Hta in European countries

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The use of Comparative Effectiveness Research and Health Technology Assessment in European countries: current situation and prospects for the future

Author: David Epstein

Affiliation: Department of Applied Economics, University of Granada

20 March 2014



Glossary 1

Introduction 3

EBM, CER and HTA and their relation to the decision making process 3

The regulatory framework in European countries. 4

Pharmaceuticals 4

Treatment and diagnostic devices 4

Coverage and reimbursement decisions in European countries 4

Decision making in practice 5

Principles of HTA 6

Application of principles of HTA 7

Organization and administration of HTA 19

Comparison of positive and negative outcomes of HTA across countries 19

Case study 1: Atypical antipsychotic for the treatment of Schizophrenia (Paliperidone) 20

Case study 2: MAO inhibitor for the treatment of Parkinson’s disease (Rasagiline mesylate) 20

Case Study 3: Orphan drug idursulfase 20

Decision pricing and spillover effects 22

Comparison of methodologies and processes across HTA bodies 22

Collaboration across agencies and HTA core model: EUnetHTA Project 22

Key methodology trends and issues 23

Bibliography 23




Spanish equivalent

Comparative effectiveness research


Estudios para comparar la efectividad

Cost benefit analysis


Análisis coste-beneficio

Cost effectiveness analysis


Análisis de coste efectividad

Cost minimization analysis


Análisis de minimización de costes

Cost utility analysis


Análisis de coste utilidad



Evidence Based Medicine


Medicina basada en la evidencia

Evidence synthesis

Síntesis de evidencia

Health policy

Política sanitaria

Health Technology Assessment


Evaluación de tecnologías sanitarias

Incremental cost effectiveness ratio


Ratio coste efectividad incremental

Marketing authorization

Autorización de comercialización

Markov model

Modelo de Markov

National Health Service


Sistema Nacional de Salud

Orphan drug

Medicamento huérfano

Personal and social services


Servicios personales y sociales

Quality adjusted life year


Años de vida ajustados por calidad (AVAC)

Randomized controlled trial


Ensayo clínico aleatorizado

Regulatory framework

Marco normativo

Reimbursement and Pricing


Reembolso y fijación de precios

Stakeholder groups

Grupos de interés

Therapeutic value / Added therapeutic value


Valor terapéutico/ Valor terapéutico añadido

Value Based Pricing


Precios basados en el valor


Since the establishment of the first national HTA agency in Sweden in the 1980s, the number of institutions involved in the assessment of health technologies has multiplied in Europe. Most European Member States have established a formal HTA programme or are considering the feasibility of establishing HTA intelligence to inform health policy-making (Eldessouki 2012, This paper:

  • Examines the regulatory and decision making framework for health technologies in European countries

  • Discusses the theoretical justification and principles of HTA

  • Compares European HTA practice against the principles

  • Describes the organization and administration of HTA in European countries

  • Compares positive and negative outcomes of decision for pharmaceuticals

  • Discusses key challenges and trends for the future

EBM, CER and HTA and their relation to the decision making process

Following the definitions of Luce et al (2010)

  1. Evidence-based medicine (EBM) is an evidence synthesis and decision process used to assist patients’ and/or physicians’ decisions. It considers evidence regarding the efficacy (“can it work?”) and effectiveness of interventions (“does it work?”) and patients’ values and is mainly concerned with individual patients’ decisions, but is also useful for developing clinical guidelines as they pertain to individual patients.

  2. Comparative effectiveness research (CER) includes both evidence generation and evidence synthesis. It is concerned with the comparative assessment of interventions in routine practice settings. The outputs of CER activities do not directly feed into a decision making process but are useful for clinical guideline development, evidence-based medicine, and the broader social and economic assessment of health technologies (i.e., HTA).

  3. Health technology assessment (HTA) is a method of evidence synthesis that considers evidence regarding clinical effectiveness, safety, cost-effectiveness and, when broadly applied, includes social, ethical, and legal aspects of the use of health technologies. The precise balance of these inputs depends on the purpose of each individual HTA. A major use of HTAs is in informing reimbursement and coverage decisions (“is it worth it?”), in which case HTAs should include benefit-harm assessment and economic evaluation.

The regulatory framework in European countries.


The regulatory body for pharmaceuticals is the EMA ( The decision focuses on whether the product does more good than harm for patients with defined indications. The evidence considered is usually pre-launch, typically evidence on efficacy from randomized controlled trials (RCTs), usually placebo-controlled, although active controls may be required particularly when placebo control would not be ethical. Post-launch, evidence on relative efficacy, effectiveness and/or relative effectiveness may also be considered when reviewing a product’s ongoing benefit-risk profile (Henshall 2011)

Treatment and diagnostic devices

The regulatory body is the EU Commission and Notify Body ( The European Commission Medical Devices Directive (93/42/EEC and subsequent Directive 2007/47/EC) defines four categories of devices, graded according to the risk assessment considering the following four dimensions: (i) duration of contact with the patient; (ii) the invasiveness; (iii) the intended use and dependence on an external source of energy; (iv) the location of the anatomical area affected. The regulatory process for diagnostics, medical devices, and medical equipment typically focuses on product safety and function (e.g., reliably detecting specified biomarkers in the case of a diagnostic). The extent to which regulators require evidence of clinical benefit for patients typically depends on the level of risk to which patients are exposed, and for many products, trials to establish efficacy or clinical benefit are not required by regulators or undertaken by manufacturers (Henshall 2011).

Coverage and reimbursement decisions in European countries

Coverage and reimbursement decisions are informed by HTA. HTA is a multidisciplinary process that summarizes information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased robust manner. It aims to inform the formulation of safe, effective, health policies that are patient-focused and seek to achieve best value. Despite its policy goals, HTA must always be firmly rooted in research and the scientific method (www.

HTA primarily aims to support policy-makers in making evidence-informed decisions on the application of health technologies. It can be regarded as a flexible, ongoing process, guiding technology from its future status to the phase of obsolescence (Drummond 2008). HTA seeks to support decisions on whether an intervention offers useful, appropriate, and affordable benefits for patients in a particular healthcare system (Henshall 2011). It considers evidence on relative effectiveness/efficacy (and costs and opportunity costs across the system) as can be assembled from all relevant trials (of the product and alternatives) with placebo or active controls, and where necessary other study designs and/or analytic techniques such as modeling

Decision making in practice

The practice of HTA within this definition varies considerably across national settings. It informs policy- and decision-making in specific political, economic and institutional contexts. In order to be useful HTA has to be designed with processes and outputs that fit the relevant context. It is recognized that HTA provides only one input for decision-making. It is usually not the only source, nor is it always the most important input. For this reason an HTA (or its recommendations) should not be confused with the actual decision taken (Figure 1) (Velasco Garrido et al 2008).

Figure 1. Role of HTA in policy making (Velasco Garrido et al 2008).

Principles of HTA

Drummond (2008) proposes 10 principles to guide HTA. These are:

  1. The Goal and Scope of the HTA Should Be Explicit and Relevant to Its Use

  2. HTA Should Be an Unbiased and Transparent Exercise

  3. HTA Should Include All Relevant Technologies

  4. A Clear System for Setting Priorities for HTA Should Exist

  5. HTA Should Incorporate Appropriate Methods for Assessing Costs and Benefits

  6. HTAs Should Consider a Wide Range of Evidence and Outcomes

  7. A Full Societal Perspective Should Be Considered When Undertaking HTA

  8. HTAs Should Explicitly Characterize Uncertainty Surrounding Estimates

  9. HTAs Should Consider and Address Issues of Generalizability and Transferability

  10. Those Conducting HTAs Should Actively Engage All Key Stakeholder Groups

Application of principles of HTA

Principle 1: The Goal and Scope of the HTA Should Be Explicit and Relevant to Its Use

A detailed scoping document should be developed before initiation of the HTA process, with broad, multidisciplinary, stakeholder involvement. The document should focus on defining the questions to be addressed by the HTA, plus the link between the HTA and any decisions about the use of the technology.

In some jurisdictions there is resistance to explicitly including considerations of cost in HTAs. In a diverse, decentralized system with multiple payers, insurers, healthcare organizations, and other providers, costs and perspectives may differ widely. More importantly, inclusion of cost into HTAs raises explicit questions of rationing of care, which is controversial and has limited public support in some countries. For example, economic evaluation in France is still in the development phase (HAS 2012).

Table 1.The goal and scope of HTA in European countries (Adapted from Paris and Belloni 2013)

Therapeutic relevance

Economic considerations


Safety, effectiveness, severity of disease, curative nature of product, interest in terms of public health

Budget impact. New products with added therapeutic value will be subject to economic evaluation from Oct 2013


Yes, but the drug must not belong to one of the categories excluded from reimbursement by Federal Law

Efficiency frontier method (Caro 2010)


Clinical effectiveness, disease relevance



Efficacy, disease relevance

Cost-effectiveness for innovative products, budget impact



Reasonable price in relation to therapeutic value


Added therapeutic value

Cost-effectiveness, budget impact


Therapeutic value

Reasonable price in relation to therapeutic value, cost-effectiveness, budget impact



Cost-effectiveness, need and solidarity, human values principles


NICE does not grade products according to therapeutic value


Principle 2: HTA Should Be an Unbiased and Transparent Exercise

Given the inherently complicated and controversial nature of HTA-based decisions and their importance to multiple decision makers and stakeholders, the HTA process is best conducted independently of the body that ultimately will be responsible for adopting, paying and implementing the HTA decisions. Furthermore, the HTA process and the detailed basis on which recommendations and decisions are made must be transparent.

HTA bodies differ widely in the amount of information which is made available to the public regarding the technology and the decision making process. Most jurisdictions publish official prices of pharmaceutical products. However, the actual price negotiated with the manufacturer is usually considered commercial-in-confidence (Gimenez 2013).

Table 2.Bodies responsible for HTA process, for reimbursement decisions and price negotiation in European countries (Adapted from Paris and Belloni 2013)

Body responsible for HTA process

Body responsible for decision on reimbursement

Body responsible for price negotiation / decision


National Institute for Sickness and Invalidity Insurance (INAMI)/Commission for Reimbursement of Medicines [Institut National d’Assurance Maladie-Invalidité/Commission de Remboursement des Médicaments]

Ministry of social affairs

Ministry of economic affairs, with advice of the committee for price setting (inter-ministry body)


Reimbursement Committee/Danish Centre for Evaluation and Health Technology Assessment (CEMTV)

Outpatient drugs: Danish health and medicines authority. Hospital drugs: KRIS

For hospital drugs, purchasing agency carries out tenders


Economic Committee on Health Products (CEPS)/Transparency Commission [Commission de la Transparence]

Ministry of Health decides on listing and Union of social health insurance funds decides on reimbursement rate

Committee on health products(inter-ministry body)


Federal Joint Committee/Institute for Quality and Efficiency in Health Care (IQWiG)/German Agency for Health Technology Assessment (DAHTA).

Federal Joint Committee (G-BA)

Prices negotiated after G-BA assessment


Committee on Pharmaceuticals/Italian Medicines Agency (AIFA) [CIP Farmaci/Agenzia Italiana del Farmaco]

AIFA technical scientific committee

AIFA pricing and reimbursement committee (inter-ministry body)


Pharmaceutical Care Committee (CFH) /Health Care Insurance Board (CVZ)

Ministry of health, welfare and sport

Ministry of health, welfare and sport


Pharmaceuticals Pricing Board (PPB)/Norwegian Medicines Agency (NoMA)

NoMA, MOH when budget impact is high



Spanish Agency for Health Technology Assessment (AETS)


Inter ministerial pricing committee


Pharmaceutical Benefits Board (LFN / TLV)/Swedish Council on Technology Assessment in Health Care (SBU)



UK (England and Wales)

NICE/National Coordinating Centre for Health Technology Assessment (NCCHTA)

There is no systematic assessment of new medicines, NICE assesses on request. All medicines with marketing licences are automatically reimbursed unless NICE says no.

In general, manufacturers are free to set list prices. The government controls profit levels of the industry. The MOH may negotiate Patient Access Schemes with manufacturers if NICE rejects a drug.

Principle 3: HTA Should Include All Relevant Technologies

Because potential inefficiencies exist in all forms of healthcare, all health technologies should be potential candidates for HTA. Otherwise, decision making concerning the use of resources is likely to be distorted.

While in some HTA programs all new technologies are candidates for formal, rigorous assessment (e.g. NICE in the United Kingdom, IQWiG and DAHTA@DIMDI in Germany, CMS and AHRQ in the United States), in practice a disproportionate amount of HTA activity is still directed toward drugs. The other common inappropriate focus of HTA is concentration on assessing new technologies (Drummond 2008).

Table 3. Decision making criteria used in countries that systematically assess all new medicines or cover all medicines at market entry by default (Adapted from Paris and Belloni 2013)

Systematically use economic evaluation to make decisions and consider cost-effectiveness as the primary condition for listing

Reimbursement conditions mainly based on clinical criteria related to efficacy or effectiveness of new product, type of disease or therapeutic alternatives

Systematic assessment of all new drugs or new indications of existing products before market entry

Belgium, Netherlands, Norway and Sweden. France (after Oct 2013)

France (before 2013), Italy

All medicines are covered as soon as they enter the market, unless they belong to a category a-priori excluded from reimbursement

UK: NICE provides advice on HTA, on request, on the coverage of NHS services, generally after market entry.

Germany: new drugs are assessed 3 months after market entry, to make sure their price represents an efficient use of resources and set a maximum price if needed

Principle 4: A Clear System for Setting Priorities for HTA Should Exist

A clear process for prioritizing and selecting topics needs to be established, because in situations where not all technologies are assessed, there will be distortions in decision making about the investment and use of resources.
In situations where only some technologies are assessed, selection priorities need to be set. In the United Kingdom, NICE sets priorities based on six criteria: (i) burden of disease; (ii) resource impact; (iii) clinical and policy importance; (iv) presence of inappropriate variation in practice; (v) potential factors affecting the timeliness of guidance; and (vi) likelihood of the guidance having an impact. A similar approach is followed by DAHTA@DIMDI (Germany), where a board of trustees uses similar criteria to derive priorities for future HTA projects.
The other common approach to determining priority for assessment is essentially a procedural one. For example, in the Netherlands an HTA is conducted if there is an a priori case that a new drug should not be clustered with other, existing drugs in the nation’s therapeutic reference price system. The HTA is used to assess the incremental value (if any) a drug provides over existing medicines, so as to determine whether a price premium is justified (and, if so, how much). A similar approach is being followed in Germany, where the G-BA can ask IQWiG to assess whether a new drug has sufficient incremental benefit to be excluded from the reference price system (Drummond 2008).
Several studies have highlighted a lack of transparency in the topic selection process (Sorenson et al 2008). Many HTA organizations lack explicit processes for prioritization, including selection methods and stakeholder involvement.
There are wide differences in the number and type of drugs appraised across agencies (Kanavos 2010). These differences, in part, are a result of the selection criteria for HTA appraisals established by each agency, as well as each country’s national priorities. Table 4 summarizes these selection criteria for each agency. For example, when considering that France (HAS) appraises all drugs, the fact that they have appraised the highest number of drugs is more easily understandable. Similarly, England and Wales (NICE), having appraised the lowest number of drugs, focuses only on those which are deemed to fulfill the highest need. National priorities may be reflected to some extent in the ICD codes of the appraised drugs. For example, in England the majority of cancer treatments (C00–D48) have been appraised as this is a priority because of the need, the severity of illnesses they treat and the cost implications for the National Health Service. In contrast, TLV (Sweden), which selects all out-patient drugs for HTA appraisals, has a more balanced amount of appraisals across indications, which may suggest that all drugs are considered equally important, regardless of the price, need, or severity of disease.
Table 4. Selection criteria for HTA appraisals per agency, based on the literature (Kanavos 2010)

Principle 5: HTA Should Incorporate Appropriate Methods for Assessing Costs and Benefits

Development and consistent implementation of rigorous, analytical methods is required to engender stakeholder and public trust in the process and its findings. This requires clarity of HTA process and methods, as well as access to experts with appropriate clinical and multidisciplinary methodological training.

A common approach in HTAs incorporating an economic evaluation is to propose a baseline analysis, or “reference case,” using a standardized approach with the best available data, with additional analyses conducted that examine the impact of alternative estimates on findings (sensitivity analyses) and the impact in specific clinically relevant subpopulations. The goal is to ensure consistency across different studies without stifling methodological developments and to examine the robustness of findings and results within the range of data uncertainty, methodological biases and limitations, and clinical populations. Given the need to use HTA resources in a cost-effective manner, it is important that the methods used are “fit-for-purpose.” A comprehensive, well-conducted, EBM review is a necessary first step in the HTA appraisal process. EBM methods should be specified in advance of conducting the review and should use the best available evidence for the questions to be addressed. Thus, while well-conducted RCTs provide high quality evidence of efficacy, evidence from rigorous quasi- and nonexperimental studies will usually be required to address issues of effectiveness (benefit under typical clinical conditions), comparative effectiveness (incremental benefit versus the best available alternative interventions) and differential effects in specific clinical populations (e.g., subgroups defined by patient age, gender, ethnic, comorbidity).

However, new analyses or re-analyses of existing data may be required to inform the HTA, considering its intended purposes and resultant decisions. Typically, these analyses will be conducted to populate economic decision-analytic or simulation models, for example to project health and economic consequences over an adequate time horizon. In particular situations, it may be difficult to have meaningful RCT data at all and short-term clinical trial data must be linked with data on patient-relevant health outcomes and long-term costs. Typical examples include the evaluation of health promotion programs, screening programs, diagnostic procedures, or treatment of chronic diseases with a relatively slow disease progression. Modeling techniques include decision tree analysis, Markov models, discrete-event simulation, and others (Drummond 2008)

Principle 6: HTAs Should Consider a Wide Range of Evidence and Outcomes

HTAs require use of data from experimental, quasiexperimental, observational, and qualitative studies, integration of both endpoint and validated surrogate data, and assessment of the incremental impact of and trade-offs among multiple clinical, economic and social outcomes in clinically relevant populations.

Clinical benefits, risks, and costs must be defined broadly to include all relevant outcomes of interest. Thus, in addition to mortality and morbidity, outcomes assessed and integrated into the decision process should include impact on patient functional status and quality of life and economic outcomes (direct and indirect medical costs, productivity effects) not only for patients but also for other relevant parties (e.g. family, employer, and the broader society).

Table 6. Definition of therapeutic value used in HTA processes in European countries (adapted from Paris and Belloni 2013)

Assesement / classification of added therapeutic value (ATV)



Class 1: ATV

Class 2: similar TV

Class 3: Generics /copies

Class 1 allowed a price above the comparators price


Health gains in natural units


ASMR 1: major improvement

ASMR2: significant improvement

ASMR3: Modest improvement

ASMR 4: Minor improvement

ASMR 5: No improvement

ASMR 1-3 allowed a price above the comparators price


Considerable improvement

Significant improvement

Small improvement

Additional benefit not quantifiable

No improvement

Less benefit than comparator

Medicines with some additional benefit are not clustered in reference price groups and allowed a price above comparators. The degree of innovation is referred to in the negotiation process


Annex 1A: similar TV

Annex 1B: ATV

Annex 1B allowed a price above the comparators price


Number of QALY gained

ICER compared to threshold


Classification of TV:




No interest

Price premium of 10-20% if drug has moderate or significant TV


Number of QALY gained

Price premium allowed based on ICER


Number of QALY gained

ICER compared to threshold

Table 7 . Thresholds used to establish cost-effectiveness in European countries (Adapted from Paris and Belloni 2013)


Comments / exceptions


No explicit threshold.

No economic evaluation required for orphan medicines

Rarely consider ICER>EUR 80,000. Bevacuzimab listed for breast cancer with an ICER > EUR 100,000


Suggested maximum of EUR 80,000 / QALY for severe diseases

Orphan medicines have been accepted at higher thresholds


No explicit threshold

Sunitinib was rejected for GIST with ICER of USD 52,000, but accepted for renal cancer with an ICER of USD 54,000


No explicit threshold

Medicines for severe diseases have been accepted with ICER around EUR 100,000 per QALY

England and Wales

Threshold ICER range around GBP 20,000-30,000 / QALY

Higher thresholds for ultra-orphan drugs (200,000-300,000 per QALY) and end-of-life (about 40.000 per QALY)

Figure 2 . Relative importance of attributes evaluated for drugs and medical devices (results of a survey of HTA agencies). Note: Proportion of respondents reporting attribute as “high” importance. (Stephens et al 2012)

Principle 7: A Full Societal Perspective Should Be Considered When Undertaking


HTAs should adopt a broad societal perspective to optimize efficiency and societal benefit and to avoid and identify potentially distorted clinical decisions and health policies resulting from adoption of narrower perspectives used by various healthcare system stakeholders.

Table 8. Perspective used in HTA in European countries (adapted from Paris and Belloni 2013)

Author of guideline


Analytic method



Social insurance and patient



No guidelines



Limited societal perspective

CMA, CEA, CUA, CBA accepted but must be justified




CEA or CUA. CBA or CMA also accepted if justified


Foundation for Health care and University





NHS and patients

CMA, CEA, CUA, CBA accepted but must be justified

England and Wales






All financing agents




No pharmacoeconomics systematically used in R&P process but HTA includes information on additional cost of treatment

Form of CEA in which costs and health benefits are only compared within a given therapeutic area (efficiency frontier) (Caro 2010).

Principle 8: HTAs Should Explicitly Characterize Uncertainty Surrounding Estimates

All data are imperfect point estimates of underlying distributions that incorporate a variety of errors. All analytical methods are subject to biases and limitations. Thus, extensive sensitivity analyses are required to determine the robustness of HTA findings and conclusions. The limitations of the analysis should always be acknowledged.
Principle 9: HTAs Should Consider and Address Issues of Generalizability and Transferability

Examination of the generalizability and transferability of HTA findings across clinical populations and policy relevant perspectives is required, given the inherent variability of disease, intervention responses, and outcomes across patients, populations, providers, healthcare delivery sites and healthcare systems


Principle 10: Those Conducting HTAs Should Actively Engage All Key Stakeholder Groups

HTA programs should actively engage all key stakeholders in all stages of the HTA process, as this is likely to result in technology assessments of higher quality that are more widely accepted and stand a greater chance of being implemented. Moreover, such an open process will enhance transparency and trust in the process as stakeholders develop a greater understanding of the criteria and standards used
HTA organizations differ widely in the degree to which stakeholders are allowed to participate in the HTA process and interact with the decision makers. However, few jurisdictions have yet taken the step of holding all HTA deliberations and committee meetings in public (Paris and Belloni 2013). In Germany, IQWiG has introduced a procedure where stakeholders are invited to participate in a formally structured manner, in hearings and by written comments. All comments and discussions are reported in the supplements of the reports (Drummond et al 2008)

Organization and administration of HTA

Figure 3. Organization, application, and use of HTA (European respondents, Stephens 2012).

Comparison of positive and negative outcomes of HTA across countries

Kanavos et al (2010) collected data on all appraisals between 2007–2009 from six HTA agencies. The data were collected from the public websites of each agency. Appraisals for all drugs and specific indications that were completed during the study period were considered, together with their corresponding recommendations, even if the latter were made outside the study period. In total, appraisals on 293 drugs were conducted.

Only 7% of the drugs were appraised by all six agencies, 19% by five agencies, 18% by four agencies, 26% by three agencies, 17% by two agencies, and 13% by only one of the agencies. This shows that, surprisingly, HTA agencies do not necessarily appraise the same drugs, or the same drug for the same indication. HTA outcomes between agencies differed in more than half of the cases, whereby some agencies accepted these drugs in most cases, while others rejected them in almost 50% of cases.

Case study 1: Atypical antipsychotic for the treatment of Schizophrenia (Paliperidone)

Paliperidone was rejected by HAS and SMC because of insufficient evidence of a clinical advantage compared to other antipsychotics. In contrast, TLV recommended paliperidone on the basis that it was deemed similar in terms of efficacy and price to olanzapine and risperidone respectively.

Case study 2: MAO inhibitor for the treatment of Parkinson’s disease (Rasagiline mesylate)

TLV accepted to list rasagiline because it was considered cost-effective in comparison with entecapone and tolcapone, but was restricted to the treatment of ‘on-off’ syndrome since its therapeutic alternative (selegiline) was deemed inappropriate for this sub-population. SMC rejected the application because no comparison with a less expensive therapeutic alternative was presented. Similarly, HAS’s rating (ASMR V) was mainly due to the conclusion that the treatment did not have additional benefit compared to existing alternatives. NICE did not appraise either drug, but instead issued guidance for the treatment and management of Schizophrenia (March 2009) and Parkinson’s disease (June 2006). In these guidelines, all antipsychotics are considered to have equal effects, and similarly MAO-inhibitors are

one of the accepted treatment options for early Parkinson’s disease. In both cases, the choice of treatment depends on patient tolerability and preferences.

Case Study 3: Orphan drug idursulfase

In the case of idursulfase, all appraising agencies focused on the same Phase III placebo-controlled random controlled trial (RCT). HAS concluded that, in the absence of alternative treatment, it demonstrated “significant superiority” compared to placebo on 6MWD** and all other secondary endpoints. SMC also concluded that the drug was “significantly more effective” than placebo, but rejected it based on insufficiently robust economic evidence.

Figure 4. Number of appraisals and HTA outcomes (N=293 appraisals) across 6 HTA agencies (Kanavos 2010)

Figure 5 Appraisals by agency and outcome

Key: L (list / positive recommendations); LWC (list with criteria or restrictions); DNL (do not list / negative recommendation)

Decision pricing and spillover effects

Kanavos (2010) examined the effect of HTA recommendations on the prices of drugs in that market. The trend effect of positive recommendations by both NICE and SMC was an immediate increase in price which moderated after 6–9 months. Prices in Sweden exhibited some volatility in either direction following a TLV recommendation, which is surprising given that prices for reimbursement are fixed during the recommendation process. Positive and negative recommendations by HAS had little or no visible effect on French prices.

Comparison of methodologies and processes across HTA bodies

Mathes (2013) compared the methodologies of 14 HTA agencies, examining published documents. Most of the recommendations are in accordance with described key principles of HTA. These concern methods for assessing cost and benefits, the range of evidence and outcomes, the perspective of analysis and uncertainty of estimates. Differences in recommendations are often explainable by differences in the structure and regulation of health care systems and, therefore, different premises and goals. However there are considerable unexplainable differences in methodological recommendations for economic evaluations. The results of HTAs always have generalizability and transferability restrictions for different populations and settings. However, there are process steps for the preparation of economic evaluations that are not at all, or only marginally, affected by transferability problems (e.g., literature search, model structure).

Collaboration across agencies and HTA core model: EUnetHTA Project

There is a challenge of avoiding duplication of work and obtaining a more effective use of national HTA. There is a need to find more standardized approaches in order to provide tools that help HTA actors to reuse the work of others. For this reason the EUnetHTA Project aimed at developing a core model and tools that help to adapt existing reports/core HTAs by defining and standardizing the elements of an HTA (Velasco-Garrido 2008). The strategic objectives of the EUnetHTA Project were to reduce duplication of effort to promote more effective use of resources, increase HTA input to decision making in European countries and the EU, to increase the impact of HTA at all levels of healthcare, strengthen the link between HTA and healthcare policy making in the EU and its Member States, and support countries with limited experience in HTA (Børlum Kristensen 2012)

Key methodology trends and issues

Table 9. Key methodology trends and issues facing health technology assessment (HTA) bodies (Stephens et al 2012)


Need for observational studies/real-life data (monitoring, registries, etc); development of “acceptable” thresholds and methods for resource allocation


Lack of good studies/data as inputs to the assessments


Early assessment of technologies with mechanism for conditional coverage, lack of evidence for emerging technologies


Development/use of methodologies for health economic evaluations


HTA moving as a priority to regional health-care agendas


Selection of comparators, identification and quantification of costs, uncertainty analysis


Link between theory and practice in HTA, uniform analyses for comparative purposes, assessment of diagnostics, timeliness, selection of topics/comparators


Transparence, rigor, quality assessments, collaboration with other HTA agencies nationally and internationally, improved methods, training of new researchers


Horizon scanning, implementation of regular reassessments

The Netherlands

Selection of comparators/study populations, model structure, and assumptions


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