Introduction
‘The mission of EUnetHTA is to support collaboration between European HTA organisations that brings added value to healthcare systems at the European, national, and regional level’ 1– this has been the guiding statement from the inception of the EUnetHTA in 2006 all the way through each of the Joint Actions 1-3 which have formed the basis of EUnetHTA 21 as we see it today. Now, the development of the EUnetHTA 21, aims to speed up European market access through the Joint Clinical Assessment (JCA). In theory, one European wide clinical assessment should reduce the current duplication of work that results when manufacturers are required to submit multiple clinical dossiers to multiple EU HTA agencies. However, in practice there are still several complications that will need to be addressed to ensure the new process delivers on its aims, whilst still accounting for the differing needs of the many different healthcare systems, each with varying treatment landscapes and payer decision drivers.
EUnetHTA 21 recently published its draft scoping guidance which details when, why and how manufacturers will be able to incorporate the nuances of individual healthcare systems into their Joint Clinical Assessment (JCA).This article summarises these details and discusses some of the key questions which remain unanswered as well as how the scoping procedure is likely to impact manufacturers, otherwise known as health technology developers (HTD).
How will scoping be carried out for Joint Clinical Assessments?
The EUnetHTA scoping process:
The EUnetHTA 21 scoping process starts with the submission of a request for assessment by the health technology developer (HTD) and ends when a consolidated final list of PICOs is communicated back to the HTD. However, for the EUnetHTA 21 scoping process to align with EU regulations (EU 2021/2282)2, scoping ‘must be inclusive of and reflect member state needs’ meaning that it would be unlawful to produce a JCA that did not include a comparator or patient population that was required by any member state. This, of course, raises considerable challenges. To ensure all voices are heard, the EUnetHTA 21 draft scoping guidance describes a survey in which member states will be invited to provide inputs related to the relevant population, intervention, comparator, and outcomes required by its healthcare system.
Expected inputs into the scoping survey:
Population:
To help define the patient population, member states will be asked to identify the relevant population(s) for assessment, based on the claimed indication by the HTD. The definition of the relevant population(s) should be as clear as possible and avoid ambiguity. To this end, relevant populations as well as final consolidated PICOs will be discussed with the Committee for Scientific Consistency and Quality (CSCQ) which meet on a regular basis. During this meeting, any ambiguity surrounding the population will be discussed and the final definitions of the population(s) will be agreed; it is this definition that will be used throughout the scoping and assessment phases.
Intervention:
HTD data used in the regulatory submission will be used to define the intervention. However, questions arise when considering instances where the intervention is an add-on therapy, and the backbone therapy differs across member states. In such cases, the draft scoping guidance states that ‘the assessor and co-assessor have to decide whether to include the background therapy in the intervention as part of the PICO during the consolidation phase’ 1. However no further details are provided, potentially leading to inconsistencies in how these types of products are scoped and potentially reducing the reliability of JCAs as a whole.
Comparator:
Considering the high degree of treatment heterogeneity across member states, by far the greatest uncertainty surrounds how comparators will be defined. To try to combat this, the draft scoping guidance indicates that member states will be required to list all potentially relevant comparators separated either by ‘OR’ if only one of a number of different comparators would be acceptable or by ‘AND’ if more than one specific comparator is more reflective (see Table 1 below for an example)
Outcome:
Member states are also expected to define their needs by listing several outcomes, which may be informed by guidance developed in Joint Action 2 (JA2)3,4,5,6,7. Guidelines on the selection of outcomes should be followed but may be clinical (e.g. morbidity events such myocardial infarction, stroke), surrogate, composite or patient reported.
Table 1 – Member State 2
| Population(s) | Full licensed indication | Subpopulation A | Subpopulation B |
| Comparator(s) Could use any of / | Comparator(s) Could use any of / | Comparator(s) | |
| Comparator 1 | Comparator 1 | ||
| Comparator 2 | |||
| Comparator 3 | Comparator 3 | Comparator 3 |
How will the needs of each member state be consolidated?
Using this system means that all possible comparators for each member state are accounted for, however even if each member state only indicated two possible comparators for the entire population, this could result in 54 different PICOs even before sub-populations are accounted for, begging the question as to how the manufacturer could possibly be expected to account for this in the JCA.
To help alleviate this potential problem, the draft guidance outlines a process by which member state requirements will be juxtaposed to create a list of the lowest possible number of PICOs; where one PICO comprises of one population, one intervention (or combination), one comparator (which can include more than one medicinal product) and at least one outcome. If a member state requires at least one comparator for a given population, this comparator is selected and each different comparator is assigned a separate PICO, preventing any member states being ‘missed out’ (see below).
Table 2 – Full Licensed Indication
| Member State 1 | Member State 2 | Member State 4 |
| Comparator(s) Could use any of / | Comparator(s) Could use any of / | Comparator(s) |
| Comparator 1 | Comparator 1 | |
| Comparator 2 | Comparator 2 | |
| Comparator 3 | Comparator 3 | |
| Comparator 4 |
Next, PICOs are assigned to each comparator. In cases where all comparators listed are required (the ‘AND’ situation) then each comparator is given a PICO. For member states where any comparator could be used (the ‘OR’ situation) then the committee will cross reference to see if any of these comparators is included in the ‘AND’ member state’s comparator list. If this is not the case then the list of ‘OR’ comparators is cross-checked for all remaining member states and the lowest number of comparators needed to satisfy all member states will be selected. If no preference can be given, the comparator definition will include alternative options which the HTD can choose from. However, there are still likely to be several (and possibly many) scenarios that will need to be included in the manufacturers JCA and it will be interesting to see if HTDs see this as time saving compared to the current process of submitting a separate dossier for each country.
Questions and challenges
Despite the intention of the PICO survey to capture the needs of each member state, several questions arise. For example, member states are expected to respond to the survey within approximately two weeks, raising concerns that these timelines are not realistic. This is especially evident considering that the UK’s NICE scoping consultation (a process similar to the survey) can take 20 working days8. This therefore raises the wider question as to whether EU member states will buy-in to the scoping process and if they do not, what is the outcome? Will this hold up the entire JCA procedure whilst the committee awaits a response from all 27 states, or will the member state be disregarded and therefore beholden to the final scope?
Similarly, in theory consolidating all the possible PICOs seems plausible however, considering that the scoping process must be completed before CHMP opinion, there is a risk that the marketing authorisation could change. In this situation, the draft guidance clearly states that ‘an update to the PICOs is expected and the evaluation process is delayed’ 1, leading to a considerable risk that if the EMA label changes, there will be market access delays. Despite this, potential solutions alluded to in the draft guidance include the possibly for a cooperation between the scoping committee and the corresponding regulatory authority, which could help to alleviate this risk. Finally, with the development of more and more combination therapies which treat highly complex diseases and with backbone therapies potentially differing between member states, it will be interesting to see whether there is any consistency from the committee as to whether these backbone therapies are included as part of the intervention in the PICO. If they are included, further questions arise such as how inclusion of backbone treatments will impact downstream economic evaluations at the member state level. It seems that individual HTA submissions are already complex enough for these types of therapies and perhaps this will be a step too far for HTDs?
Conclusion
To conclude, a single clinical dossier that is applicable in all EU markets is a bold ambition. Publication of the draft scoping guidance gives us a first impression of how this ambition might be achieved. Undoubtedly, it is not a straightforward process and satisfying the needs of a large and disparate group of stakeholders will not be easy. Ultimately, the success of the initiative will depend upon whether the needs of payers and manufacturers can be met without adversely impacting the efficiency of clinical assessments in the EU. What are your thoughts? Do you buy-in to the process highlighted in this article or are you erring on the side of caution when it comes to incorporating all 27 member states’ healthcare nuances into a single JCA? Comment below to share your thoughts.
Sources:
EUnetHTA 21 (2022). Practical Guideline D4.2 Scoping Process Guidance Document. Available at: https://www.eunethta.eu/wp-content/uploads/2022/05/4.2-Scoping-Process-Practical-Guideline-version-for-public-consultation-v0.3.pdf?x69613