he 2018 European Commission proposal for a regulation intended to strengthen EU wide co-operation among member states in the assessment of new health technologies was recently endorsed by the European Parliament with 200 amendments that aim to ensure quality in joint clinical assessment (JCA) process and methodology.  An objective, independent, and transparent co-operation among EU Member States should be based on clear, streamlined and accepted methodological guidelines.

EUnetHTA has published 15 guidelines that form the basis of a framework for JCA methodologies in the EU. The main areas covered by these documents for pharmaceuticals include comparator selection, level of evidence, evidence synthesis, health-related quality of life (HRQL) and utility measures, internal validity of studies, personalized medicine, and methods for health economic evaluations.

These published guidelines focus primarily on the methodological challenges encountered by HTA assessors during previous rapid Relative Effectiveness Assessments (REAs) of pharmaceutical and non-pharmaceutical health technologies. Indicative examples with potential challenges are presented below:

EUnetHTA Guideline

Comparators and Comparisons: Criteria for the Choice of the Most Appropriate Comparator(s), Summary of Current Policies, and Best Practice Recommendations

Challenges

• Harmonization of joint clinical assessments requires adoption of standard PICOS criteria. While patients, outcomes, interventions, and study type can be expected to be broadly similar across EU Member States, choice of comparator may vary according to treatment landscape.
• If the first choice of comparator for a JCA–the Europe-wide agreed reference according to European or international clinical practice guidelines–is not available, then a comparator may be selected according to EU marketing authorization, or for orphan diseases, published efficacy and safety data.
• Supplementary national assessments may be required if a JCA omits comparators of relevance to one or more EU member states, if there are national rules governing patient subpopulations, or economic considerations.

EUnetHTA Guideline

Endpoints Used for Relative Effectiveness Assessment: HRQL and Utility Measures

Challenges

• Choice of Health Related Quality of Life (HRQL) instrument for a REA depends on whether its purpose is to inform clinical or reimbursement decisions.
• EUnetHTA guidelines recommend that all REAs include both a disease- or population-specific measure and a generic HRQL measure. The harmonization process would be greatly simplified by all EU Member States recommending a single instrument to measure HRQL. However, a wide range of instruments are currently in use, and in evolving health care landscapes their relevance may be temporary.
• In the absence of standard measures of HRQL, and despite manufacturers investing effort to address inconsistencies between measures, there is no guidance on how output from different measures can be usefully streamlined.
• Where changes in survival and HRQL are combined into quality adjusted life years (QALYs), data for each separately, and the methodology used for their combination, should be transparent.

EUnetHTA Guideline

Comparators and Comparisons: Direct and Indirect Comparisons

Challenges

• To fully inform health technology decisions, all available randomized clinical trial (RCT) data should be considered. The best evidence of relative treatment effect is that from head-to-head RCTs. Where these are unavailable, the evidence database can be expanded by indirect comparison of individual patient data from RCTs by statistical methods such as population-adjusted indirect comparisons (e.g., matching-adjusted indirect comparisons [MAICs] and simulated treatment comparisons [STCs]) to produce a network of evidence.
• While some EU Member States will embrace the use of complex analysis methods, others may not. However, adoption of more complex methodology by the EUnetHTA guidelines may facilitate technology transfer between countries and improve evidence reliability.

HRQL evaluation, a major component in clinical HTAs, may be one of the most challenging aspects to harmonize in terms of requirements and accepted methods across jurisdictions because there is a great deal of variability in the assessment of HRQL in clinical studies (e.g., the expectations from Germany are more specific, compared with other countries, in terms of patient-reported outcome endpoints such as HRQL).

Furthermore, agreeing on the set of comparators that meet all EU Member States requirements could be a significant challenge, especially for assessments which include several competitor products. However, and depending on the EU regulation legislative outcome, when JCAs exclude appropriate comparators that are relevant to certain EU Member States, then complementary national assessments would be required.

Facilitating Harmonization Across the EU – What Next?

A single resource for clinical HTA methodological guidelines that are sufficiently prescriptive, yet allow country-specific flexibility, is essential to realize clinical HTA harmonization across EU Member States. In consideration of the potential requirement for joint scientific consultation and JCA, early work on refining the existing EUnetHTA guidelines into up-to-date and prescriptive advice is recommended. This will enable the design of clinical programs to cover all of the eventual HTA requirements and promote convergence between countries on the joint clinical assessment by having fewer requirements to meet through the regulation.

Harmonization of clinical HTA across EU Member States has the potential to reduce the cost of research waste while at the same time expediting the passage of new health technologies through the regulatory system to the EU marketplace and facilitating equal access to medicines. Further research is required to reach consensus on clinical HTA methodological standards that balance nationally preferred methods with the state-of-the-art methodology that meets the needs of all EU Member States. This research should factor in the current state of HTA in the EU, gaps and differences between the national systems, and how the EUnetHTA guidelines address these, with a view to future developments in HTA as well as novel and innovative health technologies. Considering variation in the applicable HTA methods among EU Member States, the outcomes of this research would highlight the challenges and level of uncertainty faced by both HTA bodies and manufacturers in the development of JCAs. Agreeing on a common set of methods is key to supporting timely patient access and national decision-making based on the best available evidence.