Type	Source
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Target patient population and indications (therapeutic claim) Pharmacology Safety Efficacy Effectiveness (across population subgroups) Frequency and duration of treatment^Citation55	Not specified	Preference for: Double-blind randomized controlled trials Systematic reviews and meta-analyses of randomized controlled trials complying with internationally recognized guidelines^Citation55	Published, peer-reviewed studies Unpublished reports and studies may be accepted in exceptional circumstances^Citation55 Commercial, in-confidence data^Citation55
Belgium	Minister of Social Affairs (decisions) Commission on reimbursement of medicines/Drug Reimbursement Committee (recommendations)^Citation9,Citation60	Target patient population and indications (therapeutic claim) Safety Efficacy Effectiveness (across population subgroups)^Citation11	Morbidity Adverse events/complications Quality of life Overall survival/mortality (life-years gained) Quality-adjusted life years (QALYs) – measured in patients but valued by public/society Other relevant disease-specific outcomes^Citation4 Final endpoints^Citation11	Preference for: Randomized controlled trials Observational head-to-head comparative studies^Citation11,Citation17 Effectiveness studies (over efficacy studies)^Citation17 Minimum of one positive superiority trial on primary endpoints against active control or placebo (if no alternative treatments exist)^Citation17	Published, peer-reviewed studies Unpublished reports and studies^Citation17 Abstracts not accepted^Citation9
Czech Republic	State Institute for Drug Control (decisions)^Citation65	Safety Efficacy Effectiveness^Citation66	Not specified	All clinical trials^Citation138	Not specified
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Target patient population and indications (therapeutic claim) Safety Efficacy Effectiveness (across population subgroups)^Citation38	Not specified	Preference for: Randomized controlled trials comparing pharmaceutical to standard care^Citation38	Not specified
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation67	Safety Efficacy Effectiveness^Citation139	Adverse events/complications Side effects Overall survival/mortality^Citation139,Citation140	Preference for: Randomized controlled trials^Citation84	Published, peer-reviewed studies^Citation84
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Target patient population and indications (therapeutic claim) Severity and burden of illness Effectiveness (across population subgroups)^Citation76	Not specified	Preference for: Randomized controlled trials comparing pharmaceutical to standard care^Citation76 Evidence from other available direct comparative experimental and observational studies, as well as meta-analyses, should be included^Citation76	Published, peer-reviewed studies^Citation76
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation20,Citation78	Target patient population and indications (therapeutic claim) Current management Place of technology in care pathway Safety Efficacy Effectiveness (across population subgroups)^Citation16	Morbidity Overall survival/mortality Quality of life^Citation16	Preference for: Head-to-head, double-blind randomized controlled trials Other direct comparative studies Post-market studies Systematic reviews and meta-analyses of randomized controlled trials complying with internationally recognized guidelines^Citation16	Published, peer-reviewed studies Current national and international clinical practice guidelines Expert opinion Surveys of practice Commercial, in-confidence data^Citation16
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19,Citation141	Target patient population and indications (therapeutic claim) Severity and burden of illness Safety Efficacy Effectiveness (across population subgroups)^Citation8	Morbidity Overall survival/mortality Quality of life Adverse events/complications Side effects Duration of illness Health status^Citation8,Citation83,Citation142^–^Citation144 Topic specific outcomes identified in consultation with patient organizations^Citation18 Validated surrogate outcomes^Citation83	Preference for: Randomized controlled trials comparing pharmaceutical to placebo, standard care, or no active treatment^Citation8 Evidence from other available direct comparative experimental and observational studies, as well as systematic reviews and meta-analyses complying with internationally recognized guidelines, should also be included^Citation8 If no treatment alternative exists, well-documented case series acceptable^Citation8	Published, peer-reviewed studies Commercial, in-confidence data not accepted unless it can be published^Citation18
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85	Safety Efficacy Effectiveness^Citation145	Not specified	Not specified	Not specified
Hungary	Ministers of Health and Finance (decisions) National Health Insurance Fund Administration (recommendations)^Citation88	Severity and burden of illness Current management Safety Efficacy Effectiveness (across population subgroups)^Citation90	Not specified	Preference for: Randomized controlled trials^Citation84	Published, peer-reviewed studies^Citation90
Ireland	Health Service Executive (decisions)^Citation91,Citation92	Safety Efficacy Effectiveness (across population subgroups)^Citation146	Morbidity Overall survival/mortality Quality of life QALYs – measured in patients but valued by public/society^Citation146 All other health benefits accrued by individuals^Citation147	Preference for: Randomized controlled trials^Citation147 Evidence from other available direct comparative experimental and observational studies, as well as systematic reviews and meta-analyses complying with Irish Health Technology Assessment Guidelines, should also be included^Citation146	Not specified
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Safety Efficacy Effectiveness (across population subgroups)^Citation148	Morbidity Overall survival/mortality Quality of life^Citation149	Preference for: Randomized controlled trials comparing pharmaceutical to standard care^Citation97 Evidence from other available direct experimental and observational studies comparing pharmaceutical with standard care^Citation148	Not specified
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmacoeconomics (recommendations)^Citation98	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Place of technology in care pathway Safety Efficacy Effectiveness (across population subgroups)^Citation34,Citation149	Morbidity Overall survival/mortality Quality of life^Citation144	Preference for: Head-to-head, double-blind randomized controlled trials Other direct comparative studies Systematic reviews and meta-analyses complying with internationally recognized guidelines^Citation149,Citation150	Published, peer-reviewed studies Unpublished reports and studies^Citation149,Citation150
Poland	Ministry of Health (decisions)^Citation99,Citation100	Severity and burden of illness Current management Safety Efficacy Effectiveness (across population subgroups)^Citation151	Morbidity Overall survival/mortality Quality of life^Citation151	Preference for: Randomized controlled trials^Citation151	Published, peer-reviewed studies Unpublished reports and studies^Citation151
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation44	Safety Efficacy Effectiveness (across population subgroups)^Citation101	Morbidity Overall survival/mortality Quality of life^Citation101	Preference for: Effectiveness studies of target population (over efficacy studies)^Citation101 Comparative clinical trials Other study designs accepted, but rationale must be provided^Citation101	Not specified
Scotland	National Health Service Scotland (decisions)^Citation50 Scottish Medicines Consortium (recommendations)	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Place of technology in care pathway “Comparative” safety Efficacy Effectiveness (across population subgroups)^Citation128	Morbidity Overall survival/mortality Quality of life QALYs (strongly preferred)^Citation50	Randomized controlled trials required Comparative observational studies accepted^Citation50 If no head-to head studies available, indirect comparison required^Citation50	Published, peer-reviewed studies Unpublished reports and studies Expert opinion Submissions from patient and carer organizations^Citation128
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation107,Citation130	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Patient acceptance Safety Efficacy Effectiveness Frequency and duration of treatment^Citation106	Morbidity Overall survival/mortality Adverse events/complications Quality of life^Citation106	Preference for: Comparative studies^Citation84	Published, peer-reviewed studies Unpublished reports and studies with negative findings^Citation152
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Safety Efficacy Effectiveness^Citation132	Morbidity Overall survival/mortality Quality of life QALYs^Citation132	Preference for: Randomized controlled trials Evidence from other available direct comparative experimental and observational studies should also be included^Citation132	Not specified
Sweden	Dental and Pharmaceutical Benefits Board (decisions)^Citation15,Citation109	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Safety Efficacy Effectiveness^Citation153	Morbidity Overall survival/mortality Quality of life QALYs (preferred)^Citation109	Preference for: Randomized controlled trials comparing pharmaceutical to standard care^Citation109 Evidence from other available direct comparative experimental and observational studies should also be included^Citation15	Commercial, in-confidence data^Citation109 Published, peer-reviewed studies Unpublished reports and studies Ongoing studies Submissions from patient and carer organizations^Citation51
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113^–^Citation115	Safety Efficacy Effectiveness^Citation113	Not specified	Not specified	Not specified
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Medicinal Products Reimbursement Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation116	Target patient population and indications (therapeutic claim) Severity and burden of illness Safety Efficacy Effectiveness^Citation154	Morbidity Overall survival/mortality Quality of life^Citation36,Citation155	Preference for: Head-to-head randomized controlled trials Systematic reviews or meta-analyses complying with internationally recognized guidelines^Citation35,Citation156	Published, peer-reviewed studies Unpublished reports and studies Commercial, in-confidence data Expert opinion^Citation154
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Place of technology in care pathway “Comparative” safety Efficacy Effectiveness (across population subgroups)^Citation29	Morbidity Overall survival/mortality (life years) Quality of life^Citation157 QALYs – measured in patients but valued by public/society^Citation29,Citation158	Preference for: Head-to-head randomized controlled trials conducted in “naturalistic” settings Effectiveness studies of target population (over efficacy studies) Systematic reviews or meta-analyses complying with internationally recognized guidelines^Citation159 Evidence from other available direct comparative experimental and observational studies should also be included^Citation159Registries, case series, and follow-up studies also accepted^Citation159	Published, peer-reviewed studies Unpublished reports and studies Commercial, in-confidence data^Citation159 Submissions from patient and carer organizations^Citation159 Information from health care professional associations, administrators, government, and manufacturers^Citation157
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation120	Target patient population and indications (therapeutic claim) Severity and burden of illness Current management Place of technology in care pathway “Comparative” safety Efficacy Effectiveness (across population subgroups)^Citation28	Morbidity Overall survival/mortality Quality of life QALYs (preferred)^Citation28	All types of clinical studies accepted, but greater importance given to high quality ones^Citation28	Published, peer-reviewed studies Unpublished reports and studies Expert opinion Submissions from patient and carer organizations describing experiences of those who have taken the pharmaceutical^Citation28

Table 4 Comparison of economic evidence requirements

Country	Centralized reimbursement review/decision-making body (role)	Economic analysis						Budget impact analysis		Other economic information
		Required	Economic analysis types accepted	Perspective/costs included	Comparator	Sensitivity analysis	Systematic review of economic analysis studies	Required	Costs included
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Yes for: “innovative products providing substantial therapeutic benefit “where no comparable medical preparation exists”^Citation21	Any type, but rationale for selection must be provided^Citation21 Should comply with internationally recognized pharmacoeconomic guidelines^Citation21	Payer^Citation21 Costs not specified	Most commonly used alternative^Citation21	Yes – type not specified^Citation21	Yes	No information found	N/A	3 year market sales forecast Price in other European Union countries Reimbursement status in other European Union countries^Citation55
Belgium	Minister of Social Affairs (decisions) Commission on reimbursement of medicines/drug reimbursement committee (recommendations)^Citation9,Citation60	Yes for: Pharmaceuticals with added therapeutic value relative to existing alternatives (Class I)^Citation11,Citation17 Not required for orphan pharmaceuticals^Citation62	Cost effectiveness Cost utility Cost benefit not accepted^Citation11 Should comply with Belgium pharmacoeconomic guidelines^Citation17	Payer (includes patient copayments and government)^Citation11,Citation17 Direct costs only^Citation11,Citation17	Most commonly used alternative OR Alternative most likely to be replaced If add-on: current treatment without add-on^Citation17 Off-label treatments not acceptable^Citation11 Rationale must be provided	Probabilistic^Citation17	Yes^Citation17	Yes^Citation11	Direct costs only^Citation11,Citation17	Price Reimbursement status in other European Union countries^Citation11,Citation17
Czech Republic	State Institute for Drug Control (decisions)^Citation65	Yes^Citation66	Cost effectiveness^Citation138	Payer^Citation66 Direct costs^Citation138	No information found	Method not specified	No information found	Yes^Citation138	No information found	No information found
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	No, but often included to justify high price^Citation68,Citation71,Citation160	Cost effectiveness Cost utility^Citation68 If included, methods should comply with Danish Guidelines for the Socio-economic Analysis of Medicines^Citation68	Societal (if included) Direct, indirect, and intangible; to be reported separately^Citation71	Most commonly used alternative^Citation38	Method not specified, but key parameters associated with uncertainty should be explored^Citation38	No information found	Yes^Citation38	No information found	Reimbursement status in other European Union countries Estimated consumption (number of patients and utilization)^Citation38
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	Yes^Citation84,Citation139	Cost effectiveness Cost utility Cost minimization rationale for selection must be provided^Citation139	Payer^Citation139 May present separate analysis from societal perspective^Citation84 Direct costs within and outside of the health care system (should be reported separately)^Citation139	Most commonly used alternative OR Standard care^Citation139 Rationale must be provided	Method not specified	No information found	No information found	No information found	No information found
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Yes for: Pharmaceuticals considered for reimbursement in one of the special refund categories^Citation74,Citation76	Any type, but rationale for selection must be provided^Citation76 Methods must comply with Ministry of Social Affairs and Health guidelines^Citation76	Societal^Citation76 Direct and indirect costs – presented separately^Citation76	Alternative most likely to be replaced OR Most commonly used alternative OR Most effective alternative OR Minimum management^Citation76 Rationale must be provided	Method not specified	Yes^Citation76	Yes^Citation161	No information found	Market sales forecast Reimbursement status in other European Union countries Estimated consumption (number of patients and utilization)^Citation161
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	Yes for: Multiple technology appraisals of pharmaceuticals^Citation20	Any type, but rationale for selection must be provided^Citation22 Methods must comply with French economic guidelines^Citation20	Varies, but should take the widest possible perspective – rationale for selection must be provided ^Citation84 Direct costs; may include indirect costs, but must be presented separately^Citation22	Following 3 comparators required: Most commonly used alternative Most recently reimbursed alternative Least expensive alternative^Citation16	Method not specified	Yes for pharmaceuticals^Citation22	Yes^Citation20	No information found	Market sales forecast Reimbursement status in other European Union countries Breakdown of costs for manufacturing and distribution^Citation22,Citation162
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19,Citation24,Citation144	Yes for: Technologies where alternative treatment exists^Citation8,Citation18	Any one of: Cost effectiveness Cost utility Cost minimization/cost comparison^Citation18 Efficiency frontier analysis^Citation12	Payer Patient^Citation83 Direct and indirect costs^Citation8	Most commonly used alternative OR Most effective alternative OR Minimum standard care^Citation8	One-way and multi-way (performed as probabilistic)^Citation24	Yes^Citation84	Yes, except when no alternative exists^Citation18	No information found	No information found
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85,Citation160	Yes for: Pharmaceuticals eligible for reference price system^Citation85	No information found	No information found	No information found	No information found	No information found	Yes^Citation85	No information found	Cost of daily treatment Reimbursement status in other European Union countries^Citation85
Hungary	Ministers of Health and Finance (decisions) National Health Insurance Fund Administration (recommendations)^Citation86,Citation90,Citation102	Yes^Citation84	Preference for: Cost effectiveness Cost utility^Citation163	Payer Societal (also recommended) Report results from each perspective separately^Citation163	Standard care^Citation163	Yes, but type not specified^Citation163	No information found	Yes^Citation84	If payer perspective, include direct costs only If societal perspective, include indirect costs (productivity)^Citation163	No information found
Ireland	Health Service Executive (decisions)^Citation91,Citation92	Yes^Citation146	Preference for: Cost utility^Citation10 Any one of the following may be acceptable if rationale is provided: Cost benefit Cost effectiveness Cost minimization/cost comparison^Citation147,Citation165 Methods must comply with Irish Healthcare Technology Assessment Guidelines^Citation146	Payer^Citation147 Direct costs only^Citation147	Standard care^Citation125	Probabilistic and deterministic^Citation125	No information found	Yes	Direct costs only^Citation91,Citation147	No information found
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Yes for: Pharmaceuticals with a favorable “risk/benefit profile”^Citation97,Citation148	Preference for: Cost utility Cost effectiveness^Citation148 Methods must comply with Italian pharmacoeconomic guidelines^Citation148	Societal AND Payer^Citation148 Direct and indirect costs^Citation148	Most commonly used alternative^Citation148	Methods not specified, but should involve multi-way analysis^Citation148	No information found	Yes^Citation148	No information found	Cost of treatment compared to those in same therapeutic class Market sales forecast Price in other European Union countries Reimbursement status in other European Union countries Estimated consumption (number of patients and utilization) Industrial implications^Citation97
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmaco economics (recommendations)^Citation98	Yes for: Pharmaceuticals with added therapeutic value relative to existing alternatives^Citation34	Preference for: Cost-value analysis^Citation150 Any one of the following may be acceptable if rationale is provided: Cost benefit Cost effectiveness Cost utility Cost consequence Cost minimization/cost comparison^Citation34 Methods must comply with Norwegian pharmacoeconomic guidelines^Citation34	Societal AND Payer^Citation150	Most commonly used alternative OR Least expensive alternative^Citation150	Probabilistic preferred^Citation150	No information found	Yes^Citation149 Aggregate added expense to health service for first 5 years^Citation149	No information found	Market sales forecast Price in other European Union countries Reimbursement status in other European Union countries Estimated consumption (number of patients and utilization)^Citation149,Citation150
Poland	Ministry of Health (decisions)^Citation99,Citation166	Yes for: Pharmaceuticals with added therapeutic value relative to existing alternatives^Citation84	Cost effectiveness Cost utility^Citation84	Societal AND Payer^Citation167	Alternative most likely to be replaced OR Most commonly used alternative OR Least expensive alternative OR Standard care compliant with clinical practice guidelines^Citation151	Methods not specified	No information found	Yes^Citation84	No information found	No information found
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation64,Citation160	Yes^Citation44,Citation160	Any one of : Cost benefit Cost effectiveness Cost utility Cost minimization/cost comparison; rationale for selection must be provided^Citation101	Societal^Citation101 Direct costs Indirect costs: only those related to lost productivity^Citation101	Most commonly used alternative Standard care^Citation101	Methods not specified	No information found	No^Citation101	N/A	No information found
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Yes^Citation168	Any one of : Cost benefit Cost effectiveness Cost utility Cost minimization/cost comparison; rationale for selection must be provided^Citation168 Methods must comply with SMC economic guidelines^Citation168	Payer^Citation30	Alternative most likely to be replaced OR Most commonly used alternative^Citation30	Probabilistic^Citation168	No information found	Yes^Citation30	No information found	National Health Service resource implications^Citation30
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation107	Yes^Citation105,Citation106	Cost effectiveness Cost utility (if pharmaceutical has impact on quality of life) Cost minimization/cost comparison Cost benefit not accepted^Citation169 Methods should comply with national economic guidelines^Citation170	Payer^Citation169 Direct costs^Citation169	Alternative most likely to be replaced If add-on: current treatment without add-on^Citation152	Probabilistic^Citation106,Citation152	Yes^Citation152	Yes Estimated over first 5 years^Citation84	No information found	No information found
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108,Citation171	No^Citation21	Preference for: Cost effectiveness Cost utility^Citation10,Citation21 Any one of the following may be acceptable if rationale is provided: Cost benefit Cost effectiveness Cost utility Cost consequence Cost minimization/cost comparison^Citation10	Societal AND Payer^Citation10 Presented separately	Most commonly used alternative Standard care^Citation10 Rationale must be provided	Multi-way^Citation10	No information found	Yes, comparing “corresponding products”^Citation10	No information found	No information found
Sweden	Dental and Pharmaceutical Benefits Board (decisions)^Citation15,Citation109	Yes, if requested^Citation21	Any one of: Cost effectiveness Cost utility Cost minimization/cost comparison; rationale for selection must be provided^Citation15 Methods must comply with Swedish economic guidelines^Citation15	Societal Direct costs Indirect costs: lost productivity and lost time for patients and carers^Citation14,Citation15	Most commonly used alternative^Citation15	Not specified	No information found			Estimated average duration of use Estimated consumption (number of patients and utilization) Estimated cost of use per day^Citation15
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113,Citation114	No, but should be included if available^Citation115,Citation172	No information found	No information found	No information found	No information found	No information found	Yes^Citation115,Citation172	No information found	Price in other European Union countries Reimbursement status in other European Union countries Estimated cost of use per day^Citation115,Citation172
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Medicinal Products Reimbursement Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation116	Yes for pharmaceuticals with added therapeutic value (Annex 1B), except for orphan pharmaceuticals with small budget impact or absence of active alternative^Citation154	Cost effectiveness Cost utility Methods must comply with Dutch Healthcare Insurance Board economic guidelines^Citation36,Citation84,Citation173	Societal Direct costs^Citation154 Indirect costs may be included but must be reported separately^Citation154	Most commonly used alternative OR Most relevant reimbursed alternative^Citation84,Citation173	One-way, multi-way, and probabilistic^Citation35	No information found	Yes^Citation154	No information found	Anticipated substitution effects Price Estimated consumption (number of patients and utilization)^Citation154
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Yes^Citation7	Cost effectiveness Cost utility Methods must comply with National Institute for Health and Clinical Excellence economic guidelines^Citation13,Citation157	Payer^Citation13,Citation157 Direct and indirect costs to National Health Service and Personal Social Services	Most commonly used alternative OR Best practice alternative^Citation13,Citation157	Probabilistic^Citation157	Yes^Citation13,Citation157	Yes^Citation13,Citation157	No information found	National Health Service resource implications^Citation13,Citation157
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation28	Yes^Citation174	Any one of: Cost effectiveness Cost utility Cost minimization/cost comparison; rationale for selection must be provided^Citation28,Citation174 Methods must comply with economic guidelines^Citation28,Citation174	Societal^Citation28	Most commonly used alternative^Citation28	Probabilistic^Citation28	Yes^Citation28	Yes^Citation28,Citation174	No information found	National Health Service resource implications^Citation28,Citation174

In general, centralized reimbursement systems state a preference for head-to-head randomized controlled trials comparing the candidate technology with standard care, no active treatment/best supportive care, or placebo (if no alternatives exist, Table 3). However, increased interest in evidence of “comparative effectiveness” over “comparative efficacy” among most reimbursement systems has led to requests for inclusion of head-to-head randomized controlled trials conducted in “naturalistic settings” (ie, pragmatic trials, in the UK) and other direct comparative studies (observational and experimental in design), the collective findings of which may offer a more accurate prediction of the behavior of the technology in general clinical practice (eg, France, Germany, and Sweden). Also, there appears to be emerging recognition of the need for flexibility in evidence expectations under certain circumstances. Recently, Germany’s Institute for Quality and Efficiency in Health Care, which conducts health technology assessments and makes reimbursement recommendations on selected health technologies to the Federal Joint Committee, issued methodological guidelines suggesting that when no active alternative treatment exists, well designed case series would be deemed adequate.⁸

While across systems, the preferred source of such clinical evidence is published, peer-reviewed studies, many encourage, and in several cases require if available, inclusion of unpublished or ongoing studies (eg, Austria, Belgium, Norway, Poland, Slovakia, Sweden, the Netherlands, and the UK), commercial in-confidence data (eg, Austria, France, Sweden, and the UK) and/or current national and international clinical practice guidelines (eg, France) in assessment reports. In recent years, some systems have incorporated submissions from patient and/or carer organizations into their processes (eg, Scotland, Sweden, and the UK). Such submissions are increasingly viewed as an important source of information regarding the relative value of outcome measures employed in clinical studies and the meaningfulness or significance of findings to patients and carers. Finally, while systems tend not to explicitly exclude sources of information, Belgium’s Drug Reimbursement Committee states that abstracts are not accepted.⁹

Most centralized reimbursement systems (20/23) have made mandatory the inclusion of a formal economic evaluation/analysis for either some (ie, those for which alternative(s) exist(s), eg, Germany, or those offering “added therapeutic value,” eg, Austria and Belgium, or all candidate technologies to inform deliberations around “value for money” and/or “efficiency.” In the latter case, the type of evaluation is rarely stipulated, because options available depend, in part, on the magnitude of the incremental benefit of the technology over its comparators. However, a rationale must be presented, and methods adopted must comply with economic guidelines developed or endorsed by the centralized reimbursement system (Table 4). For technologies that appear to offer “added therapeutic value” (ie, are more effective), some systems indicate a preference for certain types of evaluations, such as cost-utility analysis by Ireland’s Health Service Executive.¹⁰ Others state explicitly which types will not be accepted, such as cost-benefit analysis by Belgium’s Drug Reimbursement Committee.¹¹ In addition to a formal economic evaluation, the Institute for Quality and Efficiency in Health Care in Germany requires an efficiency frontier analysis, which assesses the relative value of different technologies within a given therapeutic area.¹² Regarding the perspective to be taken for the economic evaluation, the proportion of systems adopting a “payer,” “societal,” or both “payer” and “societal” perspective is similar. Among systems considering a payer’s perspective only, costs to be captured are often restricted to those directly related to care associated with the use of the candidate technology throughout the course of a disease or condition (ie, direct costs to the health care system). One exception is the National Institute of Health and Clinical Excellence, which specifies inclusion of direct and indirect costs to the National Health Service and Personal Social Services.¹³ In systems requiring a societal perspective, costs specified comprise direct costs to not only the health care system, but also services beyond health care and indirect (lost productivity) costs. However, they must be reported separately (eg, Finland, Portugal, and the Netherlands). In Sweden, The Dental and Pharmaceutical Benefits Board has taken a wider view on indirect costs, requesting that time lost by patients and carers be considered, along with lost productivity.^14,15 Thus, its methods broadly resemble those of “holistic” economic analysis, a technique initially developed for economic evaluations of public programs, the costs and benefits of which are often complex. Nevertheless, considerable debate over the valuation of items such as “time lost” within academic and policy communities remains. This may be why other systems employing a societal perspective have assumed a narrower position on eligible indirect costs. With respect to the choice of comparator for the economic evaluation, almost all systems specify use of one of the following: “standard care,” “the most commonly used alternative,” or “alternative most likely to be replaced.” France also requires separate analyses with two additional comparators, ie, the most recently reimbursed alternative and the least expensive alternative.¹⁶ In Belgium, if the candidate technology represents an “addon” treatment, the comparator must constitute current treatment without the candidate technology.¹⁷ Further, the use of “offlabel” treatments as the comparator is not permitted.¹¹ All systems rely upon sensitivity analyses to assess the stability of estimates generated through the economic evaluation, but few stipulate the type. Among those that do, probabilistic sensitivity analysis is the most commonly prescribed (eg, Belgium, Germany, Scotland, Slovakia, the UK, and Wales).

In recent years, affordability has become an increasingly important consideration for centralized reimbursement systems, with almost all of those included in this review (where information could be found) requiring a budget impact analysis (Table 4). However, some waive this analysis in certain circumstances, eg, when no alternative treatment exists (Belgium).¹⁷ Although information describing the specific costs to be included appears scarce, based on that available, they mirror those for the economic evaluation of the same technology. Specifically, if the economic evaluation is limited to direct costs, so must the budget impact analysis, eg, Hungary and Ireland.

Reimbursement decisions: review committee composition, procedures, and key factors

In most of the centralized reimbursement systems, the assessment and evaluation reports are sent to and scrutinized by a review committee (sometimes referred to as an appraisal committee). While the composition of this committee varies across systems, it is usually multidisciplinary, with members representing payers, administrators, health care providers, and academia (eg, health economists, Table 5). Approximately one-third have also appointed patient representatives to their respective committees (eg, Sweden, Switzerland, and the UK), although not always as voting members (Germany),^18,19 and one-fifth include manufacturers (Belgium, Switzerland, the UK, and Wales). In most systems, the authority of the review committee is advisory (ie, makes recommendations). Aside from lists of factors/criteria considered (Table 6), publicly available procedural information on committee deliberations is often limited to conditions under which presentations/testimonials from external experts (including patients) are sought or accepted and whether an incremental cost-effectiveness ratio threshold is employed. Among the exceptions is France. There, review committees (the Commission d’Evaluation des Medicaments (CEM), followed by the Transparency Commission) adhere to a two stage process. First, the CEM assigns a “medical benefit” or “SMR” level/score to the candidate technology (a new pharmaceutical). The score is based on a five-point scale, with “I” representing “major medical benefit” and “V” representing “insufficient to justify reimbursement.”^16,20–23 Upon approval of the score by the Minister, the CEM then compares the technology with already reimbursed alternatives in order to formulate an opinion on the “improvement in medical benefit” or “ASMR” level. Six possible levels exist, ranging from I (major innovation) to VI (negative opinion regarding inclusion on the benefit list). Therefore, “innovativeness” is viewed as the size of the incremental clinical benefit achieved by the candidate technology. The opinion of the CEM is forwarded to the Transparency Commission, who makes a formal recommendation on the ASMR classification. This classification is, in turn, used to negotiate price and reimbursement rate. In Germany, the “innovativeness” of a technology is also based on whether it offers “added therapeutic value.” Moreover, it plays an important role in determining the content of subsequent committee deliberations, because “cost-benefit” analyses are only taken into account when a technology has been deemed innovative.^18–24 The review committee of the Italian Medicines Agency, ie, the Technical Scientific Committee, explicitly weighs both the availability of existing treatments and the extent of clinical benefit in its assessment of a new pharmaceutical’s innovativeness. The two attributes are scored separately and then combined to determine whether it represents an “important,” “moderate,” or “modest” innovation.²⁵ This rating, along with the category of clinical value to which the pharmaceutical has been assigned, is sent to a second review committee, ie, the Pricing and Reimbursement Committee, which negotiates price and reimbursement status with the manufacturer.^26,27

Table 5 Comparison of decision-making processes

Country	Centralized reimbursement review/decision-making body (role)	Committee composition	Steps in review/decision-making process	Use of cost-effectiveness threshold	Timelines for review/decision	Appeals mechanisms
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	20 voting members: 3 academics 10 from sickness funds 2 from physicians associations 2 from economic chamber 2 from federal chamber of labour 1 from Austrian chamber of pharmacists	Manufacturer submits application for reimbursement to Association of Austrian Social Security Institutions Internal staff (Department of Pharmaceutical Affairs) prepare evaluation of application (pharmacological and therapeutic) based on evidence presented in application, and assigns pharmaceutical to 1 of 6 categories of therapeutic value – pharmaceuticals classified into categories 5 or 6 can request price above average European Union price Health economics team evaluates cost effectiveness of pharmaceutical relative to comparable alternatives Pharmaceutical Evaluation Board deliberates over both evaluation reports and prepares report Pharmaceutical Evaluation Board sends report to manufacturer for comment Pharmaceutical Evaluation Board prepares reimbursement recommendation, taking into account responses received from manufacturer Deputy director of Association of Austrian Social Security Institutions reviews recommendations and makes final decision^Citation21,Citation56,Citation58	No^Citation21	180 days (includes pricing and reimbursement decision)^Citation58	Decision may be appealed to Independent Pharmaceuticals Commission^Citation58
Belgium	Minister of Social Affairs (decisions) Drug Reimbursement Committee (recommendations)^Citation9,Citation60	31 members (23 voting including chair): 7 academics 8 from sickness funds 4 physicians 3 from pharmacist associations Nonvoting: 2 from pharmaceutical industry 1 from generic pharmaceutical industry 4 from Ministries of Public Health, Social Affairs, and Economic Affairs, and Federal Public Service Budget 1 from National Institute for Health and Disability Insurance^Citation62	Manufacturer submits application for reimbursement to Secretariat of Drug Reimbursement Committee Includes incremental cost-effectiveness ratio (ICER) if Class I claim (added therapeutic value compared to existing alternatives) and simultaneously submits pricing dossier to Federal Public Service economy Brief overview report of product characteristics prepared Staff within Bureau of Drug Reimbursement Committee, supported by experts, prepare evaluation of pharmaceutical’s safety, efficacy, effectiveness, applicability, and convenience based on evidence submitted by manufacturer; pricing commission simultaneously examines pricing dossier, determines maximum price, and notifies manufacturer Drug Reimbursement Committee discusses and approves evaluation report Drug Reimbursement Committee sends report to manufacturer Staff prepare draft recommendations, taking into account evaluation report, price from manufacturer, and responses received from manufacturer Drug Reimbursement Committee discusses and approves (by 2/3 majority vote) draft recommendations Drug Reimbursement Committee sends draft recommendations to manufacturer, who must reply within 10 days; manufacturer may request a hearing Drug Reimbursement Committee prepares final recommendations, taking into account responses received from manufacturer Minister receives recommendations, seeks advice from Minister of Budget and financial administration, and makes final decision^Citation9,Citation17,Citation21,Citation62,Citation175	No^Citation62	150 days (includes pricing and reimbursement)^Citation21	Decision may be appealed on procedural grounds only Heard by administrative court
Czech Republic	State Institute for Drug Control (decisions)^Citation65,Citation170	No information found	Manufacturer submits application for reimbursement to State Institute for Drug Control Internal staff (Department for Price and Reimbursement Regulation) consult with medical experts, health economists, and patient groups, and prepare evaluation report; assess safety, efficacy, and clinical use first, and then financial aspects State Institute for Drug Control makes decision on price and level of reimbursement, based on evaluation report^Citation176^–^Citation180	No^Citation138	75 days (includes pricing and reimbursement decision)	Decision may be appealed to Ministry of Health
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Maximum of 7 members: Must include: 2 general practitioners 1 representative of the regions^Citation69	Manufacturer submits application for reimbursement to Danish Medicines Agency Internal staff, supported by external experts (if necessary) prepare evaluation report based on evidence submitted by manufacturer; clinical effect and safety profile compared to already reimbursed pharmaceutical and non-pharmaceutical products for same indication Danish Medicines Agency simultaneously prepares price survey Health economics expert(s) evaluate(s) economic analysis, if submitted Reimbursement Committee reviews evaluation report, price survey, and review of economic analysis and makes reimbursement recommendation to Danish Medicines Agency If negative, Danish Medicines Agency sends draft recommendations to manufacturer Danish Medicines Agency Board makes final decision ^Citation21,Citation68,Citation69	No^Citation68	90 days after receipt of “adequate application”^Citation38	Decision may be appealed to Ministry of Health and Prevention^Citation38,Citation68
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	No information found	No information found	No information found	No information found	No information found
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	7 members of Pharmaceuticals Pricing Board: 2 from Ministry of Social Affairs and Health 2 from Social Insurance Institution (Kela) 1 from Ministry of Finance 1 from National Agency for Medicines 1 from National Research and Development Centre for Welfare and Health 7 members of Expert Group: Includes individuals with medical, pharmacological, health economics, and social insurance expertise^Citation75,Citation181	Manufacturer submits application for reimbursement to Pharmaceuticals Pricing Board secretariat Internal staff, with support from Expert Group, prepare evaluation report based on evidence submitted by manufacturer Expert Group reviews report and formulates opinions Pharmaceuticals Pricing Board Secretariat presents summary of report and opinions, along with written statement regarding the potential impact of the pharmaceutical on its budget provided by Kela, to Pharmaceuticals Pricing Board Pharmaceuticals Pricing Board formulates recommendations If negative, Pharmaceuticals Pricing Board sends recommendations to manufacturer, who may choose to lower price or provide additional evidence Pharmaceuticals Pricing Board makes final decision^Citation74,Citation122,Citation181,Citation182	No^Citation181	180 days (includes pricing and reimbursement decision)^Citation181	Decision may be appealed to Supreme Court^Citation181
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	Transparency Committee within French National Authority for Health: 20 voting members (includes chair): 4 from “public institutions” 3 from main health insurance fund 1 from pharmaceutical industry 12 with medical and pharmacological expertise^Citation78,Citation184 7 Specialist subcommittees of clinical experts	Single technology appraisals Manufacturer submits application for reimbursement to French National Authority for Health secretariat Internal staff prepare evaluation report based on evidence submitted by manufacturer (focuses on clinical effectiveness, target population, conditions of use, and already reimbursed technologies) External clinical and methodological experts review evaluation report Commission d’Evaluation des Medicaments reviews evaluation report and expert opinions to appraise the “medical benefit” of the pharmaceutical (on a 5 point scale; I – major to V – insufficient to justify reimbursement) Minister makes final decision on the medical benefit level/score Commission d’Evaluation des Medicaments then performs comparative assessment of pharmaceutical with already reimbursed alternatives to appraise the “improvement in medical benefit” (on a 6 point scale; 1 – major innovation to VI – negative opinion regarding inclusion on benefit list) Transparency Commission considers advice received from Commission d’Evaluation des Medicaments and assigns an “improvement in medical benefit” classification to the pharmaceutical Once positive reimbursement recommendation is received, the Comite Economique des produits de Sante = negotiates price with manufacturer and the Union Nationale des Caisses d’Assurance Maladie fixes the reimbursement rate Minister for Health and Social Security makes final decision on reimbursement level and price^Citation16,Citation20^–^Citation23 Multiple technology appraisals French National Authority for Health approves technology topic for multiple technology appraisals French National Authority for Health conducts consultations with relevant stakeholders and the Interdisciplinary Economic Evaluation and Public Health Committee to define scope and protocol for multiple technology appraisals Internal staff and/or independent academic group prepares assessment report (includes clinical review and economic analysis) Interdisciplinary Economic Evaluation and Public Health Committee and external experts review assessment report Stakeholders receive assessment report for comment Stakeholders also consulted through working group meetings Appropriate health technology assessment specialist subcommittee appraises report and comments and formulates recommendations French National Authority for Health Board reviews and approves recommendations^Citation21,Citation185	No^Citation20	90 days for inpatient pharmaceuticals (includes pricing and reimbursement) 180 days for outpatient pharmaceuticals (includes pricing and reimbursement)^Citation20	May appeal recommendation to French National Authority for Health, requesting a hearing or providing written comments Once decision has been made, may appeal to administrative court^Citation20
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19	13 members including representatives from: Associations of physicians, dentists, and physiotherapists Hospital associations Sickness funds Patient organizations (nonvoting)^Citation18,Citation19	Federal Joint Committee makes decision to assess technology and notifies Institute for Quality and Efficiency in Health Care Institute for Quality and Efficiency in Health Care appoints internal staff to manage and/or conduct assessment Institute for Quality and Efficiency in Health Care carries out consultations with external clinical experts and patient/carer organizations to define assessment scope and protocol Institute for Quality and Efficiency in Health Care posts draft scope and protocol on website for public comment Internal staff, supported by external experts, prepare assessment, first considering clinical benefit or innovativeness (ie, is the first active ingredient or offers therapeutic improvement); if deemed noninnovative, technology is assigned to 1 of 3 groups (1: identical active ingredient; 2: therapeutically comparable and one active ingredient; 3: therapeutically comparable and two active ingredients); technologies with similar efficacy/effectiveness must demonstrate comparable efficiency through findings from efficiency frontier analysis^Citation119; if deemed innovative (ie, offers added therapeutic value over already reimbursed alternatives), “cost-benefit” analysis is performed to set maximum reimbursable amount; if technology treats life-threatening condition for which there are no alternatives, cost must not be considered^Citation18,Citation19 Institute for Quality and Efficiency in Health Care steering committee reviews draft report and recommendations for quality assurance Institute for Quality and Efficiency in Health Care posts draft report and recommendations on website for public comment Staff prepare final report, incorporating comments received and recommendations, and submit it to the Institute for Quality and Efficiency in Health Care steering committee for final quality assurance review and then to the Board for final approval Board sends recommendations to Federal Joint Committee, who makes final decision^Citation19,Citation24,Citation124,Citation144	No^Citation18	No information found	May not appeal recommendations Decision may be appealed to administrative court^Citation18
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85,Citation86	7 members including representatives from: Ministry of Health Ministry of Finance Ministry of Employment and Social Protection Merchant Marine^Citation85	Manufacturer submits application for reimbursement to Transparency Committee in the Reimbursement and Medicinal Products Transparency Committee in the Reimbursement and Medicinal Products recommends classification of pharmaceutical into pre-existing therapeutic category based on “therapeutic and pharmacoeconomic effectiveness” Transparency Committee in the Reimbursement and Medicinal Products sends classification recommendation to Ministry of Health and Social Security for approval Price set taking into account products already included in assigned category or average of the 3 lowest European prices^Citation186	No information found	90 days (includes pricing and reimbursement decision)^Citation186	No information found
Hungary	Ministers of Health and Finance National Health Insurance Fund Administration Technology Appraisal Committee (recommendations)^Citation88,Citation89	Technology Appraisal Committee: includes members delegated by stakeholder groups^Citation102	Manufacturer submits application for reimbursement to Transparency Secretariat of National Health Insurance Fund Administration (pharmaceutical division) Transparency Secretariat registers and checks application for completeness and then determines whether application should undergo simplified procedure or normal procedure; normal procedure applies to new agents, indications, routes of administration, and combinations National Health Insurance Fund Administration Department of Pharmaceuticals prepares a preliminary evaluation If application is assigned to normal procedure, Transparency Secretariat transfers it to Technology Assessment Office of the National Institute for Strategic Health Research Assessment Office prepares assessment report comprising a systematic review of clinical evidence and economic analysis Technology Appraisal Committee deliberates over report, preliminary evaluation of pharmaceutical department, and advice from professional colleges, and formulates a recommendation Director of pharmaceutical division approves recommendation and forwards it to the Ministers of Health and Finance^Citation90,Citation102,Citation187	No information found	No information found	Decision may be appealed to Appeals Committee Includes representatives from: Ministry of Health Ministry of Finance Ministry of Economy National Institute of Pharmacy Prime Minister’s office^Citation90
Ireland	Products Committee of Corporate Pharmaceuticals Unit of Health Service Executive (decisions)^Citation91,Citation92	No information found	1. Products Committee of Health Service Executive selects technology for assessment OR manufacturer submits application for reimbursement to Health Service Executive 2a. If Products Committee selects technology, Health Service Executive notifies manufacturer of referral to National Centre for Pharmacoeconomics 2b. If manufacturer submits application, staff prepare preliminary evaluation report based on evidence from manufacturer 3a. Staff within National Centre for Pharmacoeconomics appointed to comprise review group 3b. Products Committee reviews evaluation report and decides whether to refer technology to National Centre for Pharmacoeconomics for formal pharmacoeconomic evaluation or recommend reimbursement 4a. Review group meets with manufacturer to determine scope and requirements for evaluation 4b. If referred, National Centre for Pharmacoeconomics conducts pharmacoeconomic evaluation 5a. Manufacturer prepares pharmacoeconomic submission, which includes cost-effectiveness and budget impact analyses 5b. National Centre for Pharmacoeconomics sends pharmacoeconomic evaluation to manufacturer for comment 6a. Review group prepares evaluation report based on manufacturer’s submission 6b. National Centre for Pharmacoeconomics prepares final pharmacoeconomic evaluation, incorporating manufacturer’s comments 7a. National Centre for Pharmacoeconomics sends report to manufacturer for comment 7b. National Centre for Pharmacoeconomics sends evaluation to Products Committee, who makes reimbursement decision 8a. Review group prepares final evaluation report, incorporating manufacturer’s comments 9a. National Centre for Pharmacoeconomics sends report to Products Committee, who makes reimbursement decision^Citation91,Citation93,Citation125,Citation147	No fixed threshold, but €45,000/QALY used as a guide^Citation91,Citation125,Citation165	90 days (for reimbursement decision)^Citation93	Decision may be appealed to designated expert committee^Citation91
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Technical Scientific Committee: Includes 17 members: Health care providers Pharmacists Pharmacologists Pricing and Reimbursement Committee: Includes 12 members: Academics Health care providers Administrators responsible for managing pharmaceuticalservices^Citation95	Manufacturer submits application for reimbursement to Italian Medicines Agency Technical Scientific Committee reviews submission and formulates advice on clinical value, assigning it to one of three reimbursement classes: A – fully reimbursable – essential products and those intended for chronic diseases; H – Fully reimbursable in hospitals; and C – non-reimbursable. Pharmaceuticals in classes A and H are further assigned to one of three classes: I – treatments for serious diseases; II – treatments to reduce or eliminate risk of serious diseases; and III – treatments for non-serious diseases Technical Scientific Committee then assesses the degree of innovation offered by the technology, considering 2 factors: 1) availability of existing treatments and 2) extent of therapeutic benefit; scores on each factor are combined to determine if pharmaceutical represents “important,” “moderate,” or “modest therapeutic innovation” Submission and Technical Scientific Committee evaluation are sent to Pricing and Reimbursement Committee Pricing and Reimbursement Committee reviews advice and contacts manufacturer to negotiate reimbursement status and price Pricing and Reimbursement Committee submits report containing negotiation outcomes to Technical Scientific Committee, who makes final decision ^Citation26,Citation27,Citation126	No^Citation126	180 days (includes pricing and reimbursement decision)^Citation188	No information found
Norway	Norwegian Medicines Agency (recommendations/decisions)^Citation34,Citation98 Ministry of Health and Care Services (recommendations/decisions) Department of Pharmacoeconomics (recommendations)^Citation98	No information found	Process depends on anticipated budget impact of pharmaceutical: If <5 million Krone/year: Manufacturer submits application for reimbursement to Norwegian Medicines Agency Norwegian Medicines Agency Department of Pharmacoeconomics staff prepare evaluation report based on evidence submitted by manufacturer Norwegian Medicines Agency reviews evaluation report and makes reimbursement decision If > 5 million Krone/year: Manufacturer submits application for reimbursement to Norwegian Medicines Agency Norwegian Medicines Agency Department of Pharmacoeconomics staff prepare evaluation report based on evidence submitted by manufacturer Norwegian Medicines Agency reviews evaluation report and consults with National Advisory Committee for Drug Reimbursement Norwegian Medicines Agency sends evaluation report to Ministry of Health and Care Services Ministry consults with National Council for Health Care Priorities to determine whether pharmaceutical would be viewed as” money well spent” Ministry formulates recommendation; if positive, it is sent to Parliament for approval^Citation34,Citation98,Citation189	No^Citation34	180 days (includes pricing and reimbursement decision)^Citation34	No information found
Poland	Ministry of Health (decisions)^Citation99 Agency for Health Technology Assessment Consultative Council and Drug Management Team (recommendations)^Citation99	Consultative Council: 12 voting members including representatives from: Ministry of Health (7) Polish Chamber of Physicians (1) Chief Pharmaceutical Council (1) Supreme Council of Nurses and Midwives National Health Fund^Citation127 Drug Management Team: Includes representatives of: Minister of Finance Minister of Economy and Labour Minister of Social Policy National Health Fund^Citation99	Manufacturer submits application for reimbursement to Ministry of Health Ministry of Health sends application to the Agency for Health Technology Assessment Agency for Health Technology Assessment staff prepare evaluation report based on evidence from the submission and information received from invited experts Agency for Health Technology Assessment Consultative Council meets to review report, hear from experts, and formulate recommendations Director of Agency for Health Technology Assessment issues reimbursement recommendation to Minister of Health Drug Management Team within Ministry of Health negotiates maximum reimbursement price Ministry of Health makes final decision on reimbursement and price^Citation100,Citation127,Citation190	No information found	180 days (includes pricing and reimbursement decision)^Citation100	None^Citation127
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation44	No information found	Manufacturer submits application for reimbursement to INFARMED following approval of maximum price by Directorate General of Economic Activities External experts prepare evaluation report based on evidence submitted by manufacturer (includes pharmacotherapeutic and pharmacoeconomic information demonstrating added therapeutic value and proposed reimbursement price) and assigns “grade” of innovation and added therapeutic value (compared to already reimbursed alternatives) Economists analyze pharmacotherapeutic information from manufacturer to determine “economic advantage”; if pharmaceutical offers added therapeutic value or treats a condition for which there are no alternative therapies, economic advantage should be demonstrated through formal Using findings from both reports, INFARMED formulates reimbursement recommendation If negative, INFARMED contacts manufacturer, who may present additional information INFARMED submits recommendations to Minister, who makes final decision^Citation36,Citation101,Citation191	No information found	90 days (includes pricing and reimbursement decision)^Citation36	Decision may be appealed to administrative court^Citation36
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	No information found	Manufacturer submits application for reimbursement to Scottish Medicines Consortium Internal staff (“assessment team”), supported by clinical and economic experts, prepare evaluation report based on evidence submitted by manufacturer New Drugs Committee reviews report and prepares draft recommendations for the Scottish Medicines Consortium New Drugs Committee also sends draft recommendations to manufacturer for comment Manufacturer sends comments to Scottish Medicines Consortium, which also considers submissions received from patient interest groups Scottish Medicines Consortium formulates final recommendations and forwards them to the National Health Service Boards, Area Drug and Therapeutics Committees, manufacturer, and competitor(s)^Citation30,Citation128	No fixed threshold, but range of £20,000–£30,000/QALY used as a guide^Citation30	No information found	Decisions may be appealed on process-related and scientific grounds For process-related appeals: Manufacturer contacts Scottish Medicines Consortium secretariat, Chair, or New Drugs Committee to resolve issues through discussion For scientific disputes: May resubmit or convene independent panel appointed by Scottish Medicines Consortium
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation107	Reimbursement Committee: Includes 11 members representing: Ministry of Health (3) Slovakian medical chamber (3) Health insurance funds (5)^Citation101	Manufacturer submits application for reimbursement, including proposed maximum retail price, to Ministry of Health Staff evaluate pharmaceutical using evidence from manufacturer to determine where its ICER lies in the accepted ICER threshold range One of 22 specialist working groups then evaluates the pharmaceutical according to its anatomic and therapeutic classification A separate working group evaluates pharmacoeconomic data Evaluations from both working groups are forwarded to the Reimbursement Committee The Reimbursement Committee reviews the reports and formulates a reimbursement decision^Citation102,Citation106,Citation107,Citation131,Citation169	No fixed threshold, but range of €20,000–€26,500/QALY used as a guide^Citation105	No information found	Decision may be appealed to Ministry
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	Inter-Ministerial Pricing Commission: Includes representatives from: Ministry of Health Ministry of Economy Ministry of Industry^Citation132	Ministry of Health initiates reimbursement decision-making process upon receipt of notice of market approval for new pharmaceutical Ministry of Health invites manufacturer to provide all relevant information to Inter-Ministerial Pricing Commission Internal staff of Ministry of Health prepare evaluation report Inter-Ministerial Pricing Commission reviews report and makes reimbursement and pricing decision^Citation108,Citation132	No^Citation132	180 days (includes pricing and reimbursement decision)^Citation132	No information found
Sweden	Dental and Pharmaceutical Benefits Board Expert Board (decisions)^Citation15,Citation109	Expert Board: Includes 11 members and a chair: Pharmacologist (1) Health economists (4) Patient representatives (2) Health care providers (3)^Citation15,Citation109	Manufacturer submits application for reimbursement Internal staff (executive officer, health economist, and legal expert) review submission to determine if application contains sufficient evidence Dental and Pharmaceutical Benefits Board sends copy of application to Pharmaceutical Benefits Group for County Councils for review Internal staff prepare evaluation report and draft recommendations in the form of a “memorandum” Dental and Pharmaceutical Benefits Board sends copy of memorandum to manufacturer for review Manufacturer may request a meeting with the Board, during which it can present case, dispute arguments which form the basis of recommendations, and refute factual errors Meeting of Expert Board held – memorandum, manufacturer’s comments, and any feedback received from the Pharmaceutical Benefits Group are reviewed; external experts may be invited to participate in deliberations; Expert Board makes final reimbursement decision^Citation33,Citation192	No fixed threshold, but €45,000/QALY used as a guide^Citation35	180 days (includes pricing and reimbursement decision)^Citation192	Decision may be appealed on procedurals grounds only^Citation15,Citation33,Citation192 Board may reconsider decision before appeal is heard by administrative court^Citation192
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113,Citation114	Federal Drug Commission: Includes 25 voting members representing: Academics (4) Physicians (3) Pharmacists (3) Health insurers (5) Hospitals (1) Patient organizations (2) Manufacturers (2) Federal Office of Social Insurance (1) Cantons (1) Swissmedic (1) Army pharmacy (1)^Citation113,Citation114	Manufacturer submits application for reimbursement Federal Drug Commission reviews application and makes a classification recommendation: pharmaceutical may be classified into one of five categories of relative effectiveness: 1 – Therapeutic breakthrough; 2 – Therapeutic progress; 3 – Saving compared to other drugs; 4 – No therapeutic progress and no savings; and 5 – Not appropriate for the social health insurance Federal Office of Public Health makes final decision, based on Federal Drug Commission’s recommendation, assessment by Swiss Agency for Therapeutic Products for market authorization and internal and external price referencing If Federal Office of Public Health plans to make a negative decision, the manufacturer is informed prior to issuing the final decision; manufacturer may apply for re-evaluation on the basis of price adjustments or availability of additional data^Citation114	No information found	No information found	Decision may be appealed to Federal Office of Public Health^Citation114
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Dutch Healthcare Insurance Board Committee (CHF) (recommendations)^Citation26	Committee of the Dutch Healthcare Insurance Board: Includes: A maximum of 24 members with expertise in various medical disciplines, health sciences and economics 2–3 nonvoting members from the Ministry^Citation21,Citation117 Includes: 3 Dutch Healthcare Insurance Board board of directors 6 members with health and social security insurance expertise^Citation21	For outpatient pharmaceuticals: Manufacturer submits application for reimbursement to Minister of Health Internal staff prepare evaluation, which includes 4 draft reports (summary, pharmacotherapeutic, pharmacoeconomic, and budget impact assessments based on evidence from manufacturer, as well as independently conducted literature review); if deemed necessary, staff may consult with manufacturer, external experts, and stakeholders CHF reviews report and consults with manufacturer and other stakeholders Staff revise report, incorporating results of CHF deliberations and comments from manufacturer and other stakeholders Dutch Healthcare Insurance Board sends revised report to manufacturer and stakeholders for comment CHF meets to discuss revised report and comments received and prepare final advice Dutch Healthcare Insurance Board board of directors receives final report, which is also sent to manufacturer and stakeholders appointed by Dutch Healthcare Insurance Board for comment Dutch Healthcare Insurance Board board of directors meet to discuss final report and comments received and formulate recommendations; may consult with the Appraisal Committee Alternatively, Steps 7 and 8 may be skipped, with the Board chair drafting a recommendation Dutch Healthcare Insurance Board sends final recommendations to the Minister of Healthcare, Welfare, and Sport Minister makes final reimbursement decision, which includes classifying the pharmaceutical into one of three categories: Annex 1A – Therapeutic equivalent value; Annex 1B – Therapeutic added value; and Annex 2 – Conditional reimbursement For high-cost inpatient pharmaceuticals: Dutch Federation of University Hospitals, Dutch Hospitals Association, Medical Specialists Association, and Dutch Health Insurance Organization may submit reimbursement application (in the form of additional funding) for high cost inpatient pharmaceuticals Dutch Healthcare Insurance Board prepares evaluation report, which includes evidence on therapeutic value, projected budget impact, and plan for collecting pharmacoeconomic information in daily practice, and formulates recommendations (process similar to that described above) Dutch Healthcare Insurance Board sends final report and recommendations to the Dutch Healthcare Authority Dutch Healthcare Authority formulates recommendation on whether pharmaceutical should be provisionally added to the Expensive Drug List Minister of Health, Welfare, and Sport makes final decision^Citation21,Citation31,Citation49,Citation116,Citation117,Citation193	No fixed threshold, but €20,000/QALY used as a guide ^Citation31	90 days for outpatient pharmaceuticals 60 days for inpatient pharmaceutical^Citation21	Decision may be appealed on procedural grounds only Appeal is heard by administrative court^Citation21
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Includes: Academics (eg, health economists) Health care providers in National Health Service Representatives from patient and carer organizations Manufacturers^Citation29	Single technology appraisal Topics selection panel selects technology for review National Institute for Health and Clinical Excellence invites stakeholders (ie, consultees and commentators (cannot make a submission or appeal recommendation)) to participate Nonmanufacturer consultees invited to nominate clinical and/or patient experts to take part in Technology Appraisals Committee meetings Manufacturer completes evidence submission (assessment) Independent academic group commissioned to review submission, along with information received from consultees and nominated experts, and prepare evaluation report Technology Appraisals Committee meets to review evaluation report and hear from nominated clinical and patient experts Technology Appraisals Committee formulates draft recommendations, which are presented in appraisal consultation document Appraisal consultation document made available to stakeholders for comment Technology Appraisals Committee meets to consider comments and formulate final recommendations (final appraisal determination) Technology Appraisals Committee submits final recommendations to Guidance Executive Guidance Executive makes final reimbursement decision^Citation29,Citation194,Citation195 Multiple technology appraisal Same as single technology appraisal process except: 1) Formal scoping process to develop review protocol is required; 2) Independent academic group conducts assessment (rather than the manufacturer); 3) Independent academic group attends Technology Appraisals Committee meetings^Citation13	No fixed threshold, but range of £20,000–£30,000/QALY used as a guide^Citation37,Citation196,Citation197	Single technology appraisal approximately 39 weeks^Citation29	Final recommendations may be appealed on procedural grounds only Appeals may only be initiated by consultees identified at the beginning of the assessment and who are not representing National Health Service trusts or local boards Appeal is heard by Appeals Panel appointed by National Institute for Health and Clinical Excellence board^Citation39
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group New Medicines Group (recommendations)^Citation120	Includes: Physicians Pharmacists Pharmacologists Health economist Nurse Patient representative Representative from pharmaceutical industry association^Citation28	Manufacturer submits application for reimbursement (“Form A”) to All Wales Medicines Strategy Group All Wales Medicines Strategy Group determines whether application requires full appraisal; if yes, manufacturer must submit “Form B” All Wales Medicines Strategy Group identifies and invites clinical experts and patient organizations to submit written statements Internal staff prepare evaluation report, which includes Form A, Form B, and additional relevant information Report sent to manufacturer for comment All Wales Medicines Strategy Group New Medicines Group meets to review evaluation report and comments received and formulate draft recommendations Staff prepare final report and draft recommendations (ie, preliminary appraisal), which is sent to manufacturer and posted on website New Medicines Group meets to deliberate over final report, recommendations, and manufacturer’s response New Medicines Group formulates final recommendation, which is included in final appraisal Minister makes reimbursement decision, based on final appraisal from New Medicines Group^Citation28,Citation120	No fixed threshold, £20,000/QALY used as a guide^Citation28	No information found	Decisions may be appealed on process-related and scientific grounds For process-related appeals: Appeals submitted to Welsh Medicines Partnership, who discusses case with All Wales Medicines Strategy Group Chair and senior staff For scientific disputes: Independent review process initiated^Citation198

Table 6 Comparison of key factors considered during committee deliberations

Country	Centralized reimbursement review/decision-making body (role)	Clinical need			Clinical benefit/value*				Cost-benefit ratio (cost-effectiveness; efficiency; “value for money”)^†	Impact on health resources/affordability (budget impact)	Innovativeness	Other
		Disease burden (severity and number of patients)	Availability of alternatives	Place of technology in care pathway/strategy	Safety (risk–benefit ratio; harm–benefit ratio)	Efficacy/effectiveness	Side effects	Acceptability (tolerance, convenience)
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Yes^Citation55	Yes^Citation58	Not specified	Not specified	Yes^Citation55	Not specified	Not specified	Yes (“pharmacoeconomic evidence”)^Citation58	Yes^Citation55	Yes^Citation50	Price in other European Union countries^Citation58
Belgium	Ministry of Health and Social Affairs (decisions) Drug Reimbursement Committee (recommendations)^Citation9,Citation60	Yes^Citation11,Citation17	Yes^Citation21	Not specified	Yes^Citation9	Yes (across patient subgroups)^Citation9	Yes^Citation9	Yes^Citation11,Citation17	Yes^Citation11,Citation17	Yes^Citation11,Citation17	Yes^Citation35	Feasibility of implementation^Citation11,Citation17 Market price^Citation11,Citation17 Social needs^Citation11,Citation17,Citation21
Czech Republic	State Institute for Drug Control (decisions)^Citation65,Citation176	Yes^Citation84	Yes^Citation84	Not specified	Yes^Citation84	Yes^Citation84	Not specified	Yes^Citation66	Yes^Citation84	Yes^Citation84	Not specified	Clinical practice guidelines^Citation138 Public interest^Citation35
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Not specified	Not specified	Not specified	Yes^Citation21,Citation68	Yes (across patient subgroups)^Citation21,Citation68	Yes^Citation21,Citation68	Not specified	Yes^Citation21,Citation68	Not specified	Not specified	Reasonableness of price relative to therapeutic value^Citation21,Citation68
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	Yes^Citation84	Yes^Citation84	Not specified	Not specified	Yes^Citation84	Not specified	Not specified	Yes^Citation84	Yes^Citation84	Not specified	“Cost efficiency”^§^Citation140
Finland	Pharmaceuticals Pricing Board (decisions)^Citation74,Citation76,Citation77 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Yes^Citation181	Yes^Citation181	Not specified	Not specified	Yes (across patient subgroups)^Citation181	Not specified	Not specified	Yes^Citation181	Yes^Citation181	Not specified	Research and development^Citation35 Level of uncertainty in supporting evidence^Citation181 Price in other European Union countries^Citation181 Market forecast and share^Citation75 Daily cost of treatment per day^Citation75
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	Yes^Citation35	Yes^Citation35	Yes^Citation35	Yes^Citation80	Yes^Citation35	Yes^Citation80	Yes^Citation80	Not specified	Yes^Citation80	Yes^Citation35	Public health impact^Citation16,Citation35 Costs relative to current treatment^Citation199
Germany	Federal Joint Committee (decisions)^Citation24 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19,Citation24	Yes^Citation19	Yes^Citation19	Not specified	Yes^Citation19	Yes^Citation19	Not specified	Not specified	Yes^‡^Citation19	Yes^Citation113	Yes^Citation19
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85	Yes^Citation186	Yes^Citation186	Not specified	Yes^Citation186	Yes^Citation186	Not specified	Not specified	Yes (“pharmacoeconomic effectiveness”)^Citation186	Not specified	Not specified	Daily cost of treatment^Citation186 Reimbursement status in other European Union countries^Citation186
Hungary	Ministers of Health and Finance National Health Insurance Fund Administration (recommendations)^Citation88	Yes^Citation186	Yes^Citation84	Not specified	Not specified	Yes^Citation84	Not specified	Not specified	Yes^Citation186	Yes^Citation84	Not specified	Equity^Citation26
Ireland	Health Service Executive (decisions)^Citation91,Citation92,Citation147	Yes^Citation125,Citation165	Yes^Citation125,Citation165	Not specified	Not specified	Yes^Citation125,Citation165	Not specified	Not specified	Yes^Citation125,Citation165	Yes^Citation125,Citation165	Yes^Citation125,Citation165	Level of uncertainty in supporting evidence^Citation125 Wider societal costs and benefits^Citation165
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Yes^Citation27	Yes^Citation27	Not specified	Yes^Citation96	Yes (across patient subgroups)^Citation27	Not specified	Yes^Citation27	Yes^Citation27	Yes^Citation27	Yes^Citation20	Daily cost of treatment^Citation27 “Special medical needs”^Citation96 Price in other European Union countries^Citation200 Market forecast and share^Citation96
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmacoeconomics (recommendations)^Citation98	Yes^Citation34	Not specified	Not specified	Yes^Citation149	Yes (across patient subgroups)^Citation34	Not specified	Not specified	Yes^Citation34	Yes^Citation34	Not specified	Equity^Citation35 “Solidarity”^Citation34 “Rationality”^Citation34
Poland	Ministry of Health (decisions)^Citation99	Yes^Citation84	Not specified	Not specified	Yes^Citation84	Yes^Citation84	Not specified	Not specified	Yes^Citation84	Yes^Citation84	Not specified
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation36,Citation44	Yes^Citation36	Yes^Citation36	Not specified	Yes^Citation36	Yes^Citation36	Not specified	Not specified	Yes^Citation36	Not specified	Not specified	Equity^Citation36 “Universality”^Citation36 “Accessibility”^Citation36
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Yes^Citation104	Yes^Citation30	Not specified	Yes^Citation104	Yes^Citation104	Not specified	Not specified	Yes^Citation104	Yes^Citation104	Yes^Citation30	Whether pharmaceutical reverses rather than stabilizes condition or bridges a gap to curative therapy^Citation104 Level of uncertainty in supporting evidence^Citation30 Wider societal costs and benefits^Citation30
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation107,Citation169	Yes^Citation106	Yes^Citation84	Not specified	Yes^Citation106	Yes^Citation106	Yes^Citation106	Yes^Citation106	Yes^Citation84,Citation105	Yes^Citation84,Citation106	Not specified	Price of other pharmaceuticals within reference category^Citation106
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	Yes^Citation132	Yes^Citation132	Not specified	Yes^Citation10	Yes (across patient subgroups)^Citation132	Not specified	Not specified	Not specified	Yes^Citation132	Yes^Citation108	“Social utility”^Citation132 Rationalization of public expenditures on pharmaceuticals^Citation132 Specific needs of certain groups of people^Citation132 Research and development^Citation132 Price in other European Union countries^Citation132 Market forecast^Citation132
Sweden	Dental and Pharmaceutical Benefits Board Expert Board (decisions)^Citation15,Citation109,Citation110	Yes^Citation21	Yes^Citation109	Not specified	Yes^Citation21	Yes (across patient subgroups)^Citation15,Citation21	Not specified	Not specified	Yes^Citation21	No^Citation21	Not specified	Equity^Citation35 “Reasonableness of cost from medical, humanitarian, and socio-economic perspective”^Citation33 Solidarity^Citation21
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113,Citation114	Not specified	Not specified	Not specified	Not specified	Yes^Citation108	Not specified	Not specified	Yes (“value for money”)^Citation109	Not specified	Yes^Citation108	Research and development^Citation109
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Dutch Healthcare Insurance Board Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation31	Yes^Citation35	Yes^Citation21	Not specified	Yes^Citation35	Yes^Citation35,Citation117	Yes^Citation35	Yes^Citation35	Yes^Citation35,Citation117	Yes^¥^Citation21,Citation201	Yes^Citation35	Rarity Feasibility of implementation^Citation117 Accessibility Level of uncertainty in supporting evidence^Citation115 Individual versus collective responsibility^Citation201 Public health impact^Citation35
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Yes^Citation202	Yes^Citation202	Yes^Citation202	Yes^Citation202	Yes (across patient subgroups)^Citation202	Not specified	Not specified	Yes^Citation202	Not specified	Yes^Citation35,Citation197	Level of uncertainty in supporting evidence^Citation196 Whether technology represents life-extending, end of life treatment^Citation37 Wider societal costs and benefits^Citation196 Public health impact^Citation35,Citation197 Alignment with broad government priorities^Citation202 ICERs of already funded programmes^Citation13,Citation157
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation120	Yes^Citation28	Not specified	Not specified	Not specified	Yes (across patient subgroups)^Citation28	Not specified	Not specified	Yes^Citation28	Yes^Citation174	Yes^Citation28	Level of uncertainty in supporting evidence^Citation174 Wider societal costs and benefits^Citation28 Alignment with broad government priorities^Citation28 ICERs of funded programmes^Citation28

Notes:

* In a well-defined population;

† price proportionate to effect;

§ cost efficiency takes into account costs of treatment per patient, as well as costs of compensatory allowance due to lost income and costs of restoring patients’ capacity to work;

‡ efficiency of resource use within a single therapeutic area relative to existing interventions;

¥ not a formal criterion.

Regardless of the reimbursement system, one of the main goals of the review committee is to determine the “therapeutic value” of a candidate technology. Broadly, its assessment combines consideration of clinical benefit with that of clinical need, taking into account key factors related to each dimension. For clinical need, they comprise, at a minimum, burden of illness (prevalence of severity) of the target condition and availability of alternatives. For clinical benefit, they include at least safety (risk–benefit ratio) and efficacy/effectiveness, on the basis of which an overall estimate of the ratio of the benefits to harms of a candidate technology is estimated (Table 6). While a further goal shared by most review committees is to formulate an opinion on whether the candidate technology represents “value for money” or an efficient use of resources, their approach to accomplishing this differs. Approximately one-third are guided by, but not compelled to adhere to, a predefined incremental cost-effectiveness threshold or threshold range.^28,29 Typically, if the incremental cost-effectiveness for a candidate technology lies below the threshold, it is deemed cost-effective or good value for money. If it lies above the threshold, additional factors are taken into account when judging acceptability (eg, uncertainties in estimates of outcomes, the severity of condition, and wider societal benefits).^30,31 Across systems whose committees do not refer to an incremental cost-effectiveness threshold, approaches to operationalizing “value or money” appear vague, with information largely limited to statements such as “reasonableness of cost relative to therapeutic value” (Table 6).³² Similarly, although all but one of the systems (Sweden²¹) list “affordability” or “impact of the candidate technology on health system resources” among factors/criteria considered by their respective review committees, no information describing processes for deciding whether or not a technology is affordable could be found.

Equity or ethical implications comprise decision-making factors/criteria (explicitly or implicitly) in one-third of systems. For example, Sweden’s Dental and Pharmaceutical Benefits Board stipulates two principles that decisions must reflect, ie, the “need and solidarity principle” (patients in the greatest need or “worse off ” must be given priority) and the “human value principle” (sociodemographic characteristics of patient populations cannot influence decisions).^21,33 Along with “solidarity,” the Norwegian Medicines Agency explicitly takes into account “equity,” as do review committees in Hungary and Poland.^26,34–36 However, the way in which this is accomplished during deliberations is not clear. Committees using an incremental cost-effectiveness threshold to guide decisions implicitly incorporate equity by virtue of the assumptions underpinning the incremental cost-effectiveness calculation (ie, each quality-adjusted life-year [QALY] carries the same weight, regardless of the characteristics of the patients receiving it (eg, age, gender, social status, income). Consideration of additional, often competing ethical principles by these committees is operationalized through “exception” conditions under which the normal “efficiency” expectations do not need to be met (eg, “last chance” therapies, orphan technologies, life-extending, end-of-life treatments).³⁷ Under such conditions, not all QALYs are deemed equal. Rather, a form of “solidarity” premium is applied, where, for example, QALYs gained in the later stages of disease are given greater weight. While there is little disagreement over the importance of instituting “exception” conditions as a means of ensuring that reimbursement decisions embody the broader values of the population, considerable debate around definitions/qualifiers (eg, what constitutes “last chance”? or by what period of time must a technology lengthen survival in order to be regarded as “life-extending”?) remains. Finally, the following factors are simply listed as criteria/factors by a small proportion of committees: alignment with government priorities; feasibility; and/or risk of off-label use of the technology (Table 6).

In general, systems aim to complete single technology reviews within 180 days of submission/identification of candidate technology, the time period prescribed by the European Union Transparency Directive. Based on tracking data, the actual time required appears to depend primarily on whether the assessment report accompanies a reimbursement application (eg, Belgium) or is undertaken (internally or externally) by the system once a technology is identified for review (eg, the UK, Table 5). In the latter case, review times can be 90 days or less (eg, Denmark and France).^20,38

The majority of systems have established mechanisms for appealing recommendations or decisions. Briefly, there are two main types of disputes, ie, those related to process and those amounting to disagreements over the interpretation of the evidence. In approximately one-third of systems, acceptable grounds for appeals are those of the first type only (“failed to act in accordance with processes”³⁹). For the most part, appeals are heard by an expert panel appointed by the respective health care organization or “payer” (eg, Ministry of Health, Table 5). Alternatively, they must be filed in an administrative court (eg, Germany and Sweden).

Conditional reimbursement enabling access to new technologies

Increasingly, reimbursement systems are expressing interest in and/or implementing reimbursement policy options that extend beyond the traditional “yes,” “no,” or “yes with restrictions” options. Such policy options take the form of provisional reimbursement arrangements, in which funding for a technology is provided in the interim while evidence needed to make a definitive decision is collected.⁴⁰ Collectively referred to as “Access with Evidence Development” (AED) schemes, they have emerged in response to calls for mechanisms that balance access to new technologies with the need to ensure their safe, effective, and efficient introduction and use in the health care system. In recent years, these calls have heightened, as tension between payers and manufacturers, patients, and providers has intensified. Many new high-cost technologies are supported by limited, albeit promising, evidence. Therefore, reimbursement decisions are made under conditions of considerable uncertainty, with significant risks and consequences of “getting it wrong” (wasted scarce resources and poor health outcomes). AED schemes attempt to reduce such risks through “managed entry” of new technologies into everyday clinical practice. There are three main types, ie, coverage linked to an outcomes guarantee, coverage as part of a study, and automatic reassessment (Table 7). Often referred to as “risk-sharing” schemes, “patient access schemes,” and “payment by results,” the first type consists of contractual arrangements between payers and manufacturers, where payment is tied to the achievement of an outcome, be it financial or health-related.^41,42 Such schemes have been employed in approximately one-third of the systems in this review (Table 7). They include financially-based price-volume agreements, where manufacturers must “pay back” the cost of sales exceeding those forecasted (eg, Belgium, France, Germany, Hungary, Portugal),^41,43,44 and expenditure caps, in which manufacturers cover the cost of “treatment” in patients for whom costs over a fixed time period exceed a prespecified amount (eg, Italy, the UK).^41,45 Health-related risk sharing arrangements, also called “no cure no pay” schemes, have been implemented by a smaller proportion of systems (Belgium, Denmark, Italy, the UK).^41,45–47 Under such schemes, continued reimbursement of a technology (usually a pharmaceutical for a rare disorder or cancer) requires evidence of a predefined treatment effect. The second type, “coverage as part of a study,” involves provision of interim funding by payers in order to conduct studies designed to collect specific information needed to fill key evidence gaps. Typically, such evidence gaps relate to the effectiveness and/or cost implications of the technology in “real world” settings. Funding may be partial (costs of the technology and/or health care associated with its use) or full (all health care and research costs). This type of scheme constitutes a policy option in approximately one quarter of the reimbursement systems, the majority of which have mandates that span pharmaceutical and nonpharmaceutical technologies (eg, France, Germany, the UK, Table 7). Eligible technologies vary across systems, but often include those defined as “innovative” (eg, granted an “innovation pass” in the UK) and those anticipated to significantly impact health care organization budgets (eg, the Netherlands).^25,48 The third type of AED scheme, “automatic reassessment,” comprises a programmed review of a reimbursement decision following a fixed period on the “benefit list” or when additional evidence is available.^49–51 It has become a part of the policy framework in half of the reimbursement systems included in this review, with most requiring reassessments of all technologies within their decision-making scope (Table 7). Despite the appeal of AED schemes, evidence of their effectiveness is both limited and mixed. Recent reviews have highlighted the challenges involved in both their design and implementation.^52,53 Such challenges primarily stem from the need to reach consensus among stakeholders on the terms of the scheme. Often, considerable time and resources have been required to resolve disagreements over elements such as the value proposition, outcomes to be measured and for what period, how the scheme should be funded, and to whom its oversight should be handed. Further, negotiations have, in some cases, resulted in complex arrangements that failed to generate the evidence needed to support a policy decision and/or created a significant administrative burden on payers and providers involved in its implementation. In an effort to address these issues, guidelines for conducting AED schemes, derived from international experiences to date, were recently published.^53,54 Moreover, some systems have proposed alternative approaches to dealing with decision uncertainties. For example, earlier this year, National Institute of Health and Clinical Excellence announced a new form of value-based reimbursement termed “flexible pricing.”^45–48 Under this approach, manufacturers adjust the price of a technology (pharmaceutical) in response to additional evidence of actual benefit to patients as it emerges. The National Institute of Health and Clinical Excellence subsequently assess this evidence, along with the proposed price, and determines whether the technology represents “value for money.” If a negative opinion is reached, the National Institute of Health and Clinical Excellence may veto the proposed price. Given the potential benefits of such an approach (eg, reduced administrative burden and system resource requirements) it has already sparked interest among the National Institute of Health and Clinical Excellence’s counterparts across Europe.

Table 7 Comparison of conditional reimbursement policy options for managing decision uncertainties

Country	Centralized reimbursement review/decision-making body (role)	Policy options for addressing decision-making uncertainties
		Reassessment	Value-based pricing/reimbursement	Reimbursement as part of a formal study	Risk-sharing schemes/payment by results	Other
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Yes Association of Austrian Social Security Institutions may remove pharmaceutical from benefit list in the wake of new clinical or economic evidence Manufacturer may suggest delisting pharmaceutical^Citation21	No^Citation56	No information found	No information found	No information found
Belgium	Minister of Social Affairs (decisions) Drug Reimbursement Committee (recommendations)^Citation9	Yes – automatic reassessment of pharmaceuticals offering added therapeutic value 1.5 to 3 years after inclusion on benefit list Minister of Social Affairs or manufacturer may suggest delisting a pharmaceutical^Citation41,Citation49	No information found	No information found	Financially or clinically based: For pharmaceuticals offering added therapeutic value for which the Drug Reimbursement Committee formulated a negative reimbursement recommendation^Citation49 Financially based: Price-volume agreements – “Provision Fund” established – Advances paid by manufacturers are used to cover 75% of overrun^Citation41	Creation of Special Solidarity Fund – Grants, on an individual basis, reimbursement of pharmaceuticals for rare diseases or rare indications unavailable in Belgium – Only granted if patient meets certain criteria and has exhausted all other treatment options – Must be prescribed by relevant specialist – Reimbursement decisions made by College of Medical Doctors Directors^Citation62
Czech Republic	State Institute for Drug Control (decisions)^Citation65	Yes – for “highly innovative” pharmaceuticals without evidence of effectiveness and “efficiency” Granted provisional reimbursement for 1 year, after which pharmaceutical is reassessed^Citation65	Manufacturer may request a surcharge of up to 30% over the basic reimbursement level if evidence suggests pharmaceutical demonstrates “superior” therapeutic benefits^Citation66	No information found	No information found	No information found
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Pharmaceuticals reassessed as part of therapeutic class reviews every 5 years Pharmaceutical may be scheduled for a separate reassessment when initial reimbursement decision is made if Reimbursement Committee considers it necessary to collect additional information about the use of the pharmaceutical in clinical practice before making a definitive decision^Citation50	No information found	No information found	Clinically based: Example: “No cure no pay” scheme for valsartan for high blood pressure Individual level schemes – Patient may apply for reimbursement on an individual basis, which requires evidence of treatment effect for continued reimbursement^Citation46 – Typically for patients who have exhausted all other options – Period of reimbursement varies^Citation68	No information found
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	No information found	No information found	No information found	Financially based: For all new pharmaceuticals – price-volume agreements mandatory for 1 year following reimbursement decision^Citation41	No information found
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Yes – for all pharmaceuticals Automatic reassessment every 3 to 5 years after inclusion on benefit list^Citation182,Citation203	No information found	No information found	No information found	No information found
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	For pharmaceuticals Yes – for all pharmaceuticals Automatic reassessment every 5 years after inclusion on benefit list^Citation20 For medical devices Yes – for devices Automatic reassessment within 5 years of inclusion on benefit list^Citation20,Citation162	No information found	May provide provisional coverage for a set period during which “real-world” effectiveness and/or economic implications must be assessed through a study: – To be carried out: By skilled teams in a limited number of selected centers Under well-defined conditions of use Using a protocol approved by French National Authority for Health Transparency Committee Applies to pharmaceuticals that: Target a large population; May be prescribed outside their labeled indications; or May have a significant impact on health care organizations^Citation16,Citation20 Also applies to medical devices – French National Authority for Health specifies study protocol^lCitation20	For pharmaceuticals Financially based: Price-volume agreements – Manufacturer must “pay back” the cost of sales exceeding those forecasted for the first 4 years ^Citation23,Citation43 – Pharmaceuticals exempt from such schemes for various periods depending on their “improvement in medical benefit” (ie, improvement in medical benefit) level: “improvement in medical benefit” I – 36 months; “improvement in medical benefit” II – 24 months; “improvement in medical benefit” III – 24 months at 50%; and “improvement in medical benefit” IV – 24 months at 25% – Also applies to “orphan drugs” (eg, eculizumab for paroxysmal nocturnal hemoglobinuria and galsulfase for mucopolysaccharidosis type VI)^Citation41	For pharmaceuticals for serious or rare diseases May be granted temporary access in a hospital setting for 1 year^Citation162 For “innovative” medical devices May establish “innovation point of contact” and an internal multidisciplinary network^Citation162
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19			For medical devices and procedures May provide provisional coverage for a set period during which “real-world” effectiveness and/or economic implications must be assessed through a study^Citation204	For pharmaceuticals Financially based: Price-volume agreements – “target agreements”: if prescription volume target is exceeded by 25%, manufacturers must “pay back” sickness funds (eg, insulin analogs, olanzapine, risperidone, clopidogrel, zolendronate, mycophenolic acid, everolimus, and cyclosporine)^Citation41	No reimbursement limit for potentially effective technologies used to manage life-threatening technologies for which there are no alternatives^Citation82
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85	No information found	No information found	No information found	No information found	No information found
Hungary	Ministers of Health and Finance National Health Insurance Fund Administration (recommendations)^Citation88,Citation89	No information found	No information found	No information found	Financially based: Price-volume agreements – 12% of reimbursed sales must be paid to the Ministry by the manufacturer – If Ministry spending on pharmaceutical exceeds agreed-to budget, the manufacturer must refund the Ministry an additional amount based on a predefined formula^Citation41	No information found
Ireland	Products Committee of Corporate Pharmaceuticals Unit of Health Service Executive (decisions)^Citation91,Citation92	No information found	No information found	No information found	No information found	No information found
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	No automatic/routine reassessment, with the exception of pharmaceuticals reimbursed under condition that additional studies would be conducted^Citation25	No information found	For pharmaceuticals classified as “potentially innovative” May require manufacturer to conduct additional studies within 3 years Pharmaceuticals for patients enrolled in the studies must be covered by the manufacturer^Citation25 Have established ongoing registries to monitor prescribing and assess “therapeutic value” in practice (real-world settings) in order to inform future management and reimbursed pricing decisions (eg, cetuximab, lenalidomide, ibritumomab, tiuxetan, palifermin, temporfin, and trastuzumab)^Citation41	Clinically based: Pharmaceutical initially reimbursed by National Health Service at 50% or 100% for a fixed number of treatment cycles, after which it is only reimbursed for patients achieving predefined clinical response; manufacturer may be required to refund the cost of pharmaceutical in non-responding patients (eg, sunitinib, sorafenib, dasatinib, and nilotinib) Registries used to track outcomes included in scheme^Citation47 Manufacturer initially provides pharmaceutical at no cost for a fixed period, after which National Health Service pays for pharmaceutical in patients achieving predefined clinical response (eg, donepezil)^Citation41 Financially based: Expenditure cap – Cost per patient per year cannot exceed a certain amount (eg, bevacizumab)^Citation41	Individual reimbursement – Patients may be granted individual reimbursement of pharmaceuticals not on the benefit list if: No alternative exists Requested pharmaceutical is available in other European Union states Clinical trials are underway Pharmaceutical is already reimbursed for a different indication^Citation96,Citation205 Establishment of “innovative medicines fund” – Commits 20% of available resources to reimbursement of “innovative” pharmaceuticals, ranked from most to least innovative using the following criteria: Treats serious conditions that are lifethreatening or cause hospitalization or permanent disability Used for risk factors for serious conditions Used for nonserious conditions^Citation25,Citation188 – If fund is overspent, manufacturers participate in refunding the system proportional to market share^Citation95
Norway	Norwegian Medicines Agency (recommendations/decisions)^Citation34,Citation98 Ministry of Health and Care Services (recommendations/decisions) Department of Pharmacoeconomics (recommendations)^Citation98	Pharmaceuticals may be reassessed as part of ongoing therapeutic class reviews^Citation34	No information found	No information found	No information found	Individual reimbursement – For patients who have exhausted all reimbursed alternatives and/or have serious or rare conditions – May be requested by specialists only – Reimbursement decision made by Norwegian Labour and Welfare Organization – Pharmaceutical does not need to have obtained market approval^Citation34
Poland	Ministry of Health (decisions)^Citation99 Drug Management Team (recommendations)^Citation99	No information found	No information found	No information found	No information found	No information found
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation44,Citation101	No information found	No information found	No information found	Financially based: Price-volume agreements – Growth rate in pharmaceutical expenditures fixed per year; if exceeded, manufacturers must refund the system up to 69.6% of the coverage up to a predetermined amount, eg, €35 million (2006)^Citation44	No information found
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Yes – for all pharmaceuticals Automatic reassessment, but review period varies with the pharmaceutical; depends upon when additional evidence is expected to be available^Citation128	No information found	No information found	No information found	No information found
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105,Citation106	No information found	No information found	No information found	No information found	No information found
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	No information found	No information found	No information found	No information found	No information found
Sweden	Dental and Pharmaceutical Benefits Board Expert Board (decisions)^Citation15,Citation206^–^Citation209	Yes – for all pharmaceuticals Automatic reassessment, but review period varies with the pharmaceutical; depends upon when additional evidence is expected to be available^Citation51,Citation135 Pharmaceuticals may also be reassessed as part of ongoing therapeutic class reviews^Citation51,Citation135	Reimbursement price may be adjusted to reflect actual costs and benefits once such information becomes available (eg, continuous intraduodenal infusion of levodopa/carbidopa for advanced Parkinson’s disease)^Citation209	May require submission of evidence from studies collecting “real-world” data on clinical, economic, and quality of life outcomes^Citation205,Citation209	No information found	No information found
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113,Citation114	No information found	“Innovation premium” – Granted to innovative pharmaceuticals (ie, therapeutic breakthrough products) – Surcharge of ≤20% of external reference price is added for a maximum of 15 years^Citation113,Citation114,Citation205	No information found	No information found	No information found
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Dutch Healthcare Insurance Board Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation31	Yes – for all pharmaceuticals Automatic reassessment – time period not specified^Citation31,Citation210,Citation211	No information found	New inpatient pharmaceuticals with projected costs >5% of hospital budget Granted provisional reimbursement for 3 years, during which studies collecting “real-world” data on cost-effectiveness must be conducted^Citation119 High-cost pharmaceuticals for rare conditions Granted provisional reimbursement for use in an academic hospital for 4 years, during which manufacturer must sponsor studies collecting “real-world” data on cost effectiveness and budget impact^Citation119	No information found	No information found
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Yes – for all technologies Automatic reassessment, but review period varies with the pharmaceutical; depends upon when additional evidence is expected to be available^Citation13,Citation29,Citation157	Proposed “flexible pricing” scheme: – Manufacturers can adjust the price of a pharmaceutical in response to emerging additional evidence on actual benefit or approval of a new indication which alters the value that the pharmaceutical offers to patients – National Institute for Health and Clinical Excellence assesses whether new price and evidence represents “value for money” and may veto a new price on an existing indication^Citation45,Citation48	“Innovation pass” – Selected “innovative” technologies are made available for 3 years, during which studies to collect data needed to inform standard National Institute for Health and Clinical Excellence processes are conducted^Citation48	For pharmaceuticals “Patient access schemes”^Citation42 Financially based: Manufacturer proposes discounts or rebates to reduce the cost of a pharmaceutical to the National Health Service, thus improving its cost-effectiveness – Manufacturer must obtain approval for such a scheme from the Department of Health prior to National Institute for Health and Clinical Excellence review^Citation29,Citation212^–^Citation214 Expenditure cap – Cost per patient per year cannot exceed a certain amount (eg, ustekinumab and erlotinib)^Citation45 Clinically based: Manufacturer covers the cost of initial fixed number of cycle(s) of treatment, after which National Health Service pays for patients achieving predefined clinical response (eg, sunitinib)^Citation45 National Health Service covers the cost of initial fixed number of cycles of treatment, after which manufacturer refunds the cost of treatment in patients failing to achieve predefined clinical response (eg, bortezomib)^Citation40 National Health Service covers the cost of the pharmaceutical for a fixed period, after which the price is reduced or refunds are issued to achieve predefined ICER (eg, interferon β, glatiramer acetate, and azathioprine)^Citation45	End-of-life medicines guidance – Pharmaceuticals used to extend life by at least 3 months for patients with less than 24 months to live may be reimbursed, even if ICER exceeds threshold range^Citation37^–^Citation48 Pharmaceuticals for rare conditions guidance – May be reimbursed when ICER exceeds threshold range if: – Target conditions in which incidence <7000 patients/year in the UK – There is sufficient evidence demonstrating that pharmaceutical offers substantial average increase in life expectancy over alternatives^Citation205
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group New Medicines Group (recommendations)^Citation120	Yes – for all pharmaceuticals Automatic reassessment, but review period varies with the pharmaceutical; depends upon when additional evidence is expected to be available^Citation174	No information found	No information found	No information found	No information found

Role of manufacturers in steps comprising the reimbursement review process

Few reimbursement systems have established roles for manufacturers beyond referral of a technology for review and the opportunity to comment on draft reports and/or preliminary recommendations (Table 8). Where “multiple technology appraisal” processes exist and assessment reports are commissioned or undertaken by the reimbursement system, manufacturers may participate in defining the scope or protocol of the assessment (France, Germany, the UK) or submit information to the group preparing such reports (Germany, Ireland, Spain, the UK). Among systems that prepare the evaluation report only, about half invite manufacturers to contribute information (Scotland, Italy, Sweden, the UK, Wales). Involvement of manufacturers otherwise appears limited to single examples, eg, able to participate in consultations during the assessment (France) or attend review committee meetings (Wales).

Table 8 Comparison of the role of manufacturers in centralized reimbursement processes

Country	Centralized reimbursement review/decision-making body (role)	Refer technology topics for reimbursement consideration	Participate in defining scope and/or protocol of assessment	Comment on draft protocol	Participate in consultations during assessment	Submit information to group preparing assessment report	Submit information to group preparing evaluation report	Present views during committee meetings	Nominate clinical and/or patient experts to make oral presentation to committee	Attend committee meeting	Comment on report and/or draft recommendations	Appeal recommendations or decisions
Austria	Association of Austrian Social Security Institutions (decisions)^Citation55 Pharmaceutical Evaluation Board (recommendations)^Citation56	Yes	N/A	N/A	N/A	N/A	No	No	No	No	No	Yes
Belgium	Minister of Social Affairs (decisions) Drug Reimbursement Committee (recommendations)^Citation9,Citation60	Yes	N/A	N/A	N/A	N/A	No	No	No	No	Yes	Yes
Czech Republic	State Institute for Drug Control (decisions)^Citation65,Citation176	Yes	N/A	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	Yes
Denmark	Danish Medicines Agency (decisions)^Citation68,Citation69,Citation121 Reimbursement Committee (recommendations)^Citation68,Citation121	Yes	N/A	N/A	N/A	N/A	No	No	No	No	Yes, if recommendation is negative	Yes
Estonia	Ministry of Social Affairs (decisions)^Citation72 Pharmaceuticals Committee (recommendations)^Citation72	Yes	N/A	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found
Finland	Pharmaceuticals Pricing Board (decisions)^Citation73,Citation74,Citation76 Pharmaceuticals Pricing Board Expert Group (recommendations)^Citation75	Yes	N/A	N/A	N/A	N/A	No	No	No	No	Yes, if recommendation is negative	Yes
France	Ministry for Health and Social Security (decisions)^Citation20,Citation78 French National Authority for Health (recommendations)^Citation78	Yes	Yes (multiple technology appraisals) N/A (single technology appraisals)	No	Yes (multiple technology appraisals) N/A (single technology appraisals)	No (multiple technology appraisals) N/A (single technology appraisals)	No	No	No	No	Yes	Yes
Germany	Federal Joint Committee (decisions)^Citation19 Institute for Quality and Efficiency in Health Care (recommendations)^Citation19	No	Yes	Yes	No	Yes	No	No	No	No	Yes	Yes (decisions only)
Greece	Transparency Committee in the Reimbursement and Medicinal Products (makes decisions)^Citation85	Yes	N/A	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found
Hungary	Ministers of Health and Finance National Health Insurance Fund Administration (recommendations)^Citation88	Yes	N/A	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	Yes
Ireland	Health Service Executive (decisions)^Citation91,Citation92,Citation147	Yes	N/A	N/A	N/A	Yes	No	No	No	No	Yes	Yes
Italy	Italian Medicines Agency Technical Scientific Committee (decisions)^Citation94 Italian Medicines Agency Pricing and Reimbursement Committee (recommendations)^Citation95	Yes	N/A	N/A	N/A	No	Yes	No	No	No	Yes	No
Norway	Norwegian Medicines Agency (decisions)^Citation98 Department of Pharmacoeconomics (recommendations)^Citation98	Yes	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found	Yes
Poland	Ministry of Health (decisions)^Citation99,Citation166	Yes	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found	No information found
Portugal	Ministry of Health (decisions) INFARMED (recommendations)^Citation36,Citation44	Yes	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found	Yes
Scotland	National Health Service Scotland (decisions)^Citation30 Scottish Medicines Consortium (recommendations)	Yes	N/A	N/A	N/A	No	Yes	No	No	No	Yes	Yes
Slovakia	Ministry of Health (decisions) Reimbursement Committee for Medicinal Products (recommendations)^Citation105^–^Citation107	Yes	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	No information found	No
Spain	Ministry of Health Directorate General of Pharmacy and Health Products; Inter-Ministerial Pricing Commission (decisions)^Citation21,Citation108	No	No	No	Yes	Yes	No	No	No	No	No	No
Sweden	Dental and Pharmaceutical Benefits Board Expert Board (decisions)^Citation10,Citation104,Citation105	Yes	N/A	N/A	N/A	N/A	Yes	Yes	No	No	Yes	Yes
Switzerland	Swiss Federal Office of Public Health (decisions) Federal Drug Commission (recommendations)^Citation113,Citation114	Yes	N/A	N/A	N/A	N/A	No information found	No information found	No information found	No information found	No information found	Yes
The Netherlands	Ministry of Health, Welfare and Sport (decisions) Dutch Healthcare Insurance Board Committee of the Dutch Healthcare Insurance Board (recommendations)^Citation31	Yes	N/A	N/A	N/A	N/A	No	No	No	No	No	Yes
United Kingdom	National Institute for Health and Clinical Excellence (decisions) Technology Appraisals Committee (recommendations)^Citation7	Yes	Yes (multiple technology appraisals) N/A (single technology appraisals)	No (multiple technology appraisals) N/A (single technology appraisals)	No (multiple technology appraisals) N/A (single technology appraisals)	Yes (multiple technology appraisals) N/A (single technology appraisals)	Yes (single technology appraisals) N/A (single technology appraisals)	No	Yes	No	Yes	Yes
Wales	Ministry for Health and Social Services (decisions) All Wales Medicines Strategy Group (recommendations)^Citation120	Yes	N/A	N/A	N/A	N/A	Yes	No	No	Yes	Yes	Yes

Conclusion

Centralized reimbursement systems have become an important policy tool in many European countries. Their introduction has, inarguably, brought greater consistency to processes and an improved sense of legitimacy to decisions. Nevertheless, there remains a lack of transparency around critical elements, such as how multiple factors or criteria are weighed during committee deliberations. Further, empirical studies evaluating the extent to which centralized reimbursement systems with advisory as opposed to decision-making authority are able to reduce inequities in access to new technologies within jurisdictions appear sparse.

Given the rapid pace with which new technologies that appear promising are now entering the market and the need to work alongside broader government industrial policies for encouraging innovation in an economic climate that demands prudent use of strained health care resources, the adoption of AED schemes by reimbursement systems seems inevitable. However, until more information on the outcomes of initiatives such as flexible pricing in the UK becomes available, their implementation should be approached with caution.

Disclosure

The authors report no conflicts of interest in this work.