Harmonisation of HTA practice: Underlying methodological differences across HTA agencies that impact national list prices

By Alexandros Soumalevris, GPI



Working towards Health Technology Assessment (HTA) harmonisation

There have been calls for the European Union (EU) countries, the European Parliament and other interested parties initiated in 2016 to the European Commission, to work on strengthening EU cooperation o HTA. On the 31st January 2018, a legislative proposal drafted by the European Commission was sent to the European Parliament and Council with the aim for Approval by 20191

To date, at least 9 cross-border collaborations have been established on horizon scanning, HTA, pricing and reimbursement. Up to 29 countries are participating in a different form of collaborations (listed below) across Europe, and many of those countries are taking part in two or three such alliances.

List of cross-border collaborations2

  • Baltic Partnership Agreement
  • BeNeLuxA Initiative
  • FINOSE collaboration
  • Nordic Council
  • Nordic Pharmaceuticals Forum (NLF: Nordisk Lægemiddel Forum)
  • Nordic Pricing and Reimbursement Group (NPT: Nordiske Pris- og Tilskudsgruppe)
  • Sofia Declaration group
  • Valletta Declaration group
  • Visegrad+2 group


The Beneluxa initiative brings together Netherlands, Belgium, Luxemburg, Austria and recently Ireland also joined the group. The following cross-country alliance is mostly focusing on evaluating and negotiating high-cost orphan drugs. The most recent achievement of this collaboration is the joint reimbursement decision from Belgium and the Netherlands of Biogen’s Spinraza (musinuren) for spinal muscular atrophy3,4.

At the beginning of 2019, the EU also launched the HTx project, which will run until 20245. The following initiative aims to provide a new framework and develop methodologies that will deliver customised information on clinical effectiveness as well as cost-effectiveness of complex and personalised health technologies6.

Industry experts regularly highlight the importance of cross-border collaborations especially in complex subjects like health technology assessments4. For instance, countries like Belgium and Greece would find these joint initiatives quite beneficiary as it would enable them to break the ‘access barrier’ due to the lack of expertise and knowledge to assess complicated and innovative new treatments via HTA, such as cell or gene therapies4,7

In the midst of the recent developments on Brexit in the United Kingdom (UK), the National Institute of Health and Care Excellence (NICE) partners with the Canadian Agency for Drugs and Technologies in Health (CADTH) and the Institute for Clinical and Economic Review (ICER) to adapt cost-effectiveness and value for money assessments8. Additionally, NICE and CADTH joined forces to provide pharmaceutical companies with an HTA service9. This service aims to answer key questions about launching a product in the UK and Canadian markets along with a joint summary as both NICE and CADTH have many methodologies in common. However, both HTA agencies differ in the way they estimate the cost of treatment (COT) under HTA. In particular, CADTH’s COT methodology assumes no product wastage while NICE’s calculations include wastage based on a single vial presentation.

The following example highlights the importance of understanding the commonalities and differences of the methods used in HTA, as national HTA agencies carry over the burden to assess a new technology and provide a recommendation for key stakeholders in reimbursement decision at national level.

Underlying different treatment cost estimations across HTA bodies

An analysis produced by GPI was presented at the ISPOR Europe 2018 conference last November in Barcelona and examined those methodological differences. The research highlighted the variation in methodologies for vial-based product cost calculations on HTA in Canada (CADTH), Germany (G-BA), Spain (AQUAS) and the United Kingdom (NICE). Vial-based treatments for melanoma were used to illustrate better how the selected HTA agencies are capturing the COT.

Utilising GPI’s proprietary platform GPI PulseTM, list prices data, ex-factory prices, for nivolumab, pembrolizumab and ipilimumab were selected to apply different calculation methods:

  • CADTH- assumes no wastage
  • NICE and AQUAS- single vial presentation is used for the calculation of wastage
  • G-BA- assumes wastage with a combination of different vial sizes

Annual COT calculations were based on cost per mg and were further adjusted for purchasing power parity10. Loading and maintenance dose, including their respective frequency and duration, as well as an average weight of 75kg, were taken into consideration. Calculations that include wastage with vial combination reflect the use of different vial sizes to reach the required dosage11,12,13. However, an arbitrary “comparable” price per mg of $100 was taken under consideration across all products and geographies in order to isolate the impact of different calculation methodologies from underlying international pack price variations.

The results of the following research (Table 1 and 2) revealed that in comparison to Canada (assumes no wastage) and based on different calculation methodologies alone, COT in Germany experienced an increase of up to 10 %; 25% and 44% in Spain and UK, respectively. Also, CADTH estimated the lowest COT per year for both price levels for all melanoma treatments in comparison to the other countries. When list prices were taken into consideration, values in COT further increased as well as their differences:  the estimated ipilimumab treatment was the most expensive in Spain and UK, exceeded the COT in Canada by more than 110%. On top of the differences based on calculation’s methodology, list price deviation increased the overall COT variation by an additional 20% to 98%.

As expected, the overall COT can vary significantly even when considering the same underlying price level. The extent of this variation (up to 44%) is particularly striking and may distort the actual therapy cost across countries or payer settings. Depending on weight and dosing, as well as vial sizes, the research demonstrated scenarios (e.g. pembrolizumab in Germany) where no vial wastage occurred in settings where a combination of vials was possible and indicated the relevance of underlying country-specific assumptions.

As cost-effectiveness analysis and price benchmarking plays a pivotal role in reimbursement recommendations of HTA agencies, different COT methodologies may affect the analysis either by improving or worsening the cost-effectiveness or cost comparison. Implementing the most realistic assumptions would help eliminate artificial cost differences versus standard of care and other comparative therapies. Thus, applying methodologies that incorporate different vial size combinations and wastage inclusion would achieve more accurate calculations which enable optimal positioning during pricing and reimbursement negotiations.

The research findings enrich the recent concerns raised which allege that the commonly used cost per quality-adjusted life year (QALY) measure, may no longer apply for many of today’s increasingly expensive new therapies14. Nevertheless, understanding the need for collaborations and methodological alignment is an important step towards HTA harmonisation and formation of cross-border alliances in a constantly changing environment.

Summary and outlook

  • HTA harmonisation is on the verge of completion in the European Union to facilitate patient access
  • Payers and consumers push towards this direction, as it would enable small countries to break the ‘access barrier’ which they are facing
  • Unexpected external environmental changes such as Brexit, force not only cross-border collaborations in the European Union but also international collaborations
  • Underlying methodological differences such as the COT estimations that HTA agencies commonly use may hinder cross-border collaboration efforts
  • GPI’s research showed that country differences in the COT calculation may lead to inaccurate estimations. For instance, ipilimumab’s COT for melanoma using NICE’s assumption (inclusion of wastage) was 44% higher (when comparable prices were used) and 113% higher (when listed prices were used) than CADTH’s (no wastage inclusion)
  • The following marginal differences in COT calculation may impact final pricing and reimbursement decision with a direct effect on national listed prices
  • Concerns raised recently about the QALY model being an outdated concept reinforces the need for methodological alignment between HTA agencies apart from the differences in COT calculation
  • Harmonised approaches with plausible and relevant assumptions for reasonable value-based pricing could emerge through a unified framework on COT assumptions
  • Thus, aligned HTA cross-border collaborations, such as the NICE-CADTH alliance and the BeNeLuxA initiative, could provide better and quicker access to patients


Global Pricing Innovations (GPI) is a market leader in business intelligence, analytics and innovative solutions for pharmaceutical pricing and access. See how we can support you on price decision-making through a combination of robust data-driven insights and bespoke analytical solutions, as well as our specialist consultant team’s knowledge of P&MA dynamics across Europe.


Alexandros Soumalevris is a Consultant in GPI, specialised in pricing data management and country healthcare system research to support daily consulting engagements in different areas of expertise such as HTA, pricing & reimbursement strategies, and market access tools.


Contact: sales@globalpricing.com





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